WO2019128113A1 - 1-o-咖啡酰奎宁酸、其衍生物、制备方法及其用途 - Google Patents

1-o-咖啡酰奎宁酸、其衍生物、制备方法及其用途 Download PDF

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WO2019128113A1
WO2019128113A1 PCT/CN2018/090091 CN2018090091W WO2019128113A1 WO 2019128113 A1 WO2019128113 A1 WO 2019128113A1 CN 2018090091 W CN2018090091 W CN 2018090091W WO 2019128113 A1 WO2019128113 A1 WO 2019128113A1
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unsubstituted
substituted
group
hydrogen
alkyl
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廖杰远
孙志国
邹德超
陈先红
季鸣
谈敦潮
陈晓光
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北京微医智慧信息技术有限责任公司
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
    • C07C69/66—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety
    • C07C69/73—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety of unsaturated acids
    • C07C69/732—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety of unsaturated acids of unsaturated hydroxy carboxylic acids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
    • C07C69/74—Esters of carboxylic acids having an esterified carboxyl group bound to a carbon atom of a ring other than a six-membered aromatic ring
    • C07C69/757—Esters of carboxylic acids having an esterified carboxyl group bound to a carbon atom of a ring other than a six-membered aromatic ring having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
    • C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
    • C07D317/44—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D317/46—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems condensed with one six-membered ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
    • C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
    • C07D317/72—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 spiro-condensed with carbocyclic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
    • C07D493/02—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains two hetero rings
    • C07D493/08—Bridged systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
    • C07D493/02—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains two hetero rings
    • C07D493/10—Spiro-condensed systems

Definitions

  • the invention belongs to the technical field of medicinal chemistry, and in particular relates to a 1-O-caffeoylquinic acid, a derivative thereof, a preparation method and the use thereof.
  • the interleukin 17, IL-17 family contains six interleukins (IL-17A, IL-17B, IL-17C, IL-17D, IL-17E and IL-17F) and their receptors (IL-17RA, IL-17RB, IL-17RC, IL-17RD, IL-17RE and IL-17RF) (Gaffen, SL et al., Nature reviews. Immunity 9 (2009): 556-567).
  • IF-17F also known as IL-24 or ML-1, is a member of the IL-17 cytokine family.
  • IF-17F is about 55% identical to IL-17A and is thought to share the same receptor as IL-17A (Kolls and Linden 2004, Immunity, 21, 467-476; Hymowitz et al, 2001, EMBO J. 20 (19), 5332- 5341; Kuestner et al, 2007, Journal of Immunology, 179, 5462-5473). Both can form homodimeric and heterodimeric proteins, both produced by activated human CD4+ T cells (Wright et al, 2007, J Biol Chem. 282 (18), 13447-13455).
  • IL-17 may promote many diseases mediated by abnormal immune responses, such as rheumatoid arthritis and respiratory inflammation, as well as organ transplant rejection and anti-tumor immunity.
  • IL-17R and anti-IL-17 monoclonal antibodies have been used to demonstrate the role of IL-17 in various rheumatoid arthritis models (Lubberts et al, J. Immunol. 2001, 167, 1004-1023; Chabaud et al. Arthritis Res. 2001, 3, 168-177). Both IL-17A and IL-17F are associated with autoimmune diseases (Iwakura, Y., H. Ishigame et al. 2011, Immunity 34(2) 149-162).
  • IL-17F antagonism is associated with protection against asthma (Kawaguchi et al, 2006, J. Allergy Clin. Immunol. 117 (4); 795-801), and IL-17F also plays a role in arthritis pathology ( Lubberts 2003, Current Opinion in Investigational Drugs, 4 (5) 572-577).
  • WO2014065413 reports that triazole derivatives and isoxazole derivatives act as ROR gamma receptor inhibitors, thereby inhibiting the differentiation and activation of Th17 cells and inhibiting IL-17.
  • WO 201400944 and WO2016014918 report on aryl sultam derivatives and benzimidazole derivatives as RORc modulators, such compounds are mainly used for the treatment of autoimmune diseases.
  • WO2016213676 reports the substitution of 2,3-dihydro-1H-indol-1-one structures as ROR ⁇ t /ROR ⁇ receptor antagonists, which are useful for the regulation of ROR ⁇ t /ROR ⁇ activity and for the treatment of ROR ⁇ t / ROR ⁇ mediated diseases and conditions.
  • WO2016072402 reports a cyclic amine derivative ⁇ t on inhibit cell receptor ROR TH17, TH17 thereby inhibiting cell differentiation, reduced IL-17 secretion.
  • WO2016120849 reports the use of methoxy substituted pyrrolopyridines for ROR gamma receptor inhibitors, thereby reducing the amount of I L-17.
  • a summary of the use of 1-O-caffeoylquinic acid analogs to affect IL-17 secretion has not been reported from the above literature.
  • 1-O-caffeoylquinic acid has the structural formula of formula (I),
  • 1-O-caffeoylquinic acid is a monosubstituted depsipeptide composed of caffeic acid and quinic acid, a positional isomer of chlorogenic acid, and a phenylpropanoid compound.
  • 1-O-caffeoylquinic acid is widely found in higher dicotyledons and ferns, mainly in Lonicera and Artemisia plants, compared with chlorogenic acid.
  • 1-O-caffeoylquinic acid is less abundant in plants and difficult to separate.
  • an object of the present invention is to provide a 1-O-caffeoylquinic acid, a derivative thereof, a preparation method thereof and use thereof, and the 1-O-caffeoylquinic acid and its derivative provided by the present invention are white Interleukin 17F has a strong inhibitory effect.
  • the present invention provides a 1-O-caffeoylquinic acid derivative represented by the formula (II):
  • Q is selected from N or O
  • R 1 or R 2 are the same or different and independently selected from hydrogen, unsubstituted or substituted alkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted aryl, unsubstituted or substituted aryl An alkyl group, an unsubstituted or substituted acyl group; or, R 1 and R 2 form an acetal with an adjacent oxygen;
  • R 3 is selected from hydrogen, unsubstituted or substituted alkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted aryl, unsubstituted or substituted acyl;
  • R 4 is selected from hydrogen, unsubstituted or substituted alkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted aryl, unsubstituted or substituted arylalkyl;
  • Q is selected from the group consisting of O, R 3 and R 4 and its adjacent oxylactone
  • R 5 or R 6 are the same or different and are selected from hydrogen, unsubstituted or substituted alkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted aryl, unsubstituted or substituted arylalkyl , unsubstituted or substituted acyl;
  • R 1 , R 2 , R 3 , R 4 , R 5 and R 6 are not simultaneously H;
  • R 1 , R 2 and R 3 are not a group represented by the formula (a):
  • the 1-O-caffeoylquinic acid derivative represented by the formula (II) is a caffeoyl quinic acid derivative, not a polycaffeoylquinic acid derivative such as dicaffeoquinine.
  • An acid derivative or a tricaffeoylquinic acid derivative does not include 1-O-caffeoylquinic acid.
  • the present application surprisingly finds that 1-O-caffeoylquinic acid, a 1-O-caffeoylquinic acid derivative represented by formula (II) and a salt thereof have an effect of inhibiting the secretion of interleukin 17, and thus Can be used as an interleukin 17 modulator.
  • interleukin 17 is interleukin 17F.
  • the present application also demonstrates that 1-O-caffeoylquinic acid, a 1-O-caffeoylquinic acid derivative represented by the formula (II), and a salt thereof have an action of preventing and treating a tumor, and thus can be used as a preventive And drug applications for the treatment of tumors.
  • the tumor includes solid tumors and non-solid tumors, including but not limited to melanoma, pancreatic cancer, colorectal cancer, lung cancer, liver cancer, gastric cancer, laryngeal cancer, nasopharyngeal cancer, esophageal cancer, multiple Myeloma, lymphoma, leukemia, bladder cancer, prostate cancer, cholangiocarcinoma, cervical cancer, ovarian cancer, breast cancer, endometrial cancer, skin cancer, etc.
  • melanoma pancreatic cancer
  • colorectal cancer lung cancer
  • liver cancer gastric cancer
  • laryngeal cancer nasopharyngeal cancer
  • esophageal cancer multiple Myeloma
  • lymphoma lymphoma
  • leukemia bladder cancer
  • prostate cancer cholangiocarcinoma
  • cervical cancer ovarian cancer
  • breast cancer endometrial cancer
  • skin cancer etc.
  • 1-O-caffeoylquinic acid a 1-O-caffeoylquinic acid derivative represented by the formula (II) and a salt thereof have an effect of preventing and treating an autoimmune disease, and therefore, As a drug application for the prevention and treatment of autoimmune diseases.
  • the autoimmune disease drugs include, but are not limited to, systemic lupus erythematosus, psoriasis, rheumatoid arthritis, scleroderma, and the like.
  • the 1-O-caffeoylquinic acid derivative represented by the formula (II) is actually a prodrug of 1-O-caffeoylquinic acid which enters the human body in various enzymes and human body. It is converted into 1-O-caffeoylquinic acid in the environment to exert an inhibitory effect on the secretion and activity of interleukin-17F, and to prevent and treat tumors or autoimmune diseases.
  • the salt of 1-O-caffeoylquinic acid or the salt of the 1-O-caffeoylquinic acid derivative represented by the formula (II) means a pharmaceutically acceptable salt, that is, in a reasonable medical judgment. Within the scope, they are suitable for contact with humans and lower animal tissues without undue toxicity, irritation, allergies, etc., commensurate with a reasonable benefit/risk ratio.
  • Salts of 1-O-caffeoylquinic acid of the invention or salts of 1-O-caffeoylquinic acid derivatives of formula (II) include those derived from suitable inorganic and organic bases.
  • the inorganic base salts include salts with ammonia, alkali metals, alkaline earth metals or transition metals, such as ammonium salts and lithium, sodium, potassium, calcium, zinc, iron, ferrous salts and the like.
  • the organic base salt includes an amine salt, and includes a 1-O-caffeoylquinic acid or a salt of a 1-O-caffeoylquinic acid derivative represented by the formula (II) and a primary, secondary or tertiary amine, which may be selected from the group consisting of Salts formed with the following organic bases: for example, arginine, ethylenediamine, triethylamine, caffeine, betaine, ethanolamine, trimethylamine, piperidine, and the like.
  • the 1-O-caffeoylquinic acid derivative is as shown in the formula (II):
  • Q is selected from O.
  • R 1 or R 2 are the same, independently selected from hydrogen, an alkyl group of 3 or less carbon atoms or an alkyl acyl group of 5 or less carbon atoms.
  • R 1 and R 2 form an acetal of formula (b) with its adjacent oxygen:
  • R 7 and R 8 are independently selected from hydrogen, an alkyl group of 5 or less carbon atoms, an alkenyl group of 5 or less carbon atoms, a substituted or unsubstituted phenyl group, or a phenyl alkenyl group; or, R 7 , R 8 forms a 4-6-membered ring with its adjacent C.
  • R 3 is selected from hydrogen or an alkyl group of 3 or less carbon atoms.
  • R 4 is selected from the group consisting of hydrogen and an alkyl group of 3 or less carbon atoms.
  • R 3 and R 4 form a lactone with its adjacent oxygen.
  • R 5 or R 6 are the same and are selected from the group consisting of hydrogen, an alkyl group having 3 or less carbon atoms, and an alkyl group having 4 or less carbon atoms.
  • the 1-O-caffeoylquinic acid derivative represented by the formula (II) has a structure of the formula (II-1):
  • R 1 or R 2 is the same, independently selected from hydrogen, an alkyl group of 3 or less carbon atoms or an alkyl group of 5 or less carbon atoms; and R 3 is selected from hydrogen or an alkyl group of 3 or less carbon atoms; 4 is selected from the group consisting of hydrogen and an alkyl group having 3 or less carbon atoms; and R 5 or R 6 is the same, and is selected from the group consisting of hydrogen, an alkyl group having 3 or less carbon atoms, and an alkyl group having 4 or less carbon atoms. That is, in the 1-O-caffeoylquinic acid derivative represented by the formula (II), R 1 and R 2 do not form an acetal, and R 3 and R 4 do not form a lactone.
  • the 1-O-caffeoylquinic acid derivative represented by the formula (II) has a structure of the formula (II-2):
  • R 1 or R 2 is the same, independently selected from hydrogen, an alkyl group having 3 or less carbon atoms or an alkyl group having 5 or less carbon atoms;
  • R 5 or R 6 is the same and is selected from the group consisting of hydrogen, an alkyl group having 3 or less carbon atoms, and an alkyl group having 4 or less carbon atoms.
  • R 1 and R 2 do not form an acetal, and R 3 and R 4 form a lactone.
  • the 1-O-caffeoylquinic acid derivative represented by the formula (II) has a structure of the formula (II-3):
  • R 7 and R 8 are independently selected from hydrogen, an alkyl group having 5 or less carbon atoms, an alkenyl group having 5 or less carbon atoms, a substituted or unsubstituted phenyl group or a phenyl alkenyl group;
  • R 3 is selected from hydrogen or an alkyl group of 3 or less carbon atoms
  • R 4 is selected from the group consisting of hydrogen and an alkyl group having 3 or less carbon atoms.
  • R 5 or R 6 is the same and is selected from the group consisting of hydrogen, an alkyl group having 3 or less carbon atoms, and an alkyl group having 4 or less carbon atoms.
  • R 1 and R 2 form an acetal, and R 3 and R 4 do not form a lactone.
  • the 1-O-caffeoylquinic acid derivative represented by the formula (II) has a structure of the formula (II-4):
  • R 3 is selected from hydrogen or an alkyl group of 3 or less carbon atoms
  • R4 is selected from the group consisting of hydrogen and an alkyl group having 3 or less carbon atoms
  • R5 or R6 is the same, and is selected from the group consisting of hydrogen, an alkyl group having 3 or less carbon atoms, and an alkyl group having 4 or less carbon atoms;
  • n is selected from 1, 2, 3 or 4.
  • R1 and R2 form an acetal, and the substituent thereon forms a 3- to 6-membered ring, and R3 and R4 do not form a lactone.
  • the 1-O-caffeoylquinic acid derivative represented by the formula (II) has a structure of the formula (II-5):
  • R 7 and R 8 are independently selected from hydrogen, an alkyl group having 5 or less carbon atoms, an alkenyl group having 5 or less carbon atoms, a substituted or unsubstituted phenyl group or a phenyl alkenyl group;
  • R 5 or R 6 is the same and is selected from the group consisting of hydrogen, an alkyl group having 3 or less carbon atoms, and an alkyl group having 4 or less carbon atoms.
  • R 1 and R 2 form an acetal
  • R 3 and R 4 form a lactone
  • the 1-O-caffeoylquinic acid derivative represented by the formula (II) has a structure of the formula (II-6):
  • R 5 or R 6 is the same, and is selected from the group consisting of hydrogen, an alkyl group having 3 or less carbon atoms, and an alkyl group having 4 or less carbon atoms;
  • n is selected from 1, 2, 3 or 4.
  • R 1 and R 2 form an acetal, the substituent thereon forms a 3- to 6-membered ring, and R 3 and R 4 are formed. Lactone.
  • 1-O-caffeoylquinic acid or a derivative thereof represented by the formula (II) can be produced by the following method:
  • the starting material quinic acid is lactone ring in the presence of a catalyst, and a protecting group is introduced at the 3,4 position to obtain compound II.
  • Compound II reacts with SM to obtain compound III, and compound III is deprotected to obtain compound of formula (I). .
  • the reaction process is as follows:
  • ⁇ R 1 , ⁇ R 2 , ⁇ R 4 , ⁇ R 5 , and R 6 are the same as those defined for R 1 , R 2 , R 3 , R 4 , R 5 , and R 6 in the formula (II), however, When the target product is 1-O-caffeoylquinic acid, all of R 1 , R 2 , R 3 , R 4 , R 5 , and R 6 may be H.
  • X is a halogen or a hydroxyl group.
  • the method of ester formation usually has two methods: when SM is the corresponding carboxylic acid, in a conventional condensing agent (for example, N, N'-bicyclic ring) Benzyl carbodiimide (DCC), 1-ethyl-(3-dimethylaminopropyl) carbodiimide (EDC), etc.
  • DCC Benzyl carbodiimide
  • EDC 1-ethyl-(3-dimethylaminopropyl) carbodiimide
  • the base used for deprotecting the compound III is lithium hydroxide, sodium hydroxide, potassium hydroxide or the like; and the acid is an aqueous hydrochloric acid solution, an aqueous sulfuric acid solution, an aqueous solution of trifluoroacetic acid or the like.
  • alkyl means a saturated straight or branched hydrocarbon group of 1 to 12 carbon atoms.
  • alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, 2 a -methylbutyl, neopentyl, n-hexyl, heptyl, octyl group.
  • alkenyl means a monovalent group derived from a hydrocarbon moiety by removing a single hydrogen atom, wherein the hydrocarbyl moiety has at least one carbon-carbon double bond and contains 2 to 12 carbon atoms, respectively.
  • Representative alkenyl groups include, but are not limited to, ethenyl, propenyl, butenyl, 1-methyl-2-buten-1-yl, heptenyl, and the like.
  • cycloalkyl means that the saturated carbocyclic compound has 3 to 12 ring atoms.
  • cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl.
  • acyl includes residues derived from an acid including, but not limited to, a carboxylic acid, a carbamic acid, a carbonic acid, a sulfonic acid, and a phosphoric acid.
  • examples include aliphatic carbonyl groups, aromatic carbonyl groups, aliphatic sulfonic acid groups.
  • aliphatic carbonyl groups include, but are not limited to, acetyl, propionyl, butyryl, and the like.
  • halogen means an atom of fluorine, chlorine, bromine or iodine.
  • aryl refers to a monocyclic, bicyclic or tricyclic carbocyclic ring system having from 1 to 3 aromatic rings including, but not limited to, phenyl, naphthyl, tetrahydronaphthyl, anthracenyl and Similar group.
  • arylalkyl refers to an aryl group, as defined herein, appended to the parent molecule through an alkyl group, as defined herein. Examples include, but are not limited to, benzyl, phenethyl and the like.
  • substituted means that one, two or three or more hydrogen atoms thereof are independently substituted by a substituent including, but not limited to, halogen, -OH, protected hydroxyl group, -NO 2 , -CN, -NH 2 , protected amino group, alkoxy group, and the like.
  • the present invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising 1-O-caffeoylquinic acid, a 1-O-caffeoylquinic acid derivative represented by formula (II) or a salt thereof, and a pharmaceutically acceptable adjuvant .
  • composition in the context of the present invention means any and all solvents, diluents or other liquid excipients, dispersing or suspending aids, surfactants, isotonic agents, etc., which are suitable for the particular dosage form desired. Thick or emulsifier, preservative, solid binder, lubricant, etc.
  • Remington's Pharmaceutical Sciences, Sixteenth Edition, E. W. Maetin (Mack Publishing Co., Easton, Pa., 1980) discloses various carriers for formulating pharmaceutically acceptable compositions and known techniques for their preparation.
  • materials that can serve as pharmaceutically acceptable carriers include, but are not limited to, ion exchangers; alumina; aluminum stearate; lecithin; buffer materials such as: phosphate; glycine; sorbic acid or potassium sorbate a mixture of fatty acid esters of saturated plant fatty acids; water; salts or electrolytes, for example: disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts; colloidal silica; magnesium trisilicate; polyvinylpyrrolidone; Acrylates; saccharides such as lactose, glucose and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives, such as sodium carboxymethylcellulose, ethylcellulose and cellulose acetate; gelatin; talc; Excipients such as waxes for cocoa butter and suppositories; oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil
  • the present invention also provides a pharmaceutical preparation comprising 1-O-caffeoylquinic acid, a 1-O-caffeoylquinic acid derivative represented by formula (II) or a salt thereof, and a pharmaceutically acceptable adjuvant.
  • the compound of the present invention or a salt thereof can be formulated into a conventional pharmaceutical preparation such as a capsule, a tablet, a pill, a granule, an emulsion, a flocculating agent, an injection, a drip, or the like according to a conventional preparation method.
  • 1-O-caffeoylquinic acid a 1-O-caffeoylquinic acid derivative represented by the formula (II) and a salt thereof have an effect of inhibiting the secretion of interleukin 17, particularly interleukin 17F, And can prevent and treat tumors.
  • the experimental results show that the inhibition rate of interleukin-17F is close to 70% when the concentration of 1-O-caffeoylquinic acid is 0.5 ⁇ M/L; the effect of 1-O-caffeoylquinic acid on melanoma at the dose of 20mg/kg Pancreatic cancer, colorectal cancer, lung cancer and other tumors have a good inhibitory effect, more than 50%, and its derivatives have a good inhibitory effect on melanoma, pancreatic cancer, colorectal cancer, lung cancer and other tumors.
  • D-(-)-Quinic acid (30.0 g, 0.156 mol, according to the literature Valentina Sinisi. Et al., "Interaction of chlorogenic acids and quinides from coffee with human serum albumin", Food Chemistry, 2015 (168): 332- Prepared by the method of 340), p-toluenesulfonic acid monohydrate (1.50 g, 7.8 mmol) and acetone (1200.0 ml) were placed in a single-mouth bottle, and a Soxhlet extractor having a molecular sieve was placed thereon, and the mixture was heated under reflux for 24 hours. When the system starts to react, it is a solid-liquid mixed phase, and as the reaction progresses, it is completely dissolved in about 8 hours.
  • Triazole (6.31g, 46.7mmol), anhydrous dichloromethane (50.0ml), stirred at room temperature for 30min, after adding white turbidity, adding 3,4-oxo-isopropylidene quinic acid-1,5-lactone ( Compound 1a) (5.0 g, 23.3 mmol) and 4-dimethylaminopyridine (0.58 g, 4.7 mmol), the whole reaction system was stirred at room temperature for 12 h, and the insoluble material was removed by suction filtration, and the solvent was evaporated to remove solvent. The column was separated by chromatography.
  • the pH of the system was adjusted to 1 with 1N HCl.
  • the reaction was stirred at room temperature for 17 h and the reaction was completed.
  • the system was adjusted to pH ⁇ 7 with 1 mol/L LiOH aqueous solution, and purified by reverse phase preparative liquid phase (the column was SHIMADZU LC Column Shim-pack PREP-ODS (k), and the mobile phase A was 0.05% aqueous solution of trifluoroacetic acid.
  • the mobile phase B was acetonitrile and subjected to gradient elution.
  • the preparation was lyophilized to give compound 1-1, 461.5 mg. Yield: 59.97%.
  • MS (ESI + ): m/z 353.
  • the compound 1-9d (500 mg, 1.22 mmol) was added to a reaction flask, dissolved in tetrahydrofuran (10.0 ml), and trifluoroacetic acid (1.0 ml) was added and stirred at room temperature for 2 h, and the reaction was completed.
  • the system was adjusted to pH ⁇ 7 with 1 mol/L LiOH aqueous solution, and purified by reverse phase preparative liquid phase (the column was SHIMADZU LC Column Shim-pack PREP-ODS (k), and the mobile phase A was 0.05% aqueous solution of trifluoroacetic acid.
  • the mobile phase B was acetonitrile and was subjected to a gradient elution. Yield: 80.17%.
  • MS (ESI+): m/z 368.1.
  • the compound 1-23b prepared in Example 4 was the compound 2-6 prepared in Example 6.
  • Compound 3-4 was prepared according to the procedure described in Step D of Example 3.
  • the intermediate 4-4b prepared in Example 11 was the compound 6-7 prepared in Example 17.
  • sample loading set blank holes respectively (the blank control hole does not add sample and enzyme standard reagent, the other steps are the same operation), standard hole, sample hole to be tested. Accurately load the standard on the enzyme label coated plate, add the sample dilution to the sample well to be tested, and then add the sample to be tested. Add the sample to the bottom of the well of the microplate, try not to touch the wall of the well, and shake gently to mix.
  • adding enzyme adding enzyme labeling reagent to each well, except for blank holes.
  • color development first add coloring agent A to each well, then add coloring agent B, gently shake and mix, coloring at 37 ° C for 10 minutes.
  • termination stop solution is added to each well to terminate the reaction (at this time, the blue color turns yellow).
  • GI (growth inhibition rate) (1-OD drug group / OD control group ) ⁇ 100%.
  • Mouse pancreatic cancer PAN02 tumor fluid was inoculated into the right axilla of C57BL/6 mice under aseptic conditions. After 10 days, the tumor tissues with good growth were taken under aseptic conditions, cut, ground, filtered, diluted with physiological saline, and counted to make a tumor cell suspension of 1.2 ⁇ 107 cells/mL, on the right side of C57BL/6 mice. Inoculate 0.2 mL/only under the armpit. The animals were randomly divided into the next day after inoculation, 6 rats in each group, and weighed and administered for 13 times. Cyclophosphamide was administered intraperitoneally and administered once. On the 14th day, the body weight was weighed, the animals were sacrificed, the tumor tissues were removed and weighed, and photographs were taken. Finally, the tumor inhibition rate was calculated, and the tumor inhibition rate was used to evaluate the antitumor effect intensity.
  • Mouse colorectal cancer MC38 tumor fluid was inoculated into the right axilla of C57BL/6 mice under aseptic conditions. After 10 days, the tumor tissues with good growth were taken under aseptic conditions, cut, ground, filtered, diluted with physiological saline, and counted to make a tumor cell suspension of 1.2 ⁇ 107 cells/mL, on the right side of C57BL/6 mice. Inoculate 0.2 mL/only under the armpit. The animals were randomly divided into the next day after inoculation, 6 rats in each group, and weighed and administered for 13 times. Cyclophosphamide was administered intraperitoneally and administered once. On the 14th day, the body weight was weighed, the animals were sacrificed, the tumor tissues were removed and weighed, and photographs were taken. Finally, the tumor inhibition rate was calculated, and the tumor inhibition rate was used to evaluate the antitumor effect intensity.
  • Mouse Lewis lung carcinoma virus solution was inoculated into the right axilla of C57BL/6 mice under aseptic conditions. After 10 days, the tumor tissues with good growth were taken under aseptic conditions, cut, ground, filtered, diluted with physiological saline, and counted to make a tumor cell suspension of 1.2 ⁇ 107 cells/mL, on the right side of C57BL/6 mice. Inoculate 0.2 mL/only under the armpit. The animals were randomly divided into the next day after inoculation, 6 rats in each group, and weighed and administered for 13 times. Cyclophosphamide was administered intraperitoneally and administered once. On the 14th day, the body weight was weighed, the animals were sacrificed, the tumor tissues were removed and weighed, and photographs were taken. Finally, the tumor inhibition rate was calculated, and the tumor inhibition rate was used to evaluate the antitumor effect intensity.
  • TGI (1-T/C) ⁇ 100.
  • T tumor weight in the treatment group
  • C tumor weight in the negative control group.
  • Table 7 is the biological activity test result of the compound provided by the examples of the present invention.
  • Compound 1-1 1-O-caffeoylquinic acid, has an inhibitory effect on interleukin-17L, and the inhibition rate is close to 70%; Compound 1-1 is at a dose of 20 mg/kg against melanoma and pancreas. Cancer, colorectal cancer, lung cancer and other tumors have a good inhibitory effect, both exceeding 50%. The derivatives also have a good inhibitory effect on tumors such as melanoma, pancreatic cancer, colorectal cancer and lung cancer.
  • mice 10 weeks old MRL/lpr self-exposure lupus mice were intragastrically or intraperitoneally injected once a day for 3 months. Skin pathology, degree of joint swelling and pathology, blood/urinary creatinine urea nitrogen, and blood dsDNA and ANA antibodies were observed and detected during the administration period and at the end of the experiment.
  • the pet hair clipper and hair removal cream were used to depilate the back of the mouse, and the area was about 1.5 ⁇ 2 cm. Except for the negative control animals, each group of animals was modeled with imiquimod cream, that is, 50 mg of imiquimod cream was applied to the skin of the back hair removal part of the mice every day, and it was applied once a day for 7 consecutive times. day. On the day of modeling, the compound was intragastrically or intraperitoneally injected once a day, and the animals were treated on the 7th day.
  • the psoriasis-like lesion area and disease severity-PASI (psoriasis area and severity index) scores were performed daily for the first day of the first modeling. According to the PASI scoring standard, the erythema, scales, and thickness of the skin lesions were given 0-4 points, and the three points were added to obtain the total score.
  • PASI scoring criteria 0, none; 1, mild; 2, moderate; 3, severe; 4, very severe.
  • Day 7 the mice were sacrificed by cervical dislocation, the skin thickness was measured with a vernier caliper, and the skin of the animal's back hair removal was removed and fixed with 4% paraformaldehyde for pathological analysis.
  • the compounds involved in the present invention have been tested to have a good effect on autoimmune diseases such as lupus erythematosus and psoriasis.

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Abstract

本发明提供了式(II)所示的1-O-咖啡酰奎宁酸衍生物，以及1-O-咖啡酰奎宁酸、式(II)所示的1-O-咖啡酰奎宁酸衍生物及其盐的应用。1-O-咖啡酰奎宁酸、如式(II)所示的1-O-咖啡酰奎宁酸衍生物及其盐具有抑制白介素17，尤其是白介素17F的分泌的作用，并且能够预防和治疗肿瘤。实验结果表明，1-O-咖啡酰奎宁酸浓度为0.5μM/L时对白介素17F的抑制率接近70％；1-O-咖啡酰奎宁酸在20mg/kg的剂量下对黑色素瘤、胰腺癌、结直肠癌、肺癌等肿瘤有较好的抑制作用，均超过50％，而其衍生物对黑色素瘤、胰腺癌、结直肠癌、肺癌等肿瘤也具有较好的抑制作用。

Description

1-O-咖啡酰奎宁酸、其衍生物、制备方法及其用途
本申请要求于2017年12月25日提交中国专利局、申请号为201711419397.8、发明名称为“1-O-咖啡酰奎宁酸、其衍生物、制备方法及其用途”的中国专利申请的优先权，其全部内容通过引用结合在本申请中。
技术领域
本发明属于药物化学技术领域，尤其涉及一种1-O-咖啡酰奎宁酸、其衍生物、制备方法及其用途。
背景技术
白细胞介素17(the interleukin 17，IL-17)家族包含6种白细胞介素(IL-17A，IL-17B，IL-17C，IL-17D，IL-17E和IL-17F)及其受体(IL-17RA，IL-17RB，IL-17RC，IL-17RD，IL-17RE和IL-17RF)(Gaffen，S.L.等，免疫学通讯(Nature reviews.Immunology)9(2009)：556-567)。IF-17F也称为IL-24或ML-1，是IL-17细胞因子家族的成员。IF-17F与IL-17A大约55％相同，并且被认为与IL-17A共享相同的受体(Kolls和Linden2004,Immunity，21,467-476；Hymowitz等，2001，EMBO J.20(19),5332-5341；Kuestner等，2007，Journal of Immunology，179,5462-5473)。二者都可以形成同型二聚体和杂二聚体蛋白，均由激活的人CD4+T细胞产生(Wright等，2007，J Biol Chem.282(18)，13447-13455)。
IL-17可能促进很多由异常免疫反应介导的疾病，如类风湿性关节炎和呼吸道炎症，以及器官移植排斥和抗肿瘤免疫。IL-17R和抗IL-17单克隆抗体已经被用来证明IL-17在各种类风湿性关节炎模型中的作用(Lubberts等，J.Immunol.2001,167,1004-1023；Chabaud等，Arthritis Res.2001,3,168-177)。IL-17A and IL-17F均与自身免疫疾病相关(Iwakura，Y.,H.Ishigame等。2011，Immunity34(2)149-162)。IL-17F拮抗作用与 对抗哮喘的保护作用相关(Kawaguchi等，2006，J.Allergy Clin.Immunol.117(4)；795-801)，并且IL-17F在关节炎病理学中也起着作用(Lubberts 2003，CurrentOpinion in Investigational Drugs，4(5)572-577)。
已有的文献报道如：WO2014065413报道了三唑类衍生物和异噁唑类衍生物作为ROR γ受体抑制剂，从而可以抑制Th17细胞的分化和活化，并且对IL-17产生抑制作用。WO201400944和WO2016014918报道了关于芳基磺内酰胺衍生物和苯并咪唑类衍生物作为RORc调节剂，此类化合物主要用于治疗自身免疫疾病。WO2016213676报道了取代2,3-二氢-1H-茚-1-酮类结构作为ROR γt/ROR γ受体拮抗剂，此类化合物可用于调节ROR γt/ROR γ活性和用于治疗ROR γt/ROR γ介导的疾病和病症。WO2016072402报道了关于环状胺衍生物对TH17细胞受体ROR γt有抑制作用，从而抑制TH17细胞分化，降低IL-17分泌。WO2016120849报道了甲氧基取代的吡咯并吡啶类化合物用于ROR γ受体抑制剂，从而减少I L-17的量。从上述文献总结未见有关于1-O-咖啡酰奎宁酸类似物用于影响I L-17分泌的报道。
1-O-咖啡酰奎宁酸具有式(I)的结构式，
Figure PCTCN2018090091-appb-000001
其分子式为C 16H 18O 9，分子量为354.31。
1-O-咖啡酰奎宁酸是由咖啡酸与奎宁酸组成的一取代的缩酚酸，是绿原酸的位置异构体，是一种苯丙素类化合物。1-O-咖啡酰奎宁酸广泛存在于高等双子叶植物和蕨类植物中，主要存在于忍冬科忍冬属(Lonicera)、菊科蒿属(Artemisia)植物中，与绿原酸相比，1-O-咖啡酰奎宁酸在植物中的含量较少，且分离困难。
早在1964年，就有关于1-O-咖啡酰奎宁酸的合成报道，其通过丙酮 叉的奎宁酸和二乙酰基保护的咖啡酰氯缩合，进一步脱除保护基得到目标产物。但是，文章中并没有详细描述合成条件和产率。
发明内容
有鉴于此，本发明的目的在于提供一种1-O-咖啡酰奎宁酸、其衍生物、制备方法及其用途，本发明提供的1-O-咖啡酰奎宁酸及其衍生物对白介素17F具有较强的抑制作用。
本发明提供了一种式(II)所示的1-O-咖啡酰奎宁酸衍生物：
Figure PCTCN2018090091-appb-000002
其中，Q选自N或O；
R 1或R 2相同或不同，独立的选自氢、未取代或取代烷基、未取代或取代烯基、未取代或取代环烷基、未取代或取代芳基、未取代或取代芳基烷基、未取代或取代酰基；或者，R 1和R 2与其相邻的氧形成缩醛；
R 3选自氢、未取代或取代烷基、未取代或取代烯基、未取代或取代环烷基、未取代或取代芳基、未取代或取代酰基；
R 4选自氢、未取代或取代烷基、未取代或取代烯基、未取代或取代环烷基、未取代或取代芳基、未取代或取代芳基烷基；
或者，Q选自O，R 3和R 4与其相邻的氧成内酯；
R 5或R 6相同或不同，选自氢、未取代或取代烷基、未取代或取代烯基、未取代或取代环烷基、未取代或取代芳基、未取代或取代芳基烷基、未取代或取代酰基；
R 1、R 2、R 3、R 4、R 5和R 6不同时为H；
R 1、R 2、R 3不为式(a)所示基团：
Figure PCTCN2018090091-appb-000003
在本发明中，式(II)所示的1-O-咖啡酰奎宁酸衍生物为一咖啡酰奎宁酸衍生物，而非多咖啡酰奎宁酸衍生物，例如二咖啡酰奎宁酸衍生物或三咖啡酰奎宁酸衍生物，也不包括1-O-咖啡酰奎宁酸。
本申请令人惊奇地发现，1-O-咖啡酰奎宁酸、如式(II)所示的1-O-咖啡酰奎宁酸衍生物及其盐具有抑制白介素17的分泌的作用，因此能够作为白介素17调节剂使用。
具体而言，所述白介素17为白介素17F。
本申请还证实，1-O-咖啡酰奎宁酸、如式(II)所示的1-O-咖啡酰奎宁酸衍生物及其盐还具有预防和治疗肿瘤的作用，因此能够作为预防和治疗肿瘤的药物应用。具体而言，所述肿瘤包括实体瘤和非实体瘤，所述肿瘤包括但不限于黑色素瘤、胰腺癌、结直肠癌、肺癌、肝癌、胃癌、喉癌、鼻咽癌、食道癌、多发性骨髓瘤、淋巴癌、白血病、膀胱癌、前列腺癌、胆管癌、宫颈癌、卵巢癌、乳腺癌、子宫内膜癌、皮肤癌等。
相应的，1-O-咖啡酰奎宁酸、如式(II)所示的1-O-咖啡酰奎宁酸衍生物及其盐在还具有预防和治疗自身免疫疾病的作用，因此，能够作为预防和治疗自身免疫疾病的药物应用。具体而言，所述自身免疫疾病药物包括但不限于系统性红斑狼疮、银屑病、类风湿性关节炎、硬皮病等。
在本发明中，式(II)所示的1-O-咖啡酰奎宁酸衍生物实际上是1-O-咖啡酰奎宁酸的药物前体，其进入人体后在各种酶以及人体环境内转变为1-O-咖啡酰奎宁酸，从而发挥抑制白介素17F分泌和活性的作用，预防和治疗肿瘤或者自身免疫疾病。
本发明中，1-O-咖啡酰奎宁酸的盐或式(II)所示的1-O-咖啡酰奎宁酸衍生物的盐指药学上可接受的盐，即在合理的医学判断范围内，它们适合用于与人体和低等动物组织接触，没有不适当的毒性、刺激性、变态反应等，与合理的利益/风险比相称。
药学上可接受的盐是本领域熟知的。例如，S.M.Berge等在J. Pharmaceutical Sciences,1977,66,1-19中详细描述了药学上可接受的盐，引用在此作为参考。本发明1-O-咖啡酰奎宁酸的盐或式(II)所示的1-O-咖啡酰奎宁酸衍生物的盐包括从适合的无机与有机碱衍生的那些。无机碱盐包括与氨、碱金属、碱土金属或过渡金属形成的盐，例如铵盐以及锂盐、钠盐、钾盐、钙盐、锌盐、铁盐、亚铁盐等。有机碱盐包括胺盐，包括1-O-咖啡酰奎宁酸或式(II)所示的1-O-咖啡酰奎宁酸衍生物与伯、仲或叔胺形成的盐，可以选自与下列有机碱形成的盐：例如精氨酸、乙二胺、三乙胺、咖啡因、甜菜碱、乙醇胺、三甲胺、哌啶等。
在本发明中，1-O-咖啡酰奎宁酸衍生物如式(II)所示：
Figure PCTCN2018090091-appb-000004
在一个实施例中，Q选自O。
在一个实施例中，R 1或R 2相同，独立的选自氢、3个碳原子以下的烷基或5个碳原子以下的烷基酰基。
在一个实施例中，R 1和R 2与其相邻的氧形成式(b)所示的缩醛：
Figure PCTCN2018090091-appb-000005
其中，R 7、R 8独立地选自氢、5个碳原子以下的烷基、5个碳原子以下的烯基、取代或未取代的苯基、苯基烯基；或者，R 7、R 8与其相邻的C形成4～6元环。
在一个实施例中，R 3选自氢或3个碳原子以下的烷基。
在一个实施例中，R 4选自氢、3个碳原子以下的烷基。
在一个实施例中，R 3和R 4与其相邻的氧成内酯。
在一个实施例中，R 5或R 6相同，选自氢、3个碳原子以下的烷基、4 个碳原子以下的烷基酰基。
具体而言，式(II)所示的1-O-咖啡酰奎宁酸衍生物具有式(II-1)结构：
Figure PCTCN2018090091-appb-000006
其中，R 1或R 2相同，独立的选自氢、3个碳原子以下的烷基或5个碳原子以下的烷基酰基；R 3选自氢或3个碳原子以下的烷基；R 4选自氢、3个碳原子以下的烷基；R 5或R 6相同，选自氢、3个碳原子以下的烷基、4个碳原子以下的烷基酰基。即，式(II)所示的1-O-咖啡酰奎宁酸衍生物中，R 1和R 2不形成缩醛，R 3和R 4也不形成内酯。
式(II-1)所示的典型化合物见表1。
表1
Figure PCTCN2018090091-appb-000007
Figure PCTCN2018090091-appb-000008
具体而言，式(II)所示的1-O-咖啡酰奎宁酸衍生物具有式(II-2)结构：
Figure PCTCN2018090091-appb-000009
其中，R 1或R 2相同，独立的选自氢、3个碳原子以下的烷基或5个碳原子以下的烷基酰基；
R 5或R 6相同，选自氢、3个碳原子以下的烷基、4个碳原子以下的烷基酰基。
即，式(II)所示的1-O-咖啡酰奎宁酸衍生物中，R 1和R 2不形成缩醛， R 3和R 4形成内酯。
式(II-2)所示的典型化合物见表2。
表2
Figure PCTCN2018090091-appb-000010
具体而言，式(II)所示的1-O-咖啡酰奎宁酸衍生物具有式(II-3)结构：
Figure PCTCN2018090091-appb-000011
其中，R 7、R 8独立地选自氢、5个碳原子以下的烷基、5个碳原子以下的烯基、取代或未取代的苯基、苯基烯基；
R 3选自氢或3个碳原子以下的烷基；
R 4选自氢、3个碳原子以下的烷基。
R 5或R 6相同，选自氢、3个碳原子以下的烷基、4个碳原子以下的烷基酰基。
即，式(II)所示的1-O-咖啡酰奎宁酸衍生物中，R 1和R 2形成缩醛，R 3和R 4不形成内酯。
式(II-3)所示的典型化合物见表3。
表3
Figure PCTCN2018090091-appb-000012
Figure PCTCN2018090091-appb-000013
具体而言，式(II)所示的1-O-咖啡酰奎宁酸衍生物具有式(II-4)结构：
Figure PCTCN2018090091-appb-000014
其中，R3选自氢或3个碳原子以下的烷基；
R4选自氢、3个碳原子以下的烷基；
R5或R6相同，选自氢、3个碳原子以下的烷基、4个碳原子以下的烷基酰基；
n选自1、2、3或4。
即，式(II)所示的1-O-咖啡酰奎宁酸衍生物中，R1和R2形成缩醛，且其上的取代基形成3～6元环，R3和R4不形成内酯。
式(II-4)所示的典型化合物见表4。
表4
Figure PCTCN2018090091-appb-000015
Figure PCTCN2018090091-appb-000016
具体而言，式(II)所示的1-O-咖啡酰奎宁酸衍生物具有式(II-5)结构：
Figure PCTCN2018090091-appb-000017
其中，R 7、R 8独立地选自氢、5个碳原子以下的烷基、5个碳原子以下的烯基、取代或未取代的苯基、苯基烯基；
R 5或R 6相同，选自氢、3个碳原子以下的烷基、4个碳原子以下的烷基酰基。
即，式(II)所示的1-O-咖啡酰奎宁酸衍生物中，R 1和R 2形成缩醛，R 3和R 4形成内酯。
式(II-5)所示的典型化合物见表5。
表5
Figure PCTCN2018090091-appb-000018
Figure PCTCN2018090091-appb-000019
具体而言，式(II)所示的1-O-咖啡酰奎宁酸衍生物具有式(II-6)结构：
Figure PCTCN2018090091-appb-000020
其中，R 5或R 6相同，选自氢、3个碳原子以下的烷基、4个碳原子以下的烷基酰基；
n选自1、2、3或4。
即，式(II)所示的1-O-咖啡酰奎宁酸衍生物中，R 1和R 2形成缩醛，其其上的取代基形成3～6元环，R 3和R 4形成内酯。
式(II-6)所示的典型化合物见表6。
表6
Figure PCTCN2018090091-appb-000021
在本发明中，1-O-咖啡酰奎宁酸或式(II)所示的其衍生物可以按照以下方法制备：
首先起始原料奎宁酸在催化剂存在下成内酯环，同时在3,4位引入保护基得到化合物Ⅱ，化合物Ⅱ与SM反应得到化合物Ⅲ，化合物Ⅲ经脱保护得到通式(Ⅰ)化合物。
反应过程如下：
Figure PCTCN2018090091-appb-000022
其中：
`R 1、`R 2、`R 4、`R 5、`R 6的定义与式(II)中R 1、R 2、R 3、R 4、R 5、、R 6定义相同，但是，目标产物为1-O-咖啡酰奎宁酸时，R 1、R 2、R 3、R 4、R 5、、R 6可以全部为H。
X为卤素或羟基，本发明合成路线中，在制备化合物Ⅲ时，成酯的方法通常有两种方法即：SM为相应的羧酸时，在常规缩合剂(例如N,N`-二环己基碳二亚胺(DCC)、1-乙基-(3-二甲基氨基丙基)碳二亚胺(EDC)等)存在下成酯；SM制备成相应的酰卤时，在碱性条件下(例如吡啶、三乙胺、N,N-二异丙基乙胺、1,8-二氮杂环[5,4,0]十一烯-7等)直接成酯。
本发明合成方法中，将化合物Ⅲ脱保护所使用的碱为氢氧化锂、氢氧化钠、氢氧化钾等；酸为盐酸水溶液、硫酸水溶液、三氟乙酸水溶液等。
在本发明中，术语“烷基”表示1至12个碳原子的饱和直链或支链烃基。烷基基团的实例包括但不限于，甲基、乙基、正丙基、异丙基、 正丁基、异丁基、仲丁基、叔丁基、正戊基、异戊基、2-甲基丁基、新戊基、正己基、庚基、辛基基团。
在本发明中，术语“烯基”表示通过去除单个氢原子衍生自烃部分的单价基团，其中烃基部分分别具有至少一个碳碳双键并且包含2至12个碳原子。代表性烯基包括但不限于，乙烯基、丙烯基、丁烯基、1-甲基-2-丁烯-1-基、庚烯基及类似基团。
在本发明中，术语“环烷基”表示饱和碳环化合物具有3至12个环原子。环烷基的实例包括但不限于，环丙基、环丁基、环戊基、环己基。
在本发明中，术语“酰基”包括衍生至酸的残基，该酸包括但不限于羧酸、氨基甲酸、碳酸、磺酸和磷酸。实例包括脂肪族羰基、芳族羰基、脂肪族磺酸基。脂肪族羰基的实例包括但不限于，乙酰基、丙酰基、丁酰基及类似基团。
在本发明中，术语“卤素”指氟、氯、溴、碘的原子。
在本发明中，术语“芳基”是指具有1至3个芳环的单环、双环或三环碳环系统，包括但不限于，苯基、萘基、四氢萘基、蒽基及类似基团。
在本发明中，术语“芳基烷基”如本文所用，是指通过如本文定义的烷基附于母体分子的如本文定义的芳基。实例包括但不限于，苄基、苯乙基及类似基团。
在本发明中，术语“取代”是指其上一个、两个或三个或更多个氢原子被取代基独立的取代，该取代基包括但不限于，卤素、-OH、被保护羟基、-NO 2、-CN、-NH 2、被保护的氨基、烷氧基等。
本发明还提供了一种药物组合物，包括1-O-咖啡酰奎宁酸、式(II)所示的1-O-咖啡酰奎宁酸衍生物或其盐以及药学上可接受的辅料。
在本发明中术语“药物组合物”是指包括适合于所需的特定剂型的任意和所有溶剂、稀释剂或其他液体赋形剂、分散或悬浮助剂、表面活性剂、等渗剂、增稠或乳化剂、防腐剂、固体粘合剂、润滑剂等。Remington`s Pharmaceutical Sciences,Sixteenth Edition,E.W.Maetin(Mack Publishing Co.,Easton,Pa.,1980)公开了用于配制药学上可接受的组合物的各种载体 和用于其制备的已知技术。除了任何常规载体介质与本发明化合物不相容以外，例如产生任何不可取得生物学效应或者以有害方式相互作用于药学上可接受的组合物的任何其他组分，它的使用涵盖在本发明的范围内。能够充当药学上可接受的载体的材料的一些实例包括，但不限于，离子交换剂；氧化铝；硬脂酸铝；卵磷脂；缓冲物质，例如：磷酸盐；甘氨酸；山梨酸或山梨酸钾；饱和植物脂肪酸的偏苷油酯混合物；水；盐或电解质，例如：磷酸氢二钠、磷酸氢钾、氯化钠、锌盐；胶体二氧化硅；三硅酸镁；聚乙烯吡咯烷酮；聚丙烯酸酯；糖类，例如乳糖、葡萄糖和蔗糖；淀粉，例如玉米淀粉和马铃薯淀粉；纤维素及其衍生物，例如羧甲基纤维素钠、乙基纤维素和乙酸纤维素；明胶；滑石；赋形剂，例如可可脂和栓剂用蜡；油类，例如花生油、棉籽油、红花油、芝麻油、橄榄油、玉米油和大豆油；二醇，例如丙二醇或聚乙二醇；酯类，例如油酸乙酯和月桂酸乙酯；琼脂；无热原的水；等渗盐水；乙醇；以及其他无毒的可相容的润滑剂，例如月桂基硫酸钠和硬脂酸镁；根据制剂人员的判断，在组合物中也可以存在着色剂、释放剂、包衣剂、甜味剂、调味剂和香料、防腐剂和抗氧化剂。
本发明还提供了一种药物制剂，包括1-O-咖啡酰奎宁酸、式(II)所示的1-O-咖啡酰奎宁酸衍生物或其盐以及药学上可接受的辅料，可以按照常规制备方法将本发明化合物或其盐配制为常规药物制剂，例如胶囊剂、片剂、丸剂、颗粒剂、乳剂、混浮剂、注射剂、滴剂等。
本申请发现，1-O-咖啡酰奎宁酸、如式(II)所示的1-O-咖啡酰奎宁酸衍生物及其盐具有抑制白介素17，尤其是白介素17F的分泌的作用，并且能够预防和治疗肿瘤。实验结果表明，1-O-咖啡酰奎宁酸浓度为0.5μM/L时对白介素17F的抑制率接近70％；1-O-咖啡酰奎宁酸在20mg/kg的剂量下对黑色素瘤、胰腺癌、结直肠癌、肺癌等肿瘤有较好的抑制作用，均超过50％，而其衍生物对黑色素瘤、胰腺癌、结直肠癌、肺癌等肿瘤也具有较好的抑制作用。
具体实施方式
下面将对本发明实施例中的技术方案进行清楚、完整地描述，显然， 所描述的实施例仅仅是本发明一部分实施例，而不是全部的实施例。基于本发明中的实施例，本领域普通技术人员在没有做出创造性劳动前提下所获得的所有其他实施例，都属于本发明保护的范围。
实施例1：(1S,3R,4R,5R)-1-[[3-(3,4-二羟基苯基)-1-氧代-2-丙烯基]氧]-3,4,5-三羟基环己烷甲酸(化合物1-1)的制备
Figure PCTCN2018090091-appb-000023
步骤B：
将咖啡酸(36.0g，0.2mol)加入到反应瓶中，加入1mol/L氢氧化钠水溶液(440ml)溶解，体系降温至0℃，缓慢滴加乙酸酐(80ml，0.84mol)，保持0℃反应1h，过滤，滤饼水洗至中性，将粗品用乙醇重结晶，烘干，得SM白色粉末44.87g，收率：84.98％，mp：182～184℃。
步骤A：
将D-(-)-Quinic acid(30.0g，0.156mol，按照文献Valentina Sinisi.Et al.,“Interaction of chlorogenic acids and quinides from coffee with human serum albumin”,Food Chemistry，2015(168)：332-340的方法制备)、对甲苯磺酸一水合物(1.50g，7.8mmol)、丙酮(1200.0ml)投入单口瓶中，上置内有分子筛的索氏提取器，加热回流反应24h。体系开始反应时为固液混合相，随着反应的不断进行，约8h左右全部溶解。每隔8h更换一次分子筛以保证生成的水被尽量除去。反应完毕，将体系降温至0℃，加入 NaHCO 3(8.7g，0.66eq)搅拌1h，过滤，旋干，得浅黄色固体。用乙酸乙酯/石油醚体系重结晶，得23.6g类白色固体3,4-氧-异丙叉奎宁酸-1,5-内酯(化合物1a)，收率：70.6％。mp：132～134℃；
Figure PCTCN2018090091-appb-000024
(c＝1，CH 3OH)。
步骤C：
向反应瓶中依次加入3,4-二乙酰基氧基苯丙烯酸(7.4g，28.0mmol)，N,N`-二环己基碳二亚胺(9.63g，46.7mmol)，1-羟基苯并三唑(6.31g，46.7mmol)，无水二氯甲烷(50.0ml)，室温搅拌30min，出现白色浑浊后，加入3,4-氧-异丙叉奎宁酸-1,5-内酯(化合物1a)(5.0g，23.3mmol)和4-二甲氨基吡啶(0.58g，4.7mmol)，整个反应体系在室温下搅拌反应12h，抽滤除去不溶物，滤液减压旋蒸除去溶剂，剩余物柱层析分离。乙酸乙酯/石油醚＝1:2洗脱酯化产品，得到白色固体5.93g(化合物1b)，收率：55.2％。mp：123～125℃；
Figure PCTCN2018090091-appb-000025
(c＝0.2，CH 2Cl 2)；MS(ESI +)：m/z＝460.1； 1H NMR(500MHz,CDCl 3):δ＝1.34(s，3H)，1.54(s，3H)，2.30(s，3H)，2.31(s，3H)，2.41(dd，J＝14.5,3.1Hz,1H)，2.53(m，1H)，2.63(d，J＝11.4Hz，1H)，3.11(dd，J＝11.4,6.4Hz，1H)，4.34(d，J＝6.4Hz，1H)，4.56(m，1H)，4.81(dd，J＝6.3,2.3Hz，1H)，6.38(d，J＝15.9Hz，1H)，7.28(d，J＝8.3Hz，1H)，7.36(d，J＝1.8Hz，1H)，7.40(dd，J＝8.3，1.8Hz，1H)，7.65(d，J＝15.9Hz，1H)。
步骤D：
向反应瓶中依次加入1-氧-[(3`,4`-二乙酰基)肉桂酰基]-3,4-氧-异丙叉奎宁酸-1,5-内酯(化合物1b，1.0g，2.17mmol)，四氢呋喃(28.0ml)、H 2O(11.0ml)，室温下搅拌溶清。将1mol/L LiOH水溶液(9.0ml，9.0mmol)加入到反应体系中，室温搅拌反应1h。TLC(PE:EA＝1:1)显示原料反应完全，反应体系直接下一步。
步骤E：
将上步反应体系直接用1N HCl将体系pH至调至1，继续室温搅拌反应17h，反应完全。用1mol/L LiOH水溶液将体系调为pH≈7，经反相制备型液相纯化(色谱柱为SHIMADZU LC Column Shim-pack PREP-ODS(k)，流动相A为0.05％三氟乙酸水溶液，流动相B为乙腈，进行梯度洗脱。)，制 备液冻干得化合物1-1，461.5mg。收率：59.97％。MS(ESI +)：m/z＝354.2。 1H NMR(500MHz,DMSO):δ＝1.746(s，1H)，2.076(d，J＝12Hz，1H)，2.201(s，1H)，3.294(s，1H)，3.822(s，1H)，3.938(s，1H)，4.28(d，J＝4Hz，1H)，4.598(s，1H)，4.773(s，1H)，6.169(d，J＝16Hz，1H)，6.743(d，J＝8Hz，1H)，6.966(d，J＝8Hz，1H)，7.007(s，1H)，7.393(d，J＝16Hz，1H)，9.158(s，1H)，9.600(s，1H)，～12.7(s，1H)。
实施例2(化合物1-4的制备)
Figure PCTCN2018090091-appb-000026
步骤A：
向100ml三口瓶中依次加入中间体1b(10.0g，21.72mmol)、DCM(100.0ml)，搅拌溶清，再加入H 2O(20.0ml)，冰水浴中缓慢滴加三氟乙酸(37.0ml)，滴毕室温搅拌5min～15min，取样TLC监控反应完全。将反应体系室温下用油泵减压浓缩，甲苯带三氟乙酸，得7.2g黄色泡沫状固体1-4a。
步骤B：
氮气保护下，将中间体1-4a(5.0g，11.89mmol)加入到反应瓶中， 加入无水DMF(50.0ml)溶解，体系降温至0℃，分批加入氢化钠(1.2g，29.72mmol，60％矿物油)，搅拌30min，缓慢滴加含有2-溴丙烷(3.2g，26.16mmol)的DMF溶液(10.0ml)，自然升至室温反应2h。向反应体系中加入2N氯化铵水溶液，用乙酸乙酯萃取三次，合并有机相，用食盐水洗涤，无水硫酸钠干燥，抽滤，减压下旋蒸得粗品，粗品经柱层析纯化，得1.3g标题化合物1-4b，收率：21.67％。MS(ESI+)：m/z＝504.2。
步骤C：
将中间体1-4b(0.85g，1.68mmol)加入到反应瓶中，加入甲醇(10.0ml)，室温下搅拌溶清。将甲醇钠(0.11g，2.22mmol)加入到反应体系中，室温搅拌反应1h。TLC显示原料反应完全。向反应体系中加入饱和氯化铵水溶液(8.0ml)，减压浓缩，剩余物用乙酸乙酯萃取三次，合并有机相，用饱和食盐水洗涤，无水硫酸钠干燥，抽滤，减压下旋蒸得粗品，粗品经柱层析纯化，得300.0mg标题化合物1-4，收率：39.46％。MS(ESI+)：m/z＝452.2。
实施例3(化合物1-9的制备)
Figure PCTCN2018090091-appb-000027
步骤D：
将实施例1的中间体1b(1.60g，3.48mmol)加入到反应瓶中，加入甲醇(20.0ml)，室温下搅拌溶清。将甲醇钠(0.23g，4.17mmol)加入到反应体系中，室温搅拌反应1h。TLC显示原料反应完全。向反应体系中加入饱和氯化铵水溶液(15.0ml)，减压浓缩，剩余物用乙酸乙酯萃取三次，合并有机相，用饱和食盐水洗涤，无水硫酸钠干燥，抽滤，减压旋蒸的粗品，粗品柱层析纯化，得中间体1-9d，1.13g。收率：79.66％。MS(ESI+)：m/z＝408.2。
步骤E：
将化合物1-9d(500mg，1.22mmol)加入到反应瓶中，加入四氢呋喃(10.0ml)溶解，加入三氟乙酸(1.0ml)室温搅拌反应2h，反应完全。用1mol/L LiOH水溶液将体系调为pH≈7，经反相制备型液相纯化(色谱柱为SHIMADZU LC Column Shim-pack PREP-ODS(k)，流动相A为0.05％三氟乙酸水溶液，流动相B为乙腈，进行梯度洗脱。)，制备液冻干得标题 化合物，361.5mg。收率：80.17％。MS(ESI+)：m/z＝368.1。
实施例4(化合物1-23的制备)
Figure PCTCN2018090091-appb-000028
步骤A：
按照实施例2中步骤B描述的操作条件制备，其中将2-溴丙烷用溴苄替代，得到目标中间体1-23b。MS(ESI +)：m/z＝600.3。
步骤B：
向反应瓶中依次加入1-23b(1.0g，1.66mmol)，四氢呋喃(28.0ml)、H 2O(11.0ml)，室温下搅拌溶清。将1mol/L LiOH水溶液(7.0ml，7.0mmol)加入到反应体系中，室温搅拌反应1h。反应完全，用1mol/L HCl水溶液将体系调为pH≈7，经反相制备型液相纯化(色谱柱为SHIMADZU LC Column Shim-pack PREP-ODS(k)，流动相A为0.05％三氟乙酸水溶液，流动相B为乙腈，进行梯度洗脱。)，制备液冻干得标题化合物1-23，241.6mg。收率：27.15％。MS(ESI +)：m/z＝534.1。
实施例5(化合物2-9的制备)
实施例2制备的化合物1-4a即实施例5制备的化合物2-9。
实施例6(化合物2-6的制备)
实施例4制备的化合物1-23b即实施例6制备的化合物2-6。
实施例7(化合物2-11的制备)
Figure PCTCN2018090091-appb-000029
步骤A：
将实施例2的中间体1-4a(1.0g，2.38mmol)加入到反应瓶中，加入二氯甲烷(20.0ml)溶解，加入N,N-二异丙基乙胺(0.92g，7.12mmol)，体系降温至0℃，缓慢滴加乙酰氯(0.47g，5.98mmol)，保持0℃反应5h，反应完全。向反应体系中加入水，分液，水相用二氯甲烷萃取，合并有机相，用水洗至中性，减压下旋蒸除去溶剂，粗品经柱层析纯化得标题化合物0.57g，收率：47.48％。MS(ESI +)：m/z＝504.1。
实施例8(化合物3-7的制备)
实施例1制备的化合物1c即实施例8制备的化合物3-7。
实施例9(化合物3-4的制备)
Figure PCTCN2018090091-appb-000030
步骤A：
向500ml单口瓶中依次加入D-(-)-Quinic acid(20.0g，0.10mol)、甲苯(120ml)、甲基异丁烯甲酮(100.0ml)、对甲苯磺酸一水合物(2.0g，0.01mol)，加毕升温至回流(外浴150℃)，架分水器，体系呈黄色浑浊液，回流后分水2h、继续回流反应2h。体系变澄清，有少量黄色不溶物贴于瓶壁，TLC(DCM:MeOH＝10:1)监控反应完全。50℃减压浓缩，剩余物中加入H 2O(80.0ml)、，用饱和NaHCO 3调pH为7～8，水相用EA(100.0ml×2)萃取，合并有机相，和brine洗(100.0ml)，无水Na2SO4干燥，过滤浓缩，得23.70g黄色固体。用乙酸乙酯\石油醚体系重结晶，析晶过夜，0℃析晶2h，抽滤，石油醚洗涤滤饼，滤饼真空干燥得13.71g白色晶体，即中间体3-4a。收率：53.92％。MS(ESI +)：m/z＝254.1。
步骤B：
按照实施例1中步骤C的操作，其中将中间体1a用3-4a替代，缩合得到 目标中间体3-4b。MS(ESI +)：m/z＝500.3。
步骤C：
按照实施例3步骤D描述的操作制备得到化合物3-4。
MS(ESI +)：m/z＝448.4。
实施例10(化合物3-8的制备)
实施例2制备的化合物1-9d即实施例10制备的化合物3-8。
实施例11(化合物4-4的制备)
Figure PCTCN2018090091-appb-000031
按照实施例9中描述的操作条件制备，其中用环己酮代替甲基异丁烯甲酮，再经缩合、醇解得到标题化合物4-4。MS(ESI +)：m/z＝448.3。
实施例12(化合物4-9的制备)
Figure PCTCN2018090091-appb-000032
步骤A：
向100ml单口瓶中依次加入4-4b(1.0g，2.0mmol)、THF(20.0ml)、H2O(5.0ml)，加毕搅拌，体系呈无色清液。冰水浴中滴加1N LiOH水溶液(8.3ml，8.3mmol)，体系由无色清液→淡黄色清液→棕色清液，室温搅拌1h，TLC显示4-4b反应完全，10℃左右用0.5N盐酸将体系调为pH≈6，用(DCM：THF＝1:1)萃取三次，合并有机相，brine洗，Na2SO4干燥，抽滤，减压浓缩得0.3g黄色泡沫状固体，即化合物4-9。MS(ESI+)：m/z＝434.2。
实施例13(化合物5-1的制备)
Figure PCTCN2018090091-appb-000033
步骤A：
按照实施例9中步骤A描述的操作条件制备，其中用甲乙酮代替甲基异丁烯甲酮，得到中间体5-1a。MS(ESI +)：m/z＝448.3。
步骤B：
将咖啡酸(18.0g，0.1mol)加入到反应瓶中，加入二氯甲烷(180.0ml)、N,N-二异丙基乙胺(105.0ml，0.6mol)，室温下滴加叔丁基二甲基氯硅烷(60.28g，0.4mol)，滴加完室温反应1.5h，TLC监控反应完全。将反应液减压旋蒸，剩余物加入乙酸乙酯溶解，分别用1N HCl、饱和食盐水洗涤，无水硫酸钠干燥，旋蒸除去溶剂，剩余物加入石油醚，搅拌15min，析出白色固体，过滤，烘干，得5-1b白色粉末28.5g，收率：69.7％。
步骤C：
按照实施例1中步骤C描述的操作条件制备，中间体5-1a与5-1b在 缩合剂存在下，得到中间体5-1c。MS(ESI +)：m/z＝618.5。
步骤D：
将中间体5-1c(1.0g，1.62mmol)加入到反应瓶中，加入四氢呋喃(20.0ml)溶解，加入四丁基氟化胺三水合物(1.0g，3.24mmol)，反应体系变成黄色，搅拌反应30min，TLC监控反应完全。减压旋蒸除去溶剂，剩余物加入乙酸乙酯，依次用1N HCl、去离子水和饱和食盐水洗涤，有机相旋蒸得粗品，柱层析纯化得0.43g标题化合物5-1，收率：68.17％。MS(ESI+)：m/z＝390.3。
实施例14(化合物5-4的制备)
Figure PCTCN2018090091-appb-000034
按照实施例13中描述的操作条件制备，其中用中间体5-4a代替5-1a，经缩合、脱保护得到标题化合物5-4。MS(ESI +)：m/z＝448.3。
实施例15(化合物5-5的制备)
Figure PCTCN2018090091-appb-000035
按照实施例9中步骤A、B描述的操作条件制备，其中用4-溴苯乙酮代替甲基异丁烯甲酮，再经缩合得到标题化合物5-5。MS(ESI +)：m/z＝448.3。
实施例16(化合物6-1的制备)
Figure PCTCN2018090091-appb-000036
按照实施例13中步骤C、D描述的操作条件制备，4-4a与5-1b在缩合剂存在下缩合，再经脱保护得到标题化合物6-1。MS(ESI +)：m/z＝416.4。
实施例17(化合物6-7的制备)
实施例11制备的中间体4-4b即实施例17制备的化合物6-7。
实施例18(化合物6-8的制备)
Figure PCTCN2018090091-appb-000037
按照实施例9中步骤A、B描述的操作条件制备，其中步骤A用环戊酮代替甲基异丁烯甲酮制备得到中间体6-8a，再经缩合得到标题化合物6-8。MS(ESI +)：m/z＝430.1。
实施例19 实施例1～18提供的化合物的生物活性实验
1、体外活性研究：利用白介素17F(IL17F)检测试剂盒，通过ELISA法检测1-O-咖啡酰奎宁酸类化合物作用24h对U87-Luc细胞IL17F分泌的影响。
操作步骤如下：
(1)、加样：分别设空白孔(空白对照孔不加样品及酶标试剂，其余各步操作相同)、标准孔、待测样品孔。在酶标包被板上标准品准确加样，待测样品孔中先加样品稀释液，然后再加待测样品。加样将样品加于酶标板孔底部，尽量不触及孔壁，轻轻晃动混匀。
(2)、温育：用封板膜封板后置37℃温育30分钟。
(3)、配液：将30倍浓缩洗涤液用蒸馏水30倍稀释后备用
(4)、洗涤：小心揭掉封板膜，弃去液体，甩干，每孔加满洗涤液，静置30秒后弃去，如此重复5次，拍干。
(5)、加酶：每孔加入酶标试剂，空白孔除外。
(6)、显色：每孔先加入显色剂A，再加入显色剂B，轻轻震荡混匀，37℃避光显色10分钟.
(7)、终止：每孔加终止液，终止反应(此时蓝色立转黄色)。
(8)、测定：以空白空调零，450nm波长依序测量各孔的吸光度(OD值)。测定应在加终止液后15分钟以内进行。
计算方法：
GI(生长抑制率)＝(1-OD 药物组/OD 对照组)×100％。
2、体内效力研究：
2.1小鼠黑色素瘤体内模型
无菌条件下将1×10 7个B16-F10细胞接种到C57BL/6腋下。10天后，无菌条件下获取肿瘤组织，匀浆用生理盐水稀释后计数制成浓度为1×10 6个/mL肿瘤细胞悬液，于小鼠右侧腋下接种0.2mL/只。接种后次日(24小时后)动物随机分组，称重后给药，待测化合物每天1次，连续腹腔给药13次。环磷酰胺腹腔给药，给药1次。第14天称量体重，处死动物，剥取肿瘤组织，称重并进行拍照。最后计算肿瘤增殖抑制率，以肿瘤抑制率评价抗肿瘤作用强度。
2.2小鼠胰腺癌PAN02体内模型
无菌条件下将小鼠胰腺癌PAN02瘤液接种到C57BL/6小鼠右侧腋下。10天后，无菌条件下取生长良好的肿瘤组织，剪碎，研磨，过滤，用生理盐水稀释后计数制成浓度为1.2×107个/mL肿瘤细胞悬液，于C57BL/6小鼠右侧腋下接种0.2mL/只。接种后次日动物随机分组，每组6只，称重后给药，连续给药13次。环磷酰胺腹腔给药，给药1次。第14天称量体重，处死动物，剥取肿瘤组织并称重，进行拍照。最后计算肿瘤抑制率，以肿瘤抑制率评价抗肿瘤作用强度。
2.3小鼠结直肠癌MC38体内模型
无菌条件下将小鼠结直肠癌MC38瘤液接种到C57BL/6小鼠右侧腋下。10天后，无菌条件下取生长良好的肿瘤组织，剪碎，研磨，过滤，用生理盐水稀释后计数制成浓度为1.2×107个/mL肿瘤细胞悬液，于C57BL/6小鼠右侧腋下接种0.2mL/只。接种后次日动物随机分组，每组6只，称重后给药，连续给药13次。环磷酰胺腹腔给药，给药1次。第14天称量体重，处死动物，剥取肿瘤组织并称重，进行拍照。最后计算肿瘤抑制率，以肿瘤抑制率评价抗肿瘤作用强度。
2.4小鼠Lewis肺癌体内模型
无菌条件下将小鼠Lewis肺癌瘤液接种到C57BL/6小鼠右侧腋下。10天后，无菌条件下取生长良好的肿瘤组织，剪碎，研磨，过滤，用生理盐水稀释后计数制成浓度为1.2×107个/mL肿瘤细胞悬液，于C57BL/6小鼠右侧腋下接种0.2mL/只。接种后次日动物随机分组，每组6只，称重后给药，连续给药13次。环磷酰胺腹腔给药，给药1次。第14天称量体重，处死动物，剥取肿瘤组织并称重，进行拍照。最后计算肿瘤抑制率，以肿瘤抑制率评价抗肿瘤作用强度。
计算方法：
肿瘤增殖抑制率TGI(％)：TGI＝(1-T/C)×100。(T：治疗组肿瘤重量；C：阴性对照组肿瘤重量)。
测试结果见表7，表7为本发明实施例提供的化合物的生物活性测试结果。
表7 本发明实施例提供的化合物的生物活性测试结果
Figure PCTCN2018090091-appb-000038
Figure PCTCN2018090091-appb-000039
Figure PCTCN2018090091-appb-000040
由表7可知，化合物1-1，即1-O-咖啡酰奎宁酸对白介素17L具有抑制作用，抑制率接近70％；化合物1-1在20mg/kg的剂量下对黑色素瘤、胰腺癌、结直肠癌、肺癌等肿瘤有较好的抑制作用，均超过50％。而其衍生物对黑色素瘤、胰腺癌、结直肠癌、肺癌等肿瘤也具有较好的抑制作用。
实施例20 自身免疫疾病动物模型
1.红斑狼疮动物模型
10周龄MRL/lpr自发型狼疮性小鼠，灌胃或腹腔注射化合物，每天1次，连续3个月。给药期间及实验结束时观察并检测皮肤病理、关节肿胀程度及病理、血/尿肌酐尿素氮以及血dsDNA和ANA抗体。
2.咪喹莫特诱导的小鼠银屑病模型
用宠物电推剪及脱毛膏给小鼠背部去毛，面积约为1.5×2cm。除了阴性对照组动物外，每组动物均用咪喹莫特乳膏进行造模，即每天给予小鼠背部去毛部位的皮肤涂抹50mg的咪喹莫特乳膏，每天涂抹1次，连续7天。造模当天灌胃或腹腔注射化合物，每天1次，第7天处理动物。首次造模次日开始每天对动物进行银屑病样皮损面积和疾病严重程度—PASI(psoriasis area and severity index)评分。依据PASI评分标准，给予小鼠皮损处红斑(erythema)，鳞屑(scales)，及浸润增厚程度(thickness)给予0-4的积分，将三者积分相加得到总分。
PASI评分标准：0，无；1，轻度；2，中度；3，重度；4，极重度。实验结束(第7天)时，将小鼠脱颈椎处死，用游标卡尺测量皮肤厚度，并将动物背部脱毛处的皮肤取下，用4％多聚甲醛固定，进行病理分析。
经试验，本发明中涉及的化合物对治疗红斑狼疮、银屑病等自身免疫疾病有很好的效果。
以上所述仅是本发明的优选实施方式，应当指出，对于本技术领域的普通技术人员来说，在不脱离本发明原理的前提下，还可以做出若干改进和润饰，这些改进和润饰也应视为本发明的保护范围。

Claims (9)

  1. 式(II)所示的1-O-咖啡酰奎宁酸衍生物：
    Figure PCTCN2018090091-appb-100001
    其中，Q选自N或O；
    R 1或R 2相同或不同，独立的选自氢、未取代或取代烷基、未取代或取代烯基、未取代或取代环烷基、未取代或取代芳基、未取代或取代芳基烷基、未取代或取代酰基；或者，R 1和R 2与其相邻的氧形成缩醛；
    R 3选自氢、未取代或取代烷基、未取代或取代烯基、未取代或取代环烷基、未取代或取代芳基、未取代或取代酰基；
    R 4选自氢、未取代或取代烷基、未取代或取代烯基、未取代或取代环烷基、未取代或取代芳基、未取代或取代芳基烷基；
    或者，Q选自O，R 3和R 4与其相邻的氧成内酯；
    R 5或R 6相同或不同，选自氢、未取代或取代烷基、未取代或取代烯基、未取代或取代环烷基、未取代或取代芳基、未取代或取代芳基烷基、未取代或取代酰基；
    R 1、R 2、R 3、R 4、R 5和R 6不同时为H；
    R 1、R 2、R 3不为式(a)所示基团：
    Figure PCTCN2018090091-appb-100002
  2. 根据权利要求1所述的1-O-咖啡酰奎宁酸衍生物，其特征在于，Q选自O；
    R 1或R 2相同，独立的选自氢、3个碳原子以下的烷基或5个碳原子 以下的烷基酰基；
    或者，R 1和R 2与其相邻的氧形成式(b)所示的缩醛：
    Figure PCTCN2018090091-appb-100003
    其中，R 7、R 8独立地选自氢、5个碳原子以下的烷基、5个碳原子以下的烯基、取代或未取代的苯基、苯基烯基；或者，R 7、R 8与其相邻的C形成4～6元环；
    R 3选自氢或3个碳原子以下的烷基；
    R 4选自氢、3个碳原子以下的烷基；
    或者，R 3和R 4与其相邻的氧成内酯；
    R 5或R 6相同，选自氢、3个碳原子以下的烷基、4个碳原子以下的烷基酰基。
  3. 根据权利要求2所述的1-O-咖啡酰奎宁酸衍生物，其特征在于，选自以下结构的化合物：
    Figure PCTCN2018090091-appb-100004
    Figure PCTCN2018090091-appb-100005
    Figure PCTCN2018090091-appb-100006
  4. 1-O-咖啡酰奎宁酸、其药物前体及其盐在制备抑制白介素17F的分泌和活性的药物中的用途，其中，所述药物前体结构式如式(II)所示：
    Figure PCTCN2018090091-appb-100007
    其中，Q选自N或O；
    R 1或R 2相同或不同，独立的选自氢、未取代或取代烷基、未取代或取代烯基、未取代或取代环烷基、未取代或取代芳基、未取代或取代芳基烷基、未取代或取代酰基；或者，R 1和R 2与其相邻的氧形成缩醛；
    R 3选自氢、未取代或取代烷基、未取代或取代烯基、未取代或取代环烷基、未取代或取代芳基、未取代或取代酰基；
    R 4选自氢、未取代或取代烷基、未取代或取代烯基、未取代或取代环烷基、未取代或取代芳基、未取代或取代芳基烷基；
    或者，Q选自O，R 3和R 4与其相邻的氧成内酯；
    R 5或R 6相同或不同，选自氢、未取代或取代烷基、未取代或取代烯基、未取代或取代环烷基、未取代或取代芳基、未取代或取代芳基烷基、 未取代或取代酰基；
    R 1、R 2、R 3、R 4、R 5和R 6不同时为H。
  5. 1-O-咖啡酰奎宁酸、其药物前体及其盐在制备预防和治疗肿瘤的药物中的用途，其中，所述药物前体结构式如式(II)所示：
    Figure PCTCN2018090091-appb-100008
    其中，Q选自N或O；
    R 1或R 2相同或不同，独立的选自氢、未取代或取代烷基、未取代或取代烯基、未取代或取代环烷基、未取代或取代芳基、未取代或取代芳基烷基、未取代或取代酰基；或者，R 1和R 2与其相邻的氧形成缩醛；
    R 3选自氢、未取代或取代烷基、未取代或取代烯基、未取代或取代环烷基、未取代或取代芳基、未取代或取代酰基；
    R 4选自氢、未取代或取代烷基、未取代或取代烯基、未取代或取代环烷基、未取代或取代芳基、未取代或取代芳基烷基；
    或者，Q选自O，R 3和R 4与其相邻的氧成内酯；
    R 5或R 6相同或不同，选自氢、未取代或取代烷基、未取代或取代烯基、未取代或取代环烷基、未取代或取代芳基、未取代或取代芳基烷基、未取代或取代酰基；
    R 1、R 2、R 3、R 4、R 5和R 6不同时为H。
  6. 1-O-咖啡酰奎宁酸、其药物前体及其盐在制备预防和治疗自身免疫疾病药物中的用途，其中，所述药物前体结构式如式(II)所示：
    Figure PCTCN2018090091-appb-100009
    其中，Q选自N或O；
    R 1或R 2相同或不同，独立的选自氢、未取代或取代烷基、未取代或取代烯基、未取代或取代环烷基、未取代或取代芳基、未取代或取代芳基烷基、未取代或取代酰基；或者，R 1和R 2与其相邻的氧形成缩醛；
    R 3选自氢、未取代或取代烷基、未取代或取代烯基、未取代或取代环烷基、未取代或取代芳基、未取代或取代酰基；
    R 4选自氢、未取代或取代烷基、未取代或取代烯基、未取代或取代环烷基、未取代或取代芳基、未取代或取代芳基烷基；
    或者，Q选自O，R 3和R 4与其相邻的氧成内酯；
    R 5或R 6相同或不同，选自氢、未取代或取代烷基、未取代或取代烯基、未取代或取代环烷基、未取代或取代芳基、未取代或取代芳基烷基、未取代或取代酰基。
  7. 根据权利要求4～6任意一项所述的用途，其特征在于，Q选自O；
    R 1或R 2相同，独立的选自氢、3个碳原子以下的烷基或5个碳原子以下的烷基酰基；
    或者，R 1和R 2与其相邻的氧形成式(b)所示的缩醛：
    Figure PCTCN2018090091-appb-100010
    其中，R 7、R 8选自氢、5个碳原子以下的烷基、5个碳原子以下的烯基、取代或未取代的苯基、苯基烯基；或者，R 7、R 8与其相邻的C形成4～6元环；
    R 3选自氢或3个碳原子以下的烷基；
    R 4选自氢、3个碳原子以下的烷基；
    或者，R 3和R 4与其相邻的氧成内酯；
    R 5或R 6相同，选自氢、3个碳原子以下的烷基、4个碳原子以下的烷基酰基。
  8. 根据权利要求7所述的用途，其特征在于，所述药物前体选自：
    Figure PCTCN2018090091-appb-100011
    Figure PCTCN2018090091-appb-100012
  9. 根据权利要求7所述的用途，其特征在于，所述盐选自与碱金属及碱土金属或过渡金属形成的无机盐；以及与有机胺形成的有机碱。
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