CN101985428A - O-anilino benzoic acid derivatives or pharmaceutically acceptable salts thereof as well as preparation method and application thereof - Google Patents
O-anilino benzoic acid derivatives or pharmaceutically acceptable salts thereof as well as preparation method and application thereof Download PDFInfo
- Publication number
- CN101985428A CN101985428A CN2009101010048A CN200910101004A CN101985428A CN 101985428 A CN101985428 A CN 101985428A CN 2009101010048 A CN2009101010048 A CN 2009101010048A CN 200910101004 A CN200910101004 A CN 200910101004A CN 101985428 A CN101985428 A CN 101985428A
- Authority
- CN
- China
- Prior art keywords
- amino
- chloro
- aminomethyl phenyl
- fluoro
- compound
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
Images
Abstract
The invention provides o-anilino benzoic acid derivatives or pharmaceutically acceptable salts thereof as well as a preparation method and applications thereof in preparing medicines or functional food for preventing and/or treating tumors and other abnormal proliferation diseases of organisms and in preparing medicines or functional food for preventing and/or treating inflammations, pains and other diseases of organisms.
Description
(1) technical field
The present invention relates to adjacent anilino benzoic acid derivative or its pharmacy acceptable salt, its preparation method and prevent and/or treat the medicine of body paraplasm diseases such as tumour in preparation or the application in the functional food, with and prevent and/or treat the medicine of diseases such as body inflammatory, pain or the application in the functional food in preparation.
(2) background technology
Malignant tumour (cancer) is the common disease and the frequently-occurring disease of serious threat human health.According to the report of World Health Organization report, the whole world had 1,240 ten thousand people to make a definite diagnosis in 2008 to suffer from certain types of cancer approximately, and wherein 7,600,000 people are therefore dead.Report estimates that by 2010, the cancer lethality rate will become global No.1 killer above heart trouble; To the year two thousand thirty, may will there be cancer patients 2,640 ten thousand people in the whole world every year, and wherein 1,700 ten thousand people will be therefore dead.In the past few decades, in order to tackle cancer, various countries medical science man and pharmaceutical science man are making great efforts always untiringly, have also obtained original achievement, still, up to now, also do not have medicine can prevent or cure cancer fully.In quite long one period, cytotoxic drug will be the main body of tumor pharmacother.At present, form at tumour and the new type antineoplastic medicine of the too many levels effect of mechanism of proliferation (tumour cell is had targeting killing effect, and very little to the human normal tissue damage, even do not have) becomes the focus that home and abroad research institution pays close attention to just gradually.
Scientist just notices that inflammation, tissue injury and cancer are closely related a long time ago, and in 1863, Rudolf Virchow just pointed out that cancer usually results from the chronic inflammatory diseases position of body.In fact, the investigation of stream venerology shows that the risk that chronic viral hepatitis B, chronic gastroenteritis and chronic pancreatitis patient suffer from liver cancer, gastrointestinal cancer and carcinoma of the pancreas significantly increases; Similarly, the cancered risk of traumatic patient also can increase.In this process, intracellular cyclooxygenase (Cyclo-oxygenase, COX), lipoxygenase (Lipoxygenase, LOX) and meta-bolites play a part very crucial.These may become the target spot (consulting: Coussens LM, Werb Z. (2002) Inflammation and cancer.Nature 420:860-7) of prevention and treatment cancer.
The generation of COX and meta-bolites thereof and tumour generation, progress, transfer and blood vessel is closely related.In human body, identified that the COX relevant with cancer has two kinds at least: COX-1 (consults: Xie W, Chipman JG, Robertson DL, et al. (1991) Expression of a mitogen-responsive gene encoding prostaglandin synthase is regulated by mRNA splicing.Proc.Natl.Acad.Sci.USA 88:2692-6) and COX-2 (consulting: Hla T, Neilson K. (1992) Human cyclooxygenase-2cDNA.Proc.Natl.Acad.Sci.USA 89:7384-8).COX-1 is physiological, and expression is all arranged in gi tract, kidney, vascular smooth muscle and thrombocyte, participates in the body normal physiological function; Yet, COX-2 can't detect in most healthy tissuess, but can be expressed and (consult: Morita I. (2002) Distinct functions of COX-1 and COX-2.Prostaglandins Other Lipid Mediat.68-69:165-75) by various stimulus (as: somatomedin, the cell medium that inflammation is relevant) rapid induction.In many tumor tissues (as: carcinoma of the pancreas, lung cancer, colorectal carcinoma, adenocarcinoma of stomach, breast cancer and prostate cancer etc.) in, COX-2 expresses and rolls up, the increase that also is accompanied by COX-2 meta-bolites prostaglandin(PG) (is consulted: Molina MA, Sitja-Amau M, Lemoine MG, et al. (1999) Increased cyclooxygenase-2 expression in human pancreatic carcinomas and cell lines:growth inhibition by nonsteroidal anti-inflammatory drugs.Cancer Res.59:4356-62; Wolff H, Saukkonen K, Anttila S, et al. (1998) Expression of cyclooxygenase-2in human lung carcinoma.Cancer Res.58:4997-5001; Uefuji K, Ichikura T, Mochizuki H, et al. (1998) Expression of cyclooxygenase-2protein in gastric adenocarcinoma.J.Surg.Oncol.69:68-72; Hwang D, Scollard D, Byrne J, et al. (1998) .Expression of cyclooxygenase-1and cyclooxygenase-2in human breast cancer.J.Natl.Cancer Inst.90:455-60; Kutchera W, Jones DA, Matsunami N, et al. (1996) Prostaglandin Hsynthase 2 is expressed abnormally in human colon cancer:evidence for a transcriptional effect.Proc.Natl.Acad.Sci.USA 93:4816-20; Gupta S, Srivastava M, Ahmad N, et al. (2000) Over-expression of cyclooxygenase-2in human prostate adenocarcinoma.Prostate 42:73-78).The COX-2 of overexpression and meta-bolites thereof participate in the hyperplasia of generation, development and the blood vessel of tumour and (consult: Qiao L, Kozoni V, Tsioulas GJ, et al. (1995) Selected eicosanoids increase the proliferation rate of human colon carcinoma cell lines and mouse colonocytes in vivo.Biochim.Biophys.Acta 128:215-23; Muller-Decker K, Neufang G, Berger I, et al. (2002) Transgenic cyclooxygenase-2overexpression sensitizes mouse skin for carcinogenesis.Proc.Natl.Acad.Sci.USA 99:12483-88; Prescott SM. (2000) Is cyclooxygenase-2 the alpha and the omega in cancer? J Clin.Invest.105:1511-94).The experimental study of gene knockout shows, COX-1 is also closely related with the development of tumour (to be consulted: Chulada PC, Thompson MB, Mahler JF, et al. (2000) Genetic disruption of Ptgs-1, as well as of Ptgs-2, reduces intestinal tumorigenesis in Min mice.Cancer Res.60:4705-8).The inhibitor of COX-2, COX1/2 inhibitor can suppress growth of tumor and (consult: Piazza GA, Rahm AK, Finm TS, et al. (1997) Apoptosis primarily accounts for the growth-inhibitory properties of sulindac metabolites and involves a mechanism that is independent of cyclooxygenase inhibition, cell cycle arrest, and p53 induction.Cancer Res.57:2452-9; Seed MP, Brown JR, Freemantle, et al. (1997) The inhibition of colon-26adenocarcinoma development and angiogenesis by topical diclofenac in 2.5% hyaluronan.Cancer Res.57:1625-9).
The generation of LOX and meta-bolites thereof and tumour generation, progress, transfer and blood vessel is also closely related.LOX is in the metabolic process of conversion of arachidonic acid, according to the difference of Sauerstoffatom being inserted the arachidonic acid position, can be divided into different hypotype 5-LOX, 8-LOX, 12-LOX and 15-LOX (consults: Brash AR. (1999) Lipoxygenases:occurrence, functions, catalysis, and acquisition of substrate.J.Biol.Chem.274:23679-82).Increasing research evidence shows, 5-LOX and meta-bolites thereof have participated in the progress of tumour and (have consulted: Steele VE, Holmes CA, Hawk ET, et al. (1999) Lipoxygenase inhibitors as potential cancer chemo-preventives.Cancer Epidemiol Biomarkers Prev.8:467-83), the medium that is tumor cell proliferation (is consulted: Anderson KM, Seed T, Jajeh A, et al. (1996) An in vivo inhibitor of 5-lipoxygenase, MK886, at micromolar concentration induces apoptosis inU937 and CML cells.Anticancer Res.16:2589-99); The inhibitor of 5-LOX can suppress growth of tumor and (consult: Gunning WT, Kramer PM, Steele VE et al. (2002) Chemo-prevention by lipoxygenase and leukotriene pathway inhibitors of vinyl carbamate-induced lung tumors in mice.Cancer Res.62:4199-201).Other 8-LOX, 12-LOX, 15-LOX and meta-bolites thereof have also participated in the survival and development of tumour, 8-LOX and 12-LOX and meta-bolites thereof may promote the generation of tumour and development (to consult: Muga SJ, Thuillier P, PavoneA, et al. (2000) 8S-lipoxyge-nase products activate peroxisome proliferators-activated receptor alpha and induce differentiation in murine keratino-cytes.Cell Growth Differ.11:447-54; Honn KV, Tang DG, Gao X, et al. (1994) 12-lipoxygenases and 12 (s)-HETE:role in cancer metastasis.Cancer Metastasis Rev.13:365-96), and may suppressing the development of tumour, 15-LOX and meta-bolites thereof (consult: His LC, Wilson LC, Eling TE. (2002) Opposing Effects of 15-Lipoxygenase-1 and-2 Metabolites on MAPK Signaling in Prostate.Alteration in peroxisome proliferatoractivated receptor gamma.J.Biol.Chem.277:40549-56).
A series of studies show that, LOX and COX, particularly 5-LOX and COX-2 express and active increasing in tumor tissues, suppress the effective way (consulting: RomanoM, Claria J. (2003) Cyclooxygenase-2 and 5-lipoxygenase converging functions on cell proliferation and tumor angiogenesis:implications for cancer therapy.FASEB J 17:1986-95) that 5-LOX and COX-2 expression and/or activity may be prevention and treatment cancer.Non-steroidal anti-inflammatory drugs be a class at present at the analgesic town of wide clinical application medicine, have plenty of the inhibitor of COX, have plenty of the double inhibitor of COX and LOX.Tolfenamic acid belongs to the nonsteroidal antipyretic and analgesic, is the double inhibitor of COX and LOX, is developed by Denmark GEA company at first, and at first in Denmark's listing, is mainly used in the treatment migraine.Nearest studies show that tolfenamic acid has the obvious suppression effect to human pancreas cancer, the colorectal cancer of laboratory animal, and can increase pancreatic cancer cell to radiocurable susceptibility; Its mechanism of action may with can degrade nuclear factor (SP1 in the tumour cell of tolfenamic acid, SP3, SP4), suppress Urogastron (Vascular Endothelial Growth Factor, VEGF) and the generation of vegf receptor, suppress survivin (Survivin) generation and activate relevant (the consulting: Abdelrahim M of ESE-1/EGR-1 signal path, Baker CH, Abbruzzese JL, et al. (2006) Tolfenamic acid and pancreatic cancer growth, angiogenesis, and Sp protein degradation.J.Natl.Cancer Inst.98:855-68; Abdelrahim MB, Abbruzzese CH, Sheikh-Hamad JL, et al. (2007) Regulation of vascular endothelial growth factor receptor-1expression by specificity proteins 1,3, and 4 in pancreatic cancer cells.Cancer Res.67:3286-94; Konduri S, Colon J, Baker CH, et al. (2009) Tolfenamic acid enhances pancreatic cancer cell and tumor response to radiation therapy by inhibiting survivin protein expression.Mol.Cancer Ther.8:533-42; Lee SH, Bahn JH, Choi CK, et al. (2008) ESE-1/EGR-1pathway plays a role in tolfenamic acid-induced apoptosis in colorectal cancer cells.Mol.Cancer Ther.7:3739-50.).Yet, the anti-tumor activity of tolfenamic acid (is not consulted: Abdelrahim M by force, Baker CH, Abbruzzese JL, et al. (2006) Tolfenamic acid and pancreatic cancer growth, angiogenesis, and Sp protein degradation.J.Natl.Cancer Inst.98:855-68.).
Non-steroidal anti-inflammatory drugs has caused investigator's attention in the potentiality of anti-tumor aspect, as far back as 1999, just there is the investigator to apply for a patent, after carboxylic non-steroidal anti-inflammatory drugs is modified into swollen sulfonamide derivatives, its alternative COX-2 that suppresses, and has an anti-tumor activity (consulting: US 6399647B2, Amide derivatives for antiangiogenic and/or antitumorigenic use).It is that activity with inhibition COX is an index when estimating modifier, and this has certain limitation, because nearest studies show that: LOX also participates in the development of tumour and the generation of blood vessel, and non-LOX and COX effect also may participate in anti-tumor activity.Although in patent, also mentioned tolfenamic acid, there is not specific embodiment.
Tolfenamic acid is that adjacent anilino is benzoic a kind of.It is lead compound that the present invention intends with adjacent anilino phenylformic acid, modifies synthetic a series of new compounds, is target to increase anti-tumor activity and to improve pharmacokinetics, finds the new compound of efficient (antitumor, antipyretic-antalgic etc.), low toxicity.
(3) summary of the invention
The object of the present invention is to provide a class to have novel low toxicity compounds of anticancer and analgesic analgesic activities and preparation method thereof.This compounds is lower to the acute toxicity of mouse, ICR mouse, intravenously administrable, medium lethal dose (LD
50) greater than 100mg/kg; Under doses, for people's lung cancer (NCI-460), liver cancer (SMMC-7721, BEL-7402), cancer of the stomach (BGC-823), squamous cell carcinoma (KB), prostate cancer (PC-3), cervical cancer (HELA), ovarian cancer (HO-8910), mammary cancer (BT549), colorectal carcinoma (Caco-2), carcinoma of the pancreas (ASPC-1, PANC-1), leukemia (HL-60, K562) and glioma (U251) cell strain have stronger restraining effect; The human tumor cells of transplanting nude mice also had the obvious suppression effect; After the intravenous injection, this compounds can be distributed to tissue rapidly, and long the elimination transformation period arranged; The pain that heat, chemical irritation are caused has the obvious suppression effect; And the preparation method of this compounds is easy, and easy handling, cost are very low, are very beneficial for industrialization.
The technical solution used in the present invention is:
Adjacent anilino benzoic acid derivative or its pharmacy acceptable salt shown in general formula I:
I
In the formula, R
1Be hydrogen, nitro or amino; R
2Be hydrogen, nitro or halogen; R
3Be hydrogen or halogen; R
4Be amino, C
1-C
10Alkane secondary amine, two C
1-C
5Alkane tertiary amine groups, benzene secondary amine, benzene C
1-C
3Alcoxyl secondary amine, hydroxyl, C
1-C
10Alkoxyl group, phenoxy group, benzene C
1-C
3Alkoxyl group; If R
4Be hydroxyl, R then
1, R
2And R
3Be not hydrogen simultaneously.
Further, adjacent anilino benzoic acid derivative or its pharmacy acceptable salt shown in the general formula I provided by the invention: in the formula, R
1Be hydrogen, nitro or amino; R
2Be hydrogen, nitro, fluorine or chlorine; R
3Be hydrogen or chlorine; R
4Be amino, C
1-C
10Alkane secondary amine, two C
1-C
5Alkane tertiary amine groups, benzene secondary amine, benzene C
1-C
3Alcoxyl secondary amine, hydroxyl, C
1-C
5Alkoxyl group, phenoxy group, benzene C
1-C
3Alkoxyl group; If R
4Be hydroxyl, R then
1, R
2And R
3Be not hydrogen simultaneously.
Further again, adjacent anilino benzoic acid derivative or its pharmacy acceptable salt shown in the general formula I provided by the invention: in the formula, R
1Be hydrogen; R
2Be nitro or fluorine; R
3Be chlorine; R
4Be amino, C
1-C
5Alkane secondary amine, two C
1-C
5Alkane tertiary amine groups, benzene secondary amine, benzene C
1-C
3Alcoxyl secondary amine, hydroxyl, C
1-C
5Alkoxyl group, phenoxy group, benzene C
1-C
3Alkoxyl group.
Further, adjacent anilino benzoic acid derivative provided by the invention or its pharmacy acceptable salt, it is selected from:
4-fluoro-2-[(3-chloro-2-aminomethyl phenyl)-amino] phenylformic acid,
4-fluoro-2-[(3-chloro-2-aminomethyl phenyl)-amino] methyl benzoate,
4-fluoro-2-[(3-chloro-2-aminomethyl phenyl)-amino] ethyl benzoate,
4-fluoro-2-[(3-chloro-2-aminomethyl phenyl)-amino] amyl benzoate,
4-fluoro-2-[(3-chloro-2-aminomethyl phenyl)-amino] the phenylamino benzoic acid methyl esters,
4-fluoro-2-[(3-chloro-2-aminomethyl phenyl)-amino] phenol benzoate,
4-fluoro-2-[(3-chloro-2-aminomethyl phenyl)-amino] the phenylformic acid direactive glyceride,
4-fluoro-2-[(3-chloro-2-aminomethyl phenyl)-amino] benzoic amide,
4-fluoro-2-[(3-chloro-2-aminomethyl phenyl)-amino] phenylformic acid acyl ethamine,
4-fluoro-2-[(3-chloro-2-aminomethyl phenyl)-amino] phenylformic acid acyl Tri N-Propyl Amine,
4-fluoro-2-[(3-chloro-2-aminomethyl phenyl)-amino] phenylformic acid acyl n-octyl amine,
4-fluoro-2-[(3-chloro-2-aminomethyl phenyl)-amino] phenylformic acid acyl benzene methanamine,
4-fluoro-2-[(3-chloro-2-aminomethyl phenyl)-amino] the phenylformic acid anilide,
4-fluoro-2-[(3-chloro-2-aminomethyl phenyl)-amino] phenylformic acid acyl benzene Vasoxyl,
4-fluoro-2-[(3-chloro-2-aminomethyl phenyl)-amino] phenylformic acid acyl diethanolamine,
4-nitro-2-[(3-chloro-2-aminomethyl phenyl)-amino] ethyl benzoate,
4-nitro-2-[(3-chloro-2-aminomethyl phenyl)-amino] phenylformic acid acyl Tri N-Propyl Amine,
6-chloro-2-[(3-chloro-2-aminomethyl phenyl)-amino] phenylformic acid,
2-[(3-chloro-2-aminomethyl phenyl)-amino] ethyl benzoate,
2-[(3-chloro-2-aminomethyl phenyl)-and amino] phenylformic acid acyl Tri N-Propyl Amine.
The present invention also provides a kind of adjacent anilino benzoic acid derivative shown in the general formula I or method of its pharmacy acceptable salt of preparing, and it is characterized in that comprising following processing step:
A). with formula II compound
II
With the reaction of formula III compound,
III
Get formula IV compound;
B). with formula IV compound
IV
With the reaction of formula V compound,
HR
4
V
Get formula I compound; Wherein, R
1Be hydrogen, nitro or amino; R
2Be hydrogen, nitro or halogen; R
3Be hydrogen or halogen; R
4Be amino, C
1-C
10Alkane secondary amine, two C
1-C
5Alkane tertiary amine groups, benzene secondary amine, benzene C
1-C
3Alcoxyl secondary amine, hydroxyl, C
1-C
10Alkoxyl group, phenoxy group, benzene C
1-C
3Alkoxyl group; If R
4Be hydroxyl, R then
1, R
2And R
3Be not hydrogen simultaneously.
The invention still further relates to this compounds in the medicine of body paraplasm diseases such as preparation prevention and treatment tumour or the application in the functional food, as: the medicine or the functional food that are used to prepare prevention and treat diseases such as lung cancer, liver cancer, cancer of the stomach, squamous cell carcinoma, prostate cancer, cervical cancer, ovarian cancer, mammary cancer, colorectal carcinoma, carcinoma of the pancreas, leukemia, glioma; And in the medicine of diseases such as preparation treatment and prevention body inflammatory, pain or the application in the functional food.
Beneficial effect of the present invention is mainly reflected in: this compounds is lower to the acute toxicity of mouse, ICR mouse, intravenously administrable, medium lethal dose (LD
50) greater than 100mg/kg; Under doses, for people's lung cancer (NCI-460), liver cancer (SMMC-7721, BEL-7402), cancer of the stomach (BGC-823), squamous cell carcinoma (KB), prostate cancer (PC-3), cervical cancer (HELA), ovarian cancer (HO-8910), mammary cancer (BT549), colorectal carcinoma (Caco-2), carcinoma of the pancreas (ASPC-1, PANC-1), leukemia (HL-60, K562) and glioma (U251) cell strain have stronger restraining effect; The human tumor cells of transplanting nude mice also had the obvious suppression effect; After the intravenous injection, this compounds can be distributed to tissue rapidly, and long the elimination transformation period arranged; The pain that heat, chemical irritation are caused has the obvious suppression effect; And the preparation method of this compounds is easy, and easy handling, cost are very low, are very beneficial for industrialization.In addition, such compound effects mechanism may compare uniqueness, and tumour cell is had targeting killing effect, and very little to the human normal tissue damage.This compounds is expected to be applied to prepare in the medicine or functional food of prevention and treatment cancer; Also be expected to be applied to prepare in nonsteroidal ntipyretic analgesic medicine or the functional food.
(4) description of drawings
Compound is to the influence of tumor bearing nude mice tumour (HO-8910) volume (mean value)
Ordinate zou: knurl volume, the mm of unit
3X-coordinate: time, unit sky
(5) embodiment
Below in conjunction with specific embodiment the present invention is further specified, but protection scope of the present invention never is limited to the disclosed scope of present embodiment.
[embodiment 1] 2-[(2-chloro-3-methyl-4-nitrophenyl)-and amino] preparation of phenylformic acid (G-1)
250 milliliters of there-necked flasks that have electronic stirring, thermometer, return line add 8.8 gram (43.5 mmole) o-bromobenzoic acids, 80 milliliters of propyl carbinols and 10.4 gram Anhydrous potassium carbonates, stir 20 minutes; Logical nitrogen protection adds 0.8 gram copper powder, 8.8 gram (47.5 mmole) 4-nitro-3-chloro-2-aminotoluenes, heating, 90 ℃ of insulation reaction 24 hours; Be cooled under 60 ℃ of violent stirring to add 44 milliliters in cold water, vacuum filtration, filtrate is poured in 250 milliliters the beaker, is cooled to 10 ℃, drips 15% concentrated hydrochloric acid, and the pH value is transferred to 3.0; Separate out the class faint yellow solid, suction filtration, cold water washing, filter cake oven dry; Sample adds 145 milliliters of ethanol, heating in water bath dissolving, gac 1.6 grams; Filtered while hot, filtrate cooling, suction filtration oven dry obtain yellow product 7.2 grams, yield 53.8%.Content 98.6% (HPLC area normalization method), fusing point 171-176 ℃.
Compound hydrocarbon element determination analysis (Flash EA-1112, ThermoFingnigan) result: C 54.753%, H3.466%; Molecular formula (C
14H
11N
2O
4Cl) calculate: C 54.812%, and H 3.589%.The compound hydrogen nuclear magnetic resonance detects (CDCl
3, 400MHz) result: 11 proton signals are arranged.ESI-HRMS：[M+H]
+306。Show that this compound is G-1.
[embodiment 2] 2-[(2-chloro-3-methyl-4-aminophenyl)-and amino] preparation of phenylformic acid (G-2)
50 milliliters of there-necked flasks that have induction stirring, thermometer, return line, add 1.6 gram (5.2 mmole) G-1 (sample of embodiment 1 method preparation), 20 ml waters and 0.4 gram iron powder, stir, drip 0.4 milliliter of concentrated hydrochloric acid, heating, 90 ℃ of insulation reaction 24 hours; Be cooled to 30 ℃, add salt of wormwood 2.2 grams under the violent stirring, vacuum filtration, filtrate is poured in 100 milliliters the beaker, is cooled to 10 ℃, drips 15% concentrated hydrochloric acid, and the pH value is transferred to 4.0; Separate out the class faint yellow solid, suction filtration, cold water washing, filter cake oven dry; Add 13 milliliters of ethanol, heating in water bath dissolving, gac 0.7 gram; Filtered while hot, filtrate cooling, suction filtration oven dry obtain white product 0.8 gram, yield 55.6%.Content 98.3% (HPLC area normalization method), fusing point 136-140 ℃.
Compound hydrocarbon element determination analysis (Flash EA-1112, ThermoFingnigan) result: C 60.679%, H4.683%; Molecular formula (C
14H
13N
2O
2Cl) calculate: C 60.759%, and H 4.702%.The compound hydrogen nuclear magnetic resonance detects (CDCl
3, 400MHz) result: 13 proton signals are arranged.ESI-HRMS：[M+H]
+276.5。Data shows that this compound is G-2.
[embodiment 3] 4-fluoro-2-[N-(3-chloro--2 aminomethyl phenyl) amino] preparation of phenylformic acid (G-3)
500 milliliters of there-necked flasks that have electronic stirring, thermometer, return line add 33 gram (151 mmole) 4-fluorine o-bromobenzoic acids, and 250 milliliters of propyl carbinols and 45 gram Anhydrous potassium carbonates stir, are heated to 60 ℃ of insulations 30 minutes; Be cooled to 40 ℃, logical N2 protection adds 6 gram copper powders, 40 gram (283 mmole) 3-chloro-2-aminotoluenes, heating, 90 ℃ of insulation reaction 24 hours; Be cooled under 60 ℃ of violent stirring to add 150 milliliters in cold water, vacuum filtration, filtrate is poured in 500 milliliters the beaker, is cooled to 10 ℃, drips 15% concentrated hydrochloric acid, and pH value to 3 is separated out white solid, suction filtration, cold water washing, filter cake oven dry; 300 milliliters of ethanol heating for dissolving, gac 5 grams, the heat filter, the cooling of filtrate frozen water, suction filtration oven dry obtain white powder crystal 3 0.3 gram, yield 71.8%.Content 99.7% (HPLC area normalization method), fusing point: 85-87 ℃.
The hydrocarbon element determination analysis of compound (Flash EA-1112, ThermoFingnigan) result: C 60.110%, H 3.929%; Molecular formula (C
14H
11NO
2FCl) calculate: C 60.107%, H3.936%.The compound hydrogen nuclear magnetic resonance detects (CDCl
3, 400MHz) result: 11 proton signals are arranged.ESI-HRMS：[M+H]
+279.5。Data shows that this compound is G-3.
[embodiment 4] 4-fluoro-2-[N-(3-chloro-2-aminomethyl phenyl) amino] preparation of methyl benzoate (G-4)
50 milliliters of there-necked flasks that have induction stirring, thermometer, return line add 1.5 gram (5.4 mmole) G-3 (embodiment 3 methods prepare sample), and 15 milliliters of methyl alcohol drip 2 milliliters in 98% sulfuric acid, heating reflux reaction 12 hours; Steaming desolventizes, and adds 10 milliliters of methyl alcohol, and crystal is separated out in cooling; Suction filtration, cold water washing, filter cake oven dry; Add 8 ml methanol, heating for dissolving adds gac 0.2 gram, filtered while hot; Filtrate is cooled off with frozen water, and the suction filtration oven dry obtains white crystals body 0.8 gram, yield 50.6%.Content 99.3% (HPLC area normalization method), fusing point 78-79 ℃.
The hydrocarbon element determination analysis of compound (Flash EA-1112, ThermoFingnigan) result: C 61.333%, H 4.415%; Molecular formula (C
15H
13NO
2FCl) calculate: C 61.329%, and H 4.429%.The compound hydrogen nuclear magnetic resonance detects (CDCl
3, 400MHz) result: 13 proton signals are arranged.ESI-HRMS：[M+H]
+293。Data shows that this compound is G-4.
[embodiment 5] 4-fluoro-2-[N-(3-chloro-2-aminomethyl phenyl) amino] preparation of ethyl benzoate (G-5)
50 milliliters of there-necked flasks that have induction stirring, thermometer, return line add 1.5 gram (5.4 mmole) G-3, and 15 milliliters of ethanol drip 2 milliliters in 98% sulfuric acid, heating reflux reaction 12 hours; Steaming desolventizes, and adds 10 milliliters of ethanol, and crystal is separated out in cooling; Suction filtration, cold water washing, filter cake oven dry; Add 8 milliliters of ethanol, heating for dissolving adds gac 0.2 gram, filtered while hot; Filtrate is cooled off with frozen water, and the suction filtration oven dry obtains white crystals body 1 gram, yield 60.2%.Content 99.3% (HPLC area normalization method), fusing point 78-79 ℃.
The hydrocarbon element determination analysis of compound (Flash EA-1112, ThermoFingnigan) result: C 62.435%, H 4.873%; Molecular formula (C
16H
15NO
2FCl) calculate: C 62.439%, and H 4.878%.The compound hydrogen nuclear magnetic resonance detects (CDCl
3, 400MHz) result: 15 proton signals are arranged.ESI-HRMS：[M+H]
+307.5。Data shows that this compound is G-5.
[embodiment 6] 4-fluoro-2-[N-(3-chloro-2-aminomethyl phenyl) amino] preparation of Pentyl benzoate (G-6)
50 milliliters of there-necked flasks that have induction stirring, thermometer, return line add 1.5 gram (5.4 mmole) G-3, and 9 milliliters of Pentyl alcohols drip 1 milliliter in 98% sulfuric acid, heat 90 ℃ of insulation reaction 12 hours; Vacuum is steamed and is desolventized, and adds 5 milliliters of ethanol, and crystal is separated out in cooling; Suction filtration, cold water washing, the filter cake oven dry; Add 8 milliliters of ethanol, heating for dissolving adds gac 0.2 gram, filtered while hot; Filtrate is cooled off with frozen water, and the suction filtration oven dry obtains white product body 0.7 gram, yield 37.1%.HPLC 93.3% (HPLC area normalization method), fusing point 117-120 ℃.
The hydrocarbon element determination analysis of compound (Flash EA-1112, ThermoFingnigan) result: C 65.189%, H 6.002%; Molecular formula (C
19H
21NO
2FCl) calculate: C 65.236%, and H 6.009%.The compound hydrogen nuclear magnetic resonance detects (CDCl
3, 400MHz) result: 21 proton signals are arranged.ESI-HRMS：[M+H]
+349.5。Data shows that this compound is G-6.
[embodiment 7] 4-fluoro-2-[N-(3-chloro-2-aminomethyl phenyl) amino] preparation of phenylamino benzoic acid methyl esters (G-7)
50 milliliters of there-necked flasks that have induction stirring, thermometer, return line add 1.5 gram (5.4 mmole) G-3, and 7 milliliters of phenylcarbinols drip 1 milliliter in 98% sulfuric acid, heat 90 ℃ of insulation reaction 12 hours; Vacuum is steamed and is desolventized, and adds 5 milliliters of phenylcarbinols, and crystal is separated out in cooling; Suction filtration, cold water washing, filter cake oven dry; Add 8 milliliters of phenylcarbinols, heating for dissolving adds gac 0.2 gram, filtered while hot; The cooling of filtrate frozen water, suction filtration oven dry obtain white product 0.9 gram, yield 45.1%.Content 97.1% (HPLC area normalization method), fusing point 97-100 ℃.
The hydrocarbon element determination analysis of compound (Flash EA-1112, ThermoFingnigan) result: C 68.217%, H 4.587%; Molecular formula (C
21H
17NO
2FCl) calculate: C 68.200%, and H 4.601%.The compound hydrogen nuclear magnetic resonance detects (CDCl
3, 400MHz) result: 17 proton signals are arranged.ESI-HRMS：[M+H]
+369。Data shows that this compound is G-7.
[embodiment 8] 4-fluoro-2-[N-(3-chloro-2-aminomethyl phenyl) amino] preparation of phenylformic acid list α glyceryl ester (G-8)
50 milliliters of there-necked flasks that have induction stirring, thermometer, return line add 1.5 gram (5.4 mmole) G-3, and glycerine 5 grams drip 1 milliliter in 98% sulfuric acid, heat 90 ℃ of insulation reaction 12 hours; Vacuum is steamed and is desolventized, and adds 5 milliliters of ethanol, and crystal is separated out in cooling; Suction filtration, cold water washing, filter cake oven dry; Add 8 milliliters of ethanol, heating for dissolving adds gac 0.2 gram, filtered while hot; The cooling of filtrate frozen water, suction filtration oven dry obtain white product 0.7 gram, yield 36.6%.Content 95.3% (HPLC area normalization method), fusing point 197-199 ℃.
The hydrocarbon element determination analysis of compound (Flash EA-1112, ThermoFingnigan) result: C 57.356%, H 4.677%; Molecular formula (C
17H
17NO
4FCl) calculate: C 57.709%, and H 4.809%.The compound hydrogen nuclear magnetic resonance detects (CDCl
3, 400MHz) result: 17 proton signals are arranged.ESI-HRMS：[M+H]
+353。Data shows that this compound is G-8.
[embodiment 9] 4-fluoro-2-[N-(3-chloro-2-aminomethyl phenyl) amino] preparation of phenylamino benzoic acid phenolic ester (G-9)
50 milliliters of there-necked flasks that have induction stirring, thermometer, return line add 1.5 gram (5.4 mmole) G-3, and phenol 3 grams drip 1 milliliter in 98% sulfuric acid, heat 90 ℃ of insulation reaction 12 hours; Add 5 milliliters of ethanol, crystal is separated out in cooling; Suction filtration, cold water washing, filter cake oven dry; Add 8 milliliters of ethanol, heating for dissolving adds gac 0.2 gram, filtered while hot; The cooling of filtrate frozen water, suction filtration oven dry obtain off-white color product 0.6 gram, yield 31.1%.Content 94.1% (HPLC area normalization method), fusing point 152-156 ℃.
The hydrocarbon element determination analysis of compound (Flash EA-1112, ThermoFingnigan) result: C 67.506%, H 4.265%; Molecular formula (C
20H
15NO
2FCl) calculate: C 67.511%, and H 4.219%.The compound hydrogen nuclear magnetic resonance detects (CDCl
3, 400MHz) result: 15 proton signals are arranged.ESI-HRMS：[M+H]
+357。Data shows that this compound is G-9.
[embodiment 10] 4-fluoro-2-[N-(3-chloro-2-aminomethyl phenyl) amino] preparation of benzoic amide (G-10)
50 milliliters of there-necked flasks that have induction stirring, thermometer, return line add 1.5 gram (5.4 mmole) G-3,10 milliliters of anhydrous tetrahydro furans, and icy salt solution is cooled to-5 ℃; Dripping thionyl chloride 0.9 gram keeps temperature less than-2 ℃, reacts 0.5 hour; Slowly be warmed up to room temperature, kept room temperature reaction 1 hour; Icy salt solution is cooled to below 0 ℃, slowly feeds 1 liter of dry ammonia, and room temperature reaction is 24 hours then; Steaming desolventizes, and with ethyl acetate petroleum ether mixed solvent recrystallization, obtains white product 0.5 gram, yield 33.3%.Content 98.2% (HPLC area normalization method), fusing point 79-81 ℃.
The hydrocarbon element determination analysis of compound (Flash EA-1112, ThermoFingnigan) result: C 60.311%, H 4.301%; Molecular formula (C
14H
12N
2OFCl) calculate: C 60.323%, and H 4.309%.The compound hydrogen nuclear magnetic resonance detects (CDCl
3, 400MHz) result: 12 proton signals are arranged.ESI-HRMS：[M+H]
+278.5。Data shows that this compound is G-10.
[embodiment 11] 4-fluoro-2-[N-(3-chloro-2-aminomethyl phenyl) amino] preparation of phenylformic acid acyl ethamine (G-11)
50 milliliters of there-necked flasks that have induction stirring, thermometer, return line add 1.5 gram (5.4 mmole) G-3,13 milliliters of anhydrous tetrahydro furans, and icy salt solution is cooled to-5 ℃, and dripping thionyl chloride 0.9 gram keeps temperature less than-2 ℃, reacts 0.5 hour; Slowly be warmed up to room temperature, kept room temperature reaction 1 hour; Icy salt solution is cooled to below 0 ℃, slowly adds 2.5 milliliters in ethamine, and room temperature reaction is 24 hours then; Steaming desolventizes, and with ethyl acetate petroleum ether mixed solvent recrystallization, obtains off-white color product 0.9 gram, yield 48.3%.Content 99.0% (HPLC area normalization method), fusing point 88-89 ℃.
The hydrocarbon element determination analysis of compound (Flash EA-1112, ThermoFingnigan) result: C 62.531%, H 5.173%; Molecular formula (C
16H
16N
2OFCl) calculate: C 62.643%, and H 5.220%.The compound hydrogen nuclear magnetic resonance detects (CDCl
3, 400MHz) result: 16 proton signals are arranged.ESI-HRMS：[M+H]
+306.5。Data shows that this compound is G-11.
[embodiment 12] 4-fluoro-2-[N-(3-chloro-2-aminomethyl phenyl) amino] preparation of phenylformic acid acyl Tri N-Propyl Amine (G-12)
50 milliliters of there-necked flasks that have induction stirring, thermometer, return line add 1.5 gram (5.4 mmole) G-3,13 milliliters of anhydrous tetrahydro furans, and icy salt solution is cooled to-5 ℃, and dripping thionyl chloride 0.9 gram keeps temperature less than-2 ℃, reacts 0.5 hour; Slowly be warmed up to room temperature, kept room temperature reaction 1 hour; Icy salt solution is cooled to below 0 ℃, drips 3 milliliters of Tri N-Propyl Amines, and room temperature reaction is 24 hours then; Steaming desolventizes, and with ethyl acetate petroleum ether mixed solvent recrystallization, obtains white crystals product 1 gram, yield 57.8%.Content 99.2% (HPLC area normalization method), fusing point 81-82 ℃.
The hydrocarbon element determination analysis of compound (Flash EA-1112, ThermoFingnigan) result: C 63.657%, H 5.622%; Molecular formula (C
17H
18N
2OFCl) calculate: C 63.651%, and H 5.616%.IRvmax(KBr)/cm
-1：3262，3075，2966，1633，1588，1568，1519，1428，1267，1154，1015，855，782，754，696，589，553；
1H?NMR(CDCl
3，400MHz)δ：9.61(s，1H，-CO-N
H-)，7.41-7.37(m，1H，Ar)，7.21-7.09(m，3H，Ar)，6.56(dd，J
1＝2.4Hz，J
2＝7.6Hz，1H，Ar)，6.39(dt，J
1＝2.4Hz，J
2＝7.6Hz，1H，Ar)，6.19(s，1H，Ar-N
H-Ar)，3.38(q，J＝6.8Hz，2H，-NH-C
H 2 -)，2.34(s，3H，Ar-C
H 3 )，1.64(m，2H，J＝7.4Hz，-CH
2-C
H 2 -CH
3)，0.99(t，3H，J＝7.6Hz，-CH
2-C
H 3 )；
13C?NMR(CDCl
3，100MHz)δ：169.0，165.4(J
C，F＝248.9Hz)，148.8(J
C，F＝11.5Hz)，140.3，135.6，130.7，129.3(J
C，F＝11.2Hz)，129.20，126.9，125.3，121.6，113.4(J
C，F＝2.2Hz)，104.4(J
C，F＝22.6Hz)，100.8(J
C，F＝26.0Hz)，41.5，22.8，14.9，11.4；EIMS?m/z(％)：320(M
+，61)，261(83)，247(2)，232(12)，226(100)，198(27)，170(6)，77(4)。ESI-HRMS：[M+H]
+320.5。Data shows that this compound is G-12.
[embodiment 13] 4-fluoro-2-[N-(3-chloro-2-aminomethyl phenyl) amino] preparation of phenylformic acid acyl n-octyl amine (G-13)
50 milliliters of there-necked flasks that have induction stirring, thermometer, return line add 1.5 gram (5.4 mmole) G-3,13 milliliters of anhydrous tetrahydro furans, and icy salt solution is cooled to-5 ℃, and dripping thionyl chloride 0.9 gram keeps temperature less than-2 ℃, reacts 0.5 hour; Slowly be warmed up to room temperature, keep reaction 1 hour; Icy salt solution is cooled to below 0 ℃, drips 6 milliliters of n-octyl amine, and room temperature reaction is 24 hours then; Steaming desolventizes, and with ethyl acetate petroleum ether mixed solvent recrystallization, obtains white crystals product 0.8 gram, yield 38.0%.Content 98.2% (HPLC area normalization method), fusing point 91-92 ℃.
The hydrocarbon element determination analysis of compound (Flash EA-1112, ThermoFingnigan) result: C 67.681%, H 7.021%; Molecular formula (C
22H
28N
2OFCl) calculate: C 67.606%, and H 7.170%.The compound hydrogen nuclear magnetic resonance detects (CDCl
3, 400MHz) result: 28 proton signals are arranged.ESI-HRMS：[M+H]
+390。Data shows that this compound is G-13.
[embodiment 14] 4-fluoro-2-[N-(3-chloro-2-aminomethyl phenyl) amino] preparation of phenylformic acid acyl benzene methanamine (G-14)
50 milliliters of there-necked flasks that have induction stirring, thermometer, return line add 1.5 gram (5.4 mmole) G-3,13 milliliters of anhydrous tetrahydro furans, and icy salt solution is cooled to-5 ℃, and dripping thionyl chloride 0.9 gram keeps temperature less than-2 ℃, reacts 0.5 hour; Slowly be warmed up to room temperature, kept room temperature reaction 1 hour; Icy salt solution is cooled to below 0 ℃, adds benzene methanamine 3 grams, and room temperature reaction is 24 hours then; Steaming desolventizes, and with ethyl acetate petroleum ether mixed solvent recrystallization, obtains off-white color product 0.7 gram, yield 35.3%.Content 96.7% (HPLC area normalization method), fusing point 101-103 ℃.
The hydrocarbon element determination analysis of compound (Flash EA-1112, ThermoFingnigan) result: C 68.326%, H 4.763%; Molecular formula (C
21H
18N
2OFCl) calculate: C 68.385%, and H 4.885%.The compound hydrogen nuclear magnetic resonance detects (CDCl
3, 400MHz) result: 18 proton signals are arranged.ESI-HRMS：[M+H]
+368.5。Data shows that this compound is G-14.
[embodiment 15] 4-fluoro-2-[N-(3-chloro-2-aminomethyl phenyl) amino] preparation of phenylformic acid anilide (G-15)
50 milliliters of there-necked flasks that have induction stirring, thermometer, return line add 1.5 gram (5.4 mmole) G-3,13 milliliters of anhydrous tetrahydro furans, and icy salt solution is cooled to-5 ℃, and dripping thionyl chloride 0.9 gram keeps temperature less than-2 ℃, reacts 0.5 hour; Slowly be warmed up to room temperature, kept room temperature reaction 1 hour; Icy salt solution is cooled to below 0 ℃, adds aniline 3 grams, and room temperature reaction is 24 hours then; Steaming desolventizes, and with ethyl acetate petroleum ether mixed solvent recrystallization, obtains white product 0.8 gram, yield 41.9%.Content 97.6% (HPLC area normalization method), fusing point 98-101 ℃.
The hydrocarbon element determination analysis of compound (Flash EA-1112, ThermoFingnigan) result: C 67.678%, H 4.456%; Molecular formula (C
20H
16N
2OFCl) calculate: C 67.701%, and H 4.513%.The compound hydrogen nuclear magnetic resonance detects (CDCl
3, 400MHz) result: 16 proton signals are arranged.ESI-HRMS：[M+H]
+354。Data shows that this compound is G-15.
[embodiment 16] 4-fluoro-2-[N-(3-chloro-2-aminomethyl phenyl) amino] preparation of phenylformic acid acyl benzene Vasoxyl (G-16)
50 milliliters of there-necked flasks that have induction stirring, thermometer, return line add 1.5 gram (5.4 mmole) G-3,13 milliliters of anhydrous tetrahydro furans, and icy salt solution is cooled to-5 ℃, and dripping thionyl chloride 0.9 gram keeps temperature less than-2 ℃, reacts 0.5 hour; Slowly be warmed up to room temperature, keep reaction 1 hour; Icy salt solution is cooled to below 0 ℃, adds benzene Vasoxyl 3.5 grams, and room temperature reaction is 24 hours then; Steaming desolventizes, and with ethyl acetate petroleum ether mixed solvent recrystallization, obtains white product 0.7 gram, yield 33.7%.Content 96.4% (HPLC area normalization method), fusing point 198-200 ℃.
The hydrocarbon element determination analysis of compound (Flash EA-1112, ThermoFingnigan) result: C 65.479%, H 4.512%; Molecular formula (C
21H
18N
2O
2FCl) calculate: C 65.540%, and H 4.681%.The compound hydrogen nuclear magnetic resonance detects (CDCl
3, 400MHz) result: 18 proton signals are arranged.ESI-HRMS：[M+H]
+384。Data shows that this compound is G-16.
[embodiment 17] 4-fluoro-2-[N-(3-chloro-2-aminomethyl phenyl) amino] preparation of phenylformic acid acyl diethanolamine (G-17)
50 milliliters of there-necked flasks that have induction stirring, thermometer, return line add 1.5 gram (5.4 mmole) G-3,13 milliliters of anhydrous tetrahydro furans, and icy salt solution is cooled to-5 ℃, and dripping thionyl chloride 0.9 gram keeps temperature less than-2 ℃, reacts 0.5 hour; Slowly be warmed up to room temperature, keep reaction 1 hour; Icy salt solution is cooled to below 0 ℃, drips 5 milliliters of diethanolamine, and room temperature reaction is 24 hours then; Steaming desolventizes, and with ethyl acetate petroleum ether mixed solvent recrystallization, obtains white crystals product 1 gram, yield 50.5%.Content 98.9% (HPLC area normalization method), fusing point 78-80 ℃.
The hydrocarbon element determination analysis of compound (Flash EA-1112, ThermoFingnigan) result: C 58.879%, H 5.436%; Molecular formula (C
18H
20N
2O
3FCl) calculate: C 58.936%, and H 5.457%.The compound hydrogen nuclear magnetic resonance detects (CDCl
3, 400MHz) result: 20 proton signals are arranged.ESI-HRMS：[M+H]
+366.5。Data shows that this compound is G-17.
[embodiment 18] 4-nitro-2-[N-(3-chloro-2-aminomethyl phenyl) amino] preparation of benzoic preparation (G-18)
100 milliliters of there-necked flasks that have electronic stirring, thermometer, return line add 10.2 gram (33 mmole) 4-nitro o-bromobenzoic acids, and 50 milliliters of propyl carbinols and 10 gram Anhydrous potassium carbonates stir, are heated to 60 ℃ of insulations 30 minutes, then, are cooled to 40 ℃, logical N
2Protection adds 1 gram copper powder, 10 gram 3-chloro-2-aminotoluenes, heating, 90 ℃ of insulation reaction 24 hours are cooled to add under 60 ℃ of violent stirring 35 milliliters in cold water, vacuum filtration, filtrate are poured in 100 milliliters the beaker, are cooled to 10 ℃, the concentrated hydrochloric acid of dropping 15%, pH value is separated out class khaki color solid, suction filtration to 1-2, cold water washing, the filter cake oven dry; 25 milliliters of ethanol heating for dissolving, gac 0.2 gram, heat filter; Crystallization is separated out in cooling, and the suction filtration oven dry obtains bright orange styloid 5.4 grams, yield 53.4%.Content 99.0% (HPLC area normalization method), fusing point 260-263 ℃.
The hydrocarbon element determination analysis of compound (Flash EA-1112, ThermoFingnigan) result: C 54.801%, H 3.575%; Molecular formula (C
14H
11N
2O
4Cl) calculate: C 54.812%, and H 3.589%.The compound hydrogen nuclear magnetic resonance detects (CDCl
3, 400MHz) result: 11 proton signals are arranged.ESI-HRMS：[M+H]
+306.5。Data shows that this compound is G-18.
[embodiment 19] 4-nitro-2-[N-(3-chloro-2-aminomethyl phenyl) amino] preparation of ethyl benzoate (G-19)
50 milliliters of there-necked flasks that have induction stirring, thermometer, return line add 1.7 gram (5.5 mmole) G-18 (sample of embodiment 18 methods preparation), and 15 milliliters of ethanol drip 2 milliliters in 98% sulfuric acid, heating reflux reaction 12 hours; Steaming desolventizes, and adds 10 milliliters of ethanol, and crystal is separated out in cooling; Suction filtration, cold water washing, filter cake oven dry; Add 10 milliliters of ethanol, heating for dissolving adds gac 0.5 gram, filtered while hot; Filtrate is cooled off with frozen water, and the suction filtration oven dry obtains yellow crystals 0.8 gram, yield 43.5%.HPLC 97.4% (HPLC area normalization method), fusing point 87-90 ℃.
The hydrocarbon element determination analysis of compound (Flash EA-1112, ThermoFingnigan) result: C 57.312%, H 4.387%; Molecular formula (C
16H
15N
2O
4Cl) calculate: C 57.399%, and H 4.484%.The compound hydrogen nuclear magnetic resonance detects (CDCl
3, 400MHz) result: 15 proton signals are arranged.ESI-HRMS：[M+H]
+334。Data shows that this compound is G-19.
[embodiment 20] 4-nitro-2-[N-(3-chloro-2-aminomethyl phenyl) amino] preparation of preparation (G-20) of phenylformic acid acyl Tri N-Propyl Amine
50 milliliters of there-necked flasks that have induction stirring, thermometer, return line add 1.7 gram (5.5 mmole) G-18,13 milliliters of anhydrous tetrahydro furans, and icy salt solution is cooled to-5 ℃, and dripping thionyl chloride 0.9 gram keeps temperature less than-2 ℃, reacts 0.5 hour; Slowly be warmed up to room temperature, keep reaction 1 hour; Icy salt solution is cooled to below 0 ℃, drips 3 milliliters of Tri N-Propyl Amines, and room temperature reaction is 24 hours then; Steaming desolventizes, and with ethyl acetate petroleum ether mixed solvent recrystallization, obtains white crystals product 1.1 grams, yield 57.6%.Content 99.0% (HPLC area normalization method), fusing point 132-136 ℃.
The hydrocarbon element determination analysis of compound (Flash EA-1112, ThermoFingnigan) result: C 58.702%, H 5.124%; Molecular formula (C
17H
18N
3O
3Cl) calculate: C 58.705%, and H 5.180%.IRvmax(KBr)/cm
-1：3343，3079，2965，1640，1588，1571，1525，1351，1288，1018，737，577；
1H?NMR(CDCl
3，400MHz)δ：9.48(s，1H，-CO-N
H-)，7.67(d，1H，J＝2.4Hz，Ar)，7.56(d，1H，J＝8.0Hz，Ar)，7.49(dd，J
1＝2.4Hz，J
2＝8.4Hz，1H，Ar)，7.28-7.15(m，3H，Ar)，6.41(s，1H，Ar-N
H-Ar)，3.44(q，J＝6.8Hz，2H，-NH-C
H 2 -)，2.34(s，3H，Ar-C
H 3 )，1.69(m，2H，J＝7.4Hz，-CH
2-C
H 2 -CH
3)，1.02(t，3H，J＝7.6Hz，-CH
2-C
H 3 )；
13C?NMR?(CDCl
3，100MHz)δ：168.0，150.3，147.3，139.5，135.9，130.9，128.3，127.2，126.0，121.8，121.6，111.2，108.7，41.8，22.7，14.9，11.4；EIMS?m/z(％)：347(M
+，100)，288(60)，253(91)，242(43)，214(15)，207(33)，179(25)，152(14)。ESI-HRMS：[M+H]
+347.5。Data shows that this compound is G-20.
[embodiment 21] 6-chloro-2-[N-(3-chloro-2-aminomethyl phenyl) amino] preparation of benzoic preparation (G-21)
100 milliliters of there-necked flasks that have electronic stirring, thermometer, return line add 4.7 gram (20 mmole) 6-chlorine o-bromobenzoic acids, and 25 milliliters of propyl carbinols and 5 gram Anhydrous potassium carbonates stir, are heated to 60 ℃ of insulations 30 minutes, then, are cooled to 40 ℃, logical N
2Protection adds 0.5 gram copper powder, 5 gram 3-chloro-2-aminotoluenes, heating, 90 ℃ of insulation reaction 24 hours are cooled to add under 60 ℃ of violent stirring 20 milliliters in cold water, vacuum filtration, filtrate are poured in 100 milliliters the beaker, are cooled to 10 ℃, the concentrated hydrochloric acid of dropping 15%, pH value is separated out off-white color look solid, suction filtration to 1-2, cold water washing, the filter cake oven dry; 15 milliliters of ethanol heating for dissolving, gac 0.2 gram, heat filter; Crystallization is separated out in cooling, and the suction filtration oven dry obtains bright orange styloid 3.5 grams, yield 59.1%.Content 97.5% (HPLC area normalization method), fusing point 175-177 ℃.
The hydrocarbon element determination analysis of compound (Flash EA-1112, ThermoFingnigan) result: C 56.689%, H 3.705%; Molecular formula (C
14H
11NO
2Cl
2) calculating: C 56.757%, and H 3.716%.The compound hydrogen nuclear magnetic resonance detects (CDCl
3, 400MHz) result: 11 proton signals are arranged.ESI-HRMS：[M+H]
+296。Data shows that this compound is G-21.
[embodiment 22] 2-[N-(3-chloro-2-aminomethyl phenyl) amino] preparation of ethyl benzoate (G-22)
50 milliliters of there-necked flasks that have induction stirring, thermometer, return line add 1.4 those acid of gram (5.4 mmole) holder phenol, and 7 milliliters of ethanol drip 1 milliliter in 98% sulfuric acid, heating reflux reaction 12 hours; Steaming desolventizes, and adds 5 milliliters of ethanol, and crystal is separated out in cooling; Suction filtration, cold water washing, the filter cake oven dry; Add 8 milliliters of ethanol, heating for dissolving adds gac 0.2 gram, filtered while hot; Filtrate is cooled off with frozen water, and the suction filtration oven dry obtains white needle-like crystals 1 gram, yield 64.0%.HPLC 99.5% (HPLC area normalization method), fusing point 64-66 ℃.
The hydrocarbon element determination analysis of compound (Flash EA-1112, ThermoFingnigan) result: C 66.232%, H 5.509%; Molecular formula (C
16H
16NO
2Cl) calculate: C 66.321%, and H 5.527%.The compound hydrogen nuclear magnetic resonance detects (CDCl
3, 400MHz) result: 16 proton signals are arranged.ESI-HRMS：[M+H]
+289。Data shows that this compound is G-22.
[embodiment 23] 2-[N-(3-chloro-2-aminomethyl phenyl) amino] preparation of phenylformic acid acyl Tri N-Propyl Amine (G-23)
50 milliliters of there-necked flasks that have induction stirring, thermometer, return line add 5.4 those acid of gram (20 mmole) holder phenol, 13 milliliters of anhydrous tetrahydro furans, and icy salt solution is cooled to-5 ℃, and dripping thionyl chloride 0.9 gram keeps temperature less than-2 ℃, reacts 0.5 hour; Slowly be warmed up to room temperature, keep reaction 1 hour; Icy salt solution is cooled to below 0 ℃, drips 10 milliliters of Tri N-Propyl Amines, and room temperature reaction is 24 hours then; Steaming desolventizes, and with ethyl acetate petroleum ether mixed solvent recrystallization, obtains white crystals product 4 grams, yield 69.1%.Content 99.2% (HPLC area normalization method), fusing point 81-82 ℃.
The hydrocarbon element determination analysis of compound (Flash EA-1112, ThermoFingnigan) result: C 67.422%, H 6.267%; Molecular formula (C
17H
19N
2OCl) calculate: C 67.438%, and H 6.281%.IR?vmax(KBr)/cm
-1：3262，3074，2956，1625，1583，1566，1514，1447，1266，1012，768，747，697，519；
1H?NMR(CDCl
3，400MHz)δ：9.32(s，1H，-CO-N
H-)，7.43-7.40(m，1H，Ar)，7.26-7.22(m，2H，Ar)，7.12-7.04(m，2H，Ar)，7.01(d，J＝8.4Hz，1H，Ar)，6.74(t，J＝7.4Hz，1H，Ar)，6.24(s，1H，Ar-N
H-Ar)，3.39(q，J＝6.8Hz，2H，-NH-C
H 2 -)，2.35(s，3H，Ar-C
H 3 )，1.65(m，2H，J＝7.4Hz，-CH
2-C
H 2 -CH
3)，0.99(t，3H，J＝7.6Hz，-CH
2-C
H 3 )；
13C?NMR(CDCl
3，100MHz)δ：169.5，145.9，141.3，135.4，132.1，129.6，127.3，126.6，124.1，120.1，118.0，117.7，115.2，41.5，22.8，14.8，11.4；EIMS?m/z(％)：302(M
+，55)，243(66)，229(3)，214(14)，208(100)，180(28)，152(8)，77(10)。ESI-HRMS：[M+H]
+302.5。Data shows that this compound is G23.
[embodiment 24] antitumour activity vitro test
Embodiment new compound G1-G23 (molecular structure of compounds sees Table 1) is carried out the biological activity test of people source growth of cancer cells such as anti-people's lung cancer, liver cancer, cancer of the stomach, squamous cell carcinoma, prostate cancer, cervical cancer, ovarian cancer, mammary cancer, colorectal carcinoma, carcinoma of the pancreas, leukemia and glioma.
Testing method: the cell seeding that will be in logarithmic phase is in 96 orifice plates, tetrazolium reduction method (mtt assay).
Cell strain (source: Shanghai cell institute): people's lung cancer (NCI-460), liver cancer (SMMC-7721, BEL-7402), cancer of the stomach BGC-823, squamous cell carcinoma KB, prostate cancer PC-3, cervical cancer HELA, ovarian cancer HO-8910, mammary cancer BT549, colorectal carcinoma Caco-2, carcinoma of the pancreas ASPC-1, PANC-1, leukemia HL-60, K562 and glioma U251.
Action time: 48 hours.
Experimental result sees Table 2.The result shows that the anti tumor activity in vitro of new compound obviously strengthens, particularly: G12, G17, G20 and G23 etc.
Table 1 compound structure
[embodiment 25] internal metabolism kinetic test
With the tolfenamic acid is contrast, and embodiment new compound G12, G20 and G23 are carried out pharmacokinetic studies in the body.
Get 16 of rats (Sprague-Dawley), male and female half and half, body weight 220～250g.Be divided into 4 groups at random, 4 every group.G12, G20, G23 and the tolfenamic acid of rat difference tail vein injection 25mg/kg after the grouping (aqueous solution, 5mg/ml, 0.5ml/100g).Respectively at after the administration 0.25,0.5,1,1.5,2,4,6,8,12 and the 24h blood sampling, after blood sample is handled, measure the amount of compound in the blood sample with high performance liquid chromatography (HPLC).Carry out match according to two Room intravenous injection models, obtain the highest Plasma Concentration (after the intravenous injection 5 minutes, C
Max) and eliminate transformation period (t
1/2).
As known from Table 3, compare with tolfenamic acid, the elimination transformation period of new compound G12, G20 and G23 obviously prolongs (1.5-2.5 doubly), shows that new compound prolongs action time in vivo; Plasma Concentration significantly reduces (1/10-1/20), shows that new compound has gone (in conjunction with eliminating the transformation period) in being distributed to organ very soon and organizing.This is very beneficial for new compound and brings into play active function in vivo.
The highest Plasma Concentration (the C of table 3G12, G20, G23, tolfenamic acid
Max, mean value) and eliminate transformation period (t
1/2, mean value)
| Compound | C max(μg/ml) | t 1/2 |
| G12 | 14.523 | 2.765 |
| G20 | 7.922 | 2.386 |
| G23 | 19.931 | 4.18 |
| Tolfenamic acid | 162.28 | 1.654 |
[embodiment 26] acute toxic test
The ICR mouse of body weight 20～25g, 1 group 10, male and female half and half.Through vein give G12, the G20 of 100mg/kg and G23 (aqueous solution, 10mg/ml, 0.1ml/10g).Observed 7 days continuously, write down the toxic reaction situation of animal and the distribution of dead animal day by day.
Experiment finds no laboratory animal death after finishing.The result shows, compound G12, G20 and G23 intravenously administrable, medium lethal dose (LD
50) greater than 100mg/kg.
[embodiment 27] anti-tumor in vivo active testing
Get 50 of the female nude mices (BALB/c) in age in 4-5 week; Peel off tumor bearing nude mice tumour (strain of HO-8910 knurl), be cut into 1mm
3About the tubercle piece, be inoculated in the right oxter of nude mice with puncture needle; Observe the tumor growth state, when tumor growth to 100-300mm
3The time, animal is divided into 5 groups at random by gross tumor volume, be respectively solvent control group (control), G12 group, G20 group, G23 group and tolfenamic acid group (TA); Give control solvent through the abdominal cavity, (aqueous solution, 5mg/ml 0.1ml/10g), give 5 days weekly continuously, stop 2 days, give for 3 weeks continuously for the G12 of 50mg/kg, G20, G23 and TA; Every 2-4 day weighs 1 time, adopts vernier caliper measurement gross tumor volume size.
The result shows that the toxicity of G12, G20 and G23 is less, does not influence the increase (normal growth) of nude mice body weight.After the administration 4 days, compound G12, G20, G23 and TA just showed certain anti-tumor activity, particularly G20 and show notable antitumor activity (as shown in drawings).
Pain relieving test in [embodiment 28] body
Test by method of acetic acid.The Male Kunming strain mice of body weight 20～25g, 1 group 10.Give through the abdominal cavity G12, the G20 of 50mg/kg and G23 (aqueous solution, 5mg/ml, 0.1ml/10g).Behind the 60min, the abdominal cavity injects 0.6% acetic acid 0.1ml/10g, and the 5-20min interocclusal record is turned round body (stretching, worithing syndromo) number of times and the number of animals of turning round body afterwards.
As known from Table 4, the new compound of test all has the pain effect that acetic acid causes that suppresses.
Table 4:G12, G20 and G23 mouse writhing method test result
Test by hot plate method.The ICR female mice of body weight 18-25g places mouse on 55 ± 1 ℃ the permanent hot plate, and each 1 is placed on the hot plate, and mouse is from being placed on the hot plate to the threshold of pain of metapedes required time (second) as this mouse occurring licking.Select threshold value and include experiment in interior mouse, one group 10 at 5-30s.Give through the abdominal cavity G12, the G20 of 50mg/kg and G23 (aqueous solution, 5mg/ml, 0.1ml/10g).After the administration 0.5,1 and 1.5h after measure the threshold of pain of each animal.
As known from Table 5, the new compound of test all has the pain effect that heat causes that suppresses.
Table 5:G12, G20 and G23 mouse hot plate method test result
* represent to compare P＜0.05 with control group.
Claims (8)
1. adjacent anilino benzoic acid derivative or its pharmacy acceptable salt shown in general formula I:
I
In the formula, R
1Be hydrogen, nitro or amino; R
2Be hydrogen, nitro or halogen; R
3Be hydrogen or halogen; R
4Be amino, C
1-C
10Alkane secondary amine, two C
1-C
5Alkane tertiary amine groups, benzene secondary amine, benzene C
1-C
3Alcoxyl secondary amine, hydroxyl, C
1-C
10Alkoxyl group, phenoxy group, benzene C
1-C
3Alkoxyl group; If R
4Be hydroxyl, R then
1, R
2And R
3Be not hydrogen simultaneously.
2. adjacent anilino benzoic acid derivative according to claim 1 or its pharmacy acceptable salt, wherein, R
1Be hydrogen, nitro or amino; R
2Be hydrogen, nitro, fluorine or chlorine; R
3Be hydrogen or chlorine; R
4Be amino, C
1-C
10Alkane secondary amine, two C
1-C
5Alkane tertiary amine groups, benzene secondary amine, benzene C
1-C
3Alcoxyl secondary amine, hydroxyl, C
1-C
5Alkoxyl group, phenoxy group, benzene C
1-C
3Alkoxyl group; If R
4Be hydroxyl, R then
1, R
2And R
3Be not hydrogen simultaneously.
3. adjacent anilino benzoic acid derivative according to claim 2 or its pharmacy acceptable salt, wherein, R
1Be hydrogen; R
2Be nitro or fluorine; R
3Be chlorine; R
4Be amino, C
1-C
5Alkane secondary amine, two C
1-C
5Alkane tertiary amine groups, benzene secondary amine, benzene C
1-C
3Alcoxyl secondary amine, hydroxyl, C
1-C
5Alkoxyl group, phenoxy group, benzene C
1-C
3Alkoxyl group.
4. adjacent anilino benzoic acid derivative according to claim 3 or its pharmacy acceptable salt, it is selected from:
4-fluoro-2-[(3-chloro-2-aminomethyl phenyl)-amino] phenylformic acid,
4-fluoro-2-[(3-chloro-2-aminomethyl phenyl)-amino] methyl benzoate,
4-fluoro-2-[(3-chloro-2-aminomethyl phenyl)-amino] ethyl benzoate,
4-fluoro-2-[(3-chloro-2-aminomethyl phenyl)-amino] amyl benzoate,
4-fluoro-2-[(3-chloro-2-aminomethyl phenyl)-amino] the phenylamino benzoic acid methyl esters,
4-fluoro-2-[(3-chloro-2-aminomethyl phenyl)-amino] phenol benzoate,
4-fluoro-2-[(3-chloro-2-aminomethyl phenyl)-amino] the phenylformic acid direactive glyceride,
4-fluoro-2-[(3-chloro-2-aminomethyl phenyl)-amino] benzoic amide,
4-fluoro-2-[(3-chloro-2-aminomethyl phenyl)-amino] phenylformic acid acyl ethamine,
4-fluoro-2-[(3-chloro-2-aminomethyl phenyl)-amino] phenylformic acid acyl Tri N-Propyl Amine,
4-fluoro-2-[(3-chloro-2-aminomethyl phenyl)-amino] phenylformic acid acyl n-octyl amine,
4-fluoro-2-[(3-chloro-2-aminomethyl phenyl)-amino] phenylformic acid acyl benzene methanamine,
4-fluoro-2-[(3-chloro-2-aminomethyl phenyl)-amino] the phenylformic acid anilide,
4-fluoro-2-[(3-chloro-2-aminomethyl phenyl)-amino] phenylformic acid acyl benzene Vasoxyl,
4-fluoro-2-[(3-chloro-2-aminomethyl phenyl)-amino] phenylformic acid acyl diethanolamine,
4-nitro-2-[(3-chloro-2-aminomethyl phenyl)-amino] ethyl benzoate,
4-nitro-2-[(3-chloro-2-aminomethyl phenyl)-amino] phenylformic acid acyl Tri N-Propyl Amine,
6-chloro-2-[(3-chloro-2-aminomethyl phenyl)-amino] phenylformic acid,
2-[(3-chloro-2-aminomethyl phenyl)-amino] ethyl benzoate,
2-[(3-chloro-2-aminomethyl phenyl)-and amino] phenylformic acid acyl Tri N-Propyl Amine.
5. prepare the method for adjacent anilino benzoic acid derivative as claimed in claim 1 or its pharmacy acceptable salt, it may further comprise the steps:
A). with formula II compound
II
With the reaction of formula III compound,
III
Get formula IV compound;
B). with formula IV compound
IV
With the reaction of formula V compound,
HR
4
V
Get formula I compound; Wherein, R
1, R
2, R
3And R
4As defined in claim 1.
6. prevent and/or treat the medicine of tumor disease or the application in the functional food according to each described adjacent anilino benzoic acid derivative of claim 1-4 or its pharmacy acceptable salt in preparation.
7. tumor disease according to claim 6 is meant lung cancer, liver cancer, cancer of the stomach, squamous cell carcinoma, prostate cancer, cervical cancer, ovarian cancer, mammary cancer, colorectal carcinoma, carcinoma of the pancreas, leukemia or glioma.
8. prevent and/or treat the medicine of body inflammatory, pain disease or the application in the functional food according to each described adjacent anilino benzoic acid derivative of claim 1-4 or its pharmacy acceptable salt in preparation.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN200910101004.8A CN101985428B (en) | 2009-07-29 | 2009-07-29 | O-anilino benzoic acid derivatives or pharmaceutically acceptable salts thereof as well as preparation method and application thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN200910101004.8A CN101985428B (en) | 2009-07-29 | 2009-07-29 | O-anilino benzoic acid derivatives or pharmaceutically acceptable salts thereof as well as preparation method and application thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN101985428A true CN101985428A (en) | 2011-03-16 |
| CN101985428B CN101985428B (en) | 2014-02-12 |
Family
ID=43709830
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN200910101004.8A Active CN101985428B (en) | 2009-07-29 | 2009-07-29 | O-anilino benzoic acid derivatives or pharmaceutically acceptable salts thereof as well as preparation method and application thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN101985428B (en) |
Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2016530317A (en) * | 2013-09-11 | 2016-09-29 | ジ・アドミニストレーターズ・オブ・ザ・チューレーン・エデュケーショナル・ファンド | Novel anthranilamides and their use |
| CN109828116A (en) * | 2019-01-08 | 2019-05-31 | 广东省人民医院(广东省医学科学院) | Application of the ESE-1 and mRNA in the diagnostic kit or drug for screening or preparing hepatopathy |
| WO2019111792A1 (en) * | 2017-12-05 | 2019-06-13 | 国立研究開発法人産業技術総合研究所 | GTP SENSOR PROTEIN PI5P4Kβ INHIBITOR |
| CN111346082A (en) * | 2020-03-18 | 2020-06-30 | 上海应用技术大学 | Application of benzoic acid compound in preparation of medicine for treating acute leukemia |
| CN111909053A (en) * | 2020-08-06 | 2020-11-10 | 湖北省生物农药工程研究中心 | Diarylamine unit-based amide derivative and preparation method and application thereof |
| CN112745237A (en) * | 2019-10-29 | 2021-05-04 | 中国科学院上海药物研究所 | 2-arylamine compound and preparation method and application thereof |
| CN114195665A (en) * | 2021-12-14 | 2022-03-18 | 武汉世吉药业有限公司 | Neutralization and acidification process and equipment for high-purity NCAA |
| CN115108931A (en) * | 2022-04-02 | 2022-09-27 | 南华大学附属第一医院 | Tofenamic acid derivative and preparation and application thereof |
Family Cites Families (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6310060B1 (en) * | 1998-06-24 | 2001-10-30 | Warner-Lambert Company | 2-(4-bromo or 4-iodo phenylamino) benzoic acid derivatives and their use as MEK inhibitors |
| PL360699A1 (en) * | 2000-08-25 | 2004-09-20 | Warner-Lambert Company Llc. | Process for making n-aryl-anthranilic acids and their derivatives |
| JP4842053B2 (en) * | 2006-08-29 | 2011-12-21 | 芦森工業株式会社 | Manufacturing method of pipe lining material |
| WO2009037707A2 (en) * | 2007-09-20 | 2009-03-26 | Ramot At Tel Aviv University Ltd. | N-phenyl anthranilic acid derivatives and uses thereof |
| KR100892591B1 (en) * | 2007-11-19 | 2009-04-08 | 한국과학기술연구원 | Novel anthranilic acid derivatives and chloride channel blocking agent containing the same |
-
2009
- 2009-07-29 CN CN200910101004.8A patent/CN101985428B/en active Active
Cited By (13)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US11465978B2 (en) | 2013-09-11 | 2022-10-11 | The Administrators Of The Tulane Educational Fund | Anthranilic amides and the use thereof |
| EP3043790A4 (en) * | 2013-09-11 | 2017-08-30 | The Administrators of the Tulane Educational Fund | Novel anthranilic amides and the use thereof |
| AU2014318748B2 (en) * | 2013-09-11 | 2019-02-28 | Duquesne University Of The Holy Ghost | Novel anthranilic amides and the use thereof |
| JP2016530317A (en) * | 2013-09-11 | 2016-09-29 | ジ・アドミニストレーターズ・オブ・ザ・チューレーン・エデュケーショナル・ファンド | Novel anthranilamides and their use |
| WO2019111792A1 (en) * | 2017-12-05 | 2019-06-13 | 国立研究開発法人産業技術総合研究所 | GTP SENSOR PROTEIN PI5P4Kβ INHIBITOR |
| CN109828116A (en) * | 2019-01-08 | 2019-05-31 | 广东省人民医院(广东省医学科学院) | Application of the ESE-1 and mRNA in the diagnostic kit or drug for screening or preparing hepatopathy |
| CN112745237A (en) * | 2019-10-29 | 2021-05-04 | 中国科学院上海药物研究所 | 2-arylamine compound and preparation method and application thereof |
| CN112745237B (en) * | 2019-10-29 | 2023-06-20 | 中国科学院上海药物研究所 | 2-arylamine compound and preparation method and application thereof |
| CN111346082A (en) * | 2020-03-18 | 2020-06-30 | 上海应用技术大学 | Application of benzoic acid compound in preparation of medicine for treating acute leukemia |
| CN111909053A (en) * | 2020-08-06 | 2020-11-10 | 湖北省生物农药工程研究中心 | Diarylamine unit-based amide derivative and preparation method and application thereof |
| CN111909053B (en) * | 2020-08-06 | 2022-12-06 | 湖北省生物农药工程研究中心 | Diarylamine unit-based amide derivative and preparation method and application thereof |
| CN114195665A (en) * | 2021-12-14 | 2022-03-18 | 武汉世吉药业有限公司 | Neutralization and acidification process and equipment for high-purity NCAA |
| CN115108931A (en) * | 2022-04-02 | 2022-09-27 | 南华大学附属第一医院 | Tofenamic acid derivative and preparation and application thereof |
Also Published As
| Publication number | Publication date |
|---|---|
| CN101985428B (en) | 2014-02-12 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN101985428B (en) | O-anilino benzoic acid derivatives or pharmaceutically acceptable salts thereof as well as preparation method and application thereof | |
| Blum et al. | Metabolism addiction in pancreatic cancer | |
| Cocetta et al. | Links between cancer metabolism and cisplatin resistance | |
| Kim et al. | Crocin suppresses LPS-stimulated expression of inducible nitric oxide synthase by upregulation of heme oxygenase-1 via calcium/calmodulin-dependent protein kinase 4 | |
| Kleszcz et al. | Targeting aberrant cancer metabolism–The role of sirtuins | |
| US20120177749A1 (en) | Family of pfkfb3 inhibitors with anti-neoplastic activities | |
| JP2010531304A (en) | PFKFB3 inhibitor family with antineoplastic activity | |
| JP2006515859A (en) | Inhibitors and uses thereof | |
| Behera et al. | Garcinol and its role in chronic diseases | |
| WO2012140504A1 (en) | Therapeutic compounds | |
| Kumar et al. | Preliminary investigation of cytotoxic potential of 2-quinolone derivatives using in vitro and in vivo (solid tumor and liquid tumor) models of cancer | |
| Vishnupriya et al. | Lipoxygenase (LOX) pathway: a promising target to combat cancer | |
| Cheng et al. | Metformin inhibits the tumor-promoting effect of low-dose resveratrol, and enhances the anti-tumor activity of high-dose resveratrol by increasing its reducibility in triple negative breast cancer | |
| Liu et al. | Use of cucurbitacins for lung cancer research and therapy | |
| Xu et al. | Evidence for the anti-NAFLD effectiveness of chlorogenic acid as a HAT inhibitor using in vivo experiments supported by virtual molecular docking | |
| Li et al. | The organic arsenical-derived thioredoxin and glutathione system inhibitor ACZ2 induces apoptosis and autophagy in gastric cancer via ROS-dependent ER stress | |
| WO2016197463A1 (en) | Formononetin aliphatic ether derivative, and preparation method and pharmaceutical use thereof | |
| Yasui et al. | PPAR ligands for cancer chemoprevention | |
| EP1426047A1 (en) | Anti-tumour pharmaceutical composition comprising N-vanillyl fatty acid amide | |
| Ojike et al. | Synthesis and in vitro bioactivity of polyunsaturated fatty acid conjugates of combretastatin A-4 | |
| CN102441167B (en) | Pharmaceutical composition having apiolin and apiolin derivant as well as histone deaceylase inhibitors and application thereof | |
| CN103965027A (en) | Trifluoromethyl-contained resveratrol derivatives, preparation method and application | |
| Ma et al. | Recent advances of antitumor leading compound Erianin: Mechanisms of action and structural modification | |
| KR20180135249A (en) | New compound having PPARα/γ dual activity and pharmaceutical composition for preventing or treating metabolic disease comprising the same | |
| Patil et al. | Mitochondriotropic derivative of ethyl ferulate, a dietary phenylpropanoid, exhibits enhanced cytotoxicity in cancer cells via mitochondrial superoxide-mediated activation of JNK and AKT signalling |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C53 | Correction of patent for invention or patent application | ||
| CB02 | Change of applicant information |
Address after: 311100 No. 36, Linping Avenue, Yuhang economic and Technological Development Zone, Zhejiang, Hangzhou Applicant after: Hangzhou Minsheng Pharmaceutical Co., Ltd. Address before: 310011, No. 108 Tong Road, Yuhang, Zhejiang, Hangzhou (high tech Zone) Applicant before: Hangzhou Minsheng Pharmaceutical Co., Ltd. |
|
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant | ||
| CP01 | Change in the name or title of a patent holder | ||
| CP01 | Change in the name or title of a patent holder |
Address after: 311100 Linping Avenue, Yuhang economic and Technological Development Zone, Hangzhou, Zhejiang 36 Patentee after: Hangzhou Minsheng Pharmaceutical Co.,Ltd. Address before: 311100 Linping Avenue, Yuhang economic and Technological Development Zone, Hangzhou, Zhejiang 36 Patentee before: HANGZHOU MINSHENG PHARMACEUTICAL Co.,Ltd. |