CN108003027B - 1-O-caffeoylquinic acid, its derivative, preparation method and use thereof - Google Patents
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Abstract
The invention provides a 1-O-caffeoylquinic acid derivative shown in a formula (II), 1-O-caffeoylquinic acid, a 1-O-caffeoylquinic acid derivative shown in the formula (II) and application of salts thereof. 1-O-caffeoylquinic acid, 1-O-caffeoylquinic acid derivatives shown in formula (II) and their salts have effects of inhibiting secretion of interleukin 17, especially interleukin 17F, and can be used for preventing and treating tumor. The experimental result shows that the inhibition rate of the 1-O-caffeoylquinic acid to the interleukin 17F is close to 70 percent when the concentration of the 1-O-caffeoylquinic acid is 0.5 mu M/L; the 1-O-caffeoylquinic acid has better inhibition effect on tumors such as melanoma, pancreatic cancer, colorectal cancer, lung cancer and the like with the dosage of 20mg/kg, which exceeds 50 percent, and the derivatives thereof also have better inhibition effect on tumors such as melanoma, pancreatic cancer, colorectal cancer, lung cancer and the like.
Description
Technical Field
The invention belongs to the technical field of pharmaceutical chemistry, and particularly relates to 1-O-caffeoylquinic acid, a derivative, a preparation method and application thereof.
Background
The interleukin 17 (IL-17) family comprises 6 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, S.L. et al, Immunology 9 (2009): 556 and 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 believed to share the same receptor as IL-17A (Kolls and Linden 2004, Immunity, 21, 467-. Both 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 contribute to a number of diseases mediated by aberrant 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; Chabauud et al, Arthritis Res.2001,3, 168-177). IL-17A and IL-17F are both associated with autoimmune diseases (Iwakura, Y., H. Ishigame et al.2011, Immunity34(2) 149-. IL-17F antagonism is associated with protection against asthma (Kawaguchi et al, 2006, J.allergy Clin.Immunol.117 (4); 795-.
The prior literature reports are as follows: WO2014065413 reports triazole derivatives and isoxazole derivatives as RORsγReceptor inhibitor, so as to inhibit the differentiation and activation of Th17 cell and inhibit IL-17.WO201400944 and WO2016014918 report on aryl sultam derivatives and benzimidazole derivatives as RORc modulators, such compounds being mainly used for the treatment of autoimmune diseases. WO2016213676 reports substituted 2, 3-dihydro-1H-inden-1-ones as RORγt/RORγReceptor antagonists, useful for modulating RORγt/RORγActivity and use for treating RORγt/RORγMediated diseases and conditions. WO2016072402 reports on the receptor ROR of TH17 cells by cyclic amine derivativesγtHas inhibitory effect on TH17 cell differentiation and IL-17 secretion. WO2016120849 reports methoxy-substituted pyrrolopyridines for RORγA receptor inhibitor, thereby reducing the amount of IL-17. No report on the use of 1-O-caffeoylquinic acid analogs to influence IL-17 secretion is available from the above literature summaries.
The 1-O-caffeoylquinic acid has a structural formula shown in a formula (I),
the molecular formula is C16H18O9And the molecular weight is 354.31.
1-O-caffeoylquinic acid is a substituted depside composed of caffeic acid and quinic acid, is a positional isomer of chlorogenic acid, and is a phenylpropanoid compound. 1-O-caffeoylquinic acid is widely present in higher dicotyledons and ferns, mainly in plants of Lonicera (Lonicera) and Artemisia (Artemisia) of Caprifoliaceae, has lower content in plants than chlorogenic acid, and is difficult to separate.
As early as 1964, there was a report on the synthesis of 1-O-caffeoylquinic acid by further deprotection to the desired product by condensation of acetonylidene quinic acid with diacetyl-protected caffeoyl chloride. However, the synthesis conditions and yields are not described in detail in the article.
Disclosure of Invention
In view of the above, the present invention aims to provide 1-O-caffeoylquinic acid, its derivatives, a preparation method and uses thereof, and the 1-O-caffeoylquinic acid and its derivatives provided by the present invention have a strong inhibitory effect on interleukin 17F.
The invention provides a 1-O-caffeoylquinic acid derivative shown as a formula (II):
wherein Q is selected from N or O;
R1or R2The same or different, independently 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; or, R1And R2Oxygen adjacent thereto forms an acetal;
R3selected from the group consisting of hydrogen, unsubstituted or substituted alkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted aryl, unsubstituted or substituted acyl;
R4selected from the group consisting of hydrogen, unsubstituted or substituted alkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted aryl, unsubstituted or substituted arylalkyl;
or Q is selected from O and R3And R4Adjacent thereto an oxo lactone;
R5or R6The same or different, 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;
R1、R2、R3、R4、R5and R6Not H at the same time;
R1、R2、R3is not a group of formula (a):
in the present invention, the 1-O-caffeoylquinic acid derivative represented by the formula (II) is a monocaffeoylquinic acid derivative, and not a polycaffeoylquinic acid derivative, such as a dicaffeoylquinic acid derivative or a tricaffeoylquinic acid derivative, nor 1-O-caffeoylquinic acid.
The application surprisingly finds that 1-O-caffeoylquinic acid, 1-O-caffeoylquinic acid derivatives shown in formula (II) and salts thereof have the effect of inhibiting secretion of interleukin 17, and therefore can be used as interleukin 17 modulators.
Specifically, the interleukin 17 is interleukin 17F.
The application also proves that the 1-O-caffeoylquinic acid, the 1-O-caffeoylquinic acid derivative shown in the formula (II) and the salt thereof also have the effects of preventing and treating tumors, so that the derivative can be applied as a medicine for preventing and treating tumors. In particular, the tumors include solid tumors and non-solid tumors, including but not limited to melanoma, pancreatic cancer, colorectal cancer, lung cancer, liver cancer, stomach cancer, laryngeal cancer, nasopharyngeal cancer, esophageal cancer, multiple myeloma, lymphoid cancer, leukemia, bladder cancer, prostate cancer, cholangiocarcinoma, cervical cancer, ovarian cancer, breast cancer, endometrial cancer, skin cancer, and the like.
Correspondingly, the 1-O-caffeoylquinic acid derivative shown in the formula (II) and the salt thereof also have the effects of preventing and treating autoimmune diseases, so the derivative can be used as a medicine for preventing and treating the autoimmune diseases. Specifically, the autoimmune disease drug includes, but is not limited to, systemic lupus erythematosus, psoriasis, rheumatoid arthritis, scleroderma, and the like.
In the present invention, the 1-O-caffeoylquinic acid derivative represented by formula (II) is actually a prodrug of 1-O-caffeoylquinic acid, which is converted into 1-O-caffeoylquinic acid in various enzymes and human environment after entering the human body, thereby exerting the effect of inhibiting secretion and activity of interleukin 17F, and preventing and treating tumors or autoimmune diseases.
In the present invention, salts of 1-O-caffeoylquinic acid or of 1-O-caffeoylquinic acid derivatives of formula (II) refer to pharmaceutically acceptable salts, i.e., within the scope of sound medical judgment, which are suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, commensurate with a reasonable benefit/risk ratio.
Pharmaceutically acceptable salts are well known in the art. Pharmaceutically acceptable salts are described in detail, for example, in j.pharmaceutical Sciences,1977,66,1-19, by s.m.berge et al, which is incorporated herein by reference. The salts of 1-O-caffeoylquinic acid or of 1-O-caffeoylquinic acid derivatives of formula (II) of the present invention include those derived from suitable inorganic and organic bases. Inorganic base salts include salts with ammonia, alkali metals, alkaline earth metals, or transition metals, such as ammonium salts, as well as lithium, sodium, potassium, calcium, zinc, iron, ferrous salts, and the like. The organic base salt includes amine salt, including salt formed by 1-O-caffeoylquinic acid or 1-O-caffeoylquinic acid derivative shown in formula (II) and primary, secondary or tertiary amine, and can be selected from salt formed by organic base: such as arginine, ethylenediamine, triethylamine, caffeine, betaine, ethanolamine, trimethylamine, piperidine, and the like.
In the present invention, the 1-O-caffeoylquinic acid derivative is represented by the formula (II):
in one embodiment, Q is selected from O.
In one embodiment, R1Or R2And the same, independently selected from hydrogen, alkyl of 3 or less carbon atoms or alkanoyl of 5 or less carbon atoms.
In one embodiment, R1And R2Oxygen adjacent thereto forms an acetal represented by the formula (b):
wherein R is7、R8Independently selected from hydrogen, alkyl of up to 5 carbon atoms, alkenyl of up to 5 carbon atoms, substituted or unsubstituted phenyl, phenylalkenyl; or, R7、R8The adjacent C forms a 4-6 membered ring.
In one embodiment, R3Selected from hydrogen or alkyl groups of 3 or less carbon atoms.
In one embodiment, R4Selected from hydrogen, alkyl groups of 3 or less carbon atoms.
In one embodiment, R3And R4The oxygen adjacent to it forms a lactone.
In one embodiment, R5Or R6And is selected from the group consisting of hydrogen, alkyl groups of 3 or less carbon atoms, and alkanoyl groups of 4 or less carbon atoms.
Specifically, the 1-O-caffeoylquinic acid derivative shown in the formula (II) has a structure shown in the formula (II-1):
wherein R is1Or R2The same, independently selected from hydrogen, alkyl of 3 carbon atoms or less, or alkanoyl of 5 carbon atoms or less; r3Selected from hydrogen or alkyl of 3 or less carbon atoms; r4Selected from hydrogen, alkyl groups of 3 carbon atoms or less; r5Or R6And is selected from the group consisting of hydrogen, alkyl groups of 3 or less carbon atoms, and alkanoyl groups of 4 or less carbon atoms. That is, in the 1-O-caffeoylquinic acid derivative represented by the formula (II), R is1And R2Without formation of acetals, R3And R4Nor formation of lactones.
Typical compounds represented by the formula (II-1) are shown in Table 1.
TABLE 1
Specifically, the 1-O-caffeoylquinic acid derivative shown in the formula (II) has a structure shown in a formula (II-2):
wherein R is1Or R2The same, independently selected from hydrogen, alkyl of 3 carbon atoms or less, or alkanoyl of 5 carbon atoms or less;
R5or R6And is selected from the group consisting of hydrogen, alkyl groups of 3 or less carbon atoms, and alkanoyl groups of 4 or less carbon atoms.
That is, in the 1-O-caffeoylquinic acid derivative represented by the formula (II), R is1And R2Without formation of acetals, R3And R4A lactone is formed.
Typical compounds represented by the formula (II-2) are shown in Table 2.
TABLE 2
Specifically, the 1-O-caffeoylquinic acid derivative shown in the formula (II) has a structure shown in a formula (II-3):
wherein R is7、R8Independently selected from hydrogen, alkyl of up to 5 carbon atoms, alkenyl of up to 5 carbon atoms, substituted or unsubstituted phenyl, phenylalkenyl;
R3selected from hydrogen or alkyl of 3 or less carbon atoms;
R4selected from hydrogen, alkyl groups of 3 or less carbon atoms.
R5Or R6And is selected from the group consisting of hydrogen, alkyl groups of 3 or less carbon atoms, and alkanoyl groups of 4 or less carbon atoms.
That is, in the 1-O-caffeoylquinic acid derivative represented by the formula (II), R is1And R2Formation of acetals, R3And R4No lactone is formed.
Typical compounds represented by the formula (II-3) are shown in Table 3.
TABLE 3
Specifically, the 1-O-caffeoylquinic acid derivative shown in the formula (II) has a structure shown in a formula (II-4):
wherein R3 is selected from hydrogen or alkyl of 3 or less carbon atoms;
r4 is selected from hydrogen, alkyl of 3 or less carbon atoms;
r5 or R6 are the same and are selected from the group consisting of hydrogen, alkyl of 3 or less carbon atoms, and alkanoyl of 4 or less carbon atoms;
n is selected from 1, 2,3 or 4.
That is, in the 1-O-caffeoylquinic acid derivative represented by formula (II), R1 and R2 form an acetal, and the substituents thereon form a 3-to 6-membered ring, and R3 and R4 do not form a lactone.
Typical compounds represented by the formula (II-4) are shown in Table 4.
TABLE 4
Specifically, the 1-O-caffeoylquinic acid derivative shown in the formula (II) has a structure shown in a formula (II-5):
wherein R is7、R8Independently selected from hydrogen, alkyl of up to 5 carbon atoms, alkenyl of up to 5 carbon atoms, substituted or unsubstituted phenyl, phenylalkenyl;
R5or R6And is selected from the group consisting of hydrogen, alkyl groups of 3 or less carbon atoms, and alkanoyl groups of 4 or less carbon atoms.
That is, in the 1-O-caffeoylquinic acid derivative represented by the formula (II), R is1And R2Formation of acetals, R3And R4A lactone is formed.
Typical compounds represented by the formula (II-5) are shown in Table 5.
TABLE 5
Specifically, the 1-O-caffeoylquinic acid derivative shown in the formula (II) has a structure shown in a formula (II-6):
wherein R is5Or R6And is selected from hydrogen, alkyl of 3 or less carbon atoms, alkanoyl of 4 or less carbon atoms;
n is selected from 1, 2,3 or 4.
That is, in the 1-O-caffeoylquinic acid derivative represented by the formula (II), R is1And R2Forming an acetal, wherein the substituents thereon form a 3-6 membered ring, R3And R4A lactone is formed.
Typical compounds represented by the formula (II-6) are shown in Table 6.
TABLE 6
In the present invention, 1-O-caffeoylquinic acid or a derivative thereof represented by formula (II) may be prepared according to the following method:
firstly, the initial raw material quinic acid forms a lactone ring in the presence of a catalyst, protective groups are introduced at 3 and 4 positions to obtain a compound II, the compound II reacts with SM to obtain a compound III, and the compound III is deprotected to obtain a compound of a general formula (I).
The reaction process is as follows:
wherein:
`R1、`R2、`R4、`R5、`R6is defined as in formula (II) and R1、R2、R3、R4、R5、、R6Same definition, however, when the target product is 1-O-caffeoylquinic acid, R1、R2、R3、R4、R5、、R6May be all H.
X is halogen or hydroxyl, and in the synthetic route of the invention, in the preparation of the compound III, the ester forming method generally comprises two methods: when SM is the corresponding carboxylic acid, in the presence of a conventional condensing agent (e.g., N' -Dicyclohexylcarbodiimide (DCC), 1-ethyl- (3-dimethylaminopropyl) carbodiimide (EDC), etc.); when SM is prepared into the corresponding acyl halide, the ester is directly formed under basic conditions (such as pyridine, triethylamine, N-diisopropylethylamine, 1, 8-diazacyclo [5,4,0] undecene-7 and the like).
In the synthetic method, the alkali used for deprotecting the compound III is lithium hydroxide, sodium hydroxide, potassium hydroxide and the like; the acid is hydrochloric acid water solution, sulfuric acid water solution, trifluoroacetic acid water solution, etc.
In the present invention, the term "alkyl" denotes a saturated straight or branched hydrocarbon group of 1 to 12 carbon atoms. Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, 2-methylbutyl, neopentyl, n-hexyl, heptyl, octyl groups.
In the present invention, the term "alkenyl" denotes a monovalent group derived from a hydrocarbon moiety by removal of a single hydrogen atom, wherein the hydrocarbon 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.
In the present invention, the term "cycloalkyl" denotes a saturated carbocyclic compound having 3 to 12 ring atoms. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl.
In the present invention, the term "acyl" includes residues derived from acids including, but not limited to, carboxylic acids, carbamic acids, carbonic acids, sulfonic acids, and phosphoric acids. Examples include aliphatic carbonyl groups, aromatic carbonyl groups, and aliphatic sulfonic acid groups. Examples of aliphatic carbonyl groups include, but are not limited to, acetyl, propionyl, butyryl, and the like.
In the present invention, the term "halogen" refers to atoms of fluorine, chlorine, bromine, iodine.
In the present invention, the term "aryl" refers to a monocyclic, bicyclic or tricyclic carbocyclic ring system having 1 to 3 aromatic rings, including, but not limited to, phenyl, naphthyl, tetrahydronaphthyl, anthracenyl and the like.
In the present invention, the term "arylalkyl" as used herein, means 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.
In the present invention, the term"substituted" refers to the replacement of one, two or three or more hydrogen atoms thereon independently with a substituent including, but not limited to, halogen, -OH, protected hydroxy, -NO2、-CN、-NH2Protected amino, alkoxy, and the like.
The invention also provides a pharmaceutical composition which comprises the 1-O-caffeoylquinic acid, the 1-O-caffeoylquinic acid derivative shown in the formula (II) or the salt thereof and pharmaceutically acceptable auxiliary materials.
The term "pharmaceutical composition" is meant to encompass any and all solvents, diluents or other liquid excipients, dispersing or suspending aids, surfactants, isotonic agents, thickening or emulsifying agents, preservatives, solid binders, lubricants and the like as appropriate for the particular dosage form desired. 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. Except insofar as any conventional carrier medium is incompatible with the compounds of the invention, e.g., any other component that produces no biological effect or interacts in a deleterious manner with a pharmaceutically acceptable composition, its use is contemplated as falling within the scope of the present invention. Some examples of materials capable of serving as pharmaceutically acceptable carriers include, but are not limited to, ion exchangers; alumina; aluminum stearate; lecithin; buffer substances, for example: a phosphate salt; glycine; sorbic acid or potassium sorbate; a mixture of partial glyceride esters of saturated vegetable fatty acids; water; salts or electrolytes, for example: disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride and zinc salt; colloidal silicon dioxide; magnesium trisilicate; polyvinylpyrrolidone; a polyacrylate; sugars such as lactose, glucose and sucrose; starches, such as corn starch and potato starch; cellulose and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; gelatin; talc; excipients, such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; glycols, such as propylene glycol or polyethylene glycol; esters such as ethyl oleate and ethyl laurate; agar; pyrogen-free water; isotonic saline; ethanol; and other non-toxic compatible lubricants such as sodium lauryl sulfate and magnesium stearate; coloring agents, releasing agents, coating agents, sweetening, flavoring and perfuming agents, preserving and anti-oxidizing agents may also be present in the composition, according to the judgment of the person skilled in the art.
The invention also provides a pharmaceutical preparation, which comprises the 1-O-caffeoylquinic acid, the 1-O-caffeoylquinic acid derivative shown in the formula (II) or the salt thereof and pharmaceutically acceptable auxiliary materials, and the compound or the salt thereof can be prepared into conventional pharmaceutical preparations according to conventional preparation methods, such as capsules, tablets, pills, granules, emulsions, floating agents, injections, drops and the like.
The application discovers that 1-O-caffeoylquinic acid, 1-O-caffeoylquinic acid derivatives shown in formula (II) and salts thereof have the effect of inhibiting secretion of interleukin 17, especially interleukin 17F, and can prevent and treat tumors. The experimental result shows that the inhibition rate of the 1-O-caffeoylquinic acid to the interleukin 17F is close to 70 percent when the concentration of the 1-O-caffeoylquinic acid is 0.5 mu M/L; the 1-O-caffeoylquinic acid has better inhibition effect on tumors such as melanoma, pancreatic cancer, colorectal cancer, lung cancer and the like with the dosage of 20mg/kg, which exceeds 50 percent, and the derivatives thereof also have better inhibition effect on tumors such as melanoma, pancreatic cancer, colorectal cancer, lung cancer and the like.
Detailed Description
The technical solutions in the embodiments of the present invention will be clearly and completely described below, and it is obvious that the described embodiments are only a part of the embodiments of the present invention, and not all embodiments. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.
Example 1: preparation of (1S,3R,4R,5R) -1- [ [3- (3, 4-dihydroxyphenyl) -1-oxo-2-propenyl ] oxy ] -3,4, 5-trihydroxycyclohexanecarboxylic acid (compound 1-1)
And B:
adding caffeic acid (36.0g, 0.2mol) into a reaction bottle, adding 1mol/L sodium hydroxide aqueous solution (440ml) for dissolving, cooling the system to 0 ℃, slowly dropwise adding acetic anhydride (80ml, 0.84mol), keeping 0 ℃ for reaction for 1h, filtering, washing a filter cake to be neutral, recrystallizing a crude product with ethanol, and drying to obtain 44.87g of SM white powder, wherein the yield is as follows: 84.98%, mp: 182 to 184 ℃.
Step A:
d- (-) -Quinic acid (30.0g, 0.156mol, prepared according to the method of the document Valentia Sinisi. Et al, "Interaction of chlorogenic acids and peptides from coffee with human serum", Food Chemistry, 2015 (168): 332-. The system is a solid-liquid mixed phase when the reaction is started, and the solid-liquid mixed phase is completely dissolved in about 8 hours along with the continuous reaction. The molecular sieve was replaced every 8h to ensure that the water produced was removed as much as possible. After the reaction is finished, cooling the system to 0 ℃, and adding NaHCO3(8.7g, 0.66eq) was stirred for 1h, filtered and spin-dried to give a pale yellow solid. Recrystallization from ethyl acetate/petroleum ether system gave 23.6g of off-white solid 3, 4-oxo-isopropylidene quinic acid-1, 5-lactone (compound 1a), yield: 70.6 percent. mp: 132-134 ℃;
and C:
adding 3, 4-diacetyloxyphenacrylic acid (7.4g, 28.0mmol), N, N' -dicyclohexylcarbodiimide (9.63g, 46.7mmol), 1-hydroxybenzotriazole (6.31g, 46.7mmol) and anhydrous dichloromethane (50.0ml) into a reaction bottle in sequence, stirring at room temperature for 30min, adding 3, 4-O-isopropylidene quinic acid-1, 5-lactone (compound 1a) (5.0g, 23.3mmol) and 4-dimethylaminopyridine (0.58g, 4.7mmol) after white turbidity appears, stirring the whole reaction system at room temperature for 12h, filtering to remove insoluble substances, carrying out reduced pressure rotary evaporation on the filtrate to remove the solvent, and remaining the restAnd (5) performing column chromatography separation. The esterified product was eluted with ethyl acetate/petroleum ether ═ 1:2 to give 5.93g of a white solid (compound 1b), yield: 55.2 percent. mp: 123-125 ℃;
MS(ESI+)：m/z＝460.1；1H NMR(500MHz,CDCl3):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)。
step D:
sequentially adding 1-oxygen- [ (3 ', 4' -diacetyl) cinnamoyl into a reaction bottle]-3, 4-O-isopropylidene-quinic acid-1, 5-lactone (compound 1b, 1.0g, 2.17mmol), tetrahydrofuran (28.0ml), H2O (11.0ml), and the solution was dissolved by stirring at room temperature. 1mol/L aqueous LiOH (9.0ml, 9.0mmol) was added to the reaction system, and the reaction was stirred at room temperature for 1 hour. TLC (PE: EA ═ 1:1) showed complete reaction of starting material and the reaction was carried forward.
Step E:
directly using 1N HCl to adjust the pH value of the reaction system to 1, and continuously stirring at room temperature for reaction for 17 hours until the reaction is complete. The system is adjusted to pH about 7 by 1mol/L LiOH aqueous solution, and is purified by a reverse phase preparative liquid phase (a chromatographic Column is SHIMADZU LC Column Shim-pack PREP-ODS (k), a mobile phase A is 0.05 percent trifluoroacetic acid aqueous solution, a mobile phase B is acetonitrile, and gradient elution is carried out), and the prepared liquid is lyophilized to obtain the compound 1-1, 461.5 mg. Yield: 59.97 percent. MS (ESI)+)：m/z＝354.2。1HNMR(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)。
Example 2 (preparation of Compounds 1-4)
Step A:
to a 100ml three-necked flask were added the intermediate 1b (10.0g, 21.72mmol) and DCM (100.0ml) in that order, stirred to dissolve it clearly, and then H was added2O (20.0ml), trifluoroacetic acid (37.0ml) is slowly dropped into the ice water bath, and after dropping, the mixture is stirred for 5min to 15min at room temperature, and the reaction is monitored by sampling TLC. The reaction system was concentrated under reduced pressure at room temperature using an oil pump, and toluene was taken with trifluoroacetic acid to give 7.2g of a yellow foamy solid 1-4 a.
And B:
under the protection of nitrogen, adding the intermediate 1-4a (5.0g, 11.89mmol) into a reaction bottle, adding anhydrous DMF (50.0ml) to dissolve, cooling the system to 0 ℃, adding sodium hydride (1.2g, 29.72mmol, 60% mineral oil) in batches, stirring for 30min, slowly dropwise adding a DMF solution (10.0ml) containing 2-bromopropane (3.2g, 26.16mmol), and naturally heating to room temperature for reaction for 2 h. Adding 2N ammonium chloride aqueous solution into a reaction system, extracting with ethyl acetate for three times, combining organic phases, washing with saline solution, drying with anhydrous sodium sulfate, performing suction filtration, performing rotary evaporation under reduced pressure to obtain a crude product, and purifying the crude product by column chromatography to obtain 1.3g of the title compounds 1-4b, wherein the yield is as follows: 21.67 percent. MS (ESI +): m/z is 504.2.
And C:
intermediate 1-4b (0.85g, 1.68mmol) was added to a reaction flask, methanol (10.0ml) was added, and the solution was stirred at room temperature. Sodium methoxide (0.11g, 2.22mmol) was added to the reaction system, and the reaction was stirred at room temperature for 1 h. TLC showed the starting material reaction was complete. Adding saturated ammonium chloride aqueous solution (8.0ml) into the reaction system, concentrating under reduced pressure, extracting the residue with ethyl acetate three times, combining the organic phases, washing with saturated saline solution, drying with anhydrous sodium sulfate, suction filtering, rotary evaporating under reduced pressure to obtain a crude product, and purifying the crude product by column chromatography to obtain 300.0mg of the title compounds 1-4 with yield: 39.46 percent. MS (ESI +): and m/z is 452.2.
Example 3 (preparation of Compounds 1-9)
Step D:
intermediate 1b (1.60g, 3.48mmol) from example 1 was added to a reaction flask, methanol (20.0ml) was added, and the solution was stirred at room temperature. Sodium methoxide (0.23g, 4.17mmol) was added to the reaction system, and the reaction was stirred at room temperature for 1 h. TLC showed the starting material reaction was complete. Adding saturated ammonium chloride aqueous solution (15.0ml) into the reaction system, concentrating under reduced pressure, extracting the residue with ethyl acetate for three times, combining organic phases, washing with saturated saline solution, drying with anhydrous sodium sulfate, filtering, decompressing and rotary steaming to obtain a crude product, and purifying the crude product by column chromatography to obtain an intermediate 1-9d, 1.13 g. Yield: 79.66 percent. MS (ESI +): and m/z is 408.2.
Step E:
the compound 1-9d (500mg, 1.22mmol) was added to a reaction flask, and dissolved in tetrahydrofuran (10.0ml), and then trifluoroacetic acid (1.0ml) was added thereto and the reaction was stirred at room temperature for 2 hours to complete the reaction. The system was adjusted to pH 7 with 1mol/L aqueous LiOH solution, and subjected to preparative liquid phase purification of reversed phase (Column chromatography, SHIMADZU LC Column, Shim PREP-ODS (k), mobile phase A was 0.05% aqueous trifluoroacetic acid, mobile phase B was acetonitrile, and gradient elution.) to obtain the title compound, 361.5mg, by lyophilization. Yield: 80.17 percent. MS (ESI +): 368.1.
Example 4 (preparation of Compounds 1-23)
Step A:
prepared according to the operating conditions described for step B in example 2, wherein the 2-bromopropane is replaced with benzyl bromide, the target intermediates 1-23B are obtained. MS (ESI)+)：m/z＝600.3。
And B:
1-23b (1.0g, 1.66mmol), tetrahydrofuran (28.0ml), and H were added to the reaction flask in this order2O (11.0ml), and the solution was dissolved by stirring at room temperature. 1mol/L aqueous LiOH (7.0ml, 7.0mmol) was added to the reaction system, and the reaction was stirred at room temperature for 1 hour. After the reaction was completed, the system was adjusted to pH 7 with 1mol/L HCl aqueous solution, and subjected to reversed-phase preparative liquid-phase purification (Column chromatography, SHIMADZU LC Column, Shim PREP-ODS (k), mobile phase A was 0.05% trifluoroacetic acid aqueous solution, mobile phase B was acetonitrile, and gradient elution), and the preparation was lyophilized to obtain the title compounds 1-23, 241.6 mg. Yield: 27.15 percent. MS (ESI)+)：m/z＝534.1。
Example 5 (preparation of Compounds 2-9)
Compounds 1-4a prepared in example 2 are compounds 2-9 prepared in example 5.
Example 6 (preparation of Compounds 2-6)
Compounds 1-23b prepared in example 4 are compounds 2-6 prepared in example 6.
Example 7 (preparation of Compounds 2-11)
Step A:
the intermediate 1-4a (1.0g, 2.38mmol) from example 2 was added to a reaction flask, dichloromethane (20.0ml) was added to dissolve, N-diisopropylethylamine (0.92g, 7.12mmol) was added, the system was cooled to 0 deg.C, acetyl chloride (0.47g, 5.98mmol) was slowly added dropwise, and the reaction was allowed to react at 0 deg.C for 5h, at completion. Adding water into the reaction system, separating liquid, extracting the water phase with dichloromethane, combining organic phases, washing with water to be neutral, removing the solvent by rotary evaporation under reduced pressure, and purifying the crude product by column chromatography to obtain the title compound with the yield of 0.57 g: 47.48 percent. MS (ESI)+)：m/z＝504.1。
Example 8 (preparation of Compounds 3-7)
Compound 1c prepared in example 1 is compound 3-7 prepared in example 8.
Example 9 (preparation of Compounds 3-4)
Step A:
d- (-) -Quinic acid (20.0g, 0.10mol), toluene (120ml), methyl isobutyl ketone (100.0ml) and p-toluenesulfonic acid monohydrate (2.0g, 0.01mol) are sequentially added into a 500ml single-mouth bottle, after the addition is finished, the temperature is raised to reflux (external bath is 150 ℃), a water separator is erected, the system is yellow turbid liquid, water is divided for 2h after the reflux, and the reflux reaction is continued for 2 h. The system became clear and a small amount of yellow insoluble was stuck to the wall of the bottle and the reaction was monitored by TLC (DCM: MeOH ═ 10:1) for completion. Concentrating under reduced pressure at 50 deg.C, adding H into the residue2O (80.0ml), saturated NaHCO3The pH was adjusted to 7-8, the aqueous phase was extracted with EA (100.0 ml. times.2), the organic phases were combined, washed with brine (100.0ml), dried over anhydrous Na2SO4, filtered and concentrated to give 23.70g of a yellow solid. Recrystallizing with ethyl acetate \ petroleum ether system, crystallizing overnight, crystallizing at 0 deg.C for 2h, vacuum filtering, washing filter cake with petroleum ether, and vacuum drying filter cake to obtain 13.71g white crystal, i.e. intermediate 3-4 a. Yield: 53.92 percent. MS (ESI)+)：m/z＝254.1。
And B:
following the procedure of step C of example 1, wherein intermediate 1a was replaced with 3-4a, the condensation gave the target intermediate 3-4 b. MS (ESI)+)：m/z＝500.3。
And C:
compound 3-4 was prepared according to the procedure described in example 3, step D.
MS(ESI+)：m/z＝448.4。
Example 10 (preparation of Compounds 3-8)
Compounds 1-9d prepared in example 2 are compounds 3-8 prepared in example 10.
Example 11 (preparation of Compounds 4-4)
According to the examples9, in which cyclohexanone was used instead of methyl isobutyl ketone, followed by condensation and alcoholysis to give the title compounds 4-4. MS (ESI)+)：m/z＝448.3。
Example 12 (preparation of Compounds 4-9)
Step A:
4-4b (1.0g, 2.0mmol), THF (20.0ml), and H2O (5.0ml) were sequentially added to a 100ml single-neck flask, and the mixture was stirred to give a colorless clear solution. 1N LiOH aqueous solution (8.3ml, 8.3mmol) is added dropwise to an ice-water bath, the system is stirred for 1h at room temperature from colorless clear solution → light yellow clear solution → brown clear solution, TLC shows that 4-4b reaction is complete, the system is adjusted to pH about 6 with 0.5N hydrochloric acid at about 10 ℃, extracted three times with (DCM: THF ═ 1:1), the organic phases are combined, washed with brine, dried with Na2SO4, filtered with suction, and concentrated under reduced pressure to obtain 0.3g of yellow foamy solid, namely the compound 4-9. MS (ESI +): and m/z is 434.2.
Example 13 (preparation of Compound 5-1)
Step A:
prepared according to the operating conditions described for step a in example 9, wherein methyl ethyl ketone is substituted for methyl isobutyl ketone, intermediate 5-1a is obtained. MS (ESI)+)：m/z＝448.3。
And B:
caffeic acid (18.0g, 0.1mol) was added to a reaction flask, dichloromethane (180.0ml), N-diisopropylethylamine (105.0ml, 0.6mol) was added, tert-butyldimethylsilyl chloride (60.28g, 0.4mol) was added dropwise at room temperature, the reaction was completed at room temperature for 1.5h, and the completion of the reaction was monitored by TLC. And (2) carrying out reduced pressure rotary evaporation on the reaction liquid, adding ethyl acetate into the residues to dissolve the residues, washing the residues with 1N HCl and saturated saline respectively, drying the residues with anhydrous sodium sulfate, carrying out rotary evaporation to remove the solvent, adding petroleum ether into the residues, stirring the mixture for 15min, separating out a white solid, filtering and drying the white solid to obtain 28.5g of 5-1b white powder, wherein the yield is as follows: 69.7 percent.
And C:
prepared according to the operating conditions described for step C in example 1, intermediates 5-1a and 5-1b in the presence of a condensing agent to give intermediate 5-1C. MS (ESI)+)：m/z＝618.5。
Step D:
the intermediate 5-1c (1.0g, 1.62mmol) was added to a reaction flask, tetrahydrofuran (20.0ml) was added to dissolve, tetrabutylammonium fluoride trihydrate (1.0g, 3.24mmol) was added to turn the reaction system yellow, the reaction was stirred for 30min, and the completion of the reaction was monitored by TLC. Removing the solvent by reduced pressure rotary evaporation, adding ethyl acetate into the residue, washing with 1N HCl, deionized water and saturated saline sequentially, carrying out rotary evaporation on the organic phase to obtain a crude product, and carrying out column chromatography purification to obtain 0.43g of the title compound 5-1, wherein the yield is as follows: 68.17 percent. MS (ESI +): and m/z is 390.3.
Example 14 (preparation of Compounds 5-4)
Prepared according to the procedure described for example 13, substituting intermediate 5-4a for 5-1a, condensing, and deprotecting to provide the title compound 5-4. MS (ESI)+)：m/z＝448.3。
Example 15 (preparation of Compounds 5-5)
Prepared according to the procedure described for step A, B in example 9, substituting 4-bromoacetophenone for methyl isobutenylketone, and condensing to give the title compounds 5-5. MS (ESI)+)：m/z＝448.3。
Example 16 (preparation of Compound 6-1)
Prepared according to the procedure described for step C, D in example 13, 4-4a was condensed with 5-1b in the presence of a condensing agent and deprotected to provide the title compound 6-1. MS (ESI)+)：m/z＝416.4。
Example 17 (preparation of Compounds 6-7)
Intermediates 4-4b prepared in example 11 are compounds 6-7 prepared in example 17.
Example 18 (preparation of Compounds 6-8)
Prepared according to the operating conditions described for step A, B in example 9, wherein step a uses cyclopentanone instead of methyl isobutyl ketone to prepare intermediate 6-8a, which is then condensed to give the title compound 6-8.
MS(ESI+)：m/z＝430.1。
Example 19 biological Activity assays for the Compounds provided in examples 1-18
1. In vitro activity studies: the influence of 24h action of the 1-O-caffeoylquinic acid compound on the IL17F secretion of U87-Luc cells is detected by an ELISA method by utilizing an interleukin 17F (IL17F) detection kit.
The operation steps are as follows:
(1) and sample adding: and blank holes (the blank reference holes are not added with the sample and the enzyme labeling reagent, and the rest steps are operated in the same way), standard holes and sample holes to be detected are respectively arranged. And accurately adding the standard sample on the enzyme-labeled coating plate, adding a sample diluent in the sample hole to be detected, and then adding the sample to be detected. Adding sample to the bottom of the plate hole of the enzyme label, keeping the sample from touching the hole wall as much as possible, and gently shaking and mixing the sample and the hole wall.
(2) And incubation: the plates were sealed with a sealing plate and incubated at 37 ℃ for 30 minutes.
(3) And liquid preparation: diluting 30 times of concentrated washing solution with 30 times of distilled water for later use
(4) And washing: carefully uncovering the sealing plate film, discarding liquid, spin-drying, filling washing liquid into each hole, standing for 30 seconds, then discarding, repeating the steps for 5 times, and patting dry.
(5) And adding enzyme: enzyme labeling reagent is added into each hole except for blank holes.
(6) And color development: adding the color developing agent A and the color developing agent B into each hole, shaking gently, mixing uniformly, and developing for 10 minutes in a dark place at 37 ℃.
(7) And terminating: stop solution was added to each well to stop the reaction (blue color turned immediately yellow).
(8) And (3) measuring: the absorbance (OD value) of each well was measured sequentially at a wavelength of 450nm with blank air conditioning of zero. The measurement should be performed within 15 minutes after the addition of the stop solution.
The calculation method comprises the following steps:
GI (growth inhibition rate) ═ 1-ODDrug group/ODControl group)×100％。
2. In vivo efficacy studies:
2.1 in vivo model of mouse melanoma
Under aseptic condition, 1 × 107A single B16-F10 cell was seeded into the C57BL/6 underarm. After 10 days, the tumor tissue was aseptically harvested, and the homogenate was diluted with physiological saline and counted to a concentration of 1X 106one/mL tumor cell suspension, 0.2 mL/mouse was inoculated in the right axilla. Animals were randomly assigned the next day after inoculation (after 24 hours), weighed and dosed, with test compound 1 time a day and 13 consecutive intraperitoneal doses. Cyclophosphamide was administered intraperitoneally 1 time. On day 14, the weight was weighed, the animals were sacrificed, tumor tissue was stripped off, weighed and photographed. And finally, calculating the tumor proliferation inhibition rate, and evaluating the anti-tumor effect strength by using the tumor inhibition rate.
2.2 in vivo model of mouse pancreatic cancer PAN02
The mouse pancreatic cancer PAN02 tumor fluid was inoculated to the right underarm of the C57BL/6 mouse under sterile conditions. After 10 days, well-grown tumor tissues were aseptically harvested, minced, ground, filtered, diluted with physiological saline and counted to make a tumor cell suspension of 1.2X 107 cells/mL, and inoculated to the right underarm of C57BL/6 mice at 0.2 mL/mouse. Animals were randomly grouped the day after inoculation, 6 animals per group, weighed, dosed, and dosed 13 times in a row. Cyclophosphamide was administered intraperitoneally 1 time. On day 14, the weight was weighed, the animals were sacrificed, tumor tissue was stripped and weighed, and photographed. And finally, calculating the tumor inhibition rate, and evaluating the anti-tumor effect intensity by using the tumor inhibition rate.
2.3 mouse colorectal cancer MC38 in vivo model
The mouse colorectal cancer MC38 tumor fluid is inoculated to the right armpit of a C57BL/6 mouse under a sterile condition. After 10 days, well-grown tumor tissues were aseptically harvested, minced, ground, filtered, diluted with physiological saline and counted to make a tumor cell suspension of 1.2X 107 cells/mL, and inoculated to the right underarm of C57BL/6 mice at 0.2 mL/mouse. Animals were randomly grouped the day after inoculation, 6 animals per group, weighed, dosed, and dosed 13 times in a row. Cyclophosphamide was administered intraperitoneally 1 time. On day 14, the weight was weighed, the animals were sacrificed, tumor tissue was stripped and weighed, and photographed. And finally, calculating the tumor inhibition rate, and evaluating the anti-tumor effect intensity by using the tumor inhibition rate.
2.4 mouse Lewis Lung cancer in vivo model
The Lewis lung cancer tumor solution of the mice is inoculated to the right armpit of the C57BL/6 mice under the aseptic condition. After 10 days, well-grown tumor tissues were aseptically harvested, minced, ground, filtered, diluted with physiological saline and counted to make a tumor cell suspension of 1.2X 107 cells/mL, and inoculated to the right underarm of C57BL/6 mice at 0.2 mL/mouse. Animals were randomly grouped the day after inoculation, 6 animals per group, weighed, dosed, and dosed 13 times in a row. Cyclophosphamide was administered intraperitoneally 1 time. On day 14, the weight was weighed, the animals were sacrificed, tumor tissue was stripped and weighed, and photographed. And finally, calculating the tumor inhibition rate, and evaluating the anti-tumor effect intensity by using the tumor inhibition rate.
The calculation method comprises the following steps:
tumor proliferation inhibition ratio TGI (%): TGI ═ 1-T/C) × 100. (T: tumor weight in treatment group; C: tumor weight in negative control group).
The test results are shown in table 7, and table 7 shows the test results of the biological activity of the compounds provided in the examples of the present invention.
Table 7 results of bioactivity test of compounds provided in the examples of the present invention
As can be seen from Table 7, the compound 1-1, namely 1-O-caffeoylquinic acid, has an inhibitory effect on interleukin 17L, and the inhibition rate is close to 70%; the compound 1-1 has better inhibition effect on melanoma, pancreatic cancer, colorectal cancer, lung cancer and other tumors with the dosage of 20mg/kg, and the inhibition effect is more than 50 percent. The derivative has good inhibition effect on melanoma, pancreatic cancer, colorectal cancer, lung cancer and other tumors.
Example 20 animal models of autoimmune diseases
1. Lupus erythematosus animal model
The compound is injected into MRL/lpr spontaneous lupus mice of 10 weeks old by intragastric or intraperitoneal injection for 1 time every day for 3 months. Skin pathology, degree and pathology of joint swelling, blood/urine creatinine urea nitrogen, and blood dsDNA and ANA antibodies were observed and examined during dosing and at the end of the experiment.
2. Mouse psoriasis model induced by imiquimod
The back of the mouse was depilated with pet hair clipper and depilatory cream, and the area was about 1.5X 2 cm. Except for the negative control animals, each group was modeled with imiquimod cream, i.e., 50mg of imiquimod cream was applied to the skin of the dehaired area of the back of the mice daily, 1 time daily for 7 consecutive days. The animals were gavaged or injected intraperitoneally on the day of molding, 1 time per day, and on day 7. The animals were scored daily for psoriasis-like lesion area and disease severity-pasi (psoriasis area and severity index) starting the day of first molding. The mice were given 0-4 points of erythema (erythema), scales (scales), and thickness of infiltration (thickness) on the skin lesions according to the PASI scoring criteria, and the points were summed to give a total score.
PASI scoring criteria: 0, none; 1, light; 2, moderate; 3, severe; 4, very severe. At the end of the experiment (day 7), the mice were sacrificed by cervical dislocation, skin thickness was measured with a vernier caliper, and the skin of the animal on the dorsal part where the hair was removed, fixed with 4% paraformaldehyde, and subjected to pathological analysis.
Tests prove that the compound has good effect on treating autoimmune diseases such as lupus erythematosus, psoriasis and the like.
The foregoing is only a preferred embodiment of the present invention, and it should be noted that, for those skilled in the art, various modifications and decorations can be made without departing from the principle of the present invention, and these modifications and decorations should also be regarded as the protection scope of the present invention.
Claims (6)
1-O-caffeoylquinic acid derivatives having the structure of formula (II-3), formula (II-4), formula (II-6), formula (1-4), formula (1-23), formula (2-6), formula (2-11), formula (5-1), formula (5-4) or formula (5-5):
wherein R is3Selected from hydrogen or alkyl of 3 or less carbon atoms;
R4selected from hydrogen, alkyl groups of 3 carbon atoms or less;
R5and R6And is selected from hydrogen, alkyl of 3 or less carbon atoms, alkanoyl of 4 or less carbon atoms;
R7、R8independently selected from hydrogen, alkyl of 5 or less carbon atoms, alkenyl of 5 or less carbon atoms;
n is selected from 1, 2,3 or 4;
2. the 1-O-caffeoylquinic acid derivative of claim 1, selected from compounds of the following structure:
use of 1-O-caffeoylquinic acid in the preparation of a medicament for inhibiting the secretion and activity of interleukin 17F.
Use of a 1-O-caffeoylquinic acid prodrug, and salts thereof, in the preparation of a medicament for the prevention and treatment of tumors, wherein the prodrug has the structure of formula (II-3), formula (II-4), formula (II-6), formula (1-4), formula (1-23), formula (2-6), formula (2-11), formula (5-1), formula (5-4), or formula (5-5):
wherein R is3Selected from hydrogen or alkyl of 3 or less carbon atoms;
R4selected from hydrogen, alkyl groups of 3 carbon atoms or less;
R5and R6And is selected from hydrogen, alkyl of 3 or less carbon atoms, alkanoyl of 4 or less carbon atoms;
R7、R8independently selected from hydrogen, alkyl of 5 or less carbon atoms, alkenyl of 5 or less carbon atoms;
n is selected from 1, 2,3 or 4;
the tumor is selected from melanoma, pancreatic cancer, colorectal cancer or lung cancer.
5. Use according to claim 4, wherein the prodrug is selected from:
6. use according to claim 4, characterized in that the salts are chosen from inorganic salts with alkali metals and alkaline earth metals or transition metals; and an organic base formed with an organic amine.
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| CN108003027B (en) * | 2017-12-25 | 2021-07-06 | 北京微医智慧信息技术有限责任公司 | 1-O-caffeoylquinic acid, its derivative, preparation method and use thereof |
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2017
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| WO1986001508A1 (en) * | 1984-08-24 | 1986-03-13 | The Commonwealth Of Australia Care Of The Departme | Opiate antagonists |
| US5395950A (en) * | 1992-08-03 | 1995-03-07 | Nestec S.A. | Production of quinic acid derivatives |
| WO2002047703A2 (en) * | 2000-12-11 | 2002-06-20 | Nutricia N.V. | Immune system stimulation |
| WO2007136858A2 (en) * | 2006-05-19 | 2007-11-29 | H. Lee Moffitt Cancer Center & Research Institute | Small molecule inhibitors of stat3 with anti-tumor activity |
| CN104546819A (en) * | 2013-10-09 | 2015-04-29 | 中国医学科学院药物研究所 | Use of dicaffeoylquinic acid in treatment of systemic autoimmune disease |
| JP2015199674A (en) * | 2014-04-04 | 2015-11-12 | 富士フイルム株式会社 | Method of producing 1,3,4,5-tetracaffeoylquinic acid and intermediate compound |
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| WO2019128113A1 (en) | 2019-07-04 |
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