WO2018019301A1 - Fluorine-substituted triptolide derivative - Google Patents

Abstract

Provided is a compound represented by formula I, or a pharmaceutically acceptable salt, enantiomer, diastereomer, tautomer, solvate, polycrystalline material, or precursor thereof, and a manufacturing method and pharmaceutical application of same. The compound has improved immunosuppressive activity and antitumor activity, and has better development and application prospects.

Description

Fluoride triptolide lactone ring derivative Technical field

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.

Background technique

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.

The traditional Chinese medicine Tripterygium wilfordii (TW) 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.

Although 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.

Therefore, there is an urgent need in the art to develop new triptolide derivatives having high activity and high safety.

Summary of the invention

It is an object of the present invention to provide a highly active, highly safe triptolide derivative.

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,

In the formula,

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 halogenated 4-8 membered saturated heterocyclic ring or carbocyclic ring; wherein said heteroaryl group and heterocyclic ring comprise 1-3 heteroatoms selected from the group consisting of N, O or S.

In another preferred embodiment, R ¹ and R ² each contain at least four carbon atoms.

In another preferred embodiment, 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.

In another preferred embodiment, R ¹ and R ² are each independently selected from the group consisting of substituted or unsubstituted butyl, substituted or unsubstituted phenyl.

In another preferred embodiment, R ¹ and R ² are each independently selected from the group consisting of n-butyl, phenyl, -Ph-COOEt.

In another preferred embodiment, the aryl or heteroaryl group is a monocyclic or fused ring.

In another preferred embodiment, the compound is selected from the group consisting of:

In another preferred embodiment, 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:

a) preparing an immunosuppressive drug;

b) preparing a drug that induces apoptosis; and/or

c) Preparation of an anti-tumor drug.

In another preferred embodiment, 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:

(i) an effective amount of a compound of formula I, or a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, solvate, polymorph or prodrug thereof ;with

(ii) a pharmaceutically acceptable carrier. 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 typical reaction step is as follows:

It is to be understood that within the scope of the present invention, the various technical features of the present invention and the various technical features specifically described hereinafter (as in the embodiments) may be combined with each other to constitute a new or preferred technical solution. Due to space limitations, we will not repeat them here.

detailed description

After long-term extensive and in-depth research, 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.

the term

Unless otherwise defined, all technical and scientific terms used herein have the same meaning meaning meaning All patents, patent applications, and publications cited herein are hereby incorporated by reference in their entirety herein in their entirety herein

The above description and the following detailed description are to be considered as illustrative and not restrictive. In the present application, the use of the singular includes the plural unless otherwise specified. It must be noted that the singular forms used in the specification and claims are in the It should also be noted that "or" or "or" is used to mean "and/or" unless otherwise indicated. In addition, the terms "comprises" and "comprising", "include", "include", and "include" are not limiting.

The definition of standard chemical terms can be found in the references. Conventional methods within the skill of the art, such as mass spectrometry, NMR, IR and UV/VIS spectroscopy and pharmacological methods, are employed unless otherwise indicated. Unless specifically defined, the terms used herein in the descriptions of analytical chemistry, organic synthetic chemistry, and pharmaceutical and pharmaceutical chemistry are known in the art. Standard techniques can be used in chemical synthesis, chemical analysis, pharmaceutical preparation, formulation and delivery, and treatment of patients. For example, the reaction can be carried out and purified using the manufacturer's instructions for use of the kit, or in a manner well known in the art or as described in the present invention. The above techniques and methods can generally be carried out according to conventional methods well known in the art, as described in the various summaries and more specific references cited and discussed in this specification. In the present specification, the group and its substituents can be selected by those skilled in the art to provide stable structural moieties and compounds.

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. For example, -CH2O- is equivalent to -OCH2-.

The section headings used herein are for the purpose of organizing articles only and are not to be construed as limiting the subject matter. All documents or parts of the literature cited in this application, including but not limited to patents, patent applications, articles, books, operating manuals and papers, are hereby incorporated by reference in their entirety.

Certain chemical groups defined herein are preceded by a simplified symbol to indicate the total number of carbon atoms present in the group. For example, 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.

In addition to the foregoing, when used in the specification and claims of the present application, the following terms have the meanings indicated below unless otherwise specifically indicated.

In the present application, the term "halogen" means fluoro, chloro, bromo or iodo.

"Hydroxy" means an -OH group.

"Hydroxyalkyl" means an alkyl group as defined below which is substituted by a hydroxy group (-OH).

"Carbonyl" means a -C(=O)- group.

"Nitro" means -NO2.

"Cyano" means -CN.

"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.

In the present application, as a group or a part of other groups (for example, in a group such as a halogen-substituted alkyl group), the term "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. Examples of 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.

In the present application, the term "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.

In the present application, the term "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.

In the present application, the term "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. Examples of 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]heptyl, bicyclo[2.2.1]heptenyl, bicyclo[2.2.2] Octyl, bicyclo [3.1.1] heptyl, bicyclo [3.2.1] octyl, bicyclo [2.2.2] octenyl, bicyclo [3.2.1] octenyl, adamantyl, VIII Hydrogen-4,7-methylene-1H-indenyl and octahydro-2,5-methylene-cyclopentadienyl and the like.

In the present application, the term "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 stable 3- to 20-membered non-aromatic cyclic group. Unless otherwise specified in the specification, 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. In the heterocyclic group containing a fused ring, 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. For the purposes of the present invention, 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. More preferably, it is a stable 4- to 8-membered non-aromatic monocyclic, bicyclic, bridged or spiro group containing from 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur. Examples of 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.

In the present application, the term "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. For the purposes of the present invention, 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. Examples of 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.

In the present application, the term "arylalkyl" refers to an alkyl group as defined above substituted with an aryl group as defined above.

In the present application, the term "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. For the purposes of the present invention, 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 A stable 5- to 10-membered aromatic group derived from a hetero atom of nitrogen, oxygen, and sulfur or a 5- to 6-membered aromatic group containing 1 to 3 hetero atoms selected from nitrogen, oxygen, and sulfur. Examples of 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, isothiazolyl, benzothiazolyl, benzothienyl, oxatriazole, porphyrin, quinazolinyl, phenylthio, guanidinium, phenanthroline, Isoxazolyl, phenoxazinyl, phenothiazine, 4,5,6,7-tetrahydrobenzo[b]thienyl, naphthopyridyl, [1,2,4]triazolo[4 , 3-b]pyridazine, [1,2,4]triazolo[4,3-a]pyrazine, [1,2,4]triazolo[4,3-c]pyrimidine, [1, 2,4]triazolo[4,3-a]pyridine, imidazo[1,2-a]pyridine, imidazo[1,2-b]pyridazine, imidazo[1,2-a]pyrazine Wait.

In the present application, the term "heteroarylalkyl" refers to an alkyl group as defined above which is substituted by a heteroaryl group as defined above.

In the present application, "optional" 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. For example, "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.

The terms "part," "structural moiety," "chemical moiety," "group," and "chemical group", as used herein, refer 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.

"Stereoisomer" 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.

When 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, or pharmaceutically acceptable salts thereof, 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.

Conventional techniques for the preparation/isolation of individual isomers include chiral synthesis from a suitable optically pure precursor, or resolution of the racemate (or racemic form of a salt or derivative) using, for example, chiral high performance liquid chromatography. ).

In the present application, the term "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, methanesulfonate, besylate, p-toluenesulfonate , alginate, ascorbate, salicylate, 4-aminosalicylate, naphthalene disulfonate, and the like. These salts can be prepared by methods known in the art.

"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. For example, 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. These salts can be prepared by methods known in the art.

"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.

Generally, crystallization will result in a solvate of the compound of the invention. The term "solvate" as used in the present invention 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. Alternatively, the solvent may be an organic solvent. Thus, 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. In the present application, the term "prodrug" means a compound which can be converted into a biologically active compound of the invention under physiological conditions or by solvolysis. Thus, the term "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.

In the present application, "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.

The term "pharmaceutically acceptable" as used herein, 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.

In the present application, "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.

The "tumor", "cell proliferation-related diseases" and the like according to the present invention 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.

The terms "preventing", "preventing" and "preventing" as used herein include the possibility of reducing the occurrence or progression of a disease or condition by a patient.

The term "treatment" and other similar synonyms as used herein includes the following meanings:

(i) preventing a disease or condition from occurring in a mammal, particularly when such a mammal is susceptible to the disease or condition, but has not been diagnosed as having the disease or condition;

(ii) inhibiting a disease or condition, ie, curbing its development;

(iii) alleviating the disease or condition, ie, causing the condition of the disease or condition to subside; or

(iv) alleviating the symptoms caused by the disease or condition.

The term "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. For example, 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.

The terms "administering," "administering," "administering," and the like, as used herein, 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.

The terms "pharmaceutical combination", "drug combination", "combination", "administering other treatments", "administering other therapeutic agents" and the like, as used herein, mean a pharmaceutical treatment obtained by mixing or combining more than one active ingredient, It includes both fixed and unfixed combinations of active ingredients. The term "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. The term "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.

It will also be understood by those skilled in the art that in the methods described below, the intermediate compound functional groups may need to be protected by a suitable protecting group. Such functional groups include a hydroxyl group, an amino group, a thiol group, and a carboxylic acid. Suitable hydroxy 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.

Compound of formula I

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,

In the formula,

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 halogenated 4-8 membered saturated heterocyclic ring or carbocyclic ring; wherein said heteroaryl group and heterocyclic ring comprise 1-3 heteroatoms selected from the group consisting of N, O or S.

In another preferred embodiment, R ¹ and R ² each contain at least four carbon atoms.

In another preferred embodiment, the aryl or heteroaryl group is a monocyclic or fused ring.

The main advantages of the invention include:

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 invention is further illustrated below in conjunction with specific embodiments. It is to be understood that the examples are not intended to limit the scope of the invention. The experimental methods in the following examples which do not specify the specific conditions are usually in accordance with conventional conditions or according to the conditions recommended by the manufacturer. Unless otherwise stated, percentages and parts are by weight and parts by weight.

Example 1

Preparation of 14-fluoro-18-deoxy-19dehydro-18-benzoyloxy-19-benzoyl triptolide (CK21S-F2)

A.14-hydroxy fluoro

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. The 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

¹ H NMR (400 M, CDCl ₃ ) δ 0.82 (d, J = 6.9 Hz, 3H), 1.08 (d, J = 6.9 Hz, 3H), 1.11 (s, 3H), 1.17-1.27 (m, 1H) , 1.53-1.57 (m, 1H), 1.90-1.98 (m, 1H), 2.10-2.22 (m, 3H), 2.29-2.35 (m, 1H), 2.70-2.75 (m, 1H), 3.49 (t, J=3.2 Hz, 1H), 3.724 (d, J=5.6 Hz, 1H), 3.79 (d, J=1.6 Hz, 1H), 4.68-4.70 (m, 2H), 5.16 (d, 1H); ¹⁹ F _{NMR (400M, CDCl 3) δ213.49} .

B. Acylation

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 crude product was separated and purified on an alkalized silica gel plate (yield: n-hexane: ethyl acetate = 5:1). 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%.

¹ H NMR (400 M, CDCl ₃ ) δ 0.89 (d, J = 6.9 Hz, 3H), 1.18 (d, J = 6.9 Hz, 3H), 1.13 (s, 3H), 1.23-1.28 (m, 1H) , 1.51-1.54 (m, 1H), 1.83-1.90 (m, 1H), 1.92-1.99 (m, 1H), 2.25-2.36 (m, 2H), 2.58-2.61 (m, 1H), 2.74-2.80 ( m, 1H), 2.98-2.99 (d, J = 6.4 Hz, 1H), 3.34 (t, J = 2.8 Hz, 1H), 3.70 (t, J = 1.6 Hz, 1H), 4.95 (d, 1H), 7.38-7.45 (m, 3H), 7.47-7.49 (m, 1H), 7.56-7.60 (m, 2H), 7.67-7.70 (m, 1H), 7.75-7.78 (m, 2H), 8.23-8.25 (m , 1H); ¹⁹ F NMR (400M, CDCl ₃ ) δ 213.49.

Example 2:

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.

¹ H NMR (400M, CDCl ₃ ) δ 0.81-0.92 (m, 6H), 1.01-1.04 (m, 3H), 1.12-1.14 (d, J = 6.4 Hz, 3H), 1.24-1.38 (m, 8H) ), 1.43-1.48 (m, 2H), 1.60-1.66 (m, 1H), 1.77-1.84 (m, 1H), 2.02-2.07 (m, 1H), 2.16-2.27 (m, 2H), 2.37-2.48 (m, 1H), 2.51 (m, 3H), 2.54-2.85 (m, 3H), 3.34 (s, 1H), 3.44-3.48 (m, 1H), 3.70-3.79 (m, 1H), 3.96-4.00 (m, 1H), 5.18 (d, 1H); ¹⁹ F NMR (400M, CDCl ₃ ) δ 212.01.

Example 3:

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.

¹ H NMR (400M, CDCl ₃ ) δ 0.86-0.88 (m, 3H), 0.89-0.96 (m, 3H), 0.98-1.02 (m, 3H), 1.03-1.08 (m, 2H), 1.09-1.15 (m, 6H), 1.22-1.28 (m, 2H), 1.82-1.92 (m, 1H), 1.93-2.02 (m, 1H), 2.10-2.30 (m, 2H), 2.30-2.41 (m, 2H) , 2.47-2.72 (m, 2H), 2.93-3.11 (m, 1H), 3.32-3.58 (m, 1H), 3.58-3.82 (m, 1H), 4.92 (d, 1H), 7.81-7.84 (m, 2H), 8.07-8.09 (m, 3H), 8.07-8.09 (m, 3H), 8.24 - 8.31 (m, 4H).

Example 4

Detection of anti-tumor activity of small molecule compounds CK21S-FS, CK21S-F1, CK21S-F2 and CK21S-F3 in vitro

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). After 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.

The in vitro anti-tumor activity IC50 values of the compounds CK21S-FS, CK21S-F1, CK21S-F2 and CK21S-F3 are shown in Table 1.

Table 1 in vitro anti-tumor activity IC50 (nM)

IC50(nM)	MDA-MB-231	MDA-MB-468	HCC70	T4-2
CK21S-F1	84.7	68.0	82.4	43.8
CK21S-F2	13.2	33.4	42.5	15.3
CK21S-F3	46.6	13.1	54.9	3.1
CK21S-FS	52.5	95.7	97.4	46.3
Triptolide	370.5	421.1	287.8	218.0

All documents mentioned in the present application are hereby incorporated by reference in their entirety in their entireties in the the the the the the the the In addition, it should be understood that various modifications and changes may be made by those skilled in the art in the form of the appended claims.

Claims (11)

1. A compound of formula I, or a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, solvate, polymorph or prodrug thereof ,

   

   In the formula,

   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 halogenated 4-8 membered saturated heterocyclic ring or carbocyclic ring; wherein said heteroaryl group and heterocyclic ring comprise 1-3 heteroatoms selected from the group consisting of N, O or S.
2. The compound of claim 1 wherein R ¹ and R ² each comprise at least four carbon atoms.
3. The compound according to claim 1, wherein R ¹ and R ² are each independently a substituted or unsubstituted C1-C4 alkyl group, or a substituted or unsubstituted C4-C8 alkyl group.
4. The compound of claim 1 wherein R ¹ and R ² are each independently selected from the group consisting of substituted or unsubstituted butyl, substituted or unsubstituted phenyl.
5. The compound of claim 1 wherein R ¹ and R ² are each independently selected from the group consisting of n-butyl, phenyl, -Ph-COOEt.
6. The compound of claim 1 wherein said aryl or heteroaryl is a monocyclic or fused ring.
7. The compound of claim 1 wherein said compound is selected from the group consisting of:

   
8. Use of a compound of formula I according to claim 1 for:

   a) preparing an immunosuppressive drug;

   b) preparing a drug that induces apoptosis; and/or

   c) Preparation of an anti-tumor drug.
9. The use according to claim 8, wherein 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 scale Cancer, 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 cavity cancer.
10. A pharmaceutical composition, characterized in that the pharmaceutical composition comprises:

    (i) an effective amount of a compound of formula I, or a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, solvate, polymorph or prodrug thereof ;with

    (ii) a pharmaceutically acceptable carrier.
11. An intermediate compound of the formula: