CN104341307A - Phenylacetic acid derivative and anti-tumor application thereof - Google Patents
Phenylacetic acid derivative and anti-tumor application thereof Download PDFInfo
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- CN104341307A CN104341307A CN201310337414.9A CN201310337414A CN104341307A CN 104341307 A CN104341307 A CN 104341307A CN 201310337414 A CN201310337414 A CN 201310337414A CN 104341307 A CN104341307 A CN 104341307A
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- 0 **C(Cc(c(*)c1*)c(*)c(*)c1N)=O Chemical compound **C(Cc(c(*)c1*)c(*)c(*)c1N)=O 0.000 description 1
- SGKNHWVDCWXDSX-UHFFFAOYSA-N CCOCOC(Cc(cc1)cc(O)c1O)=O Chemical compound CCOCOC(Cc(cc1)cc(O)c1O)=O SGKNHWVDCWXDSX-UHFFFAOYSA-N 0.000 description 1
- ATQCNDKAEUKRKY-UHFFFAOYSA-N COC(Cc(cc1O)cc(OC)c1O)=O Chemical compound COC(Cc(cc1O)cc(OC)c1O)=O ATQCNDKAEUKRKY-UHFFFAOYSA-N 0.000 description 1
- RGHMGZLQQFVXDM-UHFFFAOYSA-N COc(cc(CC(O)=O)cc1O)c1O Chemical compound COc(cc(CC(O)=O)cc1O)c1O RGHMGZLQQFVXDM-UHFFFAOYSA-N 0.000 description 1
- CFFZDZCDUFSOFZ-UHFFFAOYSA-N OC(Cc(cc1)cc(O)c1O)=O Chemical compound OC(Cc(cc1)cc(O)c1O)=O CFFZDZCDUFSOFZ-UHFFFAOYSA-N 0.000 description 1
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- 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
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- C07C235/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton
- C07C235/32—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton containing six-membered aromatic rings
- C07C235/34—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton containing six-membered aromatic rings having the nitrogen atoms of the carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
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- C07C59/40—Unsaturated compounds
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- 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
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- 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
- C07D317/48—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring
- C07D317/50—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to atoms of the carbocyclic ring
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Abstract
The invention provides a compound represented by a formula I, and an application thereof in preparing anti-tumor medicines. The substituent R1, R2, R3, R4, R5, R6 and X are defined as in the specifications.
Description
Technical field
The invention belongs to pharmaceutical field, be specifically related to phenylacetic acid derivatives and preparing the purposes in antitumor drug.
Background technology
Tumour be body under various carcinogenic factor effect, cell loses the normal regulation to its growth on gene level, causes its clonal abnormality hyperplasia and the true tumor that formed, shows as lump.Tumour cell is different from normal cell in formalness, metabolism and function aspects, presents continuous multiplication more.According to valid data statistics, tumour threatens first of three of whole world human life's health large factors at present, so the research and development of antitumor drug are focuses always.
According to traditional classification and the progress of antitumor drug, conventional antitumor drug can be divided into following several large class: one, cell toxicity medicament, comprise the medicine (as endoxan, irinotecan) destroying DNA structure and function, the medicine (as 5 FU 5 fluorouracil, cytosine arabinoside, Rheumatrex) etc. affecting Nucleic acid; Two, affect the medicine of hormonal equilibrium, comprise anti-estrogens medicine (as toremifene), antiandrogens (as bicalutamide) and arimedex (as letrozole) etc.; Three, other and ancillary drug, comprises the medicines such as body's immunity conditioning agent (as interleukin, Interferon, rabbit), biological response modifier (as erlotinib, Gefitinib), cell differentiation inducer (as vitamin A acid, arsenus acid), folic acid resisting preparation (Alimta), monoclonal antibody (as Arastin) and auxiliary analgesia, antiemetic, white corpuscle rising.But, above medicine more or less also exists side effect, middle severe Digestive tract reaction (as pernicious vomiting, stomatitis) of patient, bone marrow depression (as oligoleukocythemia, thrombopenia) and organ toxicity's (as neurotoxicity, liver renal toxicity) can be caused as cell toxicity medicament, hormonal equilibrium interference medicament then can cause light moderate gastrointestinal reaction, the reproductive system damage even spirit depressing symptom of patient, and most conditioning agent and inductor etc. also can cause patient's skin reaction in various degree and liver and kidney dysfunction.Such as irinotecan (Irinotecan Hydrochloride) is usually used in the treatment of adult's Metastatic Colorectal Cancer, effectiveness comparison is remarkable, but after medication, there is gastrointestinal side effect in the patient of 20%---severe diarrhea, all there is neutrophilic granulocytopenia in the patient of 78.7%, there are of short duration serious cholinergic syndrome (.Science such as Bret Wallace, 330,2010. in the patient of 9%; Grandson's Yi etc. China Dispensary, 18 (35), 2007.; Wu Yuhong etc. Anhui medicine, 14 (10), 2010.); Alimta (Pemetrexed disodium, Alimta) be first anti-pleural mesothelium tumor medicine, it can cause the bone marrow depression of patient, comprise Neutrophilic granulocytopenia, thrombopenia, anaemia or pancytopenia, the full person of Liver and kidney function avoid use (Zheng Hang etc. treatment and prevention of tumour is studied, 34 (4), 2007.; Wang Jianying etc. the healthy digest in China and foreign countries, 12,2011.); Arastin (Bevacizumab, Avastin) be the monoclonal antibody of vascular endothelial growth factor VEGF, by preventing the receptors bind of itself and endothelial cell surface in conjunction with VEGF, decrease microvascular generation and inhibit metastatic lesion to be in progress, but its side effect clearly, comprise gastric-intestinal perforation, wound dehiscence syndromes, hemorrhage, (the .Clinical Colorectal Cancer such as Eric O.Gamboa such as hypertensive crisis, nephrotic syndrome and congestive heart failure, 9 (1), 2010.; The .British Journal of Cancer such as A Mailliez, 103,2010.; The .Oncology such as Sanjaykumar Hapani, 79,2010.).
Therefore, the key issue that new antitumor active compound remains the research of current tumour medicine is developed.
Summary of the invention
The object of the present invention is to provide a kind of new phenylacetic acid derivatives.This compounds can suppress kinds of tumors effectively, can be used for preventing and/or treating of kinds of tumors clinically.
Technical scheme for realizing above-mentioned purpose of the present invention is as follows:
Compound shown in a kind of formula I,
Wherein, R
1, R
2, R
3, R
4and R
5be selected from hydrogen, hydroxyl, halogen, C independently of one another
1-C
5straight or branched alkyl, C
2-C
5straight or branched unsaturated alkyl or
or R
1, R
2, R
3, R
4and R
5in form the replacement of more than ternary together with carbon atom of being connected with their of adjacent two substituting groups or unsubstituted carbocyclic ring or replace or unsubstituted oxygen heterocyclic ring; Wherein
R
15be selected from C
1-C
5straight or branched alkyl, allyl group, propargyl, alkene butyl, methacrylic, alkynes butyl, methyl alkynes butyl, substituted or unsubstituted phenyl or substituted or unsubstituted benzyl;
X is selected from O or NH;
R
6be selected from hydrogen, C
1-C
5straight or branched saturated alkyl,
or
wherein
R
8be selected from hydrogen, hydroxyl, nitro, C
1-C
5straight or branched saturated alkyl or C
1-C
5straight or branched alkyl oxy,
R
9, R
10, R
11, R
12and R
13be selected from hydrogen, hydroxyl, halogen, C independently of one another
1-C
5straight or branched alkyl, C
2-C
5straight or branched unsaturated alkyl or
or R
9, R
10, R
11, R
12and R
13in form the replacement of more than ternary together with carbon atom of being connected with their of adjacent two substituting groups or unsubstituted carbocyclic ring or replace or unsubstituted oxygen heterocyclic ring;
R
14be selected from C
1-C
5straight or branched alkyl;
Condition is R
3and R
4be all hydroxyl, X is O, R
6when being hydrogen, R
1, R
2and R
5can not be hydrogen simultaneously.
A kind of preferred structure type, R
3be hydroxyl or
preferred, R
3hydroxyl, R
2or R
4be hydroxyl or
Also has a kind of preferred structure type, R
1, R
2, R
3, R
4and R
5in form five yuan or hexa-atomic replacement or unsubstituted oxygen heterocyclic ring together with carbon atom of being connected with their of adjacent two substituting groups; R
1, R
2, R
3, R
4and R
5in non-Cheng Huan be selected from hydrogen, hydroxyl, halogen, C independently of one another
1-C
5straight or branched saturated alkyl, C
2-C
5straight or branched unsaturated alkyl or
Preferred, R
3and R
4, or R
4and R
5the substituted or unsubstituted oxygen heterocyclic ring that five yuan or hexa-atomic contain two Sauerstoffatoms is formed together with the carbon atom that they are connected;
Preferred R further
3and R
4substituted or unsubstituted [1,3]-dioxolane is formed together with the carbon atom that they are connected.
The substituting group of above-mentioned carbocyclic ring, oxygen heterocyclic ring, [1,3]-dioxolane is selected from hydroxyl, halogen, carbonyl, C
1-C
5straight or branched alkyl or
Compound of the present invention, preferred R
8for hydrogen or hydroxyl.
Compound of the present invention, preferred R
9, R
10, R
11, R
12and R
13be selected from hydrogen, hydroxyl, C independently of one another
1-C
5straight or branched alkyl, C
2-C
5straight or branched unsaturated alkyl or
preferred, R
10and R
11for hydroxyl.
C of the present invention
1-C
5straight or branched alkyl, preferably from methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-, sec-butyl, the tertiary butyl, amyl group.
Described C
2-C
5straight or branched unsaturated alkyl, preferably from vinyl, allyl group, 1-propenyl, pseudoallyl, alkene butyl, alkene amyl group, 3-pentenyl, ethynyl, propargyl, 2-propynyl, alkynes butyl, alkynes amyl group.
Compound of the present invention preferably from:
3-methoxyl group-4,5-dihydroxyphenyl acetic acid (065-1),
3-methoxyl group-4,5-dihydroxyphenyl acetic acid methyl esters (070),
3,4,5-trihydroxybenzene acetic acid (065-2),
3,4,5-trihydroxybenzene methyl acetate (069),
3-benzyloxy-4,5-dihydroxyphenyl acetic acid methyl esters (077),
3-(2 '-methyl propoxy-)-4,5-dihydroxyphenyl acetic acids (079),
3-methoxyl group-4-allyloxy methyl phenylacetate (105),
3-methoxyl group-4-hydroxyl-5-allyl benzene methyl acetate (107),
3-methoxyl group-4-hydroxyl-5-propylbenzene methyl acetate (110),
3,4-dihydroxyl-5-propylbenzene methyl acetate (111),
3,4-dihydroxyl-5-propylbenzene acetic acid (112),
3-chloro-4-hydroxyl-5-methoxyphenylacetic acid methyl esters (100),
Chloro-4, the 5-dihydroxyphenyl acetic acids (067) of 3-,
Chloro-4, the 5-dihydroxyphenyl acetic acid methyl esters (072) of 3-,
3-bromo-4-hydroxy-5-methyl oxygen base methyl phenylacetate (099),
Bromo-4, the 5-dihydroxyphenyl acetic acids (073) of 3-,
Bromo-4, the 5-dihydroxyphenyl acetic acid methyl esters (071) of 3-,
Chloro-4, the 5-dihydroxyphenyl acetic acid methyl esters (102) of 2,3,6-tri-,
Chloro-4, the 5-dihydroxyphenyl acetic acids (109) of 2,3,6-tri-,
DOPAC ethyl ester (D80),
3,4-methylenedioxyphenylacetic acid (D76),
3,4-methylenedioxyphenylacetic acid methyl esters (D23),
3-methoxyl group-4 hydroxyl phenylacetic acid (T73),
DOPAC (3 ', 4 '-dihydroxyl) phenethyl ester (C17),
N-(3 ', 4 '-dihydroxyl) styroyl-(3,4-dihydroxyl) toluylic acid amine (C52),
N-2-leptodactyline-(3,4-dihydroxyl)-toluylic acid amine (C67),
DOPAC methoxy methyl alcohol ester (T33),
3-methoxyl group-4 hydroxyphenylacetic acid methyl ester (T83),
2-oxo benzo [1,3] dioxolane-5-acetic acid (T21),
3-hydroxyl-4-methoxyphenylacetic acid methyl esters (DO-2),
DOPAC (ethoxymethyl) alcohol ester (DO-3),
2-oxyethyl group-7-isopropoxy benzo [1,3] dioxolane-5-methyl acetate (076),
2-oxyethyl group-7-hydroxy benzo [1,3] dioxolane-5-methyl acetate (074),
2-oxyethyl group-7-benzyloxy benzo [1,3] dioxolane-5-methyl acetate (075).
Compound of the present invention, more preferably following compound:
3,4,5-trihydroxybenzene methyl acetate (069)
3-methoxyl group-4,5-dihydroxyphenyl acetic acid methyl esters (070),
3-(2 '-methyl propoxy-)-4,5-dihydroxyphenyl acetic acids (079),
Chloro-4, the 5-dihydroxyphenyl acetic acid methyl esters (102) of 2,3,6-tri-
3,4-dihydroxyl-5-propylbenzene methyl acetate (111),
Chloro-4, the 5-dihydroxyphenyl acetic acids (109) of 2,3,6-tri-,
N-2-leptodactyline-(3,4-dihydroxyl)-toluylic acid amine (C67),
DOPAC methoxy methyl alcohol ester (T33),
3,4-methylenedioxyphenylacetic acid methyl esters (D23),
3-methoxyl group-4,5-dihydroxyphenyl acetic acid (065-1),
3,4,5-trihydroxybenzene acetic acid (065-2),
3,4,5-trihydroxybenzene methyl acetate (071),
DOPAC ethyl ester (D80),
DOPAC (3 ', 4 '-dihydroxyl) phenethyl ester (C17),
DOPAC (ethoxymethyl) alcohol ester (DO-3).
The present invention also provide formula compound of the present invention or its pharmaceutically acceptable salt, polymorph, enantiomorph or racemic modification are preparing the purposes in anti-tumor drug.
Preferably, described tumour is solid tumor.
Preferred, described tumour be selected from lung cancer, mammary cancer, cervical cancer, rhabdosarcoma, nasopharyngeal carcinoma, carcinoma of the pancreas, laryngocarcinoma, skin carcinoma, liver cancer, neuroblastoma, the nephroblastoma, intestinal cancer, cancer of the stomach and adrenocortical tumor one or more.
Most preferred, described tumour be selected from lung cancer, mammary cancer, cervical cancer, the nephroblastoma, nasopharyngeal carcinoma, laryngocarcinoma, neuroblastoma, intestinal cancer and cancer of the stomach one or more.
Compound of the present invention is by inhibition tumor cell propagation, migration, and/or inducing apoptosis of tumour cell and produce antitumor action.
The present invention also provides a kind of pharmaceutical composition, comprising above-mentioned compound of the present invention or its pharmaceutically acceptable salt, polymorph, enantiomorph or racemic modification.
Described pharmaceutical composition is acceptable arbitrary formulation clinically, comprises through gastrointestinal administration preparation and non-through gastrointestinal administration preparation;
Preferably, described through gastrointestinal administration preparation optionally from powder, tablet, granule, capsule, dripping pill, emulsion or suspensoid;
Preferably, described non-through gastrointestinal administration preparation optionally from injection, inhalation, sprays, aerosol, suppository, filling agent, patch or ointment.
" halogen " of the present invention, refers to fluorine atom, chlorine atom, bromine atoms, atomic iodine; Preferred chlorine atom and bromine atoms.
The intake of compound of the present invention or administered dose, different and different according to the purity, action intensity, security, the age of taking object, body weight etc. of compound.As prevention or treatment tumour use, be generally adult 5mg-2g every day, once a day preferred or several takes in 10mg-1g.
External activity and Study on mechanism show, toluylic acid analog derivative of the present invention has certain antitumor action.
(1) employing mtt assay detects the restraining effect that compound of the present invention is bred kinds of tumor cells.Experiment finds, multiple compounds is to lung cell A549, nephroblastoma cell G401, nasopharyngeal carcinoma cell CNE2Z, laryngeal cancer cell HEP2, obvious restraining effect is had etc. kinds of tumor cells, especially 3, 4-dihydroxyphenyl acetic acid ethyl ester (D80), 3, 4-dihydroxyphenyl acetic acid (3 ', 4 '-dihydroxyl) phenethyl ester (C17), 3, 4-dihydroxyphenyl acetic acid methoxy methyl alcohol ester (T33), 3, 4-methylenedioxyphenylacetic acid methyl esters (D23), N-2-leptodactyline-(3, 4-dihydroxyl)-toluylic acid amine (C67), 3, 4-dihydroxyphenyl acetic acid (ethoxymethyl) alcohol ester (DO-3), 3-methoxyl group-4, 5-dihydroxyphenyl acetic acid (065-1), 3, 4, 5-trihydroxybenzene acetic acid (065-2), 3, 4, 5-trihydroxybenzene methyl acetate (069), 3-(2 '-methyl propoxy-)-4, 5-dihydroxyphenyl acetic acid (079), 3, 4-dihydroxyl-5-propylbenzene methyl acetate (111).
(2) cell migration is adopted to detect (Transwell) experiment, process kinds of tumor cells with described compound (selecting safe dose 10 μMs) and by Viola crystallina, cell dyeed, detect the number of cell migration, find DOPAC ethyl ester (D80), DOPAC methoxy methyl alcohol ester (T33), N-2-leptodactyline-(3,4-dihydroxyl)-toluylic acid amine (C67), N-(3 ', 4 '-dihydroxyl) styroyl-(3,4-dihydroxyl) toluylic acid amine (C52), DOPAC (ethoxymethyl) alcohol ester (DO-3), 3-methoxyl group-4,5-dihydroxyphenyl acetic acid (065-1), 3,4,5-trihydroxybenzene acetic acid (065-2), 3,4-dihydroxyl-5-propylbenzene methyl acetate (111), 2-oxo benzo [1,3] dioxolane-5-acetic acid (T21), 3,4,5-trihydroxybenzene methyl acetate (069), the migration of the compound on tumor cells such as chloro-4, the 5-dihydroxyphenyl acetic acid methyl esters (102) of 2,3,6-tri-has certain restraining effect.
(3) Flow Cytometry is adopted to detect cell apoptosis assay, also with Annexin V-FITC and PI, cell is dyeed by described compound (selecting safe dose 10 μMs) process kinds of tumor cells, calculate the ratio of apoptotic cell, find 3, 4-dihydroxyphenyl acetic acid ethyl ester (D80), 3, 4-dihydroxyphenyl acetic acid methoxy methyl alcohol ester (T33), 3, 4-dihydroxyphenyl acetic acid (3 ', 4 '-dihydroxyl) phenethyl ester (C17), 3, 4-dihydroxyphenyl acetic acid (ethoxymethyl) alcohol ester (DO-3), methoxyl group-4, 5-dihydroxyphenyl acetic acid (065-1), 3, 4, 5-trihydroxybenzene acetic acid (065-2), 3, 4, 5-trihydroxybenzene methyl acetate (069), N-(3 ', 4 '-dihydroxyl) styroyl-(3, 4-dihydroxyl) apoptosis of the compound on tumor cell such as toluylic acid amine (C52) has certain promotion.
Compound described in above-mentioned description of test can by antiproliferative effect and migration, and cell death inducing and play the antitumor action of wide spectrum.
Accompanying drawing explanation
Below in conjunction with accompanying drawing, the present invention will be further described.
Fig. 1: the MTT experiment result of embodiment 23; Wherein, Fig. 1-1 shows DO respectively to 1-14, the survival rate of tumour cell A549 under T83, D80, T73, T33, D23, T21, C52, D76, C17, C67, DO-1, DO-2, DO-3 different concns.
Fig. 2: in embodiment 25, the impact of each compound on tumor cell A549 transfer ability, wherein Control is blank.
Fig. 3: in embodiment 25, the impact of each compound on tumor cell A204 transfer ability, wherein Control is blank.
Fig. 4: in embodiment 25, the impact of each compound on tumor cell G401 transfer ability, wherein Control is blank.
Fig. 5: in embodiment 25, the impact of each compound on tumor cell CT26 transfer ability, wherein Control is blank.
Fig. 6: in embodiment 26, the impact of each compound on tumor cell A549 transfer ability, wherein Control is blank.
Fig. 7: in embodiment 26, the impact of each compound on tumor cell G401 transfer ability, wherein Control is blank.
Fig. 8: in embodiment 26, the impact of each compound on tumor cell HEP-2 transfer ability, wherein Control is blank.
Fig. 9: in embodiment 27, the impact of each compound on tumor cell A549 apoptosis, wherein Control is blank.
Figure 10: in embodiment 27, the impact of each compound on tumor cell G401 apoptosis, wherein Control is blank.
Figure 11: in embodiment 28, the impact of each compound on tumor cell A549 apoptosis, wherein Control is blank.
Figure 12: in embodiment 28, the impact of each compound on tumor cell G401 apoptosis, wherein Control is blank.
Figure 13: in embodiment 28, the impact of each compound on tumor cell HEP-2 apoptosis, wherein Control is blank.
Embodiment
Referring to specific embodiment, the present invention is described.It will be appreciated by those skilled in the art that these embodiments are only for illustration of the present invention, its scope do not limited the present invention in any way.
Experimental technique described in following embodiment, if no special instructions, is ordinary method; Described reagent and material, if no special instructions, all can obtain from commercial channels; Solvent for use and medicine are analytical pure or chemical pure; Solvent is before use all through re-distillation; Anhydrous solvent all processes according to standard method or literature method.
Column chromatography silica gel (100-200 order) and tlc silica gel (GF254) are Haiyang Chemical Plant, Qingdao and chemical plant, Yantai product; If not otherwise specified, all adopt sherwood oil (60-90 DEG C)/ethyl acetate (v/v) as eluent; The ethanolic soln of developer iodine or phospho-molybdic acid; All extraction solvent unexplained reference all use anhydrous Na 2SO4 dry.
1h-NMR Bruck-400 type nuclear magnetic resonance analyser record, TMS is interior mark.
LC-MS Agilent company 1100 of U.S. type HPLC-ESI-MSn combined instrument (LC-MSD Trap) record, diode-array detector (DAD), determined wavelength 214nM and 254nM, ion trap mass spectrometry (ESI source).
HPLC column is Agela Durashell C18 (4.6 × 50mm, 3.5 μm); Moving phase is the 0.1%NH4HCO3 aqueous solution: acetonitrile (in 5 minutes from 5:95 to 95:5); Flow velocity is 1.8mL/min.
embodiment 1the synthesis of 3-hydroxyl-4-methoxyphenylacetic acid methyl esters (DO-2)
3-hydroxyl-4-methoxy-phenylacetic acid (DO-1,2.5g, 13.7mmol) is dissolved in 50mL methyl alcohol, adds the vitriol oil of 0.2mL under agitation, reflux 3 hours.Be cooled to room temperature, reaction solution concentrates on a rotary evaporator, the oily matter obtained is diluted in the ethyl acetate solution of 100mL, organic phase saturated aqueous common salt (50mL*2) is washed, after anhydrous sodium sulfate drying filters, spin concentration is except desolventizing, and solute obtains colorless oil DO-2(2.1g, 79% through column chromatography refining (moving phase is sherwood oil: ethyl acetate=3:1)).
1H-NMR(400MHz,CDCl
3)δ6.80(s,1H),6.75-6.68(m,2H),5.56(s,1H),3.81(s,3H),3.62(s,3H),3.31(s,3H)。
embodiment 2the synthesis of DOPAC oxyethyl group methyl esters (DO-3)
DOPAC (DO, 5.0g, 30.0mmol) and triethylamine (9.1g, 90.0mmol) are dissolved in 30mL methylene dichloride, drip 2.84g chloromethane ether (30.0mmol) under zero degree condition, are at room temperature stirred by reaction solution and spend the night.Reaction solution uses 0.1N HCl solution (15mL) and NaHCO respectively
3solution (15mL) is washed, and after organic phase is filtered with anhydrous sodium sulfate drying, spin concentration is except desolventizing, and solute obtains colorless oil DO-3(2.0g, 29.5% through column chromatography refining (moving phase is sherwood oil: ethyl acetate=2:1)).
1H-NMR(400MHz,CDCl
3)δ6.72(d,J=2.0Hz,1H),6.69(s,1H),6.62(m,1H),5.65(brs,1H),5.45(brs,1H),5.24(s,2H),3.60(q,J=6.4Hz,2H),3.48(s,2H),1.14(t,J=6.4Hz,H)。
embodiment 3the synthesis of DOPAC ethyl ester (D80)
DOPAC (DO, 3.0g, 17.9mmol) is dissolved in 25mL ethanol, adds the vitriol oil of catalytic amount under agitation, reflux 12 hours.Be cooled to room temperature, reaction solution concentrates on a rotary evaporator, and the oily matter obtained is diluted in the ethyl acetate solution of 50mL, the saturated NaHCO of organic phase
3solution (25mL*2) and saturated aqueous common salt (25mL) are washed, and after anhydrous sodium sulfate drying filters, spin concentration is except desolventizing, and solute obtains colorless oil D80(1.1g, 88.5% through column chromatography refining (moving phase is sherwood oil: ethyl acetate=10:1)).
1H-NMR(300MHz,DMSO-d6)δ8.86(s,1H),8.77(s,1H),6.66-6.63(m,2H),6.47(dd,J=8.1,2.1Hz,1H),4.08-3.99(m,2H),3.42（s,2H）,1.20-1.14(m,3H)。
embodiment 4the synthesis of 3,4-methylenedioxyphenylacetic acid methyl esters (D23)
The synthesis of 4-1 intermediate D23-1:
DOPAC (DO, 10.0g, 59.5mmol) is dissolved in 125mL methyl alcohol, adds the vitriol oil of catalytic amount under agitation, reflux 12 hours.Be cooled to room temperature, reaction solution concentrates on a rotary evaporator, and the oily matter obtained is diluted in the ethyl acetate solution of 150mL, the saturated NaHCO of organic phase
3solution (50mL*2) and saturated aqueous common salt (50mL) are washed, and after anhydrous sodium sulfate drying filters, except desolventizing, solute obtains colorless oil D23-2(10.8g, 100% through column chromatography refining (moving phase is sherwood oil: ethyl acetate=10:1)).
The synthesis of 4-2 D23:
The D23-1 (4.4g, 23mmol) that step 4-1 obtains is dissolved in 60mL DMF, and 16.8g cesium fluoride (111mmol) and 10mL join in above-mentioned solution respectively.Reaction solution is added to backflow after 3 hours, by reaction solution cool to room temperature, add 200mL methylene dichloride, organic phase saturated common salt washing (100mL*2), after anhydrous sodium sulfate drying filters, revolve desolventizing, solute obtains colorless oil D23(1.9g, 41% through column chromatography refining (moving phase is sherwood oil: methylene dichloride=10:1)).
1H-NMR(300MHz,DMSO-d6)δ6.91-6.83(m,2H),6.71(d,J=8.1Hz,1H),5.99(s,2H),3.60(s,3H),3.58(s,2H)。
embodiment 5the synthesis of 3,4-dimethoxyphenylacetic acid (D76)
According to D23(3g prepared by the method for embodiment 4,15.5mmol) be dissolved in methyl alcohol (15mL), add the water of 0.6g lithium hydroxide (23.2mmol) and 0.5mL when stirring, above-mentioned solution at room temperature stirs 5 hours, concentrated except desolventizing, add the water of 75mL, reconcile pH value with the aqueous hydrochloric acid of 1N and equal 3, with ethyl acetate (30mL*3) extraction, after organic phase is filtered with anhydrous sodium sulfate drying, concentrate and obtain white compound D76(2.2g, 80%).
1H-NMR(300MHz,CDCl
3)δ6.79-6.78(m,2H),6.72(d,J=6.9Hz,1H),5.96(s,2H),4.78(br s,1H),3.57(s,2H)。
embodiment 6the synthesis of DOPAC methoxy methyl alcohol ester (T33):
DOPAC (DO, 3.0g, 17.9mmol) and triethylamine (2.7g, 26.7mmol) are dissolved in 40mL methylene dichloride, drip 2.5g methoxymethyl bromine (19.8mmol) under zero degree condition, are at room temperature stirred by reaction solution and spend the night.Reaction solution is concentrated adds 150mL ethyl acetate, 1N HCl solution (100mL) and the saturated common salt aqueous solution (50mL) is used to wash respectively, after organic phase is filtered with anhydrous sodium sulfate drying, except desolventizing, solute obtains colorless oil T33(500mg, 13% through column chromatography refining (moving phase is sherwood oil: ethyl acetate=5:1)).
1H-NMR(300MHz,DMSO-d6)δ8.87(br s,1H),8.80(br s,1H),6.75-6.64(m,2H),6.50(dd,J=8.1,1.8Hz,1H),5.16(s,2H),3.49(s,2H),3.31(s,3H).
embodiment 7the synthesis of 3-methoxyl group-4-hydroxyl phenylacetic acid (T73)
The synthesis of 7-1 intermediate T73-2:
3-methoxyl group-4-hydroxy-benzaldehyde (10.0g, 65.8mmol) is dissolved in 150mL acetonitrile, adds potassiumiodide and TMSCN(9.8g, the 98.6mmol of catalytic amount under the condition stirred), reaction solution at room temperature stirs 12 hours.By solvent concentration on a rotary evaporator, thick product 150mL diluted ethyl acetate, uses saturated NaHCO
3the aqueous solution (50mL) and saturated aqueous common salt (50mL) are washed, and after anhydrous sodium sulfate drying filters, except desolventizing, solute obtains colorless oil T73-2(10.5g, 89% through column chromatography refining (moving phase is sherwood oil: ethyl acetate=10:1)).
The synthesis of 7-2 intermediate T73-3:
T73-2(10g prepared by step 7-1,55.9mmol) be dissolved in methyl alcohol (15mL), the water of 6.7g sodium hydroxide (168mmol) and 75mL is added when stirring, above-mentioned solution at room temperature stirs 8 hours, reconcile pH value with the aqueous hydrochloric acid of 1N and equal 3, with ethyl acetate (30mL*3) extraction, after organic phase is filtered with anhydrous sodium sulfate drying, concentrate and obtain T73-3(7.1g, 65%).The synthesis of 7-3 product T73:
T73-3(5g, 25mmol prepared by step 7-2) be dissolved in ethanol (100mL), add the Pd/C(500mg of 10%) and the concentrated hydrochloric acid of 1mL, with hydrogen exchange 2 times, reaction solution at room temperature stirs 6 hours, filters out catalyzer, filtrate evaporate to dryness obtains T73(7.1g, and 65%).
1H-NMR(300MHz,CDCl
3)δ6.86(d,J=3.9Hz,1H),6.79-6.74(m,2H),5.57(br s,2H),3.88(s,3H),3.57(s,2H)。
embodiment 8the synthesis of 3-methoxyl group-4 hydroxyphenylacetic acid methyl ester (T83)
3-methoxyl group-4 hydroxyl phenylacetic acid (3.0g, 16.4mmol) prepared by embodiment 7 is dissolved in 100mL methyl alcohol, adds the vitriol oil of catalytic amount under agitation, reflux 12 hours.Be cooled to room temperature, reaction solution concentrates on a rotary evaporator, and the oily matter obtained is diluted in the ethyl acetate solution of 150mL, the saturated NaHCO of organic phase
3solution (50mL*2) and saturated aqueous common salt (50mL) are washed, and after anhydrous sodium sulfate drying filters, except desolventizing, solute obtains colorless oil T83(2.9g, 90% through column chromatography refining (moving phase is sherwood oil: ethyl acetate=20:1)).
1H-NMR(300MHz,DMSO-d6)δ8.86(s,1H),6.81(d,J=1.8Hz,1H),6.71-6.61(m,2H),3.74(s,3H),3.60(s,3H),3.54(s,2H)。
embodiment 9the synthesis of 3-methoxyl group-4,5-dihydroxyphenyl acetic acid (065-1) and 3,4,5-trihydroxybenzene acetic acid (065-2):
3,4,5-trimethoxy phenyl acetic acid (SM, 1g, 4.4mmol) be dissolved in 2.6mL acetic acid and 3.3mL48% hydrobromic acid solution, mixture reflux 16 hours, adds 5mL water after cooling, extract by ethyl acetate (15mL*3), organic phase 5mL washes, organic phase anhydrous sodium sulfate drying, concentrated, and solute must brown solid 065-1(220mg through column chromatography refining (moving phase is methylene dichloride: methyl alcohol=20:1 to 10:1), 25%) and 065-2(240mg, 30%).
065-1
1H NMR(400MHz,DMSO-d6)δ12.25(br s,1H),8.88(s,1H),8.10(s,1H),6.32(s,2H),3.71(s,3H),3.33(s,2H)。
065-2
1H NMR(400MHz,DMSO-d6)δ12.21(br s,1H),8.74(s,2H),7.95(br s,1H),6.16(s,2H),3.24(s,2H)。
embodiment 10the synthesis of 3-methoxyl group-4,5-dihydroxyphenyl acetic acid methyl esters (070):
065-1(300mg, 1.5mmol that embodiment 9 obtains) be dissolved in 5mL methyl alcohol, add the vitriol oil of catalytic amount under agitation, reflux 3 hours.Be cooled to room temperature, reaction solution concentrates on a rotary evaporator, the oily matter obtained is diluted in the ethyl acetate solution of 15mL, organic phase saturated aqueous common salt (5mL) is washed, after anhydrous sodium sulfate drying filters, except desolventizing, solute obtains colorless oil 070(280mg, 87% through column chromatography refining (moving phase is methylene dichloride: methyl alcohol=50:1)).
1H NMR(400MHz,CDCl
3)δ6.52(s,1H),6.41(s,1H),5.36(s,2H),3.87(s,3H),3.70(s,3H)，3.51（s，2H）。
embodiment 11the synthesis of 3,4,5-trihydroxybenzene methyl acetate (069):
065-2(2.5g, 13.6mmol prepared by embodiment 9) be dissolved in 50mL methyl alcohol, add the vitriol oil of catalytic amount under agitation, reflux 5 hours.Be cooled to room temperature, reaction solution concentrates on a rotary evaporator, the oily matter obtained is diluted in the ethyl acetate solution of 100mL, organic phase saturated aqueous common salt (40mL) is washed, after anhydrous sodium sulfate drying filters, except desolventizing, solute obtains white solid 069(2.4g, 89% through column chromatography refining (moving phase is methylene dichloride: methyl alcohol=50:1)).
1H NMR(400MHz,CDCl
3)δ6.43(s,2H),5.12(s,2H),3.70(s,3H),3.47(s,2H)。
embodiment 122-oxyethyl group-7-hydroxy benzo [1,3] dioxolane-5-methyl acetate (074), 2-oxyethyl group-7-benzyloxy benzo [1,3] synthesis of dioxolane-5-methyl acetate (075), 3-benzyloxy-4,5-dihydroxyphenyl acetic acid methyl esters (077):
069(2.0g, 10.1mmol) be dissolved in 60mL toluene, triethly orthoacetate (2.99g is added when stirring, 20.2mmol) and the amberlyst15E(200mg of catalytic amount), mixing solutions adds water trap reflux 16 hours, cold filtration, filtrate is concentrated on a rotary evaporator obtains light yellow oil 074(2.5g, 100%).
074(0.51g, 2.0mmol) be dissolved in 5mL acetone, add bromobenzyl (342mg, 2.0mmol) and salt of wormwood (276mg, 2.0mmol), mixing solutions reflux 24 hours when stirring.Be cooled to room temperature, the concentrated oily matter obtained is diluted in the ethyl acetate solution of 50mL, organic phase saturated aqueous common salt (20mL*2) is washed, after anhydrous sodium sulfate drying filters, except desolventizing, solute obtains colorless oil 075(210mg, 30% through column chromatography refining (moving phase is sherwood oil: ethyl acetate=5:1)).
075(70mg, 0.2mmol) be dissolved in 2mL2N hydrochloric acid methanol, mixture at room temperature stirs 3 hours, the concentrated oily matter obtained is diluted in the ethyl acetate solution of 10mL, organic phase saturated aqueous common salt (5mL*2) is washed, after anhydrous sodium sulfate drying filters, except desolventizing, solute obtains colorless oil 077(30mg, 51% through column chromatography refining (moving phase is methylene dichloride: methyl alcohol=50:1));
1H NMR(400MHz,CDCl
3)δ7.40（m，5H），6.54(s,1H),6.50（s，1H），5.53(br s,2H),5.06(s,2H),3.68(s,3H),3.49(s,2H)。
embodiment 132-oxyethyl group-7-isopropoxy benzo [1,3] dioxolane-5-methyl acetate (076) and 3-(2 '-methyl propoxy-) synthesis of-4,5-dihydroxyphenyl acetic acids (079):
074(0.51g prepared by embodiment 12,2.0mmol) being dissolved in 5mL acetone, adding isobutyl bromide (548mg, 4.0mmol), the tetrabutylammonium iodide (73mg) of catalytic amount and salt of wormwood (552mg when stirring, 4.0mmol), mixing solutions reflux 24 hours.Be cooled to room temperature, the concentrated oily matter obtained is diluted in the ethyl acetate solution of 50mL, organic phase saturated aqueous common salt (20mL*2) is washed, after anhydrous sodium sulfate drying filters, except desolventizing, solute obtains colorless oil 076(110mg, 18% through column chromatography refining (moving phase is sherwood oil: ethyl acetate=5:1)).
076(110mg, 0.35mmol), add 3mL6N HCl solution under agitation, reflux 3 hours, be cooled to room temperature, extract with methylene dichloride (10mL*2), organic phase saturated aqueous common salt (5mL*2) is washed, and anhydrous sodium sulfate drying revolves desolventizing after filtering, solute obtains white solid 079(51mg, 57% through column chromatography refining (moving phase is methylene dichloride: methyl alcohol=20:1)).
079
1H NMR(400MHz,DMSO-d6)δ12.12(br s,1H),8.81(s,1H),7.88(s,1H),6.31(s,1H),6.29(s,1H),3.65（d，J=6.4Hz，1H），3.31(s,2H),2.00（m，1H），0.95（d，J=6.4Hz，6H）.
embodiment 143-methoxyl group-4-allyloxy methyl phenylacetate (105), 3-methoxyl group-4-hydroxyl-5-allyl benzene methyl acetate (107), 3-methoxyl group-4-hydroxyl-5-propylbenzene methyl acetate (110), 3, the synthesis of 4-dihydroxyl-5-propylbenzene methyl acetate (111) and 3,4-dihydroxyl-5-propylbenzene acetic acid (112):
3-methoxyl group-4-hydroxyphenylacetic acid methyl ester (T83,500mg, 2.5mmol) prepared by embodiment 8 is dissolved in acetone (5mL), adds salt of wormwood (704mg, 5.1mmol) and allyl bromide 98 (370mg, 3.1mmol).Mixture reflux 5 hours, then normal temperature is cooled to, water (10mL) adds, extract by ethyl acetate (10mL*3), organic phase 5mL washes, organic phase anhydrous sodium sulfate drying, concentrated, residue through column chromatography refining (moving phase is sherwood oil: ethyl acetate=5:1) colourless liquid 105(500mg, 83%).
1H NMR(400MHz,CDCl
3)δ6.85-6.75(m,3H),6.11-6.02(m,1H),5.39(d,J=17.2Hz,1H),5.27(d,J=10.8Hz,1H),4.60(d,J=4.4Hz,2H),3.87(s,3H),3.69(s,3H)，3.56(s,2H)。
105(500mg, 2.1mmol) be dissolved in N-Methyl pyrrolidone (2mL), react 5 hours at 200 DEG C, be then cooled to normal temperature, use 10mL diluted ethyl acetate, 10mL washes three times.Organic phase anhydrous sodium sulfate drying, concentrated, residue through column chromatography refining (moving phase is sherwood oil: ethyl acetate=4:1) pale yellow oily liquid body 107(400mg, 80%).
1H NMR(400MHz,CDCl
3)δ6.69(s,1H),6.65(s,1H),6.03-5.97(m,1H),5.63(s,1H),5.11-5.03(m,2H),3.88(s,3H),3.69(s,3H)，3.53（s，2H）,3.39(d,J=6.0Hz,2H)。
107(400mg, 1.7mmol) be dissolved in ethyl acetate (4mL), add 5%Pd/C catalyzer (40mg), react 10 hours under 1 atmospheric hydrogen atmosphere, suction filtration, filtrate uses 10mL diluted ethyl acetate, and 5mL washing is once.Organic phase anhydrous sodium sulfate drying, concentrated, residue through column chromatography refining (moving phase is sherwood oil: ethyl acetate=4:1) pale yellow oily liquid body 110(300mg, 75%).
110(300mg, 1.3mmol) be dissolved in methylene dichloride (4mL), the dichloromethane solution (1mL) of 3N boron tribromide is added under ice-water bath, then normal-temperature reaction 2 hours, water (10mL) adds, and extracts by ethyl acetate (10mL*3), organic phase 5mL washes, organic phase anhydrous sodium sulfate drying, concentrated, residue through column chromatography refining (moving phase is sherwood oil: ethyl acetate=4:1) white solid 111(200mg, 71%).
1H NMR(400MHz,CDCl
3)δ6.63(s,1H),6.57(s,1H),6.06(br s,1H),5.33(br s,1H),3.70(s,3H),3.49(s,2H),2.55(t,J=6.8Hz,2H)，1.66-1.58（m，2H）,0.96(t,J=7.2Hz,3H)。
111(100mg, 0.45mmol) and 6N hydrochloric acid (3mL) under agitation reflux 2 hours, cool rear ethyl acetate (10mL*3) extraction, organic phase 5mL washes, organic phase anhydrous sodium sulfate drying, concentrated, residue obtains white solid 112(24mg, 25% through column chromatography refining (moving phase is sherwood oil: ethyl acetate=1:1)).
1H NMR(400MHz,CDCl
3)δ12.12(br s,1H),9.12(s,1H),7.95(s,1H),6.53(s,1H),6.39(s,1H),3.33(s,2H),2.50-2.42(m,2H)，1.52-1.48（m，2H）,0.88(t,J=7.2Hz,3H)。
embodiment 15the synthesis of chloro-4, the 5-dihydroxyphenyl acetic acids (067) of 3-chloro-4-hydroxyl-5-methoxyphenylacetic acid methyl esters (100) and 3-:
3-methoxyl group-4-hydroxyphenylacetic acid methyl ester (T83 prepared by embodiment 8, 400mg, 2.0mmol) be dissolved in tetrahydrofuran (THF) (5mL), N-chlorosuccinimide (300mg is added in order under stirring, 2.2mmol) with sodium hydride (160mg, 5.3mmol, 80% is scattered in mineral oil), normal-temperature reaction 16 hours, water (10mL) adds, extract by ethyl acetate (10mL*3), organic phase 5mL washes, organic phase anhydrous sodium sulfate drying, concentrated, residue obtains weak yellow liquid 100(327mg through column chromatography refining (moving phase is sherwood oil: ethyl acetate=4:1), 71%).
1H NMR(400MHz,CDCl
3)δ6.87(s,1H),6.72(s,1H),5.84(br s,1H),3.90(s,3H),3.70(s,3H)，3.52（s，2H）。
100(100mg, 0.43mmol) be dissolved in 0.26mL acetic acid and 0.33mL48% hydrobromic acid solution, mixture reflux 16 hours, 2mL water is added after cooling, with ethyl acetate (5mL*3) extraction, organic phase 2mL washes, organic phase anhydrous sodium sulfate drying, concentrated, solute obtains brown solid 067(57mg, 57% through column chromatography refining (moving phase is methylene dichloride: methyl alcohol=20:1));
1H NMR(400MHz,DMSO-d6)δ12.21(br s,1H),9.87(s,1H),8.97(s,1H),6.66(s,1H),6.64(s,1H),3.37(s,2H)。
embodiment 16the synthesis of chloro-4, the 5-dihydroxyphenyl acetic acid methyl esters (072) of 3-:
Compound 100(80mg prepared by embodiment 15,0.35mmol) be dissolved in 5mL methylene dichloride, the dichloromethane solution of 1mL3N boron tribromide is added under zero degrees celsius agitation condition, stirred at ambient temperature 3 hours, reaction solution adds water cancellation under zero degrees celsius, extract with methylene dichloride (5mL*2), organic phase saturated aqueous common salt (4mL*2) is washed, after anhydrous sodium sulfate drying filters, except desolventizing, solute obtains white solid 072(50mg, 66% through column chromatography refining (moving phase is methylene dichloride: methyl alcohol=50:1)).
1H NMR(400MHz,CDCl
3)δ6.82(s,1H),6.72(s,1H),5.42(s,1H),5.40(s,1H),3.70(s,3H),3.47(s,2H)。
embodiment 17the synthesis of bromo-4, the 5-dihydroxyphenyl acetic acid methyl esters (071) of 3-bromo-4-hydroxy-5-methyl oxygen base methyl phenylacetate (099), 3-and bromo-4, the 5-dihydroxyphenyl acetic acids (073) of 3-:
3-methoxyl group-4-hydroxyphenylacetic acid methyl ester (T83,1.6g, 8.2mmol) prepared by embodiment 8 is dissolved in 22mL acetone and 22mL water, adds Sodium Bromide (3.4g, 32.8mmol) and Oxone(5.0g, 16.4mmol in order).At room temperature react 30 minutes, 20mL water adds, extract by ethyl acetate (10mL*2), organic phase saturated aqueous common salt (10mL*2) is washed, after anhydrous sodium sulfate drying filters, except desolventizing, solute obtains faint yellow solid 099(700mg, 31% through column chromatography refining (moving phase is sherwood oil: ethyl acetate=4:1)).
1H NMR(400MHz,CDCl
3)δ7.01(s,1H),6.76(s,1H),5.90(s,1H),3.90(s,3H),3.70(s,3H)，3.53（s,2H）。
Compound 099(200mg, 0.73mmol) be dissolved in 10mL methylene dichloride, the dichloromethane solution of 2mL3N boron tribromide is added under zero degrees celsius agitation condition, stirred at ambient temperature 3 hours, reaction solution adds water cancellation under zero degrees celsius, extract with methylene dichloride (10mL*2), organic phase saturated aqueous common salt (10mL*2) is washed, after anhydrous sodium sulfate drying filters, except desolventizing, solute obtains white solid 071(130mg, 68% through column chromatography refining (moving phase is methylene dichloride: methyl alcohol=50:1)).
1H NMR(400MHz,CDCl
3)δ6.94(s,1H),6.81(s,1H),5.10(br s,2H),3.70(s,3H),3.49(s,2H)。
Compound 071(65mg, 0.25mmol), add 2mL6N HCl solution under agitation, reflux 3 hours, be cooled to room temperature, extract with methylene dichloride (10mL*2), organic phase saturated aqueous common salt (5mL*2) is washed, and anhydrous sodium sulfate drying revolves desolventizing after filtering, solute obtains white solid 073(35mg, 57% through column chromatography refining (moving phase is methylene dichloride: methyl alcohol=20:1)).
1H NMR(400MHz,DMSO-d6)δ12.21(br s,1H),9.74(s,1H),8.99(s,1H),6.80(s,1H),6.67(s,1H),3.38(s,2H)。
embodiment 18the synthesis of chloro-4, the 5-dihydroxyphenyl acetic acid methyl esters (102) of 2,3,6-tri-and chloro-4, the 5-dihydroxyphenyl acetic acids (109) of 2,3,6-tri-:
DOPAC (DO, 840mg, 5.0mmol) is dissolved in 10mL acetic acid, adds SULPHURYL CHLORIDE (3.8g, 25mmol), and mixture at room temperature reacts 48 hours, and then desolventizing is revolved in decompression, obtains crude product 1.5g.Crude product is dissolved in methyl alcohol 20mL, adds the 0.2mL vitriol oil under normal temperature, then reflux 3 hours, cool to room temperature, except desolventizing, obtains white solid 102(400mg, 28% through column chromatography refining (moving phase is sherwood oil: ethyl acetate=4:1)).
1H NMR(400MHz,CDCl
3)δ5.95(s,1H),5.77(s,1H),3.99(s,2H),3.74(s,3H)。
Compound 102(100mg, 0.37mmol), add 2mL6N HCl solution under agitation, reflux 3 hours, be cooled to room temperature, extract with methylene dichloride (10mL*2), organic phase saturated aqueous common salt (5mL*2) is washed, after anhydrous sodium sulfate drying filters, except desolventizing, solute obtains white solid 109(25mg, 25% through column chromatography refining (moving phase is sherwood oil: ethyl acetate=1:1)).
1H NMR(400MHz,DMSO-d6)δ12.51(br s,1H),10.10(s,1H),9.91(s,1H),3.82(s,2H)。
embodiment 19the synthesis of N-2-leptodactyline-(3,4-dihydroxyl)-toluylic acid amine (C67):
DOPAC (DO, 168mg, 1.0mmol) and C67-1(164mg, 1.2mmol) be dissolved in the DMF of 2mL, in this solution, add the HOBt(1.2mmol of 160mg respectively), the EDCI(1.2mmol of 230mg), mixing solutions stirs 16 hours at normal temperatures.The ethyl acetate adding 10mL is diluted, and respectively with the aqueous hydrochloric acid of 5mL1N and the saturated common salt washing of 5mL, organic phase drying is concentrated, crosses silica column purification (sherwood oil: ethyl acetate=2:3) and obtains colorless oil (230mg, 80%).
1H NMR(400MHz,DMSO-d6)δ8.78(s,1H),8.69(s,1H),7.88(s,1H),7.33–7.23(m,5H),6.66(s,1H),6.61(d,J=8.0Hz,1H),6.45(d,J=8.0Hz,1H),5.46(d,J=4.0Hz,1H),4.56(br s,1H),3.26–3.21（m,3H),3.11–3.08(m,1H).
embodiment 20the synthesis of DOPAC (3 ', 4 '-dihydroxyl) phenethyl ester (C17):
The synthesis of 20-1 intermediate C17-2:
DOPAC (DO, 3.0g, 17.9mmol) and 6.4mL bromobenzyl (53.6mmol) are dissolved in the DMF of 40mL, add 7.4g salt of wormwood (17.9mmol) in this solution, stir 12 hours under 40 degree.The ethyl acetate adding 200mL, by this solution dilution, washes three times with the saturated common salt of 100mL, and organic phase drying is concentrated, crosses silica column purification (sherwood oil: ethyl acetate=10:1) and obtains white solid C17-2(7g, 89%).
The synthesis of 20-2 intermediate C17-3:
C17-2(600mg, 1.37mmol prepared by step 20-1) be dissolved in the dry tetrahydrofuran of 10mL, under zero degree, add 104.5mg lithium aluminum hydride (2.75mmol), this solution at room temperature stirs 2 hours.Add sal glauberi cancellation and add 20mL diluted ethyl acetate and filter, the concentrated silica column purification of filtrate (sherwood oil: ethyl acetate=4:1) obtains white solid C17-3(400mg, 87%).
1H NMR(400MHz,CDCl
3)δ7.46–7.30(m,10H),6.88(d,J=8.4Hz,1H),6.82(s,1H),6.73(d,J=8.4Hz,1H),5.16(s,2H),5.14(s,2H),3.78(s,2H),2.75(t,J=6.4Hz,2H).
The synthesis of 20-3 intermediate C17-4:
C17-2(600mg, 1.37mmol prepared by step 20-1) be dissolved in the aqueous solution of the sodium hydroxide of 3mL tetrahydrofuran (THF) and 3mL2N, stirring at room temperature 8 hours.Except desolventizing adds 10mL water, wash by 5mL ethyl acetate, aqueous phase hydrochloric acid adjusts PH to 2, with 10mL extraction into ethyl acetate three times.Organic phase drying is concentrated obtains white solid C17-4(400mg, 84%).
1H NMR(400MHz,CDCl
3)δ7.46–7.30(m,10H),6.90–6.88(m,2H),6.79(d,J=8.0Hz,1H),5.14(s,4H),3.55(s,2H).
The synthesis of 20-4 intermediate C17-5:
C17-4(63mg, 0.18mmol prepared by step 20-3) be dissolved in the thionyl chloride of 1mL, reflux 4 hours.Oily matter C17-5(66mg, 0.18mmol is obtained by concentrated for reaction solution) be directly used in next step reaction.
The synthesis of 20-5 intermediate C17-6:
C17-3(50mg prepared by step 20-2,0.15mmol) be dissolved in the methylene dichloride of 2mL with 18.2mg triethylamine (0.18mmol), C17-5(66mg prepared by step 20-2 is dripped under zero degree, 0.18mmol), this reaction solution at room temperature stirs 3 hours, and reaction solution is washed with the hydrochloric acid of 2mL1N and the aqueous sodium hydroxide solution of 2mL1N respectively, and organic phase drying is concentrated, cross silica column purification (sherwood oil: ethyl acetate=10:1) and obtain white solid C17-6(80mg, 80%).
1H NMR(400MHz,CDCl
3)δ7.43–7.31(m,20H),6.86-6.83(m,3H),6.77(s,1H),6.73(d,J=8.4Hz,1H),6.64(d,J=8.4Hz,1H),5.14(s,8H),4.20(t,J=6.4Hz,2H),3.45(s,2H),2.78(t,J=6.4Hz,2H).
The synthesis of 20-6 product C 17:
C17-6(20mg, 0.03mmol prepared by step 20-2) be dissolved in 5mL ethyl acetate, add 2mg palladium carbon, with hydrogen exchange three times, stir 4 hours under 40 degree.With diatomite filtration, the concentrated silica column purification of filtrate (sherwood oil: ethyl acetate=1:1) obtains oily matter C17(48mg, 88%).
1H NMR(400MHz,DMSO-d6)δ8.86(s,1H),8.78(s,2H),8.59(s,1H),6.64–6.57(m,4H),6.47–6.42(m,2H),4.10(t,J=6.4Hz,2H),3.41(s,2H),2.67(t,J=6.4Hz,2H).
embodiment 21n-(3 ', 4 '-dihydroxyl) synthesis of styroyl-(3,4-dihydroxyl) toluylic acid amine (C52):
3, 4-dihydroxyphenyl acetic acid (DO, 2.0g, 11.9mmol) with dopamine hydrochloride (2.7g, 14.3mmol) be dissolved in dry DMF (12mL), EDCI (2.74g is added under stirring, 14.3mmol) with DIPEA (1.84g, 14.3mmol). stir 16 hours under normal temperature, then ethyl acetate (100mL) is used to dilute, wash with the dilute hydrochloric acid of 15mL1N, 3 times are washed again with 15mL saturated common salt, anhydrous sodium sulfate drying, filtering and concentrating, Compound C 52 (1.0g is obtained through column chromatography purification (moving phase is methylene dichloride: methyl alcohol=25:1), 27%), it is a white solid.
1H NMR(400MHz,DMSO-d6)δ8.79(s,1H),8.75(s,1H),8.67(s,1H),8.65(s,1H),7.91(s,1H),6.64(d,J=8.0Hz,1H),6.62（s,1H），6.61(s,1H),6.56(s,1H),6.45(d,J=8.0Hz,1H),6.40(d,J=8.0Hz,1H),3.17(s,2H),3.18-3.11(m,2H),2.51-2.40(m,2H)。
embodiment 22the synthesis of 2-oxo benzo [1,3] dioxolane-5-acetic acid (T21):
DOPAC (DO, 2.0g, 11.9mmol) and N, N '-succinimidyl carbonate (3.1g, 12.1mmol) be dissolved in dry methylene dichloride (100mL), triethylamine (1.44g, 14.3mmol) is added under stirring.Stir 16 hours under normal temperature, then dilute hydrochloric acid and the water washing of 15mL saturated common salt of 15mL1N is used respectively, anhydrous sodium sulfate drying, filtering and concentrating, compound T21 (0.8g is obtained through purification by silica gel column chromatography (moving phase is sherwood oil: ethyl acetate=1:1), 34%), be a white solid.
1H NMR(400MHz,DMSO-d6)δ12.43(br s,1H),7.42-7.40(m,2H),7.17(d,J=8.0Hz,1H),3.66(s,2H)。
embodiment 23on the impact (I) of tumor cell proliferation
Experimental program: adopt tetrazolium bromide (3-(4,5-dimethylthiazole-2)-2,5-diphenyltetrazolium bromide bromine salt, MTT) test, 3,4-resorcylic acid (DO) is contrast, choose (dose gradient are 10mg/ml, 1mg/ml, 100 μ g/ml, 10 μ g/ml, 1 μ g/ml, 100ng/ml) such as foregoing representative toluylic acid analog derivative D80, C17, T33, D23, C67 and process tumour cell 24 hours respectively, MTT dyes 4 hours afterwards, dimethyl sulfoxide (DMSO) (DMSO) is dissolved afterwards, surveys absorption photometric value under microplate reader 570nm.Calculate cell survival rate.
Experimental result: DO, D80, C17, T33, D23, C67 and DO-3 have certain restraining effect to lung cancer A549 cell propagation, and in dose-dependence.And in these compounds 100ug/ml dosage effect group, A549 cell survival rate is all more than 80%, and prompting Compound D 80, C17, T33, D23, C67 and DO-3 possess certain security, may be used for antitumor fundamental research and clinical verification.Concrete outcome is shown in Fig. 1.
embodiment 24on the impact (II) of tumour cell and normal cell proliferation
Experimental program: adopt tetrazolium bromide (3-(4,5-dimethylthiazole-2)-2,5-diphenyltetrazolium bromide bromine salt, MTT) test, testing compound (dose gradient be 10mg/ml, 1mg/ml, 100 μ g/ml, 10 μ g/ml, 1 μ g/ml, 100ng/ml) processes lung cancer A549 cell, nasopharyngeal carcinoma cells CNE-2 Z, nephroblastoma G401 cell and laryngocarcinoma HEP-2 cell 24 hours respectively, MTT dyes 4 hours, dimethyl sulfoxide (DMSO) (DMSO) is dissolved, and surveys absorption photometric value under microplate reader 570nm.With compound gradient for X-coordinate, cell survival rate is ordinate zou, drawing standard curve, and calculates half inhibiting rate IC
50.
Experimental result: in testing compound, 065-1,065-2,069,079 and 111 remarkable to the restraining effect of these tumor cell proliferations, wherein the restraining effect of 065-2 and 069 to 293 cell proliferations is less than the restraining effect to tumour cell, and the effect of prompting 065-2 and 069 pair tumour cell has certain selectivity.Concrete outcome is in table 1.
Table 1 is on the impact (IC of 5 kinds of cell proliferations
50)
embodiment 25on the impact (I) of tumor cell migration
Experimental program: adopt cell migration to detect (Transwell) experiment, 10 μMs of testing compounds T83, D80, T73, T33, D23, T21, C52, D76, C17, C67, DO-1, DO-2, DO-3 process lung cancer A549 cell, myosarcoma A204 cell, nephroblastoma G401 cell and colorectal carcinoma CT26 cell 24 hours respectively, through fixing without water-ice methyl alcohol, violet staining and taking pictures, the number of detection cell migration.Take DO as positive control, establish blank group simultaneously.
Experimental result: Compound D 80, T33, T21, C52, C67 and DO-3 significantly can suppress the migration of A549, A204, G401 and CT26 cell, effect is better than DO.Specifically see Fig. 2-Fig. 5.
embodiment 26on the impact (II) of tumor cell migration
Experimental program: adopt cell migration to detect (Transwell) experiment, 10 μMs of testing compound 065-1,065-2,067,069,070,071,072,073,077,079,099,100,102,109,111 and 122 process lung cancer A549, cancer of the stomach G401 and laryngocarcinoma HEP-2 cell 24 hours respectively, through fixing without water-ice methyl alcohol, violet staining and taking pictures, the number of detection cell migration.Take DO as positive control, establish blank group simultaneously.
Experimental result: compound 065-1,065-2,069,102 and 111 significantly can suppress the migration of A549, G401 and HEP2 cell.Specifically see Fig. 6-Fig. 8.
embodiment 27on the impact (I) of apoptosis of tumor cells
Experimental program: testing compound T83, D80, T73, T33, D23, T21, C52, D76, C17, C67, DO-1, DO-2, DO-3(10 μM, this dosage is safe dose) process lung cancer A549 cell and nephroblastoma G401 cell 24 hours, carry out the two dye of Annexin V-FITC and PI afterwards, adopt FCM analysis technology to identify apoptotic cell, and calculate apoptotic cell number.Take DO as positive control, establish blank group simultaneously.
Experimental result: compound T83, D80, T73, T33, D23, T21, C52, D76, C17, C67 and DO-3 have certain promotion to A549 and G401 apoptosis (comprising early apoptosis and late apoptic), shows that the ratio of apoptotic cell in all cells increases.Wherein D80, T33, C17, C52 and DO-3 apoptosis-promoting effect is better than DO.Concrete outcome is shown in Fig. 9-Figure 10.
embodiment 28on the impact (II) of apoptosis of tumor cells
Experimental program: adopt the experiment of apoptosis flow cytometer detection, testing compound 065-1, 065-2, 067, 069, 070, 071, 072, 073, 077, 079, 099, 100, 102, 109, 111 and 122(10 μM, this dosage is safe dose) process lung cancer A549 respectively, nephroblastoma G401 and laryngocarcinoma HEP-2 cell 24 hours, centrifugal collecting cell (1500rpm afterwards, 5min), resuspended centrifugal 2 times of PBS, to dye respectively 15min with Annexin-V FITC and PI afterwards, stream type cell analyzer detects the per-cent of apoptotic cell, the cell percentages sum of early apoptosis and late apoptic and apoptosis always than.Take DO as positive control, establish blank group simultaneously.
Experimental result: the apoptosis of compound 065-1,065-2 and 069 pair of A549, G401 and HEP2 cell has significant promoter action, and the effect of these 3 kinds of compounds significantly will be better than DO.Concrete outcome is shown in Figure 11-Figure 13.
In a word.The invention provides a kind of new phenylacetic acid derivatives, it has anti-tumor activity, can promote the migration of apoptosis of tumor cells, inhibition tumor cell, can develop the antitumor drug made new advances, for clinical cancer therapy provides new selection.
Specific description of embodiments of the present invention does not above limit the present invention, and those skilled in the art can make various change or distortion according to the present invention, only otherwise depart from spirit of the present invention, all should belong to the scope of claims of the present invention.
Claims (12)
1. the compound shown in formula I,
Wherein, R
1, R
2, R
3, R
4and R
5be selected from hydrogen, hydroxyl, halogen, C independently of one another
1-C
5straight or branched alkyl, C
2-C
5straight or branched unsaturated alkyl or
or R
1, R
2, R
3, R
4and R
5in form the replacement of more than ternary together with carbon atom of being connected with their of adjacent two substituting groups or unsubstituted carbocyclic ring or replace or unsubstituted oxygen heterocyclic ring; Wherein R
15be selected from C
1-C
5straight or branched alkyl, allyl group, propargyl, alkene butyl, methacrylic, alkynes butyl, methyl alkynes butyl, substituted or unsubstituted phenyl or substituted or unsubstituted benzyl;
X is selected from O or NH;
R
6be selected from hydrogen, C
1-C
5straight or branched alkyl,
or
wherein
R
8be selected from hydrogen, hydroxyl, nitro, C
1-C
5straight or branched alkyl or C
1-C
5straight or branched alkyl oxy,
R
9, R
10, R
11, R
12and R
13be selected from hydrogen, hydroxyl, halogen, C independently of one another
1-C
5straight or branched alkyl, C
2-C
5straight or branched unsaturated alkyl or
or R
9, R
10, R
11, R
12and R
13in form the replacement of more than ternary together with carbon atom of being connected with their of adjacent two substituting groups or unsubstituted carbocyclic ring or replace or unsubstituted oxygen heterocyclic ring;
R
14be selected from C
1-C
5straight or branched alkyl;
Condition is R
3and R
4be all hydroxyl, X is O, R
6when being hydrogen, R
1, R
2and R
5can not be hydrogen simultaneously.
2. compound according to claim 1, is characterized in that: R
3be hydroxyl or
preferably, R
3hydroxyl, R
2or R
4be hydroxyl or
3. compound according to claim 1, is characterized in that: R
1, R
2, R
3, R
4and R
5in form five yuan or hexa-atomic replacement or unsubstituted oxygen heterocyclic ring together with carbon atom of being connected with their of adjacent two substituting groups; R
1, R
2, R
3, R
4and R
5in non-Cheng Huan be selected from hydrogen, hydroxyl, halogen, C independently of one another
1-C
5straight or branched saturated alkyl, C
2-C
5straight or branched unsaturated alkyl or
Preferably, R
3and R
4, or R
4and R
5the substituted or unsubstituted oxygen heterocyclic ring that five yuan or hexa-atomic contain two Sauerstoffatoms is formed together with the carbon atom that they are connected;
More preferably, R
3and R
4substituted or unsubstituted [1,3]-dioxolane is formed together with the carbon atom that they are connected.
4. compound according to any one of claim 1 to 3, is characterized in that: the substituting group of described carbocyclic ring, oxygen heterocyclic ring, [1,3]-dioxolane is selected from hydroxyl, halogen, carbonyl, C
1-C
5straight or branched alkyl or
5., according to described compound arbitrary in Claims 1-4, it is characterized in that: R
8for hydrogen or hydroxyl.
6., according to described compound arbitrary in claim 1 to 5, it is characterized in that: R
9, R
10, R
11, R
12and R
13be selected from hydrogen, hydroxyl, C independently of one another
1-C
5straight or branched alkyl, C
2-C
5straight or branched unsaturated alkyl or
Preferably, R
10and R
11for hydroxyl.
7., according to described compound arbitrary in claim 1 to 6, it is characterized in that: described C
1-C
5straight or branched alkyl is selected from methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-, sec-butyl, the tertiary butyl, amyl group;
Described C
2-C
5straight or branched unsaturated alkyl is selected from vinyl, allyl group, 1-propenyl, pseudoallyl, alkene butyl, alkene amyl group, 3-pentenyl, ethynyl, propargyl, 2-propynyl, alkynes butyl, alkynes amyl group.
8. compound according to claim 1, is characterized in that: described compound is selected from:
3-methoxyl group-4,5-dihydroxyphenyl acetic acid,
3-methoxyl group-4,5-dihydroxyphenyl acetic acid methyl esters,
3,4,5-trihydroxybenzene acetic acid,
3,4,5-trihydroxybenzene methyl acetate,
3-benzyloxy-4,5-dihydroxyphenyl acetic acid methyl esters,
3-(2 '-methyl propoxy-)-4,5-dihydroxyphenyl acetic acids,
3-methoxyl group-4-allyloxy methyl phenylacetate,
3-methoxyl group-4-hydroxyl-5-allyl benzene methyl acetate,
3-methoxyl group-4-hydroxyl-5-propylbenzene methyl acetate,
3,4-dihydroxyl-5-propylbenzene methyl acetate,
3,4-dihydroxyl-5-propylbenzene acetic acid,
3-chloro-4-hydroxyl-5-methoxyphenylacetic acid methyl esters,
Chloro-4, the 5-dihydroxyphenyl acetic acids of 3-,
Chloro-4, the 5-dihydroxyphenyl acetic acid methyl esters of 3-,
3-bromo-4-hydroxy-5-methyl oxygen base methyl phenylacetate,
Bromo-4, the 5-dihydroxyphenyl acetic acids of 3-,
Bromo-4, the 5-dihydroxyphenyl acetic acid methyl esters of 3-,
Chloro-4, the 5-dihydroxyphenyl acetic acid methyl esters of 2,3,6-tri-,
Chloro-4, the 5-dihydroxyphenyl acetic acids of 2,3,6-tri-,
DOPAC ethyl ester,
3,4-methylenedioxyphenylacetic acid,
3,4-methylenedioxyphenylacetic acid methyl esters,
3-methoxyl group-4 hydroxyl phenylacetic acid,
DOPAC (3 ', 4 '-dihydroxyl) phenethyl ester,
N-(3 ', 4 '-dihydroxyl) styroyl-(3,4-dihydroxyl) toluylic acid amine,
N-2-leptodactyline-(3,4-dihydroxyl)-toluylic acid amine,
DOPAC methoxy methyl alcohol ester,
3-methoxyl group-4 hydroxyphenylacetic acid methyl ester,
2-oxo benzo [1,3] dioxolane-5-acetic acid,
3-hydroxyl-4-methoxyphenylacetic acid methyl esters,
DOPAC (ethoxymethyl) alcohol ester,
2-oxyethyl group-7-isopropoxy benzo [1,3] dioxolane-5-methyl acetate,
2-oxyethyl group-7-hydroxy benzo [1,3] dioxolane-5-methyl acetate,
2-oxyethyl group-7-benzyloxy benzo [1,3] dioxolane-5-methyl acetate;
Preferably, described compound is selected from:
3,4,5-trihydroxybenzene methyl acetate,
3-methoxyl group-4,5-dihydroxyphenyl acetic acid methyl esters,
3-(2 '-methyl propoxy-)-4,5-dihydroxyphenyl acetic acids,
Chloro-4, the 5-dihydroxyphenyl acetic acid methyl esters of 2,3,6-tri-,
3,4-dihydroxyl-5-propylbenzene methyl acetate,
Chloro-4, the 5-dihydroxyphenyl acetic acids of 2,3,6-tri-,
N-2-leptodactyline-(3,4-dihydroxyl)-toluylic acid amine,
DOPAC methoxy methyl alcohol ester,
3,4-methylenedioxyphenylacetic acid methyl esters,
3-methoxyl group-4,5-dihydroxyphenyl acetic acid,
3,4,5-trihydroxybenzene acetic acid,
3,4,5-trihydroxybenzene methyl acetate,
DOPAC ethyl ester,
DOPAC (3 ', 4 '-dihydroxyl) phenethyl ester,
DOPAC (ethoxymethyl) alcohol ester.
9. the compound described in any one of claim 1 to 8 or its pharmaceutically acceptable salt, polymorph, enantiomorph or racemic modification are preparing the purposes in anti-tumor drug;
Preferably, described tumour is solid tumor;
Preferred, described tumour be selected from lung cancer, mammary cancer, cervical cancer, rhabdosarcoma, nasopharyngeal carcinoma, carcinoma of the pancreas, laryngocarcinoma, skin carcinoma, liver cancer, neuroblastoma, the nephroblastoma, intestinal cancer, cancer of the stomach and adrenocortical tumor one or more;
Most preferred, described tumour be selected from lung cancer, mammary cancer, cervical cancer, the nephroblastoma, nasopharyngeal carcinoma, laryngocarcinoma, neuroblastoma, intestinal cancer and cancer of the stomach one or more.
10. purposes according to claim 9, is characterized in that: described compound is by inhibition tumor cell propagation, migration, and/or inducing apoptosis of tumour cell and produce antitumor action.
11. 1 kinds of pharmaceutical compositions, comprise compound according to any one of claim 1 to 8 or its pharmaceutically acceptable salt, polymorph, enantiomorph or racemic modification.
12. pharmaceutical compositions according to claim 11, is characterized in that: described pharmaceutical composition is acceptable arbitrary formulation clinically, comprise through gastrointestinal administration preparation and non-through gastrointestinal administration preparation;
Preferably, described through gastrointestinal administration preparation optionally from powder, tablet, granule, capsule, dripping pill, emulsion or suspensoid;
Preferably, described non-through gastrointestinal administration preparation optionally from injection, inhalation, sprays, aerosol, suppository, filling agent, patch or ointment.
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| PCT/CN2014/000750 WO2015018182A1 (en) | 2013-08-05 | 2014-08-05 | Phenylacetic acid derivative and antitumor use thereof |
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| JP6987839B2 (en) | 2016-08-04 | 2022-01-05 | 高砂香料工業株式会社 | Warm compound |
| CN113018298B (en) * | 2021-03-09 | 2022-05-03 | 四川轻化工大学 | Inhibitor for treating promyelocytic leukemia and pharmaceutical composition thereof |
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| CN111925293B (en) * | 2020-08-24 | 2022-06-14 | 山东达冠医药科技有限公司 | Preparation method of dopamine hydrochloride |
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