CN103224492B - 14-aryl ether andrographolide derivatives and preparation method and application thereof - Google Patents

14-aryl ether andrographolide derivatives and preparation method and application thereof Download PDF

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CN103224492B
CN103224492B CN201310146923.3A CN201310146923A CN103224492B CN 103224492 B CN103224492 B CN 103224492B CN 201310146923 A CN201310146923 A CN 201310146923A CN 103224492 B CN103224492 B CN 103224492B
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andrographolide
phenoxy
nitro
isopropylidene
pharmaceutically acceptable
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CN103224492A (en
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周国春
黄志伟
刘竺云
盛德宽
聂鑫
王德才
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Nanjing Tech University
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Nanjing Tech University
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Abstract

The invention discloses a 14-aryl ether andrographolide derivative, a preparation method and application thereof, wherein the derivative is of a structure shown in a formula (I). The compound, the isomer or the salt thereof can be applied to the preparation of drugs for regulating the function of the nuclear receptor FXR or drugs for preventing or treating diseases related to the nuclear receptor FXR.

Description

14-aryl ether andrographolide derivatives and preparation method and application thereof
Technical Field
The invention belongs to the field of medicinal chemistry, and particularly relates to preparation and pharmaceutical application of a 14-aryl ether andrographolide derivative, a stereoisomer, a cis-trans isomer or a pharmaceutically acceptable salt thereof. These compounds are useful for the treatment and prevention of tumors, diabetes and obesity and other metabolic disorders, cardiovascular disease, reproductive system disease, immunological disease, inflammation, including Alzheimer's disease and Parkinson's disease and other neurological disorders, for lowering cholesterol and blood lipids, and for the treatment and prevention of dengue fever, hepatitis C, diseases caused by West Nile Virus infection and HIV-induced AIDS, by modulating the function of the nuclear receptor FXR or by other identical, similar or different targets or mechanisms of action.
Background
Nuclear receptors (NHR) are a class of intracellular signaling proteins that exist in the cytoplasm or nucleus and diffuse binding to specific ligands (ligands), and receptors bound to ligands can bind to DNA response elements to form ligand-dependent transcriptional regulators to regulate intracellular carbohydrate metabolism, lipid metabolism, energy conversion, and important life processes of immune response (HandschinC,s, Rotha, LooserR, OscarsonM, Kaufmann MR, PodvinecM, GnereC, MeyerUANuclarcept 2004,2,7.), and thus they play a key role in cell proliferation, cell differentiation and intracellular and extracellular equilibrium (EvansRemmolEndocrinol 2005,19, 1429. sup. 1438.), and play an important regulatory role in life processes such as reproduction, development and metabolism (Robinson-RecoviM, Escrivagh, LaudetVJCellSci2003,116, 585-586.).
Farnesoid X Receptor (FXR) is one of the nuclear hormone receptor superfamily members, with a typical NHR family structure. Research at present finds that FXR plays an important role in regulating and controlling bile acid, lipoprotein and glucose metabolism, liver regeneration, intestinal bacterial growth, hepatotoxin response and the like. In the liver, cholesterol is metabolized to form bile acids, which not only can serve as physiological solvents to facilitate absorption, transport and distribution of fat-soluble vitamins and fats, but also can serve as signaling molecules to activate FXR to regulate bile acid and cholesterol metabolism. Therefore, synthesizing and screening compounds that can modulate FXR activity would be beneficial for the development of new drugs for the treatment of metabolic diseases.
Nuclear receptors sometimes work in conjunction with the COX (cyclooxgenase) enzyme family, which is the target of action of nonsteroidal anti-inflammatory drugs (NSAIDs), such as PPAR, RAR, RXR, and COX-2, all of which have changes in expression in colon cancer (DelageB, ruliera, capdepetontm, ruliere, cassandpnritionijournal 2007,6, 20); cholic acid (bile acid) is able to induce COX-2 expression in gastric cancer cells (ParkMJ, KimKH, KimHY, KimK, Cheong JCarcinogenesis2008,29 (1); 2385 2393); nuclear receptor Nur77 inhibits COX-2 dependent inflammatory responses (ShaoQ, ShenLH, HuLH, PuJ, QiMY, LiWQ, TianFJ, JingQ, hebj. molecular cellular cardiology2010,49(2), 304); RXRa mediates the effects of ibuprofen-like NSAIDs on the β -amyloid (β -amyloid) substance of Alzheimer's disease (YouX, zhangywjneurochemistry2009,111, 142-149.); the nuclear receptor PPARG is activated in rat microglia by the flurbiprofen NSAID HCT1026 (Bernardo A, Ajmone-CatMA, GaspariniL, Onginie, Minghetti LJNeurochem.2005,92(4), 895-903.).
The reductase reduction reaction of beta-hydroxy-beta-methylglutaryl-coenzyme A reductase (HMG-CoAreducase) is the rate-determining step of cholesterol synthesis. On one hand, considering that andrographolide and HMG-CoA reductase inhibitor-fungus metabolite Lovastatin (Lovastatin) or semisynthetic derivative Simvastatin (Simvastatin) and Pravastatin (Pravastatin) have certain spatial structure similarity from the chemical structure, therefore andrographolide and derivatives thereof can have the function of inhibiting HMG-CoA reductase; on the other hand, many nuclear receptors and their endogenous ligands are involved in the cholesterol biosynthesis process, so andrographolide and its derivatives may also inhibit cholesterol biosynthesis by other mechanisms.
Disclosure of Invention
The invention aims to provide 14-aryl ether andrographolide derivatives, stereoisomers, cis-trans isomers or pharmaceutically acceptable salts thereof with corresponding activity on the basis of the prior art.
Another object of the present invention is to provide a process for the preparation of the above compound.
The third purpose of the invention is to provide the application of the compound in pharmacy.
The object of the invention can be achieved by the following measures:
14-aryl ether andrographolide derivatives shown in formula (I), isomers or pharmaceutically acceptable salts thereof,
wherein,
the Z ring is a benzene ring, a pyridine ring, a pyridazine ring, a pyrimidine ring, a pyrazine ring, a furan ring, a thiazole ring, a pyrrole ring, an oxazole ring, a thiazole ring, an imidazole ring, an isoxazole ring, an isothiazole ring or a pyrazole ring;
R1～R5each independently selected from hydrogen, halogen, cyano, nitro, C1～6Alkyl radical, C1～6Haloalkyl, C1～6Acyl radical, C1～6Carboxylic acid group, C1～6Amide group, substituted or unsubstituted C3～6Cycloalkyl, substituted or unsubstituted C1～6Alkoxy, substituted or unsubstituted C1～6Alkylthio, substituted or unsubstituted C2～6Carboxylate, substituted or unsubstituted amino, substituted or unsubstituted sulfonyl, substituted or unsubstituted C2～6Alkylene, substituted or unsubstituted C3～6Cycloalkenylhydrocarbyl, substituted or unsubstituted C3～6A heterocyclic group, a substituted or unsubstituted aromatic alkyl group; the substituent is selected from halogen, cyano, nitro and C1～6Alkyl radical, C1～6Haloalkyl, C1～6Alkoxy radical, C1～6Alkylthio or C2～6An alkylene group;
or R1～R5Two radicals in a neighborhood ofThe group and the Z ring form a naphthalene, anthracene, phenanthrene, quinoline, isoquinoline, benzopyran, benzopyrone, benzofuran, benzothiophene, indole, purine or pteridine group;
R6or R7Each independently selected from hydrogen and C1～6Acyl, substituted or unsubstituted C1～6Alkyl, substituted or unsubstituted C3～6Cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted C2～6Alkylene, substituted or unsubstituted C3～ 6A cycloalkene group, a substituted or unsubstituted aromatic group, a substituted or unsubstituted arylalkyl group, or a substituted or unsubstituted heterocycloalkenyl group; (ii) a The substituent is selected from halogen, cyano, nitro and C1～6Alkyl radical, C1～6Haloalkyl, C1～6Alkoxy radical, C1～6Alkylthio or C2～6An alkylene group;
or R6And R7Are connected to form C1～6Alkylene or C3～6A cycloalkyl group;
unsubstituted or optionally substituted aromatic hydrocarbon group, unsubstituted or optionally substituted heterocyclic aromatic hydrocarbon group, unsubstituted or optionally substituted aromatic alkyl group, unsubstituted or optionally substituted heterocyclic aromatic alkyl group, unsubstituted or optionally substituted aromatic alkylene group, unsubstituted or optionally substituted heterocyclic aromatic alkenyl group
And the structure is represented by R or S.
Preferably, the compound of the invention is a compound shown as a formula (II), an isomer or a pharmaceutically acceptable salt thereof,
wherein,
R1、R2、R3、R4or R5Each independently selected from hydrogen, nitro, halogen, C1～6Alkyl radical, C1～6Haloalkyl, C3～6Cycloalkyl radical, C1～6Alkoxy radical, C2～6Carboxylic acid groups or C2～6A carboxylate group;
R6or R7Each independently selected from hydrogen and C1～6Acyl radical, C1～6Alkyl radical, C1～6Haloalkyl, or R6And R7Are connected to form C1～6An alkylene group;
and the structure is represented by R or S.
Further preferably, the compound of the invention is a compound shown as a formula (III), an isomer or a pharmaceutically acceptable salt thereof,
R1、R2、R3、R4or R5Each independently selected from hydrogen, nitro, halogen, C1～3Alkyl radical, C1～3Haloalkyl, C1～3Alkoxy radical, C3～6Cycloalkyl radical, C2～6Carboxylic acid groups or C2～6A carboxylate group;
R6or R7Each independently selected from hydrogen and C1～3Acyl radical, C1～3Alkyl radical, C1～3Haloalkyl, or R6And R7Are connected to form C1～6An alkylene group;
and the structure is represented by R or S.
In the formulae (I), (II) and (III), preferably, R1Or R5Each independently selected from hydrogen, nitro, C1～3Alkyl radical, C1～3Haloalkyl, C1～3Alkoxy, halogen, C2～6Carboxylic acid groups or C2～6A carboxylate group;
in the formulae (I), (II) and (III), preferably, R2Or R4Each independently selected from hydrogen, nitro, C1～3Alkyl radical, C1～3Haloalkyl, C2～6Carboxylic acid group, C2～6A carboxylate group or a halogen;
in the formulae (I), (II) and (III), preferably, R3Selected from hydrogen or nitro.
In the formulae (I), (II) and (III), preferably, R1、R2、R3、R4Or R5Each independently selected from hydrogen, nitro, methyl, methoxy, chloro, fluoro or ethyl formate.
In the formulae (I), (II) and (III), preferably, R6Or R7Each independently selected from hydrogen or acetyl, or R6And R7Linked to form an isopropylidene group.
The compounds of the invention can be prepared by the following method:
the present invention further provides a process for the preparation of a preferred compound comprising the steps of:
a) andrographolide 14-alpha configuration OH introduces acetyl through Mitsunobu reaction, and the configuration of 14-position is changed (from alpha configuration to beta configuration). In the presence of inert gas and under ice bath, sequentially adding andrographolide derivative-alcohol 14-alpha-OH (1 equivalent), triphenylphosphine (1-10 equivalents), acetic acid (1-10 equivalents) and anhydrous THF into a reaction three-neck flask, then slowly adding a THF solution of diisopropyl azodicarboxylate (DIAD, 1-10 equivalents), stirring for 1 hour under ice bath, and reacting at room temperature overnight. Most of THF is distilled off, ethyl acetate/water (1/1-1/5) is used for extraction for a plurality of times to remove most of hydrazine as a byproduct, and the organic layer is dried by anhydrous sodium sulfate and then subjected to column chromatography or recrystallization to obtain a 14-beta-OAc product.
b) Dissolving the 14-beta-OAc product in methanol, adding a catalytic amount of p-toluenesulfonic acid, stirring at room temperature for reaction for 30min, evaporating the solvent to dryness, diluting with ethyl acetate, washing with saturated sodium bicarbonate solution, water and saturated sodium chloride solution respectively, drying the organic phase with anhydrous sodium sulfate, and performing column chromatography or recrystallization to obtain the andrographolide 14-OAc epimer or 14-epimer.
c) Adding 14-epimer, catalytic amount of paratoluenesulfonic acid pyridinium (PPTS), adding a certain amount of dewatered dichloromethane, finally adding 2, 2-dimethoxypropane (1-200 equivalent), slowly heating to 40 ℃, reacting for 3-12 hours, then basically completely reacting, stopping heating, cooling to room temperature, diluting with ethyl acetate, washing with saturated sodium bicarbonate solution, drying an organic phase with anhydrous sodium sulfate, and then carrying out column chromatography or recrystallization to obtain a 14-beta-OH product.
d) In the presence of inert gas and in ice bath, sequentially adding andrographolide derivative-alcohol (1 equivalent), triphenylphosphine (1-10 equivalents), phenol (1-10 equivalents) and anhydrous THF into a reaction flask, then slowly adding a THF solution of diisopropyl azodicarboxylate (DIAD, 1-10 equivalents), stirring for 1 hour in ice bath, and reacting at room temperature-80 ℃ overnight. Most of THF is distilled off, ethyl acetate/water (1/1-1/5) is used for extraction for a plurality of times to remove most of hydrazine as a byproduct, an organic layer is dried by anhydrous sodium sulfate, and column chromatography is carried out to obtain A or D series products.
e) Dissolving the A or D series products in methanol, adding catalytic amount of p-toluenesulfonic acid, stirring at room temperature to react for 3Omin, evaporating the solvent to dryness, diluting with ethyl acetate, washing with saturated sodium bicarbonate solution, water and saturated sodium chloride solution in sequence, drying the organic phase with anhydrous sodium sulfate, and performing column chromatography to obtain B or E series products.
f) A series of products B or E (1 equivalent), zinc chloride (0.5 to 20 equivalents) and acetic anhydride (1 to 100 equivalents) are sequentially added into a reaction bottle, and the mixture is heated and reacted for 5 hours at the temperature of 30 to 90 ℃. Cooling to room temperature, adding water, ethyl acetate and saturated sodium bicarbonate solution, washing with water and saturated sodium chloride solution, drying the organic phase with anhydrous sodium sulfate, and performing column chromatography to obtain C or F series products.
Another technical problem to be solved by the present invention is to provide the use of the above 14-aryl ether andrographolide derivatives, stereoisomers, cis-trans isomers, or pharmaceutically acceptable salts thereof in medicine:
the application of the 14-aryl ether andrographolide derivative compound, stereoisomer, cis-trans isomer or pharmaceutically acceptable salt thereof in medicines for regulating the function of a nuclear receptor FXR (Farnesoidoxreceptor) and preventing and treating diseases related to FXR.
14-aryl ether andrographolide derivatives, stereoisomers, cis-trans isomers or pharmaceutically acceptable salts thereof are used for treating and preventing tumor and for treating cholesterol and dyslipidemias, such as lowering cholesterol and blood lipids.
14-aryl ether andrographolide derivatives, stereoisomers, cis-trans isomers or pharmaceutically acceptable salts thereof can be used for treating and preventing diabetes, obesity and other metabolic diseases, cardiovascular diseases, reproductive system diseases, immune diseases, inflammation, senile dementia, Parkinson's disease and other neurological disorders,
a pharmaceutical composition mainly comprises the 14-aryl ether andrographolide derivative, stereoisomer, cis-trans isomer or pharmaceutically acceptable salt thereof as an active ingredient and at least one pharmaceutically acceptable carrier.
Definition of
The invention is also directed to a pharmaceutically acceptable solvate, which may be a crystalline hydrate or a crystalline form with other solvents, such as ethanol.
Pharmaceutically acceptable salts form part of the invention:
if a compound of the invention is basic, suitable "pharmaceutically acceptable salts" include the conventional non-toxic salts of the compounds of the invention formed by the reaction of a compound of the invention with an inorganic or organic acid. For example, salts derived from inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, and the like are included, as are salts derived from organic acids such as acetic acid, propionic acid, succinic acid, glycolic acid, stearic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, maleic acid, hydroxymaleic acid, phenylacetic acid, glutamic acid, benzoic acid, salicylic acid, sulfanilic acid, fumaric acid, toluenesulfonic acid, methanesulfonic acid, ethanedisulfonic acid, oxalic acid, isethionic acid, trifluoroacetic acid, and the like.
If a compound of the invention is acidic, an appropriate "pharmaceutically acceptable salt" refers to a salt of a compound of the invention prepared by a pharmaceutically acceptable non-toxic base including inorganic and organic bases. Salts derived from inorganic bases include aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic, manganous, potassium, sodium, zinc, and the like. Salts derived from pharmaceutically acceptable organic non-toxic bases including salts of primary, secondary and tertiary amines, and substituted amines including naturally occurring and synthetic substituted amines, cyclic amines and basic ion exchange resins. Such as arginine, betaine, caffeine, choline, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, aminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucosamine, histidine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, and the like.
The compounds of the present invention may have asymmetric centers, chiral axes and chiral planes and the racemates, racemic mixtures and individual diastereomers and all possible isomers and mixtures thereof, including optical isomers, that exist are included in the present invention. In addition, the compounds disclosed herein may exist as tautomers, and both tautomeric forms are included within the scope of the invention, even if only one of the tautomeric structures is depicted. For example, any claim below to compound a is understood to include the tautomeric structure B and vice versa, including mixtures thereof as well.
The double bond cis-trans isomers present in the present invention may be present as a single isomer, or as a mixture of cis and trans isomers, even though only one of the isomeric structures is depicted.
The term "hydrocarbyl" as used herein is intended to include C1-C18 alkyl, C2-C18 alkenyl, C2-C18 alkynyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocyclyl, heterocycloalkyl. The line drawn from a substituent into the ring system indicates that the bond indicated may be attached to any atom of the ring which is capable of substitution. If the ring system is polycyclic, it means that such a bond is only attached to any suitable carbon atom of the adjacent ring.
The term "optionally substituted" is to be understood that substituents and substitution patterns on the compounds of the present invention may be selected by one of ordinary skill in the art to provide compounds that are chemically stable and may be synthesized by techniques and methods of the art from available starting materials. If a substituent is itself substituted with more than one group, it is understood that these groups may be on the same carbon atom or on different carbon atoms, so long as the structure is stable.
The term "alkyl" as used herein is intended to include branched, straight chain or cyclic saturated aliphatic hydrocarbon groups having the specified number of carbon atoms. The definition of "C1-C18" in "C1-C18 alkyl" includes groups having a main chain of 1, 2, 3, 4, 5, 6, 7, 8-18 carbon atoms in a linear or branched arrangement. For example, "C1-C18 alkyl" specifically includes methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, pentyl, hexyl, heptyl, octyl, cyclopropyl, methyl-cyclopropyl, 2-dimethyl-cyclobutyl, 2-ethyl-cyclopentyl, cyclohexyl, and the like.
The term "alkenyl" refers to a straight, branched or cyclic non-aromatic hydrocarbon group having a main chain containing 12 to 18 carbon atoms and at least one carbon-carbon double bond. Thus, "C12-C18 alkenyl" refers to alkenyl groups having 12 to 18 carbon atoms in the main chain. Alkenyl groups include ethenyl, propenyl, butenyl, 2-methylbutenyl, cyclohexenyl and the like. The straight, branched, or cyclic portion of an alkenyl group can contain a double bond and this portion can be substituted if a substituted alkenyl group is indicated.
The term "alkynyl" refers to a straight, branched or cyclic non-aromatic hydrocarbon group having a main chain containing 12 to 18 carbon atoms and at least one carbon-carbon triple bond. Thus, "C12-C18 alkynyl" refers to alkynyl groups having 12-18 carbon atoms. Alkynyl includes ethynyl, propynyl, butynyl, 3-methylbutynyl and the like. The straight, branched, or cyclic portion of the alkynyl group can contain triple bonds and this portion can be substituted if a substituted alkynyl group is indicated.
The term "aryl" refers to any stable monocyclic or bicyclic carbon ring of up to 3-10 atoms in each ring, wherein at least one ring is aromatic. Examples of aryl groups include phenyl, naphthyl, anthracenyl, and biphenyl.
The term "aralkyl" includes groups in which the above-mentioned "alkyl" is substituted with the above-mentioned "aryl". Examples of aralkyl groups include benzyl, phenethyl, naphthylmethylene, anthracenylmethylene.
The term "heteroaryl" represents a stable monocyclic or bicyclic carbon ring of up to 3-10 atoms in each ring, wherein at least one ring is aromatic and contains 1-4 heteroatoms selected from O, N and S. Heteroaryl groups within the scope of this definition include, but are not limited to, acridinyl, carbazolyl, cinnolinyl, quinoxalinyl, pyrazolyl, indolyl, benzotriazolyl, furanyl, thienyl, benzothienyl, benzofuranyl, quinolinyl, isoquinolinyl, oxazolyl, isoxazolyl, indolyl, pyrazinyl, pyridazinyl, pyridyl, pyrimidinyl, pyrrolyl.
The term "heteroaralkyl" includes groups in which the above-described "alkyl" is substituted with the above-described "heteroaryl". Examples of heteroaryl groups include furanmethylene, pyridylethyl, pyrrolymethylene.
The term "heterocyclyl" refers to a 3-12 membered aromatic or nonaromatic heterocyclic ring containing 1-4 heteroatoms selected from O, N and S, and includes bicyclic groups. "Heterocyclyl" thus includes the above-mentioned heteroaryl groups, as well as the dihydro and tetrahydro analogues thereof. Further examples of "heterocyclyl" include, but are not limited to, benzimidazolyl, benzofuranyl, benzopyranyl, benzopyrazolyl, benzotriazolyl, benzothienyl, benzoxazolyl, carbazolyl, carbolinyl, cinnolinyl, furanyl, imidazolyl, indolinyl, indolyl, indazolyl, isobenzofuranyl, isoindolyl, isoquinolyl, isothiazolyl, oxadiazolyl, oxazolyl, oxazoline, isoxazoline, oxetanyl (oxyethanyl), pyranyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridopyridyl, pyridazinyl, pyridyl, pyrimidinyl, pyrrolyl, quinazolinyl, quinolinyl, quinoxalinyl, tetrahydropyranyl, tetrazolyl, tetrazolopyridyl, thiadiazolyl, thiazolyl, thienyl, triazolyl, azetidinyl, l, 4-dioxanyl, azepanyl (hexahydrolazinyl), Piperazinyl, piperidinyl, pyridin-2-onyl, pyrrolidinyl, morpholinyl, thiomorpholinyl (thiomorpholinyl), dihydrobenzimidazolyl, dihydrobenzofuranyl, dihydrobenzothienyl, dihydrobenzoxazolyl, dihydrofuranyl, dihydroimidazolyl, dihydroindolyl, dihydroisoxazolyl, dihydroisothiazolyl, dihydrooxadiazolyl, dihydrooxazolyl, dihydropyrazinyl, dihydropyrazolyl, dihydropyridinyl, dihydropyrimidinyl, dihydropyrrolyl, dihydroquinolinyl, dihydrotetrazolyl, dihydrothiadiazolyl, dihydrothiazolyl, dihydrothienyl, dihydrotriazolyl, dihydroazetidinyl, methylenedioxybenzoyl, tetrahydrofuranyl and tetrahydrothienyl, and N-oxides thereof. Attachment of the heterocyclic substituent may be through a carbon atom or through a heteroatom.
The term "cyclic" indicates cyclic compounds containing more than 3 carbons or other atoms in the ring.
The term "polycyclic" includes structures in which at least 2 rings are formed, spiro rings in which at least two of the rings have 1 atom in common between them or fused or bridged (bridged) ring structures in which at least 2 atoms are in common between them. Typical structures are the basic structures of adamantane, norbornane, norbornene, pinane, (iso) camphane, carane, and the like. Structures which may or may not contain substituents on these rings, and these polycyclic structures may be hetero-polycyclic.
The term "heterocyclic group" includes groups in which the above-mentioned "alkyl group" is substituted with the above-mentioned "heterocyclic group". Examples of heterocyclic groups include imidazolylmethylene, pyrrolidinoethyl, tetrazolylmethylene.
The term "halogen" is meant to include fluorine, chlorine, bromine and iodine.
The term "individual" means that the variables that are applied independently vary independently between applications.
The andrographolide derivatives of the present invention may be formulated into pharmaceutical compositions for administration to a patient in accordance with a variety of suitably selected modes of administration, including systemically, e.g., orally or parenterally, intravenously, intramuscularly, transdermally, or subcutaneously, etc.
The preferred mode of administration of andrographolide derivatives is oral, but the dosage form and mode of administration used will depend on the particular physical and chemical characteristics and stability of the compound, as well as on the difference in therapeutic objectives, including but not limited to sustained release controlled administration.
Detailed Description
Example 1: synthesis of andrographolide 14-beta configuration derivative
Andrographolide 14-alpha configuration OH introduces acetyl through Mitsunobu reaction, and the configuration of 14-position is changed (from alpha configuration to beta configuration). In the presence of inert gas and under ice bath, sequentially adding andrographolide derivative-alcohol 14-alpha-OH (1 equivalent), triphenylphosphine (1-10 equivalents), acetic acid (1-10 equivalents) and anhydrous THF into a reaction three-neck flask, then slowly adding a THF solution of diisopropyl azodicarboxylate (DIAD, 1-10 equivalents), stirring for 1 hour under ice bath, and reacting at room temperature overnight. Most of THF is distilled off, ethyl acetate/water (1/1-1/5) is used for extraction for a plurality of times to remove most of hydrazine as a byproduct, and then the organic layer is dried by anhydrous sodium sulfate and is subjected to column chromatography or recrystallization to obtain a 14-beta-OAc product with the yield of 70 percent.
Dissolving the 14-beta-OAc product in methanol, adding a catalytic amount of p-toluenesulfonic acid, stirring at room temperature for reaction for 30min, evaporating the solvent to dryness, diluting with ethyl acetate, washing with saturated sodium bicarbonate solution, water and saturated sodium chloride solution in sequence, drying the organic phase with anhydrous sodium sulfate, and performing column chromatography or recrystallization to obtain the andrographolide 14-OAc epimer or 14-epimer with the yield of 90%.
14-epimer, catalytic amount of paratoluenesulfonic acid pyridinium (PPTS), a certain amount of dewatered dichloromethane, finally 2, 2-dimethoxypropane (1-200 equivalent) are added, the mixture is slowly heated to 40 ℃, the reaction is basically completed after 3-12 hours, the heating is stopped, the mixture is cooled to room temperature and diluted by ethyl acetate, saturated sodium bicarbonate solution is used for washing, the organic phase is dried by anhydrous sodium sulfate and then is subjected to column chromatography or recrystallization to obtain a 14-beta-OH product, and the yield is 82%.
Example 2: synthesis of A or D series compounds
In the presence of inert gas and in ice bath, sequentially adding andrographolide derivative-alcohol (1 equivalent), triphenylphosphine (1-10 equivalents), phenol (1-10 equivalents) and anhydrous THF into a reaction flask, then slowly adding a THF solution of diisopropyl azodicarboxylate (DIAD, 1-10 equivalents), stirring for 1 hour in ice bath, and reacting at room temperature-80 ℃ overnight. Most of THF is distilled off, ethyl acetate/water (1/1-1/5) is used for extraction for a plurality of times to remove most of hydrazine as a byproduct, an organic layer is dried by anhydrous sodium sulfate, and the A or D series products are obtained by column chromatography or recrystallization, wherein the yield is 30-80%. The above compounds1HNMR、13The CNMR, high resolution mass spectral data are shown in table 1.
Example 3: synthesis of B or E series compounds
Dissolving the A or D series products in methanol, adding catalytic amount of p-toluenesulfonic acid, stirring at room temperature to react for 3Omin, evaporating the solvent to dryness, diluting with ethyl acetate, washing with saturated sodium bicarbonate solution, water and saturated sodium chloride solution in sequence, drying the organic phase with anhydrous sodium sulfate, and performing column chromatography or recrystallization to obtain the B or E series products with the yield of 90%. The above compounds1HNMR、13The CNMR, high resolution mass spectral data are shown in table 1.
Example 4: synthesis of C or F series compounds
A series of products B or E (1 equivalent), zinc chloride (0.5 to 20 equivalents) and acetic anhydride (1 to 100 equivalents) are sequentially added into a reaction bottle, and the mixture is heated and reacted for 5 hours at the temperature of 30 to 90 ℃. And cooling to room temperature, adding water, ethyl acetate and a saturated sodium bicarbonate solution, fully washing, washing with water and a saturated sodium chloride solution, drying an organic phase with anhydrous sodium sulfate, and performing column chromatography or recrystallization to obtain C or F series products with the yield of 40-90%. The above compounds1HNMR、13The CNMR, high resolution mass spectral data are shown in table 1.
Process for preparing compounds of part of Table 11HNMR、13CNMR, high resolution mass spectrometry data
Example 5: basic scheme for screening nuclear receptor Farnesoid X Receptor (FXR) ligand
The 14-aryl ether andrographolide derivative is screened to regulate the FXR activity of the nuclear receptor by using an in vitro screening model capable of simulating in vivo biological states according to a disclosed screening method.
Usually the compounds to be tested are dissolved in DMSO to make a gradient and diluted with PBS to 2% DMSO working solution before use, the drug-free control working solution is 2% DMSO PBS, the drug-containing working solution and the drug-free control working solution are added to the experimental wells and diluted 20-fold, the final DMSO concentration in all experimental wells is 0.1%. The activity of the compound is measured by simultaneously setting a blank group, a positive drug or a control group of the positive compound.
293T cells in logarithmic growth phase at 2X104The/well was passaged in 96-well cell culture plates, cultured overnight, and used for transfection when 80-90% of the cells were full.
Lipofectamine2000 reagent (0.5. mu.l/100. mu.l) and plasmid DNA were diluted with optimized culture solution DMEM. The plasmid concentration after dilution of the optimized culture solution is pCMV-Gal4-FXR-LBD, 25 ng/well, pFR-Luci, 50 ng/well, pFRClaczeoplamid, 50 ng/well. After the Lipofectamine2000 was diluted for 5 minutes, the diluted liposome and plasmid DNA were mixed in equal volumes, and the liposome/DNA mixture was removed after standing at room temperature for 20 min.
The cells were quickly changed to 100. mu.l DMEM containing 10% fetal bovine serum. The liposome/DNA mixture was added dropwise with the applicator head deep below the liquid surface and mixed by gentle shaking.
Test compounds were dissolved in DMSO and transfected into the plasmid 6 hours after transient transfection of the cellsDifferent concentrations of compound and the same concentration of DMSO control were added. Put in 5% CO2The incubation was continued in the incubator for 24 hours. VERITAS was used according to the Promega Steady-Glokit SpecificationTMMicroplastelunometer (Turner biosystems) to determine the fluorescence of the cells, which reflects FXR activity and is calibrated with Gal as an internal standard, 20. mu.l of cell lysate are placed in a 96-well plate, 1.5. mu.l of 100 × Mg solution, 33. mu.l of 1 × ONPG solution, 0.1mol/L sodium phosphate (pH7.5), 95.5. mu.l of 0.1mol/L sodium phosphate (pH7.5) are added and the cell lysate is incubated at 37 ℃ until a yellow color appears, 50. mu.l of 0.1mol/L LNa is added2CO3End reaction read OD405。
The study of the activity of the antagonist requires the simultaneous addition of the receptor corresponding endogenous agonist chenodeoxycholic acid (CDCA) (final concentration 25 μ M).
The antagonist activity of some compounds is shown in table 2. The literature reports that FXR agonists or modulators with both partial agonist and partial antagonist characteristics are mainly used (e.g., GW4064, MFA-1, etc., see PNAS2008,105(14): 5337-5342; J. SurgeryConcepts)&Practice2010, 04 th year). The FXR antagonist compounds reported in this patent have better activity than FXR antagonist compounds reported in another document (IC of the best FXR inhibitor of j.med.chem.2012,55,7037-50At 8.9 μ M, in Table 2, 10 compounds active IC were contained, including first B2, A3, A2, 14- α -OH, A4, A6, A8, A9, A10 and A1150Less than 5.0 μ M, IC of 8 compounds in total of 14- β -OAc, E1, B1, B3, D2, B9, B10 and B1150Less than or near 8.9 μ M).
FXR antagonist Activity of the Compounds part of Table 2

Claims (7)

1. A compound represented by the formula (III) or a pharmaceutically acceptable salt thereof,
R1、R2、R3、R4or R5Each independently selected from hydrogen, nitro, halogen, C1～3Alkyl radical, C1～3Haloalkyl, C1～3Alkoxy radical, C3～6Cycloalkyl radical, C2～6Carboxylic acid groups or C2～6A carboxylate group;
R6or R7Each independently selected from hydrogen and C1～3Acyl radical, C1～3Alkyl radical, C1～3Haloalkyl, or R6And R7Are connected to form C1～6An alkylene group;
and the structure is represented by R or S.
2. A compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein
R1Or R5Each independently selected from hydrogen, nitro, C1～3Alkyl radical, C1～3Haloalkyl, C1～3Alkoxy, halogen, C2～6Carboxylic acid groups or C2～6A carboxylate group;
R2or R4Each independently selected from hydrogen, nitro, C1～3Alkyl radical, C1～3Haloalkyl, C2～6Carboxylic acid group, C2～6A carboxylate group or a halogen;
R3selected from hydrogen or nitro.
3. A compound according to claim 2, or a pharmaceutically acceptable salt thereof, wherein
R1、R2、R3、R4Or R5Each independently selected from hydrogen, nitro, methyl, methoxy, chloro, fluoro or ethyl formate;
R6or R7Each independently selected from hydrogen or acetyl, or R6And R7Linked to form an isopropylidene group.
4. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein said compound is selected from the group consisting of:
14- (R) -phenoxy-3, 19-isopropylidene andrographolide,
14- (R) - (4' -nitro-phenoxy) -3, 19-isopropylidene-andrographolide,
14- (R) -phenoxy-andrographolide,
14- (R) - (4' -nitrophenoxy) -andrographolide,
14- (R) - (2 '-methoxy-4' -nitro-phenoxy) -3, 19-isopropylidene-andrographolide,
14- (R) - (2 '-methoxy-4' -nitro-phenoxy) -andrographolide,
14- (R) - (2 '-methyl-4' -nitro-phenoxy) -3, 19-isopropylidene-andrographolide,
14- (R) - (2 '-methyl-4' -nitro-phenoxy) -andrographolide,
14- (R) - (2 '-chloro-4' -nitro-phenoxy) -3, 19-isopropylidene-andrographolide,
14- (R) - (2 '-chloro-4' -nitro-phenoxy) -andrographolide,
14- (R) - (2' -nitro-phenoxy) -3, 19-isopropylidene-andrographolide,
14- (R) - (2' -nitro-phenoxy) -andrographolide,
14- (R) - (3' -nitro-phenoxy) -3, 19-isopropylidene-andrographolide,
14- (R) - (3' -nitro-phenoxy) -andrographolide,
14- (R) - (3 '-methyl-4' -nitro-phenoxy) -3, 19-isopropylidene-andrographolide,
14- (R) - (3 '-methyl-4' -nitro-phenoxy) -andrographolide,
14- (R) - (2' -carboethoxy-phenoxy) -3, 19-isopropylidene-andrographolide,
14- (R) - (2' -ethyl formate-phenoxy) -andrographolide,
14- (R) - (2 '-fluoro-4' -nitro-phenoxy) -3, 19-isopropylidene-andrographolide,
14- (R) - (2 '-fluoro-4' -nitro-phenoxy) -andrographolide,
14- (R) - (3 '-fluoro-4' -nitro-phenoxy) -3, 19-isopropylidene-andrographolide,
14- (R) - (3 '-fluoro-4' -nitro-phenoxy) -andrographolide,
14- (R) - (2 '-methoxy-4' -nitro-phenoxy) -3, 19-diacetyl-andrographolide,
14- (S) -phenoxy-3, 19-isopropylidene-andrographolide,
14- (S) -phenoxy-andrographolide,
14- (S) - (4' -nitrophenoxy) -3, 19-isopropylidene-andrographolide,
14- (S) - (4' -nitrophenoxy) -andrographolide.
5. Use of a compound of claim 1 or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for modulating the function of nuclear receptor FXR or for the prevention or treatment of diseases associated with nuclear receptor FXR.
6. The use of a compound of claim 1, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment or prevention of a disease, wherein the disease is a tumor, cholesterol or dyslipidemia, diabetes, obesity, cardiovascular disease, a disease of the reproductive system, an immunological disease, inflammation, senile dementia, parkinson's disease or a neurological disorder.
7. A pharmaceutical composition comprising the compound of claim 1 or a pharmaceutically acceptable salt thereof as a main active ingredient, together with a pharmaceutically acceptable carrier.
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