US20150376161A1 - Antiiflammatory and antitumor 2-oxothiazoles abd 2-oxothiophenes compounds - Google Patents

Antiiflammatory and antitumor 2-oxothiazoles abd 2-oxothiophenes compounds Download PDF

Info

Publication number
US20150376161A1
US20150376161A1 US14/764,509 US201414764509A US2015376161A1 US 20150376161 A1 US20150376161 A1 US 20150376161A1 US 201414764509 A US201414764509 A US 201414764509A US 2015376161 A1 US2015376161 A1 US 2015376161A1
Authority
US
United States
Prior art keywords
cancer
compound
alkyl
group
formula
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Abandoned
Application number
US14/764,509
Other languages
English (en)
Inventor
Berit Johansen
Marcel Sanderberg
Inger-Reidun Aukrust
George Kokotos
Efrosini Barbayianni
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Coegin Pharma AS
Original Assignee
Avexxin AS
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from GBGB1301585.4A external-priority patent/GB201301585D0/en
Priority claimed from GBGB1304250.2A external-priority patent/GB201304250D0/en
Priority claimed from GB201400579A external-priority patent/GB201400579D0/en
Application filed by Avexxin AS filed Critical Avexxin AS
Priority to US14/764,509 priority Critical patent/US20150376161A1/en
Assigned to AVEXXIN AS reassignment AVEXXIN AS ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: AUKRUST, Inger-Reidun, BARBAYIANNI, EFROSINI, KOKOTOS, GEORGE, SANDERBERG, MARCEL, JOHANSEN, BERIT
Publication of US20150376161A1 publication Critical patent/US20150376161A1/en
Abandoned legal-status Critical Current

Links

Images

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/26—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur 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
    • C07D333/38—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • 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
    • A61K31/38—Heterocyclic compounds having sulfur as a ring hetero atom
    • A61K31/381—Heterocyclic compounds having sulfur as a ring hetero atom having five-membered 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/426—1,3-Thiazoles
    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/428—Thiazoles condensed with carbocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • 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
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/08—Antiseborrheics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • 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
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/22—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C07D277/24—Radicals substituted by oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/22—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C07D277/26—Radicals substituted by sulfur atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three 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
    • C07D277/56—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/60—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings condensed with carbocyclic rings or ring systems
    • C07D277/62—Benzothiazoles
    • C07D277/64—Benzothiazoles with only hydrocarbon or substituted hydrocarbon radicals attached in position 2

Definitions

  • the invention relates to certain new 2-oxothiazole or 2-oxothiophene compounds and to pharmaceutical compositions comprising said compounds.
  • This invention also relates to the use of various 2-oxothiazole or 2-oxothiophene compounds for use in the prevention, treatment or alleviation of symptoms of chronic inflammatory disorders such as glomerulonephritis, rheumatoid arthritis and psoriasis as well as chronic inflammatory disorders associated with a diabetic condition in a patient, particularly diabetes mellitus, such as diabetic nephropathy and diabetic retinopathy.
  • this invention relates to the use of various 2-oxothiazole, 2-oxooxazole or 2-oxothiophene compounds for use in the prevention or treatment of hyperproliferative disorders such as cancer.
  • Mammalian cells contain a large number of phospholipases that hydrolyse phospholipids in a structurally specific manner for production of a myriad of products, many of which have potent biological activity. There has been considerable interest in characterising these enzymes because of their role in production of lipid mediators of inflammation. Since the first studies 20 years ago showing that mammalian cells contain a cystolic calcium dependent phospholipase A2 (cPLA2) specific for arachidonic acid, an extensive amount of evidence has substantiated a primary role for cPLA 2 as the key enzyme that mediates the release of arachidonic acid for the production of eicosanoids.
  • cPLA2 cystolic calcium dependent phospholipase A2
  • the enzyme cPLA 2 contributes to the pathogenesis of a variety of diseases particularly those in which inflammation plays a primary role implicating a role for inflammatory lipid mediators in disease pathogenesis.
  • the inhibition therefore of such lipase enzymes offers a potential therapy for inflammatory conditions in particular chronic inflammatory conditions such as those above, psoriasis and glomerulonephritis.
  • the phospholipase A2s are a group of enzymes that release unsaturated fatty acids from the sn2 position of membrane phospholipids. Once released, the fatty acids are converted by various enzymes into biologically very important signalling molecules. Release of arachidonate initiates the arachidonate cascade leading to the synthesis of eicosanoids such as prostaglandins.
  • Eicosanoids are important in a variety of physiological processes and play a central role in inflammation.
  • Inflammation Vol. 18, No. 1 1994, Andersen et al identify the presence of certain phospholipase A2s in psoriatic human skin.
  • Psoriasis is a common, chronic, inflammatory skin disorder.
  • Psoriatic tissue is characterised by chronic inflammation in both epidermis and dermis, the disease being further characterised by hyperplasia of epidermal keratinocytes, fibroblast activation, alteration of eicosanoid metabolism, and leukocyte infiltration.
  • Glomerulonephritis also known as glomerular nephritis, abbreviated GN, is a renal disease characterized by inflammation of the glomeruli, or small blood vessels in the kidneys. It may present with isolated hematuria and/or proteinuria or as a nephrotic syndrome, acute renal failure, or chronic renal failure. Glomerulonephritis is categorised into several different pathological patterns, which are broadly grouped into non-proliferative or proliferative types.
  • the glomerulus is a unique vascular network with three specialised types of cell: the endothelial cell, the mesangial cell and the visceral epithelial cell.
  • Mesangial cells serve a number of functions in the renal glomerular capillary including structural support of the capillary tuft, modulation of the glomerular hemodynamics and a phagocytic function allowing removal of macromolecules and immune complexes.
  • the proliferation of MC is a prominent feature of glomerular disease including IgA nephropathy, membranoproliferative glomerulonephritis, lupus nephritis, and diabetic nephropathy.
  • MC proliferation inhibitors may therefore offer therapeutic opportunities for the treatment of proliferative glomerular disease.
  • Mesangial proliferative glomerulonephritis is a form of glomerulonephritis which involves inflammation at the kidney glomeruli.
  • the mesangial cells which are a part of the glomerular capillaries, increase in size giving the glomeruli a lumpy appearance.
  • the disorder usually causes nephritic syndrome which represents protein loss in the urine. It may be present as acute, chronic or rapidly progressive glomerulonephritis and may progress to chronic renal failure.
  • the present inventors seek new treatments for, inter alia, chronic inflammatory conditions such as glomerulonephritis and associated conditions like diabetic nephropathy and retinopathy, psoriasis, dermatitis, rheumatoid arthritis and hyperproliferative disorders such as cancer.
  • chronic inflammatory conditions such as glomerulonephritis and associated conditions like diabetic nephropathy and retinopathy, psoriasis, dermatitis, rheumatoid arthritis and hyperproliferative disorders such as cancer.
  • the present inventors have surprisingly found that certain 2-oxo-thiazoles or 2-oxothiophenes are ideal cPLA 2 inhibitors and offer new therapeutic routes to the treatment of chronic inflammatory disorders.
  • 2-oxothiazole type structures are not new. In Bioorganic and Medicinal Chemistry 16 (2008) 1562-1595, there is a review of chemistry in this field. 2-oxo (benz)thiazoles carrying peptides or amino acids on the 2-position (i.e. where the t-oxo group forms part of the backbone of an amino acid) are known in the art as thrombin inhibitors.
  • hydrolase and transferase inhibitors in particular having a 2-oxo-oleyl side chain. Similar compounds as fatty acid amide hydrolase inhibitors are reported in J Med Chem Vol. 51, No. 237329-7343. Their potential as inhibitors of cPLA 2 is not discussed.
  • the present inventors have also found that the compounds of the present invention offer value in the prevention or treatment of hyperproliferative disorders (defined below) such as cancer.
  • hyperproliferative disorders defined below
  • the compounds of the invention in particular those of formula (I), have anti-hyperproliferative properties.
  • X is O, C ⁇ O or S
  • Y is N or CH
  • R 2 and R 4 are each independently H, —(CH 2 ) p COOH, —(CH 2 ) p CON(R 5 ) 2 or —(CH 2 ) p COOC 1-6 alkyl; or R 2 and R 4 together with the atoms linking them form a 6-membered phenyl ring fused to the five membered ring;
  • each R 1 is independently selected from H, halo (e.g. fluoro or chloro), C 6-10 aryl, C 7-12 arylalkyl, C 2-12 alkenyl; OC 1-12 alkyl, OC 2-12 alkenyl or a C 1-12 alkyl group;
  • halo e.g. fluoro or chloro
  • each R 5 is H or C 1-6 alkyl
  • each p is 0 to 3;
  • n 1 to 4.
  • X is O, C ⁇ O or S
  • Y is N or CH
  • R 2 and R 4 are each independently H, —(CH 2 ) p COOH, —(CH 2 ) p CON(R 5 ) 2 or —(CH 2 ) p COOC 1-6 alkyl; or R 2 and R 4 together with the atoms linking them form a 6-membered phenyl ring fused to the five membered ring;
  • R 1 and R 3 are each independently selected from H, halo (e.g. fluoro or chloro), C 6-10 aryl, C 7-12 arylalkyl, C 2-12 alkenyl; OC 1-12 alkyl, OC 2-12 alkenyl or a C 1-12 alkyl group;
  • halo e.g. fluoro or chloro
  • each R 5 is H or C 1-6 alkyl
  • each p is 0 to 3;
  • the invention provides a pharmaceutical composition comprising a compound of formula (I) as hereinbefore defined.
  • the invention provides a compound of formula (I) as hereinbefore defined for use in therapy.
  • the invention provides a compound of formula (I) for use in the treatment of a chronic inflammatory condition.
  • the invention provides a compound of formula (I) for use in the treatment of a hyperproliferative disorder.
  • the invention provides a method of treating a chronically inflammatory disorder comprising administering to a patient in need thereof an effective amount of a compound of formula (I) as hereinbefore defined.
  • the invention provides a method of treating a hyperproliferative disorder comprising administering to a patient in need thereof an effective amount of a compound of formula (I) as hereinbefore defined.
  • Z is O or S
  • W is N or CH
  • R 6 is H, C 1-6 alkyl, —(CH 2 ) p COOH, —(CH 2 ) p COOC 1-6 alkyl, —(CH 2 ) p CONH 2 , —(CH 2 ) p CONHC 1-6 alkyl, —(CH 2 ) p CON(C 1-6 alkyl) 2 ,
  • R 7 is as defined for R 6 ;
  • R 6 and R 7 taken together with the atoms joining them can form a 6-membered aromatic or non aromatic, saturated or unsaturated, carbocyclic or heteroatom containing (e.g. O, N or S containing) ring optionally substituted by up to 4 groups R 8 ;
  • each R 8 is defined as for R 6 or is oxo
  • R 10 is the same or different and is H, C 1-6 alkylCOOR a , halo (preferably fluoro), or CHal 3 (preferably CF 3 );
  • R a is H or C 1-6 alkyl
  • V 1 is O, S, C( ⁇ O), —NHCO—, —CONH—, C 1-10 alkylene group, or a C 2-10 -mono or multiply unsaturated alkenylene group, said alkylene or alkenylene group optionally interrupted by C ⁇ O and/or one or more heteroatoms selected from O, NH, N(C 1-6 alkyl), S, SO, or SO 2 ;
  • Ar is a C 6-14 aryl group, wherein the aryl group may be optionally substituted (preferably in the meta or para position relative to V 1 ) with one or more R 9 groups;
  • each R 9 is halo, OH, CN, nitro, NH 2 , NHC 1-6 alkyl, N(C 1-6 alkyl) 2 , haloC 1-6 alkyl, C 6-10 aryl group, C 7-12 arylalkyl, a C 1-10 alkyl group, C 2-10 -mono or multiply unsaturated alkenyl group, OC 1-10 alkyl group, or OC 2-10 -mono or multiply unsaturated alkenyl group;
  • each p is 0 to 3;
  • Z is O or S
  • W is N or CH
  • R 6 is H, C 1-6 alkyl, —(CH 2 ) p COOH, —(CH 2 ) p COOC 1-6 alkyl, —(CH 2 ) p CONH 2 , —(CH 2 ) p CONHC 1-6 alkyl, —(CH 2 ) p CON(C 1-6 alkyl) 2 ,
  • R 7 is as defined for R 6 ;
  • R 6 and R 7 taken together with the atoms joining them can form a 6-membered aromatic or non aromatic, saturated or unsaturated, carbocyclic or heteroatom containing (e.g. O, N or S containing) ring optionally substituted by up to 4 groups R 8 ;
  • each R 8 is defined as for R 6 or is oxo
  • R 10 is the same or different and is H, C 1-6 alkylCOOR a , halo (preferably fluoro), or CHal 3 (preferably CF 3 );
  • R a is H or C 1-6 alkyl
  • V 1 is O, S, C( ⁇ O), —NHCO—, —CONH—, C 1-10 alkylene group, or a C 2-10 -mono or multiply unsaturated alkenylene group, said alkylene or alkenylene group optionally interrupted by C ⁇ O and/or one or more heteroatoms selected from O, NH, N(C 1-6 alkyl), S, SO, or SO 2 ;
  • Q is C 1-20 alkyl or Ar wherein
  • Ar is a C 6-14 aryl group, wherein the aryl group may be optionally substituted (preferably in the meta or para position relative to V 1 ) with one or more R 9 groups;
  • each R 9 is halo, OH, CN, nitro, NH 2 , NHC 1-6 alkyl, N(C 1-6 alkyl) 2 , haloC 1-6 alkyl group, C 7-12 , C 6-10 aryl arylalkyl, a C 1-10 alkyl group, C 2-10 -mono or multiply unsaturated alkenyl group, OC 1-10 alkyl group, or OC 2-10 -mono or multiply unsaturated alkenyl group;
  • each p is 0 to 3;
  • the invention provides a method of treating a hyperproliferative disorder comprising administering to a patient an effective amount of a compound of formula (II) or (XX) as hereinbefore defined.
  • X is O, C ⁇ O or S
  • Y is N or CH
  • R 2 and R 4 are each independently H, —(CH 2 ) p COOH, —(CH 2 ) p CON(R 5 ) 2 or —(CH 2 ) p COOC 1-6 alkyl; or R 2 and R 4 together with the atoms linking them form a 6-membered phenyl ring fused to the five membered ring;
  • D is a C 1-20 alkyl group
  • each R 5 is H or C 1-6 alkyl
  • each p is 0 to 3;
  • FIG. 1 is a graph showing results from an animal tumor model in which tumor volumes are reduced in the presence of BEZ235 (Novartis Pharma) and Compound A.
  • FIG. 2 is a graph showing that cPLA2alpha inhibitor Compound A inhibits arthritis progression than methotrexate in a mouse model.
  • the cPLA2 ⁇ inhibitor Compound A inhibits arthritis progression more efficiently than Methotrexate in the prophylactic CIA study design. *p ⁇ 0.05, # p ⁇ 0.005 vs. vehicle at study termination.
  • FIG. 3 is a graph showing that Compound A reduces parameters of joint inflammation and joint damage more efficiently than methotrexate in a mouse CIA model.
  • Compound A reduces parameters of joint inflammation and joint damage more efficiently than MTX in a prophylactic CIA study design. Histopathology analysis was performed on hind paws from mice sacrificed at Day 32.
  • FIG. 4 is a graph showing that cPLA2alpha inhibitor Compound A reduces arthritic index comparable to Enbrel in a mouse CIA model.
  • the cPLA2 ⁇ inhibitor Compound A reduces the arthritic index in a manner comparable to Enbrel in a therapeutic CIA study *p ⁇ 0.05, **p0.01. vehicle, at study termination.
  • FIG. 5A-B are graphs showing that Compound A reduces disease-induced PGE2 accumulation, suggesting that the compound is hitting its cellular target the cPLA2 enzyme.
  • A) In the prophylactic CIA study (n 11), Compound A (7.5 mg/kg) significantly reduced plasma PGE 2 levels, comparable to the effect of metothrexate (MTX) (0.3 mg/kg).
  • B) In the therapeutic CIA study (n 10), Compound A (30 mg/kg) significantly reduced plasma PGE 2 levels in the therapeutic CIA mice, whereas Enbrel (25 mg/kg) show no reduction in PGE 2 levels.
  • FIG. 6 shows the therapeutic effect of AVX235 in the rat streptozocin-induced model of human chronic renal disease and compared against losartan (positive control).
  • alkyl includes both straight and branched chain alkyl radicals and may be methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, n-pentyl, i-pentyl, t-pentyl, neo-pentyl, n-hexyl or i-hexyl, t-hexyl.
  • alkenyl includes both straight and branched chain alkenyl radicals.
  • alkenyl refers to an alkenyl radicals one or more double bonds and may be, but is not limited to vinyl, allyl, propenyl, i-propenyl, butenyl, i-butenyl, crotyl, pentenyl, i-pentenyl and hexenyl.
  • aryl refers to an optionally substituted monocyclic or bicyclic hydrocarbon ring system containing at least one unsaturated aromatic ring. Examples and suitable values of the term “aryl” are phenyl, naphtyl, 1,2,3,4-tetrahydronaphthyl, indyl, indenyl and the like.
  • arylalkyl covers aryl groups substituted with alkyl groups.
  • the arylalkyl may bind to the carbon atom to which it is attached via the aryl ring or via a carbon of an alkyl substituent such as in benzyl.
  • said alkylene or alkenylene group can be optionally interrupted by C ⁇ O and/or one or more heteroatoms selected from O, NH, N(C 1-6 alkyl), S, SO, or SO 2 .
  • the CO and/or heteroatoms can be in the middle of an alkylene or alkenylene chain or can be present at the ends of the alkylene or alkenylene chain.
  • alkylene interrupted by O includes the linkers —OCH 2 —, —CH 2 O— and —CH 2 —O—CH 2 — and so on.
  • Halo refers to fluoro, chloro, bromo or iodo, especially chloro or fluoro.
  • the invention provides 2-oxothiazole and 2-oxothiophene compounds of formula (I)
  • X is O, C ⁇ O or S
  • Y is N or CH
  • R 2 and R 4 are each independently H, —(CH 2 ) p COOH, —(CH 2 ) p CON(R 5 ) 2 or —(CH 2 ) p COOC 1-6 alkyl; or R 2 and R 4 together form a 6-membered phenyl ring fused to the five membered ring
  • R 1 and R 3 are each independently selected from H, halo (e.g. fluoro or chloro), C 6-10 aryl, C 7-12 arylalkyl, C 2-12 alkenyl; OC 1-12 alkyl, OC 2-12 alkenyl or a C 1-12 alkyl group;
  • halo e.g. fluoro or chloro
  • each R 5 is H or C 1-6 alkyl
  • each p is 0 to 3;
  • n 1 to 4.
  • Y is N and the ring system is a thiazole system.
  • R 2 or R 4 is H. It is preferred if both R 2 or R 4 are not H.
  • R 2 or R 4 is H and the other is —COOCH 3 or —COOCH 2 CH 3 .
  • R 2 is preferably —COOCH 3 or —COOCH 2 CH 3 .
  • R 4 is H.
  • n is preferably 1 or 2. Moreover, it is preferred if the substituents are positioned on adjacent carbon atoms, ideally the meta and para positions on the ring.
  • Preferred options for R 1 are a C 4-10 alkyl group, especially a C 6-8 alkyl group such as a C 8 alkyl group, a C 4-10 alkenyl group, a OC 1-10 alkyl group, C 7-12 arylalkyl or a C 6-10 aryl group.
  • R 1 or R 3 alkyl groups are preferably linear.
  • R 1 and R 3 are preferably different.
  • both R 1 and R 3 are not H.
  • R 1 and R 3 are C 4-10 alkyl group, C 2-10 alkenyl group or —OC 4-10 alkyl group and the other is H, halo or OC 1-6 alkyl.
  • R 3 is preferably H, halo or OC 1-6 alkyl.
  • R 1 or R 3 is alkenyl, it preferably contains one double bond. Ideally that double bond is on the two carbons nearest the Ar group.
  • X is O, C ⁇ O or S
  • Y is N or CH
  • R 2 and R 4 are each independently H, —(CH 2 ) p COOH or —(CH 2 ) p COOC 1-6 alkyl; or R 2 and R 4 together, with the atoms linking them form a 6-membered phenyl ring fused to the five membered ring
  • n 2;
  • R 1 is H, Hal, or OC 1-6 alkyl
  • R 1 is H, C 6-10 aryl, C 7-12 arylalkyl, C 2-10 alkenyl; OC 4-10 alkyl or a C 4-10 alkyl group;
  • each p is 0 to 2;
  • the invention provides a compound of formula (X)
  • R 2 is COOH or COOC 1-6 alkyl
  • R 1 is a C 4-10 alkyl group, OC 4-10 alkyl, C 4-10 alkenyl, C 7-12 arylalkyl or C 6-10 -aryl group;
  • R 1′ is H, Hal, e.g. F, C 7-12 arylalkyl or C 6-10 -aryl group;
  • the invention provides a compound of formula (III)
  • R 2 is COOH or COOC 1-6 alkyl
  • R 1 is a C 4-10 alkyl group, or C 6-10 -aryl group
  • R 1′ is a C 6-10 -aryl group
  • R 1 is an alkyl, it is preferably linear.
  • R 2 is —COOCH 3 or —COOCH 2 CH 3 .
  • R 1 is a C 6-10 alkyl group, especially a C8 alkyl group.
  • R 1′ is Ph.
  • the compound of formula (I) is selected from the following compounds:
  • the invention extends to salts, esters, solvates, N-oxides or prodrugs of the compounds identified above
  • the compound of formula (I) is not
  • the invention relates to compounds of Formula (I) per se, pharmaceutical compositions comprising said compounds and the compounds for use in therapy and for use in the prevention and treatment of chronic inflammatory disorders and hyperproliferative disorders.
  • the compound is not of formula (V).
  • the invention provides a compound of formula (II) for use in the prevention or treatment of hyperproliferaitve disorders.
  • Compounds of formula (II) have the following structure:
  • Z is O or S
  • W is N or CH
  • R 6 is H, —(CH 2 ) p COOH, —(CH 2 ) p COOC 1-6 alkyl, —(CH 2 ) p CONH 2 , —(CH 2 ) p CONHC 1-6 alkyl, —(CH 2 ) p CON(C 1-6 alkyl) 2 ,
  • R 7 is as defined for R 6 ;
  • R 6 and R 7 taken together with the atoms joining them can form a 6-membered aromatic or non aromatic, saturated or unsaturated, carbocyclic or heteroatom containing (e.g. O, N or S containing) ring optionally substituted by up to 4 groups R 8 ;
  • each R 8 is defined as for R 6 or is oxo
  • R 10 is the same or different and is H, C 1-6 alkylCOOR a where R a is H or C 1-6 alkyl, halo (preferably fluoro), or CHal 3 (preferably CF 3 );
  • V 1 is O, S, C( ⁇ O), —NHCO—, —CONH—, C 1-10 alkylene group, or a C 2-10 -mono or multiply unsaturated alkenylene group, said alkylene or alkenylene group optionally containing C ⁇ O and/or one or more heteroatoms selected from O, NH, N(C 1-6 alkyl), S, SO, or SO 2 ;
  • Ar is a C 644 aryl group, wherein said aryl group may be optionally substituted (preferably in the meta or para position relative to V 1 ) with one or more R 9 groups;
  • each R 9 is halo, OH, CN, nitro, NH 2 , NHC 1-6 alkyl, N(C 1-6 alkyl) 2 , haloC 1-6 alkyl, C 6-10 aryl group, C 7-12 arylalkyl, a C 1-10 alkyl group, C 2-10 -mono or multiply unsaturated alkenyl group, OC 1-10 alkyl group, or OC 2-10 -mono or multiply unsaturated alkenyl group;
  • each p is 0 to 3;
  • Z is S.
  • thiazole or thiophene rings is therefore preferred.
  • W is N.
  • the use therefore of a thiazole ring is preferred.
  • R 10 is H. It is preferred if both R 10 groups are H. If not H, it is preferred that one R 10 is halo, e.g. F.
  • R 6 and R 7 are each independently H, —(CH 2 ) p COOH, or —(CH 2 ) p COOC 1-6 alkyl, where p is 0 to 3, such as 0-2. Most preferably, R 6 is H and R 7 is H, —COOCH 3 or —COOCH 2 CH 3 . It is preferred if p is 0.
  • R 6 or R 7 is H and the other is —COOCH 3 or —COOCH 2 CH 3 .
  • R 7 is preferably —COOCH 3 or —COOCH 2 CH 3 .
  • R 6 is preferably H.
  • R 6 and R 7 together form a ring, that is preferably a phenyl ring. Ideally such a ring is unsubstituted, i.e. R 8 is H.
  • V 1 is preferably O, S or CO or is a C 1-6 alkylene group (e.g. C 24 alkylene) optionally interrupted by one or more of C ⁇ O, 0 or NH, such as —O— or —CONH—.
  • the V 1 linker can therefore be an alkylene linker or an alkoxide type linker of formula —O(CH 2 ) q — where q is 1 to 6. It is preferred of the 0 atom binds to the Ar group.
  • V 1 is —O—.
  • the V 1 linker might contain an amide linkage —CONH—.
  • Ar is preferably a C 6-10 aryl group, especially a phenyl group or naphthyl group.
  • the Ar group can be unsubstituted. It is preferred, however, if the Ar group is substituted with at least one R 9 group. Ideally there are one or two R 9 groups present.
  • R 9 is preferably halo (e.g. Cl or F), —OC 1-10 alkyl group, C 6-10 aryl, C 7-12 arylalkyl, C 2-10 alkenyl group or a —C 1-10 alkyl group. It is particularly preferred if the C 2-10 alkyl group is a C 6-10 alkyl group, especially a C 8 alkyl group.
  • R 9 alkyl groups are preferably linear.
  • R 9 substituents are preferably meta or para to the V 1 linker. If two R 9 groups are present, they are preferably on adjacent carbon atoms.
  • W is N or CH
  • R 6 is H, —(CH 2 ) p COOH, or —(CH 2 ) p COOC 1-6 alkyl,
  • R 7 is as defined for R 6 ;
  • R 6 and R 7 taken together with the atoms joining them can form a 6-membered aromatic or non aromatic, saturated or unsaturated, carbocyclic or heteroatom containing (e.g. O, N or S containing) ring;
  • V 1 is O, S, C( ⁇ O), or C 1-10 alkylene group, said alkylene group being optionally interrupted by C ⁇ O and/or one or more heteroatoms selected from O or NH;
  • Ar is a C 6-14 aryl group, wherein aryl group may be optionally substituted (preferably in the meta or para position relative to V 1 ) with one or two R 9 groups;
  • each R 9 is halo, C 6-10 aryl group, C 7-12 arylalkyl, a C 1-10 alkyl group, C 2-10 -mono or multiply unsaturated alkenyl group, OC 1-10 alkyl group, or OC 2-10 -mono or multiply unsaturated alkenyl group;
  • each p is 0 to 3;
  • compounds of formula (II) are not of formula (V) as hereinbefore defined.
  • Preferred compounds of formula (II) are those of formula (III), (IV), (IX), (X) and (XI).
  • Q is preferably C3-15 alkyl, such as C8-12 alkyl.
  • Q is preferably linear alkyl.
  • the other variables are preferably as defined for compounds of formula (II) defined above.
  • D is preferably C1-15 alkyl, such as C8-12 alkyl.
  • -D is preferably linear alkyl.
  • Other variables are as for compounds of formula (I) defined above. Particularly interesting compounds are therefore:
  • the manufacture of the compounds of the invention typically involves known literature reactions.
  • the formation of an 2-oxothiazole the precursor to many of the claimed compounds, can be achieved by reaction of an aldehyde XCOH with thiazole in the presence of a base and subsequent oxidation of the hydroxyl to a ketone.
  • the X group is obviously selected to form the desired M 1 V 1 group or a precursor thereof.
  • the formed compound can react with thiazole as described above.
  • the compounds of formula (I) of the invention may be used in the prevention or treatment of chronic inflammatory disorders, in particular those associated with phospholipase inhibition.
  • any compound of formula (I) of the invention will achieve at least 75%, such as at least 90% inhibition against group IVa PLA 2 .
  • compounds of formula (I) of the invention inhibit group IVa cPLA 2 at a low ⁇ M range such as 5 ⁇ M or less, preferably 4 ⁇ M or less.
  • the compounds of formula (I) of the invention show greater inhibition of group IVa cPLA 2 than iPLA 2 or sPLA 2 according to published assays for these enzymes (see, for example, Yang, H et al. (1999) Anal. Biochem. 269: 278).
  • the compounds of formula (I) of the invention show limited or no inhibition of iPLA 2 or sPLA 2 and they are therefore highly specific for the group IVa cPLA 2 enzyme.
  • Specific diseases of interest are glomerulonephritis, inflammatory dermatoses such as psoriasis and rheumatoid arthritis.
  • inflammatory dermatoses such as atopic dermatitis, allergic contact dermatitis, seborrheic dermatitis, pityriasis rosea, lichen planus and drug eruptions.
  • the compounds of formula (I) of the invention may have use in the treatment of other types of arthritis and dermatoses, inflammatory CNS diseases, multiple sclerosis, chronic obstructive pulmonary disease, chronic lung inflammatory conditions, inflammatory bowel disease such as ulcerative colitis and crohns disease, and cardiovascular disease. Furthermore, the compound of formula (I) of the invention may have use in the treatment of juvenile arthritis, Crohn's colitis, psoriatic arthritis and ankylosing spondylitis.
  • the invention provides for the management (typically an alleviation of symptoms), prevention or treatment of any of the conditions listed above using the compounds of formula (I) of the invention.
  • the prevention, treatment, or alleviation of symptoms of a chronic inflammatory condition such as those mentioned above can be achieved by administering at least one compound according to formula (I) (e.g., one, two or three of such compounds) to a subject as the sole active agent.
  • the chronic inflammatory condition can be prevented, treated or symptoms alleviated along with at least one suitable anti-inflammatory drug (e.g., one, two or three of such drugs).
  • Non-limiting examples of such drugs include certain steroids (e.g., corticosteroids), non-steroidal anti-inflammatory drugs (NSAIDs) such as aspirin, ibuprofen and naproxen, and analgesics such as paracetamol, acetaminophen and the like; as well as ImSAIDs.
  • steroids e.g., corticosteroids
  • NSAIDs non-steroidal anti-inflammatory drugs
  • analgesics such as paracetamol, acetaminophen and the like
  • ImSAIDs ImSAIDs.
  • the subject may be receiving or will receive a disease modifying antirheumatic drug (known as DMARD) such as methotrexate, leflunomide, hydroxychloroquine, sulfasalazine, and the like.
  • DMARD disease modifying antirheumatic drug
  • the DMARD can be administered along with at least one compound of formula (I) such as one, two or three of such compounds.
  • the subject can receive in addition to the DMARD a suitable biologic such as those mentioned below along with at least one compound of formula (I) such as one, two or three of such compounds.
  • NSAID nonsteroidal anti-inflammatory
  • corticosteroid i.e., prednisone
  • the method includes administering a compound having Formula I to a subject (e.g., using an oral, i.v, i.p or other route) followed by administration of an anti-inflammatory drug as described herein.
  • a suitable biologic e.g. an antibody therapeutic as provided herein
  • the method can be practiced by administering the anti-inflammatory drug first followed by administration of the compound having the Formula I. Choice of a particular methodology and administration route will be guided by understood parameters such as the chronic inflammatory disorder to be treated, age and sex of the subject, etc.
  • the invention provides compounds of formula (I) or (II) for use in the management, treatment or prevention of any condition or clinical situation where it is desirable (or where it may be of benefit) to prevent or inhibit the growth of cells.
  • Examples include tumors, cancers, neoplastic tissues, and other premaligant and noneoplastic hyperproliferative disorders, all of which together are referred to herein as hyperproliferative or hyperplastic disorders.
  • inhibitor is used broadly to include any reduction or decrease in cell growth as well as the prevention or abolition of cell growth “Inhibition” thus includes the reduction or prevention of cell growth. This may be determined by any appropriate or convenient means, such as determining or assessing cell number, size (e.g size of tissue in which the cells are contained), cell viability and/or cell death etc., as may be determined by techniques well known in the art.
  • “Growth” of cells as referred to herein is also used broadly to include any aspect of cell growth, including in particular the proliferation of cells.
  • the compounds of formula (I) or (II) may thus be used in the treatment of any condition (used broadly herein to include any disorder or any clinical situation) which is responsive to reduction of cell growth (particularly cell proliferation).
  • the compounds accordingly find utility in any therapy (or treatment) which targets cell growth (or proliferation).
  • the compounds may be used in any therapeutic application in which it desirable or advantageous to inhibit cell proliferation.
  • a treatment may include any clinical step or intervention which contributes to, or is a part of, a treatment programme or regimen.
  • a prophylactic treatment may include delaying, limiting, reducing or preventing the condition or the onset of the condition, or one or more symptoms thereof, for example relative to the condition or symptom prior to the prophylactic treatment.
  • Prophylaxis thus explicitly includes both absolute prevention of occurrence or development of the condition, or symptom thereof, and any delay in the onset or development of the condition or symptom, or reduction or limitation on the development or progression of the condition or symptom.
  • Treatment according to the invention thus includes killing, inhibiting or slowing the growth of cells, or the increase in size of a body or population of cells (e.g in a tissue, tumour or growth), reducing cell number or preventing spread of cells (e.g to another anatomic site), reducing the size of a cell growth etc.
  • treatment does not imply cure or complete abolition or elimination of cell growth, or a growth of cells.
  • proliferating cells may include healthy or diseased cells and cells of any tissue in which proliferation occurs.
  • proliferating cells may include in particular neoplastic cells, including both malignant and non-malignant neoplastic cells and cells of the immune system (immune cells), cells of the haematopoietic system generally, or skin cells.
  • the compounds of formula (I) or (II) can be employed to treat one or a combination of hyperproliferative disorders as the sole active agent or in combination with one or more other agents.
  • disorders or conditions involving abnormal or unwanted cell growth may be treated with known agents including known cytotoxic and/or cytostatic agents including chemotherapeutic agents.
  • the compounds of formula (I) or (II) may be used in any method of treatment which involves (or includes) the use of such cytotoxic and/or cytostatic agents. This may include the treatment of any condition responsive to a cytotoxic and/or cytostatic agent or any condition which may be treated with or which requires the use of such agent(s).
  • hyperproliferative disorder is used broadly herein to include any disorder or condition which involves increased, undesired or unwanted proliferation of cells.
  • proliferation of cells is increased, for example relative to normal or healthy cells, or cells in the absence of the condition in question (e.g. compared or relative to a healthy or control subject, or compared or relative to cells taken from healthy or unaffected tissue in the same subject), but also conditions in which cell proliferation is not increased (or not greatly or significantly increased) over normal, but in which the proliferation which occurs is unwanted or undesired, whether generally or in a particular context. This may include for example an unwanted or undesired proliferation of cells which may occur in a “normal” response.
  • a hyperproliferative disorder of particular interest involves the proliferation of cells which have the capacity for autonomous growth i.e. cells which exist and reproduce independently of normal regulatory mechanisms.
  • a hyperproliferative disorder may therefore be a neoplastic disorder, and as noted above, this may be a pre-malignant, malignant, non-malignant or non-neoplastic disorder.
  • pre-malignant or non-neoplastic or non-malignant hyperproliferative disorders include myelodysplastic disorders, cervical carcinoma-in-situ, familial intestinal polyposes (e.g.
  • Gardner syndrome oral leukoplasias, histiocytoses, keloids, hemangiomas, hyperproliferative arterial stenosis, inflammatory arthritis, hyperkeratoses, and papulosquamous eruptions, including arthritis.
  • viral-induced hyperproliferative diseases such as warts and EBV-induced disease (e.g. infectious mononucleosis), scar formation and the like.
  • the hyperproliferative disorder may thus be any hyperproliferative disorder, for example selected from neoplastic disorders such as cancer (benign or metastatic). Cancer represents a hyperproliferative disorder of particular interest, and all types of cancers, including e.g. solid tumours and haematological cancers are included.
  • neoplastic disorders such as cancer (benign or metastatic).
  • Cancer represents a hyperproliferative disorder of particular interest, and all types of cancers, including e.g. solid tumours and haematological cancers are included.
  • cancer examples include cervical cancer, uterine cancer, ovarian cancer, pancreatic cancer, kidney cancer, gallbladder cancer, liver cancer, head and neck cancer, squamous cell carcinoma, gastrointestinal cancer, breast cancer, prostate cancer, testicular cancer, lung cancer, non-small cell lung cancer, non-Hodgkin's lymphoma, multiple myeloma, leukemia (such as acute lymphocytic leukemia, chronic lymphocytic leukemia, acute myelogenous leukemia, and chronic myelogenous leukemia), brain cancer (e.g.
  • leukemia such as acute lymphocytic leukemia, chronic lymphocytic leukemia, acute myelogenous leukemia, and chronic myelogenous leukemia
  • brain cancer e.g.
  • astrocytoma glioblastoma, medulloblastoma
  • neuroblastoma sarcomas
  • colon cancer rectum cancer
  • stomach cancer anal cancer
  • bladder cancer pancreatic cancer
  • endometrial cancer plasmacytoma, lymphomas, retinoblastoma, Wilm's tumor, Ewing sarcoma, melanoma and other skin cancers.
  • the invention also features methods of treating a subject (e.g. a human that has or is suspected of having cancer) in which the method includes treating the subject with at least one compound having Formula I or II, preferably one, two or three of such compounds alone or along with an effective amount of one or more agents having cytotoxic or cytostatic activity such as a chemotherapeutic agent (e.g., one, two or three of such agents).
  • a subject e.g. a human that has or is suspected of having cancer
  • the method includes treating the subject with at least one compound having Formula I or II, preferably one, two or three of such compounds alone or along with an effective amount of one or more agents having cytotoxic or cytostatic activity such as a chemotherapeutic agent (e.g., one, two or three of such agents).
  • Illustrative chemotherapeutic agents are “small molecules” selected from the group consisting of abiraterone acetate, altretamine, anhydrovinblastine, auristatin, bexarotene, bicalutamide, BMS184476, 2,3,4,5,6-pentafluoro-N-(3-fluoro-4-methoxyphenyl)benzene sulfonamide, bleomycin, N,N-dimethyl-L-valyl-L-valyl-N-methyl-L-valyl-L-prolyl-Lproline-t-butylamide, cachectin, cemadotin, chlorambucil, cyclophosphamide, 3′,4′-didehydro-4′-deoxy-8′-norvin-caleukoblastine, docetaxol, doxetaxel, cyclophosphamide, carboplatin, carmustine (BCNU), cis
  • chemotherapeutic agents for use with the invention include biologics such as immune molecules that exhibit a cytotoxic or cytostatic activity against a targeted cell or tissue. More specific examples include antibodies and antigen-binding fragments thereof, namely monoclonal, polyclonal, chimeric and humanized antibodies.
  • Non-limiting examples include the following therapeutic antibodies that have been approved for human use for several medical indications: Abciximab (ReoPro), Adalimumab (Humira), Alemtuzumab (Campath), Basiliximab (Simulect), Belimumab (Benlysta), Bevacizumab (Avastin), Brentuximab vedotin (Adcetris), Canakinumab (Ilaris) Cetuximab (Erbitux), Certolizumab pegol[19] (Cimzia), Daclizumab (Zenapax), Denosumab (Prolia, Xgeva), Eculizumab (Soliris), Efalizumab (Raptiva), Gemtuzumab (Mylotarg), Golimumab (Simponi), Ibritumomab tiuxetan (Zevalin), Infliximab (Remicade), Ipilim
  • Suitable biologics for use with the invention are certain antibody-small molecule conjugates such as TDM1 (conjugate of trastuzumab and doxorubicin).
  • the chemotherapeutic drug may be selected from the following: Abitrexate (Methotrexate), Abraxane (Paclitaxel Albumin-stabilized Nanoparticle Formulation)Ado-Trastuzumab Emtansine, Adriamycin PFS (Doxorubicin Hydrochloride), Adriamycin RDF (Doxorubicin Hydrochloride), Adrucil (Fluorouracil), Afinitor (Everolimus), Anastrozole, Arimidex (Anastrozole), Aromasin (Exemestane), Capecitabine, Clafen (Cyclophosphamide), Cyclophosphamide, Cytoxan (Cyclophosphamide), Docetaxel, Doxorubicin Hydrochloride, Efudex (Fluorouracil), Ellence (Epirubicin Hydrochloride), Epirubicin Hydrochloride
  • the invention features methods of treating a subject (e.g. a human) having or suspected of having a hyperproliferative disorder such as cancer, involving administering to the subject an effective amount of a compound according to Formula I or II either as a sole agent or along with an effective amount of one or more chemotherapeutic agents described above (e.g., one, two or three of such agents).
  • An illustrative treatment regimen involves treating, preventing or minimizing tumor progression or metastasis in a subject having a neoplasia, where the neoplastic cell is a cancer cell or is present in a tumor.
  • the invention features a method of treating, preventing or minimizing tumor progression or metastasis in a subject where the tumor is breast cancer, melanoma, glioblastomas, colon cancer, non-small cell lung cancer, or lymphomas, involving administering to the subject an effective amount of at least one compound according to Formula I or II (e.g., one, two or three of such compounds) alone or along with one or more other chemotherapeutic agents as described herein (e.g, one or two of such agents).
  • chemotherapeutic agents as described herein
  • the invention relates to a method for preventing or treating breast cancer in a patient, the method comprising the steps of administering to the patient an effective amount of at least one chemotherapeutic agent; and administering an effective amount of at least one compound of formula (I) or formula (II).
  • a chemotherapeutic agent is administered to the patient before the administration of the compound (I) or (II), such as one or more of paclitaxel, doxorubicin, cyclophosphamide and cisplatin.
  • the method may also comprise the administration of one or more of trastuzumab (Herceptin), trastuzumab-doxorubicin conjugate (TDM1) and pertuzumab (Perj eta).
  • trastuzumab Herceptin
  • trastuzumab-doxorubicin conjugate TDM1
  • pertuzumab Perj eta
  • the method includes administering a compound having Formula I or II to a subject (e.g., using an oral, i.v, i.p or other route) followed by administration of at least one chemotherapeutic agent as described herein (e.g., one, two or three of such agents).
  • a chemotherapeutic agent as described herein (e.g., one, two or three of such agents).
  • the method can be practiced by administering the chemotherapeutic agent first followed by administration of the compound having the Formula I or II. Choice of a particular methodology and administration route will be guided by understood parameters such as the hyperproliferative disorder to be treated, age and sex of the subject, etc.
  • the method of the invention may also comprise the treatment of chronic inflammatory disorders associated a diabetic condition in a patient, particularly diabetes mellitus, such as diabetic nephropathy and diabetic retinopathy.
  • Subjects to be treated by the methods of the present invention include both human subjects (patients) and animal subjects for veterinary purposes
  • Animal subjects are generally mammalian subjects such as horses, dogs, cats, cows, rabbits, sheep and the like.
  • Suitable compounds for use with the present methods for treating, preventing or alleviating symptoms a hyperproliferative disorder can be selected by one or a combination of different strategies which are intended to detect and preferably quantify changes in cell proliferation when contacted by one or more invention compounds.
  • Non-limiting examples of such screens are provided below:
  • a compound of formula (I) or (II) is tested for efficacy in the NCI60 human humor cell line anticancer drug screen reported by Shoemaker, R. H (2006) Nat. Reviews Cancer 6, 813.
  • the NCI60 screen is a two-stage process, beginning with the evaluation of all compounds against 60 cell lines at a single dose of 10 ⁇ M.
  • Preferred compounds of formula (I) or (II) of the invention have a GI50 of about 1-5 ⁇ M in the NCI60 screen, more preferably about 0.01-0.1 ⁇ M or less with respect to at least one of the cell lines in the NCI60 screen.
  • cPLA2-alpha in another approach the expression of cPLA2-alpha can be determined in prostate cancer cells by reverse transcription-PCR, Western blot, and immunocytochemistry. Growth inhibition, apoptosis, and cPLA2-alpha activity can be determined after inhibition with cPLA2-alpha small interfering RNA or inhibitor (Wyeth-1). Cytosolic PLA2-alpha inhibitor or vehicle can also be administered to prostate cancer xenograft mouse models. Finally, the expression of phosphorylated cPLA2-alpha can be determined by immunohistochemistry in human normal, androgen-sensitive and androgen-insensitive prostate cancer specimens.
  • the compounds of formula (I) or (II) of the invention are preferably formulated as pharmaceutically acceptable compositions.
  • pharmaceutically acceptable refers to molecular entities and other ingredients of such compositions that are physiologically tolerable and do not typically produce untoward reactions when administered to a mammal (e.g. human).
  • pharmaceutically acceptable means approved by a regulatory agency of the Federal or a state government or listed in the U.S. Pharmacopoeia or other generally recognized pharmacopoeia for use in mammals, and more particularly in humans.
  • carrier applied to pharmaceutical compositions of the invention refers to a diluent, excipient, or vehicle with which an active compound is administered.
  • Such pharmaceutical carriers can be sterile liquids, such as water, saline solutions, aqueous dextrose solutions, aqueous glycerol solutions, and oils, including those of petroleum, animal, vegetable or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil and the like.
  • Suitable pharmaceutical carriers are described in “Remington's Pharmaceutical Sciences” by E. W. Martin, 18th Edition, incorporated by reference.
  • Particularly preferred for the present invention are carriers suitable for immediate-release, i.e., release of most or all of the active ingredient over a short period of time, such as 60 minutes or less, and make rapid absorption of the drug possible.
  • the compounds of formula (I) or (II) can be administered in salt, solvate, prodrug or ester form, especially salt form.
  • a pharmaceutical acceptable salt may be readily prepared by using a desired acid.
  • the salt may precipitate from solution and be collected by filtration or may be recovered by evaporation of the solvent.
  • an aqueous solution of an acid such as hydrochloric acid may be added to an aqueous suspension of a compound of formula (I) or (II) and the resulting mixture evaporated to dryness (lyophilised) to obtain the acid addition salt as a solid.
  • a compound of formula (I) or (II) may be dissolved in a suitable solvent, for example an alcohol such as isopropanol, and the acid may be added in the same solvent or another suitable solvent.
  • a suitable solvent for example an alcohol such as isopropanol
  • the resulting acid addition salt may then be precipitated directly, or by addition of a less polar solvent such as diisopropyl ether or hexane, and isolated by filtration.
  • Suitable addition salts are formed from inorganic or organic acids which form non-toxic salts and examples are hydrochloride, hydrobromide, hydroiodide, sulphate, bisulphate, nitrate, phosphate, hydrogen phosphate, acetate, trifluoroacetate, maleate, malate, fumarate, lactate, tartrate, citrate, formate, gluconate, succinate, pyruvate, oxalate, oxaloacetate, trifluoroacetate, saccharate, benzoate, alkyl or aryl sulphonates (eg methanesulphonate, ethanesulphonate, benzenesulphonate or p-toluenesulphonate) and isethionate.
  • Representative examples include trifluoroacetate and formate salts, for example the bis or tris trifluoroacetate salts and the mono or diformate salts, in particular the tris or bis trifluoroa
  • prodrug as used herein means a compound which is converted within the body, e.g. by hydrolysis in the blood, into its active form that has medical effects.
  • the compounds of formula (I) of the invention are proposed for use in the treatment of, inter alia, chronic inflammatory disorders and cancer.
  • the compounds of formula (II) of the invention are proposed for use in the treatment of, inter alia, cancer.
  • treating or treatment is meant at least one of:
  • the benefit to a subject to be treated is either statistically significant or at least perceptible to the patient or to the physician. In general a skilled man can appreciate when “treatment” occurs.
  • treatment is also used herein to cover prophylactic treatment, i.e. treating subjects who are at risk of developing a disease in question.
  • the compounds can be used on any animal subject, in particular a mammal and more particularly to a human or an animal serving as a model for a disease (e.g. mouse, monkey, etc.).
  • a mammal in particular a mammal and more particularly to a human or an animal serving as a model for a disease (e.g. mouse, monkey, etc.).
  • an “effective amount” means the amount of a compound that, when administered to an animal for treating a state, disorder or condition, is sufficient to effect such treatment.
  • the “effective amount” will vary depending on the compound, the disease and its severity and the age, weight, physical condition and responsiveness of the subject to be treated and will be ultimately at the discretion of the attendant doctor.
  • a compound of formula (I) or (II) may be administered as the bulk substance, it is preferable to present the active ingredient in a pharmaceutical formulation, for example, wherein the agent is in admixture with a pharmaceutically acceptable carrier selected with regard to the intended route of administration and standard pharmaceutical practice.
  • carrier refers to a diluent, excipient, and/or vehicle with which an active compound is administered.
  • the pharmaceutical compositions of the invention may contain combinations of more than one carrier.
  • Such pharmaceutical carriers can be sterile liquids, such as water, saline solutions, aqueous dextrose solutions, aqueous glycerol solutions, and oils, including those of petroleum, animal, vegetable or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil and the like.
  • Water or aqueous solution saline solutions and aqueous dextrose and glycerol solutions are preferably employed as carriers, particularly for injectable solutions. Suitable pharmaceutical carriers are described in “Remington's Pharmaceutical Sciences” by E. W.
  • compositions may comprise as, in addition to, the carrier any suitable binder(s), lubricant(s), suspending agent(s), coating agent(s), and/or solubilizing agent(s).
  • compositions for use in accordance with the present invention may be in the form of oral, parenteral, transdermal, inhalation, sublingual, topical, implant, nasal, or enterally administered (or other mucosally administered) suspensions, capsules or tablets, which may be formulated in conventional manner using one or more pharmaceutically acceptable carriers or excipients.
  • composition/formulation requirements may be different depending on the different delivery systems.
  • the composition comprises more than one active component, then those components may be administered by the same or different routes.
  • the pharmaceutical formulations of the present invention can be liquids that are suitable for oral, mucosal and/or parenteral administration, for example, drops, syrups, solutions, injectable solutions that are ready for use or are prepared by the dilution of a freeze-dried product but are preferably solid or semisolid as tablets, capsules, granules, powders, pellets, pessaries, suppositories, creams, salves, gels, ointments; or solutions, suspensions, emulsions, or other forms suitable for administration by the transdermal route or by inhalation.
  • the compounds of the invention can be administered for immediate-, delayed-, modified-, sustained-, pulsed- or controlled-release applications.
  • oral compositions are slow, delayed or positioned release (e.g., enteric especially colonic release) tablets or capsules.
  • This release profile can be achieved without limitation by use of a coating resistant to conditions within the stomach but releasing the contents in the colon or other portion of the GI tract wherein a lesion or inflammation site has been identified or a delayed release can be achieved by a coating that is simply slow to disintegrate or the two (delayed and positioned release) profiles can be combined in a single formulation by choice of one or more appropriate coatings and other excipients.
  • Such formulations constitute a further feature of the present invention.
  • compositions can be prepared by mixing a therapeutically effective amount of the active substance with a pharmaceutically acceptable carrier that can have different forms, depending on the way of administration.
  • composition components include one or more of binders, fillers, lubricants, odorants, dyes, sweeteners, surfactants, preservatives, stabilizers and antioxidants.
  • compositions of the invention may contain from 0.01 to 99% weight—per volume of the active material.
  • the therapeutic doses will generally be between about 10 and 2000 mg/day and preferably between about 30 and 1500 mg/day. Other ranges may be used, including, for example, 50-500 mg/day, 50-300 mg/day, 100-200 mg/day.
  • Administration may be once a day, twice a day, or more often, and may be decreased during a maintenance phase of the disease or disorder, e.g. once every second or third day instead of every day or twice a day.
  • the dose and the administration frequency will depend on the clinical signs, which confirm maintenance of the remission phase, with the reduction or absence of at least one or more preferably more than one clinical signs of the acute phase known to the person skilled in the art.
  • a compound as described herein may be administered in combination with another pharmaceutical, e.g. another drug with known efficacy against the disease in question.
  • another pharmaceutical e.g. another drug with known efficacy against the disease in question.
  • the compounds of formula (I) or (II) of the invention may therefore be used in combination therapy.
  • FIG. 1 describes Tumor volume in mice treated with Compound A.
  • Scheme 4 is applicable for compounds both of type 1 and 2, and comprises mainly standard reactions.
  • Wittig coupling with an alkylphosphonium salt of suitable length provides compounds 4.
  • By protecting the phenol as benzyl ether reduction of the double bond and deprotection can be obtained simultaneously, giving substituted octylphenols (5). If another protecting group is selected, the double bond in 4 might be possible to preserve in the final product, providing another opportunity for variation.
  • 4-Octylphenyl bromide (20) and thiol 21 are both commercially available.
  • the Pd-catalyzed conversion to the PMB-protected thiol 22 is described in the literature for unsubstituted benzene rings (Itoh and Mase, Org. Lett. 6 (2004) 4587), and should work here as well.
  • Deprotection of 22 with trifluoroacetic acid gives 23, which can be reacted with intermediate 9 (synthesis described in previously).
  • Other thioethers should also be available from a similar route; e.g. by using the two thiophenes 11 and 12 (structures given above), and by employing other phenyl bromides than 20.
  • Synthesis of the dicarbonyl compound 24 is shown in Scheme 9.
  • mice received 30 mg Compound A/kg bw by ip. injection daily for a 7 days, then every second day for 14 more days.
  • a group of control mice received DMSO only. Tumor volumes were measured throughout the study period.
  • the tumor volume in mice treated with Compound A was 36% of the control tumors, which is comparable with the inhibitory effect of the dual PI3K/mTOR inhibitor BEZ235 in the same model.
  • Mouse model MAS98.12. This model is established from a primary breast carcinoma at the Institute for Cancer Research, OUS [10].
  • the MR Cancer Group has previously characterised this model both with respect to metabolic profile, vascularisation, response to antiangiogenic treatment and response to PI3K inhibition[9,11-13].
  • mice received 30 mg/kg bw COMPOUND A in 50 ⁇ l DMSO, through intraperitoneal injection.
  • Control groups received volume-matched, drug-free DMSO injections. Tumor volume measured with electronic callipers from day ⁇ 3 until the end of the experiment (Day 19).
  • Serum approx 200 ⁇ l serum was collected from each mouse
  • Tumor tissue All tumors were harvested. Large tumors were divided in 2 specimens, and stored in 4% NBF or snap frozen in liquid nitrogen. Small tumors were only snap frozen.
  • Spleen The spleen of mice in the long-term treatment arm was collected and stored in 4% NBF.
  • mice Prior to the experiment, the mice were housed in a transit/quarantine unit as the health monitoring paperwork needed to be examined. The body weights could therefore not be recorded until day 5 after initiation of treatment.
  • the body weight In the control group, the body weight increased from 23 ⁇ 2 g (Day 5) to 27 ⁇ 2 g (Day 19).
  • the body weight In the COMPOUND A-treated group, the body weight increased from 24 ⁇ 3 g (Day 5) to 27 ⁇ 3 g (Day 19). This indicates that the COMPOUND A regimen was well tolerated.
  • the tumor volume in the control group was 103 ⁇ 65 mm 3 .
  • the tumor volume was 67 ⁇ 31 mm 3 .
  • the difference was not statistically significant.
  • the tumor volume in the control group was 759 ⁇ 401 mm 3
  • the tumor volume in the COMPOUND A-treated group was 265 ⁇ 138 mm 3 .
  • 2 mice were sacrificed at Day 12, due to tumor diameter >15 mm.
  • 2 more mice had reached this limit, forcing the decision to terminate the study.
  • 5 of 7 remaining tumors in the control group had a diameter ⁇ 11 mm, whereas the maximal tumors diameter in the COMPOUND A group was 10.5 mm.
  • FIG. 1 the tumor volumes (normalised to the volume at initiation of treatment) are plotted together with data from a study in the same animal model, using the PI3K inhibitor BEZ235 [13].
  • This drug Novartis Pharma
  • This drug is currently in clinical phase I/II trials in advanced cancers.
  • the figure demonstrates the inhibitory effect of COMPOUND A on tumor growth.
  • the control group in this pilot study had a growth rate similar to what we have seen in previous studies.
  • the data in FIG. 1 show, among other things, that Compound A had a strong inhibitory effect on tumor growth in the patient-derived cancer xenograft MAS98.12.
  • the compound was well tolerated with no overt adverse effects seen during the study. Tumor growth was significantly inhibited by Compound A.
  • the growth rate of the control groups was similar to that of the PI3K inhibitor BEZ235 up to Day 12, when 2 mice were sacrificed (the remaining mice having smaller tumors).
  • the inhibitory effect of Compound A was similar to BEZ235.
  • GIVA cPLA 2 consists of an N-terminal C2 domain and a C-terminal catalytic domain and utilizes an unusual catalytic dyad (Ser-228/Asp-549) located in the ⁇ / ⁇ hydrolase domain to catalyze the hydrolysis of the substrates. 36 Without wishing to be bound to any theory, it is proposed that the activated ketone interacts with the catalytic serine. Although these two functionalities markedly differ in the potency of their activated carbonyl group, derivatives containing either the oxoamide or the fluoroketone functionality are efficient inhibitors of GIVA cPLA 2 .
  • thiazole derivatives 32a,b and 37a-c The synthesis of thiazole derivatives 32a,b and 37a-c is presented in Schemes 10 and 11. Phenols 28a,b and 33a,b were treated with ethyl bromoacetate. Esters 29a,b were hydrolyzed and converted to their corresponding Weinreb amides. Treatment of 31a,b with lithium thiazole led to the target derivatives 32a,b. Oxothiazoles 37a-c were prepared by another procedure. Alcohols 35a,b were oxidized to aldehydes and treated with lithium thiazole or benzothiazole. Compounds 36a-c were then oxidized to the final compounds.
  • Substituted thiazoles 43a-c and 47 were synthesized as illustrated in Schemes 12 and 13. The key-step in this synthesis was the formation of the substituted heterocyclic ring. Alcohols 35b and 38 were oxidized to aldehydes and directly treated with TBDMSCN. Compounds 39a,b were converted into amides and subsequently into thioamides by reaction with Lawesson's reagent. Treatment of 41a,b with ethyl 4-chloroacetoacetate or ethyl bromopyruvate in the presence of conc. H 2 SO 4 led to heterocyclic derivatives 42a-c which were then oxidized to the final compounds 43a-c.
  • Lawesson's reagent (0.6 mmol, 243 mg) was added to a solution of amides 40a,b (1 mmol) in dry toluene (10 mL) under argon atmosphere. The reaction mixture was stirred at room temperature overnight. The solvent was evaporated under reduced pressure and the residue was purified by flash chromatography eluting with the appropriate mixture of EtOAc/petroleum ether (bp 40-60° C.).
  • the in vitro inhibition of human GIVA cPLA 2 , GVIA iPLA 2 and GV sPLA 2 was carried out using previously described mixed micelle-based assays. 31-33
  • the inhibition results are presented in Table 6, either as percent inhibition or as X I (50) values.
  • the percent of inhibition for each PLA 2 enzyme at 0.091 mole fraction of each inhibitor was determined.
  • the X I (50) values were measured for compounds that displayed greater than 90% inhibition of GIVA cPLA 2 .
  • the X I (50) is the mole fraction of the inhibitor in the total substrate interface required to inhibit the enzyme activity by 50%.
  • Compound A clearly presented a potent inhibitory effect of the GIVA cPLA 2 activity in vitro and a potent suppression of the AA release in cells.
  • the collagen-induced arthritis (CIA) mouse model which is the most commonly autoimmune model of rheumatoid arthritis, 55 was employed for the evaluation of the in vivo activity of Compound A. It has been previously shown that GIVA cPLA 2 -deficient mice are resistant to CIA, 56 while the effect of the GIVA cPLA 2 inhibitor pyrroxyphene has been studied.
  • the AI of Compound A 7.5 mg/kg group on Days 32 to 41 was significantly reduced in comparison to the CIA control group, similar to the effect of MTX ( FIG. 2 ).
  • Within the histology group there was no statistical significance of AI between Compound A group and CIA control group (p>0.05, results not shown). There was no significant difference of the AI value between the histology group and main groups (p>0.05).
  • 4 mice from each treated group and 3 mice from control groups were sacrificed and 1 hind paw of each mouse was collected for histopathology.
  • the elevated PGE 2 level was significantly reduced with Compound A (7.5 ng/ml, 139.8 ⁇ 92 ng/ml, p ⁇ 0.03) comparable to MTX (0.3 mg/ml, 107.3 ⁇ 62 ng/ml, p ⁇ 0.004) level. There were no significant differences between the treatment groups (p>0.05).
  • IL-1 ⁇ Recombinant human interleukin-1 ⁇
  • PBS Phosphate-buffered saline solution
  • Oxoid UK
  • Labeled 3 H-AA [5,6,8,9,11,12,14,15- 3 H]-arachidonic acid (specific activity 180-240 Ci/mmol)
  • 14 C-OA [1- 14 C]-oleic acid (specific activity 40-60 Ci/mmol)
  • liquid scintillation cocktail Ultima Gold were from NEN Perkin Elmer (USA).
  • Dulbecco's Modified Eagle Medium (DMEM), foetal bovine serum (FBS), fatty acid-free bovine serum albumin (fBSA), dimethyl-sulpfoxide (DMSO), gentamicin and L-glutamine were from Sigma-Aldrich (USA).
  • EIA kit for PGE2 analysis was from Cayman Chemicals (USA).
  • GIVA cPLA 2 substrate mixed-micelles were composed of 400 ⁇ M Triton X-100, 97 ⁇ M PAPC, 1.8 ⁇ M 14 C-labeled PAPC, and 3 ⁇ M PIP2 in 100 mM HEPES buffer, pH 7.5, with 90 ⁇ M CaCl 2 , 2 mM DTT, and 0.1 mg/ml BSA;
  • GVI iPLA 2 substrate mixed-micelles were composed of 400 ⁇ M Triton X-100, 98.3 ⁇ M PAPC, and 1.7 ⁇ M 14 C-labeled PAPC in buffer containing 100 mM HEPES, pH 7.5, 2 mM ATP, and 4 mM DTT;
  • GV sPLA 2 substrate mixed-micelles were composed of 400 ⁇ M Triton X-100, 98.3 ⁇ M PAPC, and 1.7 ⁇ M 14 C-labeled PAPC in buffer containing 100 mM HEPES, pH 7.5, 2
  • GIVA cPLA 2 was measured as described 51,52 with modifications. 53 In short, recombinant human GIVA cPLA 2 enzyme was pre-incubated with DMSO (1%) with or without inhibitor in assay buffer (80 sec at 37° C., 10 min at 25° C.). Lipid vesicles of L- ⁇ -1-palmitoyl-2-arachidonyl-[arachidonyl-1 14 C]-phosphatidylcholine (4.3 nmol) were dried under a steam of N 2 (g).
  • the dried lipid was re-suspended in 2 ml assay buffer and sonicated twice (7 min, output 3.5 and 50% duty cycles, on ice) in a Branson Sonifier 250 (Branson Ultrasonic Corporation, Danbury, Conn.). Sonicated lipid (0.2 ⁇ M) was added to the reaction and incubated for 1 h at 37° C. followed by addition of a chloroform/methanol stop buffer to terminate the enzymatic reaction. The reaction mixture was separated by centrifugation (5 min, 1640 ⁇ g). The lower phase was transferred to a glass tube and dried under a steam of N 2 (g), re-suspended in chloroform/methanol (9:1, by volume) and applied to a silica gel.
  • the human synovial sarcoma cell line SW982 was from ATCC (UK) and was used as a model system to monitor AA/OA release and activation of GIVA cPLA 2 .
  • SW982 cells were passaged bi-weekly by routine trypsin detachment and kept in a sub-confluent state. The cells were maintained in Dulbecco's Modified Eagle Medium (DMEM) supplemented with 10% FBS, 0.1 mg/mL gentamicin and 0.3 mg/mL L-glutamine at 37° C. with 10% CO2.
  • DMEM Dulbecco's Modified Eagle Medium
  • FBS 0.1 mg/mL gentamicin
  • 0.3 mg/mL L-glutamine 37° C. with 10% CO2.
  • 5*10 5 cells were seeded pr well in a 48-well per plate format. Experiments were performed at 3 days post-confluency following overnight serum deprivation in serum-free DMEM to ensure differentiation and synchron
  • AA and OA release was analyzed as previously described. 54 At 2 days post-confluency, SW982 cells were serum-starved and labelled overnight with 3 H-AA (0.4 ⁇ Ci/ml) and 14 C-OA (0.067 ⁇ Ci/ml) in serum-free DMEM. Prior to the addition of oxothiazoles, the cells were washed twice with PBS containing fBSA (2 mg/ml) and PBS in order to remove unincorporated radioactivity. Cells were pretreated (1 h) with oxothiazoles prior to IL-1 ⁇ stimulation (10 ng/mL, 4 h). Following IL-1 ⁇ stimulation, the supernatants were cleared of detached cells by centrifugation (13000 rpm, 5 min).
  • CIA was induced in male DBA/1 mice (except na ⁇ ve mice) by immunization with 0.1 mL emulsion containing an equal volume of bovine type II collagen solution (2 mg/mL) and Freuds Complete Adjuvant at the tail base.
  • the first injection was given on Day 0 and the second injection as booster was given on Day 21 (41-43).
  • COMPOUND A vehicle (DMSO) and MTX (0.3 mg/kg) were administered daily
  • Enbrel 25 mg/kg was administrated twice a week.
  • treatment started one hour before the second collagen injection and continued for 21 days except for the histology groups that were sacrificed at Day 13 (33 days after immunization).
  • treatment started at Day 28 and continued for 14 days.
  • CIA Assessment and Treatment were assessed in mice by two blinded observers to measure paw swelling with a capacity measurement method on Day 0, Day 20, Day 22, Day 25, Day 27, Day 29, Day 32, Day 34, Day 36, Day 39 and Day 41 after the first injection.
  • the occurrence of arthritis was observed by scoring all paws for severity of erythema and swelling, using a clinical score ranging from 0 (no swelling) to 4 (severe swelling and erythema).
  • the physical condition of the animals was observed daily. Scores and overall evaluation of the histology group arms were performed in the same way as the main groups. However, the values measured were not included in the mean value calculations of the main groups.
  • the YLS-7B Foot Volume Measuring Instrument (Huaibei China Bio Equipment) was used to measure the foot volume of mice.
  • the occurrence of arthritis was observed by scoring all paws for severity of erythema and swelling, using a clinical score ranging from 0 (no swelling) to 4 (severe swelling and erythema), i.e. yielding maximum arthritic index (AI) score 16 (46).
  • AVX235 The therapeutic effect of AVX235 was tested in the rat streptozocin-induced model of human chronic renal disease and compared against losartan (positive control).
  • AVX235 was injected intraperitoneally, once daily for the first 4 days and then every two days. Losartan was administered daily, by oral gavage. At 2 weeks post experiment initiation, urine was collected over a period of 24 h and total protein in mg was measured.
  • FIG. 6 shows the results of the performed experiment in STZ-treated rats.
  • STZ induced increased protein levels in rat urine at 2 weeks post experiment initiation; this is consistent with the progressive renal disease observed in response to STZ administration in this model.
  • losartan protected rats from the STZ effect as urine protein levels in this group were comparable to urine protein levels in the control rat group that hasn't received STZ (Sham group).
  • AVX235 at this concentration and dosing regime, showed positive and significant therapeutic effects in the STZ-model. It protected renal function at the highest dose used; the observed effect was about 50% of obtained with clinical agent losartan.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Organic Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Public Health (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Epidemiology (AREA)
  • Dermatology (AREA)
  • Immunology (AREA)
  • Rheumatology (AREA)
  • Pulmonology (AREA)
  • Oncology (AREA)
  • Pain & Pain Management (AREA)
  • Hematology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Biomedical Technology (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Orthopedic Medicine & Surgery (AREA)
  • Physical Education & Sports Medicine (AREA)
  • Urology & Nephrology (AREA)
  • Cardiology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Heterocyclic Compounds Containing Sulfur Atoms (AREA)
  • Thiazole And Isothizaole Compounds (AREA)
  • Molecular Biology (AREA)
  • Microbiology (AREA)
  • Mycology (AREA)
US14/764,509 2013-01-29 2014-01-28 Antiiflammatory and antitumor 2-oxothiazoles abd 2-oxothiophenes compounds Abandoned US20150376161A1 (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
US14/764,509 US20150376161A1 (en) 2013-01-29 2014-01-28 Antiiflammatory and antitumor 2-oxothiazoles abd 2-oxothiophenes compounds

Applications Claiming Priority (10)

Application Number Priority Date Filing Date Title
GBGB1301585.4A GB201301585D0 (en) 2013-01-29 2013-01-29 Compound
GB1301585.4 2013-01-29
US201361775223P 2013-03-08 2013-03-08
US201361775117P 2013-03-08 2013-03-08
GB1304250.2 2013-03-08
GBGB1304250.2A GB201304250D0 (en) 2013-03-08 2013-03-08 Compound
GB1400579.7 2014-01-14
GB201400579A GB201400579D0 (en) 2014-01-14 2014-01-14 Compound
US14/764,509 US20150376161A1 (en) 2013-01-29 2014-01-28 Antiiflammatory and antitumor 2-oxothiazoles abd 2-oxothiophenes compounds
PCT/EP2014/051655 WO2014118195A1 (en) 2013-01-29 2014-01-28 Antiinflammatory and antitumor 2-oxothiazoles and 2-oxothiophenes compounds

Related Parent Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP2014/051655 A-371-Of-International WO2014118195A1 (en) 2013-01-29 2014-01-28 Antiinflammatory and antitumor 2-oxothiazoles and 2-oxothiophenes compounds

Related Child Applications (1)

Application Number Title Priority Date Filing Date
US15/789,834 Continuation US10259801B2 (en) 2013-01-29 2017-10-20 Anti-inflammatory and antitumor 2-oxothiazoles ABD 2-oxothiophenes compounds

Publications (1)

Publication Number Publication Date
US20150376161A1 true US20150376161A1 (en) 2015-12-31

Family

ID=51261484

Family Applications (4)

Application Number Title Priority Date Filing Date
US14/764,509 Abandoned US20150376161A1 (en) 2013-01-29 2014-01-28 Antiiflammatory and antitumor 2-oxothiazoles abd 2-oxothiophenes compounds
US15/789,834 Active US10259801B2 (en) 2013-01-29 2017-10-20 Anti-inflammatory and antitumor 2-oxothiazoles ABD 2-oxothiophenes compounds
US16/663,931 Active US11034666B2 (en) 2013-01-29 2019-10-25 Anti-inflammatory and antitumor 2-oxothiazoles and 2-oxothiophenes compounds
US17/344,605 Active US11691959B2 (en) 2013-01-29 2021-06-10 Anti-inflammatory and antitumor 2-oxothiazoles and 2-oxothiophenes compounds

Family Applications After (3)

Application Number Title Priority Date Filing Date
US15/789,834 Active US10259801B2 (en) 2013-01-29 2017-10-20 Anti-inflammatory and antitumor 2-oxothiazoles ABD 2-oxothiophenes compounds
US16/663,931 Active US11034666B2 (en) 2013-01-29 2019-10-25 Anti-inflammatory and antitumor 2-oxothiazoles and 2-oxothiophenes compounds
US17/344,605 Active US11691959B2 (en) 2013-01-29 2021-06-10 Anti-inflammatory and antitumor 2-oxothiazoles and 2-oxothiophenes compounds

Country Status (8)

Country Link
US (4) US20150376161A1 (de)
EP (1) EP2951164B1 (de)
JP (2) JP6371312B2 (de)
KR (1) KR102268357B1 (de)
CN (2) CN105102438B (de)
AU (3) AU2014211489A1 (de)
CA (1) CA2899137C (de)
WO (1) WO2014118195A1 (de)

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10150781B2 (en) 2014-08-01 2018-12-11 Avexxin As 2-oxothiatole compounds having activity as CPLA2 inhibitors for the treatment of inflammatory disorders and hyperproliferative disorders
US10259801B2 (en) 2013-01-29 2019-04-16 Avexxin As Anti-inflammatory and antitumor 2-oxothiazoles ABD 2-oxothiophenes compounds
US10370344B2 (en) * 2009-10-02 2019-08-06 Avexxin As 2-oxothiazole compounds and method of using same for chronic inflammatory disorders
US11439625B2 (en) 2016-03-14 2022-09-13 Avexxin As Combination therapy for proliferative diseases
US11744876B2 (en) * 2019-06-10 2023-09-05 Sutro Biopharma, Inc. Immunomodulator antibody drug conjugates and uses thereof

Families Citing this family (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR20190082265A (ko) * 2016-11-04 2019-07-09 아벡신 에이에스 피부 병태를 치료하기 위한 티아졸 및 세코스테로이드를 포함하는 조합 치료
US20190255023A1 (en) * 2016-11-04 2019-08-22 Avexxin As Combination therapy comprising a thiazole and a corticosteroid to treat skin conditions
GB201806663D0 (en) * 2018-04-24 2018-06-06 Avexxin As 2-Oxothiazole compositions for treatment of fibrotic disease
GB201906864D0 (en) 2019-05-15 2019-06-26 Avexxin As Combination therapy
GB202117609D0 (en) 2021-12-06 2022-01-19 Coegin Pharma Ab 2-Oxothiazole compositions for treatment of T-cell acute lymphoblastic leukaemia

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20110136879A1 (en) * 2009-10-02 2011-06-09 Avexxin As Compound
US20170166589A1 (en) * 2014-08-01 2017-06-15 Avexxin As 2-oxothiatole compounds having activity as cpla2 inhibitors for the treatment of inflammatory disorders and hyperproliferative disorders

Family Cites Families (69)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3894152A (en) 1969-09-15 1975-07-08 Innothera Lab Sa Use of (thienyl-3)(3-N-morpholine-propy)ketone
FR2062868B1 (de) 1969-09-15 1973-08-10 Innothera Lab Sa
DE2063901A1 (en) 1970-12-28 1972-07-20 Deutsche Gold- Und Silber-Scheideanstalt Vormals Roessler, 6000 Frankfurt Phenylalkylaminoalkylthiazoles - as antiphlogistics
DE3469169D1 (en) 1983-04-21 1988-03-10 Merck Frosst Canada Inc Leukotriene antagonists, their production and use and compositions containing them
PH22520A (en) 1984-11-12 1988-10-17 Yamanouchi Pharma Co Ltd Heterocyclic compounds having 4-lover alkyl-3-hydroxy-2-lower alkyl phenoxy-lower alkylene-y-group, and process of producing them
US5177215A (en) 1984-11-12 1993-01-05 Yamanouchi Pharmaceutical Co., Ltd. Heterocyclic compounds and pharmaceutical use thereof
JPS62142168A (ja) 1985-10-16 1987-06-25 Mitsubishi Chem Ind Ltd チアゾ−ル誘導体及びそれを有効成分とするロイコトリエンきつ抗剤
NZ229761A (en) 1988-07-12 1991-10-25 Ici Pharma Substituted thiazole derivatives for use as inhibitors of enzyme 5-lipoxygenase; pharmaceutical compositions and preparatory processes
US5272986A (en) 1991-05-13 1993-12-28 British Gas Plc Towing swivel for pipe inspection or other vehicle
TW263504B (de) 1991-10-03 1995-11-21 Pfizer
GB9211706D0 (en) 1992-06-03 1992-07-15 Celltech Ltd Peptidyl derivatives
US5273986A (en) 1992-07-02 1993-12-28 Hoffmann-La Roche Inc. Cycloalkylthiazoles
US5268395A (en) 1992-10-13 1993-12-07 Martin Marietta Energy Systems, Inc. Microcellular carbon foam and method
JP3345476B2 (ja) 1993-05-18 2002-11-18 株式会社東芝 有機非線形光学材料
US5569655A (en) 1993-09-14 1996-10-29 Sterling Winthrop Inc. Substituted heterocyclylisoquinolinium salts and compositions and method of use thereof
CA2195847A1 (en) 1994-07-27 1996-02-08 John J. Talley Substituted thiazoles for the treatment of inflammation
US5693804A (en) 1994-11-17 1997-12-02 Molecular Geriatrics Corporation Substituted 1-aryl-3-piperazin-1'-yl propanones
US6214994B1 (en) 1997-04-21 2001-04-10 Molecular Geriatrics Corporation Certain substituted 1-aryl-3-piperazin-1′-yl propanones
US5658909A (en) 1994-11-17 1997-08-19 Molecular Geriatrics Corporation Certain substituted 1-aryl-3-piperazin-1'-yl propanones to treat Alzheimer's Disease
US5900426A (en) 1995-03-28 1999-05-04 Nippon Zoki Pharmaceutical Co., Ltd. Benzothiazole derivatives
CA2221692A1 (en) 1995-05-19 1996-11-21 G.D. Searle & Co. Substituted oxazoles for the treatment of inflammation
EP0846107A1 (de) 1995-06-06 1998-06-10 Pharmeco Laboratories, Inc. Verfahren zur stereoselektiven synthese von dolaphenine
EP0975603A1 (de) 1997-01-29 2000-02-02 Zeneca Limited Inhibitoren der farnesyl protein transferase
EP0867437B1 (de) * 1997-03-14 2002-11-13 Koninklijke Philips Electronics N.V. Verfahren zur Herstellung einer Thiophen oder Furan enthaltenden konjugierten Verbindung und darin verwendte Vorläuferverbindung
JPH11255700A (ja) 1998-03-12 1999-09-21 Taiho Ind Co Ltd アセチルアセトン系金属錯体及びその合成法、並びにそれを用いた有機多層型エレクトロルミネッセンス素子
US6310049B1 (en) 1998-08-11 2001-10-30 Nihon Bayer Agrochem K.K. Nematicidal pyrazoles
SE9804212D0 (sv) * 1998-12-04 1998-12-04 Astra Pharma Prod Compounds
EP2455083B1 (de) 1999-04-23 2013-09-18 Leo Pharma A/S Pharmazeutische Zusammensetzung zur Anwendung auf der Haut enthaltend Calcipotriol und Betamethason zur Behandlung von Psoriasis
CA2370500A1 (en) 1999-06-25 2001-01-04 Lekhanh O. Tran 1-(aromatic- or heteroaromatic-substituted)-3-(heteroaromatic substituted)-1,3-propanediones and uses thereof
JP2001240593A (ja) 1999-10-12 2001-09-04 Japan Tobacco Inc 高トリグリセリド血症治療薬及び抗肥満薬
US6462054B1 (en) 2000-03-27 2002-10-08 The Scripps Research Institute Inhibitors of fatty acid amide hydrolase
EP1283209A4 (de) * 2000-05-18 2003-07-09 Daiichi Seiyaku Co Neue benzothiophenderivate
US20020052373A1 (en) 2000-10-26 2002-05-02 Zorn Stevin H. Combination treatment for dementia or cognitive deficits associated with alzheimer's disease and parkinson's disease
US6734207B2 (en) 2001-04-20 2004-05-11 Parker Hughes Institute Cytotoxic compounds
US7056917B2 (en) 2001-04-26 2006-06-06 Daiichi Pharmaceutical Co., Ltd. Drug efflux pump inhibitor
GB0202002D0 (en) 2002-01-29 2002-03-13 Leiv Eiriksson Nyotek A S Use
BR0312957A (pt) 2002-07-27 2005-06-14 Astrazeneca Ab Composto ou um sal farmaceuticamente aceitável deste, uso do mesmo, composição farmacêutica, e, método para produzir um efeito inibidor de 11betahsd1 em um animal de sangue quente, tal como o homem, em necessidade de tal tratamento
SE0202463D0 (sv) 2002-08-14 2002-08-14 Astrazeneca Ab Novel compounds
US6930391B2 (en) 2002-08-27 2005-08-16 Intel Corporation Method for alloy-electroplating group IB metals with refractory metals for interconnections
AU2003275493A1 (en) 2002-10-08 2004-05-04 The Scripps Research Institute Inhibitors of fatty acid amide hydrolase
GB2394894B (en) 2002-11-04 2005-08-31 G W Pharma Ltd New use for pharmaceutical composition
EP1562574A1 (de) 2002-11-07 2005-08-17 Astrazeneca AB 2-oxo-ethansulfonamid-derivate
JP4663523B2 (ja) 2003-09-18 2011-04-06 株式会社トクヤマ クロメン化合物
TWI336697B (en) 2003-09-19 2011-02-01 Solvay Pharm Bv Thiazole derivatives as cannabinoid receptor modulators
JP4226438B2 (ja) 2003-10-23 2009-02-18 エヌ・ティ・ティ・コムウェア株式会社 パック装置およびセンステーブル装置、ならびに移動軌跡算出方法、移動軌跡算出プログラム、その記録媒体
US20050137243A1 (en) * 2003-12-23 2005-06-23 Souers Andrew J. Antagonists of melanin concentrating hormone effects on the melanin concentrating hormone receptor
JP2005343889A (ja) 2004-05-06 2005-12-15 Taisho Pharmaceut Co Ltd イミダゾピリジン誘導体
MXPA06013305A (es) 2004-05-17 2007-02-02 Otsuka Pharma Co Ltd Compuesto de tiazol y uso del mismo.
FR2871693B1 (fr) 2004-06-17 2006-08-25 Galderma Sa Utilisation d'une composition pharmaceutique comprenant du calcitriol et du propionate de clobetasol pour le traitement du psoriasis
FR2871696B1 (fr) 2004-06-17 2006-11-10 Galderma Sa Composition topique pour le traitement du psoriasis
US7178364B2 (en) 2004-07-22 2007-02-20 Shapiro Kristen M Personal adornment
WO2006016218A1 (en) * 2004-08-03 2006-02-16 Pfizer Japan Inc. Aryl or heteroaryl carbonyl derivatives derivatives useful as vanilloid receptor 1 (vr1) antagonists
WO2006057503A1 (en) 2004-11-25 2006-06-01 Lg Life Sciences, Ltd. NOVEL COMPOUNDS AS AGONIST FOR PPARϜ AND PPARα, METHOD FOR PREPARATION OF THE SAME, AND PHARMACEUTICAL COMPOSITION CONTAINING THE SAME
GB0510390D0 (en) 2005-05-20 2005-06-29 Novartis Ag Organic compounds
US20090111778A1 (en) 2005-11-18 2009-04-30 Richard Apodaca 2-Keto-Oxazoles as Modulators of Fatty Acid Amide Hydrolase
CN103214483B (zh) 2005-12-13 2014-12-17 因塞特公司 作为两面神激酶抑制剂的杂芳基取代的吡咯并[2，3-b]吡啶和吡咯并[2，3-b]嘧啶
AU2007217813A1 (en) 2006-02-17 2007-08-30 The Scripps Research Institute Oxazole ketones as modulators of fatty acid amide hydrolase
CA2658887C (en) 2006-07-28 2016-08-23 University Of Connecticut Fatty acid amide hydrolase inhibitors
WO2008105408A1 (ja) 2007-02-26 2008-09-04 Santen Pharmaceutical Co., Ltd. ウレイド基とアミノカルボニル基を置換基として有する新規ピロール誘導体
BRPI0808348A2 (pt) 2007-03-05 2014-07-15 Hoffmann La Roche Aminoamidas como antagonistas de orexina
JP2010533645A (ja) 2007-05-31 2010-10-28 ザ スクリプス リサーチ インスティテュート 脂肪酸アミドヒドロラーゼの三環系阻害剤
US20110053898A1 (en) 2009-08-26 2011-03-03 Glenmark Generics Ltd Topical composition comprising vitamin d analogue and corticosteroids
AU2015268638B2 (en) 2009-10-02 2017-08-31 Avexxin As Anti inflammatory 2-oxothiazoles and 2-oxooxazoles
WO2012070420A1 (ja) 2010-11-22 2012-05-31 日立化成工業株式会社 希土類金属錯体
CN105102438B (zh) 2013-01-29 2019-04-30 埃维克辛公司 抗炎症和抗肿瘤的2-氧代噻唑类和2-氧代噻吩类化合物
US9594742B2 (en) 2013-09-05 2017-03-14 Acxiom Corporation Method and apparatus for matching misspellings caused by phonetic variations
GB201604318D0 (en) 2016-03-14 2016-04-27 Avexxin As Combination therapy
KR20190082265A (ko) 2016-11-04 2019-07-09 아벡신 에이에스 피부 병태를 치료하기 위한 티아졸 및 세코스테로이드를 포함하는 조합 치료
US20190255023A1 (en) 2016-11-04 2019-08-22 Avexxin As Combination therapy comprising a thiazole and a corticosteroid to treat skin conditions

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20110136879A1 (en) * 2009-10-02 2011-06-09 Avexxin As Compound
US20170166589A1 (en) * 2014-08-01 2017-06-15 Avexxin As 2-oxothiatole compounds having activity as cpla2 inhibitors for the treatment of inflammatory disorders and hyperproliferative disorders

Non-Patent Citations (8)

* Cited by examiner, † Cited by third party
Title
Chemical Abstracts Registry Number 10471-74-6, indexed in the Registry file on STN CAS ONLINE November 16, 1984. *
Chemical Abstracts Registry Number 1094445-68-7, indexed in the Registry file on STN CAS ONLINE January 20, 2009. *
Chemical Abstracts Registry Number 1347363-73-8, indexed in the Registry file on STN CAS ONLINE December 2, 2011. *
Chemical Abstracts Registry Number 374754-17-3, indexed in the Registry file on STN CAS ONLINE December 12, 2001. *
Chemical Abstracts Registry Number 882284-72-2, indexed in the Registry file on STN CAS ONLINE April 30, 2006. *
Chemical Abstracts Registry Number 927974-82-1, indexed in the Registry file on STN CAS ONLINE March 23, 2007. *
Chemical Abstracts Registry Number 927975-39-1, indexed in the Registry file on STN CAS ONLINE March 23, 2007. *
Chemical Abstracts Registry Number 927975-52-8, indexed in the Registry file on STN CAS ONLINE March 23, 2007. *

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10370344B2 (en) * 2009-10-02 2019-08-06 Avexxin As 2-oxothiazole compounds and method of using same for chronic inflammatory disorders
US10259801B2 (en) 2013-01-29 2019-04-16 Avexxin As Anti-inflammatory and antitumor 2-oxothiazoles ABD 2-oxothiophenes compounds
US11034666B2 (en) 2013-01-29 2021-06-15 Avexxin As Anti-inflammatory and antitumor 2-oxothiazoles and 2-oxothiophenes compounds
US11691959B2 (en) 2013-01-29 2023-07-04 Avexxin As Anti-inflammatory and antitumor 2-oxothiazoles and 2-oxothiophenes compounds
US10150781B2 (en) 2014-08-01 2018-12-11 Avexxin As 2-oxothiatole compounds having activity as CPLA2 inhibitors for the treatment of inflammatory disorders and hyperproliferative disorders
US10851114B2 (en) 2014-08-01 2020-12-01 Avexxin As 2-oxothiatole compounds having activity as cPLA2 inhibitors for the treatment of inflammatory disorders and hyperproliferative disorders
US11439625B2 (en) 2016-03-14 2022-09-13 Avexxin As Combination therapy for proliferative diseases
US11744876B2 (en) * 2019-06-10 2023-09-05 Sutro Biopharma, Inc. Immunomodulator antibody drug conjugates and uses thereof

Also Published As

Publication number Publication date
JP2018184429A (ja) 2018-11-22
WO2014118195A1 (en) 2014-08-07
JP6371312B2 (ja) 2018-08-08
KR102268357B1 (ko) 2021-06-23
EP2951164B1 (de) 2019-06-05
US11034666B2 (en) 2021-06-15
EP2951164A1 (de) 2015-12-09
US10259801B2 (en) 2019-04-16
CA2899137A1 (en) 2014-08-07
CA2899137C (en) 2021-07-13
AU2018208695A1 (en) 2018-08-09
US11691959B2 (en) 2023-07-04
CN105102438A (zh) 2015-11-25
US20220363659A1 (en) 2022-11-17
JP2016511233A (ja) 2016-04-14
AU2016266022A1 (en) 2016-12-15
US20200299256A1 (en) 2020-09-24
AU2014211489A1 (en) 2015-08-13
US20180105507A1 (en) 2018-04-19
KR20150110781A (ko) 2015-10-02
CN110128370A (zh) 2019-08-16
CN105102438B (zh) 2019-04-30
AU2016266022B2 (en) 2018-04-26

Similar Documents

Publication Publication Date Title
US11691959B2 (en) Anti-inflammatory and antitumor 2-oxothiazoles and 2-oxothiophenes compounds
US10851114B2 (en) 2-oxothiatole compounds having activity as cPLA2 inhibitors for the treatment of inflammatory disorders and hyperproliferative disorders
JP6012468B2 (ja) 抗炎症性２−オキソチアゾールおよび２−オキソオキサゾール
JP2008521831A (ja) Ｐｐａｒ活性化合物
JP2008521829A (ja) Ｐｐａｒ活性化合物
JP2009509932A (ja) Ｐｐａｒ活性化合物
JP2006510676A (ja) ＮＦ−κＢ阻害剤
AU2003282754A1 (en) Novel heterocyclic analogs of diphenylethylene compounds
Mo et al. Synthesis and anticancer activity of novel histone deacetylase inhibitors that inhibit autophagy and induce apoptosis
US20170296515A1 (en) Thiazolidinones as cellular anandamide uptake inhibitors and their use in the treatment of psychiatric or neurological disorders and inflammation, in particular neuroinflammation
GB2550363A (en) Compound

Legal Events

Date Code Title Description
AS Assignment

Owner name: AVEXXIN AS, NORWAY

Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNORS:JOHANSEN, BERIT;SANDERBERG, MARCEL;AUKRUST, INGER-REIDUN;AND OTHERS;SIGNING DATES FROM 20150827 TO 20150915;REEL/FRAME:037048/0517

STCB Information on status: application discontinuation

Free format text: ABANDONED -- FAILURE TO RESPOND TO AN OFFICE ACTION