WO2023078127A1 - Composé sulfonamide macrocyclique, son procédé de préparation et son utilisation médicale - Google Patents

Composé sulfonamide macrocyclique, son procédé de préparation et son utilisation médicale Download PDF

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WO2023078127A1
WO2023078127A1 PCT/CN2022/127366 CN2022127366W WO2023078127A1 WO 2023078127 A1 WO2023078127 A1 WO 2023078127A1 CN 2022127366 W CN2022127366 W CN 2022127366W WO 2023078127 A1 WO2023078127 A1 WO 2023078127A1
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戴量
孙宏斌
王宇
臧永军
胡远洋
邰璐洋
温小安
孙刚
李娟红
袁浩亮
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中国药科大学
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    • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
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    • C07D515/18—Bridged systems

Definitions

  • the invention belongs to the field of biomedicine, and in particular relates to a novel macrocyclic sulfonamide compound with ATP-citrate lyase (ACLY) inhibitory activity, a preparation method and a medical application thereof.
  • ACLY ATP-citrate lyase
  • Adenosine triphosphate citrate lyase is a cytoplasmic homotetramer enzyme, which is a key enzyme in the process of linking glucose catabolism with cholesterol and fatty acid synthesis.
  • ACLY can catalyze the conversion of citric acid and coenzyme A into acetyl-coenzyme A (Acetyl-CoA) and oxaloacetate.
  • Acetyl-CoA is not only an important raw material for the de novo synthesis of cholesterol and fatty acids, but also a substrate for protein acetylation modification reactions (Trends Mol Med., 2017, 23:1047-1063).
  • ACLY inhibiting the activity of ACLY can effectively prevent the de novo synthesis of cholesterol and fatty acids, treat dyslipidemia, and reduce the risk of cardiovascular diseases.
  • Bempedoic acid trade name: NEXLETOL
  • Clinical research data show that the drug is safe and well tolerated, and the effect of the combination with atorvastatin and ezetimibe is better than that of single use (Progress in Lipid Research, 2020, 77:101006).
  • the present invention provides a novel macrocyclic sulfonamide compound, which includes pharmaceutically acceptable salts, tautomers, mesomers, Racemates, stereoisomers, metabolites, metabolic precursors, prodrugs or solvates have significant ACLY inhibitory activity, and thus can be used to prepare drugs for preventing or treating ACLY-mediated diseases.
  • the invention also provides the preparation method, medical use and pharmaceutical composition of the macrocyclic sulfonamide compound.
  • the present invention provides a macrocyclic sulfonamide compound or a pharmaceutically acceptable salt thereof as shown in the following formula (I):
  • R is selected from H, alkyl or R a CO;
  • R 1 , R 2 , R 3 , R 4 , R 6 and R 7 are each independently selected from H, F, Cl, Br, I, NH 2 , OH, SH, NO 2 , CN, CF 3 , OCF 3 , CF 2 CF 3 , OCF 2 CF 3 , substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, OR b , C(O)OH, C(O)OR b , C(O)R b , NHR b , N(R b ) 2 , C(O)NHR b , C(O)N(R b ) 2 , NHC(O)R b , CH 2 OR b , S(O) 2 R b , SR b , S(O)R b , NHSO 2 R b or S(O) 2 NHR b ;
  • R and R together with the atoms to which they are attached form a ring
  • R3 and R4 together with the atoms to which they are attached form a ring
  • R 6 and R 7 form a ring together with the atoms to which they are attached;
  • R 5 is H, alkyl, cycloalkyl or R c CO;
  • R 8 is H, substituted or unsubstituted alkyl or substituted or unsubstituted cycloalkyl
  • X is CH 2 , CHR 9 , CH 2 O, O(CH 2 )n, CHR 9 O, O(CH 2 )mCHR 9 (CH 2 )n, S, CH 2 S, SCH 2 , CHR 9 S, S (CH 2 )mCHR 9 (CH 2 )n, NH, NR 9 , N(CH 2 )mR 9 (CH 2 )n, SO 2 , SO, C(O), C(O)NR 9 , SO 2 NR 9. NR 9 C(O) or NR 9 SO 2 ;
  • R 9 is a substituted or unsubstituted alkyl group or a substituted or unsubstituted cycloalkyl group; or, R 9 and NR 8 together form a ring with the atoms they are connected to;
  • Y is (CH 2 )n or (CH 2 )nCHR 10 (CH 2 )m;
  • R 10 is a substituted or unsubstituted alkyl group or a substituted or unsubstituted cycloalkyl group; or, NR 8 and R 10 together form a ring with the atoms to which they are attached; or, R 9 and R 10 form a ring with the atoms to which they are attached Atoms together form a ring;
  • n 0, 1, 2, 3, 4, 5 or 6;
  • n 0, 1, 2, 3, 4, 5 or 6;
  • R a , R b and R c are each independently selected from substituted or unsubstituted alkyl or cycloalkyl.
  • the macrocyclic sulfonamide compound also includes its tautomers, mesoforms, racemates, stereoisomers, metabolites, metabolic precursors, prodrugs or solvate.
  • R is selected from H
  • R 1 , R 2 , R 3 , R 4 , R 6 and R 7 are each independently selected from H, F, Cl, Br, I, NH 2 , OH, SH, NO 2 , CN, CF 3 , OCF 3 , CF 2 CF 3 , OCF 2 CF 3 , substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl;
  • R 5 is H
  • R 8 is H, substituted or unsubstituted alkyl or substituted or unsubstituted cycloalkyl
  • X is CH 2 , CHR 9 , O, CH 2 O, CHR 9 O, OCH 2 , OCHR 9 (CH 2 )n, NH, NR 9 , NR 9 (CH 2 )n, S, CH 2 S, CHR 9 S, SCH 2 , SCHR 9 (CH 2 )n, SO 2 , SO, C(O), C(O)NR 9 , SO 2 NR 9 , NR 9 C(O) or NR 9 SO 2 ;
  • R 9 is a substituted or unsubstituted alkyl group or a substituted or unsubstituted cycloalkyl group; or, R 9 and NR 8 together form a ring with the atoms they are connected to;
  • Y is (CH 2 )n or (CH 2 )nCHR 10 (CH 2 )m;
  • R 10 is a substituted or unsubstituted alkyl group or a substituted or unsubstituted cycloalkyl group; or, NR 8 and R 10 together form a ring with the atoms to which they are attached; or, R 9 and R 10 form a ring with the atoms to which they are attached Atoms together form a ring;
  • n 0, 1, 2, 3, 4, 5 or 6;
  • n 0, 1, 2, 3, 4, 5 or 6.
  • the macrocyclic sulfonamide compound or its pharmaceutically acceptable salt, tautomer, mesoform, racemate, stereoisomer, metabolic is selected from any one of the compounds shown in Table 1 below:
  • the preparation of the macrocyclic sulfonamide compound of the present invention can be carried out with reference to the following synthetic route.
  • the specific synthetic routes and steps of the compounds can be carried out with reference to the examples.
  • the solvent used includes but not limited to: chlorosulfonic acid, benzene, toluene, xylene, methylene chloride, chloroform, ether, tetrahydrofuran, acetonitrile , N,N-dimethylformamide, dimethyl sulfoxide, dioxane, ethyl acetate, propyl acetate, butyl acetate, cyclohexane, 1,2-dichloroethane, acetone, methyl Base tert-butyl ether or a mixed solvent optionally composed of these solvents, preferably chlorosulfonic acid, dichloromethane; the reaction temperature is 0°C to 150°C, preferably 0°C to 80°C;
  • the solvent used includes but is not limited to: pyridine, triethylamine, N,N-diisopropylethylamine , Benzene, Toluene, Xylene, Dichloromethane, Chloroform, Diethyl Ether, Tetrahydrofuran, Acetonitrile, Dioxane, N,N-Dimethylformamide, Dimethyl Sulfoxide, Ethyl Acetate, Propyl Acetate, Acetic Acid Butyl ester, cyclohexane, 1,2-dichloroethane, acetone, methyl tert-butyl ether or a mixed solvent of these solvents, preferably pyridine and dichloromethane; the bases used include but are not limited to: Pyridine, triethylamine, N,N-diisopropylethylamine, sodium carbonate, potassium carbonate, sodium bicarbonate
  • the acids used include but are not limited to hydrochloric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, acetic acid, propionic acid, butyric acid, Formic acid, trifluoroacetic acid, preferably hydrochloric acid, trifluoroacetic acid; solvents used include but not limited to methanol, ethanol, acetone, toluene, xylene, methylene chloride, chloroform, ether, tetrahydrofuran, acetonitrile, N,N-dimethyl Dimethyl sulfoxide, ethyl acetate, dioxane, propyl acetate, butyl acetate, cyclohexane, 1,2-dichloroethane, acetone, methyl tert-butyl ether or these
  • the solvent is a mixed solvent of optional composition, preferably ethyl acetate and ethanol
  • solvents used include but are not limited to: benzene, toluene, xylene, methylene chloride, chloroform, ether, tetrahydrofuran, acetonitrile, N,N -Dimethylformamide, dimethyl sulfoxide, ethyl acetate, propyl acetate, butyl acetate, cyclohexane, 1,2-dichloroethane, acetone, methyl tert-butyl ether or any of these solvents
  • a mixed solvent of selected composition preferably N,N-dimethylformamide, dichloromethane
  • the condensing agent used includes but not limited to: HATU, EDCI, DCC, DIC, CDI, BOP, PyBOP, TBTU, T3P, preferably HATU, EDCI
  • the activators used include but not limited to HOAT, HOBT, DMAP
  • the compounds of the present invention can also be used as pharmaceutically acceptable salts.
  • the salt may be a salt of at least one of the following acids: galactaric acid, D-glucuronic acid, glycerophosphate, hippuric acid, isethionic acid, lactobionic acid, maleic acid, 1,5-naphthalene Disulfonic acid, naphthalene-2-sulfonic acid, pivalic acid, terephthalic acid, thiocyanic acid, cholic acid, n-dodecylsulfuric acid, benzenesulfonic acid, citric acid, D-glucose, glycolic acid, lactic acid, Malic acid, malonic acid, mandelic acid, phosphoric acid, propionic acid, hydrochloric acid, sulfuric acid, tartaric acid, succinic acid, formic acid, hydroiodic acid, hydrobromic acid, methanesulfonic acid, niacin, nitric acid, orotic acid
  • the salt can also be the compound of the present invention with metal (including sodium, potassium, calcium, etc.) ions or pharmaceutically acceptable amines (including ethylenediamine, tromethamine, etc.), ammonium ions or choline salt formed.
  • metal including sodium, potassium, calcium, etc.
  • pharmaceutically acceptable amines including ethylenediamine, tromethamine, etc.
  • the present invention provides the macrocyclic sulfonamide compounds, including their pharmaceutically acceptable salts, tautomers, mesoforms, racemates, stereoisomers, metabolites, metabolic precursors, Application of prodrug or solvate in the preparation of ATP-citrate lyase (ACLY) inhibitor.
  • the macrocyclic sulfonamide compound of the present invention has significant ACLY inhibitory activity, and has good safety and pharmacokinetic properties.
  • the macrocyclic sulfonamide compounds of the present invention or their pharmaceutically acceptable salts, tautomers, mesoforms, racemates, stereoisomers, metabolites, metabolic precursors, prodrugs Or the solvate can be used to prepare ACLY inhibitors, and can be used to prepare medicines for preventing or treating ACLY-mediated diseases.
  • the ACLY-mediated diseases include but are not limited to: insulin resistance, metabolic syndrome, type 1 or type 2 diabetes, hyperlipidemia, hypercholesterolemia, obesity , atherosclerosis, myocardial ischemia, myocardial infarction, arrhythmia, coronary heart disease, hypertension, heart failure, cardiac hypertrophy, myocarditis, complications of diabetes (including diabetic cardiomyopathy, diabetic nephropathy, retinopathy, neuropathy, and diabetic ulcer etc.), non-alcoholic fatty liver, non-alcoholic steatohepatitis, alcoholic fatty liver, liver cirrhosis, gout, stroke or cerebral infarction, etc.
  • the ACLY-mediated diseases include but are not limited to: bone cancer, acute myelogenous leukemia, chronic myelogenous leukemia, acute lymphocytic leukemia, chronic lymphocytic leukemia, myeloproliferative disease, multiple myeloma , myelodysplastic syndrome, Hodgkin's lymphoma, non-Hodgkin's lymphoma, hemangioma, granuloma, xanthoma, meningeal sarcoma, glioma, astrocytoma, medulloblastoma, Ependymoma, germ cell tumor (pineeal tumor), glioblastoma multiforme, oligodendroglioma, schwannoma, retinoblastoma, neurofibroma, sarcoma, esophageal cancer, Gastric cancer, pancreatic cancer, colorectal cancer, colon cancer,
  • Compounds can be used in combination with one or more other types of drugs for the prevention or treatment of ACLY-mediated diseases, including but not limited to the following combinations.
  • the drug that can be selected to be used in combination with the compound of the present invention can be one or more weight-loss drugs, including lorcaserin, orlistat and glucagon-like peptide-1 (GLP-1) drugs (such as eg Senatide, liraglutide, lixisenatide, dulaglutide, benaglutide and albiglutide, etc.) etc.
  • GLP-1 glucagon-like peptide-1
  • the drug that can be used in combination with the compound of the present invention can be one or more anti-nonalcoholic fatty liver disease drugs, including: AMPK agonist (such as metformin), farnesoid X receptor (FXR) agonist (such as Obeticholic acid, GS-9674, EDP-305 and LJN452, etc.), acetyl-CoA carboxylase (ACC) inhibitors (such as GS-0976, etc.), apoptosis signal-regulated kinase-1 (ASK1) inhibitors (such as Rhythmsertib, etc.), PPAR agonists (such as Elafibranor, Saroglitazar, IVA337 and MSDC-0602K, etc.), caspase (caspase) inhibitors (such as Emricasan, etc.), stearoyl-CoA desaturase 1 (SCD1) inhibition Agents (such as Aramchol, etc.), long-acting glucagon-like peptide-1
  • the drug that can be selected to be used in combination with the compound of the present invention can be one or more hypolipidemic drugs, including niacin, statins (such as lovastatin, simvastatin, pravastatin, mevastatin, fluvastatin, etc.) Statins, atorvastatin, cerivastatin, rosvastatin and pitavastatin), cholesterol absorption inhibitors (such as ezetimibe, etc.), fibrates (such as clofibrate, bezafibrate, fenofibrate Special class), PCSK9 inhibitors (such as Evolocumab and Alirocumab, etc.), CETP inhibitors (such as anacetrapib, etc.), AMPK agonists and ACC inhibitors (such as GS-0976, etc.), etc.
  • statins such as lovastatin, simvastatin, pravastatin, mevastatin, fluvastatin, etc.
  • Statins
  • the present invention provides a pharmaceutical composition for preventing or treating ACLY-mediated diseases, which contains a therapeutically effective amount of the compound of formula (I) or its pharmaceutically acceptable salt, tautomer, mesoform, exo Racemates, stereoisomers, metabolites, metabolic precursors, prodrugs or solvates as active ingredients and pharmaceutically acceptable excipients.
  • Optionally mixable excipients can vary depending on dosage forms, administration forms, and the like. Examples of excipients include excipients, binders, disintegrants, lubricants, correctives, fragrances, colorants or sweeteners, etc.
  • the pharmaceutical composition can be in the form of capsules, powders, tablets, granules, pills, injections, syrups, oral liquids, inhalants, ointments, suppositories or patches and other conventional pharmaceutical preparations.
  • the present invention has the following advantages:
  • the macrocyclic sulfonamide compounds of the present invention have potent ACLY inhibitory activity, and its activity is significantly better than that of the listed ACLY inhibitor Bempedoic acid, and the activity of many compounds is significantly better than that of NDI-091143 (currently reported the most active good ACLY inhibitors).
  • the macrocyclic sulfonamide compounds of the present invention have better pharmacokinetic properties such as oral bioavailability and half-life.
  • the macrocyclic sulfonamide compounds of the present invention have no obvious inhibitory effect on the human potassium ion channel hERG, and have no mutagenicity, so they have good safety. It can be used alone or in combination with one or more other types of drugs for preventing or treating ACLY-mediated diseases, and is expected to become a new drug for preventing or treating ACLY-mediated diseases.
  • the macrocyclic sulfonamide compounds of the present invention can effectively prevent and/or treat major diseases such as metabolic diseases, cardiovascular and cerebrovascular diseases, and tumors.
  • the macrocyclic sulfonamide compounds of the present invention are easy to prepare and low in cost, simple in structure, ingenious in design, cheap and easy to obtain raw materials, safe in synthesis process, environmentally friendly, and easy in large-scale production.
  • Figure 1 is an effect diagram of the binding ability of the compound to ACLY protein determined by SPR.
  • reaction was stirred under ice-bath conditions, a pre-prepared 1M lithium aluminum hydride ether solution (12.5 mL, 12.5 mmol) was added dropwise, and then reacted at room temperature for 1 hour.
  • the reaction solution was quenched with water (2 mL), added 15% sodium hydroxide solution (0.5 mL), stirred for 1 hour, filtered, the filtrate was separated into an organic layer, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain compound A-34 (colorless oil, 0.29 g, yield 57%).
  • reaction solution is extracted with ethyl acetate (30mL ⁇ 2), the organic layer is washed with saturated sodium bisulfite (15mL ⁇ 2), the organic layer is dried over anhydrous sodium sulfate, filtered, and the filtrate is concentrated under reduced pressure.

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Abstract

L'invention concerne un composé sulfonamide macrocyclique, son procédé de préparation et son utilisation médicale. Le composé sulfonamide macrocyclique présente une structure spécifique telle que représentée par la formule (I). Le composé sulfonamide macrocyclique ou un sel pharmaceutiquement acceptable, un tautomère, un mésomère, un racémate, un stéréoisomère, un métabolite, un précurseur métabolique, un promédicament ou un solvate de celui-ci présente un effet inhibiteur évident sur l'ATP-citrate lyase (ACLY), et possède également des propriétés pharmacocinétiques telles qu'une bonne biodisponibilité orale, et une très bonne innocuité ; et par conséquent, le composé sulfonamide macrocyclique est applicable à la préparation d'un inhibiteur ayant une activité inhibitrice vis-à-vis de l'ACLY, et est également utilisé pour préparer un médicament destiné à prévenir ou traiter des maladies méditées par ACLY.
PCT/CN2022/127366 2021-11-03 2022-10-25 Composé sulfonamide macrocyclique, son procédé de préparation et son utilisation médicale WO2023078127A1 (fr)

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WO2023215220A1 (fr) * 2022-05-02 2023-11-09 Esperion Therapeutics, Inc. Inhibiteurs macrocycliques de l'atp citrate lyase

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CN101087798A (zh) * 2004-12-22 2007-12-12 拜耳先灵医药股份有限公司 作为Tie2抑制剂的磺酰氨基大环
CN111417622A (zh) * 2017-10-17 2020-07-14 诺华炎症研究公司 用于治疗与nlrp活性相关的病症的磺胺类及其组合物
WO2021032588A1 (fr) * 2019-08-16 2021-02-25 Inflazome Limited Dérivés de sulfonylamide macrocycliques utiles en tant qu'inhibiteurs de nlrp3
CN113166173A (zh) * 2018-11-09 2021-07-23 普莱鲁德疗法有限公司 作为骨髓细胞白血病1(mcl-1)蛋白抑制剂的螺-磺酰胺衍生物

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US11555012B2 (en) * 2018-11-09 2023-01-17 Nimbus Artemis, Inc. ACLY inhibitors and uses thereof
US20220218659A1 (en) * 2019-05-25 2022-07-14 Institute For Cancer Research D/B/A The Research Institute Of Fox Chase Cancer Center PI3K/LYN-ACLY Signaling Inhibition

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101087798A (zh) * 2004-12-22 2007-12-12 拜耳先灵医药股份有限公司 作为Tie2抑制剂的磺酰氨基大环
CN111417622A (zh) * 2017-10-17 2020-07-14 诺华炎症研究公司 用于治疗与nlrp活性相关的病症的磺胺类及其组合物
CN113166173A (zh) * 2018-11-09 2021-07-23 普莱鲁德疗法有限公司 作为骨髓细胞白血病1(mcl-1)蛋白抑制剂的螺-磺酰胺衍生物
WO2021032588A1 (fr) * 2019-08-16 2021-02-25 Inflazome Limited Dérivés de sulfonylamide macrocycliques utiles en tant qu'inhibiteurs de nlrp3

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