Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C317/00—Sulfones; Sulfoxides
  • C07C317/44—Sulfones; Sulfoxides having sulfone or sulfoxide groups and carboxyl groups bound to the same carbon skeleton
  • C07C317/48—Sulfones; Sulfoxides having sulfone or sulfoxide groups and carboxyl groups bound to the same carbon skeleton the carbon skeleton being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
  • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
  • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
  • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
  • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
  • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
  • A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
  • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
  • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
  • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
  • A61K31/5375—1,4-Oxazines, e.g. morpholine
  • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
  • A61K31/541—Non-condensed thiazines containing further heterocyclic rings
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
  • A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
  • A61K31/553—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having at least one nitrogen and one oxygen as ring hetero atoms, e.g. loxapine, staurosporine
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
  • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P11/00—Drugs for disorders of the respiratory system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P11/00—Drugs for disorders of the respiratory system
  • A61P11/02—Nasal agents, e.g. decongestants
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P11/00—Drugs for disorders of the respiratory system
  • A61P11/06—Antiasthmatics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P17/00—Drugs for dermatological disorders
• • 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
  • A61P17/06—Antipsoriatics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P27/00—Drugs for disorders of the senses
  • A61P27/02—Ophthalmic agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P27/00—Drugs for disorders of the senses
  • A61P27/02—Ophthalmic agents
  • A61P27/06—Antiglaucoma agents or miotics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P27/00—Drugs for disorders of the senses
  • A61P27/02—Ophthalmic agents
  • A61P27/12—Ophthalmic agents for cataracts
• • 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
  • A61P37/00—Drugs for immunological or allergic disorders
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P37/00—Drugs for immunological or allergic disorders
  • A61P37/02—Immunomodulators
  • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P37/00—Drugs for immunological or allergic disorders
  • A61P37/08—Antiallergic agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system
  • A61P9/12—Antihypertensives
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
  • C07C311/01—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms
  • C07C311/02—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton
  • C07C311/08—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton having the nitrogen atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C317/00—Sulfones; Sulfoxides
  • C07C317/26—Sulfones; Sulfoxides having sulfone or sulfoxide groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton
  • C07C317/28—Sulfones; Sulfoxides having sulfone or sulfoxide groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton with sulfone or sulfoxide groups bound to acyclic carbon atoms of the carbon skeleton
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
  • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
  • C07D211/80—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
  • C07D211/84—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen directly attached to ring carbon atoms
  • C07D211/86—Oxygen atoms
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
  • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
  • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
  • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
  • C07D213/72—Nitrogen atoms
  • C07D213/74—Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
  • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
  • C07D233/66—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
  • C07D233/90—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
  • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
  • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
  • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
  • C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
  • C07D239/47—One nitrogen atom and one oxygen or sulfur atom, e.g. cytosine
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
  • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
  • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
  • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
  • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
  • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
  • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
  • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
  • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
  • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

• This invention relates, inter alia, to compounds which are antiinflammatory agents (e.g. through inhibition of one or more of members of: the family of p38 mitogen-activated protein kinase enzymes (referred to herein as p38 MAP kinase inhibitors), for example the alpha kinase sub-type thereof; Syk kinase; and the Src family of tyrosine kinases).
• p38 mitogen-activated protein kinase enzymes referred to herein as p38 mitogen-activated protein kinase enzymes (referred to herein as p38 MAP kinase inhibitors), for example the alpha kinase sub-type thereof; Syk kinase; and the Src family of tyrosine kinases).
• the invention also relates to the use of such compounds in therapy, including in mono- and combination therapies, especially in the treatment of inflammatory diseases, including inflammatory diseases of the lung (such as asthma and chronic obstructive pulmonary disease (COPD)), eye (such as uveitis) and gastrointestinal tract (such as Crohn's disease and ulcerative colitis).
• inflammatory diseases including inflammatory diseases of the lung (such as asthma and chronic obstructive pulmonary disease (COPD)), eye (such as uveitis) and gastrointestinal tract (such as Crohn's disease and ulcerative colitis).
• COPD chronic obstructive pulmonary disease
• COPD chronic obstructive pulmonary disease
• eye such as uveitis
• gastrointestinal tract such as Crohn's disease and ulcerative colitis
• p38 MAPK isoforms (alpha, beta, gamma and delta respectively) have been identified, each displaying different patterns of tissue expression.
• the p38 MAPK alpha and beta isoforms are found ubiquitously throughout the body, are present in many different cell types and are inhibited by a number of previously described small molecular weight compounds. Early classes of inhibitors were highly toxic due to the broad tissue distribution of these isoforms which resulted in off-target effects of the compounds. Some of the more recently identified inhibitors show improved selectivity for p38 MAPK alpha and beta isoforms and have wider safety margins.
• p38 MAP kinase is believed to play a pivotal role in many of the signalling pathways that are involved in initiating and maintaining chronic, persistent inflammation in human disease, for example, in severe asthma, COPD and inflammatory bowel disease (IBD).
• IBD inflammatory bowel disease
• Smith describes the inhibitory effect of p38 MAP kinase inhibitors on TNFa (but not IL-8) release from human PBMCs (Smith, S. J., Br. J. Pharmacol., 2006, 149:393-404).
• COPD is a condition in which the underlying inflammation is reported to be substantially resistant to the anti-inflammatory effects of inhaled corticosteroids. Consequently, a superior strategy for treating COPD would be to develop an intervention which has both inherent anti- inflammatory effects and the ability to increase the sensitivity of the lung tissues of COPD patients to inhaled corticosteroids.
• the recent publication of Mercado et al. (2007; American Thoracic Society Abstract A56) demonstrates that silencing p38 MAPK ⁇ has the potential to restore sensitivity to corticosteroids. Thus, there may be a dual benefit for patients in the use of a p38 MAP kinase inhibitor for the treatment of COPD.
• p38 MAPK inhibitors have also been described as inhibitors of replication of respiratory syncytial virus (Cass L. et al., WO 2011/158039).
• the precise etiology of IBD is uncertain, but is believed to be governed by genetic and environmental factors that interact to promote an excessive and poorly controlled mucosal inflammatory response directed against components of the luminal microflora. This response is mediated through infiltration of inflammatory neutrophils, dendritic cells and T-cells from the periphery.
• p38 has become an obvious target for investigation in IBD models as a consequence of its ubiquitous expression in inflammatory cells.
• T cells are known to play a key role in mediating inflammation of the gastrointestinal tract.
• SCID immunodeficient
• mucosal membranes from IBD patients showed an upregulation of CD4+ cells which were either Th1 (IFNg/IL-2) or Th2 (IL5/ TGFb) biased depending on whether the patient had Crohn's disease or ulcerative colitis (Fuss IJ. et al. J Immunol. 1996 157:1261-70.).
• T cells are known to play a key role in inflammatory disorders of the eye with several studies reporting increased levels of T cell associated cytokines (IL-17 and IL-23) in sera of Bechets patients (Chi W. et al. Invest Ophthalmol Vis Sci. 2008 49:3058-64). In support of these observations, Direskeneli and colleagues demonstrated that Bechets patients have increased Th17 cells and decreased Treg cells in their peripheral blood (Direskeneli H. et al. J Allergy Clin Immunol. 201 1 128:665-6).
• Src family kinases are known to play a key role in this pathway, where Src family kinases, Fyn and Lck, are the first signalling molecules to be activated downstream of the T cell receptor (Barber EK. et al. PNAS 1989, 86:3277- 81). They initiate the tyrosine phosphorylation of the T cell receptor leading to the recruitment of the Syk family kinase, ZAP-70. Animal studies have shown that ZAP-70 knockout results in a SCID phenotype (Chan AC. et al. Science. 1994, 10;264(5165): 1599- 601).
• Syk kinase is widely expressed in cells of the hematopoietic system, most notably in B cells and mature T cells. Through interaction with immunoreceptor tyrosine-based activation motifs (ITAM), it plays an important role in regulating T cell and B cell expansion as well as mediating immune-receptor signalling in inflammatory cells.
• ITAM immunoreceptor tyrosine-based activation motifs
• Syk activation leads to IL-6 and MMP release - inflammatory mediators commonly found upregulated in inflammatory disorders including IBD and rheumatoid arthritis (Wang YD. et al World J Gastroenterol 2007; 13: 5926-5932, Litinsky I et al. Cytokine. 2006 Jan 33: 106-10).
• kinase enzymes are now also recognised to regulate the activity of a range of cellular functions, including the maintenance of DNA integrity (Shilo, Y. Nature Reviews Cancer, 2003, 3: 155-168) and co-ordination of the complex processes of cell division. Indeed, certain kinase inhibitors (the so-called “Olaharski kinases”) have been found to alter the frequency of micronucleus formation in vitro (Olaharski, A. J. et al., PLoS Comput. Biol., 2009, 5(7), e1000446; doi: 10.1371/journal.pcbi.1000446).
• Micronucleus formation is implicated in, or associated with, disruption of mitotic processes and is therefore undesirable.
• Inhibition of glycogen synthase kinase 3a was found to be a particularly significant factor that increases the likelihood of a kinase inhibitor promoting micronucleus formation.
• inhibition of the kinase ⁇ 8 ⁇ 3 ⁇ with RNAi has been reported to promote micronucleus formation (Tighe, A. et al., BMC Cell Biology, 2007, 8:34).
• Examples of such compounds may be found in WO 99/23091 , WO 00/041698, WO 00/043384, WO 00/055139, WO 01/36403, WO 01/4115, WO 02/083628, WO 02/083642, WO 02/092576, WO 02/096876, WO 2003/005999, WO 2003/068223, WO 2003/068228, WO 2003/072569, WO 2004/014870, WO 2004/113352, WO 2005/005396, WO 2005/018624, WO 2005/023761 , WO 2005/044825, WO 2006/015775, WO 2006/043090, WO 2007/004749 and WO 2007/053394. Further examples may be found in articles published in:
• R represents
• Ci_6 alkyl C 2 _6 alkenyl, C 2 _6 alkynyl, d -6 alkoxy, which latter four groups are optionally substituted by one or more substituents selected from Ci_ 2 alkyl, halo, hydroxy, and Ci_ 2 alkoxy,
• A represents O, S or N(R A2 ),
• R represents H, Ci -4 alkyl or hydroxy
• R A2 represents H or Ci -4 alkyl
• R B represents H, halo, cyano, -Ci. 4 alkylene-CN, -Ci. 4 alkylene-OH, -NR X R X , -C(0)OR x , -C(0)NR x R Y , -S(0) 2 NR x R Y , -NR x C(0)R Y , -NR x S(0) 2 R Y , -NR X2 S(0) 2 NR x R Y , -NR x P(0)R Y R Y2 , -NR x C(0)OR Y or Het 1 optionally substituted with one or more substituents selected from halo, hydroxy, Ci_ 2 alkyl and Ci_ 2 alkoxy;
• R x and R X independently represent H or Ci_ 6 alkyl, or R x and R X together represent C 3 . 6 n- alkylene or C 4 . 5 n-alkylene interrupted between C2 and C3 by -O- or -N(R X2 )-, or R X represents Het 1 optionally substituted with one or more substituents selected from halo, hydroxy, Ci_ 2 alkyl and Ci_ 2 alkoxy;
• R Y , R Y and R Y2 independently represent Ci_ 6 alkyl, C 3 . 7 cycloalkyl, phenyl, benzyl, Het 1 or Het 2 , which latter six groups are optionally substituted by one or more substituents selected from Ci_ 2 alkyl, halo, hydroxy, Ci. 2 alkoxy, NH 2 , N(H)-Ci_ 4 alkyl, N(Ci_ 4 alkyl) 2 , C(0)OH and C(0)0-(Ci-4 alkyl),
• R Y represents H
• R x and R Y together represent C 3 . 6 n-alkylene or C 4 . 5 n-alkylene interrupted between C2 and C3 by -O- or -N(R X2 )-;
• each R X2 independently represents H or Ci_ 4 alkyl
• R C and R E independently represent H, halo, cyano or methyl; provided that at least one of R A , R B , R C and R E is other than H;
• R D represents trimethylsilyl, C 2 _ 7 alkyl, C 2 _ 7 alkenyl, C 2 _ 7 alkynyl, C 3 . 7 cycloalkyl, phenyl, Het 1 or Het 2 , which latter seven groups are optionally substituted by one or more substituents selected from Ci_ 2 alkyl, halo, cyano, hydroxy and Ci_ 2 alkoxy;
• R 2 and R 3 together with the C-atoms to which they are attached, form a fused phenyl or pyridyl ring, which latter two rings are optionally substituted by one or more substituents selected from Ci_ 3 alkyl, Ci_ 3 haloalkyl, cyano and halo,
• R 2 and R 3 represents H, halo, cyano, Ci_ 3 alkyl or Ci_ 3 haloalkyl and the other independently represents halo, cyano, Ci_ 3 alkyl or Ci_ 3 haloalkyl,
• R 2 and R 3 together combine to form C 3 . 5 alkylene or C 3 . 5 alkenylene, which latter two groups are optionally substituted by one or more substituents selected from Ci_ 3 alkyl, Ci- 3 haloalkyl, cyano and halo;
• X 1 represents N or CH
• L represents a direct bond or Ci_ 2 alkylene
• X 2 and X 3 both represent CR Z or one of X 2 and X 3 represents N and the other represents CR Z ;
• R z represents hydrogen, halo, cyano, hydroxy, Ci_ 3 alkyl or Ci_ 3 alkoxy, which latter two groups are optionally substituted by one or more halo atoms;
• R 4 represents
• R 4 may alternatively represent H, halo, cyano, hydroxy, Ci_ 3 alkyl or Ci_ 3 alkoxy, which latter two groups are optionally substituted by one or more halo atoms;
• R 5 represents Ci_ 3 alkoxy or Ci_ 3 alkyl, which latter two groups are optionally substituted by one or more halo atoms, or R 5 represents H, cyano, -C(0)NH 2 , hydroxy, halo or C 2 - 3 alkynyl;
• R 6a represents OR 7a , N(R 7 )R 7c or C0 2 H;
• R 6 represents Ci_ 8 alkyl, C 3 . 8 cycloalkyl, phenyl, Het 1 or Het 2 , which latter five groups are optionally substituted by one or more substituents selected from halo, hydroxyl, Ci_ 3 alkyl and Ci- 3 alkoxy;
• R 6c and R 6d independently represent H or methyl;
• R 7a to R 7c independently represent H or C1-4 alkyl optionally substituted by one or more halo atoms, or R 7 and R 7c , together with the N-atom to which they are attached, form a 4- to 7- membered heterocyclic group that is fully saturated, partially unsaturated or fully aromatic and which heterocyclic group contains one N atom (the atom to which R 7 and R 7c are attached) and, optionally, one or more further heteroatoms selected from O, S and N , and which heterocyclic group is optionally substituted by one or more substituents selected from halo, hydroxy, oxo, Ci_ 4 alkyl and Ci_ 4 alkoxy;
• Q and Q 2 independently represent C(0)NH, O or S(0) p ;
• n and p independently represent 0, 1 or 2
• Het 1 represents, independently upon each occurrence, a 5- or 6-membered heterocyclic group that is fully aromatic, which group contains one or more heteroatoms selected from N, O and S; Het 2 represents, independently upon each occurrence, a 4- to 7-membered heterocyclic group that is fully saturated or partially unsaturated, which group contains one or more heteroatoms selected from N , O and S; or a pharmaceutically acceptable salt, solvate or isotopic derivative thereof, which compounds may be referred to hereinafter as "the compounds of the invention”.
• salts include acid addition salts and base addition salts.
• Such salts may be formed by conventional means, for example by reaction of a free acid or a free base form of a compound of formula I with one or more equivalents of an appropriate acid or base, optionally in a solvent, or in a medium in which the salt is insoluble, followed by removal of said solvent, or said medium, using standard techniques (e.g. in vacuo, by freeze-drying or by filtration). Salts may also be prepared by exchanging a counter-ion of a compound of formula I in the form of a salt with another counter-ion, for example using a suitable ion exchange resin.
• Examples of pharmaceutically acceptable salts include acid addition salts derived from mineral acids and organic acids, and salts derived from metals.
• compounds of formula I may contain the stated atoms in any of their natural or non-natural isotopic forms.
• embodiments of the invention that may be mentioned include those in which:
• the compound of formula I is isotopically enriched or labelled with respect to one or more atoms of the compound.
• references herein to an "isotopic derivative" relate to the second of these two embodiments.
• the compound of formula I is isotopically enriched or labelled (with respect to one or more atoms of the compound) with one or more stable isotopes.
• the compounds of the invention that may be mentioned include, for example, compounds of formula I that are isotopically enriched or labelled with one or more atoms such as deuterium or the like.
• alkyl groups and alkoxy groups as defined herein may be straight-chain or, when there is a sufficient number (i.e. a minimum of three) of carbon atoms, be branched.
• Particular alkyl groups that may be mentioned include, for example, methyl, ethyl, n-propyl, iso-propyl, butyl, n-butyl and tert-butyl.
• Particular alkoxy groups that may be mentioned include, for example, methoxy, ethoxy, propoxy, and butoxy.
• cycloalkyl groups as defined herein may, when there is a sufficient number (i.e. a minimum of four) of carbon atoms, be part cyclic/acyclic.
• alkylene groups as defined herein may be straight-chain or, when there is a sufficient number (i.e. a minimum of two) of carbon atoms, be branched. In particular embodiments of the invention, alkylene refers to straight-chain alkylene.
• aryl groups may be via any atom of the ring system. However, when aryl groups are bicyclic or tricyclic, they are linked to the rest of the molecule via an aromatic ring.
• C 6 -14 aryl groups include phenyl, naphthyl and the like. Embodiments of the invention that may be mentioned include those in which aryl is phenyl.
• heterocyclic groups represented by N(R 7 )R 7c may be attached to any appropriate atoms in the heterocyclic ring including, where valencies allow, to C-, N- and/or S- atoms within the ring (thereby forming keto, N-oxide, S(O) and/or S(0) 2 groups).
• Het 1 values include oxadiazolyl (e.g. 1 ,3,4-oxadiazol-2-yl), pyrimidinyl (e.g. pyrimidin-2-yl) and triazolyl (e.g. 1 ,2,3-triazol-4-yl).
• oxadiazolyl e.g. 1 ,3,4-oxadiazol-2-yl
• pyrimidinyl e.g. pyrimidin-2-yl
• triazolyl e.g. 1 ,2,3-triazol-4-yl
• Het 2 examples include morpholinyl (e.g. morpholin-4-yl), oxetanyl (e.g. 3-oxetanyl) and tetrahydropyranyl (e.g. 4-tetrahydropyranyl).
• morpholinyl e.g. morpholin-4-yl
• oxetanyl e.g. 3-oxetanyl
• tetrahydropyranyl e.g. 4-tetrahydropyranyl
• halo includes references to fluoro, chloro, bromo or iodo, in particular to fluoro, chloro or bromo, especially fluoro or chloro.
• Embodiments of the invention that may be mentioned include those in which the compound of formula I is a co
• R A represents
• Ci_6 alkyl C 2 _6 alkenyl, C 2 _6 alkynyl, Ci. 6 alkoxy, which latter four groups are optionally substituted by one or more substituents selected from Ci_2 alkyl, halo, hydroxy, and d -2 alkoxy,
• R B represents H, halo, cyano, -NR X R X , -C(0)OR x , -C(0)NR x R Y , -S(0) 2 NR x R Y , -NR x C(0)R Y , -NR x S(0) 2 R Y , -NR x P(0)R Y R Y2 or -NR x C(0)OR Y ;
• R x and R X independently represent H or Ci_ 6 alkyl, or R x and R X together represent C 3 . 6 n- alkylene or C 4 . 5 n-alkylene interrupted between C2 and C3 by -O- or -N(R X2 )-;
• R Y , R Y and R Y2 independently represent Ci_ 6 alkyl, C 3 . 7 cycloalkyl, phenyl, Het 1 or Het 2 , which latter five groups are optionally substituted by one or more substituents selected from Ci_2 alkyl, halo, hydroxy and Ci_ 2 alkoxy,
• R Y represents H
• R x and R Y together represent C 3 . 6 n-alkylene or C 4 . 5 n-alkylene interrupted between C2 and C3 by -O- or -N(R X2 )-;
• R X2 represents H or Ci_ 4 alkyl
• R 4 represents
• R 6a represents OR 7a or N(R 7t) )R 7c ;
• Het 1 represents 5- or 6-membered heterocyclic group that is fully aromatic, which group contains one or more heteroatoms selected from N, O and S.
• R A and R B together represent m the following
• A represents O, S or N(R A2 ),
• R A represents H, Ci_ 4 alkyl or hydroxy
• R A2 represents H or Ci_ 4 alkyl
• R B represents -Ci_ 4 alkylene-CN, -Ci_ 4 alkylene-OH or, particularly, Het 1 optionally substituted with one or more substituents selected from halo, hydroxy, Ci_ 2 alkyl and Ci_ 2 alkoxy, or -NR X2 S(0) 2 NR x R Y ;
• R X represents Het 1 optionally substituted with one or more substituents selected from halo, hydroxy, Ci_ 2 alkyl and Ci_ 2 alkoxy;
• R Y , R Y and/or R Y2 represents benzyl optionally substituted by one or more substituents selected from Ci_ 2 alkyl, halo, hydroxy, Ci_ 2 alkoxy, NH 2 , N(H)-Ci_ 4 alkyl, N(Ci_ 4 alkyl) 2 , C(0)OH and C(0)0-(d. 4 alkyl),
• R Y , R Y and/or R Y2 represents Ci_ 6 alkyl, C 3 . 7 cycloalkyl, phenyl, Het 1 or Het 2 , which latter six groups are substituted by NH 2 , N(H)-Ci_ 4 alkyl, N(Ci_ 4 alkyl) 2 , C(0)OH or C(0)0-(Ci_ 4 alkyl) and optionally further substituted by one or more substituents selected from Ci_ 2 alkyl, halo, hydroxy, Ci.
• R D represents C 2 _ 7 alkyl, C 2 _ 7 alkenyl, C 2 _ 7 alkynyl, C 3 . 7 cycloalkyl, phenyl, Het or Het 2 , which latter seven groups are substituted by cyano and optionally further substituted one or more substituents selected from Ci_ 2 alkyl, halo, cyano, hydroxy and Ci_ 2 alkoxy;
• R z represents hydroxy
• R 4 represents -Q 2 -C(R 6c )(R 6d )-[Ci. 5 alkylene]-R 6a , which Ci -5 alkylene group is substituted by oxo, or, particularly, R 4 represents -CH 2 OH, -COR 6 or -Q -[C(R 6c )(R 6d )-(CH 2 ) 0 - 1 CH 2 -O] 1 . 12 - CH 2 (CH 2 )o-iCH 2 -R 6a in which R 6c and/or R 6d represents methyl (e.g.
• R 4 represents -COR 6 or -Q -[C(R 6c )(R 6d )-(CH 2 ) 0 - 1 CH 2 -0] 1 . 12 -CH 2 (CH 2 )o- 1 CH 2 -R 6a in which R 6c and/or R 6d represents methyl);
• R B represents either -C(0)NR x R Y , in which R Y represents optionally substituted Het 1 or optionally substituted Het 2 , or -NR X2 S(0) 2 NR x R Y then R 4 may alternatively represent H, halo, cyano, hydroxy, Ci_ 3 alkyl or Ci_ 3 alkoxy, which latter two groups are optionally substituted by one or more halo atoms;
• R 5 represents -C(0)NH 2 or, particularly, hydroxy
• R 6a represents C0 2 H.
• R B represents -Ci_ 4 alkylene-CN or -Ci_ 4 alkylene-OH;
• L represents Ci_ 2 alkylene
• R 4 represents -CH 2 OH
• R 5 represents -C(0)NH 2 .
• Embodiments of the invention that may be mentioned include those in which the compound of formula I (or Ix) is
• R to R E , R 2 to R 5 , L and X 1 to X 3 are as hereinbefore defined.
• Embodiments of the invention include those in which one or more of the following definitions apply to the compounds of formula I (or Ix) and la:
• R A and R B together represent a structural fragment selected from the following
• R represents phenyl optionally substituted with one or more substituents selected from methyl and methoxy
• R A represents H, halo, Ci_ 4 alkyl or Ci_ 4 alkoxy, which latter two groups are optionally substituted by one or more fluoro atoms;
• R A represents H, Ci_ 2 alkyl or hydroxy
• R B represents -CH 2 CN, -CH 2 OH or, particularly, R B represents H, halo, cyano, -NR X R X , -C(0)OR x , -C(0)NR x R Y , -S(0) 2 NR x R Y , -NR x C(0)R Y , -NR x S(0) 2 R Y , -NR x C(0)OR Y , Het or -NR X2 S(0) 2 NR x R Y (e.g.
• R B represents H, halo, cyano, -NR X R X , -C(0)OR x , -C(0)NR x R Y , -S(0) 2 NR x R Y , -NR x C(0)R Y , -NR x S(0) 2 R Y or -NR x C(0)OR Y );
• R X represents Het 1 or, particularly, R x and R X independently represent H or Ci_ 4 alkyl, or R x and R X together represent C 4 . 5 n-alkylene optionally interrupted between C2 and C3 by -O- or -N(R X2 )-;
• R Y represents benzyl, Het 2 optionally substituted by one or more substituents selected from methyl, halo, hydroxy and methoxy or, particularly,
• R Y and R Y independently represent Ci_ 4 alkyl, 0 3 . 6 cycloalkyl or phenyl, which latter three groups are optionally substituted by one or more substituents selected from methyl, halo, hydroxy, methoxy, NH 2 , N(H)-Ci_ 2 alkyl, N(Ci_ 2 alkyl) 2 , C(0)OH and C(0)0-(Ci- 2 alkyl) (e.g. by one or more substituents selected from methyl, halo, hydroxy and methoxy),
• R Y represents H
• R x and R Y together represent C 4 . 5 n-alkylene optionally interrupted between C2 and C3 by -O- or -N(R X2 )-;
• R X2 represents H or Ci_ 2 alkyl
• R C and R E independently represent H or halo
• R D represents trimethylsilyl, C 3 _ 7 alkyl, C(Ci_ 2 alkyl) 2 -C ⁇ CH, C 3 . 5 cycloalkyl, phenyl or Het 2 , which latter three groups are optionally substituted by one or more substituents selected from Ci_ 2 alkyl, halo and Ci_ 2 alkoxy;
• R 2 and R 3 together with the C-atoms to which they are attached, form a fused phenyl ring, or R 2 and R 3 independently represent halo or Ci_ 2 alkyl;
• (k) L represents CH 2 or, particularly, a direct bond
• X 2 and X 3 both represent CH or one of X 2 represents CH and X 3 represents N or CR Z ;
• R z represents H or halo
• R 4 represents
• Ci_ 4 alkylene group is optionally substituted by oxo, -S(0) n R 6 ,
• R 4 may alternatively represent H, (e.g. R 4 represents
• R 5 represents H or, particularly, cyano, chloro, fluoro, C 2 -3 alkynyl, C 1 - 2 alkyl or Ci- 2 alkoxy, which latter two groups are optionally substituted by one or more fluoro atoms;
• R 6a represents C0 2 H or, particularly, OH, O-C 1 . 2 alkyl or N(R 7 )R 7c ;
• R 6 represents Ci_ 5 alkyl or C 3 . 5 cycloalkyl
• R 7 and R 7c independently represent H or Ci -2 alkyl (e.g. methyl), or R 7 and R 7c , together with the N-atom to which they are attached, form a 4- to 7-membered heterocyclic group that is fully saturated, which heterocyclic group contains one N atom (the atom to which R 7 and R 7c are attached) and, optionally, one further heteroatom selected from O, S and N, and which heterocyclic group is optionally substituted by one or more Ci_ 2 alkyl groups;
• Q and Q 2 independently represent C(0)NH or O;
• Het 1 represents, independently upon each occurrence, a 5- or 6-membered heterocyclic group that is fully aromatic, which group contains one to three heteroatoms selected from N, O and S;
• Het 2 represents a 4- to 6-membered (e.g. 5- or 6-membered) heterocyclic group that is fully saturated or partially unsaturated, which group contains one or two heteroatoms selected from N, O and S.
• R A to R E , R 2 to R 5 , X 1 and L are as hereinbefore defined.
• Embodiments of the invention include those in which one or more of the following definitions apply to the compounds of formula I, Ix, la and lb:
• R represents H or, particularly, fluoro, chloro, methyl or Ci_ 2 alkoxy (e.g. methoxy), which latter two groups are optionally substituted by one or more fluoro atoms;
• R B represents H, cyano, -C(0)OR x or, particularly, fluoro, chloro, Het , -C(0)NR x R Y , -NR x S(0) 2 R Y or -N(H)S(0) 2 NR x R Y (e.g. H, cyano, -C(0)OR x or, particularly, fluoro, chloro, -C(0)NR x R Y or -NR x S(0) 2 R Y );
• R x represents H or methyl
• R Y represents H, Het 2 , Ci_ 3 alkyl or C 3 . 5 cycloalkyl, which latter two groups are optionally substituted by fluoro, hydroxy, methoxy, NH 2 , N(H)CH 3 , N(CH 3 ) 2 , and C(0)OCH 3 ,
• R x and R Y together represent C 4 . 5 n-alkylene optionally interrupted between C2 and C3 by -O- or -N(R X2 )-
• R Y represents H or methyl
• R X2 represents H or methyl
• R Y represents Ci_ 4 alkyl, C 3 . 6 cycloalkyl or phenyl, which latter three groups are optionally substituted by one or more substituents selected from halo, methyl and methoxy;
• R C and R E independently represent fluoro or, particularly, H
• R D represents C 4 _ 6 alkyl, C(CH 3 ) 2 -C ⁇ CH, cyclopropyl or morpholinyl (e.g. morpholin-
• R 2 and R 3 together with the C-atoms to which they are attached, form a fused phenyl ring, or R 2 and R 3 both represent methyl or, particularly, chloro;
• X 1 represents N or CH
• L represents CH 2 or, particularly, a direct bond
• R z represents chloro or, particularly, H
• R 4 represents
• Ci_ 3 alkylene group is optionally substituted by oxo
• R 4 may alternatively represent H
• R 4 represents
• R 5 represents H or, particularly, C 2 . 3 alkynyl, Ci_ 2 alkyl or Ci_ 2 alkoxy, which latter two groups are optionally substituted by one or more fluoro atoms (e.g. R 5 represents methyl, trifluoromethyl or, particularly, -C ⁇ CH or methoxy, which latter group is optionally substituted by one or more fluoro atoms);
• R 6a represents OH or, particularly, C0 2 H, 0-CH 3 or N(R 7 )R 7c (e.g. 0-CH 3 or N(R 7 )R 7c) ;
• R 6 represents C 3 . 5 cycloalkyl (e.g. cyclopropyl); (q) R and R both represent methyl, or R and R , together with the N-atom to which they are attached, form a 5- or 6-membered heterocyclic group that is fully saturated, which heterocyclic group contains one N atom (the atom to which R 7 and R 7c are attached) and, optionally, one further heteroatom selected from O, S and N, and which heterocyclic group is optionally substituted by one or more methyl groups;
• R and R both represent methyl, or R and R , together with the N-atom to which they are attached, form a 5- or 6-membered heterocyclic group that is fully saturated, which heterocyclic group contains one N atom (the atom to which R 7 and R 7c are attached) and, optionally, one further heteroatom selected from O, S and N, and which heterocyclic group is optionally substituted by one or more methyl groups;
• Het represents a 5-membered heterocyclic group that is fully aromatic, which group contains one to three heteroatoms selected from N, O and S;
• Het 2 represents a 4- to 6-membered heterocyclic group that is fully saturated or partially unsaturated, which group contains one or two heteroatoms selected from N,
• R A , R B and R D , R 2 to R 5 , X 1 , L and R z are as hereinbefore defined.
• Embodiments of the invention include those in which one or more of the following definitions apply to the compounds of formula I, Ix, la, lb and Ic:
• R A represents H or, particularly, Ci_ 2 alkoxy (e.g. methoxy) optionally substituted by one or more fluoro atoms (e.g. R A represents methoxy);
• R B represents H, cyano, -C(0)OH, -C(0)N(CH 3 ) 2 , fluoro, chloro, or, particularly, -C(0)N(H)R Y , -NHS(0) 2 CH 3 , -N(H)S(0) 2 NR x R Y or Het 1
• R B represents H, cyano, -C(0)OH, -C(0)N(CH 3 ) 2 , fluoro, -C(0)NH 2 , -C(0)N(H)CH 3 or, particularly, -NHS(0) 2 CH 3
• R B represents H, cyano, -C(0)OH, -C(0)N(CH 3 ) 2 , fluoro, -C(0)NH 2 , -C(0)N(H)CH 3 or, particularly, -NHS(0) 2 CH 3
• R x represents H or methyl
• R Y represents H, Het 2 , C 3 . 5 cycloalkyl or Ci_ 3 alkyl, which latter group is optionally substituted by hydroxy, methoxy, NH 2 , N(H)CH 3 , N(CH 3 ) 2 or C(0)OCH 3 (e.g. R Y represents H or methyl),
• R x and R Y together represent C 4 . 5 n-alkylene optionally interrupted between C2 and C3 by -0-;
• R D represents morpholinyl, cyclopropyl optionally substituted by methyl or, particularly, branched C 4 _ 6 alkyl (such as te/f-butyl) (e.g. R D represents morpholin-4- yl or, particularly, te/f-butyl); R 2 and R 3 , together with the C-atoms to which they are attached, form a fused phenyl ring, or R 2 and R 3 both represent chloro;
• X 1 represents N or CH
• L represents CH 2 or, particularly, a direct bond
• R 4 represents
• Ci-3 alkylene group is optionally substituted by oxo
• R 4 may alternatively represent H
• R 4 represents
• R 5 represents H, -C ⁇ CH, or methoxy, which latter group is optionally substituted by one or more fluoro atoms (for example, R 5 represents -C ⁇ CH or, particularly, methoxy, which latter group is optionally substituted by one or more fluoro atoms (e.g. R 5 represents -C ⁇ CH or, particularly, OCH 3 or OCHF 2 ));
• R 6a represents OH or, particularly, C0 2 H, 0-CH 3 or N(R 7 )R 7c (e.g. 0-CH 3 or N(R 7 )R 7c );
• R 7 and R 7c both represent methyl, or R 7 and R 7c , together with the N-atom to which they are attached, form a piperazinyl group optionally substituted by methyl, a pyrrolidinyl group or a morpholinyl group (e.g. a piperazinyl group optionally substituted by methyl or, particularly, a morpholinyl group); and/or
• Q represents O or, particularly, C(0)NH.
• Het 1 represents a 5-membered heterocyclic group that is fully aromatic, which group contains one to three heteroatoms selected from N and O (e.g. Het 1 represents oxadiazolyl, such as 1 ,2,4-oxadiazolyl, or triazolyl, such as 1 ,2,3-triazolyl);
• Het 2 represents a 4- to 6-membered heterocyclic group that is fully saturated or partially unsaturated, which group contains one or two heteroatoms selected from N, O and S (e.g. Het 2 represents oxetanyl, such as 3-oxetanyl).
• R A represents methoxy or ethoxy
• R B represents Het 1 or, particularly, -C(0)N(H)R Y , -NHS(0) 2 CH 3 ;
• R Y represents H, Het 2 , cyclopropyl, Ci alkyl, optionally substituted with C(0)OCH 3 , or C 2 alkyl, which latter group is optionally substituted by hydroxy, methoxy, NH 2 , N(H)CH 3 , N(CH 3 ) 2 or C(0)OCH 3 ,
• R D represents te/f-butyl
• X 1 represents N or CH (e.g. X 1 represents N or, particularly, CH);
• L represents a direct bond;
• Ci. 3 alkylene group is optionally substituted by oxo (e.g. -C(0)NH-C(H)(CH 3 )CH 2 -R 6a , -C(0)NH-CH 2 C(CH 3 ) 2 -R 6a ,
• R 4 may alternatively represent H
• R B represents -C(0)N(H)-Het 2 and R 4 represents H
• R 5 represents -C ⁇ CH or methoxy optionally substituted by one or more fluoro atoms (to give, for example, OCH 3 or OCHF 2 )
• R 5 may alternatively represent H.
• R 4 represents -C(0)NH-C(H)(R 6c )-[Ci. 3 alkylene]-R 6a , which Ci. 3 alkylene group is optionally substituted by oxo (e.g. -C(0)NH-C(H)(CH 3 )CH 2 -R 6a ,
• R 6a represents N(R 7 )R 7c ;
• R 4 represents -Q -[C(H)(R 6c )CH 2 -0] 1 . 6 -CH 2 CH 2 -R 6a , then R 6a represents OH, C0 2 H or 0-CH 3 (e.g. 0-CH 3 ).
• R B represents -NR X2 S(0) 2 NR x R Y or -C(0)NR x R Y , in which latter group R Y represents optionally substituted Het 1 or optionally substituted Het 2 ;
• both R 4 and R 5 represent H.
• Still further embodiments of the invention include those wherein, in the compound of formula I, Ix, la, lb and lc:
• R 4 represents
• R B represents either -C(0)NR x R Y , in which R Y represents optionally substituted Het 1 or optionally substituted Het 2 , or -NR X2 S(0) 2 NR x R Y , then R 4 may alternatively represent H, halo, cyano or Ci_ 3 alkyl, which latter group is optionally substituted by one or more halo atoms;
• Q and Q 2 independently represent C(0)NH or S(0) p ; and n and p independently represent 1 or 2.
• embodiments of the invention include those wherein, in the compound of formula I, Ix, la, lb and Ic:
• Ci_3 alkoxy optionally substituted by one or more halo atoms
• R 5 represents Ci_ 3 alkyl, which latter group is optionally substituted by one or more halo atoms, or R 5 represents H, cyano, -C(0)NH 2 , halo or C 2 -3 alkynyl.
• R 4 represents:
• Ci_ 5 alkylene group is optionally substituted by oxo.
• salts of compounds of formula I, Ix, la, lb or lc include all pharmaceutically acceptable salts, such as, without limitation, acid addition salts of strong mineral acids such as HCI and HBr salts and addition salts of strong organic acids such as methanesulfonic acid.
• references herein to a compound of the invention are intended to include references to the compound and to all pharmaceutically acceptable salts, solvates and/or tautomers of said compound, unless the context specifically indicates otherwise.
• solvates that may be mentioned include hydrates.
• the compounds of the invention are p38 MAP kinase inhibitors (especially of the alpha subtype) and are therefore useful in medicine, in particular for the treatment of inflammatory diseases. Further aspects of the invention that may be mentioned therefore include the following.
• a pharmaceutical formulation comprising compound of formula I, Ix, la, lb or lc, as hereinbefore defined, or pharmaceutically acceptable salt, solvate or isotopic derivative thereof, in admixture with a pharmaceutically acceptable adjuvant, diluent or carrier.
• each of components (A) and (B) is formulated in admixture with a pharmaceutically-acceptable adjuvant, diluent or carrier.
• the combination product may be either a single
• this aspect of the invention encompasses a pharmaceutical formulation including a compound of formula I, Ix, la, lb or lc, as hereinbefore defined, or pharmaceutically acceptable salt, solvate or isotopic derivative thereof, and another therapeutic agent, in admixture with a pharmaceutically acceptable adjuvant, diluent or carrier (which formulation is hereinafter referred to as a "combined preparation").
• kit of parts comprising components: (i) a pharmaceutical formulation including a compound of formula I, Ix, la, lb or Ic, as hereinbefore defined, or pharmaceutically acceptable salt, solvate or isotopic derivative thereof, in admixture with a pharmaceutically acceptable adjuvant, diluent or carrier; and
• a pharmaceutical formulation including another therapeutic agent, in admixture with a pharmaceutically-acceptable adjuvant, diluent or carrier, which components (i) and (ii) are each provided in a form that is suitable for administration in conjunction with the other.
• component (i) of the kit of parts is thus component (A) above in admixture with a pharmaceutically acceptable adjuvant, diluent or carrier.
• component (ii) is component (B) above in admixture with a pharmaceutically acceptable adjuvant, diluent or carrier.
• a process for preparing the pharmaceutical formulation of aspect (a) above comprising the step of admixing the compound of formula I, Ix, la, lb or Ic, as hereinbefore defined, or pharmaceutically acceptable salt, solvate or isotopic derivative thereof, with a pharmaceutically acceptable adjuvant, diluent or carrier.
• Embodiments of this aspect of the invention include those in which the pharmaceutically acceptable adjuvant, diluent or carrier is a topically acceptable adjuvant, diluent or carrier (and/or wherein the process is for preparing a topical pharmaceutical formulation, i.e. a pharmaceutical formulation that is adapted for topical administration).
• a method of treating or preventing an inflammatory disease comprising administering to a subject an effective amount of a compound of formula I, Ix, la, lb or lc, as hereinbefore defined, or pharmaceutically acceptable salt, solvate or isotopic derivative thereof, or
• Embodiments of this aspect of the invention include those in which the subject is one who has become refractory to the anti-inflammatory effects of a corticosteroid.
• diluents and carriers that may be mentioned include those suitable for parenteral, oral, topical, mucosal and rectal administration.
• compositions and combination products of aspects (a) and (b) above may be prepared e.g. for parenteral, subcutaneous, intramuscular, intravenous, intra-articular, intravitreous, periocular, retrobulbar, subconjunctival, sub-Tenon, topical ocular or peri- articular administration, particularly in the form of liquid solutions, emulsions or suspensions; for oral administration, particularly in the form of tablets or capsules, and especially involving technologies aimed at furnishing colon-targeted drug release (Patel, M. M. Expert Opin. Drug Deliv. 2011 , 8 (10), 1247-1258); for topical e.g.
• pulmonary or intranasal administration particularly in the form of powders, nasal drops or aerosols and transdermal administration
• topical ocular administration particularly in the form of solutions, emulsions, suspensions, ointments, implants/inserts, gels, jellies or liposomal microparticle formulations (Ghate, D.; Edelhauser, H. F. Expert Opin. Drug Deliv. 2006, 3 (2), 275-287);
• ocular administration particularly in the form of biodegradable and non-biodegradable implants, liposomes and nanoparticles (Thrimawithana, T. R. et al. Drug Discov.
• compositions and combination products of aspects (a) and (b) above may conveniently be administered in unit dosage form and may be prepared by any of the methods well-known in the pharmaceutical art, for example as described in Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, PA., (1985).
• Formulations for parenteral administration may contain as excipients sterile water or saline, alkylene glycols such as propylene glycol, polyalkylene glycols such as polyethylene glycol, oils of vegetable origin, hydrogenated naphthalenes and the like.
• Formulations for nasal administration may be solid and may contain excipients, for example, lactose or dextran, or may be aqueous or oily solutions for use in the form of nasal drops or metered sprays.
• excipients include sugars, calcium stearate, magnesium stearate, pregelatinated starch, and the like.
• Pharmaceutical formulations and combination products suitable for oral administration may comprise one or more physiologically compatible carriers and/or excipients and may be in solid or liquid form.
• Tablets and capsules may be prepared with binding agents, for example, syrup, acacia, gelatin, sorbitol, tragacanth, or poly-vinylpyrollidone; fillers, such as lactose, sucrose, corn starch, calcium phosphate, sorbitol, or glycine; lubricants, such as magnesium stearate, talc, polyethylene glycol, or silica; and surfactants, such as sodium lauryl sulfate.
• binding agents for example, syrup, acacia, gelatin, sorbitol, tragacanth, or poly-vinylpyrollidone
• fillers such as lactose, sucrose, corn starch, calcium phosphate, sorbitol, or glycine
• lubricants such as magnesium stearate, talc,
• Liquid compositions may contain conventional additives such as suspending agents, for example sorbitol syrup, methyl cellulose, sugar syrup, gelatin, carboxymethyl-cellulose, or edible fats; emulsifying agents such as lecithin, or acacia; vegetable oils such as almond oil, coconut oil, cod liver oil, or peanut oil; preservatives such as butylated hydroxyanisole (BHA) and butylated hydroxytoluene (BHT).
• suspending agents for example sorbitol syrup, methyl cellulose, sugar syrup, gelatin, carboxymethyl-cellulose, or edible fats
• emulsifying agents such as lecithin, or acacia
• vegetable oils such as almond oil, coconut oil, cod liver oil, or peanut oil
• preservatives such as butylated hydroxyanisole (BHA) and butylated hydroxytoluene (BHT).
• BHA butylated hydroxyanisole
• BHT butylated hydroxytoluen
• Solid oral dosage forms include tablets, two-piece hard shell capsules and soft elastic gelatin (SEG) capsules.
• SEG soft elastic gelatin
• Such two-piece hard shell capsules may be made from, for example, gelatin or hydroxylpropyl methylcellulose (HPMC).
• a dry shell formulation typically comprises of about 40% to 60% w/w concentration of gelatin, about a 20% to 30% concentration of plasticizer (such as glycerin, sorbitol or propylene glycol) and about a 30% to 40% concentration of water. Other materials such as preservatives, dyes, opacifiers and flavours also may be present.
• the liquid fill material comprises a solid drug that has been dissolved, solubilized or dispersed (with suspending agents such as beeswax, hydrogenated castor oil or polyethylene glycol 4000) or a liquid drug in vehicles or combinations of vehicles such as mineral oil, vegetable oils, triglycerides, glycols, polyols and surface-active agents.
• a compound of the invention may be administered topically (e.g. to the lung, eye or intestines).
• topically e.g. to the lung, eye or intestines.
• embodiments of aspects (a) and (b) above that may be mentioned include pharmaceutical formulations and combination products that are adapted for topical administration.
• Such formulations include those in which the excipients (including any adjuvant, diluent and/or carrier) are topically acceptable.
• Aerosol formulations typically comprise the active ingredient suspended or dissolved in a suitable aerosol propellant, such as a chlorofluorocarbon (CFC) or a hydrofluorocarbon (HFC).
• a suitable aerosol propellant such as a chlorofluorocarbon (CFC) or a hydrofluorocarbon (HFC).
• CFC propellants include trichloromonofluoromethane (propellant 1 1), dichlorotetrafluoroethane (propellant 114), and dichlorodifluoromethane (propellant 12).
• Suitable HFC propellants include tetrafluoroethane (HFC-134a) and heptafluoropropane (HFC-227).
• the propellant typically comprises 40% to 99.5% e.g.
• the formulation may comprise excipients including co- solvents (e.g. ethanol) and surfactants (e.g. lecithin, sorbitan trioleate and the like).
• excipients include polyethylene glycol, polyvinylpyrrolidone, glycerine and the like. Aerosol formulations are packaged in canisters and a suitable dose is delivered by means of a metering valve (e.g. as supplied by Bespak, Valois or 3M or alternatively by Aptar, Coster or Vari).
• Topical administration to the lung may also be achieved by use of a non-pressurised formulation such as an aqueous solution or suspension.
• a non-pressurised formulation such as an aqueous solution or suspension.
• This may be administered by means of a nebuliser e.g. one that can be hand-held and portable or for home or hospital use (i.e. non-portable).
• the formulation may comprise excipients such as water, buffers, tonicity adjusting agents, pH adjusting agents, surfactants and co-solvents.
• Suspension liquid and aerosol formulations (whether pressurised or unpressurised) will typically contain the compound of the invention in finely divided form, for example with a D 50 of 0.5-10 ⁇ e.g. around 1-5 ⁇ .
• Particle size distributions may be represented using Di 0 , D 50 and D 90 values.
• the D 50 median value of particle size distributions is defined as the particle size in microns that divides the distribution in half.
• the measurement derived from laser diffraction is more accurately described as a volume distribution, and consequently the D 50 value obtained using this procedure is more meaningfully referred to as a Dv 50 value (median for a volume distribution).
• Dv values refer to particle size distributions measured using laser diffraction.
• Di 0 and D 90 values used in the context of laser diffraction, are taken to mean Dvi 0 and Dv 90 values and refer to the particle size whereby 10% of the distribution lies below the Di 0 value, and 90% of the distribution lies below the D 90 value, respectively.
• Topical administration to the lung may also be achieved by use of a dry-powder formulation.
• a dry powder formulation will contain the compound of the disclosure in finely divided form, typically with a mass mean aerodynamic diameter (MMAD) of 1-10 ⁇ or a D 50 of 0.5-10 ⁇ e.g. around 1-5 ⁇ .
• Powders of the compound of the invention in finely divided form may be prepared by a micronization process or similar size reduction process. Micronization may be performed using a jet mill such as those manufactured by Hosokawa Alpine. The resultant particle size distribution may be measured using laser diffraction (e.g. with a Malvern Mastersizer 2000S instrument).
• the formulation will typically contain a topically acceptable diluent such as lactose, glucose or mannitol (preferably lactose), usually of large particle size e.g. an MMAD of 50 ⁇ or more, e.g. 100 ⁇ or more or a D 50 of 40-150 ⁇ .
• lactose refers to a lactose-containing component, including a-lactose monohydrate, ⁇ -lactose monohydrate, a-lactose anhydrous, ⁇ -lactose anhydrous and amorphous lactose. Lactose components may be processed by micronization, sieving, milling, compression, agglomeration or spray drying.
• lactose in various forms are also encompassed, for example Lactohale ® (inhalation grade lactose; DFE Pharma), lnhal_ac ® 70 (sieved lactose for dry powder inhaler; Meggle), Pharmatose ® (DFE Pharma) and Respitose ® (sieved inhalation grade lactose; DFE Pharma) products.
• the lactose component is selected from the group consisting of a-lactose monohydrate, ⁇ -lactose anhydrous and amorphous lactose.
• the lactose is a- lactose monohydrate.
• Dry powder formulations may also contain other excipients such as sodium stearate, calcium stearate or magnesium stearate.
• a dry powder formulation is typically delivered using a dry powder inhaler (DPI) device.
• dry powder delivery systems include SPINHALER, DISKHALER, TURBOHALER, DISKUS and CLICKHALER.
• Further examples of dry powder delivery systems include ECLIPSE, NEXT, ROTAHALER, HANDIHALER, AEROLISER, CYCLOHALER, BREEZHALER/NEOHALER, MONODOSE, FLOWCAPS, TWINCAPS, X- CAPS, TURBOSPIN, ELPENHALER, MIATHALER, TWISTHALER, NOVOLIZER, PRESSAIR, ELLIPTA, ORIEL dry powder inhaler, MICRODOSE, PULVINAL, EASYHALER, ULTRAHALER, TAIFUN, PULMOJET, OMNIHALER, GYROHALER, TAPER, CONIX, XCELOVAIR and PROHALER.
• DPI dry powder inhaler
• a compound of the present invention is provided in a micronized dry powder formulation, for example further comprising lactose of a suitable grade optionally together with magnesium stearate, filled into a single dose device such as AEROLISER or filled into a multi dose device such as DISKUS.
• the compounds of the present invention may also be administered rectally, for example in the form of suppositories or enemas, which include aqueous or oily solutions as well as suspensions and emulsions.
• suppositories can be prepared by mixing the active ingredient with a conventional suppository base such as cocoa butter or other glycerides, e.g., Suppocire.
• the drug is mixed with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug.
• a suitable non-irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug.
• Such materials are cocoa butter and polyethylene glycols.
• the total amount of the inhibitor will be about 0.0001 to less than 4.0% (w/w).
• compositions administered according to the present invention will be formulated as solutions, suspensions, emulsions and other dosage forms.
• Aqueous solutions are generally preferred, based on ease of formulation, as well as a patient's ability to administer such compositions easily by means of instilling one to two drops of the solutions in the affected eyes.
• the compositions may also be suspensions, viscous or semi-viscous gels, or other types of solid or semi-solid compositions. Suspensions may be preferred for compounds that are sparingly soluble in water.
• compositions administered according to the present invention may also include various other ingredients, including, but not limited to, tonicity agents, buffers, surfactants, stabilizing polymer, preservatives, co-solvents and viscosity building agents.
• Preferred pharmaceutical compositions of the present invention include the inhibitor with a tonicity agent and a buffer.
• the pharmaceutical compositions of the present invention may further optionally include a surfactant and/or a palliative agent and/or a stabilizing polymer.
• tonicity agents may be employed to adjust the tonicity of the composition, preferably to that of natural tears for ophthalmic compositions.
• sodium chloride, potassium chloride, magnesium chloride, calcium chloride simple sugars, such as dextrose, fructose, galactose, and/or simply polyols, such as the sugar alcohols mannitol, sorbitol, xylitol, lactitol, isomaltitol, maltitol, and hydrogenated starch hydrolysates may be added to the composition to approximate physiological tonicity.
• simple sugars such as dextrose, fructose, galactose
• simply polyols such as the sugar alcohols mannitol, sorbitol, xylitol, lactitol, isomaltitol, maltitol, and hydrogenated starch hydrolysates
• Such an amount of tonicity agent will vary, depending on the particular agent to be added.
• compositions will have a tonicity agent in an amount sufficient to cause the final composition to have an ophthalmically acceptable osmolality (generally about 150-450 mOsm, preferably 250-350 mOsm and most preferably at approximately 290 mOsm).
• ophthalmically acceptable osmolality generally about 150-450 mOsm, preferably 250-350 mOsm and most preferably at approximately 290 mOsm.
• the tonicity agents of the invention will be present in the range of 2 to 4% w/w.
• Preferred tonicity agents of the invention include the simple sugars or the sugar alcohols, such as D-mannitol.
• An appropriate buffer system e.g., sodium phosphate, sodium acetate, sodium citrate, sodium borate or boric acid
• the particular concentration will vary, depending on the agent employed.
• the buffer will be chosen to maintain a target pH within the range of pH 5 to 8, and more preferably to a target pH of pH 5 to 7.
• Surfactants may optionally be employed to deliver higher concentrations of inhibitor.
• the surfactants function to solubilise the inhibitor and stabilise colloid dispersion, such as micellar solution, microemulsion, emulsion and suspension.
• examples of surfactants which may optionally be used include polysorbate, poloxamer, polyoxyl 40 stearate, polyoxyl castor oil, tyloxapol, triton, and sorbitan monolaurate.
• Preferred surfactants to be employed in the invention have a hydrophile/lipophile/balance "HLB" in the range of 12.4 to 13.2 and are acceptable for ophthalmic use, such as TritonX114 and tyloxapol.
• Additional agents that may be added to the ophthalmic compositions of the present invention are demulcents which function as a stabilising polymer.
• the stabilizing polymer should be an ionic/charged example with precedence for topical ocular use, more specifically, a polymer that carries negative charge on its surface that can exhibit a zeta-potential of (-) 10-50 mV for physical stability and capable of making a dispersion in water (i.e. water soluble).
• a preferred stabilising polymer of the invention would be polyelectrolyte, or polyelectrolytes if more than one, from the family of cross-linked polyacrylates, such as carbomers, polycarbophil and Pemulen(R), specifically Carbomer 974p (polyacrylic acid), at 0.1-0.5% w/w.
• Other compounds may also be added to the ophthalmic compositions of the present invention to increase the viscosity of the carrier.
• viscosity enhancing agents include, but are not limited to: polysaccharides, such as hyaluronic acid and its salts, chondroitin sulfate and its salts, dextrans, various polymers of the cellulose family, vinyl polymers and acrylic acid polymers.
• Topical ophthalmic products are typically packaged in multidose form. Preservatives are thus required to prevent microbial contamination during use. Suitable preservatives include: benzalkonium chloride, chlorobutanol, benzododecinium bromide, methyl paraben, propyl paraben, phenylethyl alcohol, edentate disodium, sorbic acid, polyquaternium-1 , or other agents known to those skilled in the art. Such preservatives are typically employed at a level of from 0.001 to 1.0% w/v. Unit dose compositions of the present invention will be sterile, but typically unpreserved. Such compositions, therefore, generally will not contain preservatives.
• the medical practitioner or other skilled person, will be able to determine a suitable dosage for the compounds of the invention, and hence the amount of the compound of the invention that should be included in any particular pharmaceutical formulation (whether in unit dosage form or otherwise).
• the other therapeutic agent is one or more therapeutic agents that are known by those skilled in the art to be suitable for treating inflammatory diseases (e.g. the specific diseases mentioned below).
• the other therapeutic agent is one or more agents selected from the list comprising:
• steroids e.g. budesonide, beclomethasone dipropionate, fluticasone propionate, mometasone furoate, fluticasone furoate; a further example is ciclesonide;
• beta agonists particularly beta2 agonists (e.g. terbutaline, salbutamol, salmeterol, formoterol; further examples are vilanterol, olodaterol, reproterol and fenoterol); and xanthines (e.g. theophylline).
• beta2 agonists e.g. terbutaline, salbutamol, salmeterol, formoterol; further examples are vilanterol, olodaterol, reproterol and fenoterol
• xanthines e.g. theophylline
• the other therapeutic agent is one or more agents selected from the list comprising:
• muscarinic antagonists e.g. tiotropium, umeclidinium, glycopyrronium, aclidinium and daratropium, any of these for example as the bromide salt
• the other therapeutic agent may be, for example, one or more agents selected from the list comprising:
• 5-aminosalicylic acid or a prodrug thereof (such as sulfasalazine, olsalazine or bisalazide);
• corticosteroids e.g. prednisolone, methylprednisolone, or budesonide
• immunosuppressants e.g. cyclosporin, tacrolimus, methotrexate, azathioprine or 6- mercaptopurine
• anti-TNFa antibodies e.g., infliximab, adalimumab, certolizumab pegol or golimumab
• infliximab e.g., infliximab, adalimumab, certolizumab pegol or golimumab
• - anti-IL12/IL23 antibodies e.g., ustekinumab
• small molecule IL12/IL23 inhibitors e.g., apilimod
• ⁇ - ⁇ 4 ⁇ 7 antibodies e.g., vedolizumab
• MAdCAM-1 blockers e.g., PF-00547659
• antibodies against the cell adhesion molecule a4-integrin e.g., natalizumab
• IL2 receptor a subunit e.g., daclizumab or basiliximab
• JAK3 inhibitors e.g., tofacitinib or R348
• Syk inhibitors and prodrugs thereof e.g., fostamatinib and R-406;
• Phosphodiesterase-4 inhibitors e.g., tetomilast
• protein kinase C inhibitors e.g. AEB-071.
• the other therapeutic agent may be, for example, one or more agents selected from the list comprising:
• corticosteroids e.g. dexamethasone, prednisolone, triamcinolone acetonide, difluprednate or fluocinolone acetonide
• corticosteroids e.g. dexamethasone, prednisolone, triamcinolone acetonide, difluprednate or fluocinolone acetonide
• glucocorticoid agonists e.g., mapracorat
• immunosuppressants e.g. cyclosporin, voclosporin, azathioprine, methotrexate, mycophenolate mofetil or tacrolimus
• immunosuppressants e.g. cyclosporin, voclosporin, azathioprine, methotrexate, mycophenolate mofetil or tacrolimus
• anti-TNFa antibodies e.g., infliximab, adalimumab, certolizumab pegol, ESBA-105 or golimumab
• infliximab e.g., infliximab, adalimumab, certolizumab pegol, ESBA-105 or golimumab
• anti-IL-17A antibodies e.g., secukinumab
• mTOR inhibitors e.g., sirolimus
• adenosine A3 receptor agonists e.g., CF-101
• JAK3 inhibitors e.g., tofacitinib or R348.
• protein kinase C inhibitors e.g. AEB-071.
• the other therapeutic agent may be, for example, one or more agents selected from the list comprising:
• corticosteroids e.g. dexamethasone, prednisolone, triamcinolone acetonide, difluprednate or fluocinolone acetonide
• corticosteroids e.g. dexamethasone, prednisolone, triamcinolone acetonide, difluprednate or fluocinolone acetonide
• immunosuppressants e.g. cyclosporin, voclosporin, azathioprine, methotrexate, mycophenolate mofetil or tacrolimus
• anti-TNFa antibodies e.g., infliximab, adalimumab, certolizumab pegol, ESBA-105 or golimumab
• anti-IL-17A antibodies e.g., secukinumab
• mTOR inhibitors e.g., sirolimus
• JAK3 inhibitors e.g., tofacitinib or R348.
• protein kinase C inhibitors e.g. AEB-071.
• the compounds of the invention may be used as monotherapies for inflammatory diseases, or in combination therapies for such diseases.
• embodiments of aspects (e) to (g) above include those in which the compound of formula I, Ix, la, lb or Ic (or pharmaceutically acceptable salt, solvate or isotopic derivative thereof) is the sole pharmacologically active ingredient utilised in the treatment.
• the compound of formula I, Ix, la, lb or Ic (or pharmaceutically acceptable salt, solvate or isotopic derivative thereof) is administered to a subject who is also administered one or more other therapeutic agents (e.g. wherein the one or more other therapeutic agents are as defined above in connection with combination products).
• inflammatory disease specifically includes references to any one or more of the following:
• lung diseases or disorders having an inflammatory component such as cystic fibrosis, pulmonary hypertension, lung sarcoidosis, idiopathic pulmonary fibrosis or, particularly, COPD (including chronic bronchitis and emphysema), asthma or paediatric asthma;
• an inflammatory component such as cystic fibrosis, pulmonary hypertension, lung sarcoidosis, idiopathic pulmonary fibrosis or, particularly, COPD (including chronic bronchitis and emphysema), asthma or paediatric asthma;
• nasal diseases or disorders having an inflammatory component such as allergic rhinitis, rhinitis or sinusitis;
• eye diseases or disorders having an inflammatory component such as conjunctivitis, allergic conjunctivitis, glaucoma, diabetic retinopathy, macular oedema (including diabetic macular oedema), central retinal vein occlusion (CRVO), dry and/or wet age related macular degeneration (AMD), post-operative cataract inflammation, or, particularly, keratoconjunctivitis sicca (dry eye), uveitis (including posterior, anterior and pan uveitis), corneal graft and limbal cell transplant rejection; and
• gastrointestinal diseases or disorders having an inflammatory component such as gluten sensitive enteropathy (coeliac disease), eosinophilic esophagitis, intestinal graft versus host disease or, particularly, Crohn's disease or ulcerative colitis.
• References herein to diseases having an inflammatory component include references to diseases that involve inflammation, whether or not there are other (non-inflammatory) symptoms or consequences of the disease.
• a process for the preparation of a compound of formula I which process comprises: reaction of a compound of formula II,
• R A to R E , R 2 to R 5 , L and X 1 to X 3 are as hereinbefore defined, for example under conditions known to those skilled in the art, for example at a temperature from ambient (e.g. 15 to 30°C) to about 110°C in the presence of a suitable organic solvent (e.g. a polar aprotic solvent such as DMF, THF, 1 ,4-dioxane, or mixtures thereof); reaction of a compound of formula Ila,
• a suitable organic solvent e.g. a polar aprotic solvent such as DMF, THF, 1 ,4-dioxane, or mixtures thereof
• a suitable azide-forming agent i.e. a suitable source of a leaving group and activated azide ion, such as diphenyl phosphorazidate; see, for example, Tetrahedron 1974, 30, 2151-2157
• a suitable azide-forming agent i.e. a suitable source of a leaving group and activated azide ion, such as diphenyl phosphorazidate; see, for example, Tetrahedron 1974, 30, 2151-2157
• an amine base e.g. triethylamine or a sterically hindered base such as A/,A/-diisopropylethylamine
• a suitable organic solvent e.g.
• a polar aprotic solvent such as DMF, THF, 1 ,4-dioxane, or mixtures thereof
• reaction is followed, without isolation, by thermal rearrangement (e.g. under heating) of the intermediate acyl azide (of formula Z -C(0)-N 3 ) e.g. at ambient temperature (such as from 15 to 30°C) to provide, in situ, a compound of formula II, which compound is then reacted with a compound of formula III, as defined above, to provide the compound of formula I; reaction of a compound of formula lib,
• LG 1 represents a suitable leaving group (e.g. imidazolyl, chloro, or aryloxy, such as phenoxy) and Z is as defined above, with a compound of formula III, as defined above, for example under conditions known to those skilled in the art, such as at ambient temperature (e.g. from ambient to 80°C), optionally in the presence of an amine base (e.g. triethylamine or a sterically hindered base like A/./V-diisopropylethylamine) and a suitable organic solvent (e.g. an aprotic solvent, such as dichloromethane or an ester such as isopropyl acetate);
• a suitable organic solvent e.g. an aprotic solvent, such as dichloromethane or an ester such as isopropyl acetate
• LG 2 represents a suitable leaving group (e.g. a halo group such as chloro or bromo) and R A to R E , R 2 , R 3 and X 1 are as hereinbefore defined with a compound of formula VII,
• R 4 , R 5 , L, X 2 and X 3 are as hereinbefore defined, for example under conditions known to those skilled in the art (e.g. as described in J. Am. Chem. Soc. 2011 , 133, 15686- 15696), such as at elevated temperature (e.g. from 50 to 110°C) in the presence of a suitable organic solvent (e.g. a polar aprotic solvent such as DMF, THF, 1 ,4-dioxane, or mixtures thereof) and, optionally, an acidic catalyst (e.g. a sulfonic acid such as para-toluenesulfonic acid); or
• a suitable organic solvent e.g. a polar aprotic solvent such as DMF, THF, 1 ,4-dioxane, or mixtures thereof
• an acidic catalyst e.g. a sulfonic acid such as para-toluenesulfonic acid
• R 6a to R 6d are as hereinbefore defined, for example under conditions known to those skilled in the art (e.g. at 0 to 25°C in the presence of a suitable solvent (such as dichloromethane, methanol or a mixture thereof) and a peracid, such as meta- chloroperbenzoic acid);
• a suitable solvent such as dichloromethane, methanol or a mixture thereof
• a peracid such as meta- chloroperbenzoic acid
• Ci-5 alkylene group is optionally substituted by oxo, reaction of a compound of formula Vila,
• R 4' represents H or a Ci_ 3 alkyl group (e.g. methyl) and R A to R E , R 2 , R 3 , R 5 , L and X 1 to X 3 are as hereinbefore defined, with a compound of formula Vllb or Vile,
• a trialkyl aluminium reagent such as trimethylaluminium
• an aprotic organic solvent e.g. THF
• R 4' represents H
• reaction in the presence of a tertiary amine base e.g. a trialkylamine such as triethylamine or diisopropylethylamine or a cyclic amine such as N- methylpyrrolidine or N-methylmorpholine
• a tertiary amine base e.g. a trialkylamine such as triethylamine or diisopropylethylamine or a cyclic amine such as N- methylpyrrolidine or N-methylmorpholine
• an amide (peptide) coupling reagent e.g.
• T3P T3P, HATU, CDI, BOP, PyBOP, HOAt, HOBt or a carbodiimide such as DCC or diisopropylcarbodiimide
• an aprotic organic solvent e.g. a chlorinated solvent such as DCM, an ester such as ethyl acetate, an amide of dimethylamine such as DMF, or a mixture of any such solvents
• R A , R C , R D , R E , R a , R , X 1 to X 3 , L, R 4 and R 5 are as hereinbefore defined and R x represents H or Ci_ 4 alkyl, with a compound of formula Vile, wherein R x and R Y are as hereinbefore defined, under conditions known to those skilled in the art, for example
• R x represents H
• a base e.g. triethylamine or A/./V-diisopropylethylamine
• an amide (peptide) coupling reagent such as HATU, CDI, ⁇ /, ⁇ /'-dicyclohexylcarbodiimide, ⁇ /, ⁇ /'-diisopropylcarbodiimide BOP or PyB
• R x represents H
• conversion of the carboxylic acid to an acid halide e.g. by reaction with a halogenating agent such as thionyl chloride
• reaction with the compound of formula (XI) in the presence of a suitable solvent and a base e.g. triethylamine or A/./V-diisopropylethylamine, or
• R x represents Ci_ 4 alkyl (e.g. methyl)
• a trialkylaluminium e.g. trimethylaluminium
• an aprotic solvent e.g. THF
• Compounds of formula II may be prepared according to or by analogy with methods known to those skilled in the art, for example by reaction of a compound of formula lla, as defined above, with an azide-forming agent, followed by rearrangement of the intermediate acyl azide (as described at (b) above; see, for example, Tetrahedron 1974, 30, 2151-2157).
• Amines of formula IX may be prepared from carboxylic acids of formula I la through the route described in (b) above, where the intermediate isocyanate II is hydrolysed with water to give a carbamic acid that loses carbon dioxide to furnish IX.
• the intermediate isocyanate II can be reacted with an alcohol, such as f-butanol, to generate a protected version of IX.
• Certain compounds of formula III in which Z 2 represents a structural fragment of formula V, or compounds of formula IX in which Z represents a structural fragment of formula V, may be synthesised employing the route outlined in Scheme 1 (see, for example: WO 2003/072569; and WO 2008/046216), wherein R 2 , R 3 and X 1 to X 3 are as hereinbefore defined, LG 3 and LG 4 represent leaving groups, e.g., halogen or methanesulfonyl, and FG represents a real or latent NH 2 group, i.e., a group that is readily transformed into an NH 2 group, such as nitro or a protected variant NH-PG 2 , where PG 2 is a typical protecting group (see, for example: Greene, T.
• the remaining halogen or methanesulfonyl substituent (LG 4 ) of the ether XII is then displaced i) by an amine of formula VII in a second S N Ar reaction or (ii) via a Buchwald coupling (see, for example, WO 2009/017838) with an amine of formula VII to furnish the desired compound (when FG is NH 2 ), or XIII (when FG is nitro or NH-PG 2 ).
• the NH 2 group may be revealed by a reduction reaction, typically done through hydrogenation employing a suitable catalyst, e.g., palladium on carbon, or employing dissolving metal conditions, such as with iron in glacial acetic acid.
• the NH 2 group may be revealed by a deprotection reaction. Although only depicted as taking place in the final step of the sequence, it should be noted that the unmasking of the latent NH 2 group represented by FG can take place at any stage in the synthetic route shown in Scheme 1.
• amines of formula IX in which Z represents a structural fragment of formula IV may be synthesised by conversion of a latent to a real NH 2 group in a compound of formula Xllla,
• Ci-5 alkylene group is optionally substituted by oxo
• compounds of formula VI may be synthesised by analogy with the compounds of formula I (see, for example, alternative processes (a) to (c) above).
• compounds of formula VI can be prepared by reaction of a compound of formula llx with a compound of formula Mix, wherein the compounds of formulae llx and Mix take the same definitions as the compounds of formulae II and III, with the exception that one of Z and Z 2 represents a structural fragment of formula IV, as hereinbefore defined, and the other of Z and Z 2 represents a structural fragm
• FG 1 either represents FG or C(0)0-(Ci_ 6 alkyl)
• FG, R 5 , X 2 and X 3 are as hereinbefore defined, with a compound of formula XVa or XVb
• LG 5 represents a suitable leaving group such as halo, (perfluoro)alkane- sulfonate or arylsulfonate (e.g.
• R 6a , R 6c and R 6d are as hereinbefore defined, under conditions known to those skilled in the art (e.g. in the presence of an organic solvent and either a suitable base, followed by when FG represents NH-PG 2 , removal of the PG 2 protecting group, when FG 1 represents N0 2 , reduction of N0 2 to NH 2 or
• R 6a , R 6c and R 6d are as hereinbefore defined, under conditions known to those skilled in the art (e.g. under Mitsunobu conditions, i.e. in the presence of using triphenylphosphine and an azodicarboxylate, such as diethyl azodicarboxylate or diisopropyl azodicarboxylate), followed by
• LG 5 -R' XVIII wherein LG 5 and R 6 are as hereinbefore defined, under conditions known to those skilled in the art (e.g. in the presence of a suitable base and an organic solvent), followed by
• FG 1 and R 5 are as hereinbefore defined, under conditions known to those skilled in the art (e.g. in the presence of a peracid, such as mefa-chloroperbenzoic acid), followed by
• LG6 represents a suitable leaving group such as halo trifluoromethanesulfonate
• FG 1 , R 5 , X 2 and X 3 are as hereinbefore defined, with compound of formula XXI, H-S-R 6b XXI wherein R 6 is as hereinbefore defined, under conditions known to those skilled in the art (e.g. in the presence of a Pd(0) catalyst, Cu(l) iodide and a suitable base), followed by
• x and y are integers from 0 to 1 1 , the sum of x and y being from 0 to 11 , and Q , LG 5 and R 6a are as hereinbefore defined, under conditions known to those skilled in the art (e.g. at ambient temperature in the presence of a base such as sodium hydride and a polar organic solvent such as DMF).
• R' represents
• Ci-5 alkylene group is optionally substituted by oxo, reaction of a compound of formula XXV,
• M s+ is a metal cation
• s is 1 or 2 (e.g. s is 1 and M is an alkali metal such as potassium or, particularly, sodium) and R 6 is as hereinbefore defined, under conditions known to those skilled in the art (e.g. at elevated temperature (e.g. 80 to 100°C) in the presence of: a suitable transition metal catalyst, such as Cu(l) iodide; an aprotic organic solvent, such as DMSO; a suitable base, such as an alkali metal hydroxide (e.g.
• FG, LG 2 , R A and R C to R E are as hereinbefore defined, with a source of cyanide ion (e.g. NaCN), for example under conditions known to those skilled in the art, such as in the presence of a polar, aprotic organic solvent (e.g. DMSO).
• a source of cyanide ion e.g. NaCN
• a polar, aprotic organic solvent e.g. DMSO
• R" represents -CH 2 -[Ci_ 5 alkylene]-OH, with a halogenating agent (e.g. a mixture of 2,4,6-trichloro, 1 ,3,5-triazine and dimethylformamide).
• a halogenating agent e.g. a mixture of 2,4,6-trichloro, 1 ,3,5-triazine and dimethylformamide.
• FG, R X , R A and R C to R E are as hereinbefore defined, for example under conditions known to those skilled in the art, such as by reaction with borohydride or aluminium hydride-based reducing agent (e.g. an alkali metal borohydride or aluminium hydride, such as lithium borohydride or lithium aluminium hydride) in the presence of a reaction-inert organic solvent.
• borohydride or aluminium hydride-based reducing agent e.g. an alkali metal borohydride or aluminium hydride, such as lithium borohydride or lithium aluminium hydride
• Z represents a structural fragment of formula IV, in which R A , R B , R C , R D and R E are as hereinbefore defined (e.g. in which R A , R B , R C , R D and R E take the combinations of definitions illustrated in respect of those groups in any of the compounds of the examples); and
• LG 1 is as hereinbefore defined (e.g. LG 1 represents phenoxy).
• aspects of the invention described herein may have the advantage that, in the treatment of the conditions described herein, they may be more convenient for the physician and/or patient than, be more efficacious than, be less toxic than, have better selectivity over, have a broader range of activity than, be more potent than, produce fewer side effects than, have a better pharmacokinetic and/or pharmacodynamic profile than, have more suitable solid state morphology than, have better long term stability than, or may have other useful pharmacological properties over, similar compounds, combinations, methods (treatments) or uses known in the prior art for use in the treatment of those conditions or otherwise.
• the compounds of the invention may additionally (or alternatively):
• GSK 3a not strongly inhibit GSK 3a (e.g. they may have an IC 50 against GSK 3a of 1 ,000 nM or greater; such as 1 ,500, 2,000, 3,000, 4,000, 5,000, 6,000, 7,000, 8,000, 9,000 or 10,000 nM or greater);
• a relatively high local drug concentration between doses e.g. a high local concentration relative to other previously disclosed p38 MAP kinase inhibitors such as, for example, BIRB796;
• topical/local administration e.g. following topical/local administration, the generation of high target tissue concentrations but low plasma concentrations of the compounds of formula (I) and/or rapid clearance of the compounds of formula (I) from plasma, for example as a result of high renal or hepatic extraction;
• reaction mixture to be purified was first diluted with MeOH and made acidic with a few drops of AcOH. This solution was loaded directly onto the SCX and washed with MeOH. The desired material was then eluted by washing with 1 % NH 3 in MeOH.
• Analytical HPLC was carried out using a Waters Xselect CSH C18, 2.5 ⁇ , 4.6x30 mm column eluting with a gradient of 0.1 % Formic Acid in MeCN in 0.1 % aqueous Formic Acid or a Waters Xbridge BEH C18, 2.5 ⁇ , 4.6x30 mm column eluting with a gradient of MeCN in aqueous 10 mM Ammonium Bicarbonate.
• UV spectra of the eluted peaks were measured using either a diode array or variable wavelength detector on an Agilent 1100 system.
• Analytical LCMS was carried out using a Waters Xselect CSH C18, 2.5 ⁇ , 4.6x30 mm column eluting with a gradient of 0.1 % Formic Acid in MeCN in 0.1 % aqueous Formic Acid or a Waters Xbridge BEH C18, 2.5 ⁇ , 4.6x30 mm column eluting with a gradient of MeCN in aqueous 10 mM Ammonium Bicarbonate.
• UV and mass spectra of the eluted peaks were measured using a variable wavelength detector on either an Agilent 1200 or an Agilent Infinity 1260 LCMS with 6120 single quadrupole mass spectrometer with positive and negative ion electrospray.
• Preparative HPLC was carried out using a Waters Xselect CSH C18, 5 ⁇ , 19x50 mm column using either a gradient of either 0.1 % Formic Acid in MeCN in 0.1 % aqueous Formic Acid or a gradient of MeCN in aqueous 10 mM Ammonium Bicarbonate or employing a Waters Xbridge BEH C18, 5 ⁇ , 19x50 mm column using a gradient of MeCN in aqueous 10 mM Ammonium Bicarbonate.
• Fractions were collected following detection by UV at a single wavelength measured by a variable wavelength detector on a Gilson 215 preparative HPLC or Varian PrepStar preparative HPLC or by mass and UV at a single wavelength measured by a ZQ single quadrupole mass spectrometer, with positive and negative ion electrospray, and a dual wavelength detector on a Waters FractionLynx LCMS.
• H NMR Spectroscopy H NMR spectra were acquired on a Bruker Avance III spectrometer at 400 MHz. Either the central peaks of chloroform-d, dimethylsulfoxide-cfe or an internal standard of tetramethylsilane were used as references.
• Phenyl chloroformate (0.5 mL, 3.99 mmol) was added to a stirred solution of N-(3-amino-5- (tert-butyl)-2-methoxyphenyl)methanesulfonamide (see, for example, Cirillo, P. F. et al., WO 2002/083628, 24 October 2002; 1 g, 3.67 mmol) and NaHC0 3 (620 mg, 7.38 mmol) in THF (10 mL) and DCM (10 mL). The mixture was stirred for 2 h, then water (20 mL) was added. The organic layer was separated, dried (MgS0 4 ), filtered and evaporated to furnish a brown foam, which was stirred in cyclohexane (20 mL) to afford the sub-title compound (1.4 g) as a colourless solid.
• Triethylamine (5 ⁇ , 0.036 mmol) was added to a mixture of the product from step (vi) above (75 mg, 0.191 mmol) and the product from step (v) above (100 mg, 0.197 mmol) in isopropyl acetate (3 mL) and the mixture heated at 50°C (block temperature) for 6 h. The reaction was cooled to rt and left stirring for 72 h. The resulting solid was filtered and washed with isopropyl acetate (1 mL). The crude product was recrystallised from MeCN (3 mL), washed with MeCN (1 mL), filtered and dried to afford the title compound (100 mg) as a colourless solid.
• the mixture was diluted with DCM (30 mL), was washed with water (30 mL) and filtered through a phase-separating cartridge. The filtrate was evaporated and the residue was purified on a 40 g redisep silica cartridge using a gradient of 0 to 50% of ethyl acetate in isohexane as eluent to afford the sub-title compound (1.565 g) as a pink solid.
• the solid was washed with isopropyl acetate (2 x 2ml_) and digested with boiling acetonitrile (20 mL) for 20 mins. The suspension was allowed to cool then filtered. The solid washed with acetonitrile (2 x 4 mL) followed by ether (2 x 4 mL) and dried to afford the title compound (97 mg) as a buff solid.
• 3-Amino-5-methoxybenzoic acid (1.0g, 5.98 mmol) was added to an ice cold suspension of 2-(2-(2-methoxyethoxy)ethoxy)ethanamine (1.2 g, 7.35 mmol), 50% T3P in ethyl acetate (4.50 mL, 7.56 mmol) and TEA (2.5 mL, 17.94 mmol) in ethyl acetate (15 mL). The mixture was allowed to warm to rt and stir overnight. Saturated aq. NaHC0 3 solution (20 mL) was added and the mixture was extracted with ethyl acetate (3 x 10 mL).
• the solid was purified by preparative HPLC (Gilson, Acidic (0.1 % Formic acid), Waters X-Select Prep-C18, 5 ⁇ , 19x50 mm column, 20-50% MeCN in Water) to afford a white solid which was redissolved in methanol (2 mL) loaded onto an SCX column. The column was washed with methanol (3 x 3 mL) then eluted with 1 % ammonia in methanol to yield the title compound (21 mg) as a white solid.
• N 2 was bubbled through a stirred mixture of tert-butyl (4-((2-chloropyrimidin-4- yl)oxy)naphthalen-1-yl)carbamate (see, for example, Ito, K. et al., WO 2010/067130, 17 Jun 2010; 10 g, 26.9 mmol), 3-amino-5-methoxybenzoic acid (8.99 g, 53.8 mmol) and p-TSA monohydrate (1.02 g, 5.36 mmol) in THF (150 mL) for 10min. The mixture was heated under reflux for 20 h, cooled and filtered.
• tert-butyl (4-((2-chloropyrimidin-4- yl)oxy)naphthalen-1-yl)carbamate see, for example, Ito, K. et al., WO 2010/067130, 17 Jun 2010; 10 g, 26.9 mmol
• step (ii) above (570 mg, 0.927 mmol) was suspended in DCM (10 mL) and TFA (1500 ⁇ , 19.47 mmol) added. The reaction mixture was stirred for 2 h. The solvents were evaporated and the residue partitioned between water (20 mL) and DCM (20 mL). The aqueous layer was separated and basified with NaHC0 3 before extraction with DCM (3 x 20 mL). The organics were bulked, dried (MgS0 4 ), filtered and evaporated to give a brown solid. The crude product was purified by chromatography on silica gel (40 g column, 5% MeOH: DCM to 10%) to afford the sub-title compound (350 mg) as a colourless solid.
• Et 3 N (6 ⁇ _, 0.043 mmol) was added to a mixture of phenyl (5-(tert-butyl)-2-methoxy-3- (methylsulfonamido)phenyl)carbamate (see Example 1 (vi) above; 76 mg, 0.194 mmol) and the product from step (iii) above (100 mg, 0.194 mmol) in isopropyl acetate (3 mL) and the mixture heated at 70°C (block temperature) for 7 h. The reaction was diluted with DCM and MeOH then concentrated in vacuo onto silica gel.
• the crude product was purified by chromatography on the Companion (12 g column, 1-10% MeOH DCM) to afford the product as a clear oil which was purified further by preparative HPLC (Gilson, Acidic (0.1 % Formic acid), Waters X-Select Prep-C18, 5 ⁇ , 19x50 mm column, 20-50% MeCN in Water) to afford the formate salt of the product as a white solid.
• the material was dissolved in MeOH and loaded onto a pre-conditioned cartridge of SCX resin. The resin was washed with MeOH and the product released with 1 % NH 3 in MeOH. The NH 3 solution was concentrated in vacuo to afford the title compound (54 mg) as a white solid.
• the temperature was increased to 85°C and the mixture was stirred for a further 3 h.
• the mixture was diluted with water (10 mL) and saturated aq. NaHC0 3 solution (10 mL), then extracted with ethyl acetate (3 x 10 mL).
• the combined organic phases were washed with 20% brine (2 x 10 mL), saturated brine (10 mL), dried (MgS0 4 ) and concentrated under reduced pressure.
• the crude product was purified by chromatography on the Companion (40 g column, 0-100% THF/EtOAc) to afford a pale brown glass.
• Phenyl chloroformate (1.40 mL, 11.16 mmol) was added to a stirred solution of 5-(tert-butyl)- 2-methoxyaniline (2.00 g, 1 1.16 mmol) and NaHC0 3 (1.90 g, 22.62 mmol) in THF (20 mL) and DCM (20 mL). The mixture was stirred overnight then diluted with water (40 mL) and DCM (20 mL) then passed through a phase-sep cartridge. The resulting filtrate was concentrated in vacuo to afford the sub-title compound (3.53 g) as a red-brown oil.
• Phenyl chloroformate (300 ⁇ , 2.391 mmol) was added to a stirred solution of 3-amino-5- (tert-butyl)-2-methoxy-N-methylbenzamide (see, for example, Cirillo, P. F. et al., Bioorg. Med. Chem. Lett. 2009, 19, 2386-2391 ; 550 mg, 2.327 mmol) and NaHC0 3 (300 mg, 3.57 mmol) in THF (5 mL) and DCM (5 mL). The mixture was stirred for 2 h, filtered and the solvent evaporated to give a pale brown oil. Trituration with isohexane (10 mL) gave the sub-title compound (470 mg) as a colourless solid.
• the catalyst solution was added to the main reaction mixture and the whole was heated to 90°C for 48 h.
• Pd 2 (dba) 3 22 mg, 0.024 mmol
• BINAP 30 mg, 0.048 mmol
• Water was added (15 mL) and the mixture was extracted with EtOAc (3 x 15 mL).
• the combined organic phases were washed with saturated brine (15 mL), dried (MgS0 4 ) and concentrated under reduced pressure.
• the crude product was purified by chromatography on the Companion (40 g column, 50-100% EtOAc/isohexane) to afford the sub-title compound (194 mg) as a sticky brown oil.
• Phenyl chloroformate (300 ⁇ , 2.391 mmol) was added to a stirred solution of 2-methoxy-5- morpholinoaniline (500 mg, 2.401 mmol) and NaHC0 3 (400 mg, 4.76 mmol) in THF (5 mL) and DCM (5 mL) and the mixture was stirred overnight. The mixture was diluted with water (40 mL) and DCM (20 mL) then the mixture passed through a phase-sep cartridge. The resulting filtrate was concentrated in vacuo to afford the sub-title compound (789 mg) as a yellow oil which solidified on standing.
• Triethylamine (6 ⁇ , 0.043 mmol) was added to a mixture of the product from step (i) above (58 mg, 0.177 mmol) and 4-((4-aminonaphthalen-1-yl)oxy)-N-(3-methoxy-5-(2-(2-(2- methoxyethoxy)ethoxy)ethoxy)phenyl)pyrimidin-2-amine (see Example 4(v) above; 100 mg, 0.192 mmol) in isopropyl acetate (3 mL) and the mixture heated at 70°C (block temperature) for 4 days. The reaction was cooled to rt and diluted with MeOH. The solution was concentrated in vacuo onto silica gel.
• the crude product was purified by chromatography on the Companion (12 g column, 1-5% MeOH in DCM) to afford the product as an off-white solid.
• the crude product was purified by preparative HPLC (Gilson, Acidic (0.1 % Formic acid), Waters X-Select Prep-C18, 5 ⁇ , 19x50 mm column, 25-70% MeCN in Water) to afford the title compound (51 mg) as an off-white solid.
• Triethylamine (15 ⁇ _, 0.108 mmol) was added to a mixture of phenyl (5-(tert-butyl)-2- methoxy-3-(methylcarbamoyl)phenyl)carbamate (see Example 9(i) above; 150 mg, 0.421 mmol) and 4-((4-aminonaphthalen-1-yl)oxy)-N-(3-methoxy-5-(2-(2-(2-methoxyethoxy)- ethoxy)ethoxy)phenyl)pyrimidin-2-amine (see Example 4(v) above; 200 mg, 0.384 mmol) in THF (5 mL) and the mixture heated at 50°C (block temperature) for 24h.
• Iron powder (5.90 g, 106 mmol) was added to a solution of the product from step (i) above (8.24 g, 20.43 mmol) and concentrated HCI (2 mL, 23.40 mmol) in EtOH (65 mL) and water (15 mL). The mixture was heat at 75 °C (block temperature) for 1 h. Then, the reaction was cooled to rt, before being diluted with water (30 mL), filtered and concentrated in vacuo. The residue was basified (NaHC0 3 ) then partitioned between EtOAc (350 mL) and water (275 mL).
• the reaction was heated at 85 °C for 3 h, before beingcooled to rt and partitioned between EtOAc (250 mL) and brine (250 mL).
• the aqueous phase was further extracted with EtOAc (250 mL), then the combined organic extracts were washed with water (3 x 200 mL) and brine (200 mL), before being dried (MgS0 4 ), filtered and concentrated in vacuo to afford a dark brown oil.
• the crude product was purified by chromatography on silica gel (220 g column, 0-3% MeOH in DCM) to afford the sub-title compound (5.4 g) as an orange oil.
• step (I) above (1 kg, 2.56mol) was dissolved in THF (3.5 L) and AcOH (500 mL) and hydrogenated at 3 MPa (30 bar) H 2 at up to 60°C with 5% Pt/C (30 g of JM type 18 MA, 55% water). Analysis after 5 hrs showed a 1 : 1 ratio of ArNHOH and ArNH 2 . The reaction reached completion after being left overnight, with H NMR analysis showing 3% des-bromo side product. The catalyst was filtered off, then the residue was diluted with ethyl acetate (3 L) and washed with 20% potassium carbonate solution (3.5 L).
• step (IV) The dark red solution was heated to reflux for 6 h then cooled to room temperature, after which HPLC analysis indicated 0.25% the product of step (IV), 22.24% the product of step (VI), 8.98% chloropyrimidine starting material and 64.08% the product of step (V). Further product from step (IV) above (27.1 g, 22.5 g active, 73.4 mmol) was charged and the reaction was heated back to reflux and stirred overnight, with HPLC analysis subsequently revealing 0.20% the product of step (IV), 30.23% the product of step (VI), 4.50% starting chloropyrimidine and 58.61 % the product of step (V).
• step (VII) Under N 2 was charged the product of step (VII) (471 g, 2.099 mol), toluene (1880 mL) and pyridine (471 mL), then methanesulfonyl chloride (179 mL) was added dropwise over 1 h while maintaining the temperature below 35 °C. The reaction was stirred at 30-35 °C overnight, before being cooled to below 20 °C, then water (1880 mL) and 2 M HCI (1880 mL) were charged (pH 3 achieved). The layers were separated and the organic phase was washed with 2.5% brine (1880 mL). Heptane (3760 mL) was then charged to the organic layer over 0.5 h to isolate a precipitate.
• step (IX) Under N 2 was charged the product of step (IX) above (167.0 g, 613 mmol), NaHC0 3 (77.3 g, 920 mmol), THF (870 mL) and DCM (1440 mL). Phenyl chloroformate (82.6 mL, 659 mmol) was added dropwise, while maintaining the temperature below 20°C, and the reaction was stirred at room temperature for 4 h. HPLC analysis of the reaction mixture indicated 98.6% product and 0.03% starting material. The reaction mixture was filtered and the cake was washed with THF (-50 mL). The filtrate was concentrated to -900 mL and cyclohexane (2400 mL) was added, then the mixture was left to stir overnight.
• step (vi) Under N 2 was charged the product of step (vi) above (175.5g, 0.324mol), the product of step (X) above (145.0 g, 0.369 mmol) and / ' PrOAc (8800 mL). The resulting solution was heated to 60°C and NEt 3 (9.3 mL) was charged in one portion, then the mixture was left to stir at 60 °C overnight, following which HPLC analysis indicated 25.77% product of step (VI), 3.60% product of step (X) and 57.85% product of step (XI).
• step (X) Further product of step (X) (36.0 g, 0.092 mol) was charged, then the reaction was left to stir at 60 °C overnight, whereupon HPLC analysis indicated 5.47% product of step (VI), 3.72% product of step (X) and 73.33% product of step (XI).
• the reaction mixture was cooled to room temperature, before being concentrated to isolate a dark purple solid (522.9 g). This solid was recrystallised from acetonitrile (2615 mL, 5 volumes), before being collected via vacuum filtration and washed with / ' PrOAc (2 x 500 mL). The pink solid obtained was dried, under vacuum, at 40 °C overnight, yielding 181.1 g (66.5%) of the title compound with HPLC purity 99.27%. H NMR conformed to structure.
• Example 17 Example 17

Landscapes

• Chemical & Material Sciences (AREA)
• Health & Medical Sciences (AREA)
• Organic Chemistry (AREA)
• Pharmacology & Pharmacy (AREA)
• Veterinary Medicine (AREA)
• Public Health (AREA)
• General Health & Medical Sciences (AREA)
• Animal Behavior & Ethology (AREA)
• Medicinal Chemistry (AREA)
• Life Sciences & Earth Sciences (AREA)
• Epidemiology (AREA)
• General Chemical & Material Sciences (AREA)
• Engineering & Computer Science (AREA)
• Chemical Kinetics & Catalysis (AREA)
• Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
• Bioinformatics & Cheminformatics (AREA)
• Ophthalmology & Optometry (AREA)
• Immunology (AREA)
• Pulmonology (AREA)
• Dermatology (AREA)
• Heart & Thoracic Surgery (AREA)
• Pain & Pain Management (AREA)
• Rheumatology (AREA)
• Transplantation (AREA)
• Otolaryngology (AREA)
• Cardiology (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
• Plural Heterocyclic Compounds (AREA)
• Pyridine Compounds (AREA)
• Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Priority Applications (11)

Applications Claiming Priority (6)

Publications (1)

Family

ID=50434228

Family Applications (2)

Family Applications After (1)

Country Status (14)

Cited By (10)

Families Citing this family (14)

Citations (2)

Family Cites Families (62)

• 2014
  • 2014-04-01 BR BR112015024678-8A patent/BR112015024678B1/pt not_active IP Right Cessation
  • 2014-04-01 DK DK14715106.2T patent/DK2981526T3/da active
  • 2014-04-01 MX MX2015013944A patent/MX363949B/es active IP Right Grant
  • 2014-04-01 EP EP14715106.2A patent/EP2981526B1/en active Active
  • 2014-04-01 JP JP2016505887A patent/JP6464384B2/ja not_active Expired - Fee Related
  • 2014-04-01 KR KR1020157031292A patent/KR102283883B1/ko not_active Expired - Fee Related
  • 2014-04-01 ES ES14716378T patent/ES2856902T3/es active Active
  • 2014-04-01 WO PCT/GB2014/051022 patent/WO2014162126A1/en not_active Ceased
  • 2014-04-01 WO PCT/GB2014/051018 patent/WO2014162122A1/en not_active Ceased
  • 2014-04-01 EA EA201591906A patent/EA030483B1/ru not_active IP Right Cessation
  • 2014-04-01 CN CN201480031577.7A patent/CN105408315B/zh not_active Expired - Fee Related
  • 2014-04-01 ES ES14715106T patent/ES2904277T3/es active Active
  • 2014-04-01 TW TW103112073A patent/TWI641592B/zh not_active IP Right Cessation
  • 2014-04-01 JP JP2016505888A patent/JP6495238B2/ja not_active Expired - Fee Related
  • 2014-04-01 AU AU2014246870A patent/AU2014246870C1/en not_active Ceased
  • 2014-04-01 KR KR1020217023664A patent/KR102340654B1/ko not_active Expired - Fee Related
  • 2014-04-01 KR KR1020157031287A patent/KR102283876B1/ko not_active Expired - Fee Related
  • 2014-04-01 CA CA2907663A patent/CA2907663A1/en not_active Abandoned
  • 2014-04-01 CN CN201480031484.4A patent/CN105246884B/zh not_active Expired - Fee Related
  • 2014-04-01 MX MX2015013945A patent/MX363950B/es active IP Right Grant
  • 2014-04-01 EP EP14716378.6A patent/EP2981535B8/en active Active
  • 2014-04-01 AU AU2014246866A patent/AU2014246866B2/en not_active Ceased
  • 2014-04-01 US US14/242,741 patent/US9481648B2/en not_active Expired - Fee Related
  • 2014-04-01 US US14/242,531 patent/US8927563B2/en active Active
  • 2014-04-01 DK DK14716378.6T patent/DK2981535T3/da active
  • 2014-04-01 EA EA201591907A patent/EA027782B1/ru not_active IP Right Cessation
  • 2014-04-01 BR BR112015024671A patent/BR112015024671A2/pt active Search and Examination
• 2015
  • 2015-02-19 US US14/626,548 patent/US20150166483A1/en not_active Abandoned
• 2016
  • 2016-09-09 US US15/261,174 patent/US9790174B2/en not_active Expired - Fee Related
• 2017
  • 2017-10-05 US US15/726,241 patent/US10435361B2/en active Active

Patent Citations (2)

Also Published As

Similar Documents

Legal Events