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WO2018019301A1 - Dérivé de triptolide substitué par du fluor - Google Patents

Dérivé de triptolide substitué par du fluor Download PDF

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Publication number
WO2018019301A1
WO2018019301A1 PCT/CN2017/094991 CN2017094991W WO2018019301A1 WO 2018019301 A1 WO2018019301 A1 WO 2018019301A1 CN 2017094991 W CN2017094991 W CN 2017094991W WO 2018019301 A1 WO2018019301 A1 WO 2018019301A1
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Prior art keywords
group
unsubstituted
cancer
compound
halogenated
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PCT/CN2017/094991
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English (en)
Chinese (zh)
Inventor
张鹏
包丽霞
刘祥超
贺利军
肖飞
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Cinkate Pharmaceutical Intermediates Co Ltd
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Cinkate Pharmaceutical Intermediates Co Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J73/00—Steroids in which the cyclopenta[a]hydrophenanthrene skeleton has been modified by substitution of one or two carbon atoms by hetero atoms
    • C07J73/001—Steroids in which the cyclopenta[a]hydrophenanthrene skeleton has been modified by substitution of one or two carbon atoms by hetero atoms by one hetero atom
    • C07J73/003—Steroids in which the cyclopenta[a]hydrophenanthrene skeleton has been modified by substitution of one or two carbon atoms by hetero atoms by one hetero atom by oxygen as hetero atom
    • 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
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/57—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J73/00—Steroids in which the cyclopenta[a]hydrophenanthrene skeleton has been modified by substitution of one or two carbon atoms by hetero atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/07—Optical isomers

Definitions

  • the present invention relates to the field of medicinal chemistry, and in particular to a fluorologenyl lactone ring derivative having immunosuppressive activity and antitumor activity.
  • Natural products have been the main source of new anti-tumor drug structures, but because these compounds often have poor pharmacokinetic properties, only a few natural products have been developed into anti-tumor drugs in the clinic.
  • Tripterygium wilfordii is a common anti-tumor drug research object. It has been found that the compound Triptolide and its specific derivatives and prodrugs have antitumor and immunosuppressive activities. For example, treating autoimmune diseases and treating or preventing transplant rejection, including treating graft versus host disease (GVHD). It has also been reported that triptolide and its specific derivatives and prodrugs have anticancer activity.
  • triptolide derivatives and prodrugs of triptolide have been advantageous in terms of pharmacokinetics or biodistribution relative to natural triptolide, due to differences in lipid or water solubility, or as precursors
  • the activity of the drug, the biological activity of the triptolide derivative itself is usually significantly lower than that of the natural triptolide.
  • a first aspect of the invention provides a compound of formula I, or a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, solvate thereof , polymorph or prodrug,
  • R 1 and R 2 are each independently selected from: a substituted or unsubstituted C1-C8 alkyl group, a substituted or unsubstituted 5-8 membered aryl group and a heteroaryl group;
  • R 3 is F, and the positional configuration comprises two R-configurations and an S-configuration;
  • the above heteroaryl group contains 1-3 heteroatoms selected from the group consisting of N, O or S;
  • any of the above “substituted” means that one or more hydrogen atoms on the group are substituted with a substituent selected from the group consisting of halogen, -OH, NH 2 , CN, unsubstituted or halogenated C1-C8 alkyl, Unsubstituted or halogenated C3-C8 cycloalkyl, unsubstituted or halogenated C1-C8 alkoxy, unsubstituted or halogenated C2-C6 alkenyl, unsubstituted or halogenated C2-C6 alkynyl, Unsubstituted or halogenated C2-C6 acyl group, unsubstituted or halogenated C2-C6 amide group, unsubstituted or halogenated 5- to 8-membered aryl group, unsubstituted or halogenated 5- to 8-membered heteroaryl group, An unsubstituted or halogen
  • R 1 and R 2 each contain at least four carbon atoms.
  • each of R 1 and R 2 is independently a substituted or unsubstituted C1-C4 alkyl group, or a substituted or unsubstituted C4-C8 alkyl group.
  • R 1 and R 2 are each independently selected from the group consisting of substituted or unsubstituted butyl, substituted or unsubstituted phenyl.
  • R 1 and R 2 are each independently selected from the group consisting of n-butyl, phenyl, -Ph-COOEt.
  • the aryl or heteroaryl group is a monocyclic or fused ring.
  • the compound is selected from the group consisting of:
  • said R 1 and R 2 are the same or different.
  • a second aspect of the invention provides the use of a compound of formula I according to the first aspect of the invention for:
  • the tumor is selected from the group consisting of leukemia, gastrointestinal stromal tumor, histiocytic lymphoma, Non-small cell lung cancer, small cell lung cancer, pancreatic cancer, lung squamous cell carcinoma, lung adenocarcinoma, breast cancer, prostate cancer, liver cancer, skin cancer, epithelial cell carcinoma, cervical cancer, ovarian cancer, intestinal cancer, nasopharyngeal cancer, brain cancer , bone cancer, esophageal cancer, melanoma, kidney cancer, oral cancer.
  • a third aspect of the invention provides a pharmaceutical composition, the pharmaceutical composition comprising:
  • a third aspect of the invention provides an intermediate compound of the formula:
  • the present invention also provides a process for preparing a triptolide derivative.
  • the method includes the following steps:
  • a fluoro-tratolide compound is prepared by reacting a 14-hydroxyl-containing triptolide with a fluorinating reagent such as DAST; the intermediate enolate is then alkylated or acylated.
  • a fluorinating reagent such as DAST
  • the present inventors discovered for the first time a fluoro-tradominol lactone ring derivative by a large number of screening and testing.
  • the compounds of the series have better immunosuppressive activity and antitumor activity, and have low toxicity and good safety, and have good development and application prospects.
  • the present invention has been completed on this basis.
  • substituent When a substituent is described by a conventional chemical formula written from left to right, the substituent also includes the chemically equivalent substituent obtained when the structural formula is written from right to left.
  • substituent -CH2O- is equivalent to -OCH2-.
  • C1-6 alkyl refers to an alkyl group as defined below having a total of from 1 to 6 carbon atoms.
  • the total number of carbon atoms in the simplified symbol does not include carbon that may be present in the substituents of the group.
  • halogen means fluoro, chloro, bromo or iodo.
  • Haldroxy means an -OH group.
  • Hydroalkyl means an alkyl group as defined below which is substituted by a hydroxy group (-OH).
  • Niro means -NO2.
  • Amino means -NH2.
  • Substituted amino means an amino group substituted with one or two alkyl, alkylcarbonyl, aralkyl, heteroaralkyl groups as defined below, for example, monoalkylamino, dialkylamino, alkyl Amido, aralkylamino, heteroarylalkylamino.
  • Carboxyl means -COOH.
  • alkyl group means consisting only of carbon atoms and hydrogen atoms, and is not unsaturated.
  • a bond a straight or branched hydrocarbon chain group having, for example, 1 to 12 (preferably 1 to 8, more preferably 1 to 6) carbon atoms and attached to the remainder of the molecule by a single bond.
  • alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 2-methylbutyl, 2 , 2-dimethylpropyl, n-hexyl, heptyl, 2-methylhexyl, 3-methylhexyl, octyl, decyl and decyl.
  • alkenyl as a group or part of another group means consisting only of carbon atoms and hydrogen atoms, containing at least one double bond, having, for example, 2 to 14 (preferably 2 to 10) And more preferably 2 to 6) carbon atoms and a straight or branched hydrocarbon chain group attached to the remainder of the molecule by a single bond, such as, but not limited to, vinyl, propenyl, allyl, butyl- 1-Alkenyl, but-2-enyl, pent-1-enyl, pentane-1,4-dienyl and the like.
  • alkynyl as a group or part of another group means consisting solely of carbon atoms and hydrogen atoms, containing at least one triple bond and optionally one or more double bonds, having for example 2 to 14 (preferably 2 to 10, more preferably 2 to 6) carbon atoms and a straight or branched hydrocarbon chain group bonded to the remainder of the molecule by a single bond, such as, but not limited to, an ethynyl group , prop-1-ynyl, but-1-ynyl, pent-1-en-4-ynyl and the like.
  • cycloalkyl as a group or part of another group means a stable non-aromatic monocyclic or polycyclic hydrocarbon group consisting solely of carbon atoms and hydrogen atoms, which may include condensing a ring system, a bridged ring system or a spiro ring system having from 3 to 15 carbon atoms, preferably from 3 to 10 carbon atoms, more preferably from 3 to 8 carbon atoms, and which is saturated or unsaturated and may be suitably employed
  • the carbon atom is connected to the rest of the molecule by a single bond. Unless It is additionally specifically indicated in the specification that the carbon atom in the cycloalkyl group may be optionally oxidized.
  • cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cyclooctyl, 1H- Indenyl, 2,3-indanyl, 1,2,3,4-tetrahydro-naphthyl, 5,6,7,8-tetrahydro-naphthyl, 8,9-dihydro-7H-benzene And cyclohepten-6-yl, 6,7,8,9-tetrahydro-5H-benzocycloheptenyl, 5,6,7,8,9,10-hexahydro-benzocyclooctenyl , fluorenyl, bicyclo [2.2.1] heptyl, 7,7-dimethyl-bicyclo[2.2.1]hept
  • heterocyclyl as a group or part of another group means consisting of 2 to 14 carbon atoms and 1 to 6 heteroatoms selected from the group consisting of nitrogen, phosphorus, oxygen and sulfur.
  • a heterocyclic group may be a monocyclic, bicyclic, tricyclic or more cyclic ring system, which may include a fused ring system, a bridged ring system or a spiro ring system;
  • the nitrogen, carbon or sulfur atom may optionally be oxidized; the nitrogen atom may optionally be quaternized; and the heterocyclic group may be partially or fully saturated.
  • the heterocyclic group may be attached to the remainder of the molecule via a carbon atom or a hetero atom and through a single bond.
  • one or more of the rings may be an aryl or heteroaryl group as defined hereinafter, provided that the point of attachment to the rest of the molecule is a non-aromatic ring atom.
  • the heterocyclic group is preferably a stable 4 to 11 membered non-aromatic monocyclic, bicyclic, bridged or spiro group containing from 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur.
  • heterocyclic groups include, but are not limited to, pyrrolidinyl, morpholinyl, piperazinyl, homopiperazinyl, piperidinyl, thiomorpholinyl, 2,7-diaza-spiro[3.5]fluorene.
  • Alkan-7-yl 2-oxa-6-aza-spiro[3.3]heptane-6-yl, 2,5-diaza-bicyclo[2.2.1]heptan-2-yl, aza Cyclobutane, pyranyl, tetrahydropyranyl, thiopyranyl, tetrahydrofuranyl, oxazinyl, dioxocyclopentyl, tetrahydroisoquinolinyl, decahydroisoquinolinyl, imidazolinyl, Imidazolidinyl, quinazolinyl, thiazolidinyl, isothiazolidinyl, isoxazolidinyl, indanyl, octahydroindenyl, octahydroisodecyl, pyrrolidinyl, pyrazolidinyl , phthalimido and the like.
  • aryl as a group or part of another group means a conjugated hydrocarbon ring system group having 6 to 18 carbon atoms, preferably having 6 to 10 carbon atoms.
  • an aryl group may be a monocyclic, bicyclic, tricyclic or more cyclic ring system, and may also be fused to a cycloalkyl or heterocyclic group as defined above, provided that the aryl group is via The atoms on the aromatic ring are connected to the rest of the molecule by a single bond.
  • aryl groups include, but are not limited to, phenyl, naphthyl, anthryl, phenanthryl, anthracenyl, 2,3-dihydro-1H-isoindolyl, 2-benzoxazolinone, 2H-1, 4-benzoxazine-3(4H)-one-7-yl and the like.
  • arylalkyl refers to an alkyl group as defined above substituted with an aryl group as defined above.
  • heteroaryl as a group or part of another group means having from 1 to 15 carbon atoms (preferably having from 1 to 10 carbon atoms) and from 1 to 6 selected from nitrogen in the ring. a 5- to 16-membered conjugated ring system of a hetero atom of oxygen and sulfur. Unless otherwise specifically indicated in the specification, a heteroaryl group may be a monocyclic, bicyclic, tricyclic or more cyclic ring system, and may also be fused to a cycloalkyl or heterocyclic group as defined above, provided that The aryl group is attached to the remainder of the molecule via a single bond through an atom on the aromatic ring.
  • the nitrogen, carbon or sulfur atom in the heteroaryl group can be optionally oxidized; the nitrogen atom can optionally be quaternized.
  • the heteroaryl group is preferably a stable 5- to 12-membered aromatic group containing from 1 to 5 heteroatoms selected from nitrogen, oxygen and sulfur, more preferably from 1 to 4 selected
  • heteroaryl groups include, but are not limited to, thienyl, imidazolyl, pyrazolyl, thiazolyl, oxazolyl, oxadiazolyl, isoxazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, Benzimidazolyl, benzopyrazolyl, fluorenyl, furyl, pyrrolyl, triazolyl, tetrazolyl, triazinyl, pyridazinyl, isodecyl, oxazolyl, isoxazolyl , fluorenyl, quinolyl, isoquinolyl, diaza naphthyl, naphthyridinyl, quinoxalinyl, pteridinyl, oxazolyl, porphyrin, phenanthryl, phenanthroline, acridine Base, phenazinyl
  • heteroarylalkyl refers to an alkyl group as defined above which is substituted by a heteroaryl group as defined above.
  • optionally or “optionally” means that the subsequently described event or condition may or may not occur, and that the description includes both the occurrence and non-occurrence of the event or condition.
  • optionally substituted aryl means that the aryl group is substituted or unsubstituted, and the description includes both the substituted aryl group and the unsubstituted aryl group.
  • a chemical moiety refers to a particular fragment or functional group in a molecule.
  • a chemical moiety is generally considered to be a chemical entity that is embedded or attached to a molecule.
  • Stepoisomer refers to a compound composed of the same atoms bonded by the same bond but having a different three-dimensional structure.
  • the invention will cover various stereoisomers and mixtures thereof.
  • the compound of the present invention contains an olefinic double bond
  • the compound of the present invention is intended to contain, unless otherwise stated. E- and Z-geometric isomers.
  • Tautomer refers to an isomer formed by the transfer of a proton from one atom of a molecule to another atom of the same molecule. All tautomeric forms of the compounds of the invention will also be embraced within the scope of the invention.
  • the compounds of the invention may contain one or more chiral carbon atoms, and thus may give rise to enantiomers, diastereomers, and other stereoisomeric forms.
  • Each chiral carbon atom can be defined as (R)- or (S)- based on stereochemistry.
  • the invention is intended to include all possible isomers, as well as racemic and optically pure forms thereof.
  • the preparation of the compounds of the invention may employ racemates, diastereomers or enantiomers as starting materials or intermediates.
  • Optically active isomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques, such as by crystallization and chiral chromatography.
  • pharmaceutically acceptable salt includes pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts.
  • “Pharmaceutically acceptable acid addition salt” means a salt formed with an inorganic or organic acid which retains the bioavailability of the free base without any other side effects.
  • Inorganic acid salts include, but are not limited to, hydrochlorides, hydrobromides, sulfates, nitrates, phosphates, and the like; organic acid salts include, but are not limited to, formate, acetate, 2,2-dichloroacetate , trifluoroacetate, propionate, hexanoate, octoate, decanoate, undecylenate, glycolate, gluconate, lactate, sebacate, hexane Acid salt, glutarate, malonate, oxalate, maleate, succinate, fumarate, tartrate, citrate, palmitate, stearate, oleate , cinnamate, laurate, malate, glutamate, pyroglutamate, aspartate, benzoate, me
  • “Pharmaceutically acceptable base addition salt” refers to a salt formed with an inorganic or organic base which is capable of retaining the biological effectiveness of the free acid without other side effects.
  • Salts derived from inorganic bases include, but are not limited to, sodium salts, potassium salts, lithium salts, ammonium salts, calcium salts, magnesium salts, iron salts, zinc salts, copper salts, manganese salts, aluminum salts, and the like.
  • Preferred inorganic salts are ammonium, sodium, potassium, calcium and magnesium salts.
  • Salts derived from organic bases include, but are not limited to, the following salts: primary amines, secondary amines and tertiary amines, substituted amines, including naturally substituted amines, cyclic amines, and basic ion exchange resins.
  • ammonia isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, diethanolamine, triethanolamine, dimethylethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, bicyclo Hexylamine, lysine, arginine, histidine, caffeine, pu Rucaine, choline, betaine, ethylenediamine, glucosamine, methylglucosamine, theobromine, hydrazine, piperazine, piperidine, N-ethylpiperidine, polyamine resin, and the like.
  • Preferred organic bases include isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, choline, and caffeine.
  • Polymorph refers to a different solid crystalline phase of certain compounds of the invention resulting from the presence of two or more different molecular arrangements in a solid state. Certain compounds of the invention may exist in more than one crystal form, and the invention is intended to include various crystal forms and mixtures thereof.
  • solvate refers to an aggregate comprising one or more molecules of the compound of the invention and one or more solvent molecules.
  • the solvent may be water, and the solvate in this case is a hydrate.
  • the solvent may be an organic solvent.
  • the compounds of the invention may exist as hydrates, including monohydrates, dihydrates, hemihydrates, sesquihydrates, trihydrates, tetrahydrates, and the like, as well as the corresponding solvated forms.
  • the compounds of the invention may form true solvates, but in some cases, it is also possible to retain only a defined amount of water or a mixture of water plus a portion of the indefinite solvent.
  • the compound of the present invention can be reacted in a solvent or precipitated or crystallized from a solvent. Solvates of the compounds of the invention are also included within the scope of the invention.
  • the invention also includes prodrugs of the above compounds.
  • prodrug means a compound which can be converted into a biologically active compound of the invention under physiological conditions or by solvolysis.
  • prodrug refers to a pharmaceutically acceptable metabolic precursor of a compound of the invention.
  • Prodrugs may be inactive when administered to an individual in need thereof, but are converted in vivo to the active compound of the invention.
  • Prodrugs are typically rapidly converted in vivo to produce the parent compound of the invention, for example by hydrolysis in blood.
  • Prodrug compounds generally provide the advantage of solubility, tissue compatibility or sustained release in mammalian organisms.
  • Prodrugs include known amino protecting groups and carboxy protecting groups.
  • pharmaceutical composition refers to a formulation of a compound of the invention and a medium generally accepted in the art for delivery of a biologically active compound to a mammal, such as a human.
  • the medium includes a pharmaceutically acceptable carrier.
  • the purpose of the pharmaceutical composition is to promote the administration of the organism, thereby facilitating the absorption of the active ingredient and thereby exerting biological activity.
  • pharmaceutically acceptable refers to a substance (such as a carrier or diluent) that does not affect the biological activity or properties of the compound of the invention, and is relatively non-toxic, ie, the substance can be administered to an individual without causing undesirable organisms. The reaction or in an undesirable manner interacts with any of the components contained in the composition.
  • pharmaceutically acceptable carrier includes, but is not limited to, any adjuvant, carrier, excipient, glidant, sweetener approved by the relevant government authorities for acceptable use by humans or livestock. , diluents, preservatives, dyes/colorants, flavoring agents, surfactants, wetting agents, dispersing agents, suspending agents, stabilizers, isotonic agents, solvents Or an emulsifier.
  • tumor include, but are not limited to, leukemia, gastrointestinal stromal tumor, histiocytic lymphoma, non-small cell lung cancer, small cell lung cancer, pancreatic cancer, lung squamous cell carcinoma, Lung adenocarcinoma, breast cancer, prostate cancer, liver cancer, skin cancer, epithelial cell carcinoma, cervical cancer, ovarian cancer, intestinal cancer, nasopharyngeal cancer, brain cancer, bone cancer, esophageal cancer, melanoma, kidney cancer, oral cancer, etc. disease.
  • preventing include the possibility of reducing the occurrence or progression of a disease or condition by a patient.
  • treatment and other similar synonyms as used herein includes the following meanings:
  • an "effective amount,” “therapeutically effective amount,” or “pharmaceutically effective amount,” as used herein, refers to at least one agent or compound that, after administration, is sufficient to alleviate one or more symptoms of the disease or condition being treated to some extent. The amount. The result can be a reduction and/or alleviation of signs, symptoms or causes, or any other desired change in the biological system.
  • an "effective amount” for treatment is an amount of a composition comprising a compound disclosed herein that is required to provide a significant conditional relief effect in the clinic.
  • An effective amount suitable for any individual case can be determined using techniques such as dose escalation testing.
  • administering refers to a method of delivering a compound or composition to a desired site for biological action. These methods include, but are not limited to, oral routes, duodenal routes, parenteral injections (including intravenous, subcutaneous, intraperitoneal, intramuscular, intraarterial injection or infusion), topical administration, and rectal administration. Techniques of administration that are useful in the compounds and methods described herein are well known to those skilled in the art. In a preferred embodiment, the compounds and compositions discussed herein are administered orally.
  • pharmaceutical combination means a pharmaceutical treatment obtained by mixing or combining more than one active ingredient, It includes both fixed and unfixed combinations of active ingredients.
  • fixed combination refers to the simultaneous administration of at least one compound described herein and at least one synergistic agent to a patient in the form of a single entity or a single dosage form.
  • unfixed combination refers to the simultaneous administration, combination or sequential administration of at least one of the compounds described herein and at least one synergistic formulation to the patient in the form of separate entities. These are also applied to cocktail therapy, for example the administration of three or more active ingredients.
  • the intermediate compound functional groups may need to be protected by a suitable protecting group.
  • suitable protecting groups include trialkylsilyl or diarylalkylsilyl groups (e.g., tert-butyldimethylsilyl, tert-butyldiphenylsilyl or trimethylsilyl) , tetrahydropyranyl, benzyl, and the like.
  • Suitable protecting groups for amino, mercapto and fluorenyl include t-butoxycarbonyl, benzyloxycarbonyl and the like.
  • Suitable mercapto protecting groups include -C(O)-R" (wherein R" is alkyl, aryl or aralkyl), p-methoxybenzyl, trityl and the like.
  • Suitable carboxy protecting groups include alkyl, aryl or aralkyl esters.
  • Protecting groups can be introduced and removed according to standard techniques known to those skilled in the art and as described herein.
  • the protecting group can also be a polymeric resin.
  • the present invention provides a compound of formula I, or a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, solvate, polymorph thereof Or prodrug,
  • R 1 and R 2 are each independently selected from: a substituted or unsubstituted C1-C8 alkyl group, a substituted or unsubstituted 5-8 membered aryl group and a heteroaryl group;
  • R 3 is F, and the positional configuration comprises two R-configurations and an S-configuration;
  • the above heteroaryl group contains 1-3 heteroatoms selected from the group consisting of N, O or S;
  • any of the above “substituted” means that one or more hydrogen atoms on the group are substituted with a substituent selected from the group consisting of halogen, -OH, NH 2 , CN, unsubstituted or halogenated C1-C8 alkyl, Unsubstituted or halogenated C3-C8 cycloalkyl, unsubstituted or halogenated C1-C8 alkoxy, unsubstituted or halogenated C2-C6 alkenyl, unsubstituted or halogenated C2-C6 alkynyl, Unsubstituted or halogenated C2-C6 acyl group, unsubstituted or halogenated C2-C6 amide group, unsubstituted or halogenated 5- to 8-membered aryl group, unsubstituted or halogenated 5- to 8-membered heteroaryl group, An unsubstituted or halogen
  • R 1 and R 2 each contain at least four carbon atoms.
  • the aryl or heteroaryl group is a monocyclic or fused ring.
  • the present invention discloses that the inactive position of the triptolide derivative is fluorinated, and it is found that the activity of the cell line resistant to triptolide can be increased; and the structure of the prodrug is fluorinated, and the tumor is inhibited. The effect is better.
  • the triptolide (50 mg, 0.144 mmoL) was placed in a dry three-necked round bottom flask, dissolved in 3 mL of dichloromethane solvent, and the reaction was placed in an ice bath, cooled sufficiently, and the system was cooled to 0 ° C.
  • DAST F reagent (0.3mL, 2.289mmoL), added dropwise to the reaction system, stirred thoroughly, the system slowly showed a slight yellow color, after four hours of reaction, the reaction was quenched by adding saturated NaHCO 3 solution, slowly added dropwise, carefully exothermic Intense, the bubbles pop out too fast.
  • reaction solution was extracted with DCM, extracted three times, and the organic phases were combined, and the organic phase was dried over anhydrous sodium sulfate. After clarified, it was collected in a round bottom flask and evaporated by rotary evaporation. The crude product was purified by silica gel chromatography chromatography eluting eluting eluting eluting eluting
  • Fluoride triptolide (50mg, 0.138mmoL) was put into an anhydrous oxygen-free three-necked round bottom flask, and then 50mg of activated 4A molecular sieve was added, followed by extracting 5mL of dry THF solvent into the system to fully dissolve the fluorine derivative.
  • the LDA solution in heptane/THF/ethylbenzene (0.18 mL of a 2.0 M solution, 0.357 mmol) was added dropwise at -78 °C. The resulting solution was stirred at this temperature for half an hour, then pure benzoyl chloride (0.08 mL, 0.69 mmol) was added dropwise. The reaction was stirred at -78 °C for 2 hours.
  • the reaction was quenched with water and ethyl acetate (25 mL & The combined organic solution was dried over anhydrous sodium sulfate, and the solvent was evaporated on a rotary evaporator.
  • the color development area of the product on the silica gel plate was collected in an Erlenmeyer flask, dissolved in 5 mL of ethyl acetate, sonicated for ten minutes, filtered, collected, drained, and weighed 60 mg, yield: 76%.
  • CK21S-F1 was prepared from CK21S-FS in a similar manner to the preparation of CK21S-F2. The difference was that the benzoyl chloride in Example 1 was replaced with n-pentanoyl chloride, and the other conditions were the same.
  • CK21S-F3 was prepared from CK21S-FS in a similar manner to the preparation of CK21S-F2. The difference was that 4-benzoic acid-benzoyl chloride was used in place of the benzoyl chloride in Example 1, and the other conditions were the same.
  • Tumor cells include MDA-MB-231, MDA-MB-468, HCC70, and T4-2.
  • Triptolide was used as a positive control; the concentration of the test drug was 2 uM (working concentrations of 1 uM, 0.1 uM, 0.05 uM, 0.025 uM, 0.01 uM, and 0.001 uM).
  • the tumor cells were resuscitated, they were resuspended in 1640 complete medium, placed in 5% CO 2 , and cultured at 37 °C.
  • Take the logarithmic growth phase tumor cells adjust the cell concentration to 1*10 5 /mL in complete 1640 medium, add 100uL cell suspension per well, ie 1*10 4 /well, and culture for 24 hours, then add 100uL different concentrations. Inhibitor. After further 24 hours of culture, 20 uL/well of CCK8 reagent was added to measure cell proliferation.

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Abstract

L'invention concerne un composé représenté par la formule I, ou un sel pharmaceutiquement acceptable, un énantiomère, un diastéréomère, un tautomère, un solvate, un matériau polycristallin ou un précurseur de celui-ci, ainsi qu'un procédé de fabrication et une application pharmaceutique de celui-ci. Le composé présente une activité immunosuppressive et une activité antitumorale améliorées, et présente de meilleures perspectives de développement et d'application.
PCT/CN2017/094991 2016-07-29 2017-07-28 Dérivé de triptolide substitué par du fluor Ceased WO2018019301A1 (fr)

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CN201610617459.5A CN107663225A (zh) 2016-07-29 2016-07-29 一种氟代雷公藤内酯醇内酯环衍生物
CN201610617459.5 2016-07-29

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CN110551172B (zh) * 2018-05-31 2021-08-27 欣凯医药化工中间体（上海）有限公司 一种c-19位双键化雷公藤内酯醇衍生物的合成方法

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WO2014145303A1 (fr) * 2013-03-15 2014-09-18 Pharmagenesis, Inc. Émulsions intraveineuses de triptolide comme immunomodulateurs et agents anticancéreux
WO2015085447A1 (fr) * 2013-12-11 2015-06-18 香港浸会大学 Nouveaux dérivés de triptolide et procédé de préparation et d'utilisation associés

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WO2005000291A1 (fr) * 2003-06-27 2005-01-06 Pharmagenesis, Inc. Methode de traitement de la fibrose pulmonaire idiopathique au moyen de derives de triptolide
CN102634561A (zh) * 2012-03-14 2012-08-15 厦门大学 雷公藤甲素及衍生物和类似物在制备抗肿瘤药物中的应用
WO2014145303A1 (fr) * 2013-03-15 2014-09-18 Pharmagenesis, Inc. Émulsions intraveineuses de triptolide comme immunomodulateurs et agents anticancéreux
WO2015085447A1 (fr) * 2013-12-11 2015-06-18 香港浸会大学 Nouveaux dérivés de triptolide et procédé de préparation et d'utilisation associés

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Publication number Priority date Publication date Assignee Title
KR20200065056A (ko) * 2018-04-02 2020-06-08 친카테 파머시티컬 인털메디아테스 코포레이션 엘티디 트립톨라이드 유도체 및 이의 제조방법과 응용
RU2753036C1 (ru) * 2018-04-02 2021-08-11 Цинкате Фармацеутикал Интермедиатес Ко., Лтд. Производное триптолида, способ его получения и применение
RU2753036C9 (ru) * 2018-04-02 2021-10-21 Цинкaте Фaрмaцеутикaл Интермедиaтес Ко., Лтд. Производное триптолида, способ его получения и применение
KR102473019B1 (ko) 2018-04-02 2022-12-01 친카테 파머시티컬 인털메디아테스 코포레이션 엘티디 트립톨라이드 유도체 및 이의 제조방법과 응용

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