WO2013054185A1 - Dérivés de pyrimidine et de pyridine utiles en thérapie - Google Patents

Dérivés de pyrimidine et de pyridine utiles en thérapie Download PDF

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Publication number
WO2013054185A1
WO2013054185A1 PCT/IB2012/002073 IB2012002073W WO2013054185A1 WO 2013054185 A1 WO2013054185 A1 WO 2013054185A1 IB 2012002073 W IB2012002073 W IB 2012002073W WO 2013054185 A1 WO2013054185 A1 WO 2013054185A1
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Prior art keywords
heterocyclyl
phenyl
heteroaryl
compound
pharmaceutically acceptable
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PCT/IB2012/002073
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English (en)
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Scott A. Long
Atli Thorarensen
Mark E. Schnute
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Pfizer, Inc.
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Publication of WO2013054185A1 publication Critical patent/WO2013054185A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • 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

Definitions

  • This invention relates to pyrimidine and pyridine derivatives useful in therapy, to processes for the preparation of such derivatives, to compositions containing such derivatives, and to the uses of such derivatives.
  • the pyrimidine and pyridine derivatives of the present invention have a number of therapeutic applications, particularly in the treatment of pain. This is believed to result from them being inhibitors of the enzyme autotaxin.
  • Autotaxin is a member of the family of nucleotide pyrophosphatases/phosphodiesterases (NPPl-7) and is also referred to as NPP2 [Stefan et al, "NPP-type ectophosphodiesterases: unity in diversity," Trends in Biochemical Sciences, vol. 30, no. 10, pp. 542-550, 2005].
  • ATX is a constitutively active enzyme possessing activity of phospholipase D. It hydrolyzes the head groups of lysophospho lipids (LPC) to lysophosphatidic acid (1 or 2-acyl- sn-glycerol-3-phosphate, LPA) and also acts on sphingosylphosphorylcholine to produce sphingosine 1 -phosphate (SIP) [Yuelling et al, "Autotaxin (ATX): a multifunctional and multi-modular protein possessing enzymatic lysoPLD activity and matricellular properties," Biochimica et Biophysica Acta, vol. 1781, no. 9, pp.
  • LPC lysophospho lipids
  • SIP sphingosine 1 -phosphate
  • ATX is the main source of blood LPA ( ⁇ 0.1 ⁇ plasma and ⁇ 1 ⁇ serum), but not S IP [Tanaka et al, "Autotaxin stabilizes blood vessels and is required for embryonic vasculature by producing lysophosphatidic acid," Journal of Biological Chemistry, vol. 281 , no. 35, pp. 25822-25830, 2006; Alvarez et al, “Autocrine and paracrine roles of sphingosine- 1 -phosphate,” Trends in Endocrinology and Metabolism, vol. 18, no. 8, pp. 300-307, 2007].
  • ATX hydrolyzes ATP: however, the affinity to ATP is at least 50-fold lower than for lysophospholipids [Gijsbers et al, "The hydrolysis of lysophospholipids and nucleotides by autotaxin (NPP2) involves a single catalytic site," FEBS Letters, vol. 538, no. 1- 3, pp. 60-64, 2003; Van Meeteren et al, "Regulation and biological activities of the autotaxin- LPA axis," Progress in Lipid Research, vol. 46, no. 2, pp. 145-160, 2007].
  • LPA acts on target cells through specific G-protein-coupled receptors (LPAl /Edg2, LPA2/Edg4, LPA3/Edg7, LPA4/GPR23/P2Y9, LPA5/GPR92, LPA6/P2Y5).
  • LPA receptors are broadly expressed throughout the body (neuronal, peripheral and central; platelets), and up-regulated in pathological conditions including for example fibrosis (renal, liver and lung), cancer (ovarian and breast), and osteoarthritis.
  • ATX an excellent drug target for the treatment of a number of pathologies including fibrosis (eg renal, lung, and liver), cancer (including ovarian cancer, prostate cancer and breast cancer), pain, osteoarthritis, rheumatoid arthritis, multiple sclerosis, atherosclerosis, thrombosis, psoriasis, diabetic neuropathy, neuropathies and inflammatory conditions. Consequently, selective ATX inhibitors have the potential to treat a variety of diseases that involve the LPC/LPA ATX pathway.
  • the pyrimidine and pyridine derivatives of the present invention are potentially useful in the treatment of a wide range of disorders, particularly pain, acute pain, chronic pain, neuropathic pain, inflammatory pain, osteoarthritis, visceral pain, nociceptive pain including post-surgical pain, and mixed pain types involving the viscera, gastrointestinal tract, cranial structures, musculoskeletal system, spine, urogenital system, cardiovascular system and CNS, including cancer pain, back and orofacial pain.
  • cancer including ovarian cancer, prostate cancer and breast cancer
  • atherosclerosis including ovarian cancer, prostate cancer and breast cancer
  • thrombosis including psoriasis, multiple sclerosis
  • fibrotic diseases including pulmonary fibrosis, Cirrhosis, endomyocardial fibrosis, mediastinal fibrosis, myelofibrosis, retroperitoneal fibrosis, nephrogenic systemic fibrosis, Crohn's disease, Keloid, old myocardial infarction, scleroderma / systemic sclerosis, atherofibrosis and adhesive capsulitis, neurodegenerative disorders, irritable bowel syndrome, rheumatoid arthritis, neuropathological disorders, functional bowel disorders, inflammatory bowel diseases, pain associated with dysmenorrhea, pelvic pain, cystitis, pancreatitis, migraine, cluster and tension headaches, diabetic neuropathy, peripheral neuropathic pain, sci
  • ATX inhibitors that are good drug candidates.
  • preferred compounds should bind potently to the ATX enzyme whilst showing little affinity for other receptors and enzymes which could give rise to unwanted side-effects, and should show functional activity as ATX inhibitors. They should be well absorbed from the gastrointestinal tract, be metabolically stable and possess favourable pharmacokinetic properties. They should be non-toxic and demonstrate few side-effects.
  • the ideal drug candidate will exist in a physical form that is stable, non-hygroscopic and easily formulated. The invention therefore provides a compound of formula I,
  • W represents a Ci-6 alkylene group which may be straight or branched
  • R 1 represents H, phenyl, naphthyi, heteroaryl 1 , heterocyclyl 1 or C3.6 cycloalkyl
  • each phenyl, naphthyi, heteroaryl 1 , heterocyclyl 1 and C3-5 cycloalkyl group is optionally substituted with from 1 to 3 substituents selected from halo, alkyl optionally substituted with 1-3 halogen atoms, phenyl, C e alkoxy optionally substituted with 1 -3 halogen atoms, cyano, heteroaryl la and heterocyclyl la ;
  • each phenyl, naphthyi, heteroaryl 1 , heterocyclyl 1 and C3.6 cycloalkyl group is optionally fused to a 5- or 6-membered heteroaromatic or heterocyclic ring containing from 1 to 3 heteroatoms (selected from N, O and S); and each heteroaryl 1 , heterocyclyl 1 and C 3- 6 cycloalkyl group is optionally fused to a benzene ring; and when the group is substituted the substitution may occur anywhere on the optionally fused ring system as a who le;
  • heterocyclyl 1 and heterocyclyl 1 a may additionally be substituted with
  • n 1 or 2;
  • n 0, 1 or 2;
  • V represents a bond or alkylene which may be straight or branched
  • R 2 represents H, -S-(Ci -6 alkyl), -S0 2 N(C, -6 alkyl) 2 , -C0 2 -(Ci. 6 alkyl), -NHCOCH 2 -phenyl,
  • each phenyl, naphthyi, heteroaryl 2 , heterocyclyl 2 and cycloalkyl group is optionally substituted with from 1 to 3 substituents selected from halo, Ci -6 alkyl optionally substituted with 1-3 halogen atoms, phenyl (optionally substituted with CN or Ci.6 alkyl), phenoxy, benzyloxy, N0 2 , -NHS0 2 (Ci -6 alkyl), -S0 2 (Ci.6 alkyl), pyridylmethyl, C .e alkoxy optionally substituted with 1-3 halogen atoms, cyano, heteroaryl 2a and heterocyclyl 23 ;
  • each phenyl, naphthyl, heteroaryl 2 , heterocyclyl 2 and cycloalkyl group is optionally fused to a 5- or 6-membered heteroaromatic or heterocyclic ring containing from 1 to 3 heteroatoms (selected from N, O and S); and wherein each heteroaryl 2 , heterocyclyl 2 and C3-6 cycloalkyl group is optionally fused to a benzene ring; and when the group is substituted the substitution may occur anywhere on the optionally fused ring system as a whole;
  • R represents heterocyclyl 2 ;
  • R 4 represents phenyl-(Ci.6 alkylene)-, wherein the phenyl group is optionally substituted with from 1 to 3 substituents selected from halo, Cj.6 alkyl optionally substituted with 1-3 halogen atoms, Ci-6 alkoxy optionally substituted with 1-3 halogen atoms, and cyano; heteroaryl 1 , heteroaryl 13 , heteroaryl 2 and heteroaryl 23 independently represent a 5- or 6-membered heteroaryl group containing from 1 to 3 heteroatoms (selected from N, O and S); and
  • heterocyclyl 1 , heterocyclyl 13 , heterocyclyl 2 and heterocyclyl 23 independently represent a 5- or 6-membered heterocyclyl group containing from 1 to 3 heteroatoms (selected from N, O and S);
  • halo means fluoro, chloro, bromo or iodo.
  • Alkyl, alkylene, and alkoxy groups, containing the requisite number of carbon atoms, can be unbranched or branched.
  • alkyl include methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, sec-butyl and t-butyl.
  • alkoxy include methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, i-butoxy, sec-butoxy and t-butoxy.
  • alkylene include methylene,
  • cycloalkyl examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.
  • Heteroaryl is a radical formed from a heteroaromatic ring, for example thienyl, furanyl, pyrrolyl, pyrazolyl, imidazoyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl and tetrazolyl.
  • Heterocyclyl is a radical formed from a saturated or partially saturated heterocyclic ring, for example tetrahydrofuranyl, tetrahydrothiophenyl, pyrrolidinyl, tetrahydropyranyl, piperazinyl and imidazolidinyl.
  • Preferred groups of compounds are those in which:
  • W is C3 ⁇ 4, and pharmaceutically acceptable salts and solvates thereof;
  • n 1 , and pharmaceutically acceptable salts and solvates thereof;
  • n 1 , and pharmaceutically acceptable salts and solvates thereof;
  • A is CO, and pharmaceutically acceptable salts and solvates thereof;
  • R 1 is phenyl substituted by F or OCF 3 , and pharmaceutically acceptable salts and solvates thereof;
  • V is as defined herein;
  • R2 is as defined herein.
  • V is is selected from a bond or C1.5 alkylene which may be straight or branched.
  • V is C3 ⁇ 4 or CH2CH2, and pharmaceutically acceptable salts and solvates thereof;
  • R 2 is selected from H, -S-(Ci-6 alkyl), -S02N(Ci-6 alkyl)2, -C0 2 -(C,.
  • phenyl is optionally fused to tetrahydrofuran and said phenyl or dihydrobenzofuran is optionally substituted by 1 -2 substituents selected from CI, F, OCF 3 , N0 2 , OCH3, NS0 2 CH 3 , SO2CH3, OCH 2 Ph and OPh
  • heteroaryl 2 is a 5-6 membered heteroaryl group containing from 1 to 2 heteroatoms (selected from N, O and S) said heteroaryl group being optionally fused to a benzene ring and the optionally fused system may be substituted at any position by OPh;
  • R 2 is selected from H, -SCH 3 , -S0 2 N(CH3) 2 , -C0 2 -(C, -2 alkyl), -NHCOCH 2 -phenyl, -OCH 2 -phenyl, -S0 2 -phenyl, -NR 3 R 4 , phenyl, naphthyl, heteroaryl 2 , heterocyclyl 2 , -CO-4-methylpiperazin-l -yl or €3.5 cycloalkyl;
  • phenyl is optionally substituted by 1-2 substituents selected from CI, F, OCF3, N0 2 , OCH 3 , NSO2CH3, SO2CH3, OCH 2 Ph and OPh; or is optionally fused with tetrahydrofuran to form a 2,3-dihydrobenzofuran moiety.
  • heteroaryl 2 is selected from furanyl, 1 ,3-benzothiazolyl, pyridinyl substituted by a phenoxy group and an indazolyl;
  • heterocyclyl 2 is selected from oxoimidazolidinyl, isoindolin-l-one and pyrrolidin-2-one substituted by CH 2 -pyridine.
  • R 3 is tetrahydropyranyl
  • ⁇ R 4 is benzyl
  • Pharmaceutically acceptable salts of the compounds of formula I include the acid addition and base salts thereof. Suitable acid addition salts are formed from acids which form non-toxic salts. Examples include the acetate, aspartate, benzoate, besylate, bicarbonate/carbonate, bisulphate/sulphate, borate, camsylate, citrate, edisylate, esylate, formate, fumarate, gluceptate, gluconate, glucuronate, hexafluorophosphate, hibenzate, hydrochloride/chloride, hydrobromide/bromide, hydro iodide/iodide, isethionate, lactate, malate, maleate, malonate, mesylate, methylsulphate, naphthylate, 2-napsylate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate/hydrogen phosphate/dihydrogen phosphate, sac
  • Suitable base salts are formed from bases which form non-toxic salts. Examples include the aluminium, arginine, benzathine, calcium, choline, diethylamine, diolamine, glycine, lysine, magnesium, meglumine, olamine, potassium, sodium, tromethamine and zinc salts.
  • Hemisalts of acids and bases may also be formed, for example, hemisulphate and hemicalcium salts.
  • the resulting salt may precipitate out and be collected by filtration or may be recovered by evaporation of the solvent.
  • the degree of ionisation in the resulting salt may vary from completely ionised to almost non- ionised.
  • the compounds of the invention may exist in both unsolvated and solvated forms.
  • the term 'solvate' is used herein to describe a molecular complex comprising the compound of the invention and a stoichiometric amount of one or more pharmaceutically acceptable solvent molecules, for example, ethanol.
  • the term 'hydrate' is employed when said solvent is water.
  • complexes such as clathrates, drug-host inclusion complexes wherein, in contrast to the aforementioned solvates, the drug and host are present in stoichiometric or non-stoichiometric amounts.
  • complexes of the drug containing two or more organic and/or inorganic components which may be in stoichiometric or non-stoichiometric amounts.
  • the resulting complexes may be ionised, partially ionised, or non-ionised.
  • references to compounds of formula I below include references to salts, solvates and complexes thereof and to solvates and complexes of salts thereof.
  • the compounds of the invention include all polymorphs and crystal habits thereof, prodrugs and isomers thereof (including optical, geometric and tautomeric isomers) as hereinafter defined and isotopically-labeled compounds of formula I.
  • 'pro-drugs' of the compounds of formula I are also within the scope of the invention.
  • certain derivatives of compounds of formula I which may have little or no pharmacological activity themselves can, when administered into or onto the body, be converted into compounds of formula I having the desired activity, for example, by hydro lytic cleavage.
  • Such derivatives are referred to as 'prodrugs'.
  • Further information on the use of prodrugs may be found in Pro-drugs as Novel Delivery Systems, Vol. 14, ACS Symposium Series (T. Higuchi and W. Stella) and Bioreversible Carriers in Drug Design, Pergamon Press, 1987 (ed. E. B. Roche, American Pharmaceutical Association).
  • Prodrugs in accordance with the invention can, for example, be produced by replacing appropriate functionalities present in the compounds of formula I with certain moieties known to those skilled in the art as 'pro-moieties' as described, for example, in Design of Prodrugs by H. Bundgaard (Elsevier, 1985).
  • prodrugs in accordance with the invention include
  • the compound of formula I contains a primary or secondary amino functionality (-N3 ⁇ 4 or -NHR where R ⁇ H), an amide thereof, for example, a compound wherein, as the case may be, one or both hydrogens of the amino functionality of the compound of formula I is/are replaced by (Ci-Cio)alkanoyl.
  • metabolites of compounds of formula I that is, compounds formed in vivo upon administration of the drug.
  • Compounds of formula I containing one or more asymmetric carbon atoms can exist as two or more stereoisomers. Where a compound of formula I contains an alkenyl or alkenylene group, geometric cisltrans (or Z/E) isomers are possible. Where structural isomers are interconvertible via a low energy barrier, tautomeric isomerism ('tautomerism') can occur. This can take the form of proton tautomerism in compounds of formula I containing, for example, an imino, keto, or oxime group, or so-called valence tautomerism in compounds which contain an aromatic moiety. It follows that a single compound may exhibit more than one type of isomerism.
  • Cisltrans isomers may be separated by conventional techniques well known to those skilled in the art, for example, chromatography and fractional crystallisation.
  • Conventional techniques for the preparation/isolation of individual enantiomers include chiral synthesis from a suitable optically pure precursor or resolution of the racemate (or the racemate of a salt or derivative) using, for example, chiral high pressure liquid chromatography (HPLC).
  • HPLC high pressure liquid chromatography
  • the racemate (or a racemic precursor) may be reacted with a suitable optically active compound, for example, an alcohol, or, in the case where the compound of formula I contains an acidic or basic moiety, a base or acid such as 1-phenylethylamine or tartaric acid.
  • the resulting diastereomeric mixture may be separated by chromatography and/or fractional crystallization and one or both of the diastereoisomers converted to the corresponding pure enantiomer(s) by means well known to a skilled person.
  • Chiral compounds of the invention may be obtained in enantiomerically-enriched form using chromatography, typically HPLC, on an asymmetric resin with a mobile phase consisting of a hydrocarbon, typically heptane or hexane, containing from 0 to 50% by volume of isopropanol, typically from 2% to 20%, and from 0 to 5% by volume of an alkylamine, typically 0.1 % diethylamine. Concentration of the eluate affords the enriched mixture.
  • Stereoisomeric conglomerates may be separated by conventional techniques known to those skilled in the art - see, for example, Stereochemistry of Organic Compounds by E. L. Eliel and S. H.
  • the present invention includes all pharmaceutically acceptable isotopically-labelled compounds of formula I wherein one or more atoms are replaced by atoms having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number which predominates in nature.
  • isotopes suitable for inclusion in the compounds of the invention include isotopes of hydrogen, such as 2 H and 3 H, carbon, such as U C, ,3 C and 14 C, chlorine, such as 36 C1, fluorine, such as 18 F, iodine, such as 123 I and 125 1, nitrogen, such as 13 N and 15 N, oxygen, such as , 5 0, l 7 0 and l 8 0, phosphorus, such as 32 P, and sulphur, such as 3 S.
  • Certain isotopically-labelled compounds of formula I for example, those incorporating a radioactive isotope, are useful in drug and/or substrate tissue distribution studies.
  • the radioactive isotopes tritium, i.e.
  • Isotopically- labeled compounds of formula I can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described in the accompanying Examples and Preparations using an appropriate isotopically- labeled reagent in place of the non- labeled reagent previously employed.
  • Pharmaceutically acceptable solvates in accordance with the invention include those wherein the solvent of crystallization may be isotopically substituted, e.g. D 2 O, de-acetone, d 6 -DMSO. All of the compounds of the formula (I) can be prepared by the procedures described in the general methods presented below or by the specific methods described in the Examples section and the Preparations section, or by routine modifications thereof.
  • the present invention also encompasses any one or more of these processes for preparing the compounds of formula (I), in addition to any novel intermediates used therein.
  • R , W, X, Y, Z, m and n are as defined above,
  • A, V and R are as defined above, and L is a leaving group.
  • suitable leaving groups are halogen, such as CI.
  • suitable leaving groups include OH, and peptide-coupling type procedures may be used, for example using HATU (2-(7-Aza-lH-benzotriazole-l-yl)-l,l,3,3-tetramethyluronium hexafluorophosphate) and DIPEA (diisopropyl ethylamine) in THF at room temperature.
  • Hal is a halogen (such as Br or CI) and Pg is a protecting group, with a compound of formula V,
  • R 1 and W are as defined above, followed by removal of Pg.
  • the zincate coupling is carried out in the presence of a palladium(O) catalyst, such as Pd2(dba)3 [tris(dibenzylideneacetone)dipalladium(0)] in the presence of P(o-tolyl)3, in THF, at around 40-50°C.
  • a palladium(O) catalyst such as Pd2(dba)3 [tris(dibenzylideneacetone)dipalladium(0)] in the presence of P(o-tolyl)3, in THF, at around 40-50°C.
  • Suitable Pg groups include benzyl, which may be removed by hydrogenation in methanol containing aqueous HCI in the presence of Pd/C at a temperature in the range 20°C to the reflux temperature of the solvent, and a pressure of 1-100 atm (lxlO 5 - IxlO 7 N/m 2 ) hydrogen.
  • reaction by the action of PO(Hal)3.
  • the reaction is carried out in dichloromethane at room temperature.
  • the invention further provides a compound of formula I, as defined above, or a pharmaceutically acceptable salt or solvate thereof, for use in the treatment of a disorder selected from: pain, acute pain, chronic pain, neuropathic pain, inflammatory pain, visceral pain, nociceptive pain including post-surgical pain, and mixed pain types involving the viscera, gastrointestinal tract, cranial structures, musculoskeletal system, spine, urogenital system, cardiovascular system and CNS, including cancer pain, back and orofacial pain.
  • a disorder selected from: pain, acute pain, chronic pain, neuropathic pain, inflammatory pain, visceral pain, nociceptive pain including post-surgical pain, and mixed pain types involving the viscera, gastrointestinal tract, cranial structures, musculoskeletal system, spine, urogenital system, cardiovascular system and CNS, including cancer pain, back and orofacial pain.
  • the invention further provides a compound of formula I, as defined above, or a pharmaceutically acceptable salt or solvate thereof, for use in the treatment of a disorder selected from: cancer (including ovarian cancer, breast cancer and prostate cancer), atherosclerosis, thrombosis, psoriasis, multiple sclerosis, neurodegenerative disorders, irritable bowel syndrome, osteoarthritis, rheumatoid arthritis, neuropathological disorders, functional bowel disorders, inflammatory bowel diseases, pain associated with , dysmenorrhea, pelvic pain, cystitis, pancreatitis, migraine, cluster and tension headaches, diabetic neuropathy, peripheral neuropathic pain, sciatica, fibromyalgia, causalgia, and conditions of lower urinary tract dysfunction.
  • cancer including ovarian cancer, breast cancer and prostate cancer
  • atherosclerosis including ovarian cancer, breast cancer and prostate cancer
  • thrombosis psoriasis
  • multiple sclerosis neurodegenerative disorders
  • the invention further provides a compound of formula I, as defined above, or a pharmaceutically acceptable salt or solvate thereof, for use in the treatment of fibrotic diseases.
  • fibrotic diseases include pulmonary fibrosis, Cirrhosis, endomyocardial fibrosis, mediastinal fibrosis, myelofibrosis, retroperitoneal fibrosis, nephrogenic systemic fibrosis, Crohn's disease, Keloid, old myocardial infarction, scleroderma / systemic sclerosis, atherofibrosis and adhesive capsulitis,
  • the invention further provides a pharmaceutical formulation comprising a compound of formula I, as defined above, or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable adjuvant, diluent or carrier.
  • the pharmaceutical formulation may further comprise one or more additional active agents for the treatment of a disorder mentioned above.
  • the invention further provides a pharmaceutical kit comprising a compound of formula I, as defined above, or a pharmaceutically acceptable salt or solvate thereof, and one or more additional active agents, as a combined preparation for separate, simultaneous or sequential administration in the treatment of a disorder mentioned above.
  • the invention further provides a method of treatment of a disorder mentioned above in a mammal (especially a human), comprising administration of a therapeutically effective amount of a compound of formula I, as defined above, or a pharmaceutically acceptable salt or solvate thereof, to a mammal in need of such treatment.
  • Compounds of the invention intended for pharmaceutical use may be administered as crystalline or amorphous products. They may be obtained, for example, as solid plugs, powders, or films by methods such as precipitation, crystallization, freeze drying, spray drying, or evaporative drying. Microwave or radio frequency drying may be used for this purpose.
  • excipients may be administered alone or in combination with one or more other compounds of the invention or in combination with one or more other drugs (or as any combination thereof). Generally, they will be administered as a formulation in association with one or more pharmaceutically acceptable excipients.
  • excipient' is used herein to describe any ingredient other than the compound(s) of the invention. The choice of excipient will to a large extent depend on factors such as the particular mode of administration, the effect of the excipient on solubility and stability, and the nature of the dosage form.
  • compositions suitable for the delivery of compounds of the present invention and methods for their preparation will be readily apparent to those skilled in the art. Such compositions and methods for their preparation may be found, for example, in Remington's Pharmaceutical Sciences, 19th Edition (Mack Publishing Company, 1995).
  • the compounds of the invention may be administered orally.
  • Oral administration may involve swallowing, so that the compound enters the gastrointestinal tract, or buccal or sublingual administration may be employed by which the compound enters the blood stream directly from the mouth.
  • Formulations suitable for oral administration include solid formulations such as tablets, capsules containing particulates, liquids, or powders, lozenges (including
  • Liquid formulations include suspensions, solutions, syrups and elixirs. Such formulations may be employed as fillers in soft or hard capsules and typically comprise 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. Liquid formulations may also be prepared by the reconstitution of a solid, for example, from a sachet.
  • the compounds of the invention may also be used in fast-dissolving, fast-disintegrating dosage forms such as those described in Expert Opinion in Therapeutic Patents, ⁇ . (6), 981-986, by Liang and Chen (2001).
  • the drug may make up from 1 weight % to 80 weight % of the dosage form, more typically from 5 weight % to 60 weight % 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, pregelatinised starch and sodium alginate.
  • the disintegrant will comprise from 1 weight % to 25 weight %, preferably from 5 weight % to 20 weight % 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, pregelatinised 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 comprise 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 may comprise from 0.2 weight % to 5 weight % of the tablet, and glidants may comprise from 0.2 weight % to 1 weight % 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 comprise from 0.25 weight % to 10 weight %, preferably from 0.5 weight % to 3 weight % of the tablet.
  • ingredients include anti-oxidants, colourants, flavouring agents, preservatives and taste-masking agents.
  • Exemplary tablets contain up to about 80% drug, from about 10 weight % to about 90 weight % binder, from about 0 weight % to about 85 weight % diluent, from about 2 weight % to about 10 weight % disintegrant, and from about 0.25 weight % to about 10 weight % 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 comprise one or more layers and may be coated or uncoated; it may even be encapsulated.
  • the formulation of tablets is discussed in Pharmaceutical Dosage Forms: Tablets. Vol. 1, by H. Lieberman and L. Lachman (Marcel Dekker, New York, 1980).
  • Consumable oral films for human or veterinary use are typically pliable water-soluble or water-swellable thin film dosage forms which may be rapidly dissolving or mucoadhesive and typically comprise a compound of formula I, a film-forming polymer, a binder, a solvent, a humectant, a plasticiser, a stabiliser or emulsifier, a viscosity-modifying agent and a solvent. Some components of the formulation may perform more than one function.
  • the compound of the invention may be water-soluble or insoluble.
  • a water-soluble compound typically comprises from 1 weight % to 80 weight %, more typically from 20 weight % to 50 weight %, of the solutes. Less soluble compounds may comprise a greater proportion of the composition, typically up to 88 weight % of the solutes.
  • the compound of the invention may be in the form of multiparticulate beads.
  • the film-forming polymer may be selected from natural polysaccharides, proteins, or synthetic hydrocolloids and is typically present in the range 0.01 to 99 weight %, more typically in the range 30 to 80 weight %.
  • ingredients include anti-oxidants, colorants, flavourings and flavour enhancers, preservatives, salivary stimulating agents, cooling agents, co-solvents (including oils), emollients, bulking agents, anti-foaming agents, surfactants and taste-masking agents.
  • Films in accordance with the invention are typically prepared by evaporative drying of thin aqueous films coated onto a peelable backing support or paper. This may be done in a drying oven or tunnel, typically a combined coater dryer, or by freeze-drying or vacuuming.
  • 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.
  • Suitable modified release formulations for the purposes of the invention are described in US Patent No. 6,106,864. Details of other suitable release technologies such as high energy dispersions and osmotic and coated particles are to be found in Pharmaceutical Technology On-line. 25(2), 1-14, by Verma et al (2001). The use of chewing gum to achieve controlled release is described in WO 00/35298.
  • 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, intraventricular, intraurethral, intrasternal, intracranial, intramuscular and subcutaneous.
  • 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.
  • parenteral formulations under sterile conditions may readily be accomplished using standard pharmaceutical techniques well known to those skilled in the art.
  • solubility of compounds of the invention used in the preparation of parenteral solutions may be increased by the use of appropriate formulation techniques, such as the incorporation of solubility-enhancing agents.
  • Formulations for parenteral administration may be formulated to be immediate and/or modified release.
  • Modified release formulations include delayed-, sustained-, pulsed-, controlled-, targeted and programmed release.
  • compounds of the invention may be formulated as a solid, semi-solid, or thixotropic liquid for administration as an implanted depot providing modified release of the active compound.
  • examples of such formulations include drug-coated stents and poly(i#-lactic-coglycolic)acid (PGLA) microspheres.
  • the compounds of the invention may also be administered topically to the skin or mucosa, that is, dermally or transdermal ly.
  • Typical formulations for this purpose include gels, hydrogels, lotions, solutions, creams, ointments, dusting powders, dressings, foams, films, skin patches, wafers, implants, sponges, fibres, 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).
  • topical administration include delivery by electroporation, iontophoresis, phonophoresis, sonophoresis and microneedle or needle-free (e.g. PowderjectTM, BiojectTM, etc.) injection.
  • Formulations for topical administration may be formulated to be immediate and/or modified release.
  • Modified release formulations include delayed-, sustained-, pulsed-, controlled-, targeted and programmed release.
  • the compounds of the invention can also be administered intranasally or by inhalation, typically in the form of a dry powder (either alone, as a mixture, for example, in a dry blend with lactose, or as a mixed component particle, for example, mixed with phospholipids, such as phosphatidylcholine) from a dry powder inhaler or as an aerosol spray from a pressurised container, pump, spray, atomiser (preferably an atomiser using electrohydrodynamics to produce a fine mist), or nebuliser, with or without the use of a suitable propellant, such as 1,1 ,1,2-tetrafluoroethane or 1 , 1, 1,2,3,3,3-heptafluoropropane.
  • the powder may comprise a bioadhesive agent, for example, chitosan or cyclodextrin.
  • the pressurised container, pump, spray, atomizer, or nebuliser contains a solution or suspension of the compound(s) of the invention comprising, for example, ethanol, aqueous ethanol, or a suitable alternative agent for dispersing, solubilising, or extending release of the active, a propellant(s) as solvent and an optional surfactant, such as sorbitan trioleate, oleic acid, or an oligolactic acid.
  • a solution or suspension of the compound(s) of the invention comprising, for example, ethanol, aqueous ethanol, or a suitable alternative agent for dispersing, solubilising, or extending release of the active, a propellant(s) as solvent and an optional surfactant, such as sorbitan trioleate, oleic acid, or an oligolactic acid.
  • the drug product Prior to use in a dry powder or suspension formulation, the drug product is micronised to a size suitable for delivery by inhalation (typically less than 5 microns). This may be achieved by any appropriate comminuting method, such as spiral jet milling, fluid bed jet milling, supercritical fluid processing to form nanoparticles, high pressure homogenisation, or spray drying.
  • comminuting method such as spiral jet milling, fluid bed jet milling, supercritical fluid processing to form nanoparticles, high pressure homogenisation, or spray drying.
  • Capsules made, for example, from gelatin or hydroxypropylmethylcellulose
  • blisters and cartridges for use in an inhaler or insufflator may be formulated to contain a powder mix of the compound of the invention, a suitable powder base such as lactose or starch and a performance modifier such as /-leucine, mannitol, or magnesium stearate.
  • the lactose may be anhydrous or in the form of the monohydrate, preferably the latter.
  • Other suitable excipients include dextran, glucose, maltose, sorbitol, xylitol, fructose, sucrose and trehalose.
  • a suitable solution formulation for use in an atomiser using electrohydrodynamics to produce a fine mist may contain from ⁇ g to 20mg of the compound of the invention per actuation and the actuation volume may vary from ⁇ ⁇ to ⁇ .
  • a typical formulation may comprise a compound of formula I, propylene glycol, sterile water, ethanol and sodium chloride.
  • Alternative solvents which may be used instead of propylene glycol include glycerol and polyethylene glycol.
  • Suitable flavours such as menthol and Ievomenthol, or sweeteners, such as saccharin or saccharin sodium, may be added to those formulations of the invention intended for inhaled/intranasal administration.
  • Formulations for inhaled/intranasal administration may be formulated to be immediate and/or modified release using, for example, PGLA.
  • Modified release formulations include delayed-, sustained-, pulsed-, controlled-, targeted and programmed release.
  • the dosage unit is determined by means of a valve which delivers a metered amount.
  • Units in accordance with the invention are typically arranged to administer a metered dose or "puff containing from 1 to 10,000 ⁇ g of the compound of the invention.
  • the overall daily dose will typically be in the range ⁇ g to 10 mg which may be administered in a single dose or, more usually, as divided doses throughout the day.
  • the 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.
  • the compounds of the invention may also be administered directly to the eye or ear, typically in the form of drops of a micronised 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 non-biodegradable (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 heteropoly saccharide polymer, for example, gelan gum, may be incorporated together with a preservative, such as benzalkonium chloride.
  • a preservative such as benzalkonium chloride.
  • Such formulations may also be delivered by iontophoresis.
  • Formulations for ocular/aural administration may be formulated to be immediate and/or modified release.
  • Modified release formulations include delayed-, sustained-, pulsed-, controlled-, targeted, or programmed release.
  • the compounds of the invention may be combined with soluble macromolecular entities, such as cyclodextrin and suitable derivatives thereof or polyethylene gly col-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.
  • Drug-cyclodextrin complexes for example, are found to be generally useful for most dosage forms and administration routes. Both inclusion and non- inclusion complexes may be used.
  • the cyclodextrin may be used as an auxiliary additive, i.e. as a carrier, diluent, or solubiliser.
  • compositions may conveniently be combined in the form of a kit suitable for coadministration of the compositions.
  • the kit of the invention comprises two or more separate pharmaceutical compositions, at least one of which contains a compound of formula I in accordance with the invention, and means for separately retaining said compositions, such as a container, divided bottle, or divided foil packet.
  • a container, divided bottle, or divided foil packet An example of such a kit is the familiar blister pack used for the packaging of tablets, capsules and the like.
  • the kit of the invention is particularly suitable for administering different dosage forms, for example, oral and parenteral, for administering the separate compositions at different dosage intervals, or for titrating the separate compositions against one another.
  • the kit typically comprises directions for administration and may be provided with a so-called memory aid.
  • Navl .7 channel modulator such as a compound disclosed in WO 2009/012242
  • Navl .3 modulator e.g. as disclosed in WO2008/1 18758
  • Navl.8 modulator e.g. as disclosed in WO 2008/135826, more particularly N-[6-Amino-5-(2-chIoro-5-methoxyphenyl)pyridin-2-yl]-l-methyl-lH-pyrazole-5 -carboxamide
  • an inhibitor of nerve growth factor signaling such as: an agent that binds to NGF and inhibits NGF biological activity and/or downstream pathway(s) mediated by NGF signaling (e.g. tanezumab), a TrkA antagonist or a p75 antagonist;
  • a compound which increases the levels of endocannabinoid such as a compound with fatty acid amid hydrolase inhibitory (FAAH) activity, in particular those disclosed in WO 2008/047229 (e.g.
  • FAAH fatty acid amid hydrolase inhibitory
  • an opioid analgesic e.g. morphine, heroin, hydromorphone, oxymorphone, levorphanol, levallorphan, methadone, meperidine, fentanyl, cocaine, codeine, dihydrocodeine, oxycodone, hydrocodone, propoxyphene, nalmefene, nalorphine, naloxone, naltrexone, buprenorphine, butorphanol, nalbuphine or pentazocine; a nonsteroidal antiinflammatory drug (NSAID), e.g.
  • NSAID nonsteroidal antiinflammatory drug
  • a barbiturate sedative e.g. amobarbital, aprobarbital, butabarbital, butabital, mephobarbital, metharbital, methohexital, pentobarbital, phenobartital, secobarbital, talbutal, theamylal or thiopental;
  • a benzodiazepine having a sedative action e.g. chlordiazepoxide, clorazepate, diazepam, flurazepam, lorazepam, oxazepam, temazepam or triazolam;
  • an Hi antagonist having a sedative action e.g. diphenhydramine, pyrilamine, promethazine, chlorpheniramine or chlorcyclizine; a sedative such as glutethimide, meprobamate, methaqualone or dichloralphenazone;
  • a skeletal muscle relaxant e.g. baclofen, carisoprodol, chlorzoxazone, cyclobenzaprine, methocarbamol or orphrenadine;
  • an NMDA receptor antagonist e.g. dextromethorphan ((+)-3-hydroxy-N-methylmorphinan) or its metabolite dextrorphan ((+)-3-hydroxy-N-methylmorphinan), ketamine, memantine, pyrroloquinoline quinine, cis-4-(phosphonomethyl)-2-piperidinecarboxylic acid, budipine, EN-3231 (MorphiDex®, a combination formulation of morphine and dextromethorphan), topiramate, neramexane or perzinfotel including an NR2B antagonist, e.g. ifenprodil, traxoprodil or
  • an alpha-adrenergic e.g. doxazosin, tamsulosin, clonidine, guanfacine, dexmetatomidine, modafinil, or
  • a tricyclic antidepressant e.g. desipramine, imipramine, amitriptyline or nortriptyline;
  • an anticonvulsant e.g. carbamazepine, lamotrigine, topiratmate or valproate
  • a tachykinin (NK) antagonist particularly an NK-3, NK-2 or NK- antagonist, e.g. (aR,9R)-7-[3,5-bis(trifluoromethyl)benzyl]-8,9,10,l -tetrahydro-9-methyl-5-(4-m ethylphenyl)-7H-[l,4]diazocino[2,l-g][l,7]-naphthyridine-6-13-dione (TAK-637),
  • a muscarinic antagonist e.g oxybutynin, tolterodine, propiverine, tropsium chloride, darifenacin, solifenacin, temiverine and ipratropium; • a COX-2 selective inhibitor, e.g. celecoxib, rofecoxib, parecoxib, valdecoxib, deracoxib, etoricoxib, or lumiracoxib;
  • a neuroleptic such as droperidol, chlorpromazine, haloperidol, perphenazine, thioridazine, mesoridazine, trifluoperazine, fluphenazine, clozapine, olanzapine, risperidone, ziprasidone, quetiapine, sertindole, aripiprazole, sonepiprazole, blonanserin, iloperidone, perospirone, raclopride, zotepine, bifeprunox, asenapine, lurasidone, amisulpride, balaperidone, palindore, eplivanserin, osanetant, rimonabant, meclinertant, Miraxion® or sarizotan;
  • ⁇ a vanilloid receptor agonist e.g. resinferatoxin
  • antagonist e.g. capsazepine
  • a beta-adrenergic such as propranolol
  • a corticosteroid such as dexamethasone
  • a 5-HT receptor agonist or antagonist particularly a 5-HTIB / ID agonist such as eletriptan, sumatriptan, naratriptan, zolmitriptan or rizatriptan;
  • a 5-HT2A receptor antagonist such as R(+)-alpha-(2,3-dimethoxy-phenyl)-l -[2-(4-fluorophenylethyl)]-4-piperidinemeth anol (MDL- 100907);
  • a 5-HT3 antagonist such as ondansetron
  • a cholinergic (nicotinic) analgesic such as ispronicline (TC-1734), (E)-N-methyl-4-(3-pyridinyl)-3-buten-l-amine (RJR-2403), (R)-5-(2-azetidinylmethoxy)-2-chloropyridine (ABT-594) or nicotine;
  • a PDEV inhibitor such as 5-[2-ethoxy-5-(4-methyl-l-piperazinyl-sulphonyl)phenyl]-l-methyl-3-n-propyl-l ,
  • 6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one (sildenafil), (6R, 12aR)-2,3,6,7, 12,12a-hexahydro-2-methyl-6-(3,4-methylenedioxyphenyl)-pyr azino[2',l':6,l]-pyrido[3,4-b]indole-l,4-dione (IC-351 or tadalafil), 2-[2-ethoxy-5-(4-ethyl-piperazin- 1 -yl- 1 -sulphonyl)-phenyl]-5-methy l-7-propyl-3 H-imidazo[5,l-fJ[l,2,4]triazin-4-one (vardenafil), 5-(5-acetyl-2-butoxy-3-pyridinyl)-3-ethyl-2-(l-ethyl-3-azetidinyl)-2,6-d
  • an alpha-2-delta ligand such as gabapentin, pregabalin, 3-methylgabapentin, ( l a,3a,5a)(3-amino-methyl-bicyclo[3.2.0]hept-3-yl)-acetic acid, (3S,5R)-3-aminomethyl-5-methyl-heptanoic acid, (3S,5R)-3-amino-5-methyl-heptanoic acid, (3S,5R)-3-amino-5-methyl-octanoic acid, (2S,4S)-4-(3-chlorophenoxy)proline, (2S,4S)-4-(3-fluorobenzyl)-proline, [(lR,5R,6S)-6-(aminomethyl)bicyclo[3.2.0]hept-6-yl]acetic acid, 3-(l-ammomethyl-cyclohexylmethyl)-4H-[l,2,4]oxadiazol-5-one,
  • metabotropic glutamate subtype 1 receptor (mGluRl) antagonist metabotropic glutamate subtype 1 receptor (mGluRl) antagonist
  • a serotonin reuptake inhibitor such as sertraline, sertraline metabolite demethylsertraline, fluoxetine, norfluoxetine (fluoxetine desmethyl metabolite), fluvoxamine, paroxetine, citalopram, citalopram metabolite desmethylcitalopram, escitalopram, d,l- fenfluramine, femoxetine, ifoxetine, cyanodothiepin, litoxetine, dapoxetine, nefazodone, cericlamine and trazodone;
  • noradrenaline (norepinephrine) reuptake inhibitor such as maprotiline, lofepramine, mirtazepine, oxaprotiline, fezolamine, tomoxetine, mianserin, buproprion, buproprion metabolite hydroxybuproprion, nomifensine and viloxazine (Vivalan®), especially a selective noradrenaline reuptake inhibitor such as reboxetine, in particular (S,S)-reboxetine;
  • a dual serotonin-noradrenaline reuptake inhibitor such as venlafaxine, venlafaxine metabolite O-desmethylvenlafaxine, clomipramine, clomipramine metabolite desrnethylclomipramine, duloxetine, milnacipran and imipramine;
  • an inducible nitric oxide synthase (iNOS) inhibitor such as S-[2-[(l -iminoethyl)amino]ethyl]-L-homocysteine,
  • an acetylcholinesterase inhibitor such as donepezil
  • a prostaglandin E2 subtype 4 (EP4) antagonist such as N-[( ⁇ 2-[4-(2-ethyl-4,6-dimethyl-lH-imidazo[4,5-c]pyridin- l-yl)phenyl]ethyl ⁇ ami no)-carbonyl]-4-methylbenzenesulfonamide or 4-[(lS)-l -( ⁇ [5-chloro-2-(3-fluorophenoxy)pyridin-3-yl]carbonyl ⁇ amino)ethyl]ben zoic acid;
  • microsomal prostaglandin E synthase type 1 (mPGES-1) inhibitor • a microsomal prostaglandin E synthase type 1 (mPGES-1) inhibitor
  • a leukotriene B4 antagonist such as l -(3-biphenyl-4-ylmethyl-4-hydroxy-chroman-7-yl)-cyclopentanecarboxylic acid (CP- 105696), 5-[2-(2-Carboxyethyl)-3-[6-(4-methoxyphenyl)-5E- hexenyl]oxyphenoxy]-valeric acid ( ⁇ -4057) or DPC- 1870; and • a 5-lipoxygenase inhibitor, such as zileuton, 6-[(3-fluoro-5-[4-methoxy-3,4,5,6-tetrahydro-2H-pyran-4-yl])phenoxy-methyl]-l- methyl-2-quinolone (ZD-2138), or 2,3,5-trimethyl-6-(3-pyridylmethyl),l,4-benzoquinone (CV-6504).
  • a leukotriene B4 antagonist such as l -(3-biphen
  • additional active agents which may be part of a formulation or pharmaceutical kit according to the present invention, particularly for the treatment of cancer, include:
  • an anti-tumour platinum-based compound such as cisplatin or carboplatin
  • an anti-estrogen or selective estrogen receptor modulator such as tamoxifen, afimoxifene, arzoxifene, avalycoxifene, thioprine, thioprine, thioprine, thioprine, thioprine, thioprine, thioprine, thioprine, thioprine, thioprine, thioprine, thiothione, and others.
  • a tyrosine kinase inhibitor such as afatinib, imatinib, gefitinib, sorafenib, sunitinib, vandetanib, crizotinib or lapatinib.
  • the total daily dose of the compounds of the invention is typically in the range 0.5 mg to 3000 mg depending, of course, on the mode of administration.
  • oral administration may require a total daily dose of from 3 mg to 3000 mg, while an intravenous dose may only require from 0.5 mg to 500 mg.
  • the total daily dose may be administered in single or divided doses and may, at the physician's discretion, fall outside of the typical range given herein.
  • These dosages are based on an average human subject having a weight of about 60kg to 70kg. The physician will readily be able to determine doses for subjects whose weight falls outside this range, such as infants and the elderly.
  • references herein to "treatment” include references to curative, palliative and prophylactic treatment.
  • the biological activity of the compounds of the invention may be measured using the assay described below.
  • FS-3 is an LPC analogue that is conjugated with both a fluorophore and a quencher. In its native state the quencher interferes with the fluorophore's fluorescence. Once autotaxin cleaves FS-3, the fluorophore becomes liberated from the quencher, resulting in increased fluorescence. Thus increase in fluorescence is a measure of ATX activity. Any compound that inhibits the activity of Autotaxin will show less fluorescence read in presence of FS-3, which could be measured by fluorimetric analysis. See US Patent 7,989,663.
  • the FS-3 assay to identify ATX inhibitors was preformed as follows: 3 ⁇ of standard inhibitor (referred to as PF-8380 in Gierse et al above) and test compounds were added to an assay plate. To each assay well, containing test compounds or standard, 24 ⁇ of human Autotaxin enzyme (2 nM) was added. The assay plate was then centrifuged at 1000 rpm for 1 minute and allowed to incubate at 37°C for 30 minutes. Following the incubation period each plate was read in a fluorescence plate reader (Spectra Max M5: excitation: 494nm and emission: 520nm) and IC50 values were derived from inhibition of FS-3 fluorescence (as described above).
  • UV - Acquity PDA Varian ELSD (evaporative light scattering detector)

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Abstract

Cette invention concerne des composés de formule (I), et des sels et solvates pharmaceutiquement acceptables de ceux-ci, utiles en tant que produits pharmaceutiques, en particulier dans le traitement des maladies fibrosiques, du cancer et de la douleur. Dans la formule (I), l'un des X, Y et Z représente N et les deux autres représentent CH, ou X=Y-Z représente N=CH-N; W représente un groupe alkylène C1-6 qui peut être linéaire ou ramifié; R1 représente H, un phényle, naphtyle, hétéroaryle1, hétérocyclyle1 ou cycloalkyle C3-6 ; chaque groupe phényle, naphtyle, hétéroaryle1, hétérocyclyle1 et cycloalkyle C3-6 étant éventuellement substitué, et chaque groupe phényle, naphtyle, hétéroaryle1, hétérocyclyle1 et cycloalkyle C3-6 étant éventuellement lié par fusion à un cycle hétéroaromatique ou hétérocyclique à 5 ou 6 chaînons contenant de 1 à 3 hétéroatomes (choisis parmi N, O et S); et chaque groupe hétéroaryle1, hétérocyclyle1 et cycloalkyle C3-6 étant éventuellement lié par fusion à un cycle benzène; m vaut 1 ou 2; n vaut 0, 1 ou 2; A est C=O ou SO2 ; V représente une liaison ou un alkylène C1-8 qui peut être linéaire ou ramifié; R2 représente H, -S-(alkyle C1-6), -SO2N(alkyle C1-6)2, -CO2-(alkyle C1-6), -NHCOCH2-phényle, -OCH2-phényle, -SO2-phényle, -NR3R4, phényle, naphtyle, hétéroaryle2, hétérocyclyle2, -CO-hétérocyclyle2 ou cycloalkyle C3-6 ; chaque groupe phényle, naphtyle, hétéroaryle2, hétérocyclyle2 et cycloalkyle C3-6 étant éventuellement substitué, et chaque groupe phényle, naphtyle, hétéroaryle2, hétérocyclyle2 et cycloalkyle C3-6 étant éventuellement lié par fusion à un cycle hétéroaromatique ou hétérocyclique à 5 ou 6 chaînons contenant de 1 à 3 hétéroatomes (choisis parmi N, O et S); et chaque groupe hétéroaryle2, hétérocyclyle2 et cycloalkyle C3-6 étant éventuellement lié par fusion à un cycle benzène.
PCT/IB2012/002073 2011-10-13 2012-10-15 Dérivés de pyrimidine et de pyridine utiles en thérapie WO2013054185A1 (fr)

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WO2014110000A1 (fr) * 2013-01-11 2014-07-17 Eli Lilly And Company Dérivés de pyrimidine fusionnés à un pyrido ou pyrrolo à titre d'inhibiteurs d'autotaxines pour traiter la douleur
WO2015078803A1 (fr) * 2013-11-26 2015-06-04 F. Hoffmann-La Roche Ag Nouvel octahydro-cyclobuta [1,2-c; 3,4-c'] dipyrrol-2-yl
US9051320B1 (en) 2014-08-18 2015-06-09 Pharmakea, Inc. Methods for the treatment of metabolic disorders by a selective small molecule autotaxin inhibitor
US9334261B2 (en) 2013-11-22 2016-05-10 Pharmakea, Inc. Autotaxin inhibitor compounds
WO2016197009A1 (fr) 2015-06-05 2016-12-08 Vertex Pharmaceuticals Incorporated Triazoles pour le traitement de maladies liées à la démyélinisation
WO2017037146A1 (fr) * 2015-09-04 2017-03-09 F. Hoffmann-La Roche Ag Dérivés de phénoxyméthyle
US9714240B2 (en) 2013-09-17 2017-07-25 Pharmakea, Inc. Vinyl autotaxin inhibitor compounds
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