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WO2018192461A1 - Agoniste ampk de pipéridine et application médicale associée - Google Patents

Agoniste ampk de pipéridine et application médicale associée Download PDF

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Publication number
WO2018192461A1
WO2018192461A1 PCT/CN2018/083267 CN2018083267W WO2018192461A1 WO 2018192461 A1 WO2018192461 A1 WO 2018192461A1 CN 2018083267 W CN2018083267 W CN 2018083267W WO 2018192461 A1 WO2018192461 A1 WO 2018192461A1
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Prior art keywords
sulfonyl
piperidin
dimethylphenoxy
dimethyl
compound
Prior art date
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Ceased
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PCT/CN2018/083267
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English (en)
Chinese (zh)
Inventor
孙宏斌
汪鹏飞
刘耐欣
张佳
晏顶霏
孙更
黄亚平
姚智颖
冯志奇
程亚龙
韩立帅
吴文珍
刘胜杰
赵星
秦鹿柘
李明雷
张翔鹰
喻生琪
陈辉
赵文峰
王锦政
尤燕平
孙恒之
戴量
张艳春
袁浩亮
陈彩萍
许庆龙
温小安
柳军
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China Pharmaceutical University
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China Pharmaceutical University
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Publication date
Priority claimed from CN201810336935.5A external-priority patent/CN108727250A/zh
Application filed by China Pharmaceutical University filed Critical China Pharmaceutical University
Publication of WO2018192461A1 publication Critical patent/WO2018192461A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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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
    • A61K31/33—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
    • A61K31/4353—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 ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4365—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 ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system having sulfur as a ring hetero atom, e.g. ticlopidine
    • 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
    • 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
    • A61P3/04—Anorexiants; Antiobesity agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D211/56—Nitrogen atoms
    • C07D211/58—Nitrogen atoms attached in position 4

Definitions

  • the present invention relates to the field of biomedicine, and in particular to a piperidine compound having AMPK agonistic activity, and to a process for the preparation of such a compound and its use as an AMPK agonist.
  • AMPK adenylate-activated protein kinase
  • AMPK adenylate-activated protein kinase
  • Its phosphorylation activation can overcome insulin resistance, lower blood sugar, lower blood fat (by inhibiting the synthesis of fatty acids and cholesterol), anti-inflammatory, anti-aging Death, anti-fibrosis, promotion of mitochondrial synthesis, enhancement of mitochondrial oxidative metabolism, anti-aging and anti-tumor (Physiol. Rev. 2009, 89, 1025).
  • AMPK adenylate-activated protein kinase
  • the broad-spectrum ⁇ - ⁇ subunit agonist MK-8722 although it can lower blood glucose, has found irreversible cardiac hypertrophy in animal hearts in rats and monkeys. iSciencelOll, 357, 507).
  • the selective ⁇ - ⁇ subunit agonist PF-249 only lowers blood lipids but does not have hypoglycemic activity (Ce//Meto6.2017, 25, 1 147 ).
  • adiponectin is an important cytokine secreted by adipocytes that activates the AMPK signaling pathway by activating adiponectin receptor 1 (AdipoRl) (Nat. Med 2002, 8, 1288).
  • AdipoRl adiponectin receptor 1
  • small molecule adiponectin receptor agonists can mimic the biological effects of adiponectin in vivo, improve insulin resistance, lower blood sugar, and prolong the lifespan of high-fat diet mice (Blood re2013, 503, 493).
  • no small molecule adiponectin receptor agonists have entered the clinical research phase.
  • Another object of the invention is to provide a pharmaceutical use of the piperidines as AMPK agonists. These compounds have significant agonistic activity on AMPK in vitro biochemical levels and cell levels, and may activate AMPK signaling pathway by activating adiponectin receptors, and thus can be used to prepare drugs for preventing or treating AMPK-mediated diseases.
  • I 1 , R 2 , R 3 , R 6 , R 7 and R 8 are each H, R, OR, SR, S(0)R, S(0) 2 R, C(0)R , C(0)OH, C(0)OR, OC(0)R, HR, N(R) 2 , C(0) H 2 , C(0) HR, C(0)N(R) 2 , H(CO)R, R(CO)R, H(CO)OR, R(CO)OR, H(CO) H 2 , H(CO) HR, H(CO)N(R) 2 , R(CO ) HR, R(CO)N(R) 2 , S0 2 H 2 , S0 2 HR, S0 2 engraving) 2 , NHS0 2 R, RS0 2 R, HS0 2 HR, HS0 2 N(R) 2 , RS0 2 HR, RS0 2 N(R) 2 , C(0) HNOH, C(0) HNOR, C(0) HS0 2 R, C( H) H 2 , C( H( H) H 2
  • R is phenyl, heteroaryl, cyclodecyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, indenyl, alkenyl, or alkynyl; wherein said phenyl is unfused or fused R 9, R 9 is a phenyl, hetero aromatic, hydrocarbon embankment, cycloalkene, heterocycle, or heterocycle embankment hydrocarbon olefin; said heteroaryl group is not bonded or fused fused with R 1Q, R 1Q benzene a heteroaromatic hydrocarbon, a cycloalkylene hydrocarbon, a cyclic olefin, a heterocyclic anthracene or a heterocycloalkene; said cyclodecyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl group each of which is unfused or with R 11 fused, R 11 is benzene, a heteroaren
  • R 12 is a 2 to 5 carbon spiro group, each of which is unsubstituted or is OH, (0), CN, H 2 , F, Cl, Br, I, CF 3 , CF 2 CF 3 , H (CH 3 ) or N(CH 3 ) 2 substituted;
  • R 13 and R 14 are independently selected indenyl groups, or N to which they are attached are aziridine-1-yl, azetidin-1-yl, pyrrolidin-1-yl or piperidine -1-yl, each having an unsubstituted or being 0, C(0), CNOH, CH 2 moiety substituted by CNOCH 3 , S, S(0) S(0) 2 or NH;
  • R 15 is phenyl, heteroaryl, cyclodecyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, indenyl, alkenyl or alkynyl; wherein said phenyl is unfused or fused R 16, R 16 is benzene, heteroarene, embankment hydrocarbon ring, cycloalkene, heterocycle, or heterocycle embankment hydrocarbon olefin; said heteroaryl is unfused or fused with R 17, R 17 is a phenyl a heteroaromatic hydrocarbon, a cycloalkylene hydrocarbon, a cyclic olefin, a heterocyclic anthracene or a heterocycloalkene; said cyclodecyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl group each of which is unfused or with R 18 fused, R 18 is benzene, heteroarene,
  • R 19 is phenyl, heteroaryl, cyclodecyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, indenyl, alkenyl or alkynyl; wherein said phenyl is unfused or R 2Q fused, R 2Q benzene, heteroarene, embankment hydrocarbon ring, cycloalkene, heterocycle, or heterocycle embankment hydrocarbon olefin; said heteroaryl is unfused or fused with R 21, R 21 is a phenyl a heteroaromatic hydrocarbon, a cycloalkylene hydrocarbon, a cyclic olefin, a heterocyclic anthracene or a heterocycloalkene; said cyclodecyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl group each of which is unfused or with R 22 fused, R 22 is a benzene, a
  • n 0 ⁇ 10;
  • R 4 and R 5 are each H, F or a fluorenyl group of 1 to 6 carbons; or R 4 and R 5 together with the atom to which they are attached form a substituted or unsubstituted cycloterpene hydrocarbon ring, substituted or unsubstituted a heterocyclic anthracene ring or a substituted or unsubstituted heterocyclic olefin ring;
  • X is S(0) 2 , C(0) or CH 2 ;
  • P, Q, W, Y and Z are each CH, N or C substituted by one of R 6 , R 7 and R 8 , and at least three of ⁇ , Q, W, Y and Z are not N;
  • R 1 ' is 11, thiol, 0H, CN, NH 2 , H(CH 3 ), N(CH 3 ) 2 or a thiol group of 1 to 6 carbons, and R' may be a 4-amino alpha in the piperidine ring. Substituting a carbon or a carbon at the beta position; and when R' is not a purine, the compound may act as a diastereomer or a mixture or diastereomer and/or enantiomer of the enantiomer The form of enrichment of the body is provided.
  • the enantiomerically enriched form of the compound of the invention is embodied in diastereomeric excess (de) 3 ⁇ 4 70-100%, preferably 90-100%, more preferably 95 to 100%, most preferably 98 100%; the enriched form of the enantiomer of the compound of the present invention is expressed in enantiomeric excess (ee) 3 ⁇ 4 70-100%, preferably 90-100 % is more preferably 95 to 100%, and most preferably 98 to 100%.
  • a compound of Formula (I), or a pharmaceutically acceptable salt or ester or solvate thereof, of the invention :
  • RR 2 , R 3 , R 6 , R 7 and R 8 are each H, R, OR, SR, S(O)R, S(0) 2 R, C(0)R, C(0)OH,
  • R is phenyl, heteroaryl or fluorenyl; wherein the fluorenyl group is unsubstituted or substituted by one or two or three substituents independently selected from the group consisting of: OH, F, CF 3 , CF 2 CF 3 , OR 15 , SR 15 , S(0)R 15 , S(0) 2 R 15 , HR 15 , N(R 15 ) 2 , C(0)R 15 , C(0) H 2 , C (0) HR 15 , C(0)N(R 15 ) 2 , HC(0)R 15 , R 15 C(0)R 15 , HS0 2 R 15 , HC(0)OR 15 , S0 2 HR 15 , S0 2 N(R 15 ) 2 , HC(0) H 2 , HC(0) HR 15 , HC(0)CH(CH 3 ) HC(0)CH(CH 3 ) H 2 or HC(0)CH( CH 3 ) HC(0)CH(CH 3 ) HR 15 ;
  • R 15 is a fluorenyl group, and the fluorenyl group is unsubstituted or substituted by one or two or three substituents independently selected from the group consisting of OR 19 , SR 19 , S(0)R 19 , S( 0) 2 R 19 , HR 19 , N(R 19 ) 2 , C(0)R 19 , C(0) H 2 , C(0) HR 19 , C(O) Zun 19 ) 2 , HC(0) R 19 , R 19 C(0)R 19 , HS0 2 R 19 , HC(0)OR 19 , S0 2 HR 19 , S0 2 N(R 19 ) 2 , HC(0) H 2 , HC(0) HR 19 , OH, (0), C(0)OH, CN, H 2 , F, CF 3 or CF 2 CF 3; wherein R 19 is a fluorenyl group;
  • n 0 ⁇ 6;
  • R 4 and R 5 are each H, F or methyl
  • P, Q, W, Y and Z are each CH, N or C substituted by one of R 6 , R 7 and R 8 , and at least four of ⁇ , Q, W, Y and Z are not N;
  • R' is H, F or a fluorenyl group of 1 to 6 carbons, and R' may be substituted on the ex or carbon of the 4-amino group in the piperidine ring; and when R' is not hydrazine, the compound It may be provided as a diastereomer or a mixture of enantiomers or as an enriched form of diastereomers and/or enantiomers.
  • a compound of Formula (I), or a pharmaceutically acceptable salt or ester or solvate thereof, of the invention :
  • RR 2 , R 3 , R 6 , R 7 and R 8 are each H, R, OR, SR, S(O)R, S(0) 2 R, C(0)R, C(0)OH,
  • R is phenyl, heteroaryl or fluorenyl; wherein the fluorenyl group is unsubstituted or substituted by one or two or three substituents independently selected from the group consisting of: OH, F, CF 3 , CF 2 CF 3 , OR 15 , SR 15 , S(0)R 15 , S(0) 2 R 15 , HR 15 , N(R 15 ) 2 , C(0)R 15 , C(0) H 2 , C (0) HR 15 , C(0)N(R 15 ) 2 , HC(0)R 15 , R 15 C(0)R 15 , HS0 2 R 15 , HC(0)OR 15 , S0 2 HR 15 , S0 2 N(R 15 ) 2 , NHC(0) H 2 , HC(0) HR 15 ;
  • R 15 is a fluorenyl group, and the fluorenyl group is unsubstituted or substituted by one or two or three substituents independently selected from the group consisting of OR 19 , SR 19 , S(0)R 19 , S( 0) 2 R 19 , HR 19 , N(R 19 ) 2 , C(0)R 19 , C(0) H 2 , C(0) HR 19 , C(O) Zun 19 ) 2 , HC(0) R 19 , R 19 C(0)R 19 , HS0 2 R 19 , HC(0)OR 19 , S0 2 HR 19 , S0 2 N(R 19 ) 2 , HC(0) H 2 , HC(0) HR 19 , OH, (0), C(0)OH, CN, H 2 , F, CF 3 or CF 2 CF 3; wherein R 19 is a fluorenyl group;
  • n 0 ⁇ 5;
  • R 4 and R 5 are each H or methyl
  • X is S(0) 2 , C(O) or CH 2;
  • P, Q, W, Y and Z are each CH, N or C substituted by one of R 6 , R 7 and R 8 , and at least four of ⁇ , Q, W, Y and Z are not N;
  • R' is H, F or methyl, and R' may be substituted on the alpha or carbon of the 4-amino group of the piperidine ring; and when R' is not , the compound may act as a diastereomer
  • the mixture or mixture of enantiomers or enriched forms of diastereomers and/or enantiomers is provided.
  • the compound has a diastereomeric purity greater than 98%.
  • the compound can be a diastereomerically pure cis compound or a diastereomerically pure trans compound.
  • the compound has an enantiomeric purity greater than 98%.
  • the compound of the invention is a compound of Table 1, or a pharmaceutically acceptable salt or ester or solvate thereof:
  • the compounds of the present invention are also useful as pharmaceutically acceptable salts.
  • the salt may be an acid salt of at least one of the following acids: galactose diacid, D-glucuronic acid, glycerophosphoric acid, 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,
  • the salt may be a salt of a compound of the invention with a metal (including sodium, potassium, calcium, etc.) ion or a pharmaceutically acceptable amine (including ethylenediamine, tromethamine, etc.) or an ammonium ion.
  • a metal including sodium, potassium, calcium, etc.
  • a pharmaceutically acceptable amine including ethylenediamine, tromethamine, etc.
  • ammonium ion e.g., compound 596.
  • the compounds of the present invention may also constitute a pharmaceutical composition in the form of an ester, a prodrug, an N-oxide or a solvate thereof.
  • a pharmaceutical composition in the form of an ester, a prodrug, an N-oxide or a solvate thereof.
  • the compound of the present invention is a carboxylic acid (e.g., compounds 119, 411, 415, and 467, etc.)
  • a suitable alcohol e.g., N-(2-hydroxyethyl)acetamide, etc.
  • the compound of formula (I) or a pharmaceutically acceptable salt or ester or solvate thereof of the present invention is a novel AMPK agonist which may activate the AMPK signaling pathway by activating adiponectin receptors and thus may be used for the preparation of prophylaxis or A drug that treats a variety of diseases as follows.
  • the compounds of the present invention are useful for preventing or treating a variety of metabolic abnormalities or cardiovascular and cerebrovascular diseases, including: insulin resistance, metabolic syndrome, type 1 or type 2 diabetes, hyperlipidemia, obesity, atherosclerosis, Myocardial ischemia, myocardial infarction, arrhythmia, coronary heart disease, hypertension, heart failure, cardiac hypertrophy, myocarditis, diabetes Symptoms (including diabetic cardiomyopathy, diabetic nephropathy, retinopathy, neuropathy and delayed wound healing), nonalcoholic fatty liver, nonalcoholic steatohepatitis, alcoholic fatty liver, cirrhosis, hyperuricemia, gout, Osteoporosis, stroke or cerebral infarction.
  • diabetes Symptoms including diabetic cardiomyopathy, diabetic nephropathy, retinopathy, neuropathy and delayed wound healing
  • nonalcoholic fatty liver nonalcoholic steatohepatitis
  • alcoholic fatty liver cirrhosis
  • hyperuricemia gout, Ost
  • the compound of the present invention can be used for the prevention or treatment of various inflammatory diseases, autoimmune diseases, organ fibrosis diseases, nerve damage diseases or secondary diseases caused by pathogen infections, for example, pneumonia, tuberculosis, inflammatory bowel disease
  • the compounds of the invention are useful for the treatment or modulation of mitochondrial dysfunction and disorders, including: myasthenia gravis, myoclonus, exercise intolerance, Carnes-Syle syndrome, chronic fatigue syndrome, Rees' syndrome, mitochondria Myopathy - encephalopathy - hyperlactosis, stroke syndrome or stroke-like episodes.
  • the compounds of the invention may also be used to treat myasthenia dystrophies, such as Duchenne muscular dystrophy, shell muscle dystrophy or Fleetid's ataxia.
  • the compounds of the invention have anti-tumor effects.
  • tumors include, but are not limited to, bone cancer, acute myeloid leukemia, chronic myelogenous leukemia, acute lymphocytic leukemia, chronic lymphocytic leukemia, myeloproliferative diseases, multiple myeloma, myelodysplastic syndrome, Huo Chikin's lymphoma, non-Hodgkin's lymphoma, hemangioma, granuloma, xanthoma, meningosarcoma, glioma, astrocytoma, medulloblastoma, ependymoma, germ cell tumor (pineal tumor), pleomorphic glioblastoma, oligodendroglioma, schwannomas, retinoblastoma, fibrosarcoma, sarcoma, esophageal cancer, gastric cancer, pancreatic cancer, colorec
  • the pharmaceutical composition for preventing or treating the above-mentioned diseases according to the present invention which comprises a therapeutically effective amount of the compound of the formula (I) or a pharmaceutically acceptable salt or ester or solvate thereof as an active ingredient and a pharmaceutically acceptable adjuvant.
  • the excipients which may be optionally mixed may vary depending on the dosage form, administration form and the like. Examples of the excipients include excipients, binders, disintegrators, lubricants, flavoring agents, flavoring agents, coloring agents or sweeteners, and the like.
  • the pharmaceutical composition may be in the form of a pharmaceutically acceptable preparation such as a capsule, a powder, a tablet, a granule, a pill, an injection, a syrup, an oral solution, an inhalation, an ointment, a suppository or a patch.
  • a pharmaceutically acceptable preparation such as a capsule, a powder, a tablet, a granule, a pill, an injection, a syrup, an oral solution, an inhalation, an ointment, a suppository or a patch.
  • the compounds of the invention may be combined with one or more other types of agents for the prevention or treatment of the above disorders, including but not limited to the following combinations.
  • prophylactic or therapeutic agents that may be selected for use in combination with the compounds of the invention may be one or more anti-diabetic agents, including metformin, sulfonylureas, such as glibenclamide and glimepiride.
  • anti-diabetic agents including metformin, sulfonylureas, such as glibenclamide and glimepiride.
  • glucose Glycosidase inhibitors such as acarbose and miglitol
  • PPAR Y agonists such as pioglitazone and rosiglitazone
  • PPARot/ ⁇ dual agonists dipeptidyl peptidase IV (DPP-IV) Inhibitors (such as sitagliptin, saxagliptin, alogliptin, and linagliptin), glinide-type hypoglycemic agents (such as repaglinide and nateglinide, etc.), SGLT2 inhibitors (eg, cangliflozin, dapagliflozin, nglipepsin, iglegide, rugliflozin, and togliflozin), glucokinase agonists (eg, HMS5552, etc.), insulin, glucagon Peptide-l (GLP-1) drugs (such as exenatide, liragluti
  • prophylactic or therapeutic agents may be one or more weight-loss drugs, including lorcaserin, orlistat, and glucagon-like peptide-1 (GLP-l Classes of drugs (such as exenatide, liraglutide, risnatide, duraglutide, benaglutide, and albendide, etc.).
  • weight-loss drugs including lorcaserin, orlistat, and glucagon-like peptide-1 (GLP-l Classes of drugs (such as exenatide, liraglutide, risnatide, duraglutide, benaglutide, and albendide, etc.).
  • prophylactic or therapeutic agents may be one or more anti-alcoholic fatty liver disease drugs, including: AMPK agonists (e.g., metformin), farnesyl X receptor ( FXR) agonists (eg, oleic acid, GS-9674, EDP-305, and LJN452, etc.), acetyl-CoA carboxylase (ACC) inhibitors (eg, GS-0976, etc.), apoptosis signal-regulated kinase-1 ( ASK1) inhibitors (eg Rhythmsertib, etc.), PPAR agonists (eg Elafibranor, Saroglitazar, IVA337 and MSDC-0602K, etc.), caspase inhibitors (eg Emricasan, etc.), stearoyl-CoA desaturation Enzyme 1 (SCD1) inhibitors (eg Aramchol et al), long-acting
  • AMPK agonists e.g., metform
  • prophylactic or therapeutic agents may be one or more hypolipidemic drugs, including niacin, statins (eg, lovastatin, simvastatin, pravastatin, Mevastatin, fluvastatin, atorvastatin, cerivastatin, lovastatin and pitavastatin), cholesterol absorption inhibitors (eg ezetimibe, etc.), fibrates (eg clofibrate, benzal) Bet, fenofibrate, etc.), PCSK9 inhibitors (such as Evolocumab and Alirobumab, etc.), CETP inhibitors (such as anacetrapib, etc.), AMPK agonists and ACC inhibitors (such as GS-0976, etc.).
  • statins eg, lovastatin, simvastatin, pravastatin, Mevastatin, fluvastatin, atorvastatin, cerivastatin, lovastatin and pitavastatin
  • RR 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 and R′ are identical to those defined in the above formula (I); m is 0, 1, 2 , 3, 4, 5, 6, 7, 8, or 9.
  • the compound prepared by the present invention has a structure of the formula (I) having significant AMPK agonistic activity, and the present invention
  • the agonistic activity of the compound to AMPK is adiponectin 1 (AdipoRl)-dependent, a specific adiponectin receptor agonist, and the compound having the structure of the formula (I) of the present invention can be applied to the preparation of AMPK in an organism.
  • Drugs related to the disease for example, can be used to prevent diabetes and its complications, hyperlipidemia and nonalcoholic fatty liver disease, cardiomyopathy and heart failure.
  • Figure 1 is a graph showing the effect of compounds on the phosphorylation of AMPK in C2C12 cells
  • Figure 2 is a graph showing the effect of compounds on AMPK phosphorylation of AdipoRl wild type or AdipoRl knockout HEK293T cells;
  • Figure 3 is a graph showing the effect of the calcium chelator EGTA on the agonistic activity of the compound AMPK;
  • Figure 4 is a time-FBG relationship diagram of hypoglycemia of Compounds 111 and 119;
  • Fig. 5 is a graph showing the levels of TG, LDL, HDL and liver TG in serum after oral administration of compound 119 in mice;
  • Fig. 6 is a diagram showing HE staining of liver after oral administration of compound 119 in mice;
  • Figure 7 is a graph showing liver oil red staining after oral administration of Compound 119 in mice.
  • Figure 8 is a graph showing the levels of ALT and AST in serum after oral administration of Compound 119 in mice;
  • Figure 9 is a graph showing the effect of Compound 119 on the SD rat heart failure model.
  • the invention discloses a compound, a preparation method thereof, an intermediate of the compound and a preparation method thereof, and an application of the compound as an AMPK agonist, and those skilled in the art can learn from the contents of the present invention and appropriately improve the process parameters. It is to be understood that all such alternatives and modifications are obvious to those skilled in the art and are considered to be included in the present invention.
  • the method and the application of the present invention have been described by the preferred embodiments, and it is obvious that the method and application described herein may be modified or appropriately modified and combined without departing from the scope of the present invention. The technique of the present invention is applied.
  • the compound 1-6 (200 mg, 0.6275 mmol) was dissolved in anhydrous DMF (1 mL), and 1,1-carbonyldiimidazole (CDI) (117 mg, 0.7216 mmol) was added and heated at 70 ° C for 1 h. N-Boc-4-aminopiperidine (126 mg, 0.6275 mmol) was added and the reaction was continued for 2 hours.
  • CDI 1,1-carbonyldiimidazole
  • ESI-MS m/z 451.2 [M+Na] + .
  • Gemfibrozil (II-l) 250 mg, 1 mmol was dissolved in anhydrous DMF (2 mL), CDI (186 mg, 1.149 mmol) was added, and stirred at 70 ° C for 1 h, then N-Boc-4 was added -Aminopiperidine (200 mg, 1 mmol), reacted for 2 h.
  • Example 74 2-(4-Benzoylphenoxy)-N-(1-benzylpiperidin-4-yl)-2-methylpropanamide (Compound 74)
  • ESI-MS m/z 479.1 [M+Na] +
  • ESI-MS m/z 443.3 [M+H] + .
  • the compound ⁇ -2 (160 mg, 0.45 mmoL) was dissolved in DCM (5 mL), triethylamine (0.095 mL) and p-cyanobenzenesulfonyl chloride (92 mg, 0.46 mmoL).
  • ee 99.8% (Chiral HPLC analysis conditions: Chiralpak IC 4.6 mm X 250 mm, column temperature: 25 ° C; mobile phase: 70% hexane/ 30% isopropanol; flow rate: l mL/min; detection wavelength: UV254 nm ; retention time: 16.0 min).
  • the ee value was detected using the similar conditions as described above unless otherwise specified.
  • ESI-MS m/z 540.2 [M+Na] + .
  • ESI-MS m/z 579.3 [M+Na] + .
  • ESI-MS m/z 489.3 [M+Na] + .
  • ESI-MS m/z 539.3 [M+Na].
  • Compound IV-1 (1.1 mL, 10 mmoL) was dissolved in DMF (20 mL).
  • Compound IV-2 (2.23 g, lOmmoL) and potassium carbonate (2.07 g, 15 mmoL) were added in sequence, and heated to reflux under N 2 protection. . After about 8 h of reaction, it was cooled to room temperature, then added with aq. NaOH (60 mL) and ethyl acetate (60 mL ⁇ 3).
  • ESI-MS m/z 522.2 [M+Na] + .
  • ESI-MS m/z 591.3 [M+Na] + .
  • ESI-MS m/z 560.1 [M+Na] + .
  • ESI-MS m/z 528.2 [M+Na] + .
  • ESI-MS m/z 525.4 [M+H] + .

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Abstract

La présente invention concerne un composé de pipéridine ayant une activité agoniste d'AMPK, son procédé de préparation et une application médicale du composé, qui présente une formule structurale telle que représentée par la formule (I), ainsi que des sels pharmaceutiquement acceptables, des esters, des promédicaments, des N-oxydes, ou des solvates du composé. Le composé tel que représenté par la formule (I) de l'invention peut activer une voie de signalisation d'AMPK par activation d'un récepteur d'adiponectine, et peut donc être utilisé dans la préparation de médicaments pour la prévention ou le traitement de maladies induites par AMPK.
PCT/CN2018/083267 2017-04-18 2018-04-17 Agoniste ampk de pipéridine et application médicale associée Ceased WO2018192461A1 (fr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
CN201710269119 2017-04-18
CN201710269119.2 2017-04-18
CN201810336935.5A CN108727250A (zh) 2017-04-18 2018-04-13 哌啶类ampk激动剂及其医药用途
CN201810336935.5 2018-04-13

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2020146876A3 (fr) * 2019-01-11 2020-09-03 Board Of Supervisors Of Louisiana State University And Agricultural And Mechanical College Compositions anticancéreuses et méthodes d'utilisation
EP4157263A4 (fr) * 2020-05-26 2024-09-11 The Regents Of The University Of Michigan Composés de ciblage mitochondrial pour le traitement de maladies associées
WO2025018978A1 (fr) * 2023-07-14 2025-01-23 Modulation Therapeutics, Inc. Inhibiteurs de scd1 pour le traitement de néoplasmes hématolymphoïdes

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1934099A (zh) * 2004-03-22 2007-03-21 阿斯利康(瑞典)有限公司 作为ccr3调节剂的n－哌啶衍生物
EP3053911A1 (fr) * 2013-09-30 2016-08-10 The University of Tokyo Composé activateur du récepteur de l'adiponectine

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1934099A (zh) * 2004-03-22 2007-03-21 阿斯利康(瑞典)有限公司 作为ccr3调节剂的n－哌啶衍生物
EP3053911A1 (fr) * 2013-09-30 2016-08-10 The University of Tokyo Composé activateur du récepteur de l'adiponectine

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2020146876A3 (fr) * 2019-01-11 2020-09-03 Board Of Supervisors Of Louisiana State University And Agricultural And Mechanical College Compositions anticancéreuses et méthodes d'utilisation
EP4157263A4 (fr) * 2020-05-26 2024-09-11 The Regents Of The University Of Michigan Composés de ciblage mitochondrial pour le traitement de maladies associées
WO2025018978A1 (fr) * 2023-07-14 2025-01-23 Modulation Therapeutics, Inc. Inhibiteurs de scd1 pour le traitement de néoplasmes hématolymphoïdes

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