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WO2019072130A1 - Composé de 1,2,4-triazole - Google Patents

Composé de 1,2,4-triazole Download PDF

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Publication number
WO2019072130A1
WO2019072130A1 PCT/CN2018/109045 CN2018109045W WO2019072130A1 WO 2019072130 A1 WO2019072130 A1 WO 2019072130A1 CN 2018109045 W CN2018109045 W CN 2018109045W WO 2019072130 A1 WO2019072130 A1 WO 2019072130A1
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Prior art keywords
compound
disease
pharmaceutically acceptable
acceptable salt
triazole compound
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Chinese (zh)
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王义汉
李焕银
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Shenzhen Targetrx Inc
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Shenzhen Targetrx Inc
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero 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
    • A61K31/4164—1,3-Diazoles
    • 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
    • A61K31/4436—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a heterocyclic ring having sulfur as a ring hetero atom
    • 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
    • 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
    • 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
    • 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
    • A61P19/00—Drugs for skeletal disorders
    • 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
    • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
    • 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
    • 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
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • 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
    • 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
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B59/00—Introduction of isotopes of elements into organic compounds ; Labelled organic compounds per se
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B59/00—Introduction of isotopes of elements into organic compounds ; Labelled organic compounds per se
    • C07B59/002—Heterocyclic compounds
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/56—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/05—Isotopically modified compounds, e.g. labelled

Definitions

  • the invention belongs to the technical field of medicine, and in particular relates to a 1,2,4-triazole compound and a composition comprising the same and use thereof.
  • the invention relates to certain indole substituted 5-(4-cyclopropyl-1H-imidazol-1-yl)-2-fluoro-4-methyl-N-[6-(4-isopropyl- 4H-1,2,4,-triazol-3-yl)-2-pyridyl]-benzamide, these guanidine substituted compounds are used for the treatment of ASK1-mediated diseases with better pharmacokinetic properties .
  • ADME absorption, distribution, metabolism, and/or excretion
  • ADME limitation that affects many drugs is the formation of toxic or bioreactive metabolites.
  • some patients receiving the drug may be exposed to toxicity, or such drug safe doses may be limited such that the patient receives a suboptimal amount of active agent.
  • changing the dosing interval or formulation method may help reduce clinical adverse effects, but the formation of such undesirable metabolites is generally inherent in the metabolism of the compound.
  • oxime modification on the metabolic properties of the drug is not predictable, even if the ruthenium atom penetrates into a known metabolic site. It is only possible to determine whether and how the metabolic rate differs from its non-deuterated counterpart by actually preparing and testing the deuterated drug. Many drugs have multiple sites where metabolism may occur. The degree of deuteration necessary for the various drugs will be different for sites that require deuteration and for the effects of metabolism (if any).
  • the present invention relates to novel derivatives of ceremoniessertib and pharmaceutically acceptable salts thereof.
  • the invention also provides compositions comprising the compounds of the invention, and the use of such compositions in a method of treatment of diseases and conditions which are beneficially treated by administration of an ASK1 (apoptosis signal-regulated kinase 1) inhibitor.
  • ASK1 apoptosis signal-regulated kinase 1
  • Bibliosertib also known as GS-4997 and chemical name 5-(4-cyclopropyl-1H-imidazol-1-yl)-2-fluoro-4-methyl-N-[6-(4-isopropyl- 4H-1,2,4,-triazol-3-yl)-2-pyridine]-benzamide (having the structure shown below) is a small molecule inhibitor developed by Gilead Pharmaceuticals Co., Ltd., which can effectively reduce ASK1 Pathological function.
  • the clinical phase II trial of Rhythmsertib in the treatment of nonalcoholic steatohepatitis (NASH) showed anti-fibrotic effects in NASH patients only after 24 weeks.
  • BGsertib's research for the treatment of NASH is in clinical phase III
  • the study for the treatment of alcoholic hepatitis is in clinical phase II.
  • ASK1 activation and signaling have been reported to play an important role in a wide range of diseases including neurodegenerative disorders, cardiovascular disorders, inflammatory disorders and metabolic disorders.
  • ASK1 is involved in mediating organ damage following ischemia and reperfusion of the heart, brain and kidney (Watanabe et al. (2005) BBRC 333, 562-567; Zhang et al. (2003) LifeSci 74-37-43; Terada Et al. (2007) BBRC364: 1043-49).
  • the present invention discloses a 1,2,4-triazole compound and a composition comprising the same, which has a strong ASK1 inhibitor activity.
  • a first aspect of the invention relates to a 1,2,4-triazole compound of the formula (I), or a pharmaceutically acceptable salt thereof:
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , Y 1 , Y 2 , Y 3 , Y 4 , Y 5 and Y 6 are each independently hydrogen or deuterium;
  • X 1 , X 2 and X 3 are each independently CH 3 , CH 2 D, CHD 2 or CD 3 .
  • X 1 , X 2 and X 3 are each CH 3 , then R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , Y 1 , Y 2 , Y 3 , at least one of Y 4 , Y 5 and Y 6 is ⁇ .
  • the compound of the formula (I) contains at least one halogen atom, more preferably one germanium atom, more preferably two germanium atoms, more preferably three germanium atoms, more preferably four germanium atoms. More preferably, six helium atoms, more preferably seven helium atoms, more preferably nine helium atoms.
  • the cerium isotope content of cerium in the deuterated position is at least 0.015%, preferably greater than 30%, more preferably greater than 50%, more preferably greater than 75%, more preferably greater than the natural strontium isotope content.
  • the ground is greater than 95%, more preferably greater than 99%.
  • the seventeenth place contains ⁇ , preferably the eighteen ⁇ , preferably nineteen ⁇ , more preferably twenty ⁇ , more preferably twenty one ⁇ , more preferably twenty two One contains ⁇ , and more preferably
  • the compound of the formula (I) contains at least one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, ten Three, fourteen, fifteen, sixteen, seventeen, eighteen, nineteen, twenty, twenty-one, twenty-two, twenty-three atomic atoms.
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 are each independently hydrogen or deuterium.
  • R 1 , R 3 and R 4 are deuterium.
  • R 5 is deuterium
  • R 1 , R 3 , R 4 and R 5 are deuterium.
  • Y 1 , Y 2 , Y 3 , Y 4 , Y 5 and Y 6 are each independently hydrogen or deuterium.
  • Y 1 is deuterium
  • Y 2 , Y 3 , Y 4 , Y 5 and Y 6 are deuterium.
  • X 1 , X 2 and X 3 are each independently CH 3 , CH 2 D, CHD 2 or CD 3 .
  • X 1 , X 2 is CD 3 .
  • X 3 is CD 3 .
  • the compound is selected from the group consisting of the compounds or pharmaceutically acceptable salts thereof:
  • the compound does not include a non-deuterated compound.
  • the present invention also discloses a pharmaceutical composition
  • a pharmaceutical composition comprising a pharmaceutically acceptable excipient and a 1,2,4-triazole compound as described above, or a pharmaceutically acceptable compound thereof Accepted salt.
  • the present invention also discloses a method for preparing a pharmaceutical composition as described above, comprising the steps of: pharmaceutically acceptable excipients with 1, 2, 4 -3 as described above
  • the azole compound, or a pharmaceutically acceptable salt thereof, is mixed to form a pharmaceutical composition.
  • the pharmaceutical composition is an injection, a sachet, a tablet, a pill, a powder or a granule.
  • the pharmaceutical composition further comprises an additional therapeutic agent, the additional therapeutic agent being a medicament for treating cancer, cardiovascular disease, inflammation, infection, immune disease, metabolic disease or organ transplantation. .
  • a fourth aspect of the invention provides a method of treating at least a portion of a disease mediated by ASK1 in a patient in need thereof, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of the first aspect of the invention or a pharmaceutically acceptable compound thereof Accepted salt, or a pharmaceutical composition thereof.
  • the compound treatable by the compounds of the invention is selected from the group consisting of diabetes, diabetic nephropathy, nephropathy, renal fibrosis, pulmonary fibrosis, idiopathic pulmonary fibrosis (IPF), liver fibrosis, pulmonary hypertension, non-alcoholic Fatty liver hepatitis, liver disease, alcoholic liver disease, inflammatory disease, autoimmune disease, proliferative disease, transplant rejection, diseases involving impaired cartilage metabolism, congenital cartilage malformation, or diseases associated with excessive secretion of IL6 .
  • the treatable disease is nonalcoholic steatohepatitis or alcoholic liver disease.
  • the treatable condition is pulmonary hypertension or pulmonary fibrosis.
  • the treatable disease is diabetic nephropathy, kidney disease or renal fibrosis.
  • the compound of the deuterated ASK1 inhibitor of the present invention and a pharmaceutically acceptable salt thereof have superior pharmacokinetic and/or pharmacodynamic properties compared to the undeuterated compound, and thus are more suitable as an ASK1 inhibitor
  • the compounds are more suitable for the preparation of a medicament for the treatment of ASK1-mediated related diseases.
  • the present invention has been completed on this basis.
  • deuterated means that one or more hydrogens in the compound or group are replaced by deuterium; deuteration may be monosubstituted, disubstituted, polysubstituted or fully substituted.
  • deuteration may be monosubstituted, disubstituted, polysubstituted or fully substituted.
  • deuterated is used interchangeably with “one or more deuterated”.
  • non-deuterated compound means a compound containing a proportion of germanium atoms not higher than the natural helium isotope content (0.015%).
  • the invention also includes isotopically labeled compounds, equivalent to the original compounds disclosed herein.
  • isotopes which may be listed as compounds of the present invention include hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine and chlorine isotopes such as 2 H, 3 H, 13 C, 14 C, 15 N, 17 O, 18 O, respectively. , 31 P, 32 P, 35 S, 18 F and 36 Cl. a compound, or an enantiomer, a diastereomer, an isomer, or a pharmaceutically acceptable salt or solvate of the present invention, wherein an isotope or other isotopic atom containing the above compound is within the scope of the present invention .
  • isotopically-labeled compounds of the present invention such as the radioisotopes of 3 H and 14 C, are also among them, useful in tissue distribution experiments of drugs and substrates. ⁇ , ie 3 H and carbon-14, ie 14 C, are easier to prepare and detect and are preferred in isotopes.
  • Isotopically labeled compounds can be prepared in a conventional manner by substituting a readily available isotopically labeled reagent with a non-isotopic reagent using the protocol of the examples.
  • the present invention provides a compound of formula (I), or a pharmaceutically acceptable salt, prodrug, hydrate or solvate thereof, crystal form, stereoisomer or isotopic variation thereof:
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , Y 1 , Y 2 , Y 3 , Y 4 , Y 5 , Y 6 are each independently hydrogen or hydrazine;
  • X 1 , X 2 , X 3 are each independently CH 3 , CH 2 D, CHD 2 or CD 3 ;
  • X 1 , X 2 and X 3 are each CH 3 , then R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , Y 1 , Y 2 , Y 3 , at least one of Y 4 , Y 5 and Y 6 is ⁇ .
  • the cerium isotope content of cerium in the deuterated position is at least 0.015% greater than the natural isotope content, preferably greater than 30%, more preferably greater than 50%, more preferably greater than 75%, more preferably Preferably, it is greater than 95%, more preferably greater than 99%.
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 are each independently hydrogen or deuterium
  • R 1 selected from Hydrogen or hydrazine
  • R 2 is selected from hydrogen or hydrazine
  • R 3 is selected from hydrogen or hydrazine, and so on, until R 8 is selected from hydrogen or hydrazine.
  • R 1 is hydrogen or R 1 is deuterium
  • R 2 is hydrogen or R 2 is deuterium
  • R 3 is hydrogen or R 3 is deuterium
  • R 8 is hydrogen or R 8 is deuterium.
  • Y 1 , Y 2 , Y 3 , Y 4 , Y 5 and Y 6 are each independently hydrogen or deuterium
  • Y 1 being selected from hydrogen or deuterium
  • Y 2 is selected from hydrogen or hydrazine
  • Y 3 is selected from hydrogen or hydrazine
  • Y 6 is selected from hydrogen or hydrazine. More specifically, it includes that Y 1 is hydrogen or Y 1 is deuterium
  • Y 2 is hydrogen or Y 2 is deuterium
  • Y 3 is hydrogen or Y 3 is deuterium
  • Y 6 is hydrogen or Y 6 is deuterium.
  • X 1 , X 2 , X 3 are each independently CH 3 , CH 2 D, CHD 2 or CD 3 " includes X 1 selected from CH 3 , CH 2 D, CHD 2 or CD 3 , X 2 is selected from the group consisting of CH 3 , CH 2 D, CHD 2 or CD 3 , and X 3 is selected from the group consisting of CH 3 , CH 2 D, CHD 2 or CD 3 . More specifically, it includes that X 1 is CH 3 , X 1 is CH 2 D, X 1 is CHD 2 or X 1 is CD 3 , X 2 is CH 3 , X 2 is CH 2 D, and X 2 is CHD 2 or X. 2 is a technical scheme in which CD 3 , X 3 is CH 3 , X 3 is CH 2 D, X 3 is CHD 2 or X 3 is CD 3 .
  • the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt, prodrug, hydrate or solvate thereof, crystalline form, stereoisomer or isotopic variation thereof, wherein R 7 And R 8 , Y 2 -Y 6 are hydrogen, R 1 -R 8 and Y 1 are each independently hydrogen or deuterium, and X 1 , X 2 and X 3 are each independently CH 3 , CH 2 D, CHD 2 or CD 3 is additionally provided that the compound contains at least one ruthenium atom.
  • R 2 and R 6 are hydrogen.
  • R 1 , R 3 and R 4 are each independently selected from hydrogen or hydrazine. In another more preferred embodiment, R 1 , R 3 and R 4 are hydrogen. In another more preferred embodiment, R 1 , R 3 and R 4 are deuterium.
  • R 5 is hydrogen or deuterium. In another more preferred embodiment, R 5 is hydrogen. In another more preferred embodiment, R 5 is deuterium.
  • X 3 is CH 3 .
  • X 1 and X 2 are each independently selected from CH 3 or CD 3 . In another more preferred embodiment, X 1 and X 2 are CH 3 . In another more preferred embodiment, X 1 and X 2 are CD 3 .
  • Y 1 is hydrogen or deuterium. In another more preferred embodiment, Y 1 is hydrogen. In another more preferred embodiment, Y 1 is hydrazine.
  • pharmaceutically acceptable salt means that it is suitable for contact with human and lower animal tissues without undue toxicity, irritation, allergies, etc., and with reasonable benefits, within the scope of sound medical judgment. / Those dangerous proportions of those salts.
  • Pharmaceutically acceptable salts are well known in the art. For example, Berge et al., pharmaceutically acceptable salts as described in detail in J. Pharmaceutical Sciences (1977) 66: 1-19.
  • Pharmaceutically acceptable salts of the compounds of the invention include those derived from suitable inorganic and organic acids and inorganic and organic bases.
  • non-toxic acid addition salts examples include salts with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid, or salts with organic acids such as acetic acid, oxalic acid, Maleic acid, tartaric acid, citric acid, succinic acid or malonic acid. Also included are salts formed using conventional methods in the art, for example, ion exchange methods.
  • adipic acid salts alginate, ascorbate, aspartate, besylate, benzoate, disulfate, borate, butyrate, camphor Acid salt, camphor sulfonate, citrate, cyclopentanoate, digluconate, lauryl sulfate, ethanesulfonate, formate, fumarate, gluconate, glycerol Phosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate , malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate Salt, pectin
  • Pharmaceutically acceptable salts derived from suitable bases include the alkali metal, alkaline earth metal, ammonium and N + (C 1-4 alkyl) 4 salts.
  • Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium salts, and the like.
  • other pharmaceutically acceptable salts include non-toxic ammonium salts, quaternary ammonium salts and amine cations formed with counterions, counterions such as halides, hydroxides, carboxylates, sulfates, phosphates, Nitrate, lower alkyl sulfonate and aryl sulfonate.
  • solvate refers to a complex of a compound of the invention that is coordinated to a solvent molecule to form a specific ratio.
  • Hydrophilate means a complex formed by the coordination of a compound of the invention with water.
  • prodrug includes a compound of the formula (I) which is biologically active or inactive, which, when taken by a suitable method, is metabolized or chemically reacted in the human body, or converted into a compound of the formula (I), or a formula a salt or solution of a compound of (I).
  • the prodrugs include, but are not limited to, carboxylic acid esters, carbonates, phosphates, nitrates, sulfates, sulfone esters, sulfoxide esters, amino compounds, carbamates, azo compounds, phosphorus of the compound. In the form of an amide, a glucoside, an ether, an acetal or the like.
  • the compound of the present invention Since the compound of the present invention has excellent activity for inhibiting ASK1 kinase, the compound of the present invention and various crystal forms thereof, pharmaceutically acceptable salts, hydrates or solvates thereof, and a pharmaceutical composition containing the compound of the present invention as a main active ingredient Therapies can be used to treat, prevent, and alleviate ASK1-mediated diseases. According to the prior art, the compounds of the present invention are useful for the treatment of chronic liver diseases, cardiovascular diseases, metabolic disorders, respiratory disorders, gastrointestinal disorders, and neurodegenerative diseases.
  • compositions of the present invention comprise a safe or effective amount of a compound of the present invention, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient or carrier.
  • safe and effective amount it is meant that the amount of the compound is sufficient to significantly improve the condition without causing serious side effects.
  • the pharmaceutical compositions contain from 0.5 to 2000 mg of the compound of the invention per agent, more preferably from 1 to 500 mg of the compound of the invention per agent.
  • the "one dose" is a capsule or tablet.
  • “Pharmaceutically acceptable excipient” means a non-toxic carrier, adjuvant or vehicle that does not destroy the pharmacological activity of the compound formulated together.
  • Pharmaceutically acceptable carriers, adjuvants, or vehicles that can be used in the compositions of the present invention include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins (eg, human serum albumin) ), buffer substances (such as phosphate), glycine, sorbic acid, potassium sorbate, a mixture of partial glycerides of saturated plant fatty acids, water, salt or electrolyte (such as protamine sulfate), disodium hydrogen phosphate, potassium hydrogen phosphate, Sodium chloride, zinc salt, silica gel, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based material, polyethylene glycol, sodium carboxymethyl cellulose, polyacrylate, wax, polyethylene-polyoxypropylene-embedded Seg
  • the mode of administration of the compound or pharmaceutical composition of the present invention is not particularly limited, and representative modes of administration include, but are not limited to, oral, duodenal, rectal, parenteral (intravenous, intramuscular or subcutaneous) and topical administration. medicine.
  • Solid dosage forms for oral administration include capsules, tablets, pills, and granules.
  • the active compound is mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or mixed with: (a) a filler or solubilizer, for example, starch , lactose, sucrose, glucose, dry diol and silicic acid; (b) binders, for example, hydroxymethylcellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose and gum arabic; (c) humectants, For example, glycerin; (d) a disintegrant such as agar, calcium carbonate, potato starch or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) a slow solvent, for example, paraffin; An absorption accelerator, for example, a quaternary amine compound; (g) a wetting agent such as cetyl alcohol and
  • Solid dosage forms such as tablets, troches, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other materials known in the art. They may contain opacifying agents and the release of the active compound or compound in such compositions may be released in a portion of the digestive tract in a delayed manner. Examples of embedding components that can be employed are polymeric and waxy materials. If necessary, the active compound may also be in microencapsulated form with one or more of the above-mentioned excipients.
  • Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or elixirs.
  • Liquid dosage forms can contain, in addition to the active compound, inert release agents conventionally employed in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1, 3-butanediol, dimethylformamide and oils, especially cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil and sesame oil or a mixture of these substances.
  • inert release agents conventionally employed in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1, 3-butanediol, dimethylformamide and
  • compositions may contain adjuvants such as wetting agents, emulsifying and suspending agents, sweetening agents, flavoring agents and perfumes.
  • the suspension may contain suspending agents, for example, ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan, microcrystalline cellulose, aluminum methoxide and agar or mixtures of these and the like.
  • suspending agents for example, ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan, microcrystalline cellulose, aluminum methoxide and agar or mixtures of these and the like.
  • compositions for parenteral injection may comprise a physiologically acceptable sterile aqueous or nonaqueous solution, dispersion, suspension or emulsion, and a sterile powder for reconstitution into a sterile injectable solution or dispersion.
  • Suitable aqueous and nonaqueous vehicles, diluents, solvents or vehicles include water, ethanol, polyols, and suitable mixtures thereof.
  • Dosage forms for the compounds of the invention for topical administration include ointments, powders, patches, propellants and inhalants.
  • the active ingredient is admixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or, if necessary, propellants.
  • the compounds of the invention may be administered alone or in combination with other pharmaceutically acceptable compounds.
  • a safe and effective amount of a compound of the invention is administered to a mammal (e.g., a human) in need of treatment wherein the dosage is a pharmaceutically effective effective dosage, for a 60 kg body weight
  • the dose to be administered is usually 0.5 to 2000 mg, preferably 1 to 500 mg.
  • specific doses should also consider factors such as the route of administration, the health of the patient, etc., which are within the skill of the skilled physician.
  • ASK1 inhibitors have the potential to treat or improve the life of neurodegenerative diseases, cardiovascular diseases, inflammation, autoimmune diseases, and metabolic disorders in patients in need of treatment for a disease or condition.
  • ASK1 inhibitors have the potential to treat heart and kidney disease, including kidney disease, diabetic nephropathy, chronic kidney disease, fibrotic diseases (including lung and kidney fibrosis), dilated cardiomyopathy, respiratory diseases (including chronic obstruction).
  • Some embodiments described herein relate to the use of a compound described herein or a pharmaceutical composition described herein for treating a disease in a patient in need of treatment with an ASK1 inhibitor.
  • diabetes includes type 1 and type 2 diabetes, gestational diabetes, pre-diabetes, insulin resistance, metabolic syndrome, impaired fasting glucose, and impaired glucose tolerance.
  • Type 1 diabetes is also known as insulin-dependent diabetes mellitus (IDDM).
  • IDDM insulin-dependent diabetes mellitus
  • NIDDM non-insulin-dependent diabetes mellitus
  • Another embodiment is directed to a method of treating a kidney disease or diabetic nephropathy comprising administering a therapeutically effective amount of a compound of formula (I) as described herein or a pharmaceutical composition described herein.
  • Another embodiment is directed to a method of treating renal fibrosis, pulmonary fibrosis, or idiopathic pulmonary fibrosis (IPF) comprising administering a therapeutically effective amount of a form of Compound I described herein or a pharmaceutical composition described herein.
  • IPF idiopathic pulmonary fibrosis
  • Another embodiment is directed to a method of treating diabetic nephropathy, diabetic nephropathy, renal fibrosis, liver fibrosis or pulmonary fibrosis comprising administering a therapeutically effective amount of a crystalline form of Compound I described herein or a pharmaceutical combination as described herein Things.
  • the presence of active liver disease can be detected by the presence of elevated levels of enzymes in the blood.
  • blood levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) which are known to be higher than the clinically accepted normal range, indicate ongoing liver damage.
  • Routine monitoring of blood levels of ALT and AST in patients with liver disease is clinically used to measure the progression of liver disease at the time of medical treatment. Decreasing elevated ALT and AST to the normal range of acceptance as clinical evidence reflects a reduction in the severity of ongoing liver damage in patients.
  • the liver disease is chronic liver disease.
  • Chronic liver disease involves progressive destruction and regeneration of the liver parenchyma, leading to fibrosis and cirrhosis.
  • chronic liver disease can be caused by viruses (such as hepatitis B, hepatitis C, cytomegalovirus (CMV) or Epstein Barr virus (EBV)), toxic agents or drugs (such as alcohol, methotrexate or nitrofurantoin), metabolism.
  • viruses such as hepatitis B, hepatitis C, cytomegalovirus (CMV) or Epstein Barr virus (EBV)
  • toxic agents or drugs such as alcohol, methotrexate or nitrofurantoin
  • NASH nonalcoholic fatty liver disease
  • NASH nonalcoholic steatohepatitis
  • Hechromatosis hemochromatosis or Wilson's disease
  • autoimmune diseases eg autoimmune chronic hepatitis, primary biliary Cirrhosis or primary sclerosing cholangitis
  • other causes such as right heart failure
  • the liver disease is metabolic liver disease.
  • the liver disease is nonalcoholic fatty liver disease (NAFLD).
  • NAFLD is associated with insulin resistance and metabolic syndrome (obesity, mixed hyperlipidemia, diabetes (type II), and hypertension). It is believed that NAFLD covers a range of disease activities and begins to accumulate fat (hepatic steatosis) in the liver.
  • the compounds of the present invention have a number of advantages over non-deuterated compounds known in the art. Advantages of the present invention include: First, the compound using the technical scheme of the present invention has excellent inhibitory effect on ASK1 protein kinase. Second, the metabolism of the compound in the organism is improved, giving the compound better pharmacokinetic parameter characteristics. In this case, the dosage can be changed and a long-acting preparation can be formed to improve the applicability. Third, the drug concentration of the compound in the animal is increased, and the drug efficacy is improved. Fourth, certain metabolites are inhibited and the safety of the compounds is increased.
  • each reaction is usually carried out in an inert solvent at room temperature to reflux temperature (e.g., 0 ° C to 100 ° C, preferably 0 ° C to 80 ° C).
  • the reaction time is usually from 0.1 to 60 hours, preferably from 0.5 to 24 hours.
  • ASK1 Invitrogen Cat. No. PV3809, ATP (Sigma, Cat. No. A7699), DMSO (Sigma, Cat. No. D8418-1L), 384-well plate (Greiner, Cat. No. 784076), HTRF KinEASE-STK Kit (Cisbio, Cat. No. PV3809), 5x Kinase Buffer A (Life Technologies, Cat. No. PV3186), Kinase Tracer 199 (Life Technologies, Cat. No. PV5830), Eu-anti-GST antibody (Life Technologies, catalog number PV5594).
  • test compound was dissolved in DMSO to make a 20 mM mother liquor. Then, it was diluted 3 times in a medium gradient of DMSO and diluted 10 times. When dosing, dilute with buffer for 10 times.
  • ASK1 Kinase Assay ASK1 kinase was mixed with pre-diluted compounds of different concentrations in 5x Kinase Buffer A for 10 minutes at each concentration. The corresponding substrate and ATP were added and reacted at room temperature for 20 minutes (in which a negative positive control was set: a negative blank control and a positive erlotinib). After the reaction, the detection reagent (reagent in the HTRF KinEASE-STK Kit) was added, and after incubation at room temperature for 30 minutes, the enzyme activity in the presence of the compound of the present invention at each concentration was measured by an Evnvision microplate reader, and different concentrations were calculated. The inhibitory activity of the compound on the enzyme activity was then fitted to the inhibition activity of the enzyme activity at different concentrations of the compound according to the four-parameter equation according to Graphpad 5.0 software, and the IC 50 value was calculated.
  • the compound of the present invention and the undeuterated compound feldsertib were tested in the above kinase inhibition assay, and the compounds of the present invention were found to have potent or comparable activity against ASK1 kinase.
  • the results of inhibition of kinase by representative example compounds are summarized in Table 1 below.
  • Microsomal experiments human liver microsomes: 0.5 mg/mL, Xenotech; rat liver microsomes: 0.5 mg/mL, Xenotech; mouse liver microsomes: 0.5 mg/mL, Xenotech; coenzyme (NADPH/NADH): 1 mM , Sigma Life Science; magnesium chloride: 5 mM, 100 mM phosphate buffer (pH 7.4).
  • phosphate buffer 100 mM, pH 7.4.
  • the pH of the solution was adjusted to 7.4, diluted 5 times with ultrapure water before use, and magnesium chloride was added to obtain a phosphate buffer (100 mM) containing 100 mM potassium phosphate, 3.3 mM magnesium chloride, and a pH of 7.4.
  • NADPH regeneration system containing 6.5 mM NADP, 16.5 mM G-6-P, 3 U/mL G-6-P D, 3.3 mM magnesium chloride was prepared and placed on wet ice before use.
  • Formulation stop solution acetonitrile solution containing 50 ng/mL propranolol hydrochloride and 200 ng/mL tolbutamide (internal standard). Take 25057.5 ⁇ L of phosphate buffer (pH 7.4) into a 50 mL centrifuge tube, add 812.5 ⁇ L of human, rat and mouse liver microsomes, and mix to obtain a liver microsome dilution with a protein concentration of 0.625 mg/mL. . Incubation of the sample: The stock solution of the corresponding compound was diluted to 0.25 mM with an aqueous solution containing 70% acetonitrile as a working solution, and was used.
  • the corresponding compound had a reaction concentration of 1 ⁇ M and a protein concentration of 0.5 mg/mL.
  • 100 ⁇ L of the reaction solution was taken at 10, 30, and 90 min, respectively, and added to the stopper, and the reaction was terminated by vortexing for 3 min.
  • the plate was centrifuged at 5000 x g for 10 min at 4 °C.
  • 100 ⁇ L of the supernatant was taken into a 96-well plate to which 100 ⁇ L of distilled water was previously added, mixed, and sample analysis was performed by LC-MS/MS.
  • the metabolic stability of liver microsomes in human, rat and mouse was evaluated by comparing the compound of the present invention with the undeuterated compound Bibliosertib.
  • the half-life and liver intrinsic clearance as indicators of metabolic stability are shown in Table 2.
  • Table 2 in the human, rat and mouse liver microsome experiments, the compounds of the present invention significantly improved metabolic stability by comparison with the undeuterated compound Bibliosertib.
  • Rats were fed a standard diet and given water. Fasting began 16 hours before the test.
  • the drug was dissolved with PEG400 and dimethyl sulfoxide. Blood was collected from the eyelids at a time point of 0.083 hours, 0.25 hours, 0.5 hours, 1 hour, 2 hours, 4 hours, 6 hours, 8 hours, 12 hours, and 24 hours after administration.
  • Rats were briefly anesthetized after inhalation of ether, and 300 ⁇ L of blood samples were collected from the eyelids in test tubes. There was 30 ⁇ L of 1% heparin salt solution in the test tube. The tubes were dried overnight at 60 ° C before use. After the blood sample collection was completed at the last time point, the rats were anesthetized with ether and sacrificed.
  • Plasma samples were centrifuged at 5000 rpm for 5 minutes at 4 ° C to separate plasma from red blood cells. Pipette 100 ⁇ L of plasma into a clean plastic centrifuge tube, indicating the name and time of the compound. Plasma was stored at -80 °C prior to analysis. The concentration of the compound of the invention in plasma was determined by LC-MS/MS. Pharmacokinetic parameters were calculated based on the plasma concentration of each animal at different time points.

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Abstract

L'invention concerne un composé de 1,2,4-triazole représenté par la formule (I) et des sels pharmaceutiquement acceptables de celui-ci. Le composé selon l'invention possède une activité d'un inhibiteur de kinase 1 régulatrice de signal d'apoptose (" ASK1 ") ; ainsi, le composé peut être utilisé pour traiter des maladies induites par ASK1 notamment une maladie hépatique chronique, une maladie cardiovasculaire, une perturbation métabolique, un trouble du système respiratoire, un trouble gastro-intestinal et des maladies neurodégénératives. L'invention concerne également une composition pharmaceutique comprenant le composé de formule (I) et ses utilisations.
PCT/CN2018/109045 2017-10-12 2018-09-30 Composé de 1,2,4-triazole Ceased WO2019072130A1 (fr)

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104080771A (zh) * 2012-01-27 2014-10-01 吉利德科学公司 细胞凋亡信号调节激酶抑制剂
CN107108519A (zh) * 2014-12-23 2017-08-29 吉利德科学公司 制备ask1抑制剂的方法
WO2018157857A1 (fr) * 2017-03-03 2018-09-07 江苏豪森药业集团有限公司 Inhibiteur de kinase de régulation du signal apoptotique, son procédé de préparation et son application

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* Cited by examiner, † Cited by third party
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TWI625121B (zh) * 2009-07-13 2018-06-01 基利科學股份有限公司 調節細胞凋亡信號之激酶的抑制劑
BR112012033715A2 (pt) * 2010-07-02 2016-11-22 Gilead Sciences Inc inibidores de quinase de regulação de sinal de apoptose.
KR20160098463A (ko) * 2013-12-20 2016-08-18 길리애드 사이언시즈, 인코포레이티드 아폽토시스 신호-조절 키나제 억제제
MA41252A (fr) * 2014-12-23 2017-10-31 Gilead Sciences Inc Formes solides d'un inhibiteur d'ask 1

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104080771A (zh) * 2012-01-27 2014-10-01 吉利德科学公司 细胞凋亡信号调节激酶抑制剂
CN107108519A (zh) * 2014-12-23 2017-08-29 吉利德科学公司 制备ask1抑制剂的方法
WO2018157857A1 (fr) * 2017-03-03 2018-09-07 江苏豪森药业集团有限公司 Inhibiteur de kinase de régulation du signal apoptotique, son procédé de préparation et son application

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