WO2018223819A1 - 一种吲哚乙酸类衍生物及其制备方法和医药用途 - Google Patents

一种吲哚乙酸类衍生物及其制备方法和医药用途 Download PDF

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Publication number
WO2018223819A1
WO2018223819A1 PCT/CN2018/086774 CN2018086774W WO2018223819A1 WO 2018223819 A1 WO2018223819 A1 WO 2018223819A1 CN 2018086774 W CN2018086774 W CN 2018086774W WO 2018223819 A1 WO2018223819 A1 WO 2018223819A1
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Prior art keywords
compound
racemate
mixture
salt
pharmaceutically acceptable
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PCT/CN2018/086774
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English (en)
French (fr)
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刘安
程锦堂
郭丛
章军
陈畅
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中国中医科学院中药研究所
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Application filed by 中国中医科学院中药研究所 filed Critical 中国中医科学院中药研究所
Priority to EP18813675.8A priority Critical patent/EP3636642A4/en
Priority to CN201880016571.0A priority patent/CN110418787B/zh
Priority to US16/620,015 priority patent/US11008360B2/en
Priority to JP2020518115A priority patent/JP7152479B2/ja
Publication of WO2018223819A1 publication Critical patent/WO2018223819A1/zh

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
    • C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
    • C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
    • C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
    • C07H19/044—Pyrrole radicals
    • 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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • A61K31/7056—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing five-membered rings with nitrogen as a ring hetero atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/08—Bronchodilators
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/14—Antitussive agents
    • 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
    • C07D405/04—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 directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H1/00—Processes for the preparation of sugar derivatives

Definitions

  • the invention belongs to the technical field of medicine, and particularly relates to a novel indole acetic acid compound, a preparation method thereof and a pharmaceutical composition containing the same, and the use thereof as an antitussive agent in treating diseases such as cough.
  • Cough and bronchial asthma are the two most common diseases of the respiratory system, which seriously affect people's quality of life.
  • the research and development of antitussive and antiasthmatic drugs are highly valued.
  • central and peripheral antitussives mainly have two types: central and peripheral.
  • Central cough medicines include methadone, codeine, morphine, etc., which are mostly used for reflexive dry cough, but clinically have side effects such as nausea, constipation, lethargy and addiction.
  • Peripheral antitussives include lupus, honey and syrup as lung-reducing drugs, or respiratory tract inhalation of compound benzoin, sodium chloride, and eucalyptus.
  • asthma drugs are divided into bronchodilators, anti-inflammatory asthma drugs and anti-allergic antiasthmatic drugs.
  • Bronchodilators include theophylline, inhaled anticholinergics, and beta 2 receptor agonists.
  • Theophylline inhibits phosphodiesterase, directly increases the level of intracellular cyclic adenosine monophosphate/cyclic guanosine monophosphate (cAMP/cGMP), relaxes smooth muscle, but the safe range of theophylline is narrow, and blood concentration must be detected for treatment. Bring some difficulties.
  • Inhaled anticholinergic drugs have a selective effect on airway smooth muscle, but the effect is slow.
  • Non-selective ⁇ 2 receptor agonists although powerful in asthma, have many side effects, such as heart rate acceleration, heart palpitations and other cardiac reactions, which may be related to excitatory cardiac ⁇ 2 receptors, leading to serious adverse cardiac reactions.
  • Selective ⁇ 2 receptor drugs such as salbutamol have side effects such as abnormal heartbeat, increased heart rate, and dizziness.
  • Anti-inflammatory antiasthmatic drugs have become the first-line drugs in antiasthmatic drugs, which achieve long-term prevention of asthma attacks by inhibiting airway inflammation.
  • Glucocorticoid is currently the most commonly used anti-inflammatory and anti-asthmatic drugs, such as dexamethasone, but long-term use can lead to osteoporosis and severe drug withdrawal.
  • Antiasthmatic antiallergic agents include H 1 receptor blockers, such as ketotifen; membrane stabilizing agents, such as cromolyn sodium; and leukotriene blockers, cysteinyl leukotrienes.
  • H 1 receptor blockers such as ketotifen
  • membrane stabilizing agents such as cromolyn sodium
  • leukotriene blockers cysteinyl leukotrienes.
  • the mechanism of action of these drugs is to block the mediators of mast cell release mediators by inhibiting immunoglobulin IgE, and to inhibit the increase of inflammatory cells such as eosinophils, macrophages and monocytes, and to exert anti-allergic effects and lightness.
  • Degree of anti-inflammatory effect However, its onset is slow and cannot be used in acute asthma attacks. It is only used to prevent asthma.
  • the present inventors designed and synthesized a series of indole acetic acid compounds, and the results showed that the compounds have a good antitussive effect and can be developed as an effective antitussive and antiasthmatic drug.
  • R 1 is selected from the group consisting of hydrogen, halogen, hydroxy, amino, cyano, alkyl, alkoxy, haloalkyl, haloalkoxy or cycloalkyl;
  • R 2 is selected from hydrogen, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy or cycloalkyl;
  • R 3 is selected from a five carbon sugar or a six carbon sugar
  • n is an integer from 1 to 4.
  • n 1 to 4.
  • the compound of the formula (I) according to the invention or a racemate, a racemate, an enantiomer thereof, a diastereomer thereof, Or a mixture thereof, or a pharmaceutically acceptable salt thereof which is a compound of the formula (II) or a mesogen, a racemate, an enantiomer, a diastereomer thereof, Or a mixture thereof, or a pharmaceutically acceptable salt thereof,
  • R 1 , R 2 , R 3 , m and n are as defined in the formula (I).
  • Typical compounds of the invention include, but are not limited to:
  • the pharmaceutically acceptable salt is a basic addition salt, preferably a sodium salt, a potassium salt, a calcium salt, a magnesium salt, a tetramethyl quaternary ammonium salt , tetraethyl quaternary ammonium salt, methylamine salt, dimethylamine salt, trimethylamine salt, triethylamine salt or ethylamine salt.
  • the present invention further provides a compound of the formula (I) according to the present invention or a racemate, a racemate, an enantiomer, a diastereomer thereof, or a mixture thereof, or a method for preparing a pharmaceutically acceptable salt thereof, comprising the steps of
  • the activating reagent is preferably DCC, and the base is preferably NMM.
  • Another aspect of the invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a compound according to the invention or a racemate, a racemate, an enantiomer, a diastereomer thereof, or a mixture thereof Or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
  • Another aspect of the invention relates to a compound of the formula (I) according to the invention or a racemate, a racemate, an enantiomer, a diastereomer thereof, or a mixture thereof Or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, for use in the manufacture of a medicament for treating cough.
  • the compound of the formula (I) of the present invention may be a basic addition salt with a pharmaceutically acceptable salt which is conventionally used in the art, and the base may be an inorganic base or an organic A base such as a salt formed with an alkali metal, an amine or a quaternary ammonium compound. Salts formed with alkali metals include, but are not limited to, sodium salts, lithium salts, potassium salts, calcium salts, magnesium salts, and the like.
  • Salts formed with amines for example, with ammonia (NH 3 ), primary, secondary or tertiary amines, including, but not limited to, methylamine, dimethylamine, trimethylamine, triethylamine, Ethylamine salt, ethanolamine salt, lysine salt, arginine salt and the like.
  • Salts formed with quaternary ammonium compounds include, but are not limited to, tetramethyl quaternary ammonium salts, tetraethyl quaternary ammonium salts, choline salts, and the like.
  • the active ingredient-containing pharmaceutical composition may be in a form suitable for oral administration, such as tablets, dragees, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or Tincture.
  • Oral compositions can be prepared according to any method known in the art for preparing pharmaceutical compositions, such compositions may contain one or more ingredients selected from the group consisting of sweeteners, flavoring agents, coloring agents, and preservatives, Provides pleasing and tasty pharmaceutical preparations. Tablets contain the active ingredient and a non-toxic pharmaceutically acceptable carrier suitable for the preparation of a tablet.
  • These carriers may be inert carriers such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating agents and disintegrating agents such as microcrystalline cellulose, croscarmellose sodium, corn starch or alginic acid a binder such as starch, gelatin, polyvinylpyrrolidone or gum arabic; and a lubricant such as magnesium stearate, stearic acid or talc.
  • These tablets may be uncoated or may be coated by masking the taste of the drug or delaying disintegration and absorption in the gastrointestinal tract, thus providing a sustained release effect over a longer period of time.
  • water-soluble taste masking materials such as hydroxypropylmethylcellulose or hydroxypropylcellulose, or extended-time materials such as ethylcellulose, cellulose acetate butyrate may be used.
  • hard gelatin capsules in which the active ingredient is mixed with an inert solid diluent such as calcium carbonate, calcium phosphate or kaolin, or in which the active ingredient is mixed with a water-soluble carrier such as polyethylene glycol or an oil vehicle such as peanut oil, liquid paraffin or olive oil.
  • Soft gelatin capsules provide oral preparations.
  • the aqueous suspension contains the active substance and a carrier suitable for the preparation of the aqueous suspension for mixing.
  • Such carriers are suspending agents, such as sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone and acacia; dispersing or wetting agents, which may be naturally occurring a phospholipid such as lecithin, or a condensation product of an alkylene oxide with a fatty acid such as polyoxyethylene stearate, or a condensation product of ethylene oxide with a long chain fatty alcohol, such as heptadecylethyleneoxy cetyl alcohol (heptadecaethyleneoxy cetanol), or a condensation product of ethylene oxide with a partial ester derived from a fatty acid and a hexitol, such as polyethylene oxide sorbitol monooleate, or ethylene oxide with derivatives derived from fatty acids and hexitols
  • the aqueous suspensions may also contain one or more preservatives, for example, ethylparaben or n-propylparaben, one or more coloring agents, one or more flavoring agents, and one or more Sweeteners such as sucrose, saccharin or aspartame.
  • preservatives for example, ethylparaben or n-propylparaben
  • coloring agents for example, ethylparaben or n-propylparaben
  • one or more flavoring agents such as sucrose, saccharin or aspartame.
  • the oil suspension can be formulated by suspending the active ingredient in a vegetable oil such as peanut oil, olive oil, sesame oil or coconut oil, or a mineral oil such as liquid paraffin.
  • the oily suspensions may contain a thickening agent, such as beeswax, hard paraffin or cetyl alcohol.
  • the above sweeteners and flavoring agents may be added to provide a palatable preparation.
  • These compositions can be preserved by the addition of an anti-oxidant such as butylated hydroxyanisole or alpha-tocopherol.
  • Dispersible powders and granules suitable for use in the preparation of aqueous suspensions may be employed in the preparation of the active ingredient and dispersion or dispersing or suspending agents or compositions or compositions or compositions or compositions or compositions or compositions or compositions or compositions or compositions or compositions or compositions or compositions or compositions or compositions or compositions or compositions or compositions or compositions or compositions or compositions or compositions or compositions or compositions or compositions or compositions or compositions or compositions or compositions or compositions or compositions or compositions or compositions or compositions or compositions or compositions or compositions or compositions or compositions or compositions or compositions or compositions or compositions or compositions or compositions or compositions or compositions or compositions or compositions or compositions or compositions or compositions or compositions or compositions or compositions or compositions or compositions or compositions or compositions or compositions or compositions or compositions or compositions or compositions or compositions or compositions or compositions or compositions or compositions or compositions or
  • the pharmaceutical compositions of the invention may also be in the form of an oil-in-water emulsion.
  • the oil phase may be a vegetable oil such as olive oil or peanut oil, or a mineral oil such as liquid paraffin or a mixture thereof.
  • Suitable emulsifiers may be naturally occurring phospholipids, such as soy lecithin and esters or partial esters derived from fatty acids and hexitol anhydrides such as sorbitan monooleate, and condensation products of the partial esters and ethylene oxide, For example, polyethylene oxide sorbitol monooleate.
  • the emulsions may also contain sweeteners, flavoring agents, preservatives, and antioxidants.
  • Syrups and elixirs may be formulated with sweetening agents such as glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative, a colorant, and an antioxidant.
  • sweetening agents such as glycerol, propylene glycol, sorbitol or sucrose.
  • Such formulations may also contain a demulcent, a preservative, a colorant, and an antioxidant.
  • the pharmaceutical composition may be in the form of a sterile injectable aqueous solution.
  • acceptable vehicles and solvents that may be employed are water, Ringer's solution, and isotonic sodium chloride solution.
  • the sterile injectable preparation may be a sterile injectable oil-in-water microemulsion in which the active ingredient is dissolved in the oily phase.
  • the active ingredient is dissolved in a mixture of soybean oil and lecithin.
  • the oil solution is then added to a mixture of water and glycerin to form a microemulsion.
  • the injection or microemulsion can be injected into the bloodstream of the patient by a local injection.
  • the solution and microemulsion are preferably administered in a manner that maintains a constant circulating concentration of the compound of the invention. To maintain this constant concentration, a continuous intravenous delivery device can be used.
  • the pharmaceutical composition may be in the form of a sterile injectable aqueous or oily suspension for intramuscular and subcutaneous administration.
  • the suspension may be formulated according to known techniques using those suitable dispersing or wetting agents and suspending agents.
  • the sterile injectable preparation may also be a sterile injectable solution or suspension prepared in a non-toxic parenterally acceptable diluent or solvent.
  • sterile fixed oils may conveniently be employed as a solvent or suspension medium. For this purpose, any blended fixed oil including synthetic mono- or diglycerides can be used.
  • fatty acids such as oleic acid can also be prepared as an injection.
  • the dosage of the drug to be administered depends on a variety of factors including, but not limited to, the activity of the particular compound used, the age of the patient, the weight of the patient, the health of the patient, the conduct of the patient, The patient's diet, time of administration, mode of administration, rate of excretion, combination of drugs, and the like.
  • the optimal treatment modality such as the mode of treatment, the daily dosage of the compound of formula (I) or the type of pharmaceutically acceptable salt can be verified according to conventional treatment regimens.
  • the present invention may contain a compound of the formula (I) as an active ingredient, and a composition is prepared by mixing with a pharmaceutically acceptable carrier or excipient, and is prepared into a clinically acceptable dosage form.
  • a composition is prepared by mixing with a pharmaceutically acceptable carrier or excipient, and is prepared into a clinically acceptable dosage form.
  • the derivatives of the present invention can be used in combination with other active ingredients as long as they do not cause other adverse effects such as allergic reactions and the like. Combination therapy is achieved by administering the individual therapeutic components simultaneously, separately or sequentially.
  • alkyl refers to a saturated aliphatic hydrocarbon group which is a straight or branched chain group containing from 1 to 20 carbon atoms, preferably an alkyl group having from 1 to 12 carbon atoms, more preferably from 1 to 6 carbons.
  • the alkyl group of the atom is a saturated aliphatic hydrocarbon group which is a straight or branched chain group containing from 1 to 20 carbon atoms, preferably an alkyl group having from 1 to 12 carbon atoms, more preferably from 1 to 6 carbons.
  • Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1 ,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2- Methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3 - dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl, 2 -methylhexyl, 3-methylhexyl, 4-methylhexyl,
  • lower alkyl groups having from 1 to 6 carbon atoms, non-limiting examples including methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl Base, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethyl Butyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl Base, 2,3-dimethylbutyl and the like.
  • the alkyl group may be substituted or unsubstituted, and when substituted, the substituent may be substituted at any available point of attachment, preferably one or more of the following groups independently selected from the group consisting of an alkane Base, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, fluorenyl, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, naphthenic An oxy group, a heterocycloalkoxy group, a cycloalkylthio group, a heterocycloalkylthio group, an oxo group, a carboxyl group or a carboxylate group.
  • an alkane Base alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, fluorenyl, hydroxy, nitro, cyano, cycloalkyl, hetero
  • cycloalkyl refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent containing from 3 to 20 carbon atoms, preferably from 3 to 12 carbon atoms, more preferably from 3 to 6 carbon atoms. One carbon atom.
  • Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatriene
  • a polycycloalkyl group includes a spiro ring, a fused ring, and a cycloalkyl group.
  • spirocycloalkyl refers to a polycyclic group that shares a carbon atom (referred to as a spiro atom) between 5 to 20 members of a single ring, which may contain one or more double bonds, but none of the rings have a fully conjugated ⁇ electronic system. It is preferably 6 to 14 members, more preferably 7 to 10 members.
  • the spirocycloalkyl group is classified into a monospirocycloalkyl group, a bispirocycloalkyl group or a polyspirocycloalkyl group, preferably a monospirocycloalkyl group and a bispirocycloalkyl group, depending on the number of common spiro atoms between the rings.
  • spirocycloalkyl groups include:
  • fused cycloalkyl refers to 5 to 20 members, and each ring in the system shares an all-carbon polycyclic group of an adjacent pair of carbon atoms with other rings in the system, wherein one or more of the rings may contain one or Multiple double bonds, but none of the rings have a fully conjugated ⁇ -electron system. It is preferably 6 to 14 members, more preferably 7 to 10 members.
  • fused cycloalkyl groups include:
  • bridged cycloalkyl refers to an all-carbon polycyclic group of 5 to 20 members, any two rings sharing two carbon atoms which are not directly bonded, which may contain one or more double bonds, but none of the rings have complete Conjugate ⁇ -electron system. It is preferably 6 to 14 members, more preferably 7 to 10 members. Depending on the number of constituent rings, it may be classified into a bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyl group, preferably a bicyclic ring, a tricyclic ring or a tetracyclic ring, and more preferably a bicyclic ring or a tricyclic ring.
  • bridged cycloalkyl groups include:
  • the cycloalkyl ring may be fused to an aryl, heteroaryl or heterocycloalkyl ring, wherein the ring to which the parent structure is attached is a cycloalkyl group, non-limiting examples include indanyl, tetrahydronaphthalene Base, benzocycloheptyl and the like.
  • the cycloalkyl group may be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkane Thio, alkylamino, halogen, fluorenyl, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio a heterocycloalkylthio group, an oxo group, a carboxyl group or a carboxylate group.
  • alkoxy refers to -O-(alkyl) and -O-(unsubstituted cycloalkyl), wherein alkyl is as defined above.
  • alkoxy groups include: methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy.
  • the alkoxy group may be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkane Thio, alkylamino, halogen, fluorenyl, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio a heterocycloalkylthio group, a carboxyl group or a carboxylate group.
  • haloalkyl refers to an alkyl group substituted by one or more halogens, wherein alkyl is as defined above.
  • haloalkoxy refers to an alkoxy group substituted by one or more halogens, wherein alkoxy is as defined above.
  • hydroxy refers to an -OH group.
  • halogen means fluoro, chloro, bromo or iodo.
  • amino means -NH 2.
  • cyano refers to -CN.
  • carboxylate group refers to -C(O)O(alkyl) or -C(O)O(cycloalkyl), wherein alkyl is as defined above.
  • acyl refers to a compound containing a -C(O)R group wherein R is alkyl, cycloalkyl, aryl, heteroaryl.
  • heterocyclic group optionally substituted by an alkyl group means that an alkyl group may be, but not necessarily, present, and the description includes the case where the heterocyclic group is substituted with an alkyl group and the case where the heterocyclic group is not substituted with an alkyl group.
  • Substituted refers to one or more hydrogen atoms in the group, preferably up to 5, more preferably 1 to 3, hydrogen atoms, independently of each other, substituted by a corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and those skilled in the art will be able to determine (by experiment or theory) substitutions that may or may not be possible without undue effort. For example, an amino group or a hydroxyl group having a free hydrogen may be unstable when combined with a carbon atom having an unsaturated (e.g., olefinic) bond.
  • “Pharmaceutical composition” means a mixture comprising one or more of the compounds described herein, or a physiologically/pharmaceutically acceptable salt or prodrug thereof, and other chemical components, as well as other components such as physiological/pharmaceutically acceptable carriers. And excipients.
  • the purpose of the pharmaceutical composition is to promote the administration of the organism, which facilitates the absorption of the active ingredient and thereby exerts biological activity.
  • “Pharmaceutically acceptable salt” refers to a salt of a compound of the invention which is safe and effective for use in a mammal and which possesses the desired biological activity.
  • the present invention adopts the following technical solutions.
  • Step 1 Compound 1a and ethyl bromide are reacted in a solvent under basic conditions to obtain a compound Ib, and a reagent for providing basic conditions is preferably potassium carbonate; the solvent is preferably DMF;
  • Step 2 oxidizing the compound Ib in a solution of hydrochloric acid in the presence of a catalyst to obtain a compound Ic, preferably a pyridine borane;
  • Step 3 refluxing compound Ic with the corresponding sugar in an alcohol solvent to obtain compound Id, which is preferably ethanol;
  • Step 4 reducing the compound Id in toluene in the presence of a catalyst to obtain a compound Ie, the catalyst is preferably DDQ;
  • Step 5 hydrolysis of compound Ie under basic conditions to obtain compound If, the reagent providing basic conditions is preferably NaOH;
  • Step 6 coupling a compound If and a compound Ig in a solvent in the presence of a base and a catalyst to obtain a compound of the formula (I), preferably a solvent, preferably a N-methylmorpholine,
  • the catalyst is preferably DCC.
  • the structure of the compound is determined by nuclear magnetic resonance (NMR) or/and mass spectrometry (MS).
  • NMR nuclear magnetic resonance
  • MS mass spectrometry
  • the NMR shift is given in units of 10 -6 (ppm).
  • the NMR was determined by using a Brukerdps 600 type nuclear magnetic instrument.
  • the solvent was deuterated dimethyl sulfoxide (DMSO-d 6 ), deuterated chloroform (CDCl 3 ), deuterated methanol (CD 3 OD), and the internal standard was tetramethyl. Silane (TMS).
  • the MS was measured using a 1100 Series LC/MSD Trap (ESI) mass spectrometer (manufacturer: Agilent).
  • the liquid phase was prepared using an lc3000 high performance liquid chromatograph and an lc6000 high performance liquid chromatograph (manufacturer: Innovative Tongheng).
  • the HPLC was measured using a Shimadzu LC-20AD high pressure liquid chromatograph (Agilent TC-C18 250 x 4.6 mm 5 vm column) and a Shimadzu LC-2010 AHT high pressure liquid chromatograph (Phenomenex C18250 x 4.6 mm 5 um column).
  • Thin layer chromatography silica gel plate uses Qingdao Ocean Chemical GF254 silica gel plate.
  • the specification of silica gel plate used for thin layer chromatography (TLC) is 0.15mm ⁇ 0.2mm.
  • the specification for thin layer chromatography separation and purification is 0.4mm ⁇ 0.5. Mm.
  • the known starting materials of the present invention may be synthesized by or according to methods known in the art, or may be purchased from companies such as Netcom Mall, Enoch, Sigma, Anike Chemical, and the like.
  • reaction can be carried out without using an argon atmosphere or a nitrogen atmosphere.
  • the solution means an aqueous solution.
  • reaction temperature is room temperature and is 20 ° C to 30 ° C.
  • the progress of the reaction in the examples was monitored by thin layer chromatography (TLC).
  • TLC thin layer chromatography
  • the system used for the reaction was: A: dichloromethane and methanol system, B: n-hexane and ethyl acetate system, C: petroleum ether And the ethyl acetate system, D: acetone, the volume ratio of the solvent is adjusted depending on the polarity of the compound.
  • the column chromatography eluent system and the thin layer chromatography developer system include: A: dichloromethane and methanol systems, B: n-hexane and ethyl acetate systems, C: petroleum ether and acetic acid
  • A dichloromethane and methanol systems
  • B n-hexane and ethyl acetate systems
  • C petroleum ether and acetic acid
  • the volume ratio of the solvent is adjusted depending on the polarity of the compound, and a small amount of an alkaline or acidic reagent such as triethylamine or acetic acid may be added for adjustment.
  • Step 3 2-(1-((2R,3R,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl) Preparation of ethyl hydroquinone-3-yl)acetate (1d)
  • Step 4 2-(1-((2R,3R,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)- Preparation of 1H-indol-3-ylacetate (1e)
  • Step 5 2-(1-((2R,3R,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)- Preparation of 1H-indol-3-yl)acetic acid (1f)
  • Step 6 (2-(1-((2R,3R,4S,5S,6R)-3,4,5-trihydroxy-6-hydroxymethyl)tetrahydro-2H-pyran-2-yl)- Preparation of 1H-indol-3-yl)acetyl)-D-aspartic acid (1)
  • Step 1 (2-(1-((2R,3R,4S,5S,6R)-3,4,5-trihydroxy-6-hydroxymethyl)tetrahydro-2H-pyran-2-yl)- Preparation of 1H-indol-3-yl)acetyl)-D-glutamic acid (2)
  • Step 4 2-(1-((2R,3R,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)5 Preparation of ethyl-methyl-1H-indol-3-yl)acetate (3e)
  • Step 5 2-(1-((2R,3R,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)- Preparation of 5-methyl-1H-indol-3-yl)acetic acid (3f)
  • Step 6 (2-(5-Methyl-1-((2R,3R,4S,5S,6R)-3,4,5-trihydroxy-6-hydroxymethyl)tetrahydro-2H-pyran- Preparation of 2-yl)-1H-indol-3-yl)acetyl)-D-aspartic acid (3)
  • Step 3 2-(1-((2R,3R,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)5 Preparation of ethyl methoxy-indoline-3-yl)acetate (4d)
  • Step 5 2-(1-((2R,3R,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)- Preparation of 5-methoxy-1H-indol-3-yl)acetic acid (4f)
  • Step 6 (2-(5-methoxy-1-((2R,3R,4S,5S,6R)-3,4,5-trihydroxy-6-hydroxymethyl)tetrahydro-2H-pyran Preparation of 2-yl)-1H-indol-3-yl)acetyl)-D-aspartic acid (4)
  • Step 4 2-(1-((2R,3R,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)5 Of -chloro-1H-indol-3-yl)acetate (5e)
  • Step 5 2-(1-((2R,3R,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)- Preparation of 5-chloro-1H-indol-3-yl)acetic acid (5f)
  • Step 6 (2-(5-Chloro-1-((2R,3R,4S,5S,6R)-3,4,5-trihydroxy-6-hydroxymethyl)tetrahydro-2H-pyran-2 Preparation of -yl)-1H-indol-3-yl)acetyl)-D-aspartic acid (5)
  • Step 3 2-(1-((2R,3R,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)5 Preparation of ethyl bromide-dihydroindol-3-yl)acetate (6d)
  • Step 4 2-(1-((2R,3R,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)5 Preparation of ethyl bromide-1H-indol-3-yl)acetate (6e)
  • Step 5 2-(1-((2R,3R,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)- Preparation of 5-bromo-1H-indol-3-yl)acetic acid (6f)
  • Step 6 (2-(5-Bromo-1-((2R,3R,4S,5S,6R)-3,4,5-trihydroxy-6-hydroxymethyl)tetrahydro-2H-pyran-2 Of -1)-1H-indol-3-yl)acetyl)-D-aspartic acid (6)
  • Step 3 2-(1-((2R,3R,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)7 Preparation of ethyl-methyl-indoline-3-yl)acetate (7d)
  • Step 4 2-(1-((2R,3R,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)7 Preparation of ethyl-methyl-1H-indol-3-yl)acetate (7e)
  • Step 5 2-(1-((2R,3R,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)- Preparation of 7-Methyl-1H-indol-3-yl)acetic acid (7f)
  • Step 6 (2-(7-Methyl-1-((2R,3R,4S,5S,6R)-3,4,5-trihydroxy-6-hydroxymethyl)tetrahydro-2H-pyran- Preparation of 2-yl)-1H-indol-3-yl)acetyl)-D-aspartic acid (7)
  • Step 3 2-(1-((2R,3R,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)7 Preparation of ethyl-methoxyindoline-3-yl)acetate (8d)
  • Step 5 2-(1-((2R,3R,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)- Preparation of 7-methoxy-1H-indol-3-yl)acetic acid (8f)
  • Step 6 (2-(7-methoxy-1-((2R,3R,4S,5S,6R)-3,4,5-trihydroxy-6-hydroxymethyl)tetrahydro-2H-pyran Preparation of 2-yl)-1H-indol-3-yl)acetyl)-D-aspartic acid (8)
  • Step 1 (2-(5-Methyl-1-((2R,3R,4S,5S,6R)-3,4,5-trihydroxy-6-hydroxymethyl)tetrahydro-2H-pyran- Preparation of 2-yl)-1H-indol-3-yl)acetyl)-D-glutamic acid (9)
  • Step 1 (2-(5-Chloro-1-((2R,3R,4S,5S,6R)-3,4,5-trihydroxy-6-hydroxymethyl)tetrahydro-2H-pyran-2 Of -1)-1H-indol-3-yl)acetyl)-D-glutamic acid (10)
  • Test animals Kunming mice, weighing 18-22g, half male and half female. Purchased from Beijing Weitong Lihua Experimental Animal Technology Co., Ltd., experimental animal production license number: SCXK-(Beijing) 2012-001.
  • Test reagent codeine phosphate (European Pharmaceutical Co., Ltd.).
  • mice were adapted for feeding for 3 days and then screened. After preheating the ultrasonic nebulizer, the existing 40 ml aqueous ammonia solution (12.5%) was added. The mice were placed in a beaker having a volume of 1000 ml, and the beaker mouth was sealed with a plastic wrap and two ports were opened (one for inserting the ultrasonic atomizer outlet tube and the other for ventilation holes). After the ultrasonic atomizer is continuously introduced into the ammonia gas for a minimum of 60 seconds, the plastic film is immediately closed and the plastic wrap is quickly opened to allow the ammonia gas to naturally diffuse. Remove the number of coughs less than 10 times and more than 80 times within three minutes.
  • mice Qualified mice were randomized into a blank control group, a compound group of the present invention, and a codeine-positive control group. All the above groups were administered by weight gavage, and the blank control group was given equal volume of distilled water once a day for 5 consecutive days. After 1 hour of the last administration, the mice were placed one by one in an inverted 5 L sealed glass bell jar. After receiving a constant pressure ammonia spray, the stimulation was stopped after 15 seconds (ammonia spray 10 mL/time, 1 mouse each time, 1 time for ammonia change), and the mice were immediately taken out to observe the coughing latency of the mice (from the start of spraying to the production). The time of coughing and the number of coughs in 2 minutes (the mouse coughs to severely contract the abdominal muscles and open the mouth, when you can hear a slight cough).
  • Test animals guinea pigs, 180-220 g, half male and half female. Purchased from Beijing Weitong Lihua Experimental Animal Technology Co., Ltd.
  • Test reagent codeine phosphate (European Pharmaceutical Co., Ltd.).
  • the guinea pigs were fed for 1 day and then screened. Place the guinea pigs one by one in an inverted 5L sealed glass bell jar and receive constant pressure spray stimulation (17.5% citrate solution) for 1 minute. Record the number of coughs within 5 minutes from the spray and select more than 10 guinea pigs. Qualified experimental animals. The qualified guinea pigs were randomly divided into a blank control group, a compound group of the present invention, and a codeine-positive control group. All the above groups were administered by weight, and the blank control group was given equal volume of distilled water for 5 days. After 1 hour of the last administration, the guinea pigs were placed in an inverted 5L sealed glass bell jar to start the nebulizer. For 30 seconds, observe the guinea pig cough latency (injection of 17.5% niacin until the time required for coughing to occur) and the number of coughs within 5 minutes.
  • Test animals Kunming mice, weighing 18-22g, half male and half female. Purchased from Beijing Weitong Lihua Experimental Animal Technology Co., Ltd.
  • Test reagent ammonium chloride (Guangzhou Chemical Reagent Factory)
  • mice were randomly reared for 3 days and randomly divided into: blank control group, compound group of the present invention and ammonium chloride positive control group.
  • Each group of mice was given the same volume of medicine or distilled water for 5 consecutive days. After 30 minutes of the last administration, 2.5%/10 g was intraperitoneally injected with 2.5% phenol red. After 30 minutes, the animals were sacrificed and the trachea was separated. In a test tube containing physiological saline, 0.1 mL of 1.0 mol/L sodium hydroxide was added. The absorbance A value was measured at a wavelength of 546 nm using a UV-2450 spectrophotometer, and the phenol red emission was calculated from the phenol red standard curve, and the significance of the difference between the groups was compared.
  • Test animals guinea pigs, 180-220 g, half male and half female. Purchased from Beijing Weitong Lihua Experimental Animal Technology Co., Ltd.
  • Test reagent aminophylline solution (Guangzhou Mingxing Pharmaceutical Co., Ltd.), histamine phosphate (Shanghai Haoyang Biotechnology Co., Ltd.)
  • the guinea pigs were fed for 1 day and then screened.
  • the guinea pigs were placed one by one in an inverted 5 L sealed glass bell jar. After the guinea pigs were quiet, the histamine phosphate was sprayed at a constant pressure for 15 seconds. After the spray was stopped, the incubation period of the asthma was observed within 6 minutes, and if the asthmatic convulsion occurred within 150 seconds, it was a qualified experimental animal.
  • the qualified guinea pigs were randomly divided into a blank control group, a compound group of the present invention, and an aminophylline positive control group. The drug was administered once a day for 3 consecutive days.
  • the guinea pig was inhaled with histamine phosphate.
  • the time of convulsion and fall of the guinea pig was recorded as the incubation period (spray start to fall time), continuous observation for 6 minutes, and 6 minutes without falling. In 360 seconds.
  • the latency of the control group and the drug-administered group was statistically compared.

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Abstract

本发明涉及一种吲哚乙酸类衍生物及其制备方法和医药用途。特别地，本发明涉及通式(I)所示的化合物、其制备方法及含有其的药物组合物，及其作为止咳剂在治疗咳嗽等疾病中的用途。其中通式(I)中的各取代基的定义与说明书中的定义相同。

Description

一种吲哚乙酸类衍生物及其制备方法和医药用途 技术领域
本发明属于医药技术领域，具体涉及一种新的吲哚乙酸类化合物、其制备方法及含有其的药物组合物，以及其作为止咳剂在治疗咳嗽等疾病中的用途。
背景技术
咳嗽、支气管哮喘是呼吸系统最常见的两种疾病，严重影响人们的生活质量，止咳平喘类药物的研发颇受重视。
目前临床镇咳药主要有中枢性和外周性两类。中枢性止咳药有美沙芬、可待因、吗啡等，多用于反射性干咳，但临床上多有恶心、便秘、嗜睡和成瘾等副作用。外周性镇咳药包括以枇杷膏、蜂蜜和糖浆等润肺药物为代表，或是以复方安息香酊、氯化钠、桉树脑等呼吸道吸入药。
按作用机制，平喘药分为支气管扩张药、抗炎平喘药和抗过敏平喘药。支气管扩张药包括茶碱类、吸入性抗胆碱药和β 2受体激动药。茶碱类抑制磷酸二酯酶，直接使细胞内环磷酸腺苷/环磷酸鸟苷(cAMP/cGMP)水平升高，松弛平滑肌，但是茶碱安全范围窄，必须进行血药浓度检测，给治疗带来一定困难。吸入性抗胆碱药对气道平滑肌有一定选择作用，但起效慢。非选择性β 2受体激动药虽然平喘作用强大，但副作用较多，具有心率加速、心悸等心脏反应，其原因可能与兴奋心脏β 2受体有关，导致严重心脏不良反应。选择性β 2受体药物如沙丁胺醇具有使心搏异常强烈、加快心率、目眩等副作用。抗炎平喘药已成为平喘药中的一线药物，其通过抑制气道炎症反应达到长期预防哮喘发作的效果。糖皮质激素是目前抗炎平喘最常用的药，如地塞米松，但长期服用，会导致骨质疏松，并有严重停药反应。抗过敏平喘药包括H 1受体阻断剂，如酮替芬；细胞膜稳定剂，如色甘酸钠；以及白三烯阻断药，半胱氨酰白三烯等。这类药物的作用机制是通过抑制免疫球蛋白IgE阻断其介导的肥大细胞释放介质，并抑制嗜酸性粒细胞、巨噬细胞和单核细胞等炎症细胞的增加，发挥抗过敏作用和轻度的抗炎作用。但其起效缓慢，不能用于哮喘急性发作期，临床只用于预防哮喘。
因此，目前仍需要开发新型有效的镇咳平喘药物，其不但可以有效用于咳嗽、支气管哮喘等疾病的治疗，而且能够克服现有技术中存在的副作用。
发明内容
本发明人设计合成了一系列吲哚乙酸类化合物，研究结果显示该类化合物具有良好的镇咳效果，可以被开发为有效的镇咳平喘药物。
因此，本发明的目的在于提供一种通式(I)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其药学上可接受的盐，
Figure PCTCN2018086774-appb-000001
其中，
R 1选自氢、卤素、羟基、氨基、氰基、烷基、烷氧基、卤代烷基、卤代烷氧基或环烷基；
R 2选自氢、卤素、烷基、烷氧基、卤代烷基、卤代烷氧基或环烷基；
R 3选自五碳糖或六碳糖；
n为1至4的整数；
m为1至4的整数。
在本发明一个优选的实施方案中，根据本发明所述的通式(I)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其药学上可接受的盐，其为通式(II)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其药学上可接受的盐，
Figure PCTCN2018086774-appb-000002
其中，R 1、R 2、R 3、m和n如通式(I)中所定义。
在本发明另一个优选的实施方案中，根据本发明所述的通式(I)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其药学上可接受的盐，其中，R 1选自氢、卤素、烷基、烷氧基、卤代烷基、卤代烷氧基，优选氢、卤素、C 1-C 6烷基、C 1-C 6烷氧基。
在本发明另一个优选的实施方案中，根据本发明所述的通式(I)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其药学上可接受的盐，其中，R 2选自氢、卤素、C 1-C 6烷基、或C 1-C 6烷氧基。
在本发明另一个优选的实施方案中，根据本发明所述的通式(I)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或 其药学上可接受的盐，其中，R 3选自五碳糖，优选核糖、脱氧核糖和木糖，更优选D-核糖、D-脱氧核糖和D-木糖。
在本发明另一个优选的实施方案中，根据本发明所述的通式(I)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其药学上可接受的盐，其中，R 3选自六碳糖，优选葡萄糖、果糖、和半乳糖，更优选D-葡萄糖、D-果糖和D-半乳糖。
在本发明另一个优选的实施方案中，根据本发明所述的通式(I)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其药学上可接受的盐，其中，m为1或2，优选m为1。
在本发明另一个优选的实施方案中，根据本发明所述的通式(I)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其药学上可接受的盐，其中，n为1或2。
本发明典型的化合物包括但不限于：
Figure PCTCN2018086774-appb-000003
Figure PCTCN2018086774-appb-000004
Figure PCTCN2018086774-appb-000005
或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其药学上可接受的盐。
在本发明另一个优选的实施方案中，根据本发明所述的通式(I)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其药学上可接受的盐，其中所述药学上可接受的盐为碱式加成盐，优选钠盐、钾盐、钙盐、镁盐、四甲基季铵盐、四乙基季铵盐、甲胺盐、二甲胺盐、三甲胺盐、三乙胺盐或乙胺盐。
本发明进一步提供根据本发明所述的通式(I)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其药学上可接受的盐的制备方法，其包括以下步骤，
Figure PCTCN2018086774-appb-000006
将中间体Ia与中间体Ib在活化试剂和碱存在下发生偶联反应得到通式(I)化合物；
其中，所述活化试剂优选DCC，所述碱优选NMM。
本发明另一方面涉及一种药物组合物，其包含根据本发明所述的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其药学上可接受的盐，以及药学上可接受的载体。
本发明另一方面涉及根据本发明所述的通式(I)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其药学上可接受的盐，或者包含其的药物组合物在制备治疗咳嗽的药物中的用途。
按照本发明所属领域的常规方法，本发明通式(I)所示的化合物可以与本领域常规的碱生成药学上可接受的盐的碱式加成盐，所述碱可以为无机碱或有机碱，例如与碱金属、胺类或季铵类化合物形成的盐。与碱金属形成的盐包括但不限于钠盐、锂盐、钾盐、钙盐、镁盐等。与胺类形成的盐，例如与氨(NH 3)、伯胺、仲胺或叔胺形成的盐，包括但不限于，甲胺盐、二甲胺盐、三甲胺盐、三乙胺盐、乙胺盐、乙醇胺盐、赖氨酸盐和精氨酸盐等等。与季铵类化合物形成的盐包括但不限于四甲基季铵盐、四乙基季铵盐、胆碱盐等等。
含活性成分的药物组合物可以是适用于口服的形式，例如片剂、糖锭剂、锭剂、水或油混悬液、可分散粉末或颗粒、乳液、硬或软胶囊，或糖浆剂或酏剂。可按照本领域任何已知制备药物组合物的方法制备口服组合物，此类组合物可含有一种或多种选自以下的成分：甜味剂、矫味剂、着色剂和防腐剂，以提供悦目和可口的药用制剂。片剂含有活性成分和用于混合的适宜制备片剂的无毒的可药用载体。这些载体可以是惰性载体，如碳酸钙、碳酸钠、乳糖、磷酸钙或磷酸钠；造粒剂和崩解剂，例如微晶纤维素、交联羧甲基纤维素钠、玉米淀粉或藻酸；粘合剂，例如淀粉、明胶、聚乙烯吡咯烷酮或阿拉伯胶；和润滑剂，例如硬脂酸镁、硬脂酸或滑石粉。这些片剂可以不包衣或可通过掩盖药物的味道或在胃肠道中延迟崩解和吸收，因而在较长时间内提供缓释作用的已知技术将其包衣。例如，可使用水溶性味道掩蔽物质，例如羟丙基甲基纤维素或羟丙基纤维素，或延长时间物质例如乙基纤维素、醋酸丁酸纤维素。
也可用其中活性成分与惰性固体稀释剂例如碳酸钙、磷酸钙或高岭土混合的硬明胶胶囊，或其中活性成分与水溶性载体例如聚乙二醇或油溶媒例如花生油、 液体石蜡或橄榄油混合的软明胶胶囊提供口服制剂。
水悬浮液含有活性物质和用于混合的适宜制备水悬浮液的载体。此类载体是悬浮剂，例如羧甲基纤维素钠、甲基纤维素、羟丙基甲基纤维素、藻酸钠、聚乙烯吡咯烷酮和阿拉伯胶；分散剂或湿润剂，其可以是天然产生的磷脂例如卵磷脂，或烯化氧与脂肪酸的缩合产物例如聚氧乙烯硬脂酸酯，或环氧乙烷与长链脂肪醇的缩合产物，例如十七碳亚乙基氧基鲸蜡醇(heptadecaethyleneoxy cetanol)，或环氧乙烷与由脂肪酸和己糖醇衍生的部分酯的缩合产物，例如聚环氧乙烷山梨醇单油酸酯，或环氧乙烷与由脂肪酸和己糖醇酐衍生的偏酯的缩合产物，例如聚环氧乙烷脱水山梨醇单油酸酯。水混悬液也可以含有一种或多种防腐剂，例如尼泊金乙酯或尼泊金正丙酯、一种或多种着色剂、一种或多种矫味剂和一种或多种甜味剂，例如蔗糖、糖精或阿司帕坦。
油混悬液可通过使活性成分悬浮于植物油如花生油、橄榄油、芝麻油或椰子油，或矿物油例如液体石蜡中配制而成。油悬浮液可含有增稠剂，例如蜂蜡、硬石蜡或鲸蜡醇。可加入上述的甜味剂和矫味剂，以提供可口的制剂。可通过加入抗氧化剂例如丁羟茴醚或α-生育酚保存这些组合物。
通过加入水可使适用于制备水混悬液的可分散粉末和颗粒提供活性成分和用于混合的分散剂或湿润剂、悬浮剂或一种或多种防腐剂。适宜的分散剂或湿润剂和悬浮剂如上所述。也可加入其他载体例如甜味剂、矫味剂和着色剂。通过加入抗氧化剂例如抗坏血酸保存这些组合物。
本发明的药物组合物也可以是水包油乳剂的形式。油相可以是植物油例如橄榄油或花生油，或矿物油例如液体石蜡或其混合物。适宜的乳化剂可以是天然产生的磷脂，例如大豆卵磷脂和由脂肪酸和己糖醇酐衍生的酯或偏酯例如山梨坦单油酸酯，和所述偏酯和环氧乙烷的缩合产物，例如聚环氧乙烷山梨醇单油酸酯。乳剂也可以含有甜味剂、矫味剂、防腐剂和抗氧剂。可用甜味剂例如甘油、丙二醇、山梨醇或蔗糖配制糖浆和酏剂。此类制剂也可含有缓和剂、防腐剂、着色剂和抗氧剂。
药物组合物可以是无菌注射水溶液形式。可在使用的可接受的溶媒和溶剂中有水、林格氏液和等渗氯化钠溶液。无菌注射制剂可以是其中活性成分溶于油相的无菌注射水包油微乳。例如将活性成分溶于大豆油和卵磷脂的混合物中。然后将油溶液加入水和甘油的混合物中处理形成微乳。可通过局部大量注射，将注射液或微乳注入患者的血流中。或者，最好按可保持本发明化合物恒定循环浓度的方式给予溶液和微乳。为保持这种恒定浓度，可使用连续静脉内递药装置。
药物组合物可以是用于肌内和皮下给药的无菌注射水或油混悬液的形式。可按已知技术，用上述那些适宜的分散剂或湿润剂和悬浮剂配制该混悬液。无菌注射制剂也可以是在无毒肠胃外可接受的稀释剂或溶剂中制备的无菌注射溶液或混悬液。此外，可方便地用无菌固定油作为溶剂或悬浮介质。为此目的，可使用包 括合成甘油单或二酯在内的任何调和固定油。此外，脂肪酸例如油酸也可以制备注射剂。
本领域技术人员所熟知的，药物的给药剂量依赖于多种因素，包括但并非限定以下因素：所用特定化合物的活性、病人的年龄、病人的体重、病人的健康状况、病人的行被、病人的饮食、给药时间、给药方式、排泄的速率、药物的组合等。另外，最佳的治疗方式如治疗的模式、通式化合物(I)的日用量或可药用的盐的种类可以根据传统的治疗方案来验证。
本发明可以含有通式(I)的化合物作为活性成份，与药学上可接受的载体或赋型剂混合制备成组合物，并制备成临床上可接受的剂型。本发明的衍生物可以与其他活性成分组合使用，只要它们不产生其他不利的作用，例如过敏反应等。联合治疗通过将各个治疗组分同时、分开或相继给药来实现。
发明的详细说明
除非有相反陈述，在说明书和权利要求书中使用的术语具有下述含义。
术语“烷基”指饱和脂肪族烃基团，其为包含1至20个碳原子的直链或支链基团，优选含有1至12个碳原子的烷基，更优选含有1至6个碳原子的烷基。非限制性实例包括甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、仲丁基、正戊基、1,1-二甲基丙基、1,2-二甲基丙基、2,2-二甲基丙基、1-乙基丙基、2-甲基丁基、3-甲基丁基、正己基、1-乙基-2-甲基丙基、1,1,2-三甲基丙基、1,1-二甲基丁基、1,2-二甲基丁基、2,2-二甲基丁基、1,3-二甲基丁基、2-乙基丁基、2-甲基戊基、3-甲基戊基、4-甲基戊基、2,3-二甲基丁基、正庚基、2-甲基己基、3-甲基己基、4-甲基己基、5-甲基己基、2,3-二甲基戊基、2,4-二甲基戊基、2,2-二甲基戊基、3,3-二甲基戊基、2-乙基戊基、3-乙基戊基、正辛基、2,3-二甲基己基、2,4-二甲基己基、2,5-二甲基己基、2,2-二甲基己基、3,3-二甲基己基、4,4-二甲基己基、2-乙基己基、3-乙基己基、4-乙基己基、2-甲基-2-乙基戊基、2-甲基-3-乙基戊基、正壬基、2-甲基-2-乙基己基、2-甲基-3-乙基己基、2,2-二乙基戊基、正癸基、3,3-二乙基己基、2,2-二乙基己基，及其各种支链异构体等。更优选的是含有1至6个碳原子的低级烷基，非限制性实施例包括甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、仲丁基、正戊基、1,1-二甲基丙基、1,2-二甲基丙基、2,2-二甲基丙基、1-乙基丙基、2-甲基丁基、3-甲基丁基、正己基、1-乙基-2-甲基丙基、1,1,2-三甲基丙基、1,1-二甲基丁基、1,2-二甲基丁基、2,2-二甲基丁基、1,3-二甲基丁基、2-乙基丁基、2-甲基戊基、3-甲基戊基、4-甲基戊基、2,3-二甲基丁基等。烷基可以是取代的或非取代的，当被取代时，取代基可以在任何可使用的连接点上被取代，所述取代基优选为一个或多个以下基团，其独立地选自烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、巯基、羟基、硝基、氰基、环烷基、杂环烷基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基、氧代基、羧基或羧酸酯基。
术语“环烷基”指饱和或部分不饱和单环或多环环状烃取代基，环烷基环包含3至20个碳原子，优选包含3至12个碳原子，更优选包含3至6个碳原子。单环环烷基的非限制性实例包括环丙基、环丁基、环戊基、环戊烯基、环己基、环己烯基、环己二烯基、环庚基、环庚三烯基、环辛基等；多环环烷基包括螺环、稠环和桥环的环烷基。
术语“螺环烷基”指5至20元的单环之间共用一个碳原子(称螺原子)的多环基团，其可以含有一个或多个双键，但没有一个环具有完全共轭的π电子系统。优选为6至14元，更优选为7至10元。根据环与环之间共用螺原子的数目将螺环烷基分为单螺环烷基、双螺环烷基或多螺环烷基，优选为单螺环烷基和双螺环烷基。更优选为4元/4元、4元/5元、4元/6元、5元/5元或5元/6元单螺环烷基。螺环烷基的非限制性实例包括：
Figure PCTCN2018086774-appb-000007
术语“稠环烷基”指5至20元，系统中的每个环与体系中的其他环共享毗邻的一对碳原子的全碳多环基团，其中一个或多个环可以含有一个或多个双键，但没有一个环具有完全共轭的π电子系统。优选为6至14元，更优选为7至10元。根据组成环的数目可以分为双环、三环、四环或多环稠环烷基，优选为双环或三环，更优选为5元/5元或5元/6元双环烷基。稠环烷基的非限制性实例包括：
Figure PCTCN2018086774-appb-000008
术语“桥环烷基”指5至20元，任意两个环共用两个不直接连接的碳原子的全碳多环基团，其可以含有一个或多个双键，但没有一个环具有完全共轭的π电子系统。优选为6至14元，更优选为7至10元。根据组成环的数目可以分为双环、三环、四环或多环桥环烷基，优选为双环、三环或四环，更有选为双环或三环。桥环烷基的非限制性实例包括：
Figure PCTCN2018086774-appb-000009
所述环烷基环可以稠合于芳基、杂芳基或杂环烷基环上，其中与母体结构连接在一起的环为环烷基，非限制性实例包括茚满基、四氢萘基、苯并环庚烷基等。 环烷基可以是任选取代的或非取代的，当被取代时，取代基优选为一个或多个以下基团，其独立地选自烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、巯基、羟基、硝基、氰基、环烷基、杂环烷基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基、氧代基、羧基或羧酸酯基。
Figure PCTCN2018086774-appb-000010
术语“烷氧基”指-O-(烷基)和-O-(非取代的环烷基)，其中烷基的定义如上所述。烷氧基的非限制性实例包括：甲氧基、乙氧基、丙氧基、丁氧基、环丙氧基、环丁氧基、环戊氧基、环己氧基。烷氧基可以是任选取代的或非取代的，当被取代时，取代基优选为一个或多个以下基团，其独立地选自烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、巯基、羟基、硝基、氰基、环烷基、杂环烷基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基、羧基或羧酸酯基。
术语“卤代烷基”指被一个或多个卤素取代的烷基，其中烷基如上所定义。
术语“卤代烷氧基”指被一个或多个卤素取代的烷氧基，其中烷氧基如上所定义。
术语“羟基”指-OH基团。
术语“卤素”指氟、氯、溴或碘。
术语“氨基”指-NH 2。
术语“氰基”指-CN。
术语“羧基”指-C(O)OH。
术语“羧酸酯基”指-C(O)O(烷基)或-C(O)O(环烷基)，其中烷基如上所定义。
术语“酰基”指含有-C(O)R基团的化合物，其中R为烷基、环烷基、芳基、杂芳基。
“任选”或“任选地”意味着随后所描述的事件或环境可以但不必发生，该说明包括该事件或环境发生或不发生的场合。例如，“任选被烷基取代的杂环基团”意味着烷基可以但不必须存在，该说明包括杂环基团被烷基取代的情形和杂环基团不被烷基取代的情形。
“取代的”指基团中的一个或多个氢原子，优选为最多5个，更优选为1～3个氢原子彼此独立地被相应数目的取代基取代。不言而喻，取代基仅处在它们的可能的化学位置，本领域技术人员能够在不付出过多努力的情况下确定(通过实验或理论)可能或不可能的取代。例如，具有游离氢的氨基或羟基与具有不饱和(如烯属)键的碳原子结合时可能是不稳定的。
“药物组合物”表示含有一种或多种本文所述化合物或其生理学上/可药用的盐或前体药物与其他化学组分的混合物，以及其他组分例如生理学/可药用的载体 和赋形剂。药物组合物的目的是促进对生物体的给药，利于活性成分的吸收进而发挥生物活性。
“药学上可接受的盐”是指本发明化合物的盐，这类盐用于哺乳动物体内时具有安全性和有效性，且具有应有的生物活性。
本发明化合物的合成方法
为了完成本发明的目的，本发明采用如下技术方案。
本发明通式(I)所示的化合物或其盐的制备方法如下方案1所示。
Figure PCTCN2018086774-appb-000011
步骤1：化合物1a与溴乙烷在碱性条件下在溶剂中反应得到化合物Ib，提供碱性条件的试剂优选碳酸钾；所述溶剂优选DMF；
步骤2：使化合物Ib在盐酸乙醇溶液中在催化剂的存在下发生氧化反应得到化合物Ic，所述催化剂优选吡啶硼烷；
步骤3：将化合物Ic与相应的糖在醇类溶剂中回流得到化合物Id，所述醇类溶剂优选乙醇；
步骤4：使化合物Id在甲苯中在催化剂的存在下发生还原反应得到化合物Ie，所述催化剂优选DDQ；
步骤5：将化合物Ie在碱性条件下水解得到化合物If，提供碱性条件的试剂优选NaOH；
步骤6：将化合物If与化合物Ig在溶剂中在碱和催化剂的存在下发生偶联反应得到通式(I)化合物，所述溶剂优选THF，所述碱优选N-甲基吗啉，所述催化剂优选DCC。
具体实施方式
以下结合实施例进一步描述本发明，但这些实施例并非限制着本发明的范围。
化合物的结构是通过核磁共振(NMR)或/和质谱(MS)来确定的。NMR位移以10 -6(ppm)的单位给出。NMR的测定是用Brukerdps600型核磁仪，测定溶剂为氘代二甲基亚砜(DMSO-d 6)，氘代氯仿(CDCl 3)，氘代甲醇(CD 3OD)，内标为四甲基硅烷(TMS)。
MS的测定用1100Series LC/MSD Trap(ESI)质谱仪(生产商:Agilent)。
制备液相使用lc3000高效液相色谱仪以及lc6000高效液相色谱仪(生产商：创新通恒)。
HPLC的测定使用岛津LC-20AD高压液相色谱仪(Agilent TC-C18 250×4.6mm5vm色谱柱)和岛津LC-2010AHT高压液相色谱仪(Phenomenex C18250×4.6mm5um色谱柱)。
激酶平均抑制率及IC 50值的测定用多功能Cytation3酶标仪(美国Bioteck公司)。
薄层层析硅胶板使用青岛海洋化工GF254硅胶板，薄层色谱法(TLC)使用的硅胶板采用的规格是0.15mm～0.2mm，薄层层析分离纯化产品采用的规格是0.4mm～0.5mm。
柱层析一般使用青岛海洋硅胶100～200目、200～300目硅胶为载体。
本发明的已知的起始原料可以采用或按照本领域已知的方法来合成，或可购买自网化商城、伊诺凯、Sigma、安耐吉化学等公司。
实施例中无特殊说明，反应能够均无需在氩气氛或氮气氛下进行。
实施例中无特殊说明，溶液是指水溶液。
实施例中无特殊说明，反应的温度为室温，为20℃～30℃。
实施例中的反应进程的监测采用薄层色谱法(TLC)，反应所使用的展开剂的体系有：A：二氯甲烷和甲醇体系，B：正己烷和乙酸乙酯体系，C：石油醚和乙酸乙酯体系，D：丙酮，溶剂的体积比根据化合物的极性不同而进行调节。
纯化化合物采用的柱层析的洗脱剂的体系和薄层色谱法的展开剂体系包括：A：二氯甲烷和甲醇体系，B：正己烷和乙酸乙酯体系，C：石油醚和乙酸乙酯体系，溶剂的体积比根据化合物的极性不同而进行调节，也可以加入少量的三乙胺和醋酸等碱性或酸性试剂进行调节。
实施例1(2-(1-((2R,3R,4S,5S,6R)-3,4,5-三羟基-6-羟甲基)四氢-2H-吡喃-2-基)-1H-吲哚-3-基)乙酰基)-D-天冬氨酸的制备
Figure PCTCN2018086774-appb-000012
步骤1：2-(1H-吲哚-3-基)乙酸乙酯(1b)的制备
将2.0g吲哚乙酸溶解于20ml DMF中，然后向其中加入K 2CO 3(1.2当量)。将得到的混合物于室温搅拌反应30分钟，然后向其中缓慢滴加EtBr(1.2当量)。滴加完成后，将反应混合物搅拌回流反应4小时。然后，将反应液过滤，减压浓缩，残余物通过柱层析色谱法纯化，以石油醚：乙酸乙酯5：1为洗脱剂，得到化合物1b 2.17g，产率为94％。
1H-NMR(600MHz):δ8.28(1H,brs,N-H),7.66(1H,d,J＝7.8Hz),7.29(1H,d,J＝8.1Hz),7.22(1H,t,J＝7.5Hz),7.17(1H,t,J＝7.2Hz),7.04(1H,s),4.21(2H,q,J＝7.1Hz),3.81(2H,s),1.30(1H,t,J＝7.1Hz)。
13C-NMR(150MHz):δ172.4,136.0,127.0,123.3,122.0,119.5,118.8,111.3,108.0,60.8,31.4,14.1。
步骤2：2-(二氢吲哚-3-基)乙酸乙酯(1c)的制备
将2.17g化合物1b溶解于10ml浓盐酸-乙醇(1：1)混合溶液中，于0℃缓慢加入5.0当量的吡啶硼烷(BH 3.Py)溶液。将反应液升至室温，并搅拌1小时。将反应液减压浓缩，残余物中加入10％碳酸钠水溶液60ml调PH至8，用乙酸乙酯80ml萃取三次，分取乙酸乙酯层，经柱层析色谱法纯化，以石油醚：乙酸乙酯5：1为洗脱剂，得到0.87g目标化合物1c，产率40％。
1H-NMR(600MHz):δ7.09(1H,d,J＝7.3Hz),7.05(1H,t,J＝7.6Hz),6.72(1H,t,J＝7.4Hz),6.65(1H,d,J＝7.8Hz),4.18(2H,q,J＝7.1Hz),3.77(1H,t,J＝8.8Hz),3.73(1H,m),3.28(1H,dd,J＝8.9,6.7Hz),2.77(1H,dd,J＝21.2,10.6Hz),2.57(1H,dd,J＝16.0,9.1Hz),1.28(1H,t,J＝7.1Hz)。
13C-NMR(150MHz):δ172.5,151.2,131.1,127.8,123.7,118.9,109.9,60.6,53.2,39.0,38.3,14.7。
步骤3：2-(1-((2R,3R,4S,5S,6R)-3,4,5-三羟基-6-(羟甲基)四氢-2H-吡喃-2-基)二氢吲哚-3-基)乙酸乙酯(1d)的制备
将0.87g化合物1c溶解于5ml无水乙醇中，加入D-葡萄糖(1.2当量)，回流反应5小时。反应液过滤后，通过硅胶柱层析色谱法纯化，以二氯甲烷：甲醇10：1为洗脱剂，得到0.96g化合物1d，产率62％。
1H-NMR(600MHz):非对映异构体混合物，比例为1：1。
δ7.06(2H,重叠峰),6.69(2H,重叠峰),4.82(1H,d,J＝8.9Hz),4.18(2H,m),3.93(1H,t,J＝8.8Hz),3.80(1H,m),3.67(2H,m),3.54(2H,m),3.45(1H,dd,J＝9.1,2.7Hz),3.35(2H,重叠峰),2.94(1H,dd,J＝16.2,5.2Hz),2.63(1H,m),1.29(3H,t,J＝7.1Hz)。
δ7.06(2H,重叠峰),6.69(2H,重叠峰),4.82(1H,d,J＝8.9Hz),4.18(2H,m),3.84(1H,t,J＝9.1Hz),3.80(1H,m),3.67(2H,m),3.54(2H,m),3.34(3H,重叠峰),2.63(1H,m),2.55(1H,dd,J＝16.2,9.3Hz),1.25(3H,t,J＝7.1Hz)。
13C-NMR(150MHz):δ174.3,151.6,133.8,129.0,125.3,120.0,109.4,86.9,79.3,79.2,72.1,71.6,62.7,61.7,53.3,40.9,38.1,14.6。
δ174.1,151.2,133.4,128.8,124.4,119.9,109.4,86.7,79.3,79.2,72.1,71.6,62.7,61.6,52.5,39.6,38.0,14.5。
步骤4：2-(1-((2R,3R,4S,5S,6R)-3,4,5-三羟基-6-(羟甲基)四氢-2H-吡喃-2-基)-1H-吲哚-3-基)乙酸乙酯(1e)的制备
将0.96g化合物1d溶解于5ml甲苯中，加入1.1当量的DDQ，室温搅拌反应24小时。将反应液过滤后，通过硅胶柱层析色谱法纯化，以二氯甲烷：甲醇19：1为洗脱剂，得到0.36g化合物1e，产率38％。
1H-NMR(600MHz):δ7.54(2H,t,J＝8.7Hz),7.38(1H,s),7.20(1H,t,J＝8.1Hz),7.10(1H,t,J＝7.8Hz),5.45(1H,d,J＝9.0Hz),4.17(2H,q,J＝7.1Hz),3.91(2H,dt,J＝12.2,5.6Hz),3.78(2H,s),3.72(1H,dd,J＝12.2,5.7Hz),3.60(2H,m),3.52(1H,m),1.27(3H,t,J＝7.1Hz)。
13C-NMR(150MHz):δ174.1,138.3,129.5,125.6,123.0,120.8,120.0,111.5,110.0,87.0,80.5,78.7,73.7,71.1,62.7,61.7,31.8,14.6。
步骤5：2-(1-((2R,3R,4S,5S,6R)-3,4,5-三羟基-6-(羟甲基)四氢-2H-吡喃-2-基)-1H-吲哚-3-基)乙酸(1f)的制备
将0.36g化合物1e溶解于氢氧化钠-乙醇溶液(2M)中，回流反应1小时。反应完成后，用盐酸调PH至1-2，用20ml乙酸乙酯萃取2次。合并有机相，经无水硫酸钠干燥，过滤，并减压浓缩。残余物通过硅胶柱层析色谱法纯化，以二氯甲烷：甲醇3：1为洗脱剂，得到0.31g化合物1f，产率95％。
1H-NMR(600MHz):δ7.53(1H,d,J＝7.8Hz),7.49(1H,d,J＝7.6Hz),7.37(1H,s),7.18(1H,t,J＝7.0Hz),7.08(1H,t,J＝7.0Hz),5.46(1H,d,J＝8.7Hz),3.92(1H,t,8.6),3.88(1H,d,11.9),3.78-3.76(2H,s),3.73-3.68(2H,m),3.65-3.60(2H,m),3.52(1H,t,8.9)。
13C-NMR(150MHz):δ174.5,138.2,129.5,125.5,122.8,121.1,119.5,111.4,109.8,86.6,80.3,78.9,73.8,71.8,62.5,31.6。
步骤6：(2-(1-((2R,3R,4S,5S,6R)-3,4,5-三羟基-6-羟甲基)四氢-2H-吡喃-2-基)-1H-吲哚-3-基)乙酰基)-D-天冬氨酸(1)的制备
将0.31g化合物1f溶解于4ml四氢呋喃溶液中，加入D-天冬氨酸甲基酯(0.282g,1.5当量)、DCC(0.294g,1.5当量)和N-甲基吗啉(0.141g,1.5当量)，并将该反应液于室温搅拌8小时。反应完成后，将反应液减压浓缩。然后向残余物中加入2M NaOH/EtOH溶液5ml，回流反应1小时。反应完成后，用盐酸调节PH至5，然后用10ml乙酸乙酯萃取2次。合并有机相，经无水硫酸钠干燥，过滤，并减压浓缩。残余物通过柱层析色谱法纯化，以二氯甲烷：甲醇5:1作为洗脱溶剂，得到0.33g白色固体终产物1，收率80％。
1H-NMR(600MHz):δ7.52(2H,dd,J＝8.0,3.2Hz),7.36(1H,s),7.17(1H,t,J＝7.7Hz),7.07(1H,t,J＝7.4Hz),5.43(1H,d,J＝9.0Hz),4.75(1H,t,J＝4.8Hz),3.92(1H,m),3.86(1H,dd,J＝12.1,1.7Hz),3.70(3H,m),3.58(2H,m),3.51(1H,m),2.81(2H,m)。
13C-NMR(150MHz):δ174.3,174.2,174.1,138.3,129.4,125.7,123.2,121.1,119.8,111.4,110.3,86.3,80.2,78.7,73.6,71.4,62.3,49.9,36.9,33.3。
实施例2(2-(1-((2R,3R,4S,5S,6R)-3,4,5-三羟基-6-羟甲基)四氢-2H-吡喃-2-基)-1H-吲哚-3-基)乙酰基)-D-谷氨酸的制备
Figure PCTCN2018086774-appb-000013
步骤1：(2-(1-((2R,3R,4S,5S,6R)-3,4,5-三羟基-6-羟甲基)四氢-2H-吡喃-2-基)-1H-吲哚-3-基)乙酰基)-D-谷氨酸(2)的制备
将0.31g化合物1f溶解于4ml四氢呋喃溶液中，加入D-谷氨酸甲基酯(0.306g,1.5当量)、DCC(0.294g,1.5当量)和N-甲基吗啉(0.141g,1.5当量)，并将该反应液于室温搅拌8小时。反应完成后，将反应液减压浓缩。然后向残余物中加入2M NaOH/EtOH溶液5ml，回流反应1小时。反应完成后，用盐酸调节PH至5，然后用10ml乙酸乙酯萃取2次。合并有机相，经无水硫酸钠干燥，过滤，并减压浓缩。残余物通过柱层析色谱法纯化，以二氯甲烷：甲醇5:1作为洗脱溶剂，得到0.36g白色固体化合物2，收率80％。
1H-NMR(600MHz):δ7.54(2H,dd,J＝11.4,7.9Hz),7.37(1H,s),7.17(1H,m),7.09(1H,m),5.45(1H,m),4.47(1H,m),3.94(1H,dd,J＝16.1,8.1Hz),3.86(1H,d,J＝12.1Hz),3.71(3H,m),3.60(3H,m),2.38(2H,m),2.16(1H,m),1.94(1H,m)。
13C-NMR(150MHz):δ176.6,175.2,174.8,138.5,129.7,126.1,123.3,1281.2,119.9,111.6,110.7,86.7,80.5,78.7,73.8,71.5,62.9,49.5,33.4,31.3,27.8。
实施例3(2-(5-甲基-1-((2R,3R,4S,5S,6R)-3,4,5-三羟基-6-羟甲基)四氢-2H-吡喃-2-基)-1H-吲哚-3-基)乙酰基)-D-天冬氨酸的制备
Figure PCTCN2018086774-appb-000014
Figure PCTCN2018086774-appb-000015
步骤1：2-(5-甲基-1H-吲哚-3-基)乙酸乙酯(3b)的制备
将2.0g 5-甲基吲哚乙酸溶解于20ml DMF中，然后向其中加入K 2CO 3(1.2当量)。将得到的混合物于室温搅拌反应30分钟，然后向其中缓慢滴加EtBr(1.2当量)。滴加完成后，将反应混合物搅拌回流反应4小时。然后，将反应液过滤，减压浓缩，残余物通过柱层析色谱法纯化，以石油醚：乙酸乙酯5：1为洗脱剂，得到化合物3b 2.18g，产率为95％。
步骤2：2-(5-甲基-二氢吲哚-3-基)乙酸乙酯(3c)的制备
将2.18g化合物3b溶解于10ml浓盐酸-乙醇(1：1)混合溶液中，于0℃缓慢加入5.0当量的吡啶硼烷(BH 3.Py)溶液。将反应液升至室温，并搅拌1小时。将反应液减压浓缩，残余物中加入10％碳酸钠水溶液60ml调PH至8，用乙酸乙酯80ml萃取三次，分取乙酸乙酯层，通过柱层析色谱法纯化，以石油醚：乙酸乙酯5：1为洗脱剂，得到1.16g目标化合物3c，产率53％。
步骤3：2-(1-((2R,3R,4S,5S,6R)-3,4,5-三羟基-6-(羟甲基)四氢-2H-吡喃-2-基)5-甲基二氢吲哚-3-基)乙酸乙酯(3d)的制备
将1.16g化合物3c溶解于5ml无水乙醇中，加入D-葡萄糖(1.2当量)，回流反应5小时。反应液过滤后，通过硅胶柱层析色谱法纯化，以二氯甲烷：甲醇10：1为洗脱剂，得到1.20g化合物3d，产率65％。
步骤4：2-(1-((2R,3R,4S,5S,6R)-3,4,5-三羟基-6-(羟甲基)四氢-2H-吡喃-2-基)5-甲基-1H-吲哚-3-基)乙酸乙酯(3e)的制备
将1.20g化合物3d溶解于5ml甲苯中，加入1.1当量的DDQ，室温搅拌反应24小时。将反应液过滤后，通过硅胶柱层析色谱法纯化，以二氯甲烷：甲醇19：1为洗脱剂，得到0.51g化合物3e，产率43％。
步骤5：2-(1-((2R,3R,4S,5S,6R)-3,4,5-三羟基-6-(羟甲基)四氢-2H-吡喃-2-基)-5-甲基-1H-吲哚-3-基)乙酸(3f)的制备
将0.51g化合物3e溶解于氢氧化钠-乙醇溶液(2M)中，回流反应1小时。反应完成后，用盐酸调PH至1-2，用20ml乙酸乙酯萃取2次。合并有机相，用无水硫酸钠干燥，过滤，并减压浓缩。残余物通过硅胶柱层析色谱法纯化，以二氯甲烷：甲醇3：1为洗脱剂，得到0.43g化合物3f，产率92％。
步骤6：(2-(5-甲基-1-((2R,3R,4S,5S,6R)-3,4,5-三羟基-6-羟甲基)四氢-2H-吡喃-2-基)-1H-吲哚-3-基)乙酰基)-D-天冬氨酸(3)的制备
将0.43g化合物3f溶解于4ml四氢呋喃溶液中，加入D-天冬氨酸甲基酯(1.5当量)、DCC(1.5当量)和N-甲基吗啉(1.5当量)，并将该反应液于室温搅拌8小时。反应完成后，将反应液减压浓缩。然后向残余物中加入2M NaOH/EtOH溶液5ml，回流反应1小时。反应完成后，用盐酸调节PH至5，然后用10ml乙酸乙酯萃取2次。合并有机相，经无水硫酸钠干燥，过滤，并减压浓缩。残余物通过柱层析色谱法纯化，以二氯甲烷：甲醇5:1作为洗脱溶剂，得到0.50g白色固体终产物3，收率85％。
实施例4(2-(5-甲氧基-1-((2R,3R,4S,5S,6R)-3,4,5-三羟基-6-羟甲基)四氢-2H-吡喃-2-基)-1H-吲哚-3-基)乙酰基)-D-天冬氨酸的制备
Figure PCTCN2018086774-appb-000016
Figure PCTCN2018086774-appb-000017
步骤1：2-(5-甲氧基-1H-吲哚-3-基)乙酸乙酯(4b)的制备
将2.0g 5-甲氧基吲哚乙酸溶解于20ml DMF中，然后向其中加入K 2CO 3(1.2当量)。将得到的混合物于室温搅拌反应30分钟，然后向其中缓慢滴加EtBr(1.2当量)。滴加完成后，将反应混合物搅拌回流反应4小时。然后，将反应液过滤，减压浓缩，残余物通过柱层析色谱法纯化，以石油醚：乙酸乙酯5：1为洗脱剂，得到化合物4b 2.04g，产率为90％。
步骤2：2-(5-甲氧基-二氢吲哚-3-基)乙酸乙酯(4c)的制备
将2.04g化合物4b溶解于10ml浓盐酸-乙醇(1：1)混合溶液中，于0℃缓慢加入5.0当量的吡啶硼烷(BH 3.Py)溶液。将反应液升至室温，并搅拌1小时。将反应液减压浓缩，残余物中加入10％碳酸钠水溶液60ml调PH至8，用乙酸乙酯80ml萃取三次，分取乙酸乙酯层，经柱层析色谱法纯化，以石油醚：乙酸乙酯5：1为洗脱剂，得到1.03g目标化合物4c，产率50％。
步骤3：2-(1-((2R,3R,4S,5S,6R)-3,4,5-三羟基-6-(羟甲基)四氢-2H-吡喃-2-基)5-甲氧基二氢吲哚-3-基)乙酸乙酯(4d)的制备
将1.03g化合物4c溶解于5ml无水乙醇中，加入D-葡萄糖(1.2当量)，回流反应5小时。反应液过滤后，通过硅胶柱层析色谱法纯化，以二氯甲烷：甲醇10：1为洗脱剂，得到1.16g化合物4d，产率73％。
步骤4：2-(1-((2R,3R,4S,5S,6R)-3,4,5-三羟基-6-(羟甲基)四氢-2H-吡喃-2-基)5-甲氧基-1H-吲哚-3-基)乙酸乙酯(4e)的制备
将1.16g化合物4d溶解于5ml甲苯中，加入1.1当量的DDQ，室温搅拌反应24小时。将反应液过滤后，通过硅胶柱层析色谱法纯化，以二氯甲烷：甲醇19：1为洗脱剂，得到0.45g化合物4e，产率39％。
步骤5：2-(1-((2R,3R,4S,5S,6R)-3,4,5-三羟基-6-(羟甲基)四氢-2H-吡喃-2-基)-5-甲氧基-1H-吲哚-3-基)乙酸(4f)的制备
将0.45g化合物4e溶解于氢氧化钠-乙醇溶液(2M)中，回流反应1小时。反应完成后，用盐酸调PH至1-2，用20ml乙酸乙酯萃取2次。合并有机相，经无水硫酸钠干燥，过滤，并减压浓缩。残余物通过硅胶柱层析色谱法纯化，以二氯甲烷：甲醇3：1为洗脱剂，得到0.40g化合物4f，产率96％。
步骤6：(2-(5-甲氧基-1-((2R,3R,4S,5S,6R)-3,4,5-三羟基-6-羟甲基)四氢-2H-吡喃-2-基)-1H-吲哚-3-基)乙酰基)-D-天冬氨酸(4)的制备
将0.40g化合物4f溶解于4ml四氢呋喃溶液中，加入天冬氨酸甲基酯(1.5当量)、DCC(1.5当量)和N-甲基吗啉(1.5当量)，并将该反应液于室温搅拌8小时。反应完成后，将反应液减压浓缩。然后向残余物中加入2M NaOH/EtOH溶液5ml，回流反应1小时。反应完成后，用盐酸调节PH至5，然后用10ml乙酸乙酯萃取2次。合并有机相，经无水硫酸钠干燥，过滤，并减压浓缩。残余物通过柱层析色谱法纯化，以二氯甲烷：甲醇5:1作为洗脱溶剂，得到0.45g白色固体终产物4，收率85％。
实施例5(2-(5-氯-1-((2R,3R,4S,5S,6R)-3,4,5-三羟基-6-羟甲基)四氢-2H-吡喃-2-基)-1H-吲哚-3-基)乙酰基)-D-天冬氨酸的制备
Figure PCTCN2018086774-appb-000018
Figure PCTCN2018086774-appb-000019
步骤1：2-(5-氯-1H-吲哚-3-基)乙酸乙酯(5b)的制备
将2.0g 5-氯吲哚乙酸溶解于20ml DMF中，然后向其中加入K 2CO 3(1.2当量)。将得到的混合物于室温搅拌反应30分钟，然后向其中缓慢滴加EtBr(1.2当量)。滴加完成后，将反应混合物搅拌回流反应4小时。然后，将反应液过滤，减压浓缩，残余物通过柱层析色谱法纯化，以石油醚：乙酸乙酯5：1为洗脱剂，得到化合物5b 2.10g，产率为93％。
步骤2：2-(5-氯-二氢吲哚-3-基)乙酸乙酯(5c)的制备
将2.10g化合物5b溶解于10ml浓盐酸-乙醇(1：1)混合溶液中，于0℃缓慢加入5.0当量的吡啶硼烷(BH 3.Py)溶液。将反应液升至室温，并搅拌1小时。将反应液减压浓缩，残余物中加入10％碳酸钠水溶液60ml调PH至8，用乙酸乙酯80ml萃取三次，分取乙酸乙酯层，经柱层析色谱法纯化，以石油醚：乙酸乙酯5：1为洗脱剂，得到0.98g目标化合物5c，产率46％。
步骤3：2-(1-((2R,3R,4S,5S,6R)-3,4,5-三羟基-6-(羟甲基)四氢-2H-吡喃-2-基)5-氯-二氢吲哚-3-基)乙酸乙酯(5d)的制备
将0.98g化合物5c溶解于5ml无水乙醇中，加入D-葡萄糖(1.2当量)，回流反应5小时。反应液过滤后，通过硅胶柱层析色谱法纯化，以二氯甲烷：甲醇10：1为洗脱剂，得到1.05g化合物5d，产率70％。
步骤4：2-(1-((2R,3R,4S,5S,6R)-3,4,5-三羟基-6-(羟甲基)四氢-2H-吡喃-2-基)5-氯-1H-吲哚-3-基)乙酸乙酯(5e)的制备
将1.05g化合物5d溶解于5ml甲苯中，加入1.1当量的DDQ，室温搅拌反应24小时。将反应液过滤后，通过硅胶柱层析色谱法纯化，以二氯甲烷：甲醇19：1为洗脱剂，得到0.43g化合物5e，产率41％。
步骤5：2-(1-((2R,3R,4S,5S,6R)-3,4,5-三羟基-6-(羟甲基)四氢-2H-吡喃-2-基)-5-氯-1H-吲哚-3-基)乙酸(5f)的制备
将0.43g化合物5e溶解于氢氧化钠-乙醇溶液(2M)中，回流反应1小时。反应完成后，用盐酸调PH至1-2，用20ml乙酸乙酯萃取2次。合并有机相，经无水硫酸钠干燥，过滤，并减压浓缩。残余物通过硅胶柱层析色谱法纯化，以二氯甲烷：甲醇3：1为洗脱剂，得到0.38g化合物5f，产率96％。
步骤6：(2-(5-氯-1-((2R,3R,4S,5S,6R)-3,4,5-三羟基-6-羟甲基)四氢-2H-吡喃-2-基)-1H-吲哚-3-基)乙酰基)-D-天冬氨酸(5)的制备
将0.38g化合物5f溶解于4ml四氢呋喃溶液中，加入D-天冬氨酸甲基酯(1.5当量)、DCC(1.5当量)和N-甲基吗啉(1.5当量)，并将该反应液于室温搅拌8小时。反应完成后，将反应液减压浓缩。然后向残余物中加入2M NaOH/EtOH溶液5ml，回流反应1小时。反应完成后，用盐酸调节PH至5，然后用10ml乙酸乙酯萃取2次。合并有机相，经无水硫酸钠干燥，过滤，并减压浓缩。残余物通过柱层析色谱法纯化，以二氯甲烷：甲醇5:1作为洗脱溶剂，得到0.45g白色固体终产物5，收率88％。
实施例6(2-(5-溴-1-((2R,3R,4S,5S,6R)-3,4,5-三羟基-6-羟甲基)四氢-2H-吡喃-2-基)-1H-吲哚-3-基)乙酰基)-D-天冬氨酸的制备
Figure PCTCN2018086774-appb-000020
Figure PCTCN2018086774-appb-000021
步骤1：2-(5-溴-1H-吲哚-3-基)乙酸乙酯(6b)的制备
将2.0g 5-溴吲哚乙酸溶解于20ml DMF中，然后向其中加入K 2CO 3(1.2当量)。将得到的混合物于室温搅拌反应30分钟，然后向其中缓慢滴加EtBr(1.2当量)。滴加完成后，将反应混合物搅拌回流反应4小时。然后，将反应液过滤，减压浓缩，残余物通过柱层析色谱法纯化，以石油醚：乙酸乙酯5：1为洗脱剂，得到化合物6b 2.16g，产率为97％。
步骤2：2-(5-溴-二氢吲哚-3-基)乙酸乙酯(6c)的制备
将2.16g化合物6b溶解于10ml浓盐酸-乙醇(1：1)混合溶液中，于0℃缓慢加入5.0当量的吡啶硼烷(BH 3.Py)溶液。将反应液升至室温，并搅拌1小时。将反应液减压浓缩，残余物中加入10％碳酸钠水溶液60ml调PH至8，用乙酸乙酯80ml萃取三次，分取乙酸乙酯层，经柱层析色谱法纯化，以石油醚：乙酸乙酯5：1为洗脱剂，得到0.81g目标化合物6c，产率37％。
步骤3：2-(1-((2R,3R,4S,5S,6R)-3,4,5-三羟基-6-(羟甲基)四氢-2H-吡喃-2-基)5-溴-二氢吲哚-3-基)乙酸乙酯(6d)的制备
将0.81g化合物6c溶解于5ml无水乙醇中，加入D-葡萄糖(1.2当量)，回流反应5小时。反应液过滤后，以硅胶伴样，通过硅胶柱层析色谱法纯化，以二氯甲烷：甲醇10：1为洗脱剂，得到0.80g化合物6d，产率67％。
步骤4：2-(1-((2R,3R,4S,5S,6R)-3,4,5-三羟基-6-(羟甲基)四氢-2H-吡喃-2-基)5-溴-1H-吲哚-3-基)乙酸乙酯(6e)的制备
将0.80g化合物6d溶解于5ml甲苯中，加入1.1当量的DDQ，室温搅拌反应24小时。将反应液过滤后，通过硅胶柱层析色谱法纯化，以二氯甲烷：甲醇19：1为洗脱剂，得到0.37g化合物6e，产率46％。
步骤5：2-(1-((2R,3R,4S,5S,6R)-3,4,5-三羟基-6-(羟甲基)四氢-2H-吡喃-2-基)-5-溴-1H-吲哚-3-基)乙酸(6f)的制备
将0.36g化合物6e溶解于氢氧化钠-乙醇溶液(2M)中，回流反应1小时。反应完成后，用盐酸调PH至1-2，用20ml乙酸乙酯萃取2次。合并有机相，经无水硫酸钠干燥，过滤，并减压浓缩。残余物通过硅胶柱层析色谱法纯化，以二氯甲烷：甲醇3：1为洗脱剂，得到0.33g化合物6f，产率98％。
步骤6：(2-(5-溴-1-((2R,3R,4S,5S,6R)-3,4,5-三羟基-6-羟甲基)四氢-2H-吡喃-2-基)-1H-吲哚-3-基)乙酰基)-D-天冬氨酸(6)的制备
将0.33g化合物6f溶解于4ml四氢呋喃溶液中，加入D-天冬氨酸甲基酯(1.5当量)、DCC(1.5当量)和N-甲基吗啉(1.5当量)，并将该反应液于室温搅拌8小时。反应完成后，将反应液减压浓缩。然后向残余物中加入2M NaOH/EtOH溶液5ml，回流反应1小时。反应完成后，用盐酸调节PH至5，然后用10ml乙酸乙酯萃取2次。合并有机相，经无水硫酸钠干燥，过滤，并减压浓缩。残余物通过柱层析色谱法纯化，以二氯甲烷：甲醇5:1作为洗脱溶剂，得到0.39g白色固体终产物6，收率91％。
实施例7(2-(7-甲基-1-((2R,3R,4S,5S,6R)-3,4,5-三羟基-6-羟甲基)四氢-2H-吡喃-2-基)-1H-吲哚-3-基)乙酰基)-D-天冬氨酸的制备
Figure PCTCN2018086774-appb-000022
Figure PCTCN2018086774-appb-000023
步骤1：2-(7-甲基-1H-吲哚-3-基)乙酸乙酯(7b)的制备
将2.0g 7-甲基吲哚乙酸溶解于20ml DMF中，然后向其中加入K 2CO 3(1.2当量)。将得到的混合物于室温搅拌反应30分钟，然后向其中缓慢滴加EtBr(1.2当量)。滴加完成后，将反应混合物搅拌回流反应4小时。然后，将反应液过滤，减压浓缩，残余物通过柱层析色谱法纯化，以石油醚：乙酸乙酯5：1为洗脱剂，得到化合物7b 2.00g，产率为87％。
步骤2：2-(7-甲基-二氢吲哚-3-基)乙酸乙酯(7c)的制备
将2.00g化合物7b溶解于10ml浓盐酸-乙醇(1：1)混合溶液中，于0℃缓慢加入5.0当量的吡啶硼烷(BH 3.Py)溶液。将反应液升至室温，并搅拌1小时。将反应液减压浓缩，残余物中加入10％碳酸钠水溶液60ml调PH至8，用乙酸乙酯80ml萃取三次，分取乙酸乙酯层，经柱层析色谱法纯化，以石油醚：乙酸乙酯5：1为洗脱剂，得到1.11g目标化合物7c，产率55％。
步骤3：2-(1-((2R,3R,4S,5S,6R)-3,4,5-三羟基-6-(羟甲基)四氢-2H-吡喃-2-基)7-甲基-二氢吲哚-3-基)乙酸乙酯(7d)的制备
将1.11g化合物7c溶解于5ml无水乙醇中，加入D-葡萄糖(1.2当量)，回流反应5小时。反应液过滤后，通过硅胶柱层析色谱法纯化，以二氯甲烷：甲醇10：1为洗脱剂，得到1.11g化合物7d，产率63％。
步骤4：2-(1-((2R,3R,4S,5S,6R)-3,4,5-三羟基-6-(羟甲基)四氢-2H-吡喃-2-基)7-甲基-1H-吲哚-3-基)乙酸乙酯(7e)的制备
将1.11g化合物7d溶解于5ml甲苯中，加入1.1当量的DDQ，室温搅拌反应24小时。将反应液过滤后，通过硅胶柱层析色谱法纯化，以二氯甲烷：甲醇19：1为洗脱剂，得到0.44g化合物7e，产率40％。
步骤5：2-(1-((2R,3R,4S,5S,6R)-3,4,5-三羟基-6-(羟甲基)四氢-2H-吡喃-2-基)-7-甲基-1H-吲哚-3-基)乙酸(7f)的制备
将0.44g化合物7e溶解于氢氧化钠-乙醇溶液(2M)中，回流反应1小时。反应完成后，用盐酸调PH至1-2，用20ml乙酸乙酯萃取2次。合并有机相，经无水硫酸钠干燥，过滤，并减压浓缩。残余物通过硅胶柱层析色谱法纯化，以二氯甲烷：甲醇3：1为洗脱剂，得到0.39g化合物7f，产率95％。
步骤6：(2-(7-甲基-1-((2R,3R,4S,5S,6R)-3,4,5-三羟基-6-羟甲基)四氢-2H-吡喃-2-基)-1H-吲哚-3-基)乙酰基)-D-天冬氨酸(7)的制备
将0.39g化合物7f溶解于4ml四氢呋喃溶液中，加入D-天冬氨酸甲基酯(1.5当量)、DCC(1.5当量)和N-甲基吗啉(1.5当量)，并将该反应液于室温搅拌8小时。反应完成后，将反应液减压浓缩。然后向残余物中加入2M NaOH/EtOH溶液5ml，回流反应1小时。反应完成后，用盐酸调节PH至5，然后用10ml乙酸乙酯萃取2次。合并有机相，经无水硫酸钠干燥，过滤，并减压浓缩。残余物通过柱层析色谱法纯化，以二氯甲烷：甲醇5:1作为洗脱溶剂，得到0.47g白色固体终产物7，收率89％。
实施例8(2-(7-甲氧基-1-((2R,3R,4S,5S,6R)-3,4,5-三羟基-6-羟甲基)四氢-2H-吡喃-2-基)-1H-吲哚-3-基)乙酰基)-D-天冬氨酸的制备
Figure PCTCN2018086774-appb-000024
Figure PCTCN2018086774-appb-000025
步骤1：2-(7-甲氧基-1H-吲哚-3-基)乙酸乙酯(8b)的制备
将2.0g 7-甲氧基吲哚乙酸溶解于20ml DMF中，然后向其中加入K 2CO 3(1.2当量)。将得到的混合物于室温搅拌反应30分钟，然后向其中缓慢滴加EtBr(1.2当量)。滴加完成后，将反应混合物搅拌回流反应4小时。然后，将反应液过滤，减压浓缩，残余物通过柱层析色谱法纯化，以石油醚：乙酸乙酯5：1为洗脱剂，得到化合物8b 2.06g，产率为91％。
步骤2：2-(7-甲氧基-二氢吲哚-3-基)乙酸乙酯(8c)的制备
将2.06g化合物8b溶解于10ml浓盐酸-乙醇(1：1)混合溶液中，于0℃缓慢加入5.0当量的吡啶硼烷(BH 3.Py)溶液。将反应液升至室温，并搅拌1小时。将反应液减压浓缩，残余物中加入10％碳酸钠水溶液60ml调PH至8，用乙酸乙酯80ml萃取三次，分取乙酸乙酯层，经柱层析色谱法纯化，以石油醚：乙酸乙酯5：1为洗脱剂，得到1.00g目标化合物8c，产率48％。
步骤3：2-(1-((2R,3R,4S,5S,6R)-3,4,5-三羟基-6-(羟甲基)四氢-2H-吡喃-2-基)7-甲氧基二氢吲哚-3-基)乙酸乙酯(8d)的制备
将1.00g化合物8c溶解于5ml无水乙醇中，加入D-葡萄糖(1.2当量)，回流反应5小时。反应液过滤后，通过硅胶柱层析色谱法纯化，以二氯甲烷：甲醇10：1为洗脱剂，得到1.16g化合物8d，产率75％。
步骤4：2-(1-((2R,3R,4S,5S,6R)-3,4,5-三羟基-6-(羟甲基)四氢-2H-吡喃-2-基)7-甲氧基-1H-吲哚-3-基)乙酸乙酯(8e)的制备
将1.16g化合物8d溶解于5ml甲苯中，加入1.1当量的DDQ，室温搅拌反应24小时。将反应液过滤后，通过硅胶柱层析色谱法纯化，以二氯甲烷：甲醇19：1为洗脱剂，得到0.32g化合物8e，产率28％。
步骤5：2-(1-((2R,3R,4S,5S,6R)-3,4,5-三羟基-6-(羟甲基)四氢-2H-吡喃-2-基)-7-甲氧基-1H-吲哚-3-基)乙酸(8f)的制备
将0.32g化合物8e溶解于氢氧化钠-乙醇溶液(2M)中，回流反应1小时。反应完成后，用盐酸调PH至1-2，用20ml乙酸乙酯萃取2次。合并有机相，经无水硫酸钠干燥，过滤，并减压浓缩。残余物通过硅胶柱层析色谱法纯化，以二氯甲烷：甲醇3：1为洗脱剂，得到0.28g化合物8f，产率96％。
步骤6：(2-(7-甲氧基-1-((2R,3R,4S,5S,6R)-3,4,5-三羟基-6-羟甲基)四氢-2H-吡喃-2-基)-1H-吲哚-3-基)乙酰基)-D-天冬氨酸(8)的制备
将0.28g化合物8f溶解于4ml四氢呋喃溶液中，加入D-天冬氨酸甲基酯(1.5当量)、DCC(1.5当量)和N-甲基吗啉(1.5当量)，并将该反应液于室温搅拌8小时。反应完成后，将反应液减压浓缩。然后向残余物中加入2M NaOH/EtOH溶液5ml，回流反应1小时。反应完成后，用盐酸调节PH至5，然后用10ml乙酸乙酯萃取2次。合并有机相，经无水硫酸钠干燥，过滤，并减压浓缩。残余物通过柱层析色谱法纯化，以二氯甲烷：甲醇5:1作为洗脱溶剂，得到0.33g白色固体终产物8，收率86％。
实施例9(2-(5-甲基-1-((2R,3R,4S,5S,6R)-3,4,5-三羟基-6-羟甲基)四氢-2H-吡喃-2-基)-1H-吲哚-3-基)乙酰基)-D-谷氨酸的制备
Figure PCTCN2018086774-appb-000026
Figure PCTCN2018086774-appb-000027
步骤1：(2-(5-甲基-1-((2R,3R,4S,5S,6R)-3,4,5-三羟基-6-羟甲基)四氢-2H-吡喃-2-基)-1H-吲哚-3-基)乙酰基)-D-谷氨酸(9)的制备
将0.43g化合物3f溶解于4ml四氢呋喃溶液中，加入D-谷氨酸甲基酯(1.5当量)、DCC(1.5当量)和N-甲基吗啉(1.5当量)，并将该反应液于室温搅拌8小时。反应完成后，将反应液减压浓缩。然后向残余物中加入2M NaOH/EtOH溶液5ml，回流反应1小时。反应完成后，用盐酸调节PH至5，然后用10ml乙酸乙酯萃取2次。合并有机相，经无水硫酸钠干燥，过滤，并减压浓缩。残余物通过柱层析色谱法纯化，以二氯甲烷：甲醇5:1作为洗脱溶剂，得到0.53g白色固体终产物9，收率87％。
实施例10(2-(5-氯-1-((2R,3R,4S,5S,6R)-3,4,5-三羟基-6-羟甲基)四氢-2H-吡喃-2-基)-1H-吲哚-3-基)乙酰基)-D-谷氨酸的制备
Figure PCTCN2018086774-appb-000028
步骤1：(2-(5-氯-1-((2R,3R,4S,5S,6R)-3,4,5-三羟基-6-羟甲基)四氢-2H-吡喃-2-基)-1H-吲哚-3-基)乙酰基)-D-谷氨酸(10)的制备
将0.38g化合物5f溶解于4ml四氢呋喃溶液中，加入D-谷氨酸甲基酯(1.5当量)、DCC(1.5当量)和N-甲基吗啉(1.5当量)，并将该反应液于室温搅拌8小时。反应完成后，将反应液减压浓缩。然后向残余物中加入2M NaOH/EtOH溶液5ml，回流反应1小时。反应完成后，用盐酸调节PH至5，然后用10ml乙酸乙酯萃取2次。合并有机相，经无水硫酸钠干燥，过滤，并减压浓缩。残余物通过柱层析色谱法纯化，以二氯甲烷：甲醇5:1作为洗脱溶剂，得到0.45g白色固体终产物10，收率86％。
试验例1氨水引咳试验
试验动物：昆明种小鼠，体重18-22g，雌雄各半。购自北京维通利华实验动物技术有限责任公司，实验动物生产许可证号：SCXK-(京)2012-001。
试验试剂：磷酸可待因(欧化药业有限公司)。
仪器设备：YC-Y800医用超声雾化器(北京亚都科技股份有限公司产品，京药器监(准)京99第223145号)；UV-2450型紫外可见分光光度计(日本岛津公司产品)；UX420S动物小天平(日本岛津公司产品)；千分之一电子天平(德国sartorius公司产品)。
试验方法：
将小鼠适应性喂养饲养3天后，进行筛选。预热超声雾化器后，加入现配的40ml氨水溶液(12.5％)。将小鼠放入容积为1000ml的烧杯中，烧杯口用保鲜膜密闭，并开两个口(其一用于插入超声雾化器出口管，另一为通风小孔)。将超声雾化器以最小喷雾力度持续通入氨气60秒后，立即关闭并迅速打开保鲜膜，使其中氨气自然扩散。剔除三分钟内咳嗽次数少于10次及多于80次者。将合格小鼠随机分组：空白对照组、本发明化合物组和磷酸可待因阳性对照组。以上各组均按体重灌胃给药，空白对照组给予等容量蒸馏水，每日1次，连续5天，于末次给药1小时后，将小鼠逐一置于倒置5L密封玻璃钟罩内，接受恒压氨水喷雾刺激，刺激15秒后停止(氨水喷雾10mL/次，每次1只小鼠，1次1换氨水)，立即取出小鼠，观察小鼠引咳潜伏期(从开始喷雾到产生咳嗽的时间)及2分钟内的咳嗽次数(小鼠咳嗽以剧烈收缩腹肌并张嘴为准，时可闻到轻微的咳嗽声)。
统计方法：实验数据，运用SPSS 10.0统计软件进行数据分析，组间比较采用t检验。
本发明化合物和磷酸可待因的用量以及观察结果如下表1所示。
表1本发明化合物对氨水致咳小鼠的镇咳作用结果
Figure PCTCN2018086774-appb-000030
Figure PCTCN2018086774-appb-000031
注：与空白对照组比较， *P<0.05, **P<0.01.
结论：由表1可知，本发明化合物对于氨水诱导的小鼠咳嗽有明显抑制作用，其能够延长引咳潜伏期并减少咳嗽次数，与空白对照组相比具有统计学显著差异，其效果与阳性对照药物磷酸可待因相近。
试验例2枸橼酸引咳试验
试验动物：豚鼠，180-220g，雌雄各半。购自北京维通利华实验动物技术有限责任公司。
试验试剂：磷酸可待因(欧化药业有限公司)。
仪器设备与试验例1相同。
试验方法：
将豚鼠适应性喂养1天后进行初筛。将豚鼠逐一置于倒置5L密封玻璃钟罩内，接受恒压喷雾刺激(17.5％枸橼酸溶液)，持续1分钟，记录自喷雾起5分钟内咳嗽次数，挑选出多于10次的豚鼠为合格实验动物。将合格豚鼠随机分组：空白对照组、本发明化合物组和磷酸可待因阳性对照组。以上各组均按体重灌胃给药，空白对照组给予等容量蒸馏水，连续灌胃给药5天，末次给药1小时后，将豚鼠放入倒置5L密封玻璃钟罩内，开动雾化器30秒，观察豚鼠咳嗽潜伏期(注入17.5％枸橼酸开始，至发生咳嗽所需时间为潜伏期)和5分钟内的咳嗽次数。
统计方法：实验数据，运用SPSS 10.0统计软件进行数据分析，组间比较采用t检验。
本发明化合物和磷酸可待因的用量以及观察结果如下表2所示。
表2本发明化合物对枸橼酸致豚鼠的止咳作用结果
Figure PCTCN2018086774-appb-000032
Figure PCTCN2018086774-appb-000033
Figure PCTCN2018086774-appb-000034
注：与空白对照组比较， *P<0.05, **P<0.01.
结论：从表2可知，本发明化合物对于枸橼酸诱导的小鼠咳嗽有明显抑制作用，其能够延长引咳潜伏期并减少咳嗽次数，与空白对照组相比具有统计学显著差异，其效果也优于阳性对照药物磷酸可待因。
试验例3本发明化合物的化痰作用
试验动物：昆明种小鼠，体重18-22g，雌雄各半。购自北京维通利华实验动物技术有限责任公司。
试验试剂：氯化铵(广州化学试剂厂)
仪器设备与试验例1相同。
试验方法：
参照李仪奎化痰实验方法，将小鼠正常饲养3天后，随机分为：空白对照组、本发明化合物组和氯化铵阳性对照组。各组小鼠灌服等容量的药或蒸馏水，连续5天，于末次给药后30分钟，按0.1mL/10g腹腔注射2.5％酚红，30分钟后处死动物，分离气管段，放入盛有生理盐水的试管中，加入1.0mol/L的氢氧化钠0.1mL。用UV-2450型分光光度计于波长546nm处测量吸光度A值，并根据酚红标准曲线计算酚红排出量，比较组间差异的显著程度。
统计方法：实验数据，运用SPSS 10.0统计软件进行数据分析，组间比较采用t检验。
本发明化合物和氯化铵的用量以及观察结果如下表3所示。
表3本发明化合物对小鼠气管酚红排泄量的影响
Figure PCTCN2018086774-appb-000035
Figure PCTCN2018086774-appb-000036
Figure PCTCN2018086774-appb-000037
注：与空白对照组比较， *P<0.05, **P<0.01.
结论：从表3可知，本发明化合物能够显著增加酚红排泄量，具有祛痰作用，与空白对照组相比具有统计学显著差异，其效果也近似于阳性对照药物氯化铵。
试验例4本发明化合物对哮喘的作用
试验动物：豚鼠，180-220g，雌雄各半。购自北京维通利华实验动物技术有限责任公司。
试验试剂：氨茶碱溶液(广州明兴制药有限公司)，磷酸组胺(上海楷洋生物技术有限公司)
仪器设备：402AI超声雾化器(江苏鱼跃医疗设备股份有限公司)、5000ml玻璃罩、秒表。
试验方法：
将豚鼠适应性喂养1天后进行初筛。将豚鼠逐一置于倒置5L密封玻璃钟罩中，待豚鼠安静后，恒压喷入磷酸组胺15秒。停止喷雾后观察6分钟内引喘潜伏期，若在150秒内出现喘息性抽搐者为合格实验动物。将合格豚鼠随机分为：空白对照组、本发明化合物组和氨茶碱阳性对照组。给药每天一次连续3天，末次给药1小时后，使豚鼠吸入磷酸组胺，记录豚鼠出现抽搐、跌倒的时间为潜伏期(喷雾开始到跌倒时间)，连续观察6分钟，6分钟不跌倒的以360秒计。统计比较对照组与给药组潜伏期长短。
统计方法：实验数据，运用SPSS 10.0统计软件进行数据分析，组间比较采用t检验。
本发明化合物和氨茶碱的用量以及观察结果如下表4所示。
表4本发明化合物对喷雾所致豚鼠哮喘的影响
Figure PCTCN2018086774-appb-000038
Figure PCTCN2018086774-appb-000039
Figure PCTCN2018086774-appb-000040
注：与空白对照组比较， *P<0.05, **P<0.01.
结论：由表4可知，本发明化合物其能够显著延长潜伏期，具有平喘作用，与空白对照组相比具有统计学显著差异，其效果也优于阳性对照药物氨茶碱。

Claims (13)

  1. 一种通式(I)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其药学上可接受的盐，
    Figure PCTCN2018086774-appb-100001
    其中，
    R 1选自氢、卤素、羟基、氨基、氰基、烷基、烷氧基、卤代烷基、卤代烷氧基或环烷基；
    R 2选自氢、卤素、烷基、烷氧基、卤代烷基、卤代烷氧基或环烷基；
    R 3选自五碳糖或六碳糖；
    n为1至4的整数；
    m为1至4的整数。
  2. 根据权利要求1所述的通式(I)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其药学上可接受的盐，其为通式(II)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其药学上可接受的盐，
    Figure PCTCN2018086774-appb-100002
    其中，R 1、R 2、R 3、m和n如权利要求1所定义。
  3. 根据权利要求1或2所述的通式(I)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其药学上可接受的盐，其中，R 1选自氢、卤素、烷基、烷氧基、卤代烷基、卤代烷氧基，优选氢、卤素、 C 1-C 6烷基、C 1-C 6烷氧基。
  4. 根据权利要求1至3中任一项所述的通式(I)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其药学上可接受的盐，其中，R 2选自氢、卤素、C 1-C 6烷基、或C 1-C 6烷氧基。
  5. 根据权利要求1至4中任一项所述的通式(I)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其药学上可接受的盐，其中，R 3选自五碳糖，优选核糖、脱氧核糖和木糖，更优选D-核糖、D-脱氧核糖和D-木糖。
  6. 根据权利要求1至4中任一项所述的通式(I)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其药学上可接受的盐，其中，R 3选自六碳糖，优选葡萄糖、果糖、和半乳糖，更优选D-葡萄糖、D-果糖和D-半乳糖。
  7. 根据权利要求1至6中任一项所述的通式(I)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其药学上可接受的盐，其中，m为1或2，优选m为1。
  8. 根据权利要求1至7中任一项所述的通式(I)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其药学上可接受的盐，其中，n为1或2。
  9. 根据权利要求1至8中任一项所述的通式(I)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其药学上可接受的盐，其中所述化合物选自：
    Figure PCTCN2018086774-appb-100003
    Figure PCTCN2018086774-appb-100004
  10. 根据权利要求1至9中任一项所述的通式(I)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其药学上可接受的盐，其中所述药学上可接受的盐为碱式加成盐，优选钠盐、钾盐、钙盐、镁盐、四甲基季铵盐、四乙基季铵盐、甲胺盐、二甲胺盐、三甲胺盐、三乙胺盐或乙胺盐。
  11. 一种根据权利要求1至10中任一项所述的通式(I)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其药学上可接受的盐的制备方法，其包括以下步骤，
    Figure PCTCN2018086774-appb-100005
    将中间体Ia与中间体Ib在活化试剂和碱存在下发生偶联反应得到通式(I)化合物；
    其中，所述活化试剂优选DCC，所述碱优选N-甲基吗啉。
  12. 一种药物组合物，其包含根据权利要求1至10中任一项所述的通式(I)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其药学上可接受的盐，以及药学上可接受的载体。
  13. 根据权利要求1至10中任一项所述的通式(I)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其药学上可接受的盐，或者根据权利要求12所述的药物组合物，在制备治疗咳嗽的药物中的用途。
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CN110922440A (zh) * 2019-11-01 2020-03-27 天津中医药大学 吲哚氮苷类化合物及提取方法及在制备防治神经系统疾病药物中的应用

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1933830A (zh) * 2004-01-15 2007-03-21 史密丝克莱恩比彻姆公司 吲哚衍生物和其作为激酶抑制剂特别是ikk2抑制剂的用途
WO2016100281A1 (en) * 2014-12-15 2016-06-23 Merck Patent Gmbh Indole and azaindoles derivatives and their use in neurodegenerative diseases

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1933830A (zh) * 2004-01-15 2007-03-21 史密丝克莱恩比彻姆公司 吲哚衍生物和其作为激酶抑制剂特别是ikk2抑制剂的用途
WO2016100281A1 (en) * 2014-12-15 2016-06-23 Merck Patent Gmbh Indole and azaindoles derivatives and their use in neurodegenerative diseases

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See also references of EP3636642A4 *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN110922440A (zh) * 2019-11-01 2020-03-27 天津中医药大学 吲哚氮苷类化合物及提取方法及在制备防治神经系统疾病药物中的应用
CN110922440B (zh) * 2019-11-01 2023-01-17 天津中医药大学 吲哚氮苷类化合物及提取方法及在制备防治神经系统疾病药物中的应用

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EP3636642A8 (en) 2020-07-01
JP2020522579A (ja) 2020-07-30
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