WO2021254417A1 - Composé bicyclique et son utilisation - Google Patents

Composé bicyclique et son utilisation Download PDF

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Publication number
WO2021254417A1
WO2021254417A1 PCT/CN2021/100491 CN2021100491W WO2021254417A1 WO 2021254417 A1 WO2021254417 A1 WO 2021254417A1 CN 2021100491 W CN2021100491 W CN 2021100491W WO 2021254417 A1 WO2021254417 A1 WO 2021254417A1
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Prior art keywords
dihydro
tetrafluoro
difluoromethyl
oxy
indenyl
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PCT/CN2021/100491
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English (en)
Chinese (zh)
Inventor
杨荣文
孙云
张赟
王萍萍
兰宏
丁列明
王家炳
Original Assignee
贝达药业股份有限公司
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Priority to CN202180037613.0A priority Critical patent/CN115667190A/zh
Publication of WO2021254417A1 publication Critical patent/WO2021254417A1/fr

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    • 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
    • A61K31/075—Ethers or acetals
    • A61K31/085—Ethers or acetals having an ether linkage to aromatic ring nuclear carbon
    • 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
    • A61K31/275—Nitriles; Isonitriles
    • A61K31/277—Nitriles; Isonitriles having a ring, e.g. verapamil
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C13/00—Cyclic hydrocarbons containing rings other than, or in addition to, six-membered aromatic rings
    • C07C13/02—Monocyclic hydrocarbons or acyclic hydrocarbon derivatives thereof
    • C07C13/08—Monocyclic hydrocarbons or acyclic hydrocarbon derivatives thereof with a five-membered ring
    • C07C13/10—Monocyclic hydrocarbons or acyclic hydrocarbon derivatives thereof with a five-membered ring with a cyclopentane ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C15/00—Cyclic hydrocarbons containing only six-membered aromatic rings as cyclic parts
    • C07C15/20—Polycyclic condensed hydrocarbons
    • C07C15/24—Polycyclic condensed hydrocarbons containing two rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C23/00—Compounds containing at least one halogen atom bound to a ring other than a six-membered aromatic ring
    • C07C23/02—Monocyclic halogenated hydrocarbons
    • C07C23/08—Monocyclic halogenated hydrocarbons with a five-membered ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C43/00—Ethers; Compounds having groups, groups or groups
    • C07C43/02—Ethers
    • C07C43/20—Ethers having an ether-oxygen atom bound to a carbon atom of a six-membered aromatic ring
    • C07C43/225—Ethers having an ether-oxygen atom bound to a carbon atom of a six-membered aromatic ring containing halogen
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C43/00—Ethers; Compounds having groups, groups or groups
    • C07C43/02—Ethers
    • C07C43/257—Ethers having an ether-oxygen atom bound to carbon atoms both belonging to six-membered aromatic rings

Definitions

  • the present invention relates to a bicyclic compound, a composition and preparation containing such a compound, and methods of using and preparing such a compound.
  • HIFs Hypoxia inducible factors
  • HIF-1 ⁇ HIF-1 ⁇ , HIF-2 ⁇ , HIF-3 ⁇
  • HIF-1 ⁇ HIF-1 ⁇
  • HIF-1 ⁇ is always in the nucleus, while HIF ⁇ is located in the cytoplasm.
  • VHL Volt-Lindau Syndrome
  • HIF ⁇ hypoxia response element
  • HRE hypoxia response element
  • HIF-2 ⁇ mediating tumor occurrence and development mainly include: 1. Under conditions such as hypoxia or VHL mutations, the metabolic pathway of HIF-2 ⁇ is blocked, accumulates into the nucleus, and forms heterodimers with HIF-1 ⁇ . It then activates the hypoxia response element (HRE), regulates the up-regulation of downstream VEGFA, CXCR4, Cyclin D1 and other cancer-related genes, and promotes tumor angiogenesis; 2. HIF-2 ⁇ also participates in the conduction of immunosuppressive signals by up-regulating the expression of CD73, so it is targeted HIF-2 ⁇ can restore or enhance the anti-tumor immune function of mature DC cells, activated B cells and NK cells.
  • HRE hypoxia response element
  • VHL protein is an important part of E3 ubiquitin ligase, which mediates protein degradation by the proteasome.
  • VHL gene has a 57% high mutation rate or 98% loss of heterozygosity in renal cell carcinoma (RCC), which leads to pseudohypoxia and induces the activation of HIF-2 ⁇ into the nucleus.
  • RRCC renal cell carcinoma
  • clear cell renal cell carcinoma (ccRCC) accounts for 70%-75% of primary renal cell malignancies, and more than 90% of ccRCC patients have VHL protein defects.
  • HIF-2 ⁇ When gliomas are not vascularized, the unstable blood supply leads to a hypoxic microenvironment, which induces high local expression of HIF-2 ⁇ and promotes tumor growth.
  • the mutation rate of AA at positions 529-532 of HIF-2 ⁇ is as high as 81%, which directly affects the hydroxylation and degradation of HIF-2 ⁇ and makes HIF-2 ⁇ continue to be activated.
  • HIF-2 ⁇ and HIF-1 ⁇ are the key factors leading to downstream activation, and the PAS binding domain of the two is the binding site for the formation of heterodimers.
  • Peloton’s R&D team developed HIF based on this PT2977, a small molecule inhibitor of -2 ⁇ , exerts an anti-tumor effect by inhibiting the binding of HIF-2 ⁇ and HIF-1 ⁇ .
  • the present invention first provides a compound represented by formula (I) or its stereoisomer, tautomer, pharmaceutically acceptable salt, prodrug, chelate, non-covalent complex or solvate,
  • R 1 and R 2 may be independently selected from hydrogen, deuterium, halogen, C 1 -C 3 alkyl, C 3 -C 5 cycloalkyl, or,
  • R 1 and R 2 and the C atom to which they are connected together form a substituted or unsubstituted C 3 cycloalkyl or C 3 heterocyclic group;
  • R 3 is selected from hydrogen, halogen, hydroxyl, cyano, C 1 -C 5 alkyl, C 1 -C 5 alkoxy, C 1 -C 5 haloalkyl, C 1 -C 5 haloalkoxy, C 3- C 5 cycloalkyl;
  • R 4 is selected from C 1 -C 10 alkyl, C 1 -C 10 alkoxy, C 1 -C 10 haloalkyl, C 1 -C 10 haloalkoxy, C 6 -C 10 aryl, C 5 -C 18 heteroaryl group, C 3 -C 10 cycloalkyl group, C 3 -C 10 heterocyclic group; wherein, the C 5 -C 18 heteroaryl group and C 3 -C 10 heterocyclic group optionally contain 1, 2 Or 3 heteroatoms each independently selected from N, O and S; said R 4 is optionally substituted with one or more groups independently selected from R j ;
  • R j is selected from H, halogen, hydroxyl, amino, cyano, C 1 -C 5 alkyl, C 1 -C 5 alkoxy, C 2 -C 5 alkenyl, C 2 -C 5 alkynyl, C 1 -C 5 haloalkyl, C 1 -C 5 haloalkoxy, C 3 -C 5 cycloalkyl, C 3 -C 5 heterocyclic group;
  • R 5 and R 6 are each independently selected from H, deuterium, C 1 -C 8 alkyl, -C 1-8 alkyl -OC 1 - 3 alkyl group, C 1-3 alkyl group, C 3 -C 8 Silyl group, or,
  • R 5 and R 6 and the O atom to which they are connected together form a substituted or unsubstituted C 5 -C 8 heterocyclic group; the C 5 -C 8 heterocyclic group may be optionally substituted by one or more H or alkane Substituted by the group.
  • the R 1 and/or R 2 are halogen.
  • the R 1 and/or R 2 are F.
  • the R 1 and R 2 and the C atom to which they are connected together form a substituted or unsubstituted C 3 cycloalkyl or C 3 heterocyclic group.
  • the R 3 is selected from halogen, cyano or C 1 -C 5 haloalkyl.
  • the R 3 is selected from a C 1 -C 5 alkyl group or a C 3 -C 5 cycloalkyl group.
  • the R 4 is selected from C 6 -C 8 aryl, C 5 -C 8 heteroaryl, C 3 -C 5 cycloalkyl, C 3 -C 5 heterocyclyl; wherein, the The C 5 -C 8 heteroaryl group and the C 3 -C 8 heterocyclic group optionally contain 1, 2 or 3 heteroatoms independently selected from N, O and S; the R 4 is optionally substituted by one or Multiple groups independently selected from R j are substituted.
  • the R 4 is selected from a benzene ring, a pyridine ring and a pyrimidine ring.
  • the R 4 is selected from a benzene ring or a pyridine ring.
  • the R 5 and/or R 6 are H.
  • the R 5 and R 6 are each independently selected from a methyl group, an ethyl group, an acetyl group, a trimethylsilyl group, or R 5 and R 6 are formed together with the O atom to which they are connected
  • the compound is represented by formula (II),
  • the R 4 is selected from a C 6 -C 8 aryl group, a C 5 -C 8 heteroaryl group; wherein the C 5 -C 8 heteroaryl group optionally contains 1, 2, or 3, respectively Heteroatoms independently selected from N, O and S; said R 4 is optionally substituted with one or more groups independently selected from R j .
  • the R 4 is selected from phenyl, pyridyl and pyrimidinyl.
  • the R 4 is selected from phenyl or pyridyl.
  • the R 4 is phenyl
  • the R j is selected from H, halogen, cyano, C 1 -C 5 alkyl, C 1 -C 5 haloalkyl, C 3 -C 5 cycloalkyl, or C 3 -C 5 heterocycle base.
  • the R j is selected from H, halogen, cyano, or C 1 -C 5 haloalkyl.
  • the R 2 is halogen
  • the R 3 is halogen or cyano, difluoromethyl or trifluoromethyl.
  • the R 3 is difluoromethyl.
  • the R j is selected from H, halogen, cyano, methyl, ethyl, cyclopropyl, difluoromethyl or trifluoromethyl.
  • R 4 is selected from
  • the present invention further provides a compound or a pharmaceutically acceptable salt thereof, and the compound refers to:
  • the present invention also provides a method for preparing the compound.
  • the compound described in formula (I) or the compound described in the specific examples of the present invention can be prepared by using known organic synthesis techniques.
  • the present invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of at least one of the above-mentioned compounds and pharmaceutically acceptable excipients, such as hydroxypropyl methylcellulose.
  • pharmaceutically acceptable excipients such as hydroxypropyl methylcellulose.
  • the weight ratio of the compound to the excipient is about 0.001-10.
  • the present invention also provides a method for treating a subject suffering from a disease or disorder mediated by HIF-2 ⁇ , which comprises administering a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.
  • the disease or condition is selected from VHL syndrome, autoimmune diseases, inflammatory diseases, neurodegenerative diseases, cardiovascular disorders, renal disorders, viral infections, and obesity.
  • the disease or condition is selected from rheumatoid arthritis, osteoarthritis, atherosclerosis, psoriasis, systemic lupus erythematosus, multiple sclerosis, inflammatory bowel disease, asthma, chronic obstructive Airway disease, pneumonia, dermatitis, alopecia, nephritis, vasculitis, atherosclerosis, Alzheimer's disease, hepatitis, primary biliary cirrhosis, sclerosing cholangitis, diabetes (including type I diabetes), Acute rejection of transplanted organs.
  • the disease or condition is cancer, including hematological cancers, lymphomas, multiple myeloma, tumors of the digestive system, tumors of the reproductive system, brain tumors, tumors of the nervous system.
  • the disease or condition is permeabilizing glioma, pheochromocytoma, paraganglioma, colon, rectum, prostate (e.g., castrate resistant prostate cancer), lung cancer (e.g., non-small Cell lung cancer and/or small cell lung cancer), pancreas, liver, kidney, cervix, uterus, stomach, ovary, breast (e.g. basal or basal-like breast cancer and/or triple negative breast cancer), skin (e.g. melanoma) , Nervous system (including brain, meninges, and central nervous system, including neuroblastoma, glioblastoma, meningioma and medulloblastoma) tumors or cancer.
  • lung cancer e.g., non-small Cell lung cancer and/or small cell lung cancer
  • pancreas liver, kidney, cervix, uterus, stomach, ovary
  • breast e.g. basal or basal-like breast cancer and/or triple
  • the disease or condition is VHL syndrome. In certain aspects, the disease or condition is kidney cancer. In certain aspects, the subject is a human.
  • the compound is administered intravenously, intramuscularly, parenterally, nasally, or orally. In one aspect, the compound is administered orally.
  • the present invention also provides the use of the compound of formula (I) or a pharmaceutically acceptable salt thereof in the preparation of a medicament for the treatment of diseases or disorders mediated by HIF-2 ⁇ .
  • the present invention also provides a compound represented by formula (I) or a pharmaceutically acceptable salt thereof for treatment. Further provided is a compound of formula (I) or a pharmaceutically acceptable salt thereof for treating a subject suffering from a disease or condition mediated by HIF-2 ⁇ .
  • halogen refers to fluorine, chlorine, bromine or iodine.
  • Preferred halogen groups refer to fluorine, chlorine and bromine.
  • alkyl includes linear, branched or cyclic saturated monovalent hydrocarbon groups.
  • alkyl includes methyl, ethyl, propyl, isopropyl, cyclopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, cyclobutyl, n-pentyl, 3-(2 -Methyl)butyl, 2-pentyl, 2-methylbutyl, neopentyl, cyclopentyl, n-hexyl, 2-hexyl, 2-methylpentyl and cyclohexyl.
  • the "C 1-6 "in the C 1-6 alkyl group refers to a group containing 1, 2, 3, 4, 5 or 6 carbon atoms arranged in a straight chain or branched chain.
  • alkoxy refers to an oxyether formed from the above-mentioned linear, branched or cyclic alkyl group.
  • alkylene refers to a divalent alkyl linking group.
  • alkylene refers to an alkane in which two CH bonds are replaced with the point of attachment of the alkylene to the rest of the compound.
  • C 1-4 in the C 1-4 alkylene group refers to an alkylene group containing 1, 2, 3, or 4 carbon atoms.
  • haloalkyl refers to an alkyl group in which one or more H has been replaced by a halogen atom.
  • haloalkoxy refers to the group -O-haloalkyl.
  • oxo or "oxo” refers to an oxygen atom in the form of a dimethyl substituent, which forms a carbonyl group when connected to C, and forms a sulfoxide group or a sulfone group or an N-oxide group when connected to a heteroatom group.
  • aromatic ring means having aromatic characteristics (having (4n+2) non-localized ⁇ electrons, where n is Integer) carbocyclic or heterocyclic polyunsaturated ring.
  • aryl is a substituted or unsubstituted, stable, 6 to 10 ring carbon atom aromatic hydrocarbon group, which may contain one aromatic ring or multiple aromatic rings (for example, fused bicyclic rings). The aromatic ring does not contain heteroatoms. Examples of aryl groups include, but are not limited to, phenyl, naphthyl, indenyl, and the like.
  • heteroaryl refers to a monocyclic or polycyclic (eg, fused bicyclic) aromatic heterocyclic ring having at least one heteroatom ring member selected from N, O and/or S.
  • heteroaryl groups include, but are not limited to, pyridyl, pyrimidinyl, pyrrolyl, imidazolyl, thiazolyl, thienyl, benzimidazole, benzothienyl, benzofuranyl and the like.
  • cycloalkyl refers to a ring system having at least one cyclized alkyl group.
  • C 3-10 in the term C 3-10 cycloalkyl means that the cycloalkyl group may have 3, 4, 5, 6, 7, 8, 9 or 10 ring-forming atoms.
  • Cycloalkyl groups may include monocyclic and polycyclic rings (e.g., having 2, 3 or 4 fused rings, spiro rings, fused rings, etc.).
  • cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, etc.; in some embodiments, cycloalkyl groups also include those having one or more aromatic rings fused to cyclized alkyl rings. Part, such as benzo or thienyl derivatives of cyclohexane, etc.
  • cycloalkenyl refers to a ring system having at least one cyclized alkenyl group with one or more carbon-carbon double bonds in the cycloalkenyl group.
  • C 3-10 in the term C 3-10 cycloalkenyl means that the cycloalkenyl group may have 3, 4, 5, 6, 7, 8, 9 or 10 ring-forming atoms.
  • Cycloalkenyl groups can include monocyclic and polycyclic rings (e.g., having 2, 3, or 4 fused rings, spiro rings, bridged rings, etc.).
  • cycloalkenyl includes, but is not limited to, cyclohexenyl, cyclohexadiene, cycloheptatrienyl, etc.; in some embodiments, cycloalkenyl also includes those having one or more fused rings with cyclized alkenyl Part of the aromatic ring, such as benzo or thienyl derivatives of the cyclohexene ring.
  • heterocyclyl refers to a ring system having at least one cyclized alkyl or cyclized alkenyl containing a heterocyclic ring, and the heteroatom is selected from N, O and/or S.
  • the heterocyclic group may include a single ring or a polycyclic ring (for example, having 2, 3 or 4 fused rings, spiro rings, bridged rings, etc.).
  • the heterocyclic group can be connected to other parts of the compound via a ring-forming carbon atom or a ring-forming heteroatom.
  • heterocyclic group also includes moieties having one or more aromatic rings fused with a cyclized alkyl or cyclized alkenyl ring, such as benzo or thienyl derivatives of piperidine, morpholine, etc. .
  • heterocyclic groups include, but are not limited to, pyrrolidinyl, pyrrolinyl, tetrahydrothienyl, tetrahydrofuranyl, piperidinyl, morpholinyl, azepanyl, dihydrobenzofuranyl, etc. .
  • composition in the present invention is intended to include products containing specific amounts of specific components, as well as any products obtained directly or indirectly from specific amounts of specific components. Therefore, a pharmaceutical composition containing the compound of the present invention as an active ingredient and a method for preparing the compound are also the content of the present invention. Moreover, the crystal forms of some compounds may exist in polymorphic forms, and these are also included in the present invention. In addition, some compounds form solvates with water (such as hydrates) or common organic solvents, and these solvates are also included in the present invention.
  • the prodrugs (prodrugs) of the compounds of the present invention are included in the protection scope of the present invention.
  • the prodrug refers to a functional derivative that is easily converted into a desired compound in the body. Therefore, the term "administration" in the treatment method provided by the present invention includes the administration of the compound disclosed in the present invention, or the prodrug compound disclosed in the present invention that can be converted in vivo after administration to a subject although it is not clearly disclosed.
  • the conventional methods for selecting and preparing suitable prodrug derivatives have been recorded in books such as "Design of Prodrugs” (Design of Prodrugs, ed. H. Bundgaard, Elsevier, 1985).
  • the compound of the present invention may contain one or more asymmetric centers, and may produce diastereomers and optical isomers from this.
  • the present invention includes all possible diastereomers and their racemic mixtures, their substantially pure resolved enantiomers, all possible geometric isomers and their pharmaceutically acceptable salts.
  • the above formula (I) does not exactly define the three-dimensional structure of a certain position of the compound.
  • the present invention includes all stereoisomers of the compound represented by formula (I) and pharmaceutically acceptable salts thereof. Further, mixtures of stereoisomers and specific isolated stereoisomers are also included in the present invention. In the synthetic process of preparing such compounds, or in the process of using racemization or epimerization methods known to those of ordinary skill in the art, the product obtained may be a mixture of stereoisomers.
  • the present invention includes any possible tautomers, pharmaceutically acceptable salts thereof, and mixtures thereof.
  • the present invention includes any possible solvate and polymorph.
  • the type of solvent that forms the solvate is not particularly limited, as long as the solvent is pharmacologically acceptable.
  • water, ethanol, propanol, acetone and similar solvents can all be used.
  • pharmaceutically acceptable salt refers to a salt prepared from a pharmaceutically acceptable non-toxic base or acid.
  • the corresponding salt can be conveniently prepared from pharmaceutically acceptable non-toxic bases, including inorganic bases and organic bases.
  • Salts derived from inorganic bases include aluminum, ammonium, calcium, copper (high and low prices), ferric, ferrous, lithium, magnesium, manganese (high and low prices), potassium, sodium, zinc and the like. Particularly preferred are the salts of ammonium, calcium, magnesium, potassium, and sodium.
  • Non-toxic organic bases that can be derivatized into pharmaceutically acceptable salts include primary, secondary and tertiary amines, as well as cyclic amines and amines containing substituents, such as naturally occurring and synthetic amines containing substituents.
  • non-toxic organic bases capable of forming salts, including ion exchange resins and arginine, betaine, caffeine, choline, N',N'-dibenzylethylenediamine, diethylamine, 2 -Diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, reduced glucosamine, glucosamine, histidine, haamine, isopropylamine , Lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resin, procaine, chloroprocaine, purine, theobromine, triethylamine, trimethylamine, tripropylamine, ammonia Butanetriol and so on.
  • ion exchange resins and arginine betaine, caffeine, choline, N',N'-dibenzylethylenediamine, diethylamine, 2 -
  • the corresponding salt can be conveniently prepared from pharmaceutically acceptable non-toxic acids, including inorganic acids and organic acids.
  • acids include, for example, acetic acid, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, citric acid, ethanesulfonic acid, formic acid, fumaric acid, gluconic acid, glutamic acid, hydrobromic acid, hydrochloric acid, isethionic acid , Lactic acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid, mucic acid, nitric acid, hexanoic acid, pantothenic acid, phosphoric acid, succinic acid, sulfuric acid, oxalic acid, propionic acid, glycolic acid, hydroiodic acid, perchloric acid, Cyclohexanesulfonic acid, salicylic acid, 2-naphthalenesulfonic acid, saccharinic acid, trifluor
  • citric acid Preferably, citric acid, hydrobromic acid, formic acid, hydrochloric acid, maleic acid, phosphoric acid, sulfuric acid and tartaric acid. More preferably, formic acid and hydrochloric acid. Since the compound represented by formula (I) will be used as a medicine, it is preferable to use a substantially pure form, for example, at least 60% purity, more suitably at least 75% purity, especially at least 98% purity (% is a weight ratio ).
  • the pharmaceutical composition provided by the present invention includes as an active component a compound represented by formula (I) (or a pharmaceutically acceptable salt thereof), a pharmaceutically acceptable excipient and other optional therapeutic components or Accessories.
  • a pharmaceutical composition of the present invention includes oral, rectal, topical and A pharmaceutical composition for parenteral administration (including subcutaneous administration, intramuscular injection, and intravenous administration).
  • the pharmaceutical composition of the present invention can be conveniently prepared in a unit dosage form known in the art and prepared by any preparation method known in the pharmaceutical field.
  • the compound represented by formula (I) of the present invention can be used as an active component and mixed with a drug carrier to form a drug combination Things.
  • the pharmaceutical carrier can take various forms, depending on the desired mode of administration, for example, oral or injection (including intravenous injection). Therefore, the pharmaceutical composition of the present invention may take the form of a separate unit suitable for oral administration, such as a capsule, cachet or tablet containing a predetermined dose of the active ingredient.
  • the pharmaceutical composition of the present invention may take the form of powder, granule, solution, aqueous suspension, non-aqueous liquid, oil-in-water emulsion, or water-in-oil emulsion.
  • the compound represented by formula (I) or a pharmaceutically acceptable salt thereof can also be administered by a controlled release method and/or a delivery device.
  • the pharmaceutical composition of the present invention can be prepared by any pharmaceutical method. Generally, this method includes the step of associating the active ingredient with the carrier which constitutes one or more necessary ingredients.
  • the pharmaceutical composition is prepared by uniformly and intimately mixing the active ingredient with a liquid carrier or a finely divided solid carrier or a mixture of both. Then, the product can be easily prepared into the desired appearance.
  • the pharmaceutical composition of the present invention includes a pharmaceutically acceptable carrier and a compound represented by formula (I) or a pharmaceutically acceptable salt thereof.
  • the compound represented by formula (I) or a pharmaceutically acceptable salt thereof, and one or more other compounds with therapeutic activity are also included in the pharmaceutical composition of the present invention.
  • the drug carrier used in the present invention can be, for example, a solid carrier, a liquid carrier or a gas carrier.
  • Solid carriers include lactose, gypsum powder, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate, and stearic acid.
  • Liquid carriers include syrup, peanut oil, olive oil and water.
  • the gas carrier includes carbon dioxide and nitrogen.
  • any convenient pharmaceutical medium can be used. For example, water, ethylene glycol, oils, alcohols, flavor enhancers, preservatives, coloring agents, etc.
  • oral liquid preparations such as suspensions, elixirs and solutions
  • carriers such as starches, sugars, Microcrystalline cellulose, diluents, granulating agents, lubricants, binders, disintegrating agents, etc.
  • oral solid preparations such as powders, capsules and tablets.
  • tablets and capsules are preferred for oral preparations, and solid pharmaceutical carriers are used here.
  • standard aqueous or non-aqueous formulation techniques can be used for tablet coating.
  • Tablets containing the compound or pharmaceutical composition of the present invention can be prepared by compressing or molding one or more auxiliary components or adjuvants together.
  • the active ingredient is in a free-flowing form such as powder or granules, mixed with a binder, lubricant, inert diluent, surfactant or dispersant, and compressed in a suitable machine to obtain compressed tablets.
  • the powdered compound or pharmaceutical composition is soaked with an inert liquid diluent, and then molded in a suitable machine to form a molded tablet.
  • each tablet contains about 0.05 mg to 5 g of active ingredient
  • each cachet or capsule contains about 0.05 mg to 5 g of active ingredient.
  • a dosage form intended for oral administration to humans contains about 0.5 mg to about 5 g of active ingredient, compounded with a suitable and convenient metering auxiliary material, which accounts for about 5% to 95% of the total pharmaceutical composition.
  • the unit dosage form generally contains about 1 mg to about 2 g of active ingredient, typically 25 mg, 50 mg, 100 mg, 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 800 mg or 1000 mg.
  • the pharmaceutical composition suitable for parenteral administration provided by the present invention can be prepared as an aqueous solution or suspension by adding active components into water.
  • a suitable surfactant such as hydroxypropyl cellulose may be included.
  • glycerol, liquid polyethylene glycol, and their mixture in oil, dispersion systems can also be prepared.
  • a preservative may also be included in the pharmaceutical composition of the present invention to prevent the growth of harmful microorganisms.
  • the present invention provides pharmaceutical compositions suitable for injection, including sterile aqueous solutions or dispersion systems.
  • the above-mentioned pharmaceutical composition can be prepared in the form of a sterile powder that can be used for immediate preparation of sterile injection or dispersion.
  • the final injection form must be sterile, and for easy injection, it must be easy to flow.
  • the pharmaceutical composition must be stable during preparation and storage. Therefore, preservation against contamination by microorganisms such as bacteria and fungi is preferred.
  • the carrier can be a solvent or dispersion medium, for example, water, ethanol, polyol (such as glycerol, propylene glycol, liquid polyethylene glycol), vegetable oil, and suitable mixtures thereof.
  • the pharmaceutical composition provided by the present invention may be in a form suitable for topical administration, for example, aerosol, emulsion, ointment, lotion, dusting or other similar dosage forms. Further, the pharmaceutical composition provided by the present invention can be in a form suitable for use in a transdermal drug delivery device.
  • these preparations can be prepared by conventional processing methods.
  • an emulsion or ointment is prepared by adding a hydrophilic material and water to about 5 wt% to 10 wt% of the above-mentioned compound to prepare an emulsion or ointment having the desired consistency.
  • the pharmaceutical composition provided by the present invention can be made into a form that takes a solid as a carrier and is suitable for rectal administration.
  • the preferred dosage form is a suppository in which the mixture forms a unit dose.
  • Suitable auxiliary materials include cocoa butter and other materials commonly used in the art. Suppositories can be conveniently prepared by mixing the pharmaceutical composition with softened or molten excipients, then cooling and moulding.
  • the above-mentioned pharmaceutical preparations may also include, as appropriate, one or more additional adjuvant components, such as diluents, buffers, flavoring agents, binders, surfactants, and enhancers. Thickeners, lubricants and preservatives (including antioxidants), etc.
  • other adjuvants can also include penetration enhancers that regulate the isotonic pressure between the drug and the blood.
  • the pharmaceutical composition containing the compound represented by formula (I), or a pharmaceutically acceptable salt thereof can also be prepared in the form of a powder or a concentrated solution.
  • the dosage level of the drug is about 0.01 mg/kg body weight to 150 mg/kg body weight per day, or 0.5 mg to 7 g per patient per day.
  • the specific dosage level for any particular patient will depend on many factors, including age, weight, overall health, gender, diet, time of administration, route of administration, excretion rate, combination of drugs and acceptance The severity of the specific disease being treated.
  • Dess-Martin Dess-Martin oxidant
  • DMSO dimethyl sulfoxide
  • DIBAL-H Diisobutyl aluminum hydride
  • IBX 2-iodoyl benzoic acid
  • LDA lithium diisopropylamide
  • THF Tetrahydrofuran
  • compound 1-6 (0.24g), THF (5mL) were sequentially added to the reaction flask, n-butyllithium (0.25mL, 2.5M n-hexane solution) was added at -78°C, and stirred at room temperature for 1 hour.
  • the reaction mixture was quenched by adding saturated ammonium chloride, extracted with ethyl acetate, the organic phase was dried, concentrated, and purified by Prep-TLC to obtain 30 mg of target compound 1-7.
  • Example 1 Using a method basically similar to that of Example 1 to Example 4, the examples in Table 1 below were prepared.
  • the compound of Comparative Example 1 was prepared basically according to the method described in Example 2 in WO2020081695.
  • the 786-O cells grown in the logarithmic phase were seeded in a 96-well plate at a cell concentration of 65,000 cells per milliliter of culture medium, 180ul per well. Dilute the compound to the corresponding concentration, and add 20 ul of the compound solution of different concentrations to the corresponding cell wells so that the final concentration of the compound is (nM): 1.5, 4.6, 13.7, 41.2, 123.5, 370.4, 1111.1, 3333.3, 10000. After culturing for 24 hours, the cell culture supernatant was taken, and the VEGFA concentration was measured using an ELISA kit (purchased from abcam).
  • the IC 50 data of some examples are provided in Table 2, where A means IC 50 ⁇ 10nM; B means 10nM ⁇ IC 50 ⁇ 100nM; C means 100nM ⁇ IC 50 ⁇ 250nM; D means 250nM ⁇ IC 50 IC 50 ⁇ 500nM ; E represents IC 50> 500nM.
  • Example number IC 50 (nM) Example number IC 50 (nM) 1 B 40 A 2 C 42 A 3 A 52 A 4 C 53 A 5 2.8 55 B 7 A 59 A 8 A 62 A 9 A 64 A 11 A 65 A 14 A Comparative example 1 770 * 19 A Comparative example 2 >1 ⁇ 10 4 twenty one A Comparative example 3 E
  • the luciferase LUC gene was stably transferred into 786-O cells (purchased from ATCC) with Lipofectamine 3000 transfection reagent (purchased from Invitrogen) to construct HIF2 ⁇ reporter cells (786-O-HIF2 ⁇ -Luc cells).
  • RPMI MEDIUM 1640 purchased from In
  • Use Echo550 non-contact sonic pipetting system, purchased from Labcyte
  • the concentrations are 10000, 3333, 1111, 370, 123, 41.1, 13.7, 4.6, 1.5, 0.5nM, respectively.
  • the cells were cultured at 37°C and 5% CO 2 for 18-20 hours; Steady-Glo TM Luciferase Assay System (purchased from Promega) was added to a 384-well plate, 25 ⁇ l/well; the luminescence value was detected with Envision.
  • % Inhibition is calculated according to each well RLU (Record Luminescence) signal values, and fitting calculation of IC 50 through the corresponding compound Graphpad 8.0.
  • the compound was formulated with 5% DMSO, 5% Solutol and 90% NaCl.
  • SD rats and Balb/c mice were selected for administration.
  • the intravenous dose was 1 mg/kg and the oral dose was 5 mg/kg, respectively at 5 min, 15 min, 30 min, 1h, 2h, 4h, 7h, 24h Take blood from the orbit. After blood collection, centrifuge at 4000 rpm for 10 min, take the supernatant, add 200 ⁇ L of internal standard solution to 30 ⁇ L of supernatant for precipitation, vortex and centrifuge at 12000 rpm for 10 min, take 100 ⁇ L of supernatant solution and purified water in a 1:1 ratio for mixing and injection.
  • the compound concentration in the plasma is detected by a high performance liquid-mass spectrometer, and the compound concentration in the plasma sample is quantitatively analyzed by the internal standard quantification method. After the compound concentration is measured, Winnonln software is used to calculate related pharmacokinetic parameters including Cmax and AUC. It is found through experiments that the exemplary compounds of the present invention have better PK properties in vivo.

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Abstract

L'invention concerne un composé bicyclique tel que représenté par la formule (I), une composition et une préparation comprenant le composé, un procédé d'utilisation du composé et un procédé de préparation du composé.
PCT/CN2021/100491 2020-06-17 2021-06-17 Composé bicyclique et son utilisation WO2021254417A1 (fr)

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WO2016144825A1 (fr) * 2015-03-11 2016-09-15 Peloton Therapeutics, Inc. Composés aromatiques, leurs et utilisations
WO2018031680A1 (fr) * 2016-08-10 2018-02-15 Fronthera U.S. Pharmaceuticals Llc Nouveaux composés, leurs utilisations et procédés de préparation
WO2019191227A1 (fr) * 2018-03-28 2019-10-03 Peloton Therapeutics, Inc. Procédés de réduction de l'inflammation du système digestif à l'aide d'inhibiteurs de hif-2-alpha
WO2020081695A1 (fr) * 2018-10-17 2020-04-23 Nikang Therapeutics, Inc. Dérivés d'indane utilisés en tant qu'inhibiteurs du facteur 2 inductible par l'hypoxie (alpha)

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CN105530923B (zh) * 2013-09-09 2019-07-23 佩洛通治疗公司 芳基醚及其用途
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WO2016145032A1 (fr) * 2015-03-11 2016-09-15 Peloton Therapeutics, Inc. Compositions utilisées pour traiter l'hypertension artérielle pulmonaire
WO2016144825A1 (fr) * 2015-03-11 2016-09-15 Peloton Therapeutics, Inc. Composés aromatiques, leurs et utilisations
WO2018031680A1 (fr) * 2016-08-10 2018-02-15 Fronthera U.S. Pharmaceuticals Llc Nouveaux composés, leurs utilisations et procédés de préparation
WO2019191227A1 (fr) * 2018-03-28 2019-10-03 Peloton Therapeutics, Inc. Procédés de réduction de l'inflammation du système digestif à l'aide d'inhibiteurs de hif-2-alpha
WO2020081695A1 (fr) * 2018-10-17 2020-04-23 Nikang Therapeutics, Inc. Dérivés d'indane utilisés en tant qu'inhibiteurs du facteur 2 inductible par l'hypoxie (alpha)

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