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WO2017064068A1 - Nouveaux antagonistes de trpa1 - Google Patents

Nouveaux antagonistes de trpa1 Download PDF

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Publication number
WO2017064068A1
WO2017064068A1 PCT/EP2016/074352 EP2016074352W WO2017064068A1 WO 2017064068 A1 WO2017064068 A1 WO 2017064068A1 EP 2016074352 W EP2016074352 W EP 2016074352W WO 2017064068 A1 WO2017064068 A1 WO 2017064068A1
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group
methyl
atom
imidazo
pyrazin
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PCT/EP2016/074352
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English (en)
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Jose Aiguade Bosch
Stephen Connolly
Paul Robert Eastwood
Richard Spurring Roberts
Sara Sevilla Gomez
Juan Francisco Caturla Javaloyes
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Almirall, S.A.
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Publication of WO2017064068A1 publication Critical patent/WO2017064068A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders

Definitions

  • the present invention relates to novel compounds having TRPA1 activity.
  • This invention also relates to pharmaceutical compositions containing them, processes for their preparation and their use in the treatment of several disorders.
  • TRPA1 is a non-cation selective channel that belongs to the Transient Receptor Potential (TRP) superfamily. TRPA1 was first identified from cultured lung fibroblasts (Jaquemar et a/., 1999), and further studies indicated that TRPA1 was highly expressed in sensory neurons of the dorsal root, trigeminal and nodose ganglia. In sensory neurons, TRPA1 expression is most prevalent in small diameter neurons where it colocalizes with markers of peptidergic nociceptors such as TRPV1 , calcitonin gene-related peptide (CGRP) and substance P (Kaneko et a/., 2013). Moreover, TRPA1 has been identified in the small intestine, colon, pancreas, skeletal muscle, heart, brain, and T and B-lymphocytes (Stokes et a/., 2006).
  • TRP Transient Receptor Potential
  • TRPA1 is activated by a variety of noxious stimuli, including cold temperatures and pungent natural compounds (e.g., mustard, cinnamon and garlic). TRPA1 is also activated by environmental irritants, including isocyanates and heavy metals produced during the manufacturing of polymers, fertilizers and pesticides. Vehicle exhaust, burning vegetation and electrophilic tear gases used as incapacitating agents, are potent activators of TRPA1 . TRPA1 antagonists or inhibitors could also have applications in defence against such agents.
  • noxious stimuli including cold temperatures and pungent natural compounds (e.g., mustard, cinnamon and garlic).
  • TRPA1 is also activated by environmental irritants, including isocyanates and heavy metals produced during the manufacturing of polymers, fertilizers and pesticides. Vehicle exhaust, burning vegetation and electrophilic tear gases used as incapacitating agents, are potent activators of TRPA1 . TRPA1 antagonists or inhibitors could also have applications in defence against such agents.
  • TRPA1 is not only sensitive to electrophiles, but is also activated by oxidizing agents.
  • Reactive oxygen species ROS
  • ROS Reactive oxygen species
  • Reactive carbonyl species like 4- hydroxynonenal (4-HNE) and 4-oxononenal (4-ONE), resulting from lipid peroxidation act directly on TRPA1 .
  • ROS generated during inflammation excites airway sensory nerve fibres, and this response is largely reduced in TRPA1 -deficient mice.
  • TRPA1 activation is modulation by G protein-coupled receptors (GPCRs) through second-messenger signalling cascades.
  • GPCRs G protein-coupled receptors
  • Prostaglandin PGE2 and bradykinin (BK) are indirect activators of TRPA1 (Bessac, 2008).
  • TRPA1 has emerged as a key regulator of neuropeptide release and neurogenic inflammation.
  • TRPA1 is expressed in a subset of C-fibres that express TrkA and TRPV1 .
  • These afferent nerves have cell bodies in nodose, dorsal root ganglia (DRG) and trigemional neurons (TG), and project to a variety of peripheral targets, including skin, airways, and gastrointestinal (Gl) tract.
  • DDG dorsal root ganglia
  • TG trigemional neurons
  • TRP channels are present in both neuronal and non-neuronal cells in the skin where they are thought to play a key role in itch, regulation of barrier function, keratinocyte differentiation, hair growth, inflammation, and wound healing (reviewed in Moran et al., 201 1 ).
  • TRPA1 is an essential component of the pathways that promote histamine- independent itch and may act as a downstream transduction channel onto which multiple pathways converge.
  • TRPA1 role as a pain sensor is well-established.
  • a gain-of-function point mutation in TRPA1 was identified as the cause of Familial Episodic Pain Syndrome, a rare human pain disorder characterized by severe upper body pain triggered by fasting and physical stress (Kremeyer et al., 2010). Taming these hyperactive TRP channels by antagonists may prove clinically beneficial.
  • TRPA1 is required for the hypersensitivity that occurs in inflammatory pain models (Bautista et al. 2013, Julius 2013). TRPA1 expression is increased by inflammatory mediators such as nerve growth factor (NGF) and following nerve injury or inflammation. Activation of TRPA1 has been shown to cause pain and neurogenic inflammation. Intrathecal TRPA1 antisense oligonucleotides administration suppressed inflammation and nerve injury-induced cold allodynia. TRPA1 gene knock-out studies showed impaired sensory function to noxious cold, chemical and mechanical stimuli, suggesting that TRPA1 represents an important target for development of therapeutics for inflammatory and neuropathic pain conditions (Obata et al. 2003, McNamara et al. 2007, Petrus et al.
  • TRPA1 is a promising target for the treatment of this chronic diabetic neuropathy associated with peripheral demyelination and the degeneration of nerve fibres.
  • TRPA1 may have a role in the pathogenesis of cancer and other inflammatory diseases. TRPA1 antagonists have been reported to revert oxaliplatin-induced neuropathic pain (Nativi, 2005).
  • TRPA1 Some anaesthetics, such as isoflurane or lidocaine, also activate TRPA1 , suggesting a possible role for TRPA1 antagonists in post-surgical pain.
  • TRPA1 is implicated in migraine (Edelmayer et al., 2012), and dental pain (Haas et al., 201 1 ), as a result from neurogenic inflammation.
  • the activation of trigeminal TG neurons through nasal application of TRPA1 activators causes a CGRP-dependent increase in meningeal blood flow, that has been clinically shown to correlate with migraine headache.
  • TRPA1 could be considered a target for such conditions.
  • TRPA1 -/- mice to support a role for TRPA1 in the pathogenesis of different airway diseases including chronic cough, asthma, and COPD (Nassini et al., 2012b).
  • TRPA1 in the generation of irritant-induced cough reflexes.
  • Inhalation of a variety of TRPA1 agonists (acrolein, cinnamaldehyde, allyl isothiocyanate, crotonaldehyde) has been shown to produce a dose-dependent robust cough response in conscious guinea pigs and in humans (Andre et al., 2009; Birrell et al., 2009).
  • Stimulating TRPA1 channels has been demonstrated to activate vagal bronchopulmonary C-fibres in the guinea pig and rodent lung.
  • TRPA1 agonists induced cough.
  • cough can be attenuated by TRPA1 inhibitors.
  • TRPA1 channels Antagonism of TRPA1 channels is expected to inhibit afferent nerve activation induced by cough stimulants, and represents an option for anti-tussive drugs development (Grace et al., 2012 and 2013). Moreover, patients treated with angiotensin-converting enzyme (ACE) inhibitors for hypertension have chronic cough as a side effect as result of heightened bradykinin levels. TRPA1 antagonists could represent an option to treat such side effects and chronic cough conditions.
  • ACE angiotensin-converting enzyme
  • TRPA1 -/- mice show little sign of lung inflammation, near- normal airway resistance, reduced eosinophil infiltration in the bronchi, and decreased production of proinflammatory cytokines and neuropeptides release in the airways, compared to TRPA1 +/+mice (Caceres et al., 2009). These studies point to TRPA1 as a promising target for the development of drugs aimed at treating the asthmatic response, allergen-induced airways inflammation, mucus production and airways hyper-reactivity.
  • CSE cigarette smoke extract
  • aldehydes increased Ca 2+ influx in
  • TRPA1 transfected cells and promoted neuropeptide release from isolated guinea pig airway tissue. Instillation of CSE into the trachea of wild-type mice and TRPA1 -/- mice only induced plasma protein extravasation in the wild type mice (Andree et al. , 2008). These data suggest that targeting TRPA1 may have therapeutic potential in diseases caused by cigarette smoke such as COPD.
  • TRPA1 has been reported to have a critical role in mediating gastrointestinal (Gl) hypersensitivity to mechanical stimuli and serves as an important mediator of neuropeptide release triggered by inflammatory agents.
  • TRPA1 expression is elevated in the inflamed mouse gut (Yang et al., 2008; Izzo et al., 2012).
  • Experimental colitis induced by dinitrobenzene sulphonic acid (DNBS) was attenuated after both pharmacological blockade and genetic inactivation of TRPA1 (Engel et al., 201 1 ), pointing at potential of the target in Gl inflammatory conditions such as inflammatory bowel disease, Crohn's disease and ulcerative colitis, and colicky pain of Gl origin (Blackshaw ei a/., 2013).
  • TRPA1 is highly expressed in sensory neurons innervating bladder, urothelium, sub-urothelial space, muscle layers and around blood vessels (Streng et al. , 2008). Similar to TRPM8, TRPA1 is up-regulated in bladder mucosa in patients with bladder outlet obstruction (Du et al., 2008). TRPA1 agonists increased the micturition frequency models of cyclophosphamide-induced cystitis and spinal cord injury
  • TRPA1 antagonists could show potential for the treatment of bladder instability, urinary incontinence and cystitis.
  • TRPA1 antagonists could show potential for the treatment of bladder instability, urinary incontinence and cystitis.
  • TRPA1 antagonists could show potential for the treatment of bladder instability, urinary incontinence and cystitis.
  • TRPA1 Several properties of TRPA1 make it an attractive drug target to treat inflammatory disorders; its ability to be activated by a large variety of endogenous and exogenous inflammatory compounds makes it an ideal detector of inflammatory cues, both in acute and in chronic conditions. Its peripheral expression of TRPA1 allows systemic, but also selective targeting of drugs by inhalation, ingestion, or topical application.
  • TRPA1 modulators of varied chemical structures have been recently disclosed for the treatment or prevention of chronic and acute inflammatory diseases and other pathological conditions, diseases and disorders known to be susceptible to amelioration by inhibition or antagonism of TRPA1 .
  • TRPA1 modulators of varied chemical structures have been recently disclosed for the treatment or prevention of chronic and acute inflammatory diseases and other pathological conditions, diseases and disorders known to be susceptible to amelioration by inhibition or antagonism of TRPA1 .
  • Several structural families of antagonists are observed. These include alcohols
  • Compounds having the capacity to selectively antagonise TRPA1 are in active development by several companies. Examples of these compounds are GRC-17536 and HX-100.
  • TRPA1 antagonists or inhibitors being suitable for the treatment of the above-mentioned diseases.
  • a byciclic heterocyclic derivative which is a compound of Formula (I), or a pharmaceutically acceptable salt, or a solvate, or a N- oxide, or a a tautomer, or a a stereoisomer, or an isotopically-labeled derivative thereof,
  • G 1 is selected from the group consisting of a C atom and a N atom;
  • G 2 , G 3 , G 4 and G 5 are each independently selected from the group consisting of a N atom, a N(R b ) group, a C(R b ) group and a C(R C ) group;
  • n is an integer selected from 0 to 1 ;
  • G 6 , G 7 and G 8 are each independently selected from the group consisting of a N atom and a C(R b ) group;
  • G 9 and G 10 are each independently selected from the group consisting of a N atom and a N(R b ) group;
  • L is selected from the group consisting of a direct bond, a -CH2- group, an oxygen atom, a sulphur atom and a N(R b ) group;
  • m is an integer selected from 0 to 1 ;
  • R a is selected from the group consisting of a halogen atom, a cyano group, a linear or branched C1-4 haloalkyl group, a linear or branched C1-4 alkyl group, a linear or branched C1-4 alkoxy group and a linear or branched C1-4 haloalkoxy group;
  • R b is selected from the group consisting of a hydrogen atom and a linear or branched C1-4 alkyl group, and
  • R c is selected from the group consisting of a hydrogen atom, a halogen atom, a cyano group, a linear or branched C1-4 alkyl group, a linear or branched C1-4 alkoxy group, an oxo group, a linear or branched C1-4 haloalkyl group, an amino group, a hydroxyl group, a C1-4 monoalkylamino group, a C1-4 dialkylamino group, a monocyclic C3-7 cycloalkyl group, a monocyclic 3- to 7-membered heterocyclyl group containing at least one heteroatom selected from O, S and N, and a benzyl group.
  • the invention further provides synthetic processes and intermediates described herein, which are useful for preparing compounds of the invention.
  • the invention is also directed to a compound of the invention as described herein for use in the treatment of the human or animal body by therapy.
  • the invention also provides a pharmaceutical composition comprising a compound of the invention and a pharmaceutically-acceptable diluent or carrier.
  • the invention also provides a compound of the invention for use in the treatment of a disease or condition susceptible to amelioration by TRPA1 antagonists or inhibitors, in a mammal, in particular wherein the pathological condition or disease is selected from acute and/or chronic pruritus, acute and/or chronic pain, inflammatory
  • dermatological diseases respiratory disorders, gastrointestinal inflammatory disorders and urinary tract disorders.
  • the invention also provides the use of a compound of the invention in the manufacture of a formulation or medicament for treating a disease or condition susceptible to amelioration by TRPA1 antagonists or inhibitors, in particular wherein the condition or disease is as described above.
  • the invention also provides a method of treating a disease or condition as described above; comprising such method administering to the mammal, a therapeutically effective amount of a compound of the invention.
  • the invention further provides a method of treatment comprising administering a therapeutically effective amount of a combination of a compound of the invention together with one or more other therapeutic agents.
  • the invention also provides a combination product comprising (i) a compound of the invention as described herein; and (ii) one or more additional active substances.
  • C1-4 alkyl embraces unsubstituted or substituted, linear or branched radicals having 1 to 4 carbon atoms. Examples include methyl, ethyl, n-propyl, /-propyl, n-butyl, sec-butyl or i-butyl.
  • C1-4 alkoxy (or alkyloxy) embraces unsubstituted or substituted, linear or branched oxy-containing radicals each having alkyl portions of 1 to 4 carbon atoms.
  • Examples of C1-4 alkoxy radicals include methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, sec-butoxy and t-butoxy.
  • C1-4 haloalkyl is a linear or branched alkyl group, which is substituted by one or more, preferably 1 , 2 or 3 halogen atoms.
  • haloalkyl groups include CCI3, CFs and CHF2.
  • Ci-4 haloalkoxy is typically a C1-4 alkoxy group substituted by one or more halogen atoms. Typically, it is substituted by 1 , 2 or 3 halogen atoms. Examples of haloalkoxy groups include -OCF3 and -OCCI3.
  • monocyclic C3-7 cycloalkyl radical embraces saturated monocyclic ring having from 3 to 7 carbon atoms. Examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.
  • monocyclic 3- to 7-membered heterocyclyl radical embraces typically a non-aromatic, monocyclic, saturated or unsaturated C3-7 carbocyclic ring system in which one or more, for example 1 , 2 or 3 of the carbon atoms are replaced preferably by a heteroatom selected from N, O and S.
  • Representative examples include aziridinyl, azetidinyl, piperidyl, pyrrolidyl, pyrrolinyl, piperazinyl, morpholinyl thiomorpholinyl, pyrazolinyl and pirazolidinyl.
  • halogen atom embraces chlorine, fluorine, bromine or iodine atoms typically a fluorine, chlorine or bromine atom.
  • halo when used as a prefix has the same meaning.
  • C1-4 monoalkylamino is represented by the formula -NH(Ci-4 alkyl) where C1-4 alkyl is as described above.
  • Representative examples include methylamino group, ethylamino group, propylamino group, isopropylamino group, butylamino group, isobutylamino group, (sec-butyl)amino group, and (iert-butyl)amino group.
  • C1-4 dialkylamino as used herein is represented by the formula - N(Ci-4 alkyl)2 where C1-4 alkyl is a described above.
  • Representative examples include dimethylamino group, diethylamino group, dipropylamino group, diisopropylamino group, dibutylamino group, diisobutylamino group, di(sec-butyl)amino group and di(ferf- butyl)amino group.
  • atoms, radicals, moieties, chains and cycles present in the general structures of the invention are "unsubstituted or substituted". This means that these atoms, radicals, moieties, chains and cycles can be either unsubstituted or substituted in any position by one or more, for example 1 , 2, 3 or 4, substituents, whereby the hydrogen atoms bound to the unsubstituted atoms, radicals, moieties, chains and cycles are replaced by chemically acceptable atoms, radicals, moieties, chains and cycles.
  • therapeutically effective amount refers to an amount sufficient to effect treatment when administered to a patient in need of treatment.
  • treatment refers to the treatment of a disease or medical condition in a human patient which includes:
  • pathological condition or disease susceptible to amelioration by inhibition or antagonism of TRPA1 includes all disease states and/or conditions that are acknowledged now, or that are found in the future, to be associated with an increased TRPA1 activity.
  • disease states include, but are not limited to, acute and/or chronic pruritus, acute and/or chronic pain, inflammatory dermatological diseases, respiratory disorders, gastrointestinal inflammatory disorders and urinary tract disorders.
  • the term "pruritus” is used herein in the broadest sense and refers to all types of itching and stinging sensations localized and generalized, acute intermittent and persistent.
  • the pruritus may be dermatologic, idiopathic, allergic, metabolic, infectious, drug-induced, due to liver, kidney disease or cancer.
  • pain is used herein in the broadest sense and refers to all types of pain, including acute and chronic pain, such as nociceptive pain, e.g. somatic pain and visceral pain; inflammatory pain; dysfunctional pain; idiopathic pain; neuropathic pain, e.g., centrally generated pain and peripherally generated pain; migraine and cancer pain.
  • inflammatory dermatological disease includes the following dermatological diseases as non-limiting examples of such dermatological diseases: acne vulgaris, actinic keratosis, eczema, atopic dermatitis, insect bite inflammation, drug-induced skin reactions, psoriasis, rosacea and seborrheic dermatitis.
  • respiratory disorder any condition or disease related to respiration or the respiratory system and includes, but is not limited to, airway inflammation, asthma, emphysema, bronchitis, COPD, sinusitis, rhinitis, cough, idiopathic pulmonary fibrosis (IPF), cystic fibrosis, bronchiectasis, respiratory depression, reactive airways dysfunction syndrome (RADS), acute respiratory distress syndrome (ARDS), inflammatory respiratory diseases conditions poorly responder to corticosteroids (i.e. severe COPD and asthma), sensory hyper-reactivity, multiple chemical sensitivity and aid in smoking cessation therapy.
  • airway inflammation asthma, emphysema, bronchitis, COPD, sinusitis, rhinitis, cough, idiopathic pulmonary fibrosis (IPF), cystic fibrosis, bronchiectasis, respiratory depression, reactive airways dysfunction syndrome (RADS), acute respiratory distress syndrome (ARDS), inflammatory respiratory diseases conditions poorly responder to cortico
  • cough refers to both acute and/or chronic cough and includes interstitial lung disease cough, post-viral cough, gastroesophageal reflux disease
  • GFD gastrointestinal inflammatory disorders
  • UACS upper airways cough syndrome
  • IPF idiopathic pulmonary fibrosis
  • gastrointestinal inflammatory disorders includes, but is not limited to, disorders such as inflammatory bowel disease, ulcerative colitis and Crohn's disease.
  • urinary tract disorders includes, but is not limited to, disorders such as urinary incontinence, bladder instability and cystitis.
  • pharmaceutically-acceptable salt refers to a salt prepared from a base or acid which is acceptable for administration to a patient, such as a mammal.
  • Such salts can be derived from pharmaceutically-acceptable inorganic or organic bases and from pharmaceutically-acceptable inorganic or organic acids.
  • Salts derived from pharmaceutically-acceptable acids include acetic, benzenesulfonic, benzoic, camphosulfonic, citric, ethanesulfonic, formic, fumaric, gluconic, glutamic, hydrobromic, hydrochloric, hydrofluoric, lactic, maleic, malic, mandelic, methanesulfonic, mucic, nitric, pantothenic, phosphoric, succinic, sulfuric, tartaric, p-toluenesulfonic, xinafoic (1 -hydroxy-2-naphthoic acid), napadisilic (1 ,5-naphthalenedisulfonic acid), triphenyl acetic and the like.
  • salts derived from formic, fumaric, hydrobromic, hydrochloric, hydrofluoric, acetic, sulfuric, methanesulfonic, xinafoic, tartaric, maleic, succinic and napadisilic acids are particularly preferred.
  • Salts derived from pharmaceutically-acceptable inorganic bases include aluminium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic, manganous, potassium, sodium, zinc and the like. Particularly preferred are calcium, magnesium, potassium and sodium salts.
  • Salts derived from pharmaceutically-acceptable organic bases include salts of ammonia, primary, secondary and tertiary amines, including substituted amines, cyclic amines, naturally-occurring amines and the like, such as ammonia, arginine, betaine, caffeine, choline, A/J ⁇ -dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, /V-ethylmorpholine, /V-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine and the like.
  • X " may be an anion of various mineral acids such as, for example, chloride, bromide, iodide, sulphate, nitrate, phosphate, or an anion of an organic acid such as, for example, acetate, maleate, fumarate, citrate, oxalate, succinate, tartrate, malate, mandelate, trifluoroacetate, methanesulphonate and p-toluenesulphonate.
  • mineral acids such as, for example, chloride, bromide, iodide, sulphate, nitrate, phosphate
  • organic acid such as, for example, acetate, maleate, fumarate, citrate, oxalate, succinate, tartrate, malate, mandelate, trifluoroacetate, methanesulphonate and p-toluenesulphonate.
  • X " is preferably an anion selected from chloride, bromide, iodide, sulphate, nitrate, acetate, maleate, oxalate, succinate or trifluoroacetate. More preferably X " is chloride, bromide, trifluoroacetate or methanesulphonate.
  • an /V-oxide is formed from the tertiary basic amines or imines present in the molecule, using a convenient oxidising agent.
  • solvate means a compound which further includes a stoichiometric or non-stoichiometric amount of solvent such as water, acetone, ethanol, methanol, dichloromethane, 2-propanol, or the like, bound by non-covalent intermolecular forces.
  • solvent such as water, acetone, ethanol, methanol, dichloromethane, 2-propanol, or the like
  • hydrate is used instead of solvate.
  • the invention also includes isotopically-labeled compounds of the invention, wherein one or more atoms is replaced by an atom having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number usually found in nature.
  • isotopes suitable for inclusion in the compounds of the invention 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 l and 125 l, nitrogen, such as 13 N and 15 N, oxygen, such as 15 0, 17 0 and 18 0, phosphorus, such as 32 P, and sulfur, such as 35 S.
  • Isotopically-labeled compounds of the invention can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described herein, using an appropriate isotopically-labeled reagent in place of the non-labeled reagent otherwise employed.
  • Preferred isotopically-labeled compounds include deuterated derivatives of the compounds of the invention.
  • deuterated derivative embraces compounds of the invention where in a particular position at least one hydrogen atom is replaced by deuterium.
  • Deuterium (D or 2 H) is a stable isotope of hydrogen which is present at a natural abundance of 0.015 molar %.
  • stereoisomer means a compound that has the same molecular formula and sequence of bonded atoms (constitution), but differs in the three-dimensional orientations of their atoms in the space.
  • the compounds of the invention may contain one or more chiral centers. Accordingly, the invention includes racemic mixtures, enantiomers, diastereomers and mixtures enriched in one or more stereoisomer.
  • the scope of the invention as described and claimed encompasses the racemic forms of the compounds as well as the individual enantiomers, diastereomers, and stereoisomer-enriched mixtures.
  • tautomer means two or more forms or isomers of an organic compound that readily could be interconverted into each other via a common chemical reaction called tautomerization. This reaction commonly results in the formal migration of a hydrogen atom or proton, accompanied by a switch of a single bond and adjacent double bond.
  • tautomerism The concept of tautomerizations is called tautomerism. Because of the rapid interconversion, tautomers are generally considered to be the same chemical compound. In solutions in which tautomerization is possible, a chemical equilibrium of the tautomers will be reached. The exact ratio of the tautomers depends on several factors, including temperature, solvent and pH.
  • G 4 is a CH group
  • G 6 and G 8 are each independently selected from the group consisting of a N atom and a CH group;
  • L is selected from a direct bond and an oxygen atom
  • ⁇ R a is selected from the group consisting of a halogen atom, a cyano group and a linear or branched C1-4 haloalkyl group;
  • R c is selected from the group consisting of a hydrogen atom, a halogen atom, a cyano group, a linear or branched C1-4 alkyl group, a linear or branched C1-4 alkoxy group, an oxo group, an amino group, a hydroxyl group, a C1-4 monoalkylamino group, a C1-4 dialkylamino group, a monocyclic C3-7 cycloalkyl group, a monocyclic 3- to 7-membered heterocyclyl group containing at least one heteroatom selected from O, S and N, and a benzyl group.
  • G 1 is a N atom
  • G 2 is a C(R C ) group
  • G 3 is N atom
  • n represents 0, and
  • G 5 is a C(R C ) group; preferably G 2 is a CH group a C- benzyl group or a C-cyclopropyl group and G 5 is a C(CH3) group or a C(CN) group; more preferably G 2 is a CH group and G 5 is a C(CH3) group.
  • G 1 is a N atom
  • G 2 is a N atom
  • G 3 is a CH group
  • n represents 0,
  • G 5 is a C(R b ) group; preferably G 5 is C(CH3) group.
  • G 1 is a C atom
  • G 2 is a N atom
  • G 3 is a N atom
  • n represents 0, and
  • G 5 is N(R b ) group; preferably G 5 is a N(CH3) group.
  • G 1 is a C atom
  • G 2 is a C(R b ) group
  • G 3 is a N atom
  • n represents 0, and
  • G 5 is a N(R b ) group; preferably G 2 is a C(CH3) group or a CH group, and G 5 is a N(CH3) group.
  • G 1 is a C atom
  • G 2 is a N(R b ) group
  • G 3 is a N atom
  • n represents 0
  • G 5 is a C(R b ) group; preferably G 2 is a N(CH3) group and G 5 is a C(CH3) group.
  • G 1 is a C atom
  • G 2 is a N atom
  • G 3 is a C(R b ) group
  • n represents 0
  • G 5 is a N(R b ) group
  • G 3 is a CH group and G 5 is a N(CH 3 ) group.
  • G 1 is a C atom
  • G 2 is a N(R b ) group
  • G 3 is a
  • G 1 is a C atom
  • G 2 is a C(R C ) group
  • G 3 is a N atom
  • n represents 1
  • G 4 is a CH group
  • G 5 is a C(R C ) group
  • G 2 is a CH group and G 5 is a C(CI) group.
  • G 1 is a C atom
  • G 2 is a N atom
  • G 3 is a C(R C ) group
  • n represents 1
  • G 4 is a CH group
  • G 5 is a C(R C ) group; preferably G 3 is a C(OCH 3 ) group and G 5 is a C(CH 3 ) group.
  • G 1 is a C atom
  • G 2 is a N(R b ) group
  • G 3 is a C(R C ) group
  • n represents 1
  • G 4 is a CH group
  • G 5 is a C(R C ) group
  • G 2 is a NH or a N(CH 3 ) group
  • G 3 is a C(O) group
  • G 5 is a C(CH 3 ) group.
  • n 0 and the bicydic heterocyclic derivative of Formula (I) is represented by Formula (la) to Formula (Ig)
  • n 1 and the bicydic heterocyclic derivative of Formula (I) is represented by Formula (Ih) to Formula (Ij)
  • G 9 and G 10 are each independently selected from the group consisting of a N atom, a NH group and a N(CH3) group; preferably G 9 and G 10 are each independently selected from the group consisting of a N atom and a NH group; more preferably G 9 is a N atom and G 10 is a NH group or G 9 is a NH group and G 10 is a N atom;
  • G 8 is a N atom.
  • G 9 and G 10 are each independently selected from the group consisting of a N atom and a NH group; preferably G 9 is a N atom and G 10 is a NH group or G 9 is a NH group and G 10 is a N atom;
  • G 7 is selected from the group consisting of a N atom, a CH group and a C(CH3) group;
  • G 8 is selected from the group consisting of a N atom and a CH group. Still in another embodiment:
  • G 9 and G 10 are each independently selected from the group consisting of a N atom and a NH group; preferably G 9 is a N atom and G 10 is a NH group or G 9 is a NH group and G 10 is a N atom;
  • G 7 is selected from the group consisting of a N atom and a CH group; and • G 8 is a CH group.
  • R a is selected from the group consisting of a halogen atom, a cyano group and a C1-2 haloalkyl group; preferably R a is selected from the group consisting of a CI atom, a Br atom, a cyano group, and a CF3 group.
  • R b is selected from the group consisting of a hydrogen atom and a C1-2 alkyl group.
  • ⁇ R c is selected from the group consisting of a hydrogen atom, a halogen atom, a cyano group, a C1-2 alkyl group, a C1-2 alkoxy group, an oxo group, an amino group, a hydroxyl group, a C1-2 monoalkylamino group, a C1-2 dialkylamino group, a monocyclic C3-6 cycloalkyl group, a monocyclic 6-membered heterocyclyl group containing at least one heteroatom selected from O, S and N, and a benzyl group; preferably R c is selected from the group consisting of a hydrogen atom, a CI atom, a cyano group, a methyl group, an ethyl group, a methoxy group, an oxo group, a methylamino group, a dimethylamino group, a cyclopropyl group, a morpholinyl group and a benzyl
  • the bicyclic heterocyclic derivative according to Formula (I) is represented by Formula (la)' to Formula (Ig)'
  • L is an oxygen atom
  • n is an integer selected from 0 to 1 , preferably m is 1 ;
  • R a is selected from the group consisting of a CI atom, a Br atom, and a CF3 group, preferably R a is a CI atom;
  • R b is selected from the group consisting of a hydrogen atom and a methyl group, preferably is a methyl group;
  • R c is selected from the group consisting of a hydrogen atom, a methyl group, cyclopropyl group, a benzyl group, and an oxo group.
  • the bicyclic heterocyclic derivative according to Formula (I) is represented by Formula (Ih)' to Formula (lj)'
  • m is an integer selected from 0 to 1 , preferably m is 1 ;
  • R a is selected from the group consisting of a CI atom, a Br atom, and a CF3 group, preferably R a is a CI atom;
  • R b is selected from the group consisting of a hydrogen atom and a methyl group
  • R c is selected from the group consisting of a hydrogen atom, a CI atom, a methyl group, a methoxy group, and an oxo group.
  • Particular individual compounds of the invention include:
  • the compounds of the invention can be prepared using the methods and procedures described herein, or using similar methods and procedures. It will be appreciated that where typical or preferred process conditions are given (i.e., reaction temperatures, times, mole ratios of reactants, solvents, pressures, etc.) other process conditions can also be used unless otherwise stated. Optimum reaction conditions may vary with the particular reactants or solvent used, but such conditions can be determined by one skilled in the art by routine optimization procedures.
  • protecting groups may be necessary to prevent certain functional groups from undergoing undesired reactions.
  • the choice of a suitable protecting group for a particular functional group, as well as suitable conditions for protection and de-protection, are well known in the art. For example, numerous protecting groups, and their introduction and removal are described in T. W. Greene and G. M. Wuts, Protecting Groups in Organic Synthesis, Third Edition, Wiley, New York, 1999, and references cited therein.
  • Compounds of general formula (6) may be prepared from compounds of formula (2) wherein R 11 represents a hydrogen atom, an alkyl group such as methyl, ethyl, propyl, iert-butyl group or a benzyl group, and a formamide equivalent such as formamide or formamidine and salts thereof.
  • R 11 represents a hydrogen atom or an alkyl group such as methyl, ethyl, propyl, iert-butyl group or a benzyl group
  • the reaction is carried out by mixing a compound of formula ⁇ 2 ⁇ with formamide in the presence or absence of an acid such as acetic acid at a temperature from 50°C to 200 °C to give a compound of formula ⁇ 6 ⁇ .
  • reaction is carried out by mixing a compound of formula ⁇ 2 ⁇ with formamidine acetic acid salt in the presence or absence of an acid such as acetic acid, in a solvent such as n-butanol at a temperature from 50 °C to 150 °C to give a compound of formula (6).
  • Compounds of general formula (6) may also be prepared from compounds of formula (3).
  • the reaction is carried out by mixing a compound of formula (3) with formamide in the presence or absence of an acid such as acetic acid at a temperature from 50°C to 200 °C to give a compound of formula (6).
  • the reaction is carried out by mixing a compound of formula (3) with an ortho- formate of formula (5) wherein R 12 represents an alkyl group such as methyl or ethyl, in the presence or absence of a solvent such as acetic anhydride at a temperature from 50 °C to 200 °C.
  • Compounds of general formula (6) may also be prepared from compounds of formula ⁇ 4 ⁇ and formic acid, in the presence or absence of an acid such as sulphuric acid at a temperature from 50 °C to 200 °C.
  • Intermediates of formula (2), wherein wherein R 11 is a an alkyl group such as methyl, ethyl, propyl, iert-butyl group or a benzyl group may be prepared from intermediates of formula (7) in the presence of a base such as lithium hexamethyldisilazide and an aminating agent such as O- (diphenylphosphoryl)hydroxylamine, in a solvent such as tetrahydrofuran, dimethylformamide or mixtures thereof at a temperature from -78 °C to room temperature under an inert atmosphere such as nitrogen or argon.
  • a base such as lithium hexamethyldisilazide and an aminating agent such as O- (diphenylphosphoryl)hydroxylamine
  • Intermediates of formula [3] may be prepared from intermediates of formula (7) in the presence of a base such as lithium hexamethyldisilazide and an aminating agent such as O- (diphenylphosphoryl)hydroxylamine, in a solvent such as tetrahydrofuran, dimethylformamide or mixtures thereof at a temperature from -78 °C to room temperature under an inert atmosphere such as nitrogen or argon.
  • Bicyclic heterocycles of general formula (8 ⁇ wherein G 1 to G 5 and n are as defined in Claim 1 and independently of their attachment to other groups through the amide nitrogen may be further modified to compounds such as (9], (10) or (1 1 ) following the synthetic routes depicted in Scheme 3.
  • compounds containing a bicyclic heterocycle of formula (9) wherein one or more of the groups G 2 to G 5 is a carbon atom substituted with a W 3 group, wherein W 3 is a halogen atom such as chlorine, bromine or iodine may be synthesized from a compound containing a bicyclic heterocycle of formula (8) wherein one or more of the groups G 2 to G 5 is a CH group.
  • the reaction may be carried out by mixing a compound of formula (8) with a halogenating reagent such as copper(ll) bromide, /V-chlorosuccinimide, /V-bromosuccinimide, /V-iodoosuccinimide, bromine or iodine, in a solvent such as acetonitrile, chloroform or dimethylformamide at a temperature from 0 °C to 100 °C.
  • a halogenating reagent such as copper(ll) bromide, /V-chlorosuccinimide, /V-bromosuccinimide, /V-iodoosuccinimide, bromine or iodine
  • the reaction may be carried out by mixing a compound of formula ⁇ 9 ⁇ with an amine of general formula NHR 13 R 14 , in the presence or absence of a base such as diisopropylethylamine of potassium carbonate, in a solvent such as tetrahydrofuran, dimethylformamide or mixtures thereof at a temperature from 50 °C to 150 °C.
  • a base such as diisopropylethylamine of potassium carbonate
  • a solvent such as tetrahydrofuran, dimethylformamide or mixtures thereof
  • Compounds containing a bicyclic heterocycle of formula (1 1 ) wherein R 15 represents an alkyl group such as methyl, ethyl, isopropyl, cyclopropyl group, or a benzyl group may be synthesized from a compound containing a bicyclic heterocycle of formula (9) wherein W 3 represents a halogen atom such as chlorine, bromine or iodine.
  • the halogenated derivative (9 ⁇ is treated with an organometallic reagent of general formula M 1 -R 15 wherein M 1 is selected from lithium or salts or complexes of magnesium, zinc, copper, tin or boron.
  • the reaction is carried out by treating the halogenated derivative according to standard literature methods known to those skilled in the art of carbon-carbon cross-coupling reactions.
  • the reaction can be carried out by treating the halogenated derivative with a potassium trifluoroborate reagent in the presence of a transition metal catalyst such as palladium(ll) acetate, in the presence of a phosphine such as di(1-adamantyl)-n-butylphosphine and a base such as caesium carbonate, in a solvent such as water, toluene or mixtures thereof at a temperature from 50 °C to 150 °C under an inert atmosphere such as argon.
  • a transition metal catalyst such as palladium(ll) acetate
  • a phosphine such as di(1-adamantyl)-n-butylphosphine
  • a base such as caesium carbonate
  • Compounds of general formula (13) wherein A is as hereinbefore defined and R 10 represents an alkyl group such as methyl, ethyl, propyl, iert-butyl group, or a benzyl group may be prepared from heterobicyclic compounds of formula ⁇ 6 ⁇ and an alkylating agent of formula (12) wherein W 1 represents a halogen atom such as chlorine, bromine or iodine or a pseudohalogen such as para-toluenesulphonate or methylsulfonate.
  • the reaction is carried out by mixing a compound of formula (6) and compound of formula (12) in the presence of a base such as potassium carbonate in a solvent such as dimethylformamide at a temperature from room temperature to 80 °C.
  • Compounds of general formula (14) wherein A is as hereinbefore defined may be prepared from compounds of formula (13) wherein R 10 is as hereinbefore defined by hydrolysis according to standard literature methods known to those skilled in the art of ester hydrolysis.
  • this may be through the use of a base such as sodium hydroxide in a solvent such as water, methanol, ethanol or tetrahydrofuran, or mixtures thereof, at a temperature from room temperature to 50 °C.
  • a base such as sodium hydroxide in a solvent such as water, methanol, ethanol or tetrahydrofuran, or mixtures thereof, at a temperature from room temperature to 50 °C.
  • an acid such as hydrochloric acid or trifluoroacetic acid in water, dichloromethane, chloroform or dioxane or a mixture thereof at a temperature from room temperature to 50 °C.
  • W 1 represents a halogen atom such as chlorine, bromine or iodine or a pseudohalogen such as para-toluenesulphonate or methylsulfonate
  • W 2 represents a halogen atom such as chlorine, bromine or iodine
  • W 3 represents either a OH group and hence (20) is a carboxylic acid, a chlorine atom and hence (20) is an acyl chloride or a half-stoichiometric oxygen atom and hence (20) is an anhydride.
  • the reaction is carried out by mixing a compound of formula (15) and a compound of formula (20) with a dehydrating agent such as phosphorous oxychloride, either neat or in a solvent such as toluene, at a temperature from 50 °C to 150 °C.
  • a dehydrating agent such as phosphorous oxychloride
  • Intermediates of formula (17) may also be synthesized from a compound of formula (15) wherein G 6 to G 10 and W 2 are as hereinbefore defined and a compound of formula (14), wherein A is as hereinbefore defined.
  • the reaction is carried out by first mixing a compound of formula (14) with an acyl activating reagent known to those skilled in the art of peptide coupling.
  • the activating reagent is carbonyl diimidazole in a solvent such as butyronitrile at room temperature.
  • the mixture is then subsequently treated with a compound of formula (15) at a temperature from 50 °C to 200 °C to give a compound of formula (17).
  • a compound of formula (15) is treated with a compound of formula (14) and wherein the acyl activating agent is phosphorous oxychloride, either neat or in a solvent such as toluene, at a temperature from 50 °C to 200 °C to give a compound of formula (17).
  • the acyl activating agent is phosphorous oxychloride, either neat or in a solvent such as toluene, at a temperature from 50 °C to 200 °C to give a compound of formula (17).
  • the reaction is carried out by treating the halogenated derivative (15) with the organometallic reagent (21 ) according to standard literature methods known to those skilled in the art of carbon-carbon cross- coupling reactions.
  • the reaction can be carried out by treating the halogenated derivative (15) with a boronic acid (21 ) in the presence of a transition metal catalyst such as [1 , 1 '-bis(diphenylphosphino)ferrocene]dichloropalladium(ll), in the presence of a base such as caesium carbonate, in a solvent such as dioxane, water or mixtures thereof at a temperature from room temperature to 150 °C under an inert atmosphere such as argon.
  • a transition metal catalyst such as [1 , 1 '-bis(diphenylphosphino)ferrocene]dichloropalladium(ll)
  • a base such as caesium carbonate
  • a solvent such as dioxane, water or mixtures thereof at a temperature from room temperature to 150 °C under an inert atmosphere such as argon.
  • the reaction may be carried out by treating the halogenated derivative (15) with a compound of formula (21 ) wherein M 2 is a hydrogen atom in the presence or absence of a catalyst such as copper(l) iodide and in the presence or absence of a ligand such as ⁇ , ⁇ -dimethylglycine and in the presence or absence of a base such as caesium carbonate either neat or in a solvent such as dioxane at a temperature from room temperature to 150 °C under an inert atmosphere such as nitrogen.
  • a catalyst such as copper(l) iodide
  • a ligand such as ⁇ , ⁇ -dimethylglycine
  • a base such as caesium carbonate
  • the reaction is carried out by mixing a compound of formula (18) and a compound of formula (20) in a dehydrating agent such as phosphorous oxychloride, either neat or in a solvent such as toluene, at a temperature from 50 °C to 150 °C.
  • a dehydrating agent such as phosphorous oxychloride
  • Compounds of formula (1 ⁇ , wherein G 6 to G 10 , R a , L and m are as defined in Claim 1 , and A represents the heterobicyclic ring as defined by G 1 to G 5 in Claim 1 may be be synthesized from a compound of formula (17), wherein W 2 represents a halogen such as chlorine, bromine or iodine and a compound of formula (21 ) wherein M 2 is lithium or salts or complexes of magnesium, zinc, copper, tin or boron when either L is a -CH2- group or a direct bond, or alternatively M 2 is a hydrogen atom in the case where L is an oxygen atom, a sulphur atom or a NH group.
  • W 2 represents a halogen such as chlorine, bromine or iodine
  • M 2 is lithium or salts or complexes of magnesium, zinc, copper, tin or boron when either L is a -CH2- group or a direct bond, or alternatively
  • the reaction is carried out by treating the halogenated derivative (17) with the organometallic reagent (21 ) according to standard literature methods known to those skilled in the art of carbon-carbon cross-coupling reactions.
  • the reaction can be carried out by treating the halogenated derivative (17) with a boronic acid (21 ) in the presence of a transition metal catalyst such as [1 ,1 '-tetrakis(triphenylphosphine)palladium(0), in the presence of a base such as sodium carbonate, in a solvent such as dioxane, water or mixtures thereof at a temperature from room temperature to 150 °C under an inert atmosphere such as nitrogen.
  • a transition metal catalyst such as [1 ,1 '-tetrakis(triphenylphosphine)palladium(0)
  • the reaction may be carried out by treating the halogenated derivative (17) with a compound of formula (21 ) wherein M 2 is a hydrogen atom in the presence or absence of a catalyst such as copper(l) iodide and in the presence or absence of a ligand such as ⁇ , ⁇ -dimethylglycine and in the presence or absence of a base such as caesium carbonate either neat or in a solvent such as dioxane at a temperature from room temperature to 150 °C under an inert atmosphere such as nitrogen.
  • a catalyst such as copper(l) iodide
  • a ligand such as ⁇ , ⁇ -dimethylglycine
  • a base such as caesium carbonate
  • Compounds of formula £ ⁇ may also be synthesized from a compound of formula (18) wherein G 6 to G 10 , R a , L and m are as hereinbefore defined and a compound of formula (14), wherein A is as hereinbefore defined.
  • the reaction is carried out by first mixing a compound of formula (14) with an acyl activating reagent known to those skilled in the art of peptide coupling.
  • the acyl activating reagent is carbonyl diimidazole in a solvent such as butyronitrile at room temperature.
  • the mixture is then subsequently treated with a compound of formula (18) at a temperature from 50 °C to 200 °C to give a compound of formula (1 ⁇ .
  • a compound of formula (18) is treated with a compound of formula (14) and wherein the acyl activating agent is phosphorous oxychloride, either neat or in a solvent such as toluene, at a temperature from 50 °C to 200 °C to give a compound of formula £ ⁇ .
  • the acyl activating agent is phosphorous oxychloride, either neat or in a solvent such as toluene, at a temperature from 50 °C to 200 °C to give a compound of formula £1 ⁇ .
  • Compounds of formula £ ⁇ may also be synthesized from a compound of formula (19) wherein G 6 to G 10 , R a , L and m are as hereinbefore defined and wherein W 1 represents a halogen atom such as chlorine, bromine or iodine or a pseudohalogen such as para-toluenesulphonate or methylsulfonate and a compound of formula £6], wherein A is hereinbefore defined.
  • the reaction is carried out by mixing a compound of formula (19) with a compound of formula £6] in the presence of a base such as caesium carbonate, in a solvent such as dimethylformamide, at a temperature from room temperature to 50 °C to give a compound of formula (1 ).
  • Reagents, starting materials, and solvents were purchased from commercial suppliers and used as received. Commercial intermediates are referred to in the experimental section by their lUPAC name. Ether refers to diethyl ether, unless otherwise specified. Concentration or evaporation refer to evaporation under vacuum using a Buchi rotatory evaporator.
  • Reaction products were purified, when necessary, by flash chromatography on silica gel (40-63 ⁇ ) with the solvent system indicated. Purifications in reverse phase were made in a Biotage Isolera® automated purification system equipped with a C18 column and using a gradient, unless otherwise stated, of water-acetonitrile/MeOH (1 :1 ) (0.1 % v/v ammonium formate both phases) from 0% to 100% acetonitrile/MeOH (1 :1 ) in 40 column volumes.
  • the conditions "formic acid buffer” refer to the use of 0.1 % v/v formic acid in both phases.
  • the appropriate fractions were collected and the solvents evaporated under reduced pressure and/or liofilized.
  • the chromatographic separations were obtained using a Waters 2795 system equipped with a Symmetry C18 (2.1 x 50 mm, 3.5 ⁇ ) column for methods A, B and C and a Symmetry C18 (2.1 x 100 mm, 3.5 ⁇ ) for method D.
  • the mobile phases were (B): formic acid (0.4 ml), ammonia (0.1 ml), methanol (500 ml) and acetonitrile (500 ml) and (A): formic acid (0.5 ml), ammonia (0.125 ml) and water (1000 ml) (A), the gradients are specified in the following table for each method used.
  • the flow rate was 0.8 ml/min for method A and 0.4 ml/min for method B, C and D.
  • the injection volume was 5 microliters.
  • a Waters 2996 diode array was used as a UV detector.
  • Chromatograms were processed at 210 nM or 254 nM. Mass spectra of the chromatograms were acquired using positive and negative electrospray ionization in a Micromass ZMD or in a Waters ZQ detectors coupled to the HPLC.
  • the UPLC chromatographic separations were obtained using a Waters Acquity UPLC system coupled to a SQD mass spectrometer detector.
  • the system was equipped with an ACQUITY UPLC BEH C-18 (2.1 x50mm, 1 .7 mm) column.
  • the mobile phase was formic acid (0.4 ml), ammonia (0.1 ml), methanol (500 ml) and acetonitrile (500 ml) (B) and formic acid (0.5 ml), ammonia (0.125 ml) and water (1000 ml) (A).
  • a gradient between 0 to 95% of B was used.
  • the run time was 3 or 5 minutes.
  • the injection volume was 0.5 microliter. Chromatograms were processed at 210 nM or 254 nM. Mass spectra of the chromatograms were acquired using positive and negative electrospray ionization.
  • Lithium hexamethyldisilazide (1 M in tetrahydrofuran, 21 .4 mL, 21 .4 mmol) was added dropwise over 15 min to a stirred, cooled (-10 °C) suspension of ethyl 4-methyl-1 H- imidazole-5-carboxylate (3.00 g, 19.5 mmol) in dry dimethylformamide (200 mL) under an atmosphere of argon. After stirring for a further 10 min, O- (diphenylphosphoryl)hydroxylamine (5.45 g, 23.4 mmol) was added and the mixture was warmed to room temperature.
  • N-Bromosuccinimide (0.25 g, 1 .40 mmol) was added to a stirred suspension of the title compound of PREPARATION 5 (0.20 g, 1 .33 mmol) in dimethylformamide (8 mL). After 6 h, further N-bromosuccinimide (0.25 g, 1 .40 mmol) was added and stirring was continued at room temperature. After 7.5 h, the mixture was diluted with 4% aqueous sodium hydrogen carbonate solution and the solid that formed was filtered, washed with water and dried to give 0.178 g (0.78 mmol, 58% yield) of the title compound as a white solid. Purity 98%. 1 H NMR (400 MHz, DMSO-d6) ⁇ ppm 1 1 .81 (s, 1 H), 7.88 (s, 1 H), 2.44 (s, 3H).
  • Methyl 1 -amino-4-methyl-1 H-pyrazole-5-carboxylate Synthesized from methyl 4-methyl-1 H-pyrazole-5-carboxylate and O- (diphenylphosphoryl)hydroxylamine following the procedure of PREPARATION 4. Yield: 49%. Purity 100%.
  • PREPARATION 24 6-(Methylamino)pyrimidin-4(3H)-one hydrochloride hydrate
  • the title compound of PREPARATION 23 (7.80 g, 56 mmol) was suspended in 1 10 ml concentrated hydrochloric acid and the mixture was stirred at 60 °C for 2 days. The mixture was then evaporated under reduced pressure to give 10.0 g (56 mmol, 99% yield) of the title compound as a white solid. Purity 100%. UPLC/MS (3 min) retention time 0.32 min.
  • N-methyl-3-oxobutanamide (400 mg, 2.43 mmol) and malonitrile (160 mg, 2.43 mmol) were suspended in 10 mL of ethanol. Five drops of piperidine were added and the mixture was stirred and heated at 80°C overnight. The mixture was then cooled to room temperature and was concentrated in vacuo. The residue was purified by flash chromatography using the Isolera purification system (ethyl acetate-hexane gradient, 0: 100 rising to 100:0) to give 95 mg (0.58 mmol, 24% yield) of the title compound as a yellow solid. Purity 100%.
  • PREPARATION 38 tert-Butyl (1 ,3-dimethyl-4-oxo-1 ,4-dihydro-5H-pyrazolo[3,4-d]pyrimidin-5- yl)acetate
  • Tert-butyl 2-bromoacetate (2.20 mL, 14.9 mmol) was added dropwise to a suspension of the title compound of PREPARATION 1 (2.20 g, 13.4 mmol) and potassium carbonate (3.70 g, 26.8 mmol) in dimethylformamide (34 mL) and the mixture was stirred at room temperature. After 2 h, the reaction was diluted with water and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulphate and evaporated to give 3.73 g (13.4 mmol, 100% yield) of the title compound as a yellow oil. Purity 95%.
  • PREPARATION 44 tert-Butyl (5-methyl-4-oxoimidazo[5,1 -f][1 ,2,4]triazin-3(4H)-yl)acetate Synthesized from the title compound of PREPARATION 5 and tert-butyl bromoacetate following the method of PREPARATION 38. Yield: 98%. Purity 100%.
  • PREPARATION 46 tert-Butyl (5,7-dimethyl-4-oxoimidazo[5,1 -f][1 ,2,4]triazin-3(4H)-yl)acetate Synthesized from the title compound of PREPARATION 8 and tert-butyl bromoacetate following the method of PREPARATION 38. Yield: 90%. Purity 95%.
  • PREPARATION 60 tert-Butyl (5-methyl-4-oxopyrazolo[5,1 -f][1 ,2,4]triazin-3(4H)-yl)acetate Synthesized from the title compound of PREPARATION 20 and tert-butyl bromoacetate following the method of PREPARATION 38. Yield: 97%. Purity 98%.
  • PREPARATION 71 tert-Butyl (7,9-dimethyl-6,8-dioxo-6,7,8,9-tetrahydro-1 H-purin-1 -yl)acetate
  • the title compound of PREPARATION 70 (180 mg, 0.64 mmol) was dissolved in 4 ml dimethylformamide and the solution was cooled to 0°C in an ice-bath.
  • Sodium hydride (60% suspension in oil, 41 mg, 1 .0 mmol) was added and the mixture was stirred for 30 min.
  • Methyl iodide (42 ⁇ , 0.67 mmol) was added and the mixture was stirred overnight, warming to room temperature.
  • the mixture was partitioned between ethyl acetate and water. The organics were washed with brine, dried over anhydrous sodium sulphate, filtered and evaporated to give 190 mg (0.64 mmol, 100% yield) of the title compound as a yellow oil. Purity 9
  • 3,5-Dibromopyrazin-2-amine (10.0 g, 39.5 mmol) was suspended in 200 ml concentrated (32%) aqueous ammonia and the mixture was stirred at 130 °C in a pressure tube for 5 days. The mixture was allowed to cool, forming a precipitate. The solid was collected by filtration, washed with water and dried in vacuo to give 5.10 g (27.0 mmol, 68% yield) of the title compound as a pale brown solid. Purity 100%.
  • 6-(4-Chlorophenyl)-5-methylpyridine-2,3-diamine 5-Bromo-6-methylpyridine-2,3-diamine (50 mg, 0.25 mmol), 4-chlorophenylboronic acid (45 mg, 0.29 mmol), and cesium carbonate (240 mg, 0.74 mmol) were suspended in dioxane/water (4: 1 ; v/v) (1 .25 ml) and this mixture was degassed (3 x vacuum- nitrogen cycles).
  • [1 , 1 '-Bis(diphenylphosphino)ferrocene]dichloropalladium(ll) (1 : 1 ) dichloromethane complex was added and the mixture degassed again (3 x vacuum- nitrogen cycles).
  • the title compound of PREPARATION 5 (14 mg, 0.09 mmol) was dissolved in 0.5 ml dry dimethylformamide. Caesium carbonate (82 mg, 0.25 mmol) was added and the suspension was stirred at room temperature for 15 min. A solution of the crude title compound of PREPARATION 85 (26 mg) dissolved in 0. 5ml dry dimethylformamide was added and the mixture was stirred at room temperature overnight. The mixture was diluted with water and extracted three times with ethyl acetate. The combined organics were washed with water, brine, dried over anhydrous magnesium sulphate, filtered and evaporated under reduced pressure.
  • 5 ⁇ of compound plate content were added by the FLIPR Tetra from Molecular Devices into assay plates and fluorescence (Ex: 485 nm; Em: 525 nm) recorded during 15 minutes to assess
  • Peak and base line were taken for the calculation of the ratio (Peak/Base Line). Percentage activation or inhibition for each compound was calculated by normalizing compound ratios to maximal and minimal ratios obtained for 100 ⁇ and 1 ⁇ of AITC, for agonist and antagonist mode respectively, as total response and vehicle (0.1 % DMSO) for basal response.
  • IC50 values are represented by letters according to the value:
  • the compounds of the invention may also be combined with other active compounds in the treatment of diseases indicated above.
  • the compounds of the present invention can be combined with active substances which are known to be useful in the treatment of these diseases.
  • Examples of such active substances are: a. Corticoids and glucocorticoids, such as beclomethasone, betamethasone, betamethasone dipropionate, budesonide, dexamethasone, fluticasone furoate, fluticasone propionate, hydrocortisone, methylprednisolone, mometasone furoate, prednicarbate, prednisolone or prednisone; b. Calcineurin inhibitors, such as cyclosporine A, tacrolimus, pimecrolimus or voclosporin; c. Kappa opioid agonists, such as nalfurafine, nalbuphine, asimadoline or CR- d.
  • Corticoids and glucocorticoids such as beclomethasone, betamethasone, betamethasone dipropionate, budesonide, dexamethasone, fluticasone furoate, fluticasone propionate
  • Neurokinin receptor 1 antagonists such as aprepitant, fosaprepitant, rolapitant, orvepitant, tradipitant or serlopitant; e. Dihydropteroate synthase inhibitors, such as dapsone or sulfadoxine; f. Histamine 1 (H1 ) receptor antagonists, such as azelastine, ebastine,
  • DHODH Dihydroorotate dehydrogenase
  • I. Purine antagonists such as azathioprine, mercaptopurine or tioguanine
  • m. Antimalarials such as hydroxichloroquine, chloroquine or quinacrine
  • n. Inosine-monophosphate dehydrogenase (IMPDH) inhibitors such as
  • ⁇ mycophenolate mophetyl, ribavirin or mizoribine
  • o Fumaric acid esters, such as dimethyl fumarate
  • p Vitamine D3 derivatives such as calcipotriol, calcitriol or tacalcitol
  • q Retinoids, such as tazarotene, alitretinoin, acitretin or isotretinoin
  • Anti-tumor necrosis factor-alpha (Anti-TNF-alpha) monoclonal antibodies such as infliximab, adalimumab, certolizumab pegol or golimumab
  • Soluble Tumor necrosis factor-alpha (TNF-alpha) receptors such as
  • IL-6R Anti-lnterleukin 6 Receptor
  • IL-12R Anti-lnterleukin 12 Receptor
  • IL-23R Interleukin 23 Receptor
  • IL-17R Anti-lnterleukin 17 Receptor
  • Anti-CD20 (B lymphocyte protein) antibody such as rituximab, ofatumumab, obinutuzumab, ocrelizumab, ublituximab, veltuzumab, ocaratuzumab; x. Anti-lnterleukin 5 (IL-5) antibody, such as mepolizumab; y. Anti-lnterleukin 5 Receptor (IL-5R) antibody, such as benralizumab; z. Anti-lnterleukin 13 (IL-13) antibody, such as lebrikizumab or tralokinumab; aa. Anti-lnterleukin 4 Receptor (IL-4R) / Interleukin 13 Receptor (IL-13R)
  • Anti-lnterleukin 17 (IL-17) antibody such as secukinumab, ixekizumab or bimekizumab
  • IL-1 R Anti-lnterleukin 1 Receptor
  • Anti-lnmunoglobuline E (IgE) antibody such as omalizumab or quilizumab
  • BAFF Anti-B-cell activating factor
  • B lymphocyte protein monoclonal antibody
  • Cysteinyl leukotriene (CysLT) receptor antagonists such as montelukast, zafirlukast, tipelukast, masilukast
  • hh Chemoattractant receptor homologous molecule expressed on TH2 cells (CRTH2) inhibitors, such as OC-459, AZD-1981 , ADC-3680, ARRY-502 or setipripant
  • Topical anti-septics such as triclosan, chlorhexidine, crystal violet 0.3% or sodium hypochlorite water-baths.
  • another embodiment of the invention is a combination product comprising (i) at least a compound of formula (I) as defined previously, and (ii) one or more active ingredients as described above, for simultaneous, separate or sequential use in the treatment of the human or animal body.
  • the combinations of the invention may be used in the treatment of disorders which are susceptible to amelioration by TRPA1 inhibition or antagonism.
  • the present application encompasses methods of treatment of these disorders, as well as the use of the combinations of the invention in the manufacture of a medicament for the treatment of these disorders.
  • each active which is required to achieve a therapeutic effect will, of course, vary with the particular active, the route of administration, the subject under treatment, and the particular disease or disorder being treated. However, an effective dosage is typically in the range of 0.01 -3000 mg, more preferably 0.5-1000 mg of active ingredient or the equivalent amount of a pharmaceutically acceptable salt thereof per day.
  • the active ingredients may be administered from 1 to 6 times a day, sufficient to exhibit the desired activity.
  • the active ingredients are administered once or twice a day, most preferably once a day.
  • the active compounds in the combination product may be administered together in the same pharmaceutical composition or in different compositions intended for separate, simultaneous, concomitant or sequential administration by the same or a different route.
  • compositions according to the present invention comprise the compounds of the invention in association with a pharmaceutically acceptable diluent or carrier.
  • composition refers to a mixture of one or more of the compounds described herein, or physiologically/pharmaceutically acceptable salts, solvates, /V-oxides, tautomers, stereoisomers, or isotopically-labeled derivatives thereof, with other chemical components, such as
  • compositions are physiologically/pharmaceutically acceptable carriers and excipients.
  • the purpose of a pharmaceutical composition is to facilitate administration of a compound to an organism.
  • a physiologically/pharmaceutically acceptable diluent or carrier refers to a carrier or diluent that does not cause significant irritation to an organism and does not abrogate the biological activity and properties of the administered compound.
  • a pharmaceutically acceptable excipient refers to an inert substance added to a pharmaceutical composition to further facilitate administration of a compound.
  • the invention further provides pharmaceutical compositions comprising the compounds of the invention in association with a pharmaceutically acceptable diluent or carrier together with one or more other therapeutic agents such as the previously described for use in the treatment of a pathological condition or disease susceptible to amelioration by TRPA1 antagonists or inhibitors, in particular wherein the pathological condition or disease is selected from acute and/or chronic pruritus, acute and/or chronic pain, inflammatory dermatological diseases, respiratory disorders,
  • the invention is also directed to pharmaceutical compositions of the invention for use in the treatment of a pathological disease or disorder susceptible to
  • TRPA1 antagonists or inhibitors in particular wherein the pathological disease or disorder is as described above.
  • the invention also provides a method of treatment of a pathological condition or disease susceptible to amelioration by TRPA1 receptor antagonists in particular wherein the pathological condition or disease is as described above, comprising administering a therapeutically effective amount of a pharmaceutical composition of the invention.
  • compositions which comprise, as an active ingredient, at least a compound of formula (I) or a
  • compositions are made up in a form suitable for oral, oral mucosa, inhaled, topical, nasal mucosa, rectal/intravaginal, percutaneous, parenteral, ocular or aural administration. More preferably the compositions are made up in a form suitable for oral administration.
  • compositions suitable for the delivery of compounds of the invention and methods for their preparation will be readily apparent to those skilled in the art. Such compositions and methods for their preparation can be found, for example, in Remington: The Science and Practice of Pharmacy, 21 st Edition,
  • compositions of this invention are well-known per se and the actual excipients used depend inter alia on the intended method of administering the compositions.
  • excipients include calcium carbonate, calcium phosphate, various sugars and types of starch, cellulose derivatives, gelatin, vegetable oils and polyethylene glycols. Additional suitable carriers for formulations of the compounds of the present invention can be found in Remington: The Science and Practice of Pharmacy, 21 st Edition, Lippincott Williams & Wilkins, Philadelphia, Pa., 2001.
  • the compounds of the invention may be administered orally (peroral administration; per os (latin)). Oral administration involve swallowing, so that the compound is absorbed from the gut and delivered to the liver via the portal circulation (hepatic first pass metabolism) and finally enters the gastrointestinal (Gl) tract.
  • oral administration per os (latin)
  • Oral administration involve swallowing, so that the compound is absorbed from the gut and delivered to the liver via the portal circulation (hepatic first pass metabolism) and finally enters the gastrointestinal (Gl) tract.
  • compositions for oral administration may take the form of tablets, retard tablets, sublingual tablets, capsules, inhalation aerosols, inhalation solutions, dry powder inhalation, or liquid preparations, such as mixtures, solutions, elixirs, syrups or suspensions, all containing the compound of the invention; such preparations may be made by methods well-known in the art.
  • the active ingredient may also be presented as a bolus, electuary or paste.
  • any pharmaceutical carrier routinely used for preparing solid formulations may be used. Examples of such carriers include magnesium stearate, talc, gelatine, acacia, stearic acid, starch, lactose and sucrose.
  • a tablet may be made by compression or moulding, optionally with one or more accessory ingredients.
  • Compressed tablets may be prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as a powder or granules, optionally mixed with a binder, lubricant, inert diluent, lubricating, surface active or dispersing agent.
  • Moulded tablets may be made by moulding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.
  • the tablets may optionally be coated or scored and may be formulated so as to provide slow or controlled release of the active ingredient therein.
  • the drug may make up from 1 wt% to 80 wt% of the dosage form, more typically from 5 wt% to 60 wt% of the dosage form.
  • tablets generally contain a disintegrant.
  • disintegrants include sodium starch glycolate, sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, croscarmellose sodium, crospovidone, polyvinylpyrrolidone, methyl cellulose, microcrystalline cellulose, lower alkyl- substituted hydroxypropyl cellulose, starch, pregelatinized starch and sodium alginate.
  • the disintegrant will comprise from 1 wt% to 25 wt%, preferably from 5 wt% to 20 wt% of the dosage form.
  • Binders are generally used to impart cohesive qualities to a tablet formulation. Suitable binders include microcrystalline cellulose, gelatin, sugars, polyethylene glycol, natural and synthetic gums, polyvinylpyrrolidone, pregelatinized starch, hydroxypropyl cellulose and hydroxypropyl methylcellulose. Tablets may also contain diluents, such as lactose (monohydrate, spray-dried monohydrate, anhydrous and the like), mannitol, xylitol, dextrose, sucrose, sorbitol, microcrystalline cellulose, starch and dibasic calcium phosphate dihydrate.
  • lactose monohydrate, spray-dried monohydrate, anhydrous and the like
  • mannitol xylitol
  • dextrose sucrose
  • sorbitol microcrystalline cellulose
  • starch dibasic calcium phosphate dihydrate
  • Tablets may also optionally include surface active agents, such as sodium lauryl sulfate and polysorbate 80, and glidants such as silicon dioxide and talc.
  • surface active agents such as sodium lauryl sulfate and polysorbate 80
  • glidants such as silicon dioxide and talc.
  • surface active agents are typically in amounts of from 0.2 wt% to 5 wt% of the tablet, and glidants typically from 0.2 wt% to 1 wt% of the tablet.
  • Tablets also generally contain lubricants such as magnesium stearate, calcium stearate, zinc stearate, sodium stearyl fumarate, and mixtures of magnesium stearate with sodium lauryl sulphate.
  • Lubricants generally are present in amounts from 0.25 wt% to 10 wt%, preferably from 0.5 wt% to 3 wt% of the tablet.
  • Other conventional ingredients include anti-oxidants, colorants, flavoring agents, preservatives and taste-masking agents.
  • Exemplary tablets contain up to about 80 wt% drug, from about 10 wt% to about 90 wt% binder, from about 0 wt% to about 85 wt% diluent, from about 2 wt% to about 10 wt% disintegrant, and from about 0.25 wt% to about 10 wt% lubricant.
  • Tablet blends may be compressed directly or by roller to form tablets. Tablet blends or portions of blends may alternatively be wet-, dry-, or melt-granulated, melt congealed, or extruded before tabletting.
  • the final formulation may include one or more layers and may be coated or uncoated; or encapsulated. The formulation of tablets is discussed in detail in "Pharmaceutical Dosage
  • composition is in the form of a capsule
  • any routine encapsulation is suitable, for example using the aforementioned carriers in a hard gelatine capsule.
  • composition is in the form of a soft gelatine capsule
  • any pharmaceutical carrier routinely used for preparing dispersions or suspensions may be considered, for example aqueous gums, celluloses, silicates or oils, and are incorporated in a soft gelatine capsule.
  • Solid formulations for oral administration may be formulated to be immediate and/or modified release.
  • Modified release formulations include delayed-, sustained-, pulsed-, controlled-, targeted and programmed release.
  • Liquid formulations include suspensions, solutions, syrups and elixirs. Such formulations may be used as fillers in soft or hard capsules and typically include a carrier, for example, water, ethanol, polyethylene glycol, propylene glycol,
  • methylcellulose or a suitable oil, and one or more emulsifying agents and/or suspending agents.
  • the solutions may be aqueous solutions of a soluble salt or other derivative of the active compound in association with, for example, sucrose to form a syrup.
  • the suspensions may comprise an insoluble active compound of the invention or a pharmaceutically acceptable salt thereof in association with water, together with a suspending agent or flavouring agent.
  • Liquid formulations may also be prepared by the reconstitution of a solid, for example, from a sachet.
  • Oral mucosa administration The compounds of the invention can also be administered via the oral mucosa administration.
  • delivery of drugs is classified into three categories: (a) sublingual delivery, which is systemic delivery of drugs through the mucosal membranes lining the floor of the mouth, (b) buccal delivery, which is drug administration through the mucosal membranes lining the cheeks (buccal mucosa), and (c) local delivery, which is drug delivery into the oral cavity.
  • Pharmaceutical products to be administered via the oral mucosa can be designed using mucoadhesive, quick dissolve tablets and solid lozenge formulations, which are formulated with one or more mucoadhesive (bioadhesive) polymers (such as hydroxy propyl cellulose, polyvinyl pyrrolidone, sodium carboxymethyl cellulose, hydroxy propyl methyl cellulose, hydroxy ethyl cellulose, polyvinyl alcohol,
  • mucoadhesive polymers such as hydroxy propyl cellulose, polyvinyl pyrrolidone, sodium carboxymethyl cellulose, hydroxy propyl methyl cellulose, hydroxy ethyl cellulose, polyvinyl alcohol,
  • polyisobutylene or polyisoprene examples include butanol, butyric acid, propranolol, sodium lauryl sulphate and others.
  • oral mucosal permeation enhancers such as butanol, butyric acid, propranolol, sodium lauryl sulphate and others
  • the compounds of the invention can also be administered by inhalation, typically in the form of a dry powder from a dry powder inhaler or as an aerosol spray from a pressurized container, pump, spray, atomizer, or nebulizer, with or without the use of a suitable propellant.
  • the powder may include a bioadhesive agent, for example, chitosan or cyclodextrin.
  • the compounds of the invention may also be administered via the nasal mucosa.
  • compositions for nasal mucosa administration are typically applied by a metering, atomizing spray pump and are in the form of a solution or suspension in an inert vehicle such as water optionally in combination with conventional excipients such as buffers, anti-microbials, tonicity modifying agents and viscosity modifying agents.
  • parenteral administration The compounds of the invention may also be administered directly into the blood stream, into muscle, or into an internal organ. Suitable means for parenteral administration include intravenous, intraarterial, intraperitoneal, intrathecal,
  • Suitable devices for parenteral administration include needle (including microneedle) injectors, needle-free injectors and infusion techniques.
  • Parenteral formulations are typically aqueous solutions which may contain excipients such as salts, carbohydrates and buffering agents (preferably to a pH of from 3 to 9), but, for some applications, they may be more suitably formulated as a sterile non-aqueous solution or as a dried form to be used in conjunction with a suitable vehicle such as sterile, pyrogen-free water.
  • excipients such as salts, carbohydrates and buffering agents (preferably to a pH of from 3 to 9)
  • a suitable vehicle such as sterile, pyrogen-free water.
  • the compounds of the invention may also be administered topically to the skin or mucosa, that is, dermally or transdermally.
  • Typical formulations for this purpose include gels, hydrogels, lotions, solutions, creams, ointments, dusting powders, dressings, foams, films, skin patches, wafers, implants, sponges, fibers, bandages and microemulsions.
  • Liposomes may also be used.
  • Typical carriers include alcohol, water, mineral oil, liquid petrolatum, white petrolatum, glycerin, polyethylene glycol and propylene glycol.
  • Penetration enhancers may be incorporated; see, for example, J Pharm Sci, 88 (10), 955-958 by Finnin and Morgan (October 1999).
  • Other means of topical administration include delivery by electroporation, iontophoresis,
  • Compounds of the invention may be administered rectally or vaginally, for example, in the form of a suppository, pessary, or enema. Cocoa butter is a traditional suppository base, but various alternatives may be used as appropriate.
  • Formulations for rectal/vaginal administration may be formulated to be immediate and/or modified release. Modified release formulations include delayed-, sustained-, pulsed-, controlled-, targeted and programmed release. viii) Ocular and aural administration.
  • Compounds of the invention may also be administered directly to the eye or ear, typically in the form of drops of a micronized suspension or solution in isotonic, pH- adjusted, sterile saline.
  • Other formulations suitable for ocular and aural administration include ointments, biodegradable ⁇ e.g. absorbable gel sponges, collagen) and nonbiodegradable (e.g. silicone) implants, wafers, lenses and particulate or vesicular systems, such as niosomes or liposomes.
  • a polymer such as
  • crossed-linked polyacrylic acid, polyvinylalcohol, hyaluronic acid, a cellulosic polymer, for example, hydroxypropylmethylcellulose, hydroxyethylcellulose, or methyl cellulose, or a heteropolysaccharide polymer, for example, gelan gum, may be incorporated together with a preservative, such as benzalkonium chloride. Such formulations may also be delivered by iontophoresis. ix) Other Technologies
  • Compounds of the invention may be combined with soluble macromolecular entities, such as cyclodextrin and suitable derivatives thereof or polyethylene glycol-containing polymers, in order to improve their solubility, dissolution rate, taste-masking, bioavailability and/or stability for use in any of the aforementioned modes of administration.
  • soluble macromolecular entities such as cyclodextrin and suitable derivatives thereof or polyethylene glycol-containing polymers
  • 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.
  • the composition is in unit dosage form, for example a tablet, capsule or metered aerosol dose, so that the patient may administer a single dose.

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Abstract

La présente invention concerne des dérivés hétérocycliques bicyliques de formule (I), un procédé de préparation de tels composés et leur utilisation pour le traitement d'un état pathologique ou d'une maladie susceptible d'être amélioré(e) par une activité antagoniste ou inhibitrice des canaux TRPA1. Formule (I)
PCT/EP2016/074352 2015-10-14 2016-10-11 Nouveaux antagonistes de trpa1 WO2017064068A1 (fr)

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Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2020073011A1 (fr) * 2018-10-05 2020-04-09 Annapurna Bio, Inc. Composés et compositions destinés au traitement d'états pathologiques associés à une activité du récepteur de l'apj
US10617671B2 (en) 2013-06-24 2020-04-14 Menlo Therapeutics Inc. Use of NK-1 receptor antagonist serlopitant in pruritus
US10702499B2 (en) 2013-06-24 2020-07-07 Menlo Therapeutics Inc. Use of NK-1 receptor antagonists in pruritus
US10913742B2 (en) 2016-11-28 2021-02-09 Genentech, Inc. Oxadiazolones as transient receptor potential channel inhibitors
US11332459B2 (en) 2017-10-19 2022-05-17 Teijin Pharma Limited Benzimidazole derivatives and their uses
CN114845709A (zh) * 2019-11-05 2022-08-02 德米拉公司 用于治疗炎性病症的mrgprx2拮抗剂
IT202100015098A1 (it) 2021-06-09 2022-12-09 Flonext S R L Composto antagonista del canale trpa1 per uso in patologie degenerative della retina
WO2024121552A1 (fr) * 2022-12-06 2024-06-13 Autifony Therapeutics Limited Composés pour le traitement de troubles du système nerveux central

Citations (33)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000035298A1 (fr) 1996-11-27 2000-06-22 Wm. Wrigley Jr. Company Chewing-gum contenant des agents medicamenteux actifs
US6106864A (en) 1995-09-15 2000-08-22 Pfizer Inc. Pharmaceutical formulations containing darifenacin
WO2007073505A2 (fr) 2005-12-22 2007-06-28 Hydra Biosciences, Inc. Méthodes et compositions de traitement de la douleur
WO2007098252A2 (fr) 2006-02-21 2007-08-30 Irm Llc Méthodes et compositions pour traiter une hyperalgésie
WO2009002933A1 (fr) 2007-06-22 2008-12-31 Hydra Biosciences, Inc. Procédés et compositions pour le traitement de troubles
WO2009089083A1 (fr) 2008-01-04 2009-07-16 Abbott Laboratories Antagonistes de trpa1
WO2009089082A1 (fr) 2008-01-04 2009-07-16 Abbott Laboratories Antagonistes de trpa1
WO2009118596A2 (fr) 2008-03-26 2009-10-01 Glenmark Pharmaceuticals, S. A. Dérivés de phtalimide en tant que modulateurs de trpa1
WO2009144548A1 (fr) 2008-05-28 2009-12-03 Glenmark Pharmaceuticals S.A. Dérivés d’imidazo[2,1-b]purine en tant que modulateurs de trpa1
WO2009147079A1 (fr) 2008-06-02 2009-12-10 Janssen Pharmaceutica Nv Antagonistes des trpa1 constitués par des 3,4-dihydropyrimidines
WO2009158719A2 (fr) 2008-06-27 2009-12-30 Hydra Biosciences, Inc. Méthodes et compositions de traitement de troubles
WO2010004390A1 (fr) 2008-06-17 2010-01-14 Glenmark Pharmaceuticals, S.A. Dérivés de quinazoline dione en tant que modulateurs de trpa1
WO2010036821A1 (fr) 2008-09-24 2010-04-01 Hydra Biosciences, Inc. Méthodes et compositions pour le traitement de troubles respiratoires
WO2010075353A1 (fr) 2008-12-22 2010-07-01 Hydra Biosciences, Inc. Compositions utiles pour traiter des troubles associés au trpa1
WO2010109329A1 (fr) 2009-03-23 2010-09-30 Glenmark Pharmaceuticals, S.A. Dérivés de furopyrimidinedione à titre de modulateurs de trpa1
WO2010109287A1 (fr) 2009-03-23 2010-09-30 Glenmark Pharmaceuticals S.A. Dérivés de pyrimidinediones fusionnés utilisés comme modulateurs des récepteurs trpa1
WO2010109328A1 (fr) 2009-03-23 2010-09-30 Glenmark Pharmaceuticals, S.A. Dérivés d'isothiazolo-pyrimidinedione utiles comme modulateurs de la trpa1
WO2010125469A1 (fr) 2009-04-29 2010-11-04 Glenmark Pharmaceuticals, S.A. Composés hétérocycliques fusionnés à une pyrimidine dione en tant que modulateurs de trpa1
WO2010132838A1 (fr) 2009-05-14 2010-11-18 Hydra Biosciences, Inc. Composés utiles pour traiter des troubles associés à trpa1
WO2010138879A1 (fr) 2009-05-29 2010-12-02 Hydra Biosciences, Inc. Composés utiles dans le traitement de troubles associés à trpa1
WO2010141805A1 (fr) 2009-06-05 2010-12-09 Janssen Pharmaceutica Nv Amides hétérocycliques en tant que modulateurs de la trpa1
WO2011043954A1 (fr) 2009-10-07 2011-04-14 Merck Sharp & Dohme Corp. Nouveaux antagonistes de trpa1
WO2011114184A1 (fr) 2010-03-15 2011-09-22 Glenmark Pharmaceuticals S.A. Amides de composés hétérocycliques à titre d'inhibiteurs de trpa1
WO2011132017A1 (fr) 2010-04-19 2011-10-27 Glenmark Pharmaceuticals S.A. Dérivés de pyrido[3,4-d]pyrimidinyl acétamide comme modulateurs de trpa1
WO2012050512A1 (fr) 2010-10-12 2012-04-19 Astrazeneca Ab Antagoniste du récepteur trpa1
WO2012085662A1 (fr) 2010-12-20 2012-06-28 Glenmark Pharmaceuticals S.A. Composés 2-amino-4-arylthiazoles en tant qu'antagonistes de la trpa1
EP2520566A1 (fr) 2011-05-06 2012-11-07 Orion Corporation Nouveaux composés pharmaceutiques
WO2012152940A2 (fr) 2011-05-12 2012-11-15 B.R.A.I.N. Biotechnology Research And Information Network Ag Inhibiteurs de trpa1 à petite molécule
WO2012176105A1 (fr) 2011-06-22 2012-12-27 Glenmark Pharmaceuticals Sa Composition pharmaceutique comprenant un antagoniste du trpa1 et un antagoniste du récepteur de leucotriènes
WO2013023102A1 (fr) 2011-08-09 2013-02-14 Hydra Biosciences, Inc. Inhibition du canal ionique à potentiel de récepteur transitoire trpa1
WO2013103155A1 (fr) 2012-01-05 2013-07-11 Kao Corporation Agent pour la réduction de l'irritation sensorielle
WO2013108857A1 (fr) 2012-01-17 2013-07-25 味の素株式会社 Dérivé d'amine hétérocyclique et produit pharmaceutique le contenant
WO2014049047A1 (fr) 2012-09-27 2014-04-03 F. Hoffmann-La Roche Ag Composés de sulfonamide substitués

Patent Citations (34)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6106864A (en) 1995-09-15 2000-08-22 Pfizer Inc. Pharmaceutical formulations containing darifenacin
WO2000035298A1 (fr) 1996-11-27 2000-06-22 Wm. Wrigley Jr. Company Chewing-gum contenant des agents medicamenteux actifs
WO2007073505A2 (fr) 2005-12-22 2007-06-28 Hydra Biosciences, Inc. Méthodes et compositions de traitement de la douleur
WO2007098252A2 (fr) 2006-02-21 2007-08-30 Irm Llc Méthodes et compositions pour traiter une hyperalgésie
WO2009002933A1 (fr) 2007-06-22 2008-12-31 Hydra Biosciences, Inc. Procédés et compositions pour le traitement de troubles
WO2009089082A1 (fr) 2008-01-04 2009-07-16 Abbott Laboratories Antagonistes de trpa1
WO2009089083A1 (fr) 2008-01-04 2009-07-16 Abbott Laboratories Antagonistes de trpa1
WO2009118596A2 (fr) 2008-03-26 2009-10-01 Glenmark Pharmaceuticals, S. A. Dérivés de phtalimide en tant que modulateurs de trpa1
WO2009144548A1 (fr) 2008-05-28 2009-12-03 Glenmark Pharmaceuticals S.A. Dérivés d’imidazo[2,1-b]purine en tant que modulateurs de trpa1
WO2009147079A1 (fr) 2008-06-02 2009-12-10 Janssen Pharmaceutica Nv Antagonistes des trpa1 constitués par des 3,4-dihydropyrimidines
WO2010004390A1 (fr) 2008-06-17 2010-01-14 Glenmark Pharmaceuticals, S.A. Dérivés de quinazoline dione en tant que modulateurs de trpa1
WO2009158719A2 (fr) 2008-06-27 2009-12-30 Hydra Biosciences, Inc. Méthodes et compositions de traitement de troubles
WO2010036821A1 (fr) 2008-09-24 2010-04-01 Hydra Biosciences, Inc. Méthodes et compositions pour le traitement de troubles respiratoires
WO2010075353A1 (fr) 2008-12-22 2010-07-01 Hydra Biosciences, Inc. Compositions utiles pour traiter des troubles associés au trpa1
WO2010109328A1 (fr) 2009-03-23 2010-09-30 Glenmark Pharmaceuticals, S.A. Dérivés d'isothiazolo-pyrimidinedione utiles comme modulateurs de la trpa1
WO2010109287A1 (fr) 2009-03-23 2010-09-30 Glenmark Pharmaceuticals S.A. Dérivés de pyrimidinediones fusionnés utilisés comme modulateurs des récepteurs trpa1
WO2010109329A1 (fr) 2009-03-23 2010-09-30 Glenmark Pharmaceuticals, S.A. Dérivés de furopyrimidinedione à titre de modulateurs de trpa1
WO2010109334A2 (fr) 2009-03-23 2010-09-30 Glenmark Pharmaceuticals, S.A. Dérivés de thiénopyrimidinedione comme modulateurs de trpa1
WO2010125469A1 (fr) 2009-04-29 2010-11-04 Glenmark Pharmaceuticals, S.A. Composés hétérocycliques fusionnés à une pyrimidine dione en tant que modulateurs de trpa1
WO2010132838A1 (fr) 2009-05-14 2010-11-18 Hydra Biosciences, Inc. Composés utiles pour traiter des troubles associés à trpa1
WO2010138879A1 (fr) 2009-05-29 2010-12-02 Hydra Biosciences, Inc. Composés utiles dans le traitement de troubles associés à trpa1
WO2010141805A1 (fr) 2009-06-05 2010-12-09 Janssen Pharmaceutica Nv Amides hétérocycliques en tant que modulateurs de la trpa1
WO2011043954A1 (fr) 2009-10-07 2011-04-14 Merck Sharp & Dohme Corp. Nouveaux antagonistes de trpa1
WO2011114184A1 (fr) 2010-03-15 2011-09-22 Glenmark Pharmaceuticals S.A. Amides de composés hétérocycliques à titre d'inhibiteurs de trpa1
WO2011132017A1 (fr) 2010-04-19 2011-10-27 Glenmark Pharmaceuticals S.A. Dérivés de pyrido[3,4-d]pyrimidinyl acétamide comme modulateurs de trpa1
WO2012050512A1 (fr) 2010-10-12 2012-04-19 Astrazeneca Ab Antagoniste du récepteur trpa1
WO2012085662A1 (fr) 2010-12-20 2012-06-28 Glenmark Pharmaceuticals S.A. Composés 2-amino-4-arylthiazoles en tant qu'antagonistes de la trpa1
EP2520566A1 (fr) 2011-05-06 2012-11-07 Orion Corporation Nouveaux composés pharmaceutiques
WO2012152940A2 (fr) 2011-05-12 2012-11-15 B.R.A.I.N. Biotechnology Research And Information Network Ag Inhibiteurs de trpa1 à petite molécule
WO2012176105A1 (fr) 2011-06-22 2012-12-27 Glenmark Pharmaceuticals Sa Composition pharmaceutique comprenant un antagoniste du trpa1 et un antagoniste du récepteur de leucotriènes
WO2013023102A1 (fr) 2011-08-09 2013-02-14 Hydra Biosciences, Inc. Inhibition du canal ionique à potentiel de récepteur transitoire trpa1
WO2013103155A1 (fr) 2012-01-05 2013-07-11 Kao Corporation Agent pour la réduction de l'irritation sensorielle
WO2013108857A1 (fr) 2012-01-17 2013-07-25 味の素株式会社 Dérivé d'amine hétérocyclique et produit pharmaceutique le contenant
WO2014049047A1 (fr) 2012-09-27 2014-04-03 F. Hoffmann-La Roche Ag Composés de sulfonamide substitués

Non-Patent Citations (11)

* Cited by examiner, † Cited by third party
Title
"Remington: The Science and Practice of Pharmacy", 2001, LIPPINCOTT WILLIAMS & WILKINS
ANTONIO FERRER-MONTIEL ET AL: "Advances in modulating thermosensory TRP channels", EXPERT OPINION ON THERAPEUTIC PATENTS, vol. 22, no. 9, 1 September 2012 (2012-09-01), pages 999 - 1017, XP055183481, ISSN: 1354-3776, DOI: 10.1517/13543776.2012.711320 *
BIOORG. MED. CHEM. LETT, vol. 22, 2012, pages 797
BIOORG. MED. CHEM. LETT., vol. 20, 2010, pages 276
FINNIN; MORGAN, J PHARM SCI, vol. 88, no. 10, October 1999 (1999-10-01), pages 955 - 958
H. LIEBERMAN; L. LACHMAN: "Pharmaceutical Dosage Forms: Tablets", vol. 1, 1980, MARCEL DEKKER
HARTMAN ET AL., J. MED. CHEM., vol. 27, no. 12, 1984, pages 1634 - 9
MED. CHEM. COMM., vol. 3, 2012, pages 187
T. W. GREENE; G. M. WUTS: "Protecting Groups in Organic Synthesis", 1999, WILEY
VERMA ET AL., PHARMACEUTICAL TECHNOLOGY ON-LINE, vol. 25, no. 2, 2001, pages 1 - 14
WILSON ET AL., CELL, 2013

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10617671B2 (en) 2013-06-24 2020-04-14 Menlo Therapeutics Inc. Use of NK-1 receptor antagonist serlopitant in pruritus
US10702499B2 (en) 2013-06-24 2020-07-07 Menlo Therapeutics Inc. Use of NK-1 receptor antagonists in pruritus
US11026920B2 (en) 2013-06-24 2021-06-08 Vyne Therapeutics Inc. Use of NK-1 receptor antagonist serlopitant in pruritus
US10913742B2 (en) 2016-11-28 2021-02-09 Genentech, Inc. Oxadiazolones as transient receptor potential channel inhibitors
US11332459B2 (en) 2017-10-19 2022-05-17 Teijin Pharma Limited Benzimidazole derivatives and their uses
JP2022508648A (ja) * 2018-10-05 2022-01-19 アンナプルナ バイオ インコーポレイテッド Ａｐｊ受容体活性に関連する状態を処置するための化合物および組成物
WO2020073011A1 (fr) * 2018-10-05 2020-04-09 Annapurna Bio, Inc. Composés et compositions destinés au traitement d'états pathologiques associés à une activité du récepteur de l'apj
CN113490668A (zh) * 2018-10-05 2021-10-08 安娜普尔纳生物股份有限公司 用于治疗与apj受体活性有关的疾病的化合物和组合物
US11471455B2 (en) 2018-10-05 2022-10-18 Annapurna Bio, Inc. Compounds and compositions for treating conditions associated with APJ receptor activity
AU2019353144B2 (en) * 2018-10-05 2023-11-16 Annapurna Bio, Inc. Compounds and compositions for treating conditions associated with APJ receptor activity
US11944622B2 (en) 2018-10-05 2024-04-02 Annapurna Bio, Inc. Compounds and compositions for treating conditions associated with APJ receptor activity
EP4364798A3 (fr) * 2018-10-05 2024-06-19 Annapurna Bio Inc. Composés et compositions pour le traitement d'états associés à l'activité du récepteur apj
CN114845709A (zh) * 2019-11-05 2022-08-02 德米拉公司 用于治疗炎性病症的mrgprx2拮抗剂
IT202100015098A1 (it) 2021-06-09 2022-12-09 Flonext S R L Composto antagonista del canale trpa1 per uso in patologie degenerative della retina
WO2024121552A1 (fr) * 2022-12-06 2024-06-13 Autifony Therapeutics Limited Composés pour le traitement de troubles du système nerveux central

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