WO2023104201A1 - 芳基c-葡萄糖苷衍生物、其制备方法及其用途 - Google Patents

芳基c-葡萄糖苷衍生物、其制备方法及其用途 Download PDF

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WO2023104201A1
WO2023104201A1 PCT/CN2022/138093 CN2022138093W WO2023104201A1 WO 2023104201 A1 WO2023104201 A1 WO 2023104201A1 CN 2022138093 W CN2022138093 W CN 2022138093W WO 2023104201 A1 WO2023104201 A1 WO 2023104201A1
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heteroatoms
aryl
formula
independently
group
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PCT/CN2022/138093
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French (fr)
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杨新春
李剑
赵金龙
徐以香
成佳兴
许祥诚
陈亮
张超
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珠海市藤栢医药有限公司
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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
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A61K31/351—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom not condensed with another ring
    • 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
    • A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D309/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings
    • C07D309/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
    • C07D309/08—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings 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
    • C07D309/10—Oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D407/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00
    • C07D407/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings
    • C07D407/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the invention relates to the fields of medicinal chemistry and pharmacotherapeutics, in particular to aryl C-glucoside derivatives, their preparation methods and uses.
  • Heart failure referred to as heart failure
  • HF Heart failure
  • the common clinical symptoms are dyspnea and general fatigue. and fatigue, accompanied by signs of systemic/pulmonary congestion and peripheral edema.
  • heart failure As a late clinical symptom of various cardiovascular diseases, heart failure has extremely high morbidity, hospitalization and mortality rates, and has become the main reason for hospitalization of the elderly over 65 years old.
  • the occurrence and development of heart failure are often affected by a variety of factors, so the pathological mechanism is relatively complex.
  • the current research on its mechanism has found that the incentives mainly focus on two aspects: (1) sympathetic nervous system and/or renin-angiotensin-aldosterone The system is abnormally activated for a long time; (2) The secretion of pro-inflammatory and anti-inflammatory cytokines increases, triggering a continuous inflammatory response, resulting in myocardial damage and decreased cardiac function.
  • SGLT2 inhibitors can reduce major adverse cardiovascular events in patients with high-risk cardiovascular diabetes, and are expected to become a new standard in the field of heart failure drug therapy.
  • NHE1 sodium-hydrogen converter
  • the main purpose of the present invention is to provide an aryl C-glucoside derivative that is effective against heart failure and inhibits NHE1, its preparation method and its use.
  • the present invention provides an aryl C-glucoside derivative as shown in formula I - a glucoside derivative, its tautomer, its stereoisomer, its prodrug, or a pharmaceutically acceptable salt of any of the foregoing, or a solvate of any of the foregoing, and a preparation method thereof, And its use in preparing a) NHE1 inhibitor; and/or b) anti-heart failure medicine.
  • the present invention provides aryl C-glucoside derivatives as shown in formula I, its tautomers, its stereoisomers, its prodrugs, or any of the foregoing (referring to the aforementioned as shown in formula I Aryl C-glucoside derivatives, their tautomers, their stereoisomers or their prodrugs), or any of the foregoing (referring to the aforementioned aryl group shown in formula I A solvate of a C-glucoside derivative, its tautomer, its stereoisomer, its prodrug or a pharmaceutically acceptable salt of any of the foregoing);
  • R 1 , R 2 and R 3 are independently H, C 1 -C 6 alkyl, C 1 -C 6 alkyl substituted by 1, 2 or 3 R 1-2 , C 2 -C 6 alkenyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl substituted by 1, 2 or 3 R 1-3 , C 2 -C 6 alkynyl substituted by 1, 2 or 3 R 1-4 , C 3 -C 6 cycloalkyl, C 3 -C 6 cycloalkyl substituted by 1, 2 or 3 R 1-4 or -COR 1-1 ; R 1-1 is C 1 -C 6 alkyl;
  • R 1-2 , R 1-3 and R 1-4 are independently NR 1-2-1 R 1-2-2 , NO 2 , CN, halogen, C 1 -C 4 alkyl, substituted by 1, 2 or C 1 -C 4 alkyl, C 1 -C 4 alkoxy substituted by 3 halogens, C 1 -C 4 alkoxy or OH substituted by 1, 2 or 3 halogens;
  • R 1-2-1 and R 1-2-2 are independently H or C 1 -C 4 alkyl
  • R 4 is COOH or CH 2 OR 4-1 ;
  • R 4-1 is H, C 1 -C 6 alkyl or -COR 4-1-1 ;
  • R 4-1-1 is C 1 -C 6 alkyl;
  • R 4 is CH 2 OR 4-1 , R 4-1 is H or -COR 4-1-1 , at least one of R 1 -R 3 is C 1 -C 6 alkyl or C 2 -C 6 alkyne base;
  • R 5 is "a 3-12 membered heterocycloalkyl group with 1, 2 or 3 heteroatoms selected from one, two or three of N, O and S", C 1 -C 6 Alkyl or -LR 5-1 ;
  • L is -(CH 2 ) m -or -C(O)-(CH 2 ) n -;
  • n 0, 1, 2, 3, 4 or 5;
  • R 5-1 is a C 6 -C 10 aryl group, a C 6 -C 10 aryl group substituted by 1, 2 or 3 R 5-1-1 , "the heteroatom is selected from one of N, O and S , 2 or 3 kinds, 3-12 membered heteroaryl with 1, 2 or 3 heteroatoms", “ heteroatoms selected from N , O and 1, 2 or 3 of S, 3-12 membered heteroaryl with 1, 2 or 3 heteroatoms", “heteroatoms are selected from 1 or 2 of N, O and S Or 3 kinds, 3-12 membered heterocycloalkyl with 1, 2 or 3 heteroatoms” or “heteroatoms selected from N, O and S substituted by 1, 2 or 3 R 5-1-3 1, 2 or 3 of them, a 3-12 membered heterocycloalkyl group with 1, 2 or 3 heteroatoms";
  • R 5-1-1 , R 5-1-2 and R 5-1-3 are independently halogen, C 1 -C 6 alkyl, C 2 -C 6 alkynyl substituted by 1, 2 or 3 halogens , C 6 -C 10 aryl or C 1 -C 6 alkoxy;
  • R 6 is halogen
  • the aryl C-glucoside derivative shown in formula I, its tautomer, its stereoisomer, its prodrug, or any of the foregoing referring to the pharmaceutically acceptable salt of the aforementioned aryl C-glucoside derivative shown in formula I, its tautomer, its stereoisomer or its prodrug), or any of the foregoing (referring to In the solvates of the aforementioned aryl C-glucoside derivatives shown in formula I, their tautomers, their stereoisomers, their prodrugs or any of the aforementioned pharmaceutically acceptable salts)
  • Certain groups are defined as follows, and unmentioned groups are described in any scheme of the present invention (referred to as "in a certain scheme of the present invention"),
  • the C 1 -C 6 alkyl group is independently methyl, ethyl, n-propyl, iso Propyl, n-butyl, isobutyl, sec-butyl or tert-butyl, eg methyl, ethyl or n-propyl.
  • the C 1 -C 4 alkyl group is methyl , ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl.
  • the C 1 -C 4 alkoxy group is methoxy, ethoxy, n-propoxy, isopropyl oxy, n-butoxy, isobutoxy, sec-butoxy or tert-butoxy.
  • the C 1 -C 6 alkyl group is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl groups, such as n-propyl.
  • the halogen is independently F, Cl, Br or I, such as F;
  • the C 1 -C 6 alkyl is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl radical, sec-butyl or tert-butyl, such as methyl;
  • said C 1 -C 6 alkyl substituted by 1, 2 or 3 halogens is independently CF 3 .
  • the halogen is independently F, Cl, Br or I, such as F.
  • the C 2 -C 6 alkenyl is independently vinyl, propenyl, allyl, 1-butenyl, 2-butene base or 3-butenyl.
  • the C 2 -C 6 alkynyl is independently ethynyl, propynyl, propargyl, 1-butynyl, 2-butynyl Alkynyl or 3-butynyl, e.g. propargyl
  • the C 3 -C 6 cycloalkyl is independently cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, for example cyclopropyl .
  • the C 2 -C 6 alkynyl is independently ethynyl, propynyl, alkyne Propyl, 1-butynyl, 2-butynyl or 3-butynyl, eg 3-butynyl.
  • heteroatom is selected from 1, 2 or 3 kinds of N, O and S, and the number of heteroatoms is 1, 2 or 3 3-12 members
  • Heterocycloalkyl is "a 3-6 membered heterocycloalkyl group with 1, 2 or 3 heteroatoms selected from one, two or three of N, O and S", such as tetrahydrofuran base, another example another example
  • the C 6 -C 10 aryl is phenyl or naphthyl.
  • the C 6 -C 10 aryl group in R 5-1 , in the C 6 -C 10 aryl group substituted by 1, 2 or 3 R 5-1-1 , the C 6 -C 10 aryl group is Phenyl or naphthyl, eg phenyl.
  • R 5-1-1 , R 5-1-2 and R 5-1-3 , the C 6 -C 10 aryl groups are independently phenyl or naphthyl, such as phenyl .
  • R 5-1-1 , R 5-1-2 and R 5-1-3 , the C 1 -C 6 alkoxy group is independently methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy or tert-butoxy, for example methoxy.
  • the "heteroatom is selected from 1, 2 or 3 of N, O and S, and the number of heteroatoms is 1, 2 or 3 3- 12-membered heteroaryl" and the "heteroatoms substituted by 1, 2 or 3 R 5-1-2 are selected from 1, 2 or 3 of N, O and S, and the number of heteroatoms is 1 , 2 or 3 3-12-membered heteroaryl" in “the heteroatom is selected from 1, 2 or 3 of N, O and S, and the number of heteroatoms is 1, 2 or 3 3- 12-membered heteroaryl” is independently "a 3-10-membered heteroaryl with 1, 2 or 3 heteroatoms selected from one, two or three of N, O and S", such as diazinyl (eg ), furyl (eg ), pyridyl (for example ), pyrazinyl (eg ) or quinolinyl (e.g. ).
  • diazinyl eg
  • furyl eg
  • pyridyl for example
  • the "heteroatom is selected from 1, 2 or 3 of N, O and S, and the number of heteroatoms is 1, 2 or 3 3- 12-membered heterocycloalkyl" and the "heteroatoms substituted by 1, 2 or 3 R 5-1-3 are selected from 1, 2 or 3 of N, O and S, and the number of heteroatoms is 1, 2 or 3 3-12 membered heterocycloalkyl" in "heteroatoms are selected from 1, 2 or 3 of N, O and S, and the number of heteroatoms is 1, 2 or 3 3-12-membered heterocycloalkyl" is independently "a 3-6-membered heterocyclic ring with 1, 2 or 3 heteroatoms selected from one, two or three of N, O and S Alkyl", such as dithiopentyl (e.g. ).
  • the halogen is F, Cl, Br or I, such as Cl.
  • R5 is "a 3-12 membered heterocycloalkane with 1, 2 or 3 heteroatoms selected from one, two or three of N, O and S.”group", propyl group or -LR 5-1 .
  • m is 1 or 2.
  • n 0 or 4.
  • R 5-1 is C 6 -C 10 aryl, C 6 -C 10 aryl substituted by 1, 2 or 3 R 5-1-1 , "heteroatom is selected from N , 1, 2 or 3 of O and S, 3-12 membered heteroaryl with 1, 2 or 3 heteroatoms", substituted by 1, 2 or 3 R 5-1-2 "Heteroatoms are selected from 1, 2 or 3 of N, O and S, and 3-12 membered heteroaryl groups with 1, 2 or 3 heteroatoms" or "heteroatoms are selected from N, O and 1, 2 or 3 of S, 3-12 membered heterocycloalkyl with 1, 2 or 3 heteroatoms".
  • R 4 is CH 2 OH, at least one of R 1 -R 3 is C 1 -C 6 alkyl or C 2 -C 6 alkynyl, and the rest are H; or, R 4 is COOH Or CH 2 OR 4-1 , R 1 -R 3 are independently H, C 1 -C 6 alkyl or C 2 -C 6 alkynyl, R 4-1 is C 1 -C 6 alkyl;
  • R5 is "a 3-12 membered heterocycloalkyl group with 1, 2 or 3 heteroatoms selected from one, two or three of N, O and S";
  • R6 is Cl.
  • R 1 -R 3 are independently H, methyl, ethyl, n-propyl, propargyl or acetyl.
  • R 4 is COOH, CH 2 OH, CH 2 OCH 3 or CH 2 OCOCH 3 .
  • R 5 is
  • R 6 is Cl.
  • aryl C-glucoside derivative as shown in formula I is any of the following compounds:
  • the present invention also provides a method for preparing aryl C-glucoside derivatives as shown in formula I, which includes any of the following methods:
  • silanes such as tert-butyldimethylsilyl chloride and imidazole are treated with the compound of formula II A in DMF to obtain the compound of intermediate formula II B ;
  • the formula II A compound is treated with a halogenated hydrocarbon in the presence of an inorganic base such as sodium hydroxide, and after the reaction is completed, the aryl C-glucoside derivative (target compound) is treated with 90% aqueous acetic acid.
  • an inorganic base such as sodium hydroxide
  • the present invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising:
  • Aryl C-glucoside derivatives as shown in formula I according to any one of the present invention, its tautomers, its stereoisomers, its prodrugs, or any of the foregoing ( Refer to the pharmaceutically acceptable salt of the aforementioned aryl C-glucoside derivative shown in formula I, its tautomer, its stereoisomer or its prodrug), or any of the aforementioned (referring to the aforementioned A solvate of the aryl C-glucoside derivative as shown in formula I, its tautomer, its stereoisomer, its prodrug or a pharmaceutically acceptable salt of any of the foregoing); and
  • the dosage form of the pharmaceutical composition is an oral dosage form or a non-oral dosage form.
  • the dosage form of the pharmaceutical composition is selected from tablet, capsule, granule, suspension, pill, solution, syrup and injection.
  • the present invention also provides aryl C-glucoside derivatives as shown in formula I according to any one of the present invention, its tautomers, its stereoisomers, its prodrugs, or any of the foregoing (referring to the pharmaceutically acceptable salt of the aforementioned aryl C-glucoside derivative shown in formula I, its tautomer, its stereoisomer or its prodrug), or any of the aforementioned ( Refer to the solvate of the aforementioned aryl C-glucoside derivatives shown in formula I, its tautomers, its stereoisomers, its prodrugs or any of the aforementioned pharmaceutically acceptable salts) or The use of the pharmaceutical composition, which is used to prepare a) an inhibitor for inhibiting a sodium-hydrogen exchanger; and/or b) a medicament for preventing and/or alleviating and/or treating diseases related to a sodium-hydrogen exchanger.
  • the present invention also provides a method for preventing and/or alleviating and/or treating diseases related to sodium-hydrogen exchangers, which includes: administering a therapeutically effective amount of the formula as described in any one of the present invention to an individual in need
  • the aryl C-glucoside derivative shown in I, its tautomer, its stereoisomer, its prodrug, or any of the foregoing referring to the aforementioned aryl C-glucoside shown in formula I derivatives, their tautomers, their stereoisomers or their prodrugs), or any of the foregoing (referring to the aforementioned aryl C-glucoside derivatives as shown in formula I , a tautomer thereof, a stereoisomer thereof, a prodrug thereof, or a pharmaceutically acceptable salt of any of the foregoing) or the pharmaceutical composition.
  • the sodium-hydrogen exchanger is preferably NHE1.
  • the diseases related to the sodium-hydrogen exchanger include heart failure.
  • the aryl C-glucoside derivative shown in formula I, its tautomer, its stereoisomer, its prodrug, or any of the above A pharmaceutically acceptable salt of one (referring to the aforementioned aryl C-glucoside derivative shown in formula I, its tautomer, its stereoisomer or its prodrug), or any of the aforementioned (Referring to the solvate of the aforementioned aryl C-glucoside derivatives shown in formula I, its tautomers, its stereoisomers, its prodrugs or any of the aforementioned pharmaceutically acceptable salts)
  • the pharmaceutical composition is used for the preparation of medicines with one or more of the following effects:
  • the cardiomyocytes include: H9c2, primary cardiomyocytes of rat neonatal rats.
  • the heart failure includes: heart failure with reduced ejection fraction and heart failure with preserved ejection fraction.
  • pharmaceutically acceptable means that salts, solvents, auxiliary materials, etc. are generally non-toxic, safe and suitable for use by patients.
  • the "patient” is preferably a mammal, more preferably a human.
  • pharmaceutically acceptable salt refers to a salt prepared from a compound of the present invention with a relatively non-toxic, pharmaceutically acceptable acid or base.
  • the base addition can be obtained by contacting the neutral form of such compounds with a sufficient amount of a pharmaceutically acceptable base in pure solution or in a suitable inert solvent.
  • Pharmaceutically acceptable base addition salts include, but are not limited to: lithium salts, sodium salts, potassium salts, calcium salts, aluminum salts, magnesium salts, zinc salts, bismuth salts, ammonium salts, diethanolamine salts.
  • acid addition can be achieved by contacting the neutral form of such compounds with a sufficient amount of a pharmaceutically acceptable acid in neat solution or in a suitable inert solvent.
  • a pharmaceutically acceptable acid includes inorganic acids, including but not limited to: hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, carbonic acid, phosphoric acid, phosphorous acid, sulfuric acid and the like.
  • the pharmaceutically acceptable acids include organic acids, including but not limited to: acetic acid, propionic acid, oxalic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid , fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, salicylic acid, tartaric acid, methanesulfonic acid, isonicotinic acid, acid citric acid, oleic acid , tannic acid, pantothenic acid, hydrogen tartrate, ascorbic acid, gentisic acid, fumaric acid, gluconic acid, sugar acid, formic acid, ethanesulfonic acid, pamoic acid (ie 4,4'-methylene-bis( 3-hydroxy-2-naphthoic acid)), amino acids (eg glutamic acid, arginine) and the like.
  • the compounds of the present invention When the compounds of the present invention contain relatively acidic and relatively basic functional groups, they can be converted into base addition salts or acid addition salts.
  • base addition salts For details, see Berge et al., "Pharmaceutical Salts", Journal of Pharmaceutical Science 66:1-19 (1977), or, Handbook of Pharmaceutical Salts: Properties, Selection, and Use (P. Heinrich Stahl and Camille G. Wermuth, ed., Wiley-VCH, 2002).
  • solvate refers to a compound of the present invention in combination with a stoichiometric or non-stoichiometric solvent.
  • Solvent molecules in solvates can exist in an ordered or non-ordered arrangement.
  • the solvent includes but not limited to: water, methanol, ethanol and the like.
  • stereoisomer refers to cis-trans isomers or optical isomers. These stereoisomers can be separated, purified and enriched by asymmetric synthesis methods or chiral separation methods (including but not limited to thin layer chromatography, rotary chromatography, column chromatography, gas chromatography, high pressure liquid chromatography, etc.), and can also be obtained by It can be obtained by chiral resolution through bond formation (chemical combination, etc.) or salt formation (physical combination, etc.) with other chiral compounds.
  • single stereoisomer means that the mass content of one stereoisomer of the compound of the present invention relative to all stereoisomers of the compound is not less than 95%.
  • variable such as halogen
  • the definition at each position of the variable has nothing to do with the definitions at other positions, and their meanings are independent of each other and do not affect each other. Therefore, if a group is substituted by 1, 2 or 3 halogens, that is, the group may be substituted by up to 3 halogens, the definition of halogen at this position is independent of the definition of halogen at other positions. Also, combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.
  • halogen refers to fluorine, chlorine, bromine or iodine.
  • alkyl refers to a straight or branched chain alkyl group having the indicated number of carbon atoms.
  • alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, sec-butyl, n-pentyl, n-hexyl, and the like.
  • alkoxy refers to the group -ORx , wherein Rx is alkyl as defined above.
  • alkenyl means a straight or branched chain alkene having the indicated number of carbon atoms containing one or more carbon-carbon double bonds, which may be internal, and no carbon-carbon triple bonds. It may also be terminal, and examples of olefins include vinyl, allyl, methylvinyl, propenyl, butenyl, pentenyl, 1,1-dimethyl-2-propenyl, hexenyl, and the like.
  • alkynyl refers to a straight-chain or branched hydrocarbon group having one or more triple bonds with the specified number of carbon atoms (eg C 2 -C 6 alkynyl, also eg C 2 -C 4 alkynyl).
  • the one or more carbon-carbon triple bonds may be internal or terminal, such as propynyl with a triple bond internal or propynyl with a triple bond at the end wait.
  • cycloalkyl refers to a saturated monocyclic, bridged, or spirocyclic cyclic group having the specified number of ring carbon atoms (eg, C3 - C6 ), the ring atoms consisting only of carbon atoms.
  • Monocycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.
  • heterocycloalkyl refers to a group having a specified number of ring atoms (such as 3-12 members), a specified number of heteroatoms (such as 1, 2 or 3), a specified type of heteroatom (N, O, and S 1, 2 or 3) of the cyclic group, which is a monocyclic, bridged or spiro ring, and each ring is saturated.
  • Heterocycloalkyl includes, but is not limited to, azetidinyl, tetrahydropyrrolyl, tetrahydrofuranyl, morpholinyl, piperidinyl, and the like.
  • aryl refers to a C 6 -C 10 aryl group such as phenyl or naphthyl.
  • heteroaryl refers to an aromatic group containing heteroatoms, preferably containing 1, 2 or 3 aromatic ring groups independently selected from nitrogen, oxygen and sulfur, which are monocyclic or bicyclic, when When bicyclic, at least one ring is aromatic, such as furyl, pyridyl, pyridazinyl, pyrimidyl, pyrazinyl, thienyl, isoxazolyl, oxazolyl, diazolyl, imidazolyl, pyrrolyl , pyrazolyl, triazolyl, tetrazolyl, thiazolyl, isothiazolyl, thiadiazolyl, benzimidazolyl, indolyl, indazolyl, benzothiazolyl, benzisothiazolyl, benzene Azoxazolyl, benzisoxazolyl, quinolinyl, isoquinolyl, etc.
  • pharmaceutically acceptable carrier refers to the excipients and additives used in the production of medicines and the formulation of prescriptions, and refers to all substances contained in pharmaceutical preparations except the active ingredient.
  • Can refer to Pharmacopoeia of the People's Republic of China (2015 edition) four, or, Handbook of Pharmaceutical Excipients (Raymond C Rowe, 2009Sixth Edition).
  • treatment refers to therapeutic therapy.
  • treatment means: (1) interfering with (a) one or more points in the biological cascade leading to or causing the condition or (b) one or more biological manifestations of the condition, or (2) ameliorating One or more symptoms, effects or side effects associated with a condition, or one or more symptoms, effects or side effects associated with a condition or its treatment.
  • prevention refers to a reduction in the risk of acquiring or developing a disease or disorder.
  • terapéuticaally effective amount refers to an amount of a compound sufficient to effectively treat a disease or condition described herein when administered to a patient.
  • a “therapeutically effective amount” will vary depending on the compound, the condition and its severity, and the age of the patient to be treated, but can be adjusted as necessary by those skilled in the art.
  • the inhibitor for inhibiting the sodium-hydrogen exchanger can be used in mammalian organisms; it can also be used in vitro, mainly as experimental purposes, for example: as a standard sample or a control sample for comparison, or according to this
  • the conventional method in the field is made into a kit to provide rapid detection for the inhibitory effect of the sodium-hydrogen exchanger.
  • the compound of the invention has simple structure, simple preparation process and low production cost.
  • Fig. 1 is a diagram of crystal violet staining of cardiomyocytes treated with compound I-2 and EMPA.
  • Fig. 2 is a quantification diagram of crystal violet staining of cardiomyocytes treated with compound I-2 and EMPA.
  • Fig. 3 is a graph showing the release of LDH in cardiomyocytes after treatment with compound I-2 and EMPA.
  • Fig. 4 is a graph showing the survival rate of cardiomyocytes treated with compound I-2, EMPA and positive drug Cariporide.
  • Fig. 5 is a diagram of the fluorescence intensity of cardiomyocytes treated with compound I-2, EMPA and the positive drug Cariporide.
  • Fig. 6 is a representative diagram of echocardiography (M mode) of a mouse model of heart failure induced by isoproterenol treated with compound I-2 and EMPA.
  • Fig. 7 is a heart rate diagram of a mouse model of heart failure induced by isoproterenol treated with compound I-2 and EMPA.
  • Fig. 8 is a graph of ejection fraction of a mouse model of heart failure induced by isoproterenol treated with compound I-2 and EMPA.
  • Fig. 9 is a graph showing the short-axis shortening rate of the mouse model of heart failure induced by isoproterenol treated with compound I-2 and EMPA.
  • Fig. 10 is a graph showing the inner systolic diameter of the left ventricle in the mouse model of heart failure induced by isoproterenol treated with compound I-2 and EMPA.
  • Fig. 11 is a diastolic diameter diagram of the left ventricle of a mouse model of heart failure induced by isoproterenol treated with compound I-2 and EMPA.
  • Figure 12 is a graph showing the thickness of the posterior wall of the left ventricle during systole in a mouse model of heart failure induced by isoproterenol treated with compound I-2 and EMPA.
  • Figure 13 is a graph showing the thickness of the posterior wall of the left ventricle during diastole in a mouse model of heart failure induced by isoproterenol treated with compound I-2 and EMPA.
  • Figure 14 is a representative diagram of Masson staining in the mouse model of heart failure induced by isoproterenol treated with compound I-2 and EMPA.
  • Figure 15 is a quantitative diagram of Masson staining in the mouse model of heart failure induced by isoproterenol treated with compound I-2 and EMPA.
  • Figure 16 shows the heart-to-body ratio of a mouse model of heart failure induced by isoproterenol treated with compound I-2 and EMPA.
  • Fig. 17 is a pharmacodynamic survival rate diagram of the improvement of heart function in the MI-induced heart failure mouse model treated with compound I-2.
  • Fig. 18 is a representative diagram of echocardiography (M mode) of a mouse model of heart failure induced by MI treated with compound I-2.
  • Fig. 19 is a heart rate diagram of a mouse model of heart failure induced by MI treated with compound I-2.
  • Fig. 20 is a graph of ejection fraction in MI-induced heart failure mouse model treated with compound I-2.
  • Fig. 21 is a graph of short-axis shortening rate of MI-induced heart failure mouse model treated with compound I-2.
  • Fig. 22 is a diastolic diastolic diameter diagram of the left ventricle in a mouse model of heart failure induced by compound I-2.
  • Fig. 23 is a graph showing the inner systolic diameter of the left ventricle in the MI-induced heart failure mouse model treated with compound I-2.
  • Figure 24 is a graph showing the thickness of the posterior wall of the left ventricle during diastole in the MI-induced heart failure mouse model treated with compound I-2.
  • Figure 25 shows the rear wall thickness of the left ventricle during systole in the MI-induced heart failure mouse model treated with compound I-2.
  • Fig. 26 is a representative diagram of Masson staining of compound I-2 on MI-induced heart failure mouse model.
  • Fig. 27 is a quantitative diagram of Masson staining of compound I-2 on MI-induced heart failure mouse model.
  • Fig. 28 is a graph showing the effect of compound I-2 on the heart-to-body ratio of a mouse model of heart failure induced by MI.
  • the white solid was dissolved in 10 mL of 90% acetic acid aqueous solution, reacted at 60°C for 12 h, cooled to room temperature, poured the reaction liquid into ice water, adjusted the pH to neutral with saturated NaHCO 3 solution, added water and ethyl acetate to extract , the organic phase was dried with saturated brine and sodium sulfate, evaporated to dryness, separated and purified by silica gel column chromatography (V ethyl acetate ), and the final product was obtained as a white solid with a yield of 35%.
  • the white solid (200 mg) was dissolved in 10 mL of 90% acetic acid aqueous solution, reacted at 60 ° C for 12 h, cooled to room temperature, poured the reaction solution into ice water, adjusted the pH to neutral with saturated NaHCO 3 solution, added water and ethyl acetate After extraction, the organic phase was dried with saturated brine and sodium sulfate, evaporated to dryness, separated and purified by silica gel column chromatography (V ethyl acetate ), and the final product was obtained as a white solid with a yield of 76%.
  • Rat cardiomyocytes were purchased from the Stem Cell Bank of the Chinese Academy of Sciences. Cardiomyocytes were cultured in a high-glucose DMEM (containing 10% fetal bovine serum, 1% penicillin/streptomycin) medium and placed in an incubator at 37°C and 5% CO 2 . After the cardiomyocytes basically covered the cell culture dish (10 cm), the cells were digested with trypsin, and seeded in a 96-well plate at a cell density of 8000 cells/well, 100 uL per well. After culturing overnight, the drug solution diluted with DMEM medium was added to the plate, 100 ⁇ L per well. Incubate for 48h in a cell culture incubator.
  • DMEM containing 10% fetal bovine serum, 1% penicillin/streptomycin
  • the compound was diluted to the target concentration with sugar-free and serum-free DMEM, added to the plate, and subjected to glucose deprivation (GD) treatment. After GD for 36-48h, the cell survival status was observed (the survival rate of the model group (ie, DMSO group) should be controlled at 50%, which can better highlight the cytoprotective effect of the compound), and the cell survival rate was detected by cck8.
  • the control group is a normal culture group, no drug (no DMSO added) and no sugar deprivation treatment is performed on the cells, and the survival rate is taken as 100%.
  • the compounds in the table and the cells in the DMSO group were all treated with sugar deprivation, and the activity data are shown in Tables 1 and 2.
  • the compounds involved in the present invention all exhibit anti-heart failure effects superior to EMPA, especially the onset concentration of compound I-2 is reduced to 1 ⁇ M, which is 50 times lower than the low-efficiency concentration of empagliflozin. Potential anti-heart failure candidate compounds.
  • H9c2 cells were seeded into 24-well plates, and after adhering to the wall, EMPA and compound I-2 dilutions prepared in DMEM were added for pre-administration for 48 hours.
  • the NG group was not treated with sugar deprivation; both the DMSO group and the treatment group were treated with GD.
  • the medium was removed, the cells were placed on ice, and washed twice with pre-cooled PBS, each time for 3-5 minutes. Fix with pre-cooled methanol for 10 minutes at -20°C. Remove methanol, return to room temperature, add a sufficient amount of 0.5% crystal violet staining solution, and incubate at room temperature for 10 minutes. Remove the crystal violet and wash the cells with water until the color does not fade. The cells were dried in an oven at 37°C, photographed under a microscope, and quantified by Image J.
  • BCECF AM is a fluorescent dye that can penetrate cell membranes. BCECF AM itself has no fluorescence, and after entering the cell, it can be cleaved into BCECF by intracellular esterase, thereby being retained in the cell. BCECF can be excited to form green fluorescence at an appropriate pH value. When detecting, the excitation wavelength is 488nm, the emission wavelength is 535nm, and the fluorescence intensity increases with the increase of pH.
  • the positive drugs used in this example are Cariporide (Car) and EMPA.
  • Caliber is represented by the following formula:
  • Figure 4 shows that the positive drugs Cariporide, EMPA, and Compound I-2 did not produce cytotoxicity when the cells were treated for 30 minutes at a concentration of 200 ⁇ M and 500 ⁇ M, and Figure 5 showed that Compound I-2 had better inhibitory activity on NHE1 at the same concentration. at EMPA.
  • Isoproterenol hydrochloride is a common inducer for establishing heart failure models. Subcutaneous injection of isoproterenol hydrochloride will increase the heart rate of the mice, and the myocardium will continue to contract strongly, increasing the oxygen consumption of the myocardium, increasing the load on the heart, and eventually causing heart failure.
  • mice with an average body weight of about 21-22g were divided into 5 groups: control group (Sham), model group (Vehicle), empagliflozin 30mg/kg group, empagliflozin 10mg/kg group, Compound I-2 10mg/kg group, 8 mice in each group. Oral administration was administered every morning, and the control group and the model group were given the same amount of vehicle (5% DMSO+95% water).
  • isoproterenol hydrochloride was subcutaneously injected twice a day, in the morning and in the evening, with each dose of 40 mg/kg on the 1st-2nd day, 20 mg/kg on the 3rd-7th day, and 20 mg/kg on the 3rd-7th day.
  • the dose for 8-14 days was 10 mg/kg, and the control group was injected with the same amount of normal saline without isoproterenol hydrochloride.
  • the Visual-Sonics Vevo 3100 small animal high-resolution micro-ultrasound imaging system was used to evaluate the cardiac structure and function of the experimental mice in each group.
  • IVSs interventricular septal thickness
  • IVSd diastolic ventricular septal thickness
  • LVIDs left ventricular inner systolic diameter
  • LVIDd left ventricular inner diastolic diameter
  • LVPWs left ventricular systolic posterior wall thickness
  • EF ejection fraction
  • FS fractional shortening rate
  • Graph Pad software for data processing to calculate significant differences (Unpaired t-test).
  • the heart function of the mice in the model group was significantly reduced, the thickness of the left ventricular septum and posterior wall thickness during systole/diastole was significantly thinner, the inner diameter became larger, and the ejection fraction and short-axis shortening rate decreased to normal Below the range (the reference value of mice with normal ejection fraction is 55-85%, and the reference value of mice with normal short-axis shortening rate is 30-50%), myocardial fibrosis increases significantly.
  • Empagliflozin 30mg/kg dose administration group can effectively improve the cardiac dysfunction and fibrosis caused by isoproterenol hydrochloride, but the dose of 10mg/kg can not significantly improve cardiac function, while the compound I-2 at 10mg/kg kg dose can significantly improve the cardiac function of mice and reduce the degree of myocardial fibrosis, indicating that the effective dose of compound I-2 in vivo is lower than that of empagliflozin, and the drug effect at the same dose is due to empagliflozin.
  • the data are mean ⁇ SD, t test, # P ⁇ 0.05, ## P ⁇ 0.01, ### P ⁇ 0.001, #### P ⁇ 0.0001vs sham, * P ⁇ 0.05, ** P ⁇ 0.01, *** P ⁇ 0.001, **** P ⁇ 0.0001 vs vehicle.
  • the data are mean ⁇ SD, t test, # P ⁇ 0.05, ## P ⁇ 0.01, ### P ⁇ 0.001, #### P ⁇ 0.0001vs sham, * P ⁇ 0.05, ** P ⁇ 0.01, *** P ⁇ 0.001, **** P ⁇ 0.0001 vs vehicle.
  • Coronary artery ligation leads to myocardial infarction and myocardial hypertrophy, and eventually transitions to heart failure, which can be used to evaluate the preventive effect of long-term medication on heart failure.
  • mice C57/6J male mice were divided into two groups, DMSO treatment group and I-2 treatment group, 20 rats in each group, DMSO or I-2 were pre-administered for 1 week before left anterior descending coronary artery ligation, and administered by intragastric administration every day , Group I-2 was given 10 mg/kg of compound I-2, and group DMSO was given the same volume of aqueous solution containing 5% DMSO.
  • the surgical modeling was carried out, and the procedure was as follows: turn on the gas anesthesia machine for small animals, put the mouse into the chamber of the gas anesthesia machine, and after the mouse was relaxed and comatose, the mouse was taken out and fixed on the self-made mouse board.
  • the coronary artery is ligated with 7-0 surgical silk suture 2 mm below the line, and the needle depth is about 1 mm to avoid puncturing the heart.
  • the color of the front wall of the left ventricle can be seen to change from bright red to dark purple to pale.
  • the heart is quickly pushed into the chest cavity, the pericardium is covered, and the air in the chest is squeezed out. The ribs and skin are sutured sequentially, and the neck wound is sutured. Disinfect the wound with povidone iodine until the mice wake up. No drug intervention was given after the operation. The survival rate of the mice was recorded after the operation, and the survival curve was drawn.
  • the heart function test, myocardial infarction area and fibrosis area were detected respectively.
  • I-2 at a dose of 10 mg/kg can significantly increase the survival rate of postoperative mice, and significantly improve the cardiac function, cardiac hypertrophy and myocardial fibrosis of postoperative mice, while in our previous In the study, EMPA at a dose of 10mg/kg could not improve the survival rate of postoperative mice.
  • This experiment further shows that the anti-heart failure effect of I-2 is better than that of EMPA.
  • the data are mean ⁇ SD, t test, * P ⁇ 0.05, ** P ⁇ 0.01, *** P ⁇ 0.001, **** P ⁇ 0.0001vs DMSO.
  • the data are mean ⁇ SD, t test, * P ⁇ 0.05, ** P ⁇ 0.01, *** P ⁇ 0.001, **** P ⁇ 0.0001 vs DMSO.

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Abstract

一种芳基C-葡萄糖苷衍生物、其制备方法及其用途。具体提供了如式I所示的芳基C-葡萄糖苷衍生物、其互变异构体、其立体异构体、其前药，或前述任一者的药学上可接受的盐，或前述任一者的溶剂化物。芳基C-葡萄糖苷衍生物的肌细胞保护作用、NHE1抑制活性均优于现有技术的恩格列净，且能在较低给药剂量下发挥有效的抗心衰作用，因此可以用于制备抗心衰的药物。该化合物结构简单，制备工艺简洁，生产成本低。

Description

芳基C-葡萄糖苷衍生物、其制备方法及其用途
本申请要求申请日为2021/12/28的中国专利申请PCT/CN2021/142041的优先权与申请日为2021/12/09的中国专利申请PCT/CN2021/136887的优先权。本申请引用上述中国专利申请的全文。
技术领域
本发明涉及药物化学和药物治疗学领域，具体涉及芳基C-葡萄糖苷衍生物、其制备方法及其用途。
背景技术
心力衰竭(Heart failure，HF)简称心衰，是心脏收缩和/或舒张功能受损、射血及充盈能力减退导致组织灌注不足的一组临床疾病，其常见的临床症状为呼吸困难、周身疲惫和乏力，并伴有体循环/肺循环淤血及周围水肿等体征。作为多种心血管疾病的后期临床病征，心衰导致的患病率、住院率和死亡率极高，已成为65岁以上老年人住院的主要原因。
心衰的发生发展常受多种因素综合影响，故病理机制较复杂，目前针对它的机制研究发现诱因主要集中于两方面：(1)交感神经系统和/或肾素-血管紧张素-醛固酮系统长期异常激活；(2)促炎与抗炎细胞因子分泌增加，引发持续炎症反应，导致心肌损伤和心功能下降。
随着对心衰发生机制的认识加深，心衰的治疗方案也从“强心、利尿、扩血管”的传统模式逐渐转变成神经内分泌阻断及逆转心室重构等新型手段，包括血管紧张素转化酶抑制剂/血管紧张素Ⅱ受体抑制剂(ACEI/ARB)、醛固酮抑制剂、β-受体阻滞剂等。这些新型手段治疗药物虽然能在一定程度上减缓了心衰患者的临床症状和病死率，但仍然存在不良反应多、需长期用药等临床局限性，且无法显著提高患者的生存质量。相关数据显示，目前心衰患者的5年病死率仍高达50％以上。
近几年，临床研究发现SGLT2抑制剂可降低合并高危心血管糖尿病患者的主要不良心血管事件，有望成为心力衰竭药物治疗领域的新标准。研究表明，SGLT2抑制剂可以通过抑制心肌细胞上I型钠氢转换器(NHE1)发挥心血管保护作用。因此本领域迫切需要研发一种新型的抑制NHE1的芳基C-葡萄糖苷衍生物，用于心衰治疗。
发明内容
本发明的主要目的在于提供一种有效抗心衰，并且抑制NHE1的芳基C-葡萄糖苷衍生物、其制备方法及其用途，具体地，本发明提供了如式I所示的芳基C-葡萄糖苷衍生物、其互变异构体、其立体异构体、其前药，或前述任一者的药学上可接受的盐，或前述任一者的溶剂化物，及其制备方法，以及其在制备a)NHE1抑制剂；和/或b)抗心衰药物中的用途。
本发明是通过下述技术方案来解决上述技术问题：
本发明提供了如式I所示的芳基C-葡萄糖苷衍生物、其互变异构体、其立体异构体、其前药，或前述任一者(指前述如式I所示的芳基C-葡萄糖苷衍生物、其互变异构体、其立体异构体或其前药)的药学上可接受的盐，或前述任一者(指前述如式I所示的芳基C-葡萄糖苷衍生物、其互变异构体、其立体异构体、其前药或前述任一者的药学上可接受的盐)的溶剂化物；
Figure PCTCN2022138093-appb-000001
其中，
R 1、R 2和R 3独立地为H、C 1-C 6烷基、被1、2或3个R 1-2取代的C 1-C 6烷基、C 2-C 6烯基、被1、2或3个R 1-3取代的C 2-C 6烯基、C 2-C 6炔基、被1、2或3个R 1-4取代的C 2-C 6炔基、C 3-C 6环烷基、被1、2或3个R 1-4取代的C 3-C 6环烷基或-COR 1-1；R 1-1为C 1-C 6烷基；
R 1-2、R 1-3和R 1-4独立地为NR 1-2-1R 1-2-2、NO 2、CN、卤素、C 1-C 4烷基、被1、2或3个卤素取代的C 1-C 4烷基、C 1-C 4烷氧基、被1、2或3个卤素取代的C 1-C 4烷氧基或OH；
R 1-2-1和R 1-2-2独立地为H或C 1-C 4烷基；
R 4为COOH或CH 2OR 4-1；R 4-1为H、C 1-C 6烷基或-COR 4-1-1；R 4-1-1为C 1-C 6烷基；
当R 4为CH 2OR 4-1，R 4-1为H或-COR 4-1-1时，R 1-R 3至少有一个为C 1-C 6烷基或C 2-C 6炔基；
R 5为“杂原子选自N、O和S中的1种、2种或3种，杂原子数为1、2或3个的3-12元杂环烷基”、C 1-C 6烷基或-L-R 5-1；
L为-(CH 2) m-或-C(O)-(CH 2) n-；
m为1、2或3，n为0、1、2、3、4或5；
R 5-1为C 6-C 10芳基、被1、2或3个R 5-1-1取代的C 6-C 10芳基、“杂原子选自N、O和S中的1种、2种或3种，杂原子数为1、2或3个的3-12元杂芳基”、被1、2或3个R 5- 1-2取代的“杂原子选自N、O和S中的1种、2种或3种，杂原子数为1、2或3个的3-12元杂芳基”、“杂原子选自N、O和S中的1种、2种或3种，杂原子数为1、2或3个的3-12元杂环烷基”或被1、2或3个R 5-1-3取代的“杂原子选自N、O和S中的1种、2种或3种，杂原子数为1、2或3个的3-12元杂环烷基”；
R 5-1-1、R 5-1-2和R 5-1-3独立地为卤素、被1、2或3个卤素取代的C 1-C 6烷基、C 2-C 6炔基、C 6-C 10芳基或C 1-C 6烷氧基；
R 6为卤素。
在本发明某些优选实施方案中，所述的如式I所示的芳基C-葡萄糖苷衍生物、其互变异构体、其立体异构体、其前药，或前述任一者(指前述如式I所示的芳基C-葡萄糖苷衍生物、其互变异构体、其立体异构体或其前药)的药学上可接受的盐，或前述任一者(指前述如式I所示的芳基C-葡萄糖苷衍生物、其互变异构体、其立体异构体、其前药或前述任一者的药学上可接受的盐)的溶剂化物中的某些基团如下定义，未提及的基团同本发明任一方案所述(简称“在本发明某一方案中”)，
R 1、R 2、R 3、R 1-1、R 4-1和R 4-1-1中，所述C 1-C 6烷基独立地为甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基或叔丁基，例如甲基、乙基或正丙基。
在本发明某一方案中，R 1-2、R 1-3、R 1-4、R 1-2-1和R 1-2-2中，所述C 1-C 4烷基为甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基或叔丁基。
在本发明某一方案中，R 1-2、R 1-3和R 1-4中，所述C 1-C 4烷氧基为甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、异丁氧基、仲丁氧基或叔丁氧基。
在本发明某一方案中，R 5中，所述C 1-C 6烷基为甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基或叔丁基，例如正丙基。
在本发明某一方案中，R 5-1-1、R 5-1-2和R 5-1-3中，所述被1、2或3个卤素取代的C 1-C 6烷基中，所述卤素独立地为F、Cl、Br或I，例如F；所述C 1-C 6烷基独立地为甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基或叔丁基，例如甲基；较佳地，所述被1、2或3个卤素取代的C 1-C 6烷基独立地为CF 3。
在本发明某一方案中，R 1-2、R 1-3、R 1-4、R 1-2、R 1-3、R 1-4、R 5-1-1、R 5-1-2和R 5-1-3中，所述卤素独立地为F、Cl、Br或I，例如F。
在本发明某一方案中，R 1、R 2和R 3中，所述C 2-C 6烯基独立地为乙烯基、丙烯基、烯丙基、1-丁烯基、2-丁烯基或3-丁烯基。
在本发明某一方案中，R 1、R 2和R 3中，所述C 2-C 6炔基独立地为乙炔基、丙炔基、炔丙基、1-丁炔基、2-丁炔基或3-丁炔基，例如炔丙基
Figure PCTCN2022138093-appb-000002
在本发明某一方案中，R 1、R 2和R 3中，所述C 3-C 6环烷基独立地为环丙基、环丁基、环戊基或环己基，例如环丙基。
在本发明某一方案中，R 5-1-1、R 5-1-2和R 5-1-3中，所述C 2-C 6炔基独立地为乙炔基、丙炔基、炔丙基、1-丁炔基、2-丁炔基或3-丁炔基，例如3-丁炔基。
在本发明某一方案中，R 5中，所述“杂原子选自N、O和S中的1种、2种或3种，杂原子数为1、2或3个的3-12元杂环烷基”为“杂原子选自N、O和S中的1种、2种或3种，杂原子数为1、2或3个的3-6元杂环烷基”，例如四氢呋喃基，再例如
Figure PCTCN2022138093-appb-000003
又例如
Figure PCTCN2022138093-appb-000004
在本发明某一方案中，R 5-1中，所述C 6-C 10芳基为苯基或萘基。
在本发明某一方案中，R 5-1中，所述被1、2或3个R 5-1-1取代的C 6-C 10芳基中，所述C 6-C 10芳基为苯基或萘基，例如苯基。
在本发明某一方案中，R 5-1-1、R 5-1-2和R 5-1-3，所述C 6-C 10芳基独立地为苯基或萘基，例如苯基。
在本发明某一方案中，R 5-1-1、R 5-1-2和R 5-1-3，所述C 1-C 6烷氧基独立地为甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、异丁氧基、仲丁氧基或叔丁氧基，例如甲氧基。
在本发明某一方案中，R 5-1中，所述“杂原子选自N、O和S中的1种、2种或3种，杂原子数为1、2或3个的3-12元杂芳基”和所述被1、2或3个R 5-1-2取代的“杂原子选自N、O和S中的1种、2种或3种，杂原子数为1、2或3个的3-12元杂芳基”中的“杂原子选自N、O和S中的1种、2种或3种，杂原子数为1、2或3个的3-12元杂芳基”独立地为“杂原子选自N、O和S中的1种、2种或3种，杂原子数为1、2或3个的3-10元杂芳基”，例如二嗪基(例如
Figure PCTCN2022138093-appb-000005
)、呋喃基(例如
Figure PCTCN2022138093-appb-000006
)、吡啶基(例 如
Figure PCTCN2022138093-appb-000007
)、吡嗪基(例如
Figure PCTCN2022138093-appb-000008
)或喹啉基(例如
Figure PCTCN2022138093-appb-000009
)。
在本发明某一方案中，R 5-1中，所述“杂原子选自N、O和S中的1种、2种或3种，杂原子数为1、2或3个的3-12元杂环烷基”和所述被1、2或3个R 5-1-3取代的“杂原子选自N、O和S中的1种、2种或3种，杂原子数为1、2或3个的3-12元杂环烷基”中的“杂原子选自N、O和S中的1种、2种或3种，杂原子数为1、2或3个的3-12元杂环烷基”独立地为“杂原子选自N、O和S中的1种、2种或3种，杂原子数为1、2或3个的3-6元杂环烷基”，例如二硫戊烷基(例如
Figure PCTCN2022138093-appb-000010
)。
在本发明某一方案中，R 6中，所述卤素为F、Cl、Br或I，例如Cl。
在本发明某一方案中，R 5为“杂原子选自N、O和S中的1种、2种或3种，杂原子数为1、2或3个的3-12元杂环烷基”、丙基或-L-R 5-1。
在本发明某一方案中，m为1或2。
在本发明某一方案中，n为0或4。
在本发明某一方案中，R 5-1为C 6-C 10芳基、被1、2或3个R 5-1-1取代的C 6-C 10芳基、“杂原子选自N、O和S中的1种、2种或3种，杂原子数为1、2或3个的3-12元杂芳基”、被1、2或3个R 5-1-2取代的“杂原子选自N、O和S中的1种、2种或3种，杂原子数为1、2或3个的3-12元杂芳基”或“杂原子选自N、O和S中的1种、2种或3种，杂原子数为1、2或3个的3-12元杂环烷基”。
在本发明某一方案中，R 4为CH 2OH，R 1-R 3至少有一个为C 1-C 6烷基或C 2-C 6炔基，其余为H；或者，R 4为COOH或CH 2OR 4-1，R 1-R 3独立地为H、C 1-C 6烷基或C 2-C 6炔基，R 4-1为C 1-C 6烷基；
R 5为“杂原子选自N、O和S中的1种、2种或3种，杂原子数为1、2或3个的3-12元杂环烷基”；
R 6为Cl。
在本发明某一方案中，R 1-R 3独立地为H、甲基、乙基、正丙基、炔丙基或乙酰基。
在本发明某一方案中，R 4为COOH、CH 2OH、CH 2OCH 3或CH 2OCOCH 3。
在本发明某一方案中，R 5为
Figure PCTCN2022138093-appb-000011
在本发明某一方案中，R 6为Cl。
在本发明某一方案中，如式I所示的芳基C-葡萄糖苷衍生物为如下任一化合物：
Figure PCTCN2022138093-appb-000012
Figure PCTCN2022138093-appb-000013
本发明还提供了如式I所示的芳基C-葡萄糖苷衍生物的制备方法，其包括以下任一方法：
方法一：
冰浴下，用氧化剂如2,2,6,6-四甲基哌啶氧化物在四氢呋喃/饱和碳酸氢钠溶液中处理恩格列净(EMPA)制备所述芳基C-葡萄糖苷衍生物(I-1)，如下流程1所示：
流程1
Figure PCTCN2022138093-appb-000014
方法二：
(1)在室温下，EMPA用苯甲醛二甲缩醛和樟脑磺酸在N,N-二甲基甲酰胺(DMF)中处理得中间体式II A化合物；
(2)在冰浴下，硅烷如叔丁基二甲基氯硅烷和咪唑在DMF中处理式II A化合物得中间体式II B化合物；
(3)在室温下，式II B化合物在无机碱如钠氢的存在下经C 1-3碘代烷烃处理，待反应结束后再经90％的醋酸水溶液处理得芳基C-葡萄糖苷衍生物(目标化合物I-2～I-4)；所述步骤如流程2所示：
流程2：
Figure PCTCN2022138093-appb-000015
方法三：
在室温下，式II A化合物在无机碱如氢氧化钠的存在下经卤代烃处理，待反应结束后再经90％的醋酸水溶液处理得所述芳基C-葡萄糖苷衍生物(目标化合物I-5、I-6、I-10)；所述步骤如流程3所示：
流程3：
Figure PCTCN2022138093-appb-000016
方法四：
包括步骤：
(1)在60℃下，将EMPA溶于甲醇中，与2,3-丁二酮和三乙氧基甲烷反应，得中间体式II C化合物。
(2)在室温下，碘甲烷和氧化银在DMF中处理式II C化合物，待反应结束后再经80％三氟乙酸处理，得所述芳基C-葡萄糖苷衍生物(目标化合物I-7)；所述步骤如流程4所示：
流程4
Figure PCTCN2022138093-appb-000017
方法五：
包括步骤：
(1)在60℃下，将EMPA溶于甲醇中，与2,3-丁二酮和三乙氧基甲烷反应，得中间体式II D化合物。
(2)在冰浴下，四氟硼酸和三甲基硅烷化重氮甲烷在二氯甲烷中处理式II D化合物，待反应结束后再经80％三氟乙酸处理得芳基C-葡萄糖苷衍生物(目标化合物I-8)；所述步骤如流程5所示：
流程5：
Figure PCTCN2022138093-appb-000018
方法六：
在室温下，EMPA用碘甲烷和钠氢在DMF中处理得所述芳基C-葡萄糖苷衍生物(目标化合物I-9)；所述步骤如流程6所示：
流程6
Figure PCTCN2022138093-appb-000019
本发明还提供了一种药物组合物，其包括：
(1)如本发明任一项所述的如式I所示的芳基C-葡萄糖苷衍生物、其互变异构体、其立体异构体、其前药，或前述任一者(指前述如式I所示的芳基C-葡萄糖苷衍生物、其互变异构体、其立体异构体或其前药)的药学上可接受的盐，或前述任一者(指前述如式I所示的芳基C-葡萄糖苷衍生物、其互变异构体、其立体异构体、其前药或前述任一者的药学上可接受的盐)的溶剂化物；和
(2)药学上可接受的载体或赋形剂。
在本发明某一方案中，所述药物组合物的剂型为口服剂型或非口服剂型。
在本发明某一方案中，所述药物组合物的剂型选自片剂、胶囊剂、颗粒剂、混悬剂、丸剂、溶液剂、糖浆剂和注射剂。
本发明还提供了如本发明任一项所述的如式I所示的芳基C-葡萄糖苷衍生物、其互变异构体、其立体异构体、其前药，或前述任一者(指前述如式I所示的芳基C-葡萄糖苷衍生物、其互变异构体、其立体异构体或其前药)的药学上可接受的盐，或前述任一者(指前述如式I所示的芳基C-葡萄糖苷衍生物、其互变异构体、其立体异构体、其前药或前述任一者的药学上可接受的盐)的溶剂化物或所述药物组合物的用途，其用于制备a)抑制钠氢交换器的抑制剂；和/或b)预防和/或缓解和/或治疗钠氢交换器相关的疾病的药物。
本发明还提供了一种预防和/或缓解和/或治疗钠氢交换器相关的疾病的方法，其包括：向有需要的个体施用治疗有效量的如本发明任一项所述的如式I所示的芳基C-葡萄糖苷衍生物、其互变异构体、其立体异构体、其前药，或前述任一者(指前述如式I所示的芳基C-葡萄糖苷衍生物、其互变异构体、其立体异构体或其前药)的药学上可接受的盐，或前述任一者(指前述如式I所示的芳基C-葡萄糖苷衍生物、其互变异构体、其立体异构体、其前药或前述任一者的药学上可接受的盐)的溶剂化物或所述药物组合物。
在本发明某一方案中，所述的钠氢交换器优选地为NHE1。
在本发明某一方案中，所述钠氢交换器相关的疾病包括心力衰竭。
在本发明某一方案中，所述用途中，所述如式I所示的芳基C-葡萄糖苷衍生物、其互变异构体、其立体异构体、其前药，或前述任一者(指前述如式I所示的芳基C-葡萄糖苷衍生物、其互变异构体、其立体异构体或其前药)的药学上可接受的盐，或前述任一者(指前述如式I所示的芳基C-葡萄糖苷衍生物、其互变异构体、其立体异构体、其前药或前述任一者的药学上可接受的盐)的溶剂化物或所述药物组合物用于制备具有以下一种或多种作用的药物：
A1)保护心肌细胞；
A2)收缩/舒张期左心室室间隔厚度变厚；
A3)收缩/舒张期左心室后壁厚度变厚；
A4)收缩/舒张期左心室内径变小；
A5)射血分数升高；
A6)短轴缩短率升高。
在本发明某一方案中，所述心肌细胞包括：H9c2、大鼠乳鼠原代心肌细胞。
在本发明某一方案中，所述的心力衰竭包括：射血分数降低的心力衰竭、射血分数保留的心力衰竭。
如无特别说明，本发明所用术语具有如下含义：
本领域技术人员可以理解，根据本领域中使用的惯例，本发明描述基团的结构式中所使用的
Figure PCTCN2022138093-appb-000020
是指，相应的基团通过该位点与化合物中的其它片段、基团进行连接。
术语“药学上可接受的”是指盐、溶剂、辅料等一般无毒、安全，并且适合于患者使用。所述的“患者”优选哺乳动物，更优选为人类。
术语“药学上可接受的盐”是指本发明化合物与相对无毒的、药学上可接受的酸或碱制备得到的盐。当本发明的化合物中含有相对酸性的功能团时，可以通过在纯的溶液或合适的惰性溶剂中用足够量的药学上可接受的碱与这类化合物的中性形式接触的方式获 得碱加成盐。药学上可接受的碱加成盐包括但不限于：锂盐、钠盐、钾盐、钙盐、铝盐、镁盐、锌盐、铋盐、铵盐、二乙醇胺盐。当本发明的化合物中含有相对碱性的官能团时，可以通过在纯的溶液或合适的惰性溶剂中用足够量的药学上可接受的酸与这类化合物的中性形式接触的方式获得酸加成盐。所述的药学上可接受的酸包括无机酸，所述无机酸包括但不限于：盐酸、氢溴酸、氢碘酸、硝酸、碳酸、磷酸、亚磷酸、硫酸等。所述的药学上可接受的酸包括有机酸，所述有机酸包括但不限于：乙酸、丙酸、草酸、异丁酸、马来酸、丙二酸、苯甲酸、琥珀酸、辛二酸、反丁烯二酸、乳酸、扁桃酸、邻苯二甲酸、苯磺酸、对甲苯磺酸、柠檬酸、水杨酸、酒石酸、甲磺酸、异烟酸、酸式柠檬酸、油酸、单宁酸、泛酸、酒石酸氢、抗坏血酸、龙胆酸、富马酸、葡糖酸、糖酸、甲酸、乙磺酸、双羟萘酸(即4,4’-亚甲基-双(3-羟基-2-萘甲酸))、氨基酸(例如谷氨酸、精氨酸)等。当本发明的化合物中含有相对酸性和相对碱性的官能团时，可以被转换成碱加成盐或酸加成盐。具体可参见Berge et al.,"Pharmaceutical Salts",Journal of Pharmaceutical Science 66:1-19(1977)、或、Handbook of Pharmaceutical Salts:Properties,Selection,and Use(P.Heinrich Stahl and Camille G.Wermuth,ed.,Wiley-VCH,2002)。
术语“溶剂化物”是指本发明化合物与化学计量或非化学计量的溶剂结合形成的物质。溶剂化物中的溶剂分子可以有序或非有序排列的形式存在。所述的溶剂包括但不限于：水、甲醇、乙醇等。
术语“立体异构体”是指顺反异构体或旋光异构体。这些立体异构体可以通过不对称合成方法或手性分离法(包括但不限于薄层色谱、旋转色谱、柱色谱、气相色谱、高压液相色谱等)分离、纯化及富集，还可以通过与其它手性化合物成键(化学结合等)或成盐(物理结合等)等方式进行手性拆分获得。术语“单一的立体异构体”是指本发明化合物的一种立体异构体相对于该化合物的所有立体异构体的质量含量不低于95％。
当任意变量(例如卤素)在化合物的定义中多次出现时，该变量每一位置出现的定义与其余位置出现的定义无关，它们的含义互相独立、互不影响。因此，若某基团被1个、2个或3个卤素取代，也就是说，该基团可能会被最多3个卤素取代，该位置卤素的定义与其余位置卤素的定义是互相独立的。另外，取代基及/或变量的组合只有在该组合产生稳定的化合物时才被允许。
术语“卤素”是指氟、氯、溴或碘。
术语“烷基”是指具有指定的碳原子数的直链或支链烷基。烷基的实例包括甲基、乙基、正丙基、异丙基、正丁基、叔丁基、异丁基、仲丁基、正戊基、正己基及其类似烷基。
术语“烷氧基”是指基团-O-R X，其中，R X为如上文所定义的烷基。
术语“烯基”是指具有指定碳原子数的含一个或多个碳碳双键并且没有碳碳三键的直链或支链的烯烃，该一个或多个碳碳双键可以是内部的也可以是末端的，烯烃的实例包括乙烯基、烯丙基、甲基乙烯基、丙烯基、丁烯基、戊烯基、1,1-二甲基-2丙烯基、己烯基等。
术语“炔基”是指具有指定碳原子数的一个或多个叁键的直链或支链的烃基(例如C 2-C 6炔基，又例如C 2-C 4炔基)。该一个或多个碳碳叁键可以是内部的也可以是末端的，例如叁键在内部的丙炔基
Figure PCTCN2022138093-appb-000021
或叁键在末端的丙炔基
Figure PCTCN2022138093-appb-000022
等。
术语“环烷基”是指具有指定的环碳原子数(例如C 3-C 6)、环原子仅由碳原子组成的、饱和的单环、桥环或螺环环状基团。单环烷基包括但不限于环丙基、环丁基、环戊基、环己基等。
术语“杂环烷基”是指具有指定环原子数(例如3-12元)的、指定杂原子数(例如1个、2个或3个)的、指定杂原子种类(N、O和S中的1种、2种或3种)的环状基团，其为单环、桥环或螺环，且每一个环均为饱和的。杂环烷基包括但不限于氮杂环丁烷基、四氢吡咯基、四氢呋喃基、吗啉基和哌啶基等。
术语“芳基”是指C 6-C 10芳基，例如苯基或萘基。
术语“杂芳基”是指含有杂原子的芳香基团，优选含有1个、2个或3个独立选自氮、氧和硫的芳族环状基团，其为单环或双环，当为双环时，至少有一个环具有芳香性，例如呋喃基、吡啶基、哒嗪基、嘧啶基、吡嗪基、噻吩基、异唑基、噁唑基、二唑基、咪唑基、吡咯基、吡唑基、三唑基、四唑基、噻唑基、异噻唑基、噻二唑基、苯并咪唑基、吲哚基、吲唑基、苯并噻唑基、苯并异噻唑基、苯并唑基、苯并异唑基、喹啉基、异喹啉基等。
术语“药学上可接受的载体”是指生产药品和调配处方时使用的赋形剂和附加剂，是除活性成分以外，包含在药物制剂中的所有物质。可参见中华人民共和国药典(2015年版)四部、或、Handbook of Pharmaceutical Excipients(Raymond C Rowe,2009Sixth Edition)。
术语“治疗”指治疗性疗法。涉及具体病症时，治疗指：(1)干扰(a)导致或引起病症的生物级联中的一个或多个点或(b)病症的一种或多种生物学表现，或(2)改善与病症相关的一种或多种症状、影响或副作用，或者与病症或其治疗相关的一种或多种症状、影响或副作用。
术语“预防”是指获得或发生疾病或障碍的风险降低。
术语“治疗有效量”是指在给予患者时足以有效治疗本文所述的疾病或病症的化合物的量。“治疗有效量”将根据化合物、病症及其严重度、以及欲治疗患者的年龄而变化，但可由本领域技术人员根据需要进行调整。
在所述的用途中，所述抑制钠氢交换器的抑制剂可用于哺乳动物生物体内；也可用于生物体外，主要作为实验用途，例如：作为标准样或对照样提供比对，或按照本领域常规方法制成试剂盒，为钠氢交换器的抑制效果提供快速检测。
本发明的积极进步效果在于：
本发明实验表明本发明的芳基C-葡萄糖苷衍生物的肌细胞保护作用、NHE1抑制活性均优于现有技术的恩格列净，且能在较低给药剂量下发挥有效的抗心衰作用，因此可以用于制备抗心衰的药物。
本发明化合物结构简单，制备工艺简洁，生产成本低。
附图说明
图1为化合物I-2和EMPA处理后心肌细胞结晶紫染色图。
图2为化合物I-2和EMPA处理后心肌细胞结晶紫染色定量图。
图3为化合物I-2和EMPA处理后心肌细胞LDH释放作用图。
图4为化合物I-2、EMPA及阳性药卡立伯来德(Cariporide)处理心肌细胞心肌细胞存活率图。
图5为化合物I-2、EMPA及阳性药卡立伯来德(Cariporide)处理心肌细胞后荧光强度图。
图6为化合物I-2和EMPA处理异丙肾上腺素诱导的心衰小鼠模型心脏超声(M模式)代表性图。
图7为化合物I-2和EMPA处理异丙肾上腺素诱导的心衰小鼠模型心率图。
图8为化合物I-2和EMPA处理异丙肾上腺素诱导的心衰小鼠模型射血分数图。
图9为化合物I-2和EMPA处理异丙肾上腺素诱导的心衰小鼠模型短轴缩短率图。
图10为化合物I-2和EMPA处理异丙肾上腺素诱导的心衰小鼠模型左心室收缩期内径图。
图11为化合物I-2和EMPA处理异丙肾上腺素诱导的心衰小鼠模型左心室舒张期内径图。
图12为化合物I-2和EMPA处理异丙肾上腺素诱导的心衰小鼠模型左心室收缩期后壁厚度图。
图13为化合物I-2和EMPA处理异丙肾上腺素诱导的心衰小鼠模型左心室舒张期后壁厚度图。
图14为化合物I-2和EMPA处理异丙肾上腺素诱导的心衰小鼠模型Masson染色代表性 图。
图15为化合物I-2和EMPA处理异丙肾上腺素诱导的心衰小鼠模型Masson染色定量图。
图16为化合物I-2和EMPA处理异丙肾上腺素诱导的心衰小鼠模型心体比。
图17为化合物I-2处理MI诱导的心衰小鼠模型心功能改善的药效生存率图。
图18为化合物I-2处理MI诱导的心衰小鼠模型心脏超声(M模式)代表性图。
图19为化合物I-2处理MI诱导的心衰小鼠模型心率图。
图20为化合物I-2处理MI诱导的心衰小鼠模型射血分数图。
图21为化合物I-2处理MI诱导的心衰小鼠模型短轴缩短率图。
图22为化合物I-2处理MI诱导的心衰小鼠模型左心室舒张期内径图。
图23为化合物I-2处理MI诱导的心衰小鼠模型左心室收缩期内径图。
图24为化合物I-2处理MI诱导的心衰小鼠模型左心室舒张期后壁厚度图。
图25为化合物I-2处理MI诱导的心衰小鼠模型左心室收缩期后壁厚度。
图26为化合物I-2对MI诱导的心衰小鼠模型Masson染色代表性图。
图27为化合物I-2对MI诱导的心衰小鼠模型Masson染色定量图。
图28为化合物I-2对MI诱导的心衰小鼠模型心体比图。
具体实施方式
下面通过实施例的方式进一步说明本发明，但并不因此将本发明限制在所述的实施例范围之中。
一、制备实施例
实施例1(2S,3S,4R,5R,6S)-6-(4-氯-3-(4-(((S)-四氢呋喃-3-基)氧基)苄基)苯基)-3,4,5-三羟基四氢-2H-吡喃-2-羧酸(目标化合物I-1)的制备
Figure PCTCN2022138093-appb-000023
将恩格列净(EMPA,2.00g,4.44mmol)溶于50mL的无水THF中和50mL饱和NaHCO 3混合溶剂中，0℃加入2,2,6,6-四甲基哌啶氧化物(TEMPO,139mg,887μmol)和溴化钾(KBr,106mg,887μmol)，恒温15min后，滴加50mL的次氯酸钠溶液，继续反应1h，停止反应，反应加入50mL的水稀释，用2M的稀盐酸调节pH至2-3左右，加入乙酸乙酯萃取，有机相经饱和食盐水和硫酸钠干燥处理后蒸干，硅胶柱层析分离纯化(V 甲醇：V 二氯甲烷＝1：5)，得到产物白色固体，收率52％。 1H NMR(400MHz,DMSO-d 6)δ 12.74(s,1H),7.39(d,J＝8.2Hz,1H),7.31(d,J＝2.0Hz,1H),7.21(dd,J＝8.3,2.1Hz,1H),7.13–7.07(m,2H),6.86–6.79(m,2H),5.15(s,1H),5.02–4.91(m,2H),4.11(d,J＝9.4Hz,1H),3.99(d,J＝4.3Hz,2H),3.89–3.69(m,5H),3.46(t,J＝9.3Hz,1H),3.30(t,J＝8.8Hz,2H),3.24–3.15(m,1H),2.17(m,1H),1.97–1.88(m,1H). 13C NMR(151MHz,DMSO-d 6)δ173.03,155.94,139.91,138.23,132.46,131.99,131.37,130.12,129.20,127.98,115.63,81.23,79.27,78.53,77.39,74.78,72.76,72.66,66.86,38.06,32.91.HRMS(ESI)m/z cacld C 23H 25ClO 8Na +[M+Na] +487.1130,found 487.1134.
实施例2(4aR,6S,7R,8R,8aS)-6-(4-氯-3-(4-(((S)-四氢呋喃-3-基)氧基)苄基)苯基)-2-苯基六氢吡喃[3,2-d][1,3]二噁英-7,8-二醇(式II A所示化合物)的制备
Figure PCTCN2022138093-appb-000024
将恩格列净(EMPA,2.00g,4.44mmol)溶于35mL的无水DMF中，室温下加入苯甲醛二甲缩醛((dimethoxymethyl)benzene，810mg，5.32mmol)和(+)-10-樟脑磺酸(CAS,100mg)，N 2保护，110℃反应3h，加入水和乙酸乙酯萃取，有机相经饱和食盐水和硫酸钠干燥处理后蒸干，硅胶柱层析分离纯化(V 乙酸乙酯：V 石油醚＝1：10)，得到产物白色固体，收率90％。 1H NMR(400MHz,DMSO-d 6)δ7.47(dd,J＝6.8,2.9Hz,2H),7.43–7.37(m,4H),7.31(d,J＝2.1Hz,1H),7.23(dd,J＝8.2,2.1Hz,1H),7.15–7.08(m,2H),6.84(d,J＝8.7Hz,2H),5.62(s,1H),5.36(s,1H),5.18(d,J＝6.0Hz,1H),4.97(td,J＝4.6,2.3Hz,1H),4.28–4.15(m,2H),4.00(d,J＝4.0Hz,2H),3.87(dd,J＝10.0,4.6Hz,1H),3.84–3.79(m,1H),3.78–3.66(m,3H),3.56–3.49(m,3H),3.29(s,1H),2.19(dtd,J＝14.3,8.2,6.3Hz,1H),1.94(dt,J＝12.5,5.6Hz,1H). 13C NMR(151MHz,DMSO-d 6)δ155.98,139.44,138.46,138.29,132.70,131.95,131.16,130.16,129.35,129.30,128.49,127.76,126.83,115.66,101.15,82.02,81.48,77.40,75.70,74.72,72.75,70.86,68.46,66.86,38.03,32.91.HRMS(ESI)m/z cacld C 30H 31ClO 7Na +[M+Na] +561.1651,found 561.1658.
实施例3((4aR,6R,7S,8R,8aR)-8-((叔丁基二甲基硅烷基)氧基)-6-(4-氯-3-(4-(((S)-四氢呋喃-3-基)氧基)苄基)苯基)-2-苯基六氢吡喃[3,2-d][1,3]二噁英-7-醇(式II B所示化合物)的制备
Figure PCTCN2022138093-appb-000025
将式II A所示化合物(2.10g,3.90mmol)溶于35mL无水DMF中，0℃加入咪唑(Imidazole,1.06g,15.58mmol)，恒温15min后加入叔丁基二甲基氯硅烷(tert-Butyldimethylsilyl chloride,763mg,5.06mmol)，70℃反应6h。加入水和乙酸乙酯萃取，有机相经饱和食盐水和硫酸钠干燥处理后蒸干，硅胶柱层析分离纯化(V 乙酸乙酯：V 石油醚＝1：5)，得到白色固体，收率55％。 1H NMR(400MHz,DMSO-d 6)δ7.47–7.43(m,2H),7.43–7.35(m,4H),7.32(d,J＝2.1Hz,1H),7.25(dd,J＝8.3,2.1Hz,1H),7.14–7.08(m,2H),6.86–6.82(m,2H),5.64(s,1H),5.14(d,J＝7.6Hz,1H),4.97(ddd,J＝6.4,4.3,2.0Hz,1H),4.25(d,J＝9.5Hz,1H),4.19(dd,J＝10.1,4.5Hz,1H),4.06–3.95(m,2H),3.90–3.80(m,2H),3.78–3.67(m,4H),3.61–3.50(m,2H),3.29(dt,J＝9.6,8.1Hz,1H),2.19(dtd,J＝13.5,8.2,6.3Hz,1H),1.98–1.89(m,1H),0.82(s,9H),0.04(s,3H),0.01(s,3H).
实施例4(2R,3S,4S,5R,6S)-6-(4-氯-3-(4-(((S)-四氢呋喃-3-基)氧基)苄基)苯基)-2-(羟甲基)-5-甲氧基四氢-2H-吡喃-3,4-二醇(目标化合物I-2)的制备
Figure PCTCN2022138093-appb-000026
将式II B所示化合物(650mg,0.995mmol)溶于10mL无水THF中，加入钠氢(NaH(60％),26.3mg,1.09mmol)和碘甲烷(Iodomethane,211.8mg,1.49mmol)，室温反应12h，停止反应，蒸干溶剂，加入水和乙酸乙酯萃取，有机相经饱和食盐水和硫酸钠干燥处理后蒸干，硅胶柱层析分离纯化(V 乙酸乙酯：V 石油醚＝1：10)，得到白色固体。紧接着将白色固体溶于10mL 90％的醋酸水溶液中，60℃反应12h，冷却至室温，将反应液倒入冰水中，用饱和NaHCO 3溶液调节pH至中性，加入水和乙酸乙酯萃取，有机相经饱和食盐水和硫酸钠干燥处理后蒸干，硅胶柱层析分离纯化(V 乙酸乙酯)，得到终产物白色固体，收率35％。 1H NMR(400MHz,DMSO-d 6)δ7.40(d,J＝8.2Hz,1H),7.35(d,J＝2.1Hz,1H),7.28(dd,J＝8.2,2.1Hz,1H),7.10(d,J＝8.2Hz,2H),6.83(d,J＝8.2Hz,2H),5.12(d,J＝5.1Hz,1H),5.03(d,J＝4.6Hz,1H),4.99–4.91(m,1H),4.47(t,J＝5.8Hz,1H),4.06–3.97(m,4H),3.92–3.64(m,6H),3.44(dt,J＝11.5,5.6Hz,1H),3.39–3.33(m,1H),2.95(s,3H),2.88(t,J＝ 9.2Hz,1H),2.18(dtd,J＝14.2,8.1,5.8Hz,1H),1.92(tt,J＝8.9,3.5Hz,1H). 13C NMR(151MHz,DMSO-d 6)δ155.95,139.93,138.21,132.45,131.99,131.35,130.15,129.17,127.84,115.63,88.68,81.70,81.23,77.39,74.54,72.75,70.10,66.86,61.58,60.55,38.07,32.91.HRMS(ESI)m/z cacld C 24H 29ClO 7Na +[M+Na] +487.1494,found 487.1504.
实施例5(2R,3S,4S,5R,6S)-6-(4-氯-3-(4-(((S)-四氢呋喃-3-基)氧基)苄基)苯基)-2-(羟甲基)-5-乙氧基四氢-2H-吡喃-3,4-二醇(目标化合物I-3)的制备
Figure PCTCN2022138093-appb-000027
除以碘乙烷替换碘甲烷外，其他步骤与实施例4相同，得终产物白色固体，收率31％。 1H NMR(400MHz,CD 3OD)δ7.39–7.35(m,1H),7.30(d,J＝7.0Hz,2H),7.12–7.08(m,2H),6.82–6.77(m,2H),4.97(ddt,J＝6.1,4.0,1.8Hz,1H),4.11–4.02(m,3H),3.97–3.91(m,2H),3.91–3.84(m,3H),3.69(dd,J＝12.0,5.4Hz,1H),3.49(t,J＝8.7Hz,1H),3.43–3.34(m,3H),3.01(t,J＝9.1Hz,1H),2.81(dq,J＝9.1,7.1Hz,1H),2.21(dtd,J＝13.5,8.4,5.9Hz,1H),2.12–2.04(m,1H),0.79(t,J＝7.0Hz,3H). 13C NMR(151MHz,DMSO-d 6)δ155.95,139.98,138.34,132.47,132.07,131.11,130.03,129.28,127.59,115.63,83.95,81.49,79.95,78.14,77.38,72.73,70.91,67.39,66.85,61.73,37.91,32.88,15.64.HRMS(EI)m/z cacld C 25H 31ClO 7 +[M] +478.1753,found 478.1754.
实施例6(2R,3S,4S,5R,6S)-6-(4-氯-3-(4-(((S)-四氢呋喃-3-基)氧基)苄基)苯基)-2-(羟甲基)-5-丙氧基四氢-2H-吡喃-3,4-二醇(目标化合物I-4)的制备
Figure PCTCN2022138093-appb-000028
除以碘丙烷替换碘甲烷外，其他步骤与实施例4相同，白色固体，收率24％。 1H NMR(400MHz,DMSO-d 6)δ7.40(d,J＝8.2Hz,1H),7.33(d,J＝2.0Hz,1H),7.27(dd,J＝8.2,2.1Hz,1H),7.12–7.06(m,2H),6.85–6.79(m,2H),5.04(dd,J＝9.9,5.1Hz,2H),4.96(dt,J＝6.2,3.0Hz,1H),4.48(t,J＝5.8Hz,1H),4.05–3.98(m,3H),3.86(dd,J＝10.1,4.6Hz,1H),3.80(t,J＝7.7Hz,1H),3.76–3.66(m,3H),3.47–3.41(m,2H),3.25–3.14(m,3H),2.95(t,J＝9.1Hz,1H),2.72(dt,J＝9.1,6.9Hz,1H),2.23–2.13(m,1H),1.92(dt,J＝12.6,5.8Hz,1H),1.10(q,J ＝7.1Hz,2H),0.49(t,J＝7.4Hz,3H). 13C NMR(151MHz,DMSO-d 6)δ155.94,139.95,138.35,132.48,132.09,131.29,130.02,129.26,127.80,115.60,83.95,81.54,80.08,78.33,77.38,73.89,72.73,71.00,66.85,61.75,37.90,32.88,23.07,10.67.HRMS(EI)m/z cacld C 26H 33ClO 7 +[M] +492.1909,found 492.1912.
实施例7(2R,3S,4S,5R,6S)-6-(4-氯-3-(4-(((S)-四氢呋喃-3-基)氧基)苄基)苯基)-2-(羟甲基)-4-甲氧基四氢-2H-吡喃-3,4-二醇(目标化合物I-5)的制备
Figure PCTCN2022138093-appb-000029
将式II A所示化合物(2.10g,3.90mmol)溶于35mL无水THF中，加入NaOH(312mg,7.79mmol)和碘甲烷(Iodomethane,1.11g,7.79mmol)，50℃反应4h，冷却至室温，加入水和乙酸乙酯萃取，有机相经饱和食盐水和硫酸钠干燥处理后蒸干，硅胶柱层析分离纯化(V 乙酸乙酯：V 石油醚＝1：5)，得到白色固体。接着将白色固体(200mg)溶于10mL90％的醋酸水溶液中，60℃反应12h，冷却至室温，将反应液倒入冰水中，用饱和NaHCO 3溶液调节pH至中性，加入水和乙酸乙酯萃取，有机相经饱和食盐水和硫酸钠干燥处理后蒸干，硅胶柱层析分离纯化(V 乙酸乙酯)，得到最终产物白色固体，收率76％。 1H NMR(400MHz,DMSO-d 6)δ7.37(d,J＝8.2Hz,1H),7.33(d,J＝2.0Hz,1H),7.23(dd,J＝8.2,2.1Hz,1H),7.13–7.08(m,2H),6.86–6.80(m,2H),5.11(d,J＝5.4Hz,1H),5.00(d,J＝6.5Hz,1H),4.96(ddt,J＝6.3,4.0,1.8Hz,1H),4.46(t,J＝5.8Hz,1H),4.01–3.95(m,3H),3.86(dd,J＝10.1,4.6Hz,1H),3.80(dd,J＝8.2,7.0Hz,1H),3.77–3.65(m,3H),3.52(s,3H),3.43(dd,J＝12.0,6.0Hz,1H),3.27–3.13(m,3H),3.04(t,J＝8.3Hz,1H),2.18(dtd,J＝16.4,8.2,6.2Hz,1H),1.96–1.88(m,1H). 13C NMR(151MHz,DMSO-d 6)δ155.95,139.93,138.22,132.46,131.99,131.36,130.15,129.18,127.84,115.63,88.69,81.70,81.24,77.39,74.54,72.75,70.11,66.86,61.59,60.56,38.08,32.91.HRMS(EI)m/z cacld C 24H 29ClO 7 +[M] +464.1596,found464.1598.
实施例8(2R,3R,4S,5S,6S)-2-(4-氯-3-(4-(((S)-四氢呋喃-3-基)氧基)苄基)苯基)-2-(羟甲基)-4,5-二甲氧基四氢-2H-吡喃-3-醇(目标化合物I-6)的制备
Figure PCTCN2022138093-appb-000030
除将式II A所示化合物的量调整为400mg外，其他步骤与实施例7相同，白色固体，收率74％。 1H NMR(400MHz,DMSO-d 6)δ7.41(d,J＝8.2Hz,1H),7.36(d,J＝2.1Hz,1H),7.29(dd,J＝8.2,2.1Hz,1H),7.12–7.07(m,2H),6.86–6.80(m,2H),5.20(d,J＝5.8Hz,1H),4.96(ddt,J＝6.4,4.0,1.8Hz,1H),4.50(t,J＝5.8Hz,1H),4.07(d,J＝9.5Hz,1H),4.00(s,2H),3.86(dd,J＝10.1,4.6Hz,1H),3.82–3.77(m,1H),3.76–3.65(m,3H),3.52(s,3H),3.44(dt,J＝11.7,5.9Hz,1H),3.31–3.20(m,2H),3.14(t,J＝8.6Hz,1H),2.95(t,J＝9.2Hz,1H),2.90(s,3H),2.23–2.12(m,1H),1.92(h,J＝5.5Hz,1H). 13C NMR(151MHz,DMSO-d 6)δ155.96,139.46,138.62,132.74,132.02,131.20,130.09,129.44,127.70,115.65,88.16,85.00,81.57,79.79,77.39,72.73,70.27,66.85,61.47,60.46,59.81,37.94,32.89.HRMS(EI)m/z cacld C 25H 31ClO 7 +[M] +478.1753,found 478.1759.
实施例9(2S,3S,4R,5R,6R)-2-(4-氯-3-(4-(((S)-四氢呋喃-3-基)氧基)苄基)苯基)-6-(羟甲基)-4-(丙-2-炔-1-基氧基)四氢-2H-吡喃-3,5-二醇(目标化合物I-10)的制备
Figure PCTCN2022138093-appb-000031
除以溴丙炔替换碘甲烷外，其他步骤与实施例7相同，白色固体，收率63％。 1H NMR(400MHz,DMSO-d 6)δ7.40–7.32(m,2H),7.23(dd,J＝8.3,2.1Hz,1H),7.13–7.08(m,2H),6.86–6.80(m,2H),5.17(d,J＝4.8Hz,1H),5.04(d,J＝6.3Hz,1H),4.99–4.93(m,1H),4.49(t,J＝5.8Hz,1H),4.44(d,J＝2.5Hz,2H),4.05–3.92(m,3H),3.86(dd,J＝10.1,4.6Hz,1H),3.83–3.77(m,1H),3.76–3.64(m,3H),3.44(dt,J＝11.5,5.8Hz,1H),3.36(t,J＝2.4Hz,1H),3.24(ddd,J＝19.0,8.2,5.6Hz,4H),2.18(dtd,J＝14.2,8.2,6.2Hz,1H),1.92(dt,J＝12.7,5.8Hz,1H). 13C NMR(151MHz,DMSO-d 6)δ155.95,139.74,138.25,132.54,131.98,131.41,130.16,129.21,127.89,115.63,86.00,81.79,81.64,81.21,77.39,76.95,74.52,72.76,70.19,66.86,61.52,59.77,38.10,32.91.HRMS(EI)m/z cacld C 26H 29ClO 7 +[M] +488.1596,found488.1599.
实施例10(4aS,5S,7R,8R,8aS)-5-(4-氯-3-(4-((((S)-四氢呋喃-3-基)氧基)苄基)苯基)-2,3,8-三甲氧基-2,3-二甲基六氢-5H-吡喃并[3,4-b][1,4]二噁英-7-基)甲醇(式II C-1所示化合物)的制备
Figure PCTCN2022138093-appb-000032
将恩格列净(EMPA,3.00g,6.65mmol)溶于20mL甲醇中，室温下加入2,3-丁二酮(2,3-Butanedione,1.5mL,17.25mmol)、三乙氧基甲烷(triethoxymethane,3.6mL,21.62mmol)与三氟化硼乙醚(Boron trifluoride etherate,1.92mL)，60℃反应4h，自然冷却至室温，加入9mL三乙胺，反应0.5h，停止反应，蒸干溶剂，硅胶柱层析分离纯化(V 石油 醚：V 乙酸乙酯＝2：1)，得到白色固体，收率42％。将上述白色固体(350mg,619.41μmol)、氧化银(Silver oxide,143.54mg,619.41μmol)与碘甲烷(Iodomethane,158.25mg,1.11μmol)溶于5mL DMF中，室温反应8h，停止反应，加入乙酸乙酯，然后硅藻土抽滤，再加入水和乙酸乙酯萃取，有机相经饱和食盐水和硫酸钠干燥处理后蒸干，硅胶柱层析分离纯化(V 乙酸乙酯：V 石油醚＝1：3)，得到式II C-1化合物，白色固体，收率51％。 1H NMR(400MHz,DMSO-d 6)δ7.41(d,J＝8.2Hz,1H),7.33(d,J＝2.1Hz,1H),7.28(dd,J＝8.2,2.1Hz,1H),7.08(d,J＝8.5Hz,2H),6.85–6.78(m,2H),4.96(td,J＝4.6,2.2Hz,1H),4.66(dd,J＝6.6,5.0Hz,1H),4.30(d,J＝9.7Hz,1H),3.99(d,J＝2.0Hz,2H),3.89–3.70(m,5H),3.62(dd,J＝11.3,5.1Hz,1H),3.55–3.50(m,1H),3.49(s,3H),3.36(dd,J＝7.2,3.0Hz,1H),3.32(m,1H),3.30–3.24(m,1H),3.21(s,3H),2.56(s,3H),2.18(dtd,J＝14.2,8.2,6.2Hz,1H),1.96–1.87(m,1H),1.18(s,3H),1.00(s,3H).
实施例11(2S,3R,4R,5S,6R)-2-(4-氯-3-(4-((((S)-四氢呋喃-3-基)氧基)苄基)苯基)-6-(羟甲基)-5-甲氧基四氢-2H-吡喃-3,4-二醇(目标化合物I-7)的制备
Figure PCTCN2022138093-appb-000033
将式II C-1所示化合物(170mg)加入到5mL的80％的三氟乙酸水溶液，室温反应2h，用NaOH水溶液调节溶液pH至碱性，加入水和乙酸乙酯萃取，有机相经饱和食盐水和硫酸钠干燥处理后蒸干，硅胶柱层析分离纯化(V 甲醇：V 二氯甲烷＝1：30)，得到终产物， 白色固体，收率40％。 1H NMR(400MHz,DMSO-d 6)δ7.37(d,J＝8.2Hz,1H),7.33(d,J＝2.0Hz,1H),7.23(dd,J＝8.2,2.1Hz,1H),7.11(d,J＝8.5Hz,2H),6.85–6.81(m,2H),5.12(d,J＝5.3Hz,1H),4.96(td,J＝4.6,2.3Hz,1H),4.90(d,J＝5.8Hz,1H),4.57(dd,J＝6.4,5.0Hz,1H),4.04–3.95(m,3H),3.86(dd,J＝10.1,4.6Hz,1H),3.80(t,J＝7.8Hz,1H),3.77–3.71(m,2H),3.66–3.58(m,1H),3.49(s,1H),3.46(s,3H),3.38(td,J＝8.8,5.4Hz,1H),3.23(dd,J＝10.2,4.5Hz,1H),3.11(td,J＝9.1,5.9Hz,1H),3.03(t,J＝9.3Hz,1H),2.23–2.13(m,1H),1.97–1.89(m,1H). 13C NMR(151MHz,DMSO-d 6)δ155.95,139.99,138.22,132.41,132.00,131.24,130.14,129.16,127.80,115.63,80.97,80.30,80.04,78.52,77.39,75.38,72.75,66.86,61.26,60.19,38.08,32.91.HRMS(EI)m/z cacld C 24H 29ClO 7 +[M] +464.1596,found 464.1603.
实施例12(2S,3R,4R,5S,6R)-2-(4-氯-3-(4-((((S)-四氢呋喃-3-基)氧基)苄基)苯基)-6-(甲氧基甲基)四氢-2H-吡喃-3,4,5-三醇(目标化合物I-8)的制备
Figure PCTCN2022138093-appb-000034
将恩格列净(EMPA,3.00g,6.65mmol)溶于20mL甲醇中，室温下加入2,3-丁二酮(2,3-Butanedione,1.5mL,17.25mmol)、三乙氧基甲烷(triethoxymethane,3.6mL,21.62mmol)与三氟化硼乙醚(Boron trifluoride etherate,1.92mL)，60℃反应4h，自然冷却至室温，加入9mL三乙胺，反应0.5h，停止反应，蒸干溶剂，硅胶柱层析分离纯化(V 石油 醚：V 乙酸乙酯＝2：1)，得到白色固体，收率36％。将上述白色固体(250mg,619.41μmol)与四氟硼酸(42％in water,Tetrafluoroborate,73μL)溶于5mL二氯甲烷中，0℃滴加三甲基硅烷化重氮甲烷(Trimethylsilanated diazomethane,0.25mL)，20min后再滴加0.13mL三甲基硅烷化重氮甲烷，20min后再滴加0.06mL三甲基硅烷化重氮甲烷，20min后再滴加0.06mL三甲基硅烷化重氮甲烷，恢复室温反应0.5h，停止反应，加入水和二氯甲烷萃取，有机相经饱和食盐水和硫酸钠干燥处理后蒸干，得到白色固体，收率54％。将上述白色固体(130mg)溶于5mL的80％的三氟乙酸水溶液，室温反应2h，停止反应，用NaOH水溶液调节溶液pH至碱性，加入水和乙酸乙酯萃取，有机相经饱和食盐水和硫酸钠干燥处理后蒸干，硅胶柱层析分离纯化(V 甲醇：V 二氯甲烷＝1：30)，得到终产物，产物白色固体，收率42％。 1H NMR(400MHz,DMSO-d 6)δ7.38(d,J＝8.2Hz,1H),7.27(d,J＝2.1Hz,1H),7.19(dd,J＝8.2,2.1Hz,1H),7.13–7.08(m,2H),6.86–6.80(m,2H),5.06(d,J＝5.5Hz,1H),5.00(d,J＝4.8Hz,1H),4.98–4.94(m,1H),4.86(d,J＝5.7Hz,1H),4.01–3.96 (m,3H),3.86(dd,J＝10.0,4.6Hz,1H),3.82–3.77(m,1H),3.76–3.70(m,2H),3.57(d,J＝10.5Hz,1H),3.44–3.35(m,2H),3.27–3.22(m,1H),3.21(s,3H),3.12(dtd,J＝11.6,9.2,5.7Hz,2H),2.18(dtd,J＝14.2,8.2,6.3Hz,1H),1.93(dt,J＝12.6,5.7Hz,1H). 13C NMR(151MHz,DMSO-d 6)δ155.96,140.01,138.32,132.41,131.96,131.08,130.19,129.20,127.70,115.63,81.15,80.00,78.71,77.39,75.06,72.75,72.69,70.71,66.86,58.97,38.03,32.91.HRMS(EI)m/z cacld C 24H 29ClO 7 +[M] +464.1596,found 464.1604.
实施例13(2S,3S,4R,5R,6R)-2-(4-氯-3-(4-((((S)-四氢呋喃-3-基)氧基)苄基)苯基)-3,4,5-三甲氧基-6-(甲氧基甲基)四氢-2H-吡喃(目标化合物I-9)的制备
Figure PCTCN2022138093-appb-000035
将恩格列净(EMPA,1.00g,2.22mmol)、氢化钠(Sodium hydride,234.17mg,9.76mmol)与碘甲烷(Iodomethane,1.57g,11.09mmol)溶于10mL DMF中，室温反应4h，停止反应，加入水和乙酸乙酯萃取，有机相经饱和食盐水和硫酸钠干燥处理后蒸干，硅胶柱层析分离纯化(V 乙酸乙酯：V 石油醚＝1：5)，得到产物终产物，白色固体，收率94％。 1H NMR(400MHz,DMSO-d 6)δ7.42(d,J＝8.2Hz,1H),7.28(d,J＝2.1Hz,1H),7.23(dd,J＝8.2,2.1Hz,1H),7.12–7.07(m,2H),6.83(d,J＝8.7Hz,2H),4.96(ddt,J＝6.4,4.0,1.8Hz,1H),4.08(d,J＝9.5Hz,1H),4.00(s,2H),3.86(dd,J＝10.0,4.6Hz,1H),3.82–3.77(m,1H),3.76–3.71(m,2H),3.52(s,3H),3.47(d,J＝3.4Hz,2H),3.44(s,3H),3.42–3.39(m,1H),3.27(d,J＝8.9Hz,1H),3.24(s,3H),3.10(t,J＝9.2Hz,1H),2.99(t,J＝9.2Hz,1H),2.90(s,3H),2.18(dtd,J＝13.4,8.2,6.2Hz,1H),1.96–1.88(m,1H). 13C NMR(151MHz,DMSO-d 6)δ156.00,139.05,138.83,132.83,131.93,130.94,130.16,129.55,127.46,115.66,87.89,85.12,79.86,79.71,78.52,77.39,72.73,71.72,66.85,60.41,60.13,59.88,59.01,37.88,32.90.HRMS(EI)m/z cacld C 27H 35ClO 7 +[M] +506.2066,found 506.2069.
二、药效评价
效果实施例1本发明芳基C-葡萄糖衍生物对心肌细胞的保护作用
大鼠心肌细胞(H9c2)购买于中国科学院干细胞库。心肌细胞用高糖DMEM(含10％胎牛血清，1％青霉素/链霉素)培养基，并置于37℃，5％CO 2的培养箱中培养。待心肌细胞基本长满细胞培养皿(10cm)后，用胰酶将细胞消化下来，并以8000个/孔的细胞 密度种到96孔板中，每孔100uL。培养过夜后，将用DMEM培养基稀释后的药物溶液加到板中，每孔100μL。在细胞培养箱中孵育48h。
去除DMEM培养基，用PBS洗1次。化合物用无糖无血清的DMEM稀释至目标浓度，加入到板中，进行糖剥夺(Glucose deprivation，GD)处理。GD 36-48h后，观察细胞存活状态(模型组(即DMSO组)存活率控制在50％为宜，能够较好的突出化合物的细胞保护作用)，用cck8检测细胞存活率。其中对照组为正常培养组，未加药(未加DMSO)且细胞未进行糖剥夺处理，其存活率作为100％。表中的化合物和DMSO组的细胞均进行了糖剥夺处理，活性数据如表1和2所示。
表1化合物I-1～I-10在GD模型下对心肌细胞的保护作用(0.1μM～50μM)
Figure PCTCN2022138093-appb-000036
数据为平均值±SD，n＝3，####p<0.0001vs对照组,*p<0.05,**p<0.01,***p<0.001,****p<0.0001vs DMSO组。在每个化合物不同浓度下的存活率中，第一次出现星号的浓度表示最低起效浓度，第二次出现星号的浓度表示最大药效浓度。
表2化合物I-1～I-10在GD模型下对心肌细胞的保护作用(100μM～400μM)
Figure PCTCN2022138093-appb-000037
Figure PCTCN2022138093-appb-000038
数据为平均值±SD，n＝3，####p<0.0001vs对照组,*p<0.05,**p<0.01,***p<0.001,****p<0.0001vs DMSO组。在每个化合物不同浓度下的存活率中，第一次出现星号的浓度表示最低起效浓度，第二次出现星号的浓度表示最大药效浓度。
由表格数据可以看出，I-2～I-8衍生物对心肌细胞的最大保护作用均明显优于阳性药恩格列净，化合物I-1在400μM浓度下的细胞保护作用优于恩格列净，化合物I-9在50μM浓度下的细胞保护作用优于恩格列净，化合物I-10最大细胞保护作用据恩格列净相当，但起效浓度较恩格列净降低5倍。综上所述，本发明所涉及的化合物均表现出优于EMPA的抗心衰作用，特别是化合物I-2起效浓度降至1μM，较恩格列净的低效浓度降低50倍，是具有潜力的抗心衰候选化合物。
效果实施例2优选衍生物在大孔板中的心肌细胞保护作用
为进一步验证这类衍生物的抗心衰药效，将H9c2细胞种到24孔板中，贴壁后加入用DMEM配制的EMPA和化合物I-2稀释液，预给药48h。移除高糖DMEM，用PBS洗一次，加入用无糖无血清的DMEM配制的EMPA和化合物I-2稀释液，缺糖处理48h。取50uL培养基至96孔板中，用LDH检测试剂盒检测培养基中LDH的释放。其中，NG组未进行糖剥夺处理；DMSO组和给药组均进行GD处理。
实验结果如图3所示，化合物I-2在50μM和100μM浓度下LDH的释放都低于恩格列净组，说明其细胞保护作用要优于恩格列净。
将培养基移除，细胞置于冰上，用预冷的PBS洗两次，每次3～5分钟。用预冷的甲醇于-20℃固定10分钟。移除甲醇，恢复至室温，加入足量的0.5％结晶紫染色液，室温孵育10分钟。移除结晶紫，用清水清洗细胞，直至不褪色。将细胞置于37℃烘箱烘干，显微镜进行拍照，Image J进行染色定量。
实验结果如图1和图2所示。与LDH释放的结果一致，I-2给药组的细胞存活率要高于恩格列净处理组，进一步说明化合物I-2抗心衰药效要优于恩格列净。
图1、2和3中，数据为平均值±SD，t检验， #P<0.05, ##P<0.01, ###P<0.001, ####P<0.0001vs NG, *P<0.05, **P<0.01, ***P<0.001, ****P<0.0001vs DMSO。
效果实施例3优选的衍生物对NHE1的抑制作用
1、实验原理
在本实验中，我们通过NH 4Cl溶液将细胞内的环境调成酸性，pH值下降。当移除NH 4Cl后，细胞内的H +外流，使胞内pH恢复正常水平，如果化合物抑制NHE1，那么胞内H +无法外流，导致细胞内的pH仍处于较低的水平，胞内pH水平可以通过荧光探针检测。BCECF AM是一种可以穿透细胞膜的荧光染料。BCECF AM本身没有荧光，进入细胞后可以被细胞内的酯酶剪切成BCECF，从而被滞留在细胞内。BCECF在适当的pH值情况下可以被激发形成绿色荧光。检测时激发波长为488nm,发射波长为535nm，且荧光强度随着pH的增加而增大。
本实施例中应用到的阳性药为卡立伯来德(Cariporide，Car)、EMPA。卡立伯来德如下式所示：
Figure PCTCN2022138093-appb-000039
2、实验步骤
(1)在检测pH变化之前，先检测化合物在高浓度下是否对细胞存活造成影响。用HBSS将化合物稀释成目标浓度。待检测的细胞(长满)去除培养基，HBSS洗3次，加入稀释后的化合物，37℃孵育30min，用cck8检测细胞存活率。
(2)取适量BCECF AM(S1006,Beyotime)母液，用HBSS稀释至10μM的工作液；
(3)对于待检测的培养细胞(长满)，去除培养液，用HBSS洗3次；
(4)每孔加入50μL的BCECF AM工作液。将待测化合物与80mM的NH 4Cl溶液1：1混合，然后每孔加入50μL的化合物与NH 4Cl混合溶液；
(5)37℃，孵育30min进行荧光探针装载；
(6)随后用HBSS洗涤3次，每孔再加入100μL HBSS，用多功能荧光酶标仪(激发 488nm,发射波长535nm)定量检测BCECF AM的荧光，以确定细胞内PH值的变化。
实验结果如图4和图5所示。其中，图4表明，阳性药Cariporide、EMPA、化合物I-2在200μM和500μM的浓度下处理细胞30分钟没有产生细胞毒性，图5表明化合物I-2在同等浓度下对NHE1的抑制活性要优于EMPA。
其中，图4和图5中，数据为平均值±SD，t检验， *P<0.05, **P<0.01, ***P<0.001, ****P<0.0001vs DMSO。
效果实施例4优选的衍生物体内抗心衰作用
1、实验原理
盐酸异丙肾上腺素是建立心力衰竭模型常用的诱导剂。皮下注射盐酸异丙肾上腺素会使小鼠心率加快、心肌持续强烈收缩，使心肌耗氧量增大，加重心脏负荷，最终引起心力衰竭。
2、实验方法
将平均体重在21-22g左右的C57/6J雄鼠分为5组分别为对照组(Sham)、模型组(Vehicle)、恩格列净30mg/kg组、恩格列净10mg/kg组、化合物I-2 10mg/kg组，每组8只小鼠。每天上午灌胃给药，对照组和模型组给等量溶媒(5％DMSO+95％水)。模型组和给药组中，盐酸异丙肾上腺素每天皮下注射两次，上午和晚上，第1-2天每次剂量为40mg/kg，第3-7天每次剂量为20mg/kg，第8-14天剂量为10mg/kg，对照组注射等量不含盐酸异丙肾上腺素的生理盐水。第15天采用Visual-Sonics Vevo 3100小动物高分辨率显微超声成像系统评价各组实验小鼠的心脏结构及功能,取3个心动周期，测量收缩期室间隔厚度(IVSs)、舒张期室间隔厚度(IVSd)、左心室收缩期内径(LVIDs)、左心室舒张期内径(LVIDd)、左心室收缩期后壁厚度(LVPWs)、左心室舒张期后壁厚度(LVPWd)，计算射血分数(EF)、短轴缩短率(FS)，用Graph Pad软件进行数据处理，计算显著性差异(Unpaired t-test)。
3、结果
如图6～16所示，模型组的小鼠心功能显著减退，收缩/舒张期左心室室间隔厚度和后壁厚度明显变薄，内径变大，射血分数和短轴缩短率降至正常范围以下(射血分数正常小鼠参考值为55-85％，短轴缩短率正常小鼠参考值为30-50％)，心肌纤维化显著增加。恩格列净30mg/kg剂量给药组能有效的改善盐酸异丙肾上腺素造成的心功能减退及纤维化，但10mg/kg的剂量并不能明显改善心功能，而化合物I-2在10mg/kg剂量就能明显改善小鼠的心功能，降低心肌纤维化程度，说明化合物I-2在体内起效剂量要低于恩格列 净，同等剂量下药效由于恩格列净。
其中，图6至图13中，数据为平均值±SD，t检验， #P<0.05, ##P<0.01, ###P<0.001, ####P<0.0001vs sham, *P<0.05, **P<0.01, ***P<0.001, ****P<0.0001vs vehicle。图14至图16中，数据为平均值±SD，t检验， #P<0.05, ##P<0.01, ###P<0.001, ####P<0.0001vs sham, *P<0.05, **P<0.01, ***P<0.001, ****P<0.0001vs vehicle。
效果实施例5
1、实验原理
冠脉结扎后导致心肌梗死与心肌肥厚，最终过渡到心力衰竭，可用于评价长期服用药物对心衰的预防作用。
2、实验方法
C57/6J雄鼠分为2组，DMSO处理组和I-2处理组，每组20只，左前降支冠状动脉结扎手术前DMSO或I-2分别预给药1周，每天灌胃给药，I-2组给予10mg/kg的化合物I-2，DMSO组给予相同体积的含5％DMSO的水溶液。1周后进行手术建模，流程入下：开启小动物气体麻醉机，将小鼠放入气体麻醉机chamber中，待小鼠全身放松昏迷后，将小鼠取出，固定在自制鼠板上，用脱毛膏将小鼠的左胸部和脖子处的皮毛脱掉，快速切开下巴以下的肌肉组织，找到气管，将连有呼吸机和麻醉机的插管经口腔插到气管中，辅助呼吸。在小鼠心脏部位第3、4肋间隙位置沿着腋窝与胸骨下端连线做1.5cm的切口，钝性分离胸大肌肉与肋骨外肌肉，于第3～4肋间穿破肋间隙，用自制撑开器撑开胸腔，剥开心包。在光源下，于左心耳右下缘可见左冠状动脉，以左心耳下缘水平线为标志，在线下2mm处以7-0手术丝线结扎冠脉，进针深度1mm左右，避免刺破心脏。结扎完毕，可见左心室前壁颜色由鲜红变为暗紫至苍白色，快速将心脏推入胸腔，盖上心包膜，挤出胸内气体，依次将肋骨、皮肤缝合，脖子处伤口缝合，用碘伏消毒伤口，待小鼠苏醒。术后不再给予药物干预，术后记录小鼠的生存率，并绘制生存曲线，并在第9天分别进行心功能检测以及心肌梗死面积和纤维化面积的检测。
3、结果
如图17-28所示，I-2在10mg/kg的剂量下可明显提高术后小鼠的生存率，显著改善术后小鼠的心功能、心肌肥厚以及心肌纤维化，而在我们以前的研究中，EMPA在10mg/kg的剂量下无法提高术后小鼠的生存率。该实验进一步说明，I-2的抗心衰药效优于EMPA。
其中，图17至图25中，数据为平均值±SD，t检验， *P<0.05, **P<0.01, ***P<0.001, ****P<0.0001vs DMSO。图26至图28中，数据为平均值±SD，t检验， *P<0.05, **P<0.01, ***P<0.001, ****P<0.0001vs DMSO。

Claims (13)

  1. 如式I所示的芳基C-葡萄糖苷衍生物、其互变异构体、其立体异构体、其前药，或前述任一者的药学上可接受的盐，或前述任一者的溶剂化物；
    Figure PCTCN2022138093-appb-100001
    其中，
    R 1、R 2和R 3独立地为H、C 1-C 6烷基、被1、2或3个R 1-2取代的C 1-C 6烷基、C 2-C 6烯基、被1、2或3个R 1-3取代的C 2-C 6烯基、C 2-C 6炔基、被1、2或3个R 1-4取代的C 2-C 6炔基、C 3-C 6环烷基、被1、2或3个R 1-4取代的C 3-C 6环烷基或-COR 1-1；R 1-1为C 1-C 6烷基；
    R 1-2、R 1-3和R 1-4独立地为NR 1-2-1R 1-2-2、NO 2、CN、卤素、C 1-C 4烷基、被1、2或3个卤素取代的C 1-C 4烷基、C 1-C 4烷氧基、被1、2或3个卤素取代的C 1-C 4烷氧基或OH；
    R 1-2-1和R 1-2-2独立地为H或C 1-C 4烷基；
    R 4为COOH或CH 2OR 4-1；R 4-1为H、C 1-C 6烷基或-COR 4-1-1；R 4-1-1为C 1-C 6烷基；
    当R 4为CH 2OR 4-1，R 4-1为H或-COR 4-1-1时，R 1-R 3至少有一个为C 1-C 6烷基或C 2-C 6炔基；
    R 5为“杂原子选自N、O和S中的1种、2种或3种，杂原子数为1、2或3个的3-12元杂环烷基”、C 1-C 6烷基或-L-R 5-1；
    L为-(CH 2) m-或-C(O)-(CH 2) n-；
    m为1、2或3，n为0、1、2、3、4或5；
    R 5-1为C 6-C 10芳基、被1、2或3个R 5-1-1取代的C 6-C 10芳基、“杂原子选自N、O和S中的1种、2种或3种，杂原子数为1、2或3个的3-12元杂芳基”、被1、2或3个R 5- 1-2取代的“杂原子选自N、O和S中的1种、2种或3种，杂原子数为1、2或3个的3-12元杂芳基”、“杂原子选自N、O和S中的1种、2种或3种，杂原子数为1、2或3个的3-12元杂环烷基”或被1、2或3个R 5-1-3取代的“杂原子选自N、O和S中的1种、2种或3种，杂原子数为1、2或3个的3-12元杂环烷基”；
    R 5-1-1、R 5-1-2和R 5-1-3独立地为卤素、被1、2或3个卤素取代的C 1-C 6烷基、C 2-C 6炔基、C 6-C 10芳基或C 1-C 6烷氧基；
    R 6为卤素。
  2. 如权利要求1所述的如式I所示的芳基C-葡萄糖苷衍生物、其互变异构体、其立体异构体、其前药，或前述任一者的药学上可接受的盐，或前述任一者的溶剂化物，其特征在于，所述的如式I所示的芳基C-葡萄糖苷衍生物满足下述条件中的一种或多种：
    (1)R 1、R 2、R 3、R 1-1、R 4-1和R 4-1-1中，所述C 1-C 6烷基独立地为甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基或叔丁基；
    (2)R 5中，所述C 1-C 6烷基为甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基或叔丁基；
    (3)R 1-2、R 1-3、R 1-4、R 1-2、R 1-3、R 1-4、R 5-1-1、R 5-1-2和R 5-1-3中，所述被1、2或3个卤素取代的C 1-C 6烷基中，所述卤素独立地为F、Cl、Br或I；
    (4)R 5-1-1、R 5-1-2和R 5-1-3中，所述被1、2或3个卤素取代的C 1-C 6烷基中，所述C 1-C 6烷基独立地为甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基或叔丁基；
    (5)R 5-1-1、R 5-1-2和R 5-1-3中，所述卤素独立地为F、Cl、Br或I；
    (6)R 1、R 2和R 3中，所述C 2-C 6炔基独立地为乙炔基、丙炔基、炔丙基、1-丁炔基、2-丁炔基或3-丁炔基；
    (7)R 5-1-1、R 5-1-2和R 5-1-3中，所述C 2-C 6炔基独立地为乙炔基、丙炔基、炔丙基、1-丁炔基、2-丁炔基或3-丁炔基；
    (8)R 5中，所述“杂原子选自N、O和S中的1种、2种或3种，杂原子数为1、2或3个的3-12元杂环烷基”为“杂原子选自N、O和S中的1种、2种或3种，杂原子数为1、2或3个的3-6元杂环烷基”；
    (9)R 5-1中，所述C 6-C 10芳基为苯基或萘基；
    (10)R 5-1中，所述被1、2或3个R 5-1-1取代的C 6-C 10芳基中，所述C 6-C 10芳基为苯基或萘基；
    (11)R 5-1-1、R 5-1-2和R 5-1-3，所述C 6-C 10芳基独立地为苯基或萘基；
    (12)R 5-1-1、R 5-1-2和R 5-1-3，所述C 1-C 6烷氧基独立地为甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、异丁氧基、仲丁氧基或叔丁氧基；
    (13)R 5-1中，所述“杂原子选自N、O和S中的1种、2种或3种，杂原子数为1、2或3个的3-12元杂芳基”和所述被1、2或3个R 5-1-2取代的“杂原子选自N、O和S中的1种、2种或3种，杂原子数为1、2或3个的3-12元杂芳基”中的“杂原子选自N、O和S中的1种、2种或3种，杂原子数为1、2或3个的3-12元杂芳基”独立地为“杂原子选自N、O和S中的1种、2种或3种，杂原子数为1、2或3个的3-10元杂芳 基”；
    (14)R 5-1中，所述“杂原子选自N、O和S中的1种、2种或3种，杂原子数为1、2或3个的3-12元杂环烷基”和所述被1、2或3个R 5-1-3取代的“杂原子选自N、O和S中的1种、2种或3种，杂原子数为1、2或3个的3-12元杂环烷基”中的“杂原子选自N、O和S中的1种、2种或3种，杂原子数为1、2或3个的3-12元杂环烷基”独立地为“杂原子选自N、O和S中的1种、2种或3种，杂原子数为1、2或3个的3-6元杂环烷基”；
    (15)R 6中，所述卤素为F、Cl、Br或I；
    (16)R 1-2、R 1-3、R 1-4、R 1-2-1和R 1-2-2中，所述C 1-C 4烷基为甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基或叔丁基；
    (17)R 1-2、R 1-3和R 1-4中，所述C 1-C 4烷氧基为甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、异丁氧基、仲丁氧基或叔丁氧基；
    (18)R 1、R 2和R 3中，所述C 2-C 6烯基独立地为乙烯基、丙烯基、烯丙基、1-丁烯基、2-丁烯基或3-丁烯基；
    (19)R 1、R 2和R 3中，所述C 3-C 6环烷基独立地为环丙基、环丁基、环戊基或环己基。
  3. 如权利要求1-2中的至少一项所述的如式I所示的芳基C-葡萄糖苷衍生物、其互变异构体、其立体异构体、其前药，或前述任一者的药学上可接受的盐，或前述任一者的溶剂化物，其特征在于，所述的如式I所示的芳基C-葡萄糖苷衍生物满足下述条件中的一种或多种：
    (1)R 1、R 2、R 3、R 1-1、R 4-1和R 4-1-1中，所述C 1-C 6烷基独立地为甲基、乙基或正丙基；
    (2)R 5中，所述C 1-C 6烷基为正丙基；
    (3)R 1-2、R 1-3、R 1-4、R 1-2、R 1-3、R 1-4、R 5-1-1、R 5-1-2和R 5-1-3中，所述被1、2或3个卤素取代的C 1-C 6烷基中，所述卤素独立地为F；
    (4)R 5-1-1、R 5-1-2和R 5-1-3中，所述被1、2或3个卤素取代的C 1-C 6烷基中，所述C 1-C 6烷基独立地为甲基；
    (5)R 5-1-1、R 5-1-2和R 5-1-3中，所述卤素独立地为F；
    (6)R 1、R 2和R 3中，所述C 2-C 6炔基独立地为炔丙基；
    (7)R 5-1-1、R 5-1-2和R 5-1-3中，所述C 2-C 6炔基独立地为3-丁炔基；
    (8)R 5中，所述“杂原子选自N、O和S中的1种、2种或3种，杂原子数为1、 2或3个的3-12元杂环烷基”为四氢呋喃基；
    (9)R 5-1中，所述被1、2或3个R 5-1-1取代的C 6-C 10芳基中，所述C 6-C 10芳基为苯基；
    (10)R 5-1-1、R 5-1-2和R 5-1-3，所述C 6-C 10芳基独立地为苯基；
    (11)R 5-1-1、R 5-1-2和R 5-1-3，所述C 1-C 6烷氧基独立地为甲氧基；
    (12)R 5-1中，所述“杂原子选自N、O和S中的1种、2种或3种，杂原子数为1、2或3个的3-12元杂芳基”和所述被1、2或3个R 5-1-2取代的“杂原子选自N、O和S中的1种、2种或3种，杂原子数为1、2或3个的3-12元杂芳基”中的“杂原子选自N、O和S中的1种、2种或3种，杂原子数为1、2或3个的3-12元杂芳基”独立地为二嗪基、呋喃基、吡啶基、吡嗪基或喹啉基；
    (13)R 5-1中，所述“杂原子选自N、O和S中的1种、2种或3种，杂原子数为1、2或3个的3-12元杂环烷基”和所述被1、2或3个R 5-1-3取代的“杂原子选自N、O和S中的1种、2种或3种，杂原子数为1、2或3个的3-12元杂环烷基”中的“杂原子选自N、O和S中的1种、2种或3种，杂原子数为1、2或3个的3-12元杂环烷基”独立地为二硫戊烷基；
    (14)R 6中，所述卤素为Cl；
    (15)R 1、R 2和R 3中，所述C 3-C 6环烷基独立地为环丙基。
  4. 如权利要求1-3中的至少一项所述的如式I所示的芳基C-葡萄糖苷衍生物、其互变异构体、其立体异构体、其前药，或前述任一者的药学上可接受的盐，或前述任一者的溶剂化物，其特征在于，所述的如式I所示的芳基C-葡萄糖苷衍生物满足下述条件中的一种或多种：
    (1)R 5-1-1、R 5-1-2和R 5-1-3中，所述被1、2或3个卤素取代的C 1-C 6烷基独立地为CF 3；
    (2)R 5中，所述“杂原子选自N、O和S中的1种、2种或3种，杂原子数为1、2或3个的3-12元杂环烷基”为
    Figure PCTCN2022138093-appb-100002
    例如
    Figure PCTCN2022138093-appb-100003
    (3)R 5-1中，所述“杂原子选自N、O和S中的1种、2种或3种，杂原子数为1、2或3个的3-12元杂芳基”和所述被1、2或3个R 5-1-2取代的“杂原子选自N、O和S中的1种、2种或3种，杂原子数为1、2或3个的3-12元杂芳基”中的“杂原子选自N、O和S中的1种、2种或3种，杂原子数为1、2或3个的3-12元杂芳基”独立地为
    Figure PCTCN2022138093-appb-100004
    (4)R 5-1中，所述“杂原子选自N、O和S中的1种、2种或3种，杂原子数为1、2或3个的3-12元杂环烷基”和所述被1、2或3个R 5-1-3取代的“杂原子选自N、O和S中的1种、2种或3种，杂原子数为1、2或3个的3-12元杂环烷基”中的“杂原子选自N、O和S中的1种、2种或3种，杂原子数为1、2或3个的3-12元杂环烷基”独立地为
    Figure PCTCN2022138093-appb-100005
  5. 如权利要求1-4中的至少一项所述的如式I所示的芳基C-葡萄糖苷衍生物、其互变异构体、其立体异构体、其前药，或前述任一者的药学上可接受的盐，或前述任一者的溶剂化物，其特征在于，所述的如式I所示的芳基C-葡萄糖苷衍生物满足下述条件中的一种或多种：
    (1)R 5为“杂原子选自N、O和S中的1种、2种或3种，杂原子数为1、2或3个的3-12元杂环烷基”、丙基或-L-R 5-1；
    (2)m为1或2；
    (3)n为0或4；
    (4)R 5-1为C 6-C 10芳基、被1、2或3个R 5-1-1取代的C 6-C 10芳基、“杂原子选自N、O和S中的1种、2种或3种，杂原子数为1、2或3个的3-12元杂芳基”、被1、2或3个R 5-1-2取代的“杂原子选自N、O和S中的1种、2种或3种，杂原子数为1、2或3个的3-12元杂芳基”或“杂原子选自N、O和S中的1种、2种或3种，杂原子数为1、2或3个的3-12元杂环烷基”。
  6. 如权利要求1-5中的至少一项所述的如式I所示的芳基C-葡萄糖苷衍生物、其互变异构体、其立体异构体、其前药，或前述任一者的药学上可接受的盐，或前述任一者的溶剂化物，其特征在于，R 4为CH 2OH，R 1-R 3至少有一个为C 1-C 6烷基或C 2-C 6炔基，其余为H；或者，R 4为COOH或CH 2OR 4-1，R 1-R 3独立地为H、C 1-C 6烷基或C 2-C 6炔基，R 4-1为C 1-C 6烷基；
    R 5为“杂原子选自N、O和S中的1种、2种或3种，杂原子数为1、2或3个的3-12元杂环烷基”；
    R 6为Cl。
  7. 如权利要求1-6中的至少一项所述的如式I所示的芳基C-葡萄糖苷衍生物、其互变异构体、其立体异构体、其前药，或前述任一者的药学上可接受的盐，或前述任一者的溶剂化物，其特征在于，所述的如式I所示的芳基C-葡萄糖苷衍生物满足下述条件中的一种或多种：
    (1)R 1-R 3独立地为H、甲基、乙基、正丙基、炔丙基或乙酰基；
    (2)R 4为COOH、CH 2OH、CH 2OCH 3或CH 2OCOCH 3；
    (3)R 5为
    Figure PCTCN2022138093-appb-100006
    (4)R 6为Cl。
  8. 如权利要求1-7中的至少一项所述的如式I所示的芳基C-葡萄糖苷衍生物、其互变异构体、其立体异构体、其前药，或前述任一者的药学上可接受的盐，或前述任一者的溶剂化物，其特征在于，如式I所示的芳基C-葡萄糖苷衍生物为如下任一化合物：
    Figure PCTCN2022138093-appb-100007
    Figure PCTCN2022138093-appb-100008
  9. 如权利要求1-8中至少一项所述的如式I所示的芳基C-葡萄糖苷衍生物的制备方法，其包括以下任一方法：
    方法一：
    冰浴下，用氧化剂如2,2,6,6-四甲基哌啶氧化物在四氢呋喃/饱和碳酸氢钠溶液中处理EMPA制备如式I-1所示的芳基C-葡萄糖苷衍生物，如下流程1所示：
    流程1
    Figure PCTCN2022138093-appb-100009
    方法二：
    (1)在室温下，EMPA用苯甲醛二甲缩醛和樟脑磺酸在N,N-二甲基甲酰胺中处理得中间体式II A化合物；
    (2)在冰浴下，硅烷如叔丁基二甲基氯硅烷和咪唑在DMF中处理式II A化合物得中间体式II B化合物；
    (3)在室温下，式II B化合物在无机碱如钠氢的存在下经C 1-3碘代烷烃处理，待反应结束后再经90％的醋酸水溶液处理得如式I-2～I-4所示的芳基C-葡萄糖苷衍生物；如 流程2所示：
    流程2：
    Figure PCTCN2022138093-appb-100010
    方法三：
    在室温下，式II A化合物在无机碱如氢氧化钠的存在下经卤代烃处理，待反应结束后再经90％的醋酸水溶液处理得如式I-5、I-6、I-10所示的芳基C-葡萄糖苷衍生物；如流程3所示：
    流程3：
    Figure PCTCN2022138093-appb-100011
    方法四：
    包括步骤：
    (1)在60℃下，将EMPA溶于甲醇中，与2,3-丁二酮和三乙氧基甲烷反应，得中间体式II C化合物；
    (2)在室温下，碘甲烷和氧化银在DMF中处理式II C化合物，待反应结束后再经80％三氟乙酸处理，得如式I-7所示的芳基C-葡萄糖苷衍生物；如流程4所示：
    流程4
    Figure PCTCN2022138093-appb-100012
    方法五：
    包括步骤：
    (1)在60℃下，将EMPA溶于甲醇中，与2,3-丁二酮和三乙氧基甲烷反应，得中间体式II D化合物；
    (2)在冰浴下，四氟硼酸和三甲基硅烷化重氮甲烷在二氯甲烷中处理式II D化合物，待反应结束后再经80％三氟乙酸处理得如式I-8所示芳基C-葡萄糖苷衍生物；如流程5所示：
    流程5：
    Figure PCTCN2022138093-appb-100013
    方法六：
    在室温下，EMPA用碘甲烷和钠氢在DMF中处理得如式I-9所示的芳基C-葡萄糖苷衍生物；如流程6所示：
    流程6
    Figure PCTCN2022138093-appb-100014
  10. 一种药物组合物，其特征在于，所述药物组合物包括：
    (1)如权利要求1-8中的至少一项所述的如式I所示的芳基C-葡萄糖苷衍生物、其互变异构体、其立体异构体、其前药，或前述任一者的药学上可接受的盐，或前述任一者 的溶剂化物；和
    (2)药学上可接受的载体或赋形剂。
  11. 如权利要求1-8中的至少一项所述的如式I所示的芳基C-葡萄糖苷衍生物、其互变异构体、其立体异构体、其前药，或前述任一者的药学上可接受的盐，或前述任一者的溶剂化物或如权利要求10所述药物组合物的用途，其用于制备a)抑制钠氢交换器的抑制剂；和/或b)预防和/或缓解和/或治疗钠氢交换器相关的疾病的药物。
  12. 如权利要求11所述的用途，其特征在于，所述的钠氢交换器为NHE1；
    和/或，所述钠氢交换器相关的疾病为心力衰竭。
  13. 如权利要求1-8中的至少一项所述的如式I所示的芳基C-葡萄糖苷衍生物、其互变异构体、其立体异构体、其前药，或前述任一者的药学上可接受的盐，或前述任一者的溶剂化物或如权利要求10所述药物组合物用于制备具有以下一种或多种作用的药物的用途：
    A1)保护心肌细胞；
    A2)收缩/舒张期左心室室间隔厚度变厚；
    A3)收缩/舒张期左心室后壁厚度变厚；
    A4)收缩/舒张期左心室内径变小；
    A5)射血分数升高；
    A6)短轴缩短率升高。
PCT/CN2022/138093 2021-12-09 2022-12-09 芳基c-葡萄糖苷衍生物、其制备方法及其用途 WO2023104201A1 (zh)

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