WO2011041461A2 - Polycyclic compounds as lysophosphatidic acid receptor antagonists - Google Patents

Polycyclic compounds as lysophosphatidic acid receptor antagonists Download PDF

Info

Publication number
WO2011041461A2
WO2011041461A2 PCT/US2010/050786 US2010050786W WO2011041461A2 WO 2011041461 A2 WO2011041461 A2 WO 2011041461A2 US 2010050786 W US2010050786 W US 2010050786W WO 2011041461 A2 WO2011041461 A2 WO 2011041461A2
Authority
WO
WIPO (PCT)
Prior art keywords
methyl
isoxazol
compound
biphenyl
cyclopropanecarboxylic acid
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.)
Ceased
Application number
PCT/US2010/050786
Other languages
English (en)
French (fr)
Other versions
WO2011041461A3 (en
Inventor
Ryan Clark
Brian Andrew Stearns
Lucy Zhao
Thomas Jon Seiders
Deborah Volkots
Jeannie M. Arruda
David Nathan Zalatan
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.)
Amira Pharmaceuticals Inc
Original Assignee
Amira Pharmaceuticals Inc
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
Family has litigation
First worldwide family litigation filed litigation Critical https://patents.darts-ip.com/?family=43128100&utm_source=google_patent&utm_medium=platform_link&utm_campaign=public_patent_search&patent=WO2011041461(A2) "Global patent litigation dataset” by Darts-ip is licensed under a Creative Commons Attribution 4.0 International License.
Priority to BR112012007102A priority Critical patent/BR112012007102A2/pt
Priority to MX2012003723A priority patent/MX2012003723A/es
Priority to IN2702DEN2012 priority patent/IN2012DN02702A/en
Priority to AU2010300594A priority patent/AU2010300594A1/en
Priority to EP10821201.0A priority patent/EP2483269A4/en
Priority to CA2776779A priority patent/CA2776779A1/en
Priority to PH1/2012/500572A priority patent/PH12012500572A1/en
Application filed by Amira Pharmaceuticals Inc filed Critical Amira Pharmaceuticals Inc
Priority to CN201080054537.6A priority patent/CN102656168B/zh
Priority to JP2012532286A priority patent/JP2013506679A/ja
Priority to EA201270467A priority patent/EA201270467A1/ru
Publication of WO2011041461A2 publication Critical patent/WO2011041461A2/en
Publication of WO2011041461A3 publication Critical patent/WO2011041461A3/en
Priority to TNP2012000126A priority patent/TN2012000126A1/en
Priority to IL218962A priority patent/IL218962A0/en
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole 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
    • C07D231/38—Nitrogen atoms
    • 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
    • A61K31/42—Oxazoles
    • 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
    • A61K31/42—Oxazoles
    • A61K31/422—Oxazoles not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—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
    • A61K31/4245—Oxadiazoles
    • 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
    • A61K31/427—Thiazoles not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/4965—Non-condensed pyrazines
    • A61K31/497—Non-condensed pyrazines containing further heterocyclic rings
    • 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
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • 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
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • 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
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • 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
    • A61P35/00—Antineoplastic agents
    • A61P35/04—Antineoplastic agents specific for metastasis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/08—Antiallergic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/08—Vasodilators for multiple indications
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D261/00—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings
    • C07D261/02—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings
    • C07D261/06—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more double bonds between ring members or between ring members and non-ring members
    • C07D261/08—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D261/00—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings
    • C07D261/02—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings
    • C07D261/06—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more double bonds between ring members or between ring members and non-ring members
    • C07D261/10—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D261/14—Nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • R D is H or Ci-C 6 alkyl
  • L 4 is absent, or a substituted or unsubstituted C 1 -C4 alkylene, where if L 4 is
  • ring A is a substituted or unsubstituted 5-membered monocyclic Ci-C 4 heteroarylene containing 1-4 N atoms, 0 or 1 O atoms and 0 or 1 S atoms, where if ring A is substituted, then ring A is substituted with 1 or 2 R 14 .
  • the compound of Formula (I) is an antagonist of LPA 3 .
  • presented herein are compounds selected from active metabolites, tautomers, solvates, pharmaceutically acceptable salts or prodrugs of a compound of Formula (I).
  • the one or more additional therapeutically active agents other than a compound of Formula (I) are selected from: corticosteroids, immunosuppresants, analgesics, anti-cancer agent, anti-inflammatories, chemokine receptor antagonists, bronchodilators, leukotriene receptor antagonists, leukotriene formation inhibitors, monoacylglycerol kinase inhibitors, phospholipase A 1 inhibitors, phospholipase A 2 inhibitors, and lysophospholipase D (lysoPLD) inhibitors, autotaxin inhibitors,
  • NASH steatohepatitis
  • biliary duct injury primary biliary cirrhosis
  • infection induced liver fibrosis viral induced liver fibrosis
  • autoimmune hepatitis corneal scarring
  • scleroderma spinal cord injury/fibrosis; myelofibrosis; vascular restenosis; atherosclerosis; arteriosclerosis; Wegener's granulomatosis; Peyronie's disease, chronic lymphocytic leukemia, tumor metastasis, transplant organ rejection, endometreosis, neonatal respiratory distress syndrome and neuropathic pain.
  • compounds disclosed herein are used to treat post-transplant fibrosis associated with chronic rejection in a mammal: Bronchiolitis obliterans for lung transplant.
  • the mammal is a human.
  • LPA and LPAi are involved in the etiology of kidney fibrosis.
  • LPAi LPAi receptor
  • UUO animal model of renal fibrosis mice treated with the LPA receptor antagonist Ki 16425 closely resembled the LPAi ( ⁇ / ⁇ ) mice.
  • a mammal suffering from one of the following non-limiting exemplary diseases, disorders, or conditions will benefit from therapy with a compound of Formula (I): atherosclerosis, thrombosis, heart disease, vasculitis, formation of scar tissue, restenosis, phlobitis, COPD (chronic obstructive pulmonary disease), pulmonary hypertension, pulmonary fibrosis, pulmonary inflammation, bowel adhesions, bladder fibrosis and cystitis, fibrosis of the nasal passages, sinusitis, inflammation mediated by neutrophils, and fibrosis mediated by fibroblasts.
  • atherosclerosis atherosclerosis, thrombosis, heart disease, vasculitis, formation of scar tissue, restenosis, phlobitis, COPD (chronic obstructive pulmonary disease), pulmonary hypertension, pulmonary fibrosis, pulmonary inflammation, bowel adhesions, bladder fibrosis and cystitis, fibrosis of the nasal passages, sinusitis
  • the nervous system is a major locus for LPAi expression.
  • a compound of Formula (I) for use in the treatment or prevention of a nervous system disorder in a mammal.
  • the term "nervous system disorder,” as used herein includes, but is not limited to, Alzheimer's Disease, cerebral edema, cerebral ischemia, stroke, multiple sclerosis, neuropathies, Parkinson's Disease, multiple sclerosis, retinal ischemia, postsurgical cognitive dysfunction, migraine, peripheral neuropathy/neuropathic pain, spinal cord injury, cerebral edema and head injury.
  • LPA-dependent conditions or diseases include those wherein an absolute or relative excess of LPA is present and/or observed.
  • the LPA-dependent or LPA-mediated diseases or conditions include, but are not limited to, organ fibrosis, asthma, allergic disorders, chronic obstructive pulmonary disease, pulmonary hypertension, lung or pleural fibrosis, peritoneal fibrosis, arthritis, allergy, cancer, cardiovascular disease, aldult respiratory distress syndrome, myocardial infarction, aneurysm, stroke, and cancer.
  • R E is Ci-C 6 alkyl or a substituted or unsubstituted phenyl
  • r is 1 or 2. In some embodiments, r is 1.
  • ring A is a substituted or unsubstituted phenyl, or a substituted or unsubstituted monocyclic Ci-Csheteroarylene, where if ring A is substituted, then ring A is substituted with 1 or 2 R 14 .
  • ring A is a substituted or unsubstituted monocyclic Ci- Csheteroarylene containing 1-4 N atoms, 0 or 1 O atoms and 0 or 1 S atoms, where if ring A is substituted, then ring A is substituted with 1 or 2 R 14 .
  • compounds described herein may coordinate with an organic base, such as, but not limited to, ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methylglucamine, dicyclohexylamine, tris(hydroxymethyl)methylamine.
  • compounds described herein may form salts with amino acids such as, but not limited to, arginine, lysine, and the like.
  • Acceptable inorganic bases used to form salts with compounds that include an acidic proton include, but are not limited to, aluminum hydroxide, calcium hydroxide, potassium hydroxide, sodium carbonate, sodium hydroxide, and the like.
  • a sodium salt of the compound of Formula (I) is prepared.
  • the effective amount of the compound of Formula (I) is: (a) systemically administered to the mammal; and/or (b) administered orally to the mammal; and/or (c) intravenously administered to the mammal; and/or (d) administered by inhalation to the mammal; and/or (e) administered by nasal administration to the mammal; or and/or (f) administered by injection to the mammal; and/or (g) administered topically to the mammal; and/or (h) administered by ophthalmic administration; and/or (i) administered rectally to the mammal; and/or (j) adminstered non- systemically or locally to the mammal.
  • compounds of Formula (I) are prepared as transdermal dosage forms.
  • Step 9 l-[4-(4,4,5,5-Tetramethyl-[l,3,2]dioxaborolan-2-yl)-phenyl]- cyclopropanecarboxylic acid ethyl ester: l-(4-Bromo-phenyl)-cyclopropanecarboxylic acid ethyl ester (3.6 g, 13.4 mmol), bis(pinacolato)diboron (3.37 g, 16.1 mmol), and potassium acetate (2.8 g, 29.0 mmol) were combined in 1,4-dioxane (30 mL) under N 2 atmosphere.
  • Step 10 l-[4'-(4-tei"i-Butoxycarbonylamino-3-methyl-isoxazol-5-yl)-biphenyl-4- yl]-cyclopropanecarboxylic acid ethyl ester: [5-(4-Bromo-phenyl)-3-methyl-isoxazol-4- yl]-carbamic acid tert-butyl ester (2.0 g, 5.6 mmol), l-[4-(4,4,5,5-tetramethyl- [l,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropanecarboxylic acid ethyl ester (1.78 g, 5.6 mmol), tetrakis(triphenylphosphine)palladium(0) (0.65 g, 0.56 mmol), and sodium bicarbonate (1.4 g, 16.8 mmol) were combined in DME (30 ).
  • Step 2 l-(4'- ⁇ 3-Methyl-4-[(5-phenyl-[l,3,4]oxadiazol-2-ylamino)-methyl]- isoxazol-5-yl ⁇ -biphenyl-4-yl)-cyclopropanecarboxylic acid ethyl ester: Prepared according to the procedure described in Example 1, Step 10, using [5-(4-bromo-phenyl)-3- methyl-isoxazol-4-ylmethyl]-(5-phenyl-[l,3,4]oxadiazol-2-yl)-amine and l-[4-(4,4,5,5- tetramethyl-[l,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropanecarboxylic acid ethyl ester.
  • Step 3 The ester from Step 2 was hydro lyzed to the acid according to the procedure described in Example 3.
  • Step 2 l-[4'-(4- ⁇ [l-(4-Chloro-benzyl)-lH-[l,2,3]triazol-4-yl]-hydroxy-methyl ⁇ - 3-methyl-isoxazol-5-yl)-biphenyl-4-yl]-cyclopropanecarboxylic acid ethyl ester:
  • Step 1 ((S)-l-Bromo-ethyl)-benzene: Bromine (3.2 g, 20.0 mmol) was added to a suspension of triphenylphosphine (5.2 g, 19.8 mmol) stirring in ACN at -15 °C. The reaction was warmed to room temperature and stirred for 50 mintues then cooled to -35 °C and (Pv)-(+)-l-phenylethanol (1.6 g, 13.1 mmol) was added. The reaction was allowed to warm to -10 °C over 70 minutes and was then quenched with H 2 0 and submitted to standard aqueous workup to afford the title compound which was used without further purification.
  • Step 2 (6-Benzyl-pyridin-2-yl)-[5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]- methanol: Prepared according to the procedure described in Example 34, Step 3, using 5- (4-bromo-phenyl)-3-methyl-isoxazole-4-carbaldehyde and 2-benzyl-6-bromo-pyridine.
  • Step 2 l-[4'-(4- ⁇ Hydroxy-[l-(2-methyl-benzyl)-lH-[l,2,3]triazol-4-yl]-methyl ⁇ - 3-methyl-isoxazol-5-yl)-biphenyl-4-yl] -cyclopropanecarboxylic acid ethyl ester:
  • Step 1 2-Bromo-6-phenyl-pyrazine: Prepared according to the procedure described in Example 1, Step 10, using 2,6-dibromo-pyrazine and phenylboronic acid. Additionally, (l, -bis(diphenylphosphino)ferrocene)-dichloropalladium(II) was used as the catalyst in place of tetrakis(triphenylphosphine)palladium(0).
  • Step 2 l- ⁇ 4'-[3-Methyl-4-(6-phenyl-pyrazin-2-ylamino)-isoxazol-5-yl]-biphenyl- 4-yl ⁇ -cyclopropanecarboxylic acid ethyl ester: Prepared according to the procedure described in Example 41, Step 2, using l-[4'-(4-amino-3-methyl-isoxazol-5-yl)-biphenyl-4- yl]-cyclopropanecarboxylic acid ethyl ester and 2-bromo-6-phenyl-pyrazine.
  • Step 3 l- ⁇ 4'-[4-(5-Benzyl-[l,3,4]oxadiazol-2-ylamino)-3-methyl-isoxazol-5-yl]- biphenyl-4-yl ⁇ -cyclopropanecarboxylic acid ethyl ester: Prepared according to the procedure described in Example 1, Step 10, using (5-benzyl-[l,3,4]oxadiazol-2-yl)-[5-(4- bromo-phenyl)-3-methyl-isoxazol-4-yl]-amine and l-[4-(4,4,5,5-tetramethyl- [l,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropanecarboxylic acid ethyl ester.
  • Step 3 l-(4'- ⁇ 4-[6-(2-Fluoro-benzyl)-pyridin-2-ylamino]-3-methyl-isoxazol-5- yl ⁇ -biphenyl-4-yl)-cyclopropanecarboxylic acid ethyl ester: Prepared according to the procedure described in Example 41, Step 2, using l-[4'-(4-amino-3-methyl-isoxazol-5-yl)- biphenyl-4-yl]-cyclopropanecarboxylic acid ethyl ester and 2-bromo-6-(2-fluoro-benzyl)- pyridine.
  • Step 3 l-(4'- ⁇ 4-[6-(3-Fluoro-benzyl)-pyridin-2-ylamino]-3-methyl-isoxazol-5- yl ⁇ -biphenyl-4-yl)-cyclopropanecarboxylic acid ethyl ester: Prepared according to the procedure described in Example 41, Step 2, using l-[4'-(4-amino-3-methyl-isoxazol-5-yl)- biphenyl-4-yl]-cyclopropanecarboxylic acid ethyl ester and 2-bromo-6-(3-fluoro-benzyl)- pyridine.
  • Step 3 l-(4'- ⁇ 4-[6-(4-Fluoro-benzyl)-pyridin-2-ylamino]-3-methyl-isoxazol-5- yl ⁇ -biphenyl-4-yl)-cyclopropanecarboxylic acid ethyl ester: Prepared according to the procedure described in Example 41, Step 2, using l-[4'-(4-amino-3-methyl-isoxazol-5-yl)- biphenyl-4-yl]-cyclopropanecarboxylic acid ethyl ester and 2-bromo-6-(4-fluoro-benzyl)- pyridine.
  • Step 1 l- ⁇ 4'-[4-(3-Benzyl-phenylamino)-3-methyl-isoxazol-5-yl]-biphenyl-4-yl ⁇ - cyclopropanecarboxylic acid ethyl ester: Prepared according to the procedure described in Example 41, Step 2, using l-[4'-(4-amino-3-methyl-isoxazol-5-yl)-biphenyl-4-yl]- cyclopropanecarboxylic acid ethyl ester and l-benzyl-3-bromo-benzene.
  • Step 3 The ester from Step 2 was hydro lyzed to the acid according to the procedure described in Example 3.
  • Step 1 l-[4'-(4- ⁇ Hydroxy-[5-(3-trifluoromethyl-phenyl)-pyridin-3-yl]-methyl ⁇ - 3-methyl-isoxazol-5-yl)-biphenyl-4-yl] -cyclopropanecarboxylic acid ethyl ester:
  • Step 1 l- ⁇ 4'-[3-Methyl-4-(6-phenylethynyl-pyridin-2-ylamino)-isoxazol-5-yl]- biphenyl-4-yl ⁇ -cyclopropanecarboxylic acid ethyl ester: l- ⁇ 4'-[4-(6-Bromo-pyridin-2- ylamino)-3-methyl-isoxazol-5-yl]-biphenyl-4-yl ⁇ -cyclopropanecarboxylic acid ethyl ester (0.200 g, 0.386 mmol) was dissolved in toluene along with phenylacetylene (0.051 mL, 0.46 mmol), copper(I) iodide (0.367 g, 1.93 mmol), triethylamine (0.269 mL, 1.93 mmol) and bis(triphenylphosphine)pal
  • Step 2 The ester from Step 1 was hydro lyzed to the acid according to the procedure described in Example 3.
  • Step 2 The ester from Step 1 was hydro lyzed to the acid according to the procedure described in Example 3.
  • Step 3 The ester from Step 2 was hydrolyzed to the acid according to the procedure described in Example 3.
  • Example 103 Synthesis of l-(4'- ⁇ 4-[5-(2,5-Difluoro-phenyl)-pyridin-3-ylamino]-3- methyl-isoxazol-5-yl ⁇ -biphenyl-4-yl)-cyclopropanecarboxylic acid (Compound 89)
  • Step 1 l-(4'- ⁇ 4-[6-(3-Chloro-phenyl)-pyridin-2-ylamino]-3-methyl-isoxazol-5- yl ⁇ -biphenyl-4-yl)-cyclopropanecarboxylic acid ethyl ester: Prepared according to the procedure described in Example 1, Step 10, using l- ⁇ 4'-[4-(6-bromo-pyridin-2-ylamino)-3- methyl-isoxazol-5-yl]-biphenyl-4-yl ⁇ -cyclopropanecarboxylic acid ethyl ester and 3- chlorophenylboronic acid. (1,1 '-bis(diphenylphosphino)ferrocene)-dichloropalladium(II) was used in place of tetrakis(triphenylphosphine)palladium(0).
  • Step 7 l-[4'-(4-Amino-3-ethyl-isoxazol-5-yl)-biphenyl-4-yl]- cyclopropanecarboxylic acid ethyl ester: Prepared according to the procedure described in Example 1, Step 11, using l-[4'-(4-tert-butoxycarbonylamino-3-ethyl-isoxazol-5-yl)- biphenyl-4-yl]-cyclopropanecarboxylic acid ethyl ester.
  • Example 109 Establishment of a CHO Cell Line Stably Expressing Human LPA 3
  • the full-length cDNA fragment for human LP A3 was obtained by PCR from the vector.
  • the nucleotide sequence of the cloned human LPA 3 was determined by sequencing and confirmed to be identical to the published human LP A3 sequence (NCBI accession number NM 012152).
  • the cDNA was cloned into the pCDNA5/FRT expression plasmid and transfected in CHO cells using lipofectamine 2000 (Invitrogen Corp., USA). Clones stably expressing human LPA 3 were selected using hygromycin and identified as cells that show Ca-influx in response to LPA.
  • A less than 0.3 ⁇
  • B greater than 0.3 ⁇ and less than 1 ⁇
  • mice are returned to their cages and monitored daily for the duration of the experiment.
  • Test compound or vehicle is delivered po, ip or sc daily. The route and frequency of dosing is based on previously determined
  • BALF is centrifuged for 10 min at 800 x g to pellet the cells and the cell supernatant removed and frozen at -80 °C for subsequent protein analysis using the DC protein assay kit (Biorad, Hercules, CA.) and soluble collagen analysis using Sircol (Biocolor Ltd, UK).
  • BALF is analyzed for concentrations of inflammatory, pro-fibrotic and tissue injury biomarkers including transforming growth factor ⁇ , hyaluronic acid, tissue inhibitor of metalloproteinase-1, matrix matelloproteinase- 7, connective tissue growth factor and lactate dehydrogenase activity, using commercially available ELISA.
  • the cell pellet is re-suspended in PBS.
  • kidneys are harvested and one half of the kidney is frozen at -80°C and the other half is fixed in 10% neutral buffered formalin for histological assessment of kidney fibrosis using light microscopy (lOx magnification).
  • Kidney tissue homogenates are analyzed for collagen levels using Sircol (Biocolor Ltd, UK). Fixed kidney tissue is also stained using hematoxylin and eosin (H&E) and trichrome and kidney fibrosis is determined by quantitative, computer-assisted densitometry of collagen in liver tissue sections using light microscopy and collagen content in kidney lysate.
  • H&E hematoxylin and eosin
  • Plasma and kidney tissue lysates are also analyzed for concentrations of inflammatory, pro-fibrotic and tissue injury biomarkers including transforming growth factor ⁇ , hyaluronic acid, tissue inhibitor of metalloproteinase-1, and plasminogen activator inhibitor -1, using commercially available ELISA.
  • the resulting data are plotted using Graphpad prism and statistical differences between groups determined.
  • a pharmaceutical composition for oral delivery 100 mg of a compound of Formula (I) is mixed with 750 mg of starch. The mixture is incorporated into an oral dosage unit for, such as a hard gelatin capsule, which is suitable for oral administration.
  • Example 121 Sublingual (Hard Lozenge) Pharmaceutical Composition
  • a pharmaceutical composition for buccal delivery such as a hard lozenge
  • a pharmaceutical composition for buccal delivery such as a hard lozenge
  • the mixture is gently blended and poured into a mold to form a lozenge suitable for buccal administration.
  • a pharmaceutical opthalmic solution composition 100 mg of a compound of Formula (I) is mixed with 0.9 g of NaCl in 100 mL of purified water and filterd using a 0.2 micron filter. The resulting isotonic solution is then incorporated into ophthalmic delivery units, such as eye drop containers, which are suitable for ophthalmic administration.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Epidemiology (AREA)
  • Immunology (AREA)
  • Pulmonology (AREA)
  • Urology & Nephrology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Cardiology (AREA)
  • Diabetes (AREA)
  • Pain & Pain Management (AREA)
  • Hematology (AREA)
  • Oncology (AREA)
  • Emergency Medicine (AREA)
  • Dermatology (AREA)
  • Obesity (AREA)
  • Endocrinology (AREA)
  • Biomedical Technology (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Ophthalmology & Optometry (AREA)
  • Rheumatology (AREA)
  • Transplantation (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Vascular Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
PCT/US2010/050786 2009-10-01 2010-09-29 Polycyclic compounds as lysophosphatidic acid receptor antagonists Ceased WO2011041461A2 (en)

Priority Applications (12)

Application Number Priority Date Filing Date Title
JP2012532286A JP2013506679A (ja) 2009-10-01 2010-09-29 リゾホスファチジン酸受容体アンタゴニストとしての多環式化合物
CN201080054537.6A CN102656168B (zh) 2009-10-01 2010-09-29 作为溶血磷脂酸受体拮抗剂的多环化合物
IN2702DEN2012 IN2012DN02702A (enExample) 2009-10-01 2010-09-29
AU2010300594A AU2010300594A1 (en) 2009-10-01 2010-09-29 Polycyclic compounds as lysophosphatidic acid receptor antagonists
EP10821201.0A EP2483269A4 (en) 2009-10-01 2010-09-29 POLYCYCLIC COMPOUNDS USEFUL AS LYSOPHOSPHATIDE ACID RECEPTOR ANAGONISTS
CA2776779A CA2776779A1 (en) 2009-10-01 2010-09-29 Polycyclic compounds as lysophosphatidic acid receptor antagonists
PH1/2012/500572A PH12012500572A1 (en) 2009-10-01 2010-09-29 Polycyclic compounds as lysophosphatidic acid receptor antagonists
BR112012007102A BR112012007102A2 (pt) 2009-10-01 2010-09-29 compostos policíclicos como antagonistas de receptores do ácido lisofosfatpidico
EA201270467A EA201270467A1 (ru) 2009-10-01 2010-09-29 Полициклические соединения в качестве антагонистов рецепторов лизофосфатидной кислоты
MX2012003723A MX2012003723A (es) 2009-10-01 2010-09-29 Compuestos policiclicos como antagonistas del receptor de acido lisofosfatidico.
TNP2012000126A TN2012000126A1 (en) 2009-10-01 2012-03-21 Polycyclic compounds as lysophosphatidic acid receptor antagonists
IL218962A IL218962A0 (en) 2009-10-01 2012-03-29 Polycyclic compounds as lysophosphatidic acid receptor antagonists

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US24787709P 2009-10-01 2009-10-01
US61/247,877 2009-10-01

Publications (2)

Publication Number Publication Date
WO2011041461A2 true WO2011041461A2 (en) 2011-04-07
WO2011041461A3 WO2011041461A3 (en) 2011-08-25

Family

ID=43128100

Family Applications (2)

Application Number Title Priority Date Filing Date
PCT/US2010/050787 Ceased WO2011041462A2 (en) 2009-10-01 2010-09-29 Polycyclic compounds as lysophosphatidic acid receptor antagonists
PCT/US2010/050786 Ceased WO2011041461A2 (en) 2009-10-01 2010-09-29 Polycyclic compounds as lysophosphatidic acid receptor antagonists

Family Applications Before (1)

Application Number Title Priority Date Filing Date
PCT/US2010/050787 Ceased WO2011041462A2 (en) 2009-10-01 2010-09-29 Polycyclic compounds as lysophosphatidic acid receptor antagonists

Country Status (21)

Country Link
US (3) US8778983B2 (enExample)
EP (2) EP2483269A4 (enExample)
JP (2) JP2013506680A (enExample)
KR (1) KR20120097490A (enExample)
CN (2) CN102656168B (enExample)
AR (1) AR078495A1 (enExample)
AU (1) AU2010300594A1 (enExample)
BR (1) BR112012007102A2 (enExample)
CA (1) CA2776779A1 (enExample)
CL (1) CL2012000812A1 (enExample)
EA (1) EA201270467A1 (enExample)
GB (1) GB2474748B (enExample)
IL (1) IL218962A0 (enExample)
IN (2) IN2012DN02702A (enExample)
MX (1) MX2012003723A (enExample)
PE (1) PE20120997A1 (enExample)
PH (1) PH12012500572A1 (enExample)
TN (1) TN2012000126A1 (enExample)
TW (1) TWI415849B (enExample)
UY (1) UY32923A (enExample)
WO (2) WO2011041462A2 (enExample)

Cited By (42)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011041729A2 (en) 2009-10-01 2011-04-07 Amira Pharmaceuticals, Inc. Compounds as lysophosphatidic acid receptor antagonists
US8048902B2 (en) 2008-12-15 2011-11-01 Amira Pharmaceuticals, Inc. Antagonists of lysophosphatidic acid receptors
US8058300B2 (en) 2009-06-03 2011-11-15 Amira Pharmaceuticals, Inc. Polycyclic antagonists of lysophosphatidic acid receptors
WO2013070879A1 (en) 2011-11-10 2013-05-16 Bristol-Myers Squibb Company Methods for treating spinal cord injury with lpa receptor antagonists
WO2013078283A1 (en) 2011-11-22 2013-05-30 Intermune, Inc. Methods of diagnosing and treating idiopathic pulmonary fibrosis
US8455499B2 (en) 2008-12-11 2013-06-04 Amira Pharmaceuticals, Inc. Alkyne antagonists of lysophosphatidic acid receptors
US8541587B2 (en) 2011-04-05 2013-09-24 Amira Pharmaceuticals, Inc. Lysophosphatidic acid receptor antagonists
US8592402B2 (en) 2009-08-04 2013-11-26 Amira Pharmaceuticals, Inc. Compounds as lysophosphatidic acid receptor antagonists
US8664220B2 (en) 2009-10-01 2014-03-04 Amira Pharmaceuticals, Inc. Polycyclic compounds as lysophosphatidic acid receptor antagonists
WO2014104372A1 (ja) 2012-12-28 2014-07-03 宇部興産株式会社 ハロゲン置換へテロ環化合物
WO2016197009A1 (en) 2015-06-05 2016-12-08 Vertex Pharmaceuticals Incorporated Triazoles for the treatment of demyelinating diseases
KR20170016988A (ko) 2014-06-27 2017-02-14 우베 고산 가부시키가이샤 할로겐 치환 헤테로환 화합물의 염
WO2018106643A1 (en) 2016-12-06 2018-06-14 Vertex Pharmaceuticals Incorporated Heterocyclic azoles for the treatment of demyelinating diseases
WO2018106641A1 (en) 2016-12-06 2018-06-14 Vertex Pharmaceuticals Incorporated Pyrazoles for the treatment of demyelinating diseases
WO2018106646A1 (en) 2016-12-06 2018-06-14 Vertex Pharmaceuticals Incorporated Aminotriazoles for the treatment of demyelinating diseases
WO2019126087A1 (en) * 2017-12-19 2019-06-27 Bristol-Myers Squibb Company Cyclohexyl acid isoxazole azoles as lpa antagonists
US10576062B2 (en) 2016-06-21 2020-03-03 Bristol-Myers Squibb Company Carbamoyloxymethyl triazole cyclohexyl acids as LPA antagonists
US10647705B2 (en) 2017-11-14 2020-05-12 Merck Sharp & Dohme Corp. Substituted biaryl compounds as indoleamine 2,3-dioxygenase (IDO) inhibitors
US10662172B2 (en) 2017-12-19 2020-05-26 Bristol-Myers Squibb Company Triazole N-linked carbamoyl cyclohexyl acids as LPA antagonists
US11180488B2 (en) 2017-12-19 2021-11-23 Bristol-Myers Squibb Company Isoxazole o-linked carbamoyl cyclohexyl acids as LPA antagonists
US11261174B2 (en) 2017-12-19 2022-03-01 Bristol-Myers Squibb Company Pyrazole O-linked carbamoyl cyclohexyl acids as LPA antagonists
US11267800B2 (en) 2017-12-19 2022-03-08 Bristol-Myers Squibb Company Cyclohexyl acid triazole azines as LPA antagonists
US11312706B2 (en) 2017-12-19 2022-04-26 Bristol-Myers Squibb Company Cyclohexyl acid pyrazole azines as LPA antagonists
US11319315B2 (en) 2017-12-19 2022-05-03 Bristol-Myers Squibb Company Cyclohexyl acid triazole azoles as LPA antagonists
US11319309B2 (en) 2017-12-19 2022-05-03 Bristol-Myers Squibb Company Cyclohexyl acid isoxazole azines as LPA antagonists
US11352345B2 (en) 2017-12-19 2022-06-07 Bristol-Myers Squibb Company Cyclohexyl acid pyrazole azoles as LPA antagonists
US11384067B2 (en) 2017-12-19 2022-07-12 Bristol-Myers Squibb Company Pyrazole n-linked carbamoyl cyclohexyl acids as LPA antagonists
US11447475B2 (en) 2017-12-19 2022-09-20 Bristol-Myers Squibb Company Isoxazole N-linked carbamoyl cyclohexyl acids as LPA antagonists
US11498904B2 (en) 2017-11-14 2022-11-15 Merck Sharp & Dohme Llc Substituted biaryl compounds as indoleamine 2,3-dioxygenase (IDO) inhibitors
US11548871B2 (en) 2019-11-15 2023-01-10 Gilead Sciences, Inc. Triazole carbamate pyridyl sulfonamides as LPA receptor antagonists and uses thereof
US11572353B2 (en) 2016-09-19 2023-02-07 Beijing Innocare Pharma Tech Co., Ltd. Alkynyl-substituted heterocyclic compound, preparation method therefor and medical use thereof
US11584738B2 (en) 2020-06-03 2023-02-21 Gilead Sciences, Inc. LPA receptor antagonists and uses thereof
US11702407B2 (en) 2020-06-03 2023-07-18 Gilead Sciences, Inc. LPA receptor antagonists and uses thereof
US11884627B2 (en) 2022-02-25 2024-01-30 Lhotse Bio, Inc. Compounds and compositions for treating conditions associated with LPA receptor activity
US11939318B2 (en) 2021-12-08 2024-03-26 Gilead Sciences, Inc. LPA receptor antagonists and uses thereof
RU2818246C2 (ru) * 2018-06-18 2024-04-26 Эпиджен Байосайенсиз, Инк. Гетероциклические соединения, применимые в лечении заболевания
US11980609B2 (en) 2021-05-11 2024-05-14 Gilead Sciences, Inc. LPA receptor antagonists and uses thereof
US12209072B2 (en) 2018-09-18 2025-01-28 Bristol-Myers Squibb Company Cyclopentyl acids as LPA antagonists
WO2025026266A1 (zh) * 2023-07-28 2025-02-06 武汉朗来科技发展有限公司 作为lpar1拮抗剂的化合物、其药物组合物和用途
US12378229B2 (en) 2021-02-02 2025-08-05 Liminal Biosciences Limited GPR84 antagonists and uses thereof
US12428430B2 (en) 2018-09-18 2025-09-30 Bristol-Myers Squibb Company Oxabicyclo acids as LPA antagonists
US12503454B2 (en) 2021-05-13 2025-12-23 Gilead Sciences, Inc. LPA receptor antagonists and uses thereof

Families Citing this family (36)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CA3007787C (en) 2010-06-03 2020-03-10 Pharmacyclics Llc The use of inhibitors of bruton's tyrosine kinase (btk)
US9044479B2 (en) 2010-06-16 2015-06-02 Bruce Chandler May Use of levocetirizine and montelukast in the treatment of influenza, common cold and inflammation
WO2012100436A1 (en) 2011-01-30 2012-08-02 Curegenix Inc. Compound as antagonist of lysophosphatidic acid receptor, composition, and use thereof
KR101369584B1 (ko) 2011-04-19 2014-03-06 일양약품주식회사 페닐-이속사졸 유도체 및 그의 제조방법
MX2013013752A (es) * 2011-05-25 2014-08-01 Intermune Inc Pirfenidona y tratamiento anti-fibrotico en pacientes seleccionados.
US8912202B2 (en) 2011-08-08 2014-12-16 Merck Patent Gmbh N-(benzimimdazol-2-yl)-cyclopropane carboxamides as lysophosphatidic acid antagonists
AU2012296662A1 (en) 2011-08-15 2014-03-27 Intermune, Inc. Lysophosphatidic acid receptor antagonists
GB2493914A (en) * 2011-08-19 2013-02-27 Univ Jw Goethe Frankfurt Main Flurbiprofen and related compounds for the treatment of skin diseases
US20140329871A1 (en) * 2011-12-04 2014-11-06 Angion Biomedica Corp. Small molecule anti-fibrotic compounds and uses thereof
EA201492285A1 (ru) * 2012-06-20 2015-04-30 Ф. Хоффманн-Ля Рош Аг Соединения n-алкилтриазола в качестве антагонистов лизофосфатидной кислоты (lpar)
CA2879570A1 (en) 2012-07-24 2014-01-30 Pharmacyclics, Inc. Mutations associated with resistance to inhibitors of bruton's tyrosine kinase (btk)
CN103965664B (zh) * 2013-01-25 2015-07-22 中国石油化工股份有限公司 一种碳黑粒子分散剂及其制备方法和应用
ES2745041T3 (es) 2013-03-13 2020-02-27 Inflammatory Response Res Inc Uso de levocetirizina y montelukast en el tratamiento de trastornos autoinmunitarios
JP2016512262A (ja) 2013-03-13 2016-04-25 インフラマトリー・レスポンス・リサーチ・インコーポレイテッド 血管炎の処置におけるレボセチリジン及びモンテルカストの使用
AU2014249531B2 (en) 2013-03-13 2018-11-29 IRR, Inc. Use of levocetirizine and montelukast in the treatment of traumatic injury
US10000459B2 (en) 2013-03-15 2018-06-19 Epigen Biosciences, Inc. Heterocyclic compounds useful in the treatment of disease
CA2938626A1 (en) 2013-07-26 2015-01-29 John Rothman Compositions to improve the therapeutic benefit of bisantrene
GB201314926D0 (en) 2013-08-20 2013-10-02 Takeda Pharmaceutical Novel Compounds
US9981942B2 (en) * 2013-12-20 2018-05-29 Laboratorios Del Dr. Esteve S.A. Piperidine derivatives having multimodal activity against pain
JP2017078022A (ja) * 2014-02-28 2017-04-27 クミアイ化学工業株式会社 イソキサゾール誘導体及びそれを用いた農園芸用植物病害防除剤
JP2017526728A (ja) 2014-09-15 2017-09-14 インフラマトリー・レスポンス・リサーチ・インコーポレイテッド 炎症介在性状態の治療におけるレボセチリジン及びモンテルカスト
HK1245153A1 (zh) * 2014-12-23 2018-08-24 Pharmacyclics Llc Btk抑制剂组合和给药方案
US9729562B2 (en) 2015-03-02 2017-08-08 Harris Corporation Cross-layer correlation in secure cognitive network
WO2019041340A1 (en) * 2017-09-04 2019-03-07 Eli Lilly And Company LYSOPHOSPHATIDE ACID RECEPTOR 1 RECEPTOR INHIBITORS (LPAR1)
CN109776351B (zh) * 2017-11-15 2021-11-09 江苏优士化学有限公司 一种重氮乙酸酯连续化合成方法
CN108379275B (zh) * 2018-05-29 2020-05-22 中国医学科学院阜外医院 溶血磷脂酸、溶血磷脂酸受体3以及溶血磷脂酸受体3激动剂的应用
SG11202105276TA (en) 2018-12-03 2021-06-29 Univ Texas Oligo-benzamide analogs and their use in cancer treatment
US12466804B2 (en) 2019-06-18 2025-11-11 Bristol-Myers Squibb Company Cyclobutyl carboxylic acids as LPA antagonists
EP3986552B1 (en) 2019-06-18 2024-09-18 Bristol-Myers Squibb Company Isoxazole carboxylic acids as lpa antagonists
US11091447B2 (en) 2020-01-03 2021-08-17 Berg Llc UBE2K modulators and methods for their use
CA3171979A1 (en) 2020-03-27 2021-09-30 Josep Bassaganya-Riera Plxdc2 ligands
WO2021236518A1 (en) 2020-05-19 2021-11-25 IRR, Inc. Levocetirizine and montelukast in the treatment of sepsis and symptoms thereof
US12383547B2 (en) 2020-07-01 2025-08-12 Vanderbilt University Methods of treatment for a kidney disease
KR102809527B1 (ko) * 2021-01-22 2025-05-21 서울대학교산학협력단 G 단백질 연결 수용체의 억제제를 이용한 상아질 재생 촉진용 조성물 및 제제
CN114907282B (zh) * 2022-05-24 2023-08-22 华南理工大学 一种合成4-苯基烯基异噁唑衍生物的方法
KR20260019497A (ko) * 2023-06-02 2026-02-10 주식회사 메타이뮨 섬유성 질환 치료용 화합물

Family Cites Families (59)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5612359A (en) 1994-08-26 1997-03-18 Bristol-Myers Squibb Company Substituted biphenyl isoxazole sulfonamides
CA2276034A1 (en) 1996-12-23 1998-07-02 Mimi Lifen Quan Oxygen or sulfur containing 5-membered heteroaromatics as factor xa inhibitors
JP3237608B2 (ja) 1997-04-21 2001-12-10 住友製薬株式会社 イソキサゾール誘導体
AU4327600A (en) 1999-04-02 2000-10-23 Du Pont Pharmaceuticals Company Aryl sulfonyls as factor xa inhibitors
ATE420878T1 (de) * 2000-02-18 2009-01-15 Kyowa Hakko Kirin Co Ltd Isoxazol- und thiazolverbindungen und ihre verwendung als medikamente
WO2001072723A1 (en) * 2000-03-28 2001-10-04 Nippon Soda Co.,Ltd. Oxa(thia)zolidine derivative and anti-inflammatory drug
AU2001273040A1 (en) 2000-06-27 2002-01-08 Du Pont Pharmaceuticals Company Factor xa inhibitors
EP1340749A4 (en) 2000-11-17 2007-09-05 Takeda Pharmaceutical ISOXAZOLE DERIVATIVES
DE60234318D1 (de) 2001-02-08 2009-12-24 Ono Pharmaceutical Co Mittel zur behandlung von harnwegserkrankungen, umfassend mittel zur kontrolle des lpa-rezeptors
US7521192B2 (en) 2001-04-18 2009-04-21 Rigel Pharmaceuticals, Inc. EDG: modulators of lymphocyte activation and migration
ATE406915T1 (de) 2001-07-17 2008-09-15 Ono Pharmaceutical Co Mittel zur regulierung der sekretion von pankreassaft mit einem lpa-rezeptor-regler
MY151199A (en) 2001-11-02 2014-04-30 Rigel Pharmaceuticals Inc Substituted diphenyl heterocycles useful for treating hcv infection
AU2002367129A1 (en) 2001-12-25 2003-07-15 Ajinomoto Co., Inc. Organ fibrosis inhibitors
JP2003261545A (ja) 2001-12-28 2003-09-19 Takeda Chem Ind Ltd 神経栄養因子産生・分泌促進剤
US20050261298A1 (en) 2002-01-18 2005-11-24 David Solow-Cordero Methods of treating conditions associated with an Edg-7 receptor
JP2005519915A (ja) 2002-01-18 2005-07-07 セレテック・リミテッド・ライアビリティ・カンパニー Ｅｄｇ受容体に関連する症状の処置方法
US20050113283A1 (en) 2002-01-18 2005-05-26 David Solow-Cordero Methods of treating conditions associated with an EDG-4 receptor
US20050101518A1 (en) 2002-01-18 2005-05-12 David Solow-Cordero Methods of treating conditions associated with an EDG-2 receptor
JP4547912B2 (ja) * 2002-03-05 2010-09-22 小野薬品工業株式会社 ８−アザプロスタグランジン誘導体化合物およびその化合物を有効成分として含有する薬剤
WO2003094965A2 (en) 2002-05-08 2003-11-20 Neuronova Ab Modulation of neural stem cells with s1p or lpa receptor agonists
CA2484233A1 (en) 2002-05-13 2003-11-27 Eli Lilly And Company Multicyclic compounds for use as melanin concentrating hormone antagonists in the treatment of obesity and diabetes
JP4596314B2 (ja) 2002-05-28 2010-12-08 小野薬品工業株式会社 β−アラニン誘導体およびその用途
WO2004002530A1 (ja) 2002-06-26 2004-01-08 Ono Pharmaceutical Co., Ltd. 慢性疾患治療剤
TW200408393A (en) 2002-10-03 2004-06-01 Ono Pharmaceutical Co Antagonist of lysophosphatidine acid receptor
CA2506243A1 (en) 2002-11-19 2004-06-03 Amgen Inc. Amplified genes involved in cancer
US20050065194A1 (en) 2003-01-16 2005-03-24 Geetha Shankar Methods of treating conditions associated with an Edg-2 receptor
US20040167132A1 (en) 2003-01-16 2004-08-26 Geetha Shankar Methods of treating conditions associted with an Edg-2 receptor
US20040192739A1 (en) 2003-01-16 2004-09-30 David Solow-Cordero Methods of treating conditions associated with an Edg-2 receptor
US7135469B2 (en) 2003-03-18 2006-11-14 Bristol Myers Squibb, Co. Linear chain substituted monocyclic and bicyclic derivatives as factor Xa inhibitors
JP2007525449A (ja) 2003-04-11 2007-09-06 ザ ユニバーシティー オブ テネシー リサーチ ファウンデーション リゾホスファチジン酸アナログおよび新生内膜形成の阻害方法
WO2004099164A1 (en) 2003-05-02 2004-11-18 Rigel Pharmaceuticals, Inc. Substituted diphenyl isoxazoles, pyrazoles and oxadiazoles useful for treating hcv infection
EP1638551B1 (en) 2003-05-19 2011-12-21 Irm Llc Immunosuppressant compounds and compositions
WO2005012269A1 (ja) 2003-08-05 2005-02-10 Ajinomoto Co., Inc. 新規アゾール化合物
US7217704B2 (en) 2003-10-09 2007-05-15 The University Of Tennessee Research Foundation LPA receptor agonists and antagonists and methods of use
US7875745B2 (en) 2003-12-19 2011-01-25 Ono Pharmaceutical Co., Ltd. Compounds having lysophosphatidic acid receptor antagonism and uses thereof
DE10360369A1 (de) 2003-12-22 2005-07-14 Bayer Cropscience Ag Amide
WO2005123671A1 (ja) * 2004-06-22 2005-12-29 Taisho Pharmaceutical Co., Ltd. ピロール誘導体
JP2006096712A (ja) 2004-09-30 2006-04-13 Senju Pharmaceut Co Ltd Ｌｐａ受容体拮抗剤を含有する角膜知覚改善剤
EP1893591A1 (en) 2005-06-08 2008-03-05 Novartis AG POLYCYCLIC OXADIAZOLES OR I SOXAZOLES AND THEIR USE AS SlP RECEPTOR LIGANDS
WO2007007588A1 (ja) 2005-07-08 2007-01-18 Ono Pharmaceutical Co., Ltd. 平面性を有する環状基を母核とする化合物
CA2619101A1 (en) 2005-08-23 2007-03-01 Irm Llc Immunosuppressant compounds and compositions
CA2643670A1 (en) 2006-02-27 2007-08-30 Sterix Limited Diaryl compounds as non-steroidal inhibitors of 17-beta hydroxysteroid dehydrogenase and/or steroid sulphatase for the treatment of oestrogen-related diseases such as hormone dependent breast cancer
US20090029949A1 (en) 2006-05-25 2009-01-29 Parrill-Baker Abby L GPCR Ligands Identified by Computational Modeling
JP2009545531A (ja) 2006-07-24 2009-12-24 ユニバーシティ オブ バージニア パテント ファンデーション ホスホン酸ビニルリゾホスファチジン酸受容体拮抗薬
WO2008024979A2 (en) 2006-08-24 2008-02-28 The Scripps Research Institute Methods utilizing cell-signaling lysophospholipids
US20080051372A1 (en) 2006-08-24 2008-02-28 The Scripps Research Institute Methods utilizing cell-signaling lysophospholipids
WO2008112201A2 (en) 2007-03-12 2008-09-18 The General Hospital Corporation Lysophosphatidic acid receptor targeting for lung disease
US9163091B2 (en) 2007-05-30 2015-10-20 Lpath, Inc. Compositions and methods for binding lysophosphatidic acid
WO2009011850A2 (en) 2007-07-16 2009-01-22 Abbott Laboratories Novel therapeutic compounds
CN105418450A (zh) 2008-05-05 2016-03-23 赛诺菲-安万特 酰基氨基取代的稠合环戊烷羧酸衍生物及它们作为药物的用途
JP4933512B2 (ja) 2008-10-09 2012-05-16 住友化学株式会社 導光板
WO2010068775A2 (en) 2008-12-11 2010-06-17 Amira Pharmaceuticals, Inc. Alkyne antagonists of lysophosphatidic acid receptors
GB2466121B (en) 2008-12-15 2010-12-08 Amira Pharmaceuticals Inc Antagonists of lysophosphatidic acid receptors
GB2470833B (en) 2009-06-03 2011-06-01 Amira Pharmaceuticals Inc Polycyclic antagonists of lysophosphatidic acid receptors
IN2012DN00754A (enExample) 2009-08-04 2015-06-19 Amira Pharmaceuticals Inc
WO2011041551A1 (en) * 2009-10-01 2011-04-07 Intermune, Inc. Therapeutic antiviral peptides
GB2474120B (en) 2009-10-01 2011-12-21 Amira Pharmaceuticals Inc Compounds as Lysophosphatidic acid receptor antagonists
GB2474748B (en) * 2009-10-01 2011-10-12 Amira Pharmaceuticals Inc Polycyclic compounds as lysophosphatidic acid receptor antagonists
AU2010340369B2 (en) * 2010-01-06 2014-06-05 Apple Inc. Device, method, and graphical user interface for mapping directions between search results

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
None
See also references of EP2483269A4

Cited By (67)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8455499B2 (en) 2008-12-11 2013-06-04 Amira Pharmaceuticals, Inc. Alkyne antagonists of lysophosphatidic acid receptors
US8440707B2 (en) 2008-12-15 2013-05-14 Amira Pharmaceuticals, Inc. Antagonists of lysophosphatidic acid receptors
US8048902B2 (en) 2008-12-15 2011-11-01 Amira Pharmaceuticals, Inc. Antagonists of lysophosphatidic acid receptors
US8058300B2 (en) 2009-06-03 2011-11-15 Amira Pharmaceuticals, Inc. Polycyclic antagonists of lysophosphatidic acid receptors
US8273780B2 (en) 2009-06-03 2012-09-25 Amira Pharmaceuticals, Inc. Polycyclic antagonists of lysophosphatidic acid receptors
US8592402B2 (en) 2009-08-04 2013-11-26 Amira Pharmaceuticals, Inc. Compounds as lysophosphatidic acid receptor antagonists
WO2011041729A2 (en) 2009-10-01 2011-04-07 Amira Pharmaceuticals, Inc. Compounds as lysophosphatidic acid receptor antagonists
US9624182B2 (en) 2009-10-01 2017-04-18 Amira Pharmaceuticals, Inc. Compounds as lysophosphatidic acid receptor antagonists
EP2483252A4 (en) * 2009-10-01 2013-04-03 Amira Pharmaceuticals Inc COMPOUNDS AS LYSOPHOSPHIC ACID RECEPTOR ANTAGONISTS
US8217066B2 (en) 2009-10-01 2012-07-10 Amira Pharmaceuticals, Inc. Compounds as lysophosphatidic acid receptor antagonists
US8664220B2 (en) 2009-10-01 2014-03-04 Amira Pharmaceuticals, Inc. Polycyclic compounds as lysophosphatidic acid receptor antagonists
US10000456B2 (en) 2009-10-01 2018-06-19 Amira Pharmaceuticals, Inc. Polycyclic compounds as lysophosphatidic acid receptor antagonists
US8778983B2 (en) 2009-10-01 2014-07-15 Amira Pharmaceuticals, Inc. Polycyclic compounds as lysophosphatidic acid receptor antagonists
US9090573B2 (en) 2009-10-01 2015-07-28 Amira Pharmaceuticals, Inc. Compounds as lysophosphatidic acid receptor antagonists
EP2483253A4 (en) * 2009-10-01 2013-04-03 Amira Pharmaceuticals Inc COMPOUNDS USEFUL AS ANTAGONISTS OF LYSOPHOSPHATIDE ACID RECEPTOR (LPA)
US8541587B2 (en) 2011-04-05 2013-09-24 Amira Pharmaceuticals, Inc. Lysophosphatidic acid receptor antagonists
WO2013070879A1 (en) 2011-11-10 2013-05-16 Bristol-Myers Squibb Company Methods for treating spinal cord injury with lpa receptor antagonists
WO2013078283A1 (en) 2011-11-22 2013-05-30 Intermune, Inc. Methods of diagnosing and treating idiopathic pulmonary fibrosis
KR20150100756A (ko) 2012-12-28 2015-09-02 우베 고산 가부시키가이샤 할로겐 치환 헤테로환 화합물
WO2014104372A1 (ja) 2012-12-28 2014-07-03 宇部興産株式会社 ハロゲン置換へテロ環化合物
US10000463B2 (en) 2012-12-28 2018-06-19 Ube Industries, Ltd. Halogen-substituted heterocyclic compound
EP3360869A1 (en) 2012-12-28 2018-08-15 Ube Industries, Ltd. Halogen-substituted heterocyclic compound useful for the treatment of diseases caused by lpa
US10597375B2 (en) 2012-12-28 2020-03-24 Ube Industries, Ltd. Halogen-substituted heterocyclic compound
KR20170016988A (ko) 2014-06-27 2017-02-14 우베 고산 가부시키가이샤 할로겐 치환 헤테로환 화합물의 염
US10023554B2 (en) 2014-06-27 2018-07-17 Ube Industries, Ltd. Halogen-substituted heterocyclic compound salt
WO2016197009A1 (en) 2015-06-05 2016-12-08 Vertex Pharmaceuticals Incorporated Triazoles for the treatment of demyelinating diseases
US10576062B2 (en) 2016-06-21 2020-03-03 Bristol-Myers Squibb Company Carbamoyloxymethyl triazole cyclohexyl acids as LPA antagonists
USRE49352E1 (en) 2016-06-21 2023-01-03 Bristol-Myers Squibb Company Carbamoyloxymethyl triazole cyclohexyl acids as LPA antagonists
US11007180B2 (en) 2016-06-21 2021-05-18 Bristol-Myers Squibb Company Carbamoyloxymethyl triazole cyclohexyl acids as LPA antagonists
US11572353B2 (en) 2016-09-19 2023-02-07 Beijing Innocare Pharma Tech Co., Ltd. Alkynyl-substituted heterocyclic compound, preparation method therefor and medical use thereof
WO2018106643A1 (en) 2016-12-06 2018-06-14 Vertex Pharmaceuticals Incorporated Heterocyclic azoles for the treatment of demyelinating diseases
WO2018106646A1 (en) 2016-12-06 2018-06-14 Vertex Pharmaceuticals Incorporated Aminotriazoles for the treatment of demyelinating diseases
WO2018106641A1 (en) 2016-12-06 2018-06-14 Vertex Pharmaceuticals Incorporated Pyrazoles for the treatment of demyelinating diseases
US11498904B2 (en) 2017-11-14 2022-11-15 Merck Sharp & Dohme Llc Substituted biaryl compounds as indoleamine 2,3-dioxygenase (IDO) inhibitors
US10647705B2 (en) 2017-11-14 2020-05-12 Merck Sharp & Dohme Corp. Substituted biaryl compounds as indoleamine 2,3-dioxygenase (IDO) inhibitors
US10995085B2 (en) 2017-11-14 2021-05-04 Merck Sharp & Dohme Corp. Substituted biaryl compounds as indoleamine 2,3-dioxygenase (IDO) inhibitors
US11319309B2 (en) 2017-12-19 2022-05-03 Bristol-Myers Squibb Company Cyclohexyl acid isoxazole azines as LPA antagonists
US11447475B2 (en) 2017-12-19 2022-09-20 Bristol-Myers Squibb Company Isoxazole N-linked carbamoyl cyclohexyl acids as LPA antagonists
US11261180B2 (en) 2017-12-19 2022-03-01 Bristol-Myers Squibb Company Cyclohexyl acid isoxazole azoles as LPA antagonists
US11267800B2 (en) 2017-12-19 2022-03-08 Bristol-Myers Squibb Company Cyclohexyl acid triazole azines as LPA antagonists
US11312706B2 (en) 2017-12-19 2022-04-26 Bristol-Myers Squibb Company Cyclohexyl acid pyrazole azines as LPA antagonists
US11319315B2 (en) 2017-12-19 2022-05-03 Bristol-Myers Squibb Company Cyclohexyl acid triazole azoles as LPA antagonists
US12195444B2 (en) 2017-12-19 2025-01-14 Bristol-Myers Squibb Company Triazole n-linked carbamoyl cyclohexyl acids as LPA antagonists
US11352345B2 (en) 2017-12-19 2022-06-07 Bristol-Myers Squibb Company Cyclohexyl acid pyrazole azoles as LPA antagonists
US11384067B2 (en) 2017-12-19 2022-07-12 Bristol-Myers Squibb Company Pyrazole n-linked carbamoyl cyclohexyl acids as LPA antagonists
US11261174B2 (en) 2017-12-19 2022-03-01 Bristol-Myers Squibb Company Pyrazole O-linked carbamoyl cyclohexyl acids as LPA antagonists
US11180488B2 (en) 2017-12-19 2021-11-23 Bristol-Myers Squibb Company Isoxazole o-linked carbamoyl cyclohexyl acids as LPA antagonists
US11008300B2 (en) 2017-12-19 2021-05-18 Bristol-Myers Squibb Company Triazole n-linked carbamoyl cyclohexyl acids as LPA antagonists
WO2019126087A1 (en) * 2017-12-19 2019-06-27 Bristol-Myers Squibb Company Cyclohexyl acid isoxazole azoles as lpa antagonists
US10662172B2 (en) 2017-12-19 2020-05-26 Bristol-Myers Squibb Company Triazole N-linked carbamoyl cyclohexyl acids as LPA antagonists
US11697646B2 (en) 2017-12-19 2023-07-11 Bristol-Myers Squibb Company Triazole N-linked carbamoyl cyclohexyl acids as LPA antagonists
RU2818246C2 (ru) * 2018-06-18 2024-04-26 Эпиджен Байосайенсиз, Инк. Гетероциклические соединения, применимые в лечении заболевания
US12428430B2 (en) 2018-09-18 2025-09-30 Bristol-Myers Squibb Company Oxabicyclo acids as LPA antagonists
US12209072B2 (en) 2018-09-18 2025-01-28 Bristol-Myers Squibb Company Cyclopentyl acids as LPA antagonists
US11548871B2 (en) 2019-11-15 2023-01-10 Gilead Sciences, Inc. Triazole carbamate pyridyl sulfonamides as LPA receptor antagonists and uses thereof
US11999717B2 (en) 2019-11-15 2024-06-04 Gilead Sciences, Inc. Triazole carbamate pyridyl sulfonamides as LPA receptor antagonists and uses thereof
US11912686B2 (en) 2020-06-03 2024-02-27 Gilead Sciences, Inc. LPA receptor antagonists and uses thereof
US12139474B2 (en) 2020-06-03 2024-11-12 Gilead Sciences, Inc. LPA receptor antagonists and uses thereof
US11702407B2 (en) 2020-06-03 2023-07-18 Gilead Sciences, Inc. LPA receptor antagonists and uses thereof
US11584738B2 (en) 2020-06-03 2023-02-21 Gilead Sciences, Inc. LPA receptor antagonists and uses thereof
US12378229B2 (en) 2021-02-02 2025-08-05 Liminal Biosciences Limited GPR84 antagonists and uses thereof
US11980609B2 (en) 2021-05-11 2024-05-14 Gilead Sciences, Inc. LPA receptor antagonists and uses thereof
US12503454B2 (en) 2021-05-13 2025-12-23 Gilead Sciences, Inc. LPA receptor antagonists and uses thereof
US11939318B2 (en) 2021-12-08 2024-03-26 Gilead Sciences, Inc. LPA receptor antagonists and uses thereof
US11884627B2 (en) 2022-02-25 2024-01-30 Lhotse Bio, Inc. Compounds and compositions for treating conditions associated with LPA receptor activity
US12428375B2 (en) 2022-02-25 2025-09-30 Lhotse Bio, Inc. Compounds and compositions for treating conditions associated with LPA receptor activity
WO2025026266A1 (zh) * 2023-07-28 2025-02-06 武汉朗来科技发展有限公司 作为lpar1拮抗剂的化合物、其药物组合物和用途

Also Published As

Publication number Publication date
EP2483269A4 (en) 2013-05-01
PE20120997A1 (es) 2012-08-01
CN102770415A (zh) 2012-11-07
TW201125862A (en) 2011-08-01
AR078495A1 (es) 2011-11-09
IN2012DN02702A (enExample) 2015-09-04
TWI415849B (zh) 2013-11-21
US10000456B2 (en) 2018-06-19
GB2474748B (en) 2011-10-12
MX2012003723A (es) 2012-05-08
GB2474748A (en) 2011-04-27
EP2483251A2 (en) 2012-08-08
US20110082164A1 (en) 2011-04-07
US8664220B2 (en) 2014-03-04
WO2011041461A3 (en) 2011-08-25
CL2012000812A1 (es) 2012-09-07
CN102656168A (zh) 2012-09-05
EA201270467A1 (ru) 2012-09-28
JP2013506680A (ja) 2013-02-28
TN2012000126A1 (en) 2013-09-19
WO2011041462A2 (en) 2011-04-07
IL218962A0 (en) 2012-07-31
GB201016312D0 (en) 2010-11-10
IN2012DN02730A (enExample) 2015-09-11
WO2011041462A3 (en) 2011-08-11
CN102770415B (zh) 2014-09-24
US20140256744A1 (en) 2014-09-11
KR20120097490A (ko) 2012-09-04
US8778983B2 (en) 2014-07-15
JP2013506679A (ja) 2013-02-28
EP2483251B1 (en) 2016-10-26
US20130072490A1 (en) 2013-03-21
BR112012007102A2 (pt) 2016-04-26
EP2483269A2 (en) 2012-08-08
PH12012500572A1 (en) 2012-10-22
UY32923A (es) 2010-11-30
EP2483251A4 (en) 2013-05-01
CA2776779A1 (en) 2011-04-07
CN102656168B (zh) 2015-04-01
AU2010300594A1 (en) 2012-05-17

Similar Documents

Publication Publication Date Title
US8778983B2 (en) Polycyclic compounds as lysophosphatidic acid receptor antagonists
EP2438048B1 (en) Polycyclic antagonists of lysophosphatidic acid receptors
US8217066B2 (en) Compounds as lysophosphatidic acid receptor antagonists
KR101323054B1 (ko) 리소포스파티딘산 수용체의 길항 물질
HK1163085B (en) Polycyclic antagonists of lysophosphatidic acid receptors

Legal Events

Date Code Title Description
WWE Wipo information: entry into national phase

Ref document number: 201080054537.6

Country of ref document: CN

121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 10821201

Country of ref document: EP

Kind code of ref document: A1

WWE Wipo information: entry into national phase

Ref document number: 12012500572

Country of ref document: PH

WWE Wipo information: entry into national phase

Ref document number: 2702/DELNP/2012

Country of ref document: IN

Ref document number: MX/A/2012/003723

Country of ref document: MX

WWE Wipo information: entry into national phase

Ref document number: 218962

Country of ref document: IL

Ref document number: 12053559

Country of ref document: CO

Ref document number: 000410-2012

Country of ref document: PE

ENP Entry into the national phase

Ref document number: 20127008251

Country of ref document: KR

Kind code of ref document: A

WWE Wipo information: entry into national phase

Ref document number: 2776779

Country of ref document: CA

Ref document number: 2012532286

Country of ref document: JP

Ref document number: 2010821201

Country of ref document: EP

WWE Wipo information: entry into national phase

Ref document number: 1201001438

Country of ref document: TH

NENP Non-entry into the national phase

Ref country code: DE

WWE Wipo information: entry into national phase

Ref document number: 2012000812

Country of ref document: CL

WWE Wipo information: entry into national phase

Ref document number: 2010300594

Country of ref document: AU

WWE Wipo information: entry into national phase

Ref document number: 201270467

Country of ref document: EA

WWE Wipo information: entry into national phase

Ref document number: DZP2012000276

Country of ref document: DZ

ENP Entry into the national phase

Ref document number: 2010300594

Country of ref document: AU

Date of ref document: 20100929

Kind code of ref document: A

REG Reference to national code

Ref country code: BR

Ref legal event code: B01A

Ref document number: 112012007102

Country of ref document: BR

ENP Entry into the national phase

Ref document number: 112012007102

Country of ref document: BR

Kind code of ref document: A2

Effective date: 20120329