[go: up one dir, main page]
More Web Proxy on the site http://driver.im/

CN102898363B - Carbamate compound and application thereof in antitumor drug - Google Patents

Carbamate compound and application thereof in antitumor drug Download PDF

Info

Publication number
CN102898363B
CN102898363B CN201110309841.7A CN201110309841A CN102898363B CN 102898363 B CN102898363 B CN 102898363B CN 201110309841 A CN201110309841 A CN 201110309841A CN 102898363 B CN102898363 B CN 102898363B
Authority
CN
China
Prior art keywords
pyridine
oxygen base
methylamino
formyl
chloro
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.)
Expired - Fee Related
Application number
CN201110309841.7A
Other languages
Chinese (zh)
Other versions
CN102898363A (en
Inventor
王勇
张仓
张小猛
唐海涛
张文萍
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Nanjing Sanhome Pharmaceutical Co Ltd
Original Assignee
Nanjing Sanhome Pharmaceutical Co Ltd
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by Nanjing Sanhome Pharmaceutical Co Ltd filed Critical Nanjing Sanhome Pharmaceutical Co Ltd
Priority to CN201110309841.7A priority Critical patent/CN102898363B/en
Publication of CN102898363A publication Critical patent/CN102898363A/en
Application granted granted Critical
Publication of CN102898363B publication Critical patent/CN102898363B/en
Expired - Fee Related legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Landscapes

  • Pyridine Compounds (AREA)

Abstract

The present invention relates to a carbamate compound. The compound can block the formation of tumor new vessels by inhibiting a VEGF receptor and can also inhibit the Raf/MEK/ERK signal conduction path so as to achieve the effect of treatment of cancer. The present invention also relates to a preparation method of the compounds and application thereof in treatment or prevention of tumors, or in preparing a pharmaceutical composition for treating or preventing tumors.

Description

Amino formate compounds and the application in antitumor drug thereof
Technical field
The invention belongs to field of medicaments, relate in particular to carboxylamine lipoid substance and preparation method thereof, also relate to the application of this compounds in treatment cancer simultaneously.
Background technology
Tumour is with abnormal cells hyperplasia out of control and the disease that is diffused as feature.The internal cause of body (hormone, immune state, heritable variation) and external cause (chemistry, optical considerations and virus) may be all carcinogenic factors, along with day by day worsening of environment and continuing to increase of people's operating pressure, cancer becomes one of main killer of mankind's death gradually.According to American Cancer Society's statistics, within 2007, the whole world has 7,600,000 people to die from malignant tumour; New tumor cases 1,230 ten thousand, existing ill example is nearly 4,500 ten thousand, and cancer has become the first cause of the death of developed country, accounts for 21.6% of its death toll.Expect the year two thousand twenty and the year two thousand fifty, global pathogenesis of cancer example will reach respectively 1,652 ten thousand and 2,702 ten thousand, and death toll will reach respectively 1,036 ten thousand and 1,750 ten thousand, replaces cardiovascular diseases, becomes the disease that world's death toll is maximum.。
Along with the further further investigation to tumour molecular mechanism, its unique targeting anti-tumor effect of molecular targeted antitumor drug receives people's concern increasingly, is bringing into play certain effect, and demonstrate good application prospect in preclinical therapy.
The exploitation of the targeted drug that various enzyme inhibitorss, angiogensis inhibitor and the various intracellular signal transduction pathway agent interferings etc. of growth of tumour cell regulation and control are representative has changed the set looks of antitumor drug greatly.Cell signalling is to rely on identification mutually between signaling molecule, activates downstream albumen, realizes signal transduction.In signal transduction pathway, the sudden change of oncogene and cancer suppressor gene and transition are expressed, and irritation cell fast breeding and indeterminate growth or apoptosis suppress, and all will cause tumour to occur.The signal path of tumour cell is interrelated, uses single target spot inhibitor for treating cancer to be difficult to the effect that reaches desirable, and therefore, many target spots kinase inhibitor just demonstrates very large advantage at curative effect and patient's the aspects such as tolerance.Compare with other signal pathway, Raf-Mek-Erk signal pathway merged a large amount of former-oncogene, comprise part, tyrosine kinase receptor, G-albumen, kinases and nuclear factor.Tyrosylprotein kinase, the tumour situation middle and lower reaches Raf-Mek-Erk the signal pathway frequently mediation of constitutive activity signal extremely being caused because of overexpression and sudden change such as EGFR (Mendelsohn J. etc. 2000).For c-Raf, in various tumours, found that the imbalance of this gene is expressed and/or activation (Hoshino R. etc. 1999, McPhillips F. etc. 2001).In Raf/MEK/ERK signal transduction pathway, Raf kinases is being brought into play extremely important effect, and the rise of Raf gene and the overexpression of albumen are present among multiple noumenal tumour.Increasing data demonstration, the Raf/MEK/ERK path of Raf kinases and mediation thereof has remarkable effect in tumour progression and transfer process, and comprises that with many somatomedins EGFR, VEGF and Thr6 PDGF BB (PDGF) etc. are closely related.Growth and transfer that the vascularization of VEGF induction and vascular permeability increase contribute to tumour, suppress and the signal of blocking VEGF R shifts and will contribute to the treatment of cancer.
Xarelto (Nexavar) is that the whole world is first for the kinase whose oral many target drugs of Raf, not only can hinder the signal conduction that Raf/MEK/ERK path mediates, can also suppress multiple receptor tyrosine kinase (RTK), comprising VEGER-2, the VEGER-3 relevant with short new vessel and PDGFR-β, and the c-kit relevant to tumor growth and Flt-3 etc.Cancer in China magazine the 17th phase the 1st volume in 2007 and Cancer Res 64 phases in 2004 have all been described the action principle of Raf kinase inhibitor.As target drug more than, Xarelto has for the extensive tyrosine kinase receptor inhibitor function that comprises VEGFR and PDGFR, but the oral administration biaavailability of Xarelto is lower, thereby has affected absorbing of medicine.
Summary of the invention
The object of the invention is to study and develop a kind of inhibiting carbaniloyl ester compound of protein kinase that has, this compounds can be blocked tumor neovasculature formation by suppressing vegf receptor, also can pass through to suppress Raf/MEK/ERK signal transduction pathway, thereby reach the effect for the treatment of cancer.This compounds can be used as single-activity agent, also can be united and applied in the medicine for the preparation of diseases such as treatment cancer etc. with other activeconstituents, for clinical treatment or prophylaxis of tumours provide new medicament selection.
Meanwhile, the present invention also aims to the new urethane ester compound or its salt that provide a class to there is pharmaceutical use, to find the protein tyrosine kinase inhibitor of many target spots, show more efficiently anti-tumor activity.
In addition, another object of the present invention is by structural modification, improves the oral administration biaavailability of this compounds of Xarelto, thereby effectively improves absorbing of medicine.
In order to realize foregoing invention object, the invention provides compound or pharmaceutically acceptable salt thereof shown in general formula (I):
Figure 2011103098417100002DEST_PATH_IMAGE001
Wherein
Each R 1and R 2identical or different and be independently selected from hydrogen, halogen, alkyl, cycloalkyl, nonaro-maticity heterocyclic radical, OR respectively 3, nitro, NR 4r 5or cyano group;
R 3, R 4and R 5independently be selected from hydrogen, alkyl, cycloalkyl, nonaro-maticity heterocyclic radical or C (O) R 6;
R 6be selected from alkyl, cycloalkyl, aryl, heteroaryl or nonaro-maticity heterocyclic radical;
Described alkyl, cycloalkyl, aryl, heteroaryl or nonaro-maticity heterocyclic radical are optionally by one or more halogen, alkyl, cycloalkyl, OR of being independently selected from 3, nitro, NR 4r 5or the substituting group of cyano group replaces;
A, m and n are independently selected from 0,1,2,3,4 or 5;
B is independently selected from 0,1,2,3 or 4.
Wherein, n be preferably 0,1 or 2, m be preferably 0 or 1.
In one embodiment, R 1and R 2independently be selected from hydrogen, fluorine, chlorine, bromine, methyl, ethyl, trifluoromethyl, methoxyl group, trifluoromethoxy, hydroxyl, nitro, amino, dimethylin, diethylin or cyano group.
R wherein 2more preferred hydrogen, fluorine, chlorine, bromine, methyl, nitro, amino or cyano group again.
In another embodiment, the invention provides following particular compound:
Figure 491035DEST_PATH_IMAGE002
Phenmethyl-4-(2-(methylamino formyl) pyridine-4-oxygen base) phenyl urethan (SH-007)
Phenmethyl-2-methyl-4-(2-(methylamino formyl) pyridine-4-oxygen base) phenyl urethan (SH-019)
The chloro-4-(2-(methylamino of phenmethyl-2-formyl) pyridine-4-oxygen base) phenyl urethan (SH-020)
The fluoro-4-(2-(methylamino of phenmethyl-2-formyl) pyridine-4-oxygen base) phenyl urethan (SH-021)
Figure 208455DEST_PATH_IMAGE004
4-chlorophenylmethyl-4-(2-(methylamino formyl) pyridine-4-oxygen base) phenyl urethan (SH-023)
4-chlorophenylmethyl-2-methyl-4-(2-(methylamino formyl) pyridine-4-oxygen base) phenyl urethan (SH-023-2)
The fluoro-4-(2-(methylamino of 4-chlorophenylmethyl-2-formyl) pyridine-4-oxygen base) phenyl urethan (SH-023-3)
The chloro-4-(2-(methylamino of 4-chlorophenylmethyl-2-formyl) pyridine-4-oxygen base) phenyl urethan (SH-023-4)
Figure 2011103098417100002DEST_PATH_IMAGE005
Styroyl-4-(2-(methylamino formyl) pyridine-4-oxygen base) phenyl urethan (SH-024)
Phenmethyl-4-(2-(methylamino formyl) pyridine-4-oxygen base) aminotoluene carbamate (SH-025)
Figure 541348DEST_PATH_IMAGE006
3-trifluoromethyl-4-(2-(methylamino formyl) pyridine-4-oxygen base) aminotoluene carbamate (SH-027)
3-trifluoromethyl-2-methyl-4-(2-(methylamino formyl) pyridine-4-oxygen base) aminotoluene carbamate (SH-027-2)
The fluoro-4-(2-(methylamino of 3-trifluoromethyl-2-formyl) pyridine-4-oxygen base) aminotoluene carbamate (SH-027-3)
The chloro-4-(2-(methylamino of 3-trifluoromethyl-2-formyl) pyridine-4-oxygen base) aminotoluene carbamate (SH-027-4)
The chloro-3-trifluoromethyl phenmethyl-4-(2-(of 4-methylamino formyl) pyridine-4-oxygen base) phenyl urethan (SH-028)
The chloro-3-trifluoromethyl phenmethyl-2-of 4-methyl-4-(2-(methylamino formyl) pyridine-4-oxygen base) phenyl urethan (SH-028-2)
The fluoro-4-(2-(methylamino of the chloro-3-trifluoromethyl of 4-phenmethyl-2-formyl) pyridine-4-oxygen base) phenyl urethan (SH-028-3)
The chloro-4-(2-(methylamino of the chloro-3-trifluoromethyl of 4-phenmethyl-2-formyl) pyridine-4-oxygen base) phenyl urethan (SH-028-4)
Figure 2011103098417100002DEST_PATH_IMAGE009
2-chlorophenylmethyl-4-(2-(methylamino formyl) pyridine-4-oxygen base) phenyl urethan (SH-032)
The chloro-3-fluorobenzene methyl-4-(2-(of 4-methylamino formyl) pyridine-4-oxygen base) phenyl urethan (SH-034)
The chloro-3-fluorobenzene methyl-2-of 4-methyl-4-(2-(methylamino formyl) pyridine-4-oxygen base) phenyl urethan (SH-034-2)
The fluoro-4-(2-(methylamino of the chloro-3-fluorobenzene of 4-methyl-2-formyl) pyridine-4-oxygen base) phenyl urethan (SH-039)
The chloro-4-(2-(methylamino of the chloro-3-fluorobenzene of 4-methyl-2-formyl) pyridine-4-oxygen base) phenyl urethan (SH-034-4)
The chloro-3-trifluoromethyl of 4-phenmethyl-4-(2-(methylamino formyl) pyridine-4-oxygen base) aminotoluene carbamate (SH-036)
4-fluorobenzene methyl-4-(2-(methylamino formyl) pyridine-4-oxygen base) phenyl urethan (SH-037)
4-fluorobenzene methyl-2-methyl-4-(2-(methylamino formyl) pyridine-4-oxygen base) phenyl urethan (SH-037-2)
The fluoro-4-of 4-fluorobenzene methyl-2-(2-(methylamino formyl) pyridine-4-oxygen base) phenyl urethan (SH-040)
The chloro-4-of 4-fluorobenzene methyl-2-(2-(methylamino formyl) pyridine-4-oxygen base) phenyl urethan (SH-037-4)
Figure 270215DEST_PATH_IMAGE014
4-trifluoromethyl phenmethyl-4-(2-(methylamino formyl) pyridine-4-oxygen base) phenyl urethan (SH-038)
4-trifluoromethyl phenmethyl-2-methyl-4-(2-(methylamino formyl) pyridine-4-oxygen base) phenyl urethan (SH-038-2)
The fluoro-4-of 4-trifluoromethyl phenmethyl-2-(2-(methylamino formyl) pyridine-4-oxygen base) phenyl urethan (SH-038-3)
The chloro-4-of 4-trifluoromethyl phenmethyl-2-(2-(methylamino formyl) pyridine-4-oxygen base) phenyl urethan (SH-038-4)
Figure 2011103098417100002DEST_PATH_IMAGE015
4-trifluoromethyl phenmethyl-4-(2-(methylamino formyl) pyridine-4-oxygen base) aminotoluene carbamate (SH-043)
The chloro-3-fluorobenzene methyl-4-(2-(of 4-methylamino formyl) pyridine-4-oxygen base) aminotoluene carbamate (SH-044).
Simultaneously, the present invention also further discloses, and described pharmaceutical salts is by having the compound of logical formula I and preferably forming from sulfuric acid, hydrochloric acid, Hydrogen bromide, phosphoric acid, phenylformic acid, toluylic acid, Phenylsulfonic acid, methylsulfonic acid, tosic acid, trifluoromethanesulfonic acid, acetic acid, trifluoroacetic acid, tartrate, oxysuccinic acid, citric acid, lactic acid, oxalic acid, fumaric acid, toxilic acid, Whitfield's ointment, tussol, succsinic acid.
Unless otherwise indicated, term used herein " the compounds of this invention " refers to compound shown in general formula (I), preferred above-mentioned particular compound, particularly preferably embodiment compound.
Unless otherwise indicated, term used herein " halogen " represents fluorine, chlorine, bromine or iodine, preferably fluorine or chlorine.
Unless otherwise indicated, term used herein " alkyl " is saturated straight or branched alkyl, preferably C 1-20straight or branched alkyl, more preferably C 1-10straight or branched alkyl, especially preferably C 1-6straight or branched alkyl.The most preferably example of described alkyl comprises methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-, sec-butyl, the tertiary butyl, amyl group.Described alkyl is optionally by one or more halogen, alkyl, cycloalkyl, OR of being independently selected from 3, nitro, NR 4r 5or the replacement of the substituting group of cyano group, suitable example comprises for example chloromethyl, dichloromethyl, trichloromethyl, methyl fluoride, difluoromethyl, trifluoromethyl.
Unless otherwise indicated, term used herein " cycloalkyl " represents saturated cyclic hydrocarbon group, preferably C 3-20cycloalkyl, more preferably C 3-10cycloalkyl, especially preferably C 3-8cycloalkyl.The example of described cycloalkyl comprises for example cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, suberyl and ring octyl group.Described cycloalkyl is optionally by one or more halogen, alkyl, cycloalkyl, OR of being independently selected from 3, nitro, NR 4r 5or the substituting group of cyano group replaces.
Unless otherwise indicated, term used herein " aryl " represents to replace or unsubstituted carbocyclic ring aromatic group, preferably C 6-20aryl, more preferably C 6-10aryl, especially preferably phenyl, naphthyl.Described aryl is optionally by one or more halogen, alkyl, cycloalkyl, OR of being independently selected from 3, nitro, NR 4r 5or the substituting group of cyano group replaces.
Unless otherwise indicated, term used herein " heteroaryl " represents to comprise 1-4 heteroatomic aromatic group that is selected from N, O and S, the preferably aromatic group of 5-10 unit.The example of described heteroaryl comprises for example pyrryl, furyl, thienyl, oxazolyl, imidazolyl, isoxazolyl, isothiazolyl, triazolyl, thiadiazolyl group, pyridyl, pyridazinyl, pyrimidyl, pyrazinyl, pyranyl, indyl, indazolyl, benzofuryl, benzothiazolyl, quinolyl or isoquinolyl.Described heteroaryl is optionally by one or more halogen, alkyl, cycloalkyl, OR of being independently selected from 3, nitro, NR 4r 5or the substituting group of cyano group replaces.
Unless otherwise indicated, term used herein " nonaro-maticity heterocyclic radical " represents to comprise 1-4 the undersaturated nonaro-maticity ring structure of heteroatomic saturated or part that is selected from N, O and S, preferably 5-8 unit heterocyclic radical.The example of suitable nonaro-maticity heterocyclic radical comprises for example pyrrolidyl, tetrahydrofuran base, imidazolinyl, piperidyl, piperazinyl, alkyl dioxin or morpholinyl.Described nonaro-maticity heterocyclic radical is optionally by one or more halogen, alkyl, cycloalkyl, OR of being independently selected from 3, nitro, NR 4r 5or the substituting group of cyano group replaces.
Unless otherwise indicated, " a plurality of substituting group " herein represents at least 2 substituting groups;
Meanwhile, the invention discloses the preparation method who prepares the compounds of this invention and pharmaceutical salts thereof.
Shown in logical formula I of the present invention, compound can be prepared by the following method:
1) take N-methyl-4-Chloro-2-Pyridyle methane amide is raw material, with the ether of formula (II) compound formation formula (III), then reacts and obtains target compound with formula (IV) compound:
Figure 752143DEST_PATH_IMAGE018
Or
2) take N-methyl-4-Chloro-2-Pyridyle methane amide is raw material, with the ether of formula (II) compound formation formula (III), then reacts and obtains target compound with formula V compound in the medium that has dicarbapentaborane imidazoles (CDI):
Figure 2011103098417100002DEST_PATH_IMAGE019
Being prepared as optionally of pharmaceutical salts of the present invention, by described method 1) or 2) product that obtains prepares its pharmaceutical salts with corresponding acid-respons;
Wherein, the preparation method 2 of compound shown in logical formula I) medium in represents suitable solvent, herein described solvent is not particularly limited.Suitable solvent comprises for example aromatic hydrocarbon solvent, alcoholic solvent or halogenated alkane kind solvent, preferably benzene, toluene, methyl alcohol, ethanol, methylene dichloride, trichloromethane etc.
Meanwhile, the present invention also further discloses compound or pharmaceutically acceptable salt thereof shown in described logical formula I as the medicine of preparation treatment or prophylaxis of tumours or as the application in the pharmaceutical composition of preparation treatment or prophylaxis of tumours.Wherein pharmaceutical composition preferably also comprises auxiliary material, the pharmaceutically useful carrier of described Optimization of Adjuvant and/or vehicle, wherein said vehicle preferred diluent.
Above-mentioned tumour is preferably cancer of the stomach, liver cancer, lung cancer, the esophageal carcinoma, cervical cancer, mammary cancer, colorectal carcinoma, the rectum cancer, nasopharyngeal carcinoma, ovarian cancer, kidney, bladder cancer, thyroid carcinoma, skin carcinoma, myosarcoma, fibrosarcoma, liposarcoma, osteosarcoma, chondrosarcoma, angiosarcoma, lymphosarcoma, leukemia, melanoma, retinocytoma, withered Bo Shi knurl, Ewing' s tumor, malignant hemangioendothelioma, lymphatic cancer, bladder cancer, prostate cancer, uterus carcinoma, ovarian cancer, hysteromyoma and/or oral carcinoma.
Embodiment
Embodiment 1: phenmethyl-4-(2-(methylamino formyl) pyridine-4-oxygen base) phenyl urethan (SH-007)
Figure 2011103098417100002DEST_PATH_IMAGE021
Taking 0.710g(0.003 mol) 4-(4-amino-benzene oxygen)-N-picoline acid amides is in 100 ml tri-neck round-bottomed flasks, add 20 ml methylene dichloride stirring and dissolving, add again 0.4 ml triethylamine, under ice bath, slowly drip chloroformic acid benzyl ester 0.4ml, dropwise, room temperature reaction 1 h, washing, extracts organic layer, column chromatography for separation (eluent: petrol ether/ethyl acetate=1:1), obtain white solid.Fusing point: 119.2～120.2 ℃.
1H?NMR?(CDCl 3)?δ?(ppm):?8.37?~?8.35?(d,?1H,?pyridine- H),?8.01?(s,?1H,?N HCO),?7.70?(s,?1H,?pyridine- H),?7.47?~?7.34?(m,?7H,?Ar- H,),?7.05?~?7.02?(d,?2H,?Ar- H),?6.95?~?6.92?(m,?1H,?pyridine- H),?6.79?(s,?1H,?N HCO),?5.22?(s,?2H,?C H 2),?3.01?~?3.00?(d,?3H,?C H 3)。
ESI-MS m/z:378 (M+1) +, calculated value: 378
Embodiment 2: phenmethyl-2-methyl-4-(2-(methylamino formyl) pyridine-4-oxygen base) phenyl urethan (SH-019)
Figure 110619DEST_PATH_IMAGE022
The method that adopts embodiment 1, changes 4-(4-amino-benzene oxygen)-N-picoline acid amides into 4-(4-amino-3-methylphenoxy)-N-picoline acid amides, obtains this target compound, pale solid.Fusing point: 144.4～144.7 ℃.
1H?NMR?(CDCl 3)?δ?(ppm):?8.37?~?8.35?(d,?1H,?pyridine- H),?8.04?(s,?1H,?N HCO),?7.87?~?7.84?(s,?1H,?N HCO),?7.70?~?7.69?(s,?1H,?pyridine- H),?7.44?~?7.33?(m,?5H,?Ar- H),?6.96?~?6.90?(m,?3H,?Ar- H,?pyridine- H),?6.46?(s,?1H,?Ar- H),?5.22?(s,?2H,?C H 2),?3.01?~?3.00?(d,?3H,?C H 3),?2.25?(s,?3H,?C H 3)。
ESI-MS m/z:392 (M+1) +, calculated value: 392.
Embodiment 3: the chloro-4-(2-(methylamino of phenmethyl-2-formyl) pyridine-4-oxygen base) phenyl urethan (SH-020)
Figure 802631DEST_PATH_IMAGE024
Adopt the method for embodiment 1,4-(4-amino-3-chlorophenoxy)-N-picoline acid amides is replaced to 4-(4-amino-benzene oxygen)-N-picoline acid amides, obtain this target compound, brown color solid.Fusing point: 133.4～134.7 ℃.
1H?NMR?(CDCl 3)?δ?(ppm):?8.40?~?8.38?(d,?1H,?pyridine- H),?8.27?~?8.25?(d,?1H,?N HCO),?8.00?(s,?1H,?N HCO),?7.70?~?7.69?(d,?1H,?pyridine- H),?7.45?~?7.35?(m,?5H,?Ar- H),?7.17?(s,?1H,?Ar- H),?7.14?~?7.13?(d,?1H,?Ar- H),?7.04?~?7.02?(m,?1H,?Ar- H),?6.96?~?6.94?(m,?1H,?pyridine- H?),?5.24?(s,?2H,?C H 2),?3.01?~?3.00?(d,?3H,?C H 3)。
ESI-MS m/z:412 (M+1) +, calculated value: 412.
Embodiment 4: the fluoro-4-(2-(methylamino of phenmethyl-2-formyl) pyridine-4-oxygen base) phenyl urethan (SH-021)
Adopt the method for embodiment 1, with 4-(4-amino-3-fluorophenoxy)-N-picoline acid amides, replace 4-(4-amino-benzene oxygen)-N-picoline acid amides, obtain this target compound, rose pink solid.Fusing point: 141.2～145.1 ℃.
1H?NMR?(CDCl 3)?δ?(ppm):?8.40?~?8.38?(d,?1H,?pyridine- H),?8.20?~?8.14?(t,?1H,?N HCO),?8.04?(s,?1H,?N HCO),?7.71?~?7.70?(d,?1H,?pyridine- H),?7.44?~?7.34?(m,?5H,?Ar- H?),?6.98?~?6.95?(m,?1H,?pyridine- H),?6.92?~?6.85?(m,?3H,?Ar- H,?),?5.24?(s,?2H,?C H 2),?3.02?~?3.00?(d,?3H,?C H 3)。
ESI-MS m/z:396 (M+1) +, calculated value: 396.
Embodiment 5:4-chlorophenylmethyl-4-(2-(methylamino formyl) pyridine-4-oxygen base) phenyl urethan (SH-023)
Taking 0.710 g(0.003 mol) 4-(4-amino-benzene oxygen)-N-picoline acid amides is in 100 ml tri-neck round-bottomed flasks, add 20 ml methylene dichloride stirring and dissolving, add 0.535 g(0.0033 mol) dicarbapentaborane imidazoles (CDI), after stirring at room 2 h, add 0.426 g(0.003 mol) p-Chlorobenzyl alcohol, continues at room temperature to stir, after question response stops, after concentrated, column chromatography for separation (eluent: petrol ether/ethyl acetate=1:1), faint yellow solid.Fusing point: 90.2～92.6 ℃.
1H?NMR?(CDCl 3)?δ?(ppm):?8.37?~?8.36?(d,?1H,?pyridine- H),?8.05?(s,?1H,?N HCO),?7.68?~?7.67?(d,?1H,?pyridine- H),?7.46?~?7.44?(d,?2H,?Ar- H)?7.35?~?7.31?(m,?4H,?Ar- H),?7.03?~?7.00?(m,?2H,?Ar- H)，6.98?~?6.97?(s,?1H,?N HCO),?6.96?~?6.94?(m,?1H,?pyridine- H),?5.16?(s,?2H,?C H 2),?3.00?~?2.99?(d,?3H,?C H 3)。
ESI-MS m/z:412 (M+1) +, calculated value: 412.
Embodiment 6:4-chlorophenylmethyl-2-methyl-4-(2-(methylamino formyl) pyridine-4-oxygen base) phenyl urethan (SH-023-2)
Figure 804457DEST_PATH_IMAGE030
Adopt the method for embodiment 5, with 4-(4-amino-3-methylphenoxy)-N-picoline acid amides, replace 4-(4-amino-benzene oxygen)-N-picoline acid amides, obtain this target compound, white solid.Fusing point: 123.4～124.8 ℃.
1H?NMR?(CDCl 3)?δ?(ppm):?8.35?~?8.34?(d,?1H,?pyridine- H),?8.01?(s,?1H,?N HCO),?7.67?~?7.65?(d,?1H,?pyridine- H),?7.45?~?7.43?(d,?2H,?Ar- H)?7.33?~?7.31?(m,?3H,?Ar- H),?7.02?~?7.01?(m,?2H,?Ar- H),6.95?(s,?1H,?N HCO),?6.95?~?6.94?(m,?1H,?pyridine- H),?5.15?(s,?2H,?C H 2),?3.00?~?2.99?(d,?3H,?C H 3)，2.25?(s,?3H,?C H 3)。
ESI-MS m/z:426 (M+1) +, calculated value: 426.
The fluoro-4-(2-(methylamino of embodiment 7:4-chlorophenylmethyl-2-formyl) pyridine-4-oxygen base) phenyl urethan (SH-023-3)
Figure 983766DEST_PATH_IMAGE032
Adopt the method for embodiment 5, with 4-(4-amino-3-fluorophenoxy)-N-picoline acid amides, replace 4-(4-amino-benzene oxygen)-N-picoline acid amides, obtain this target compound, white solid.Fusing point: 140.4～142.3 ℃.
1H?NMR?(CDCl 3)?δ?(ppm):?8.38?~?8.37?(d,?1H,?pyridine- H),?8.06?(s,?1H,?N HCO),?7.68?~?7.67?(d,?1H,?pyridine- H),?7.47?~?7.45?(d,?2H,?Ar- H)，?7.35?~?7.33?(m,?3H,?Ar- H),?7.05?~?7.03?(m,?2H,?Ar- H),?6.98?(s,?1H,?N HCO),?6.95?~?6.94?(m,?1H,?pyridine- H),?5.25?(s,?2H,?C H 2),?3.00?~?2.99?(d,?3H,?C H 3)。
ESI-MS m/z:430 (M+1) +, calculated value: 430.
The chloro-4-(2-(methylamino of embodiment 8:4-chlorophenylmethyl-2-formyl) pyridine-4-oxygen base) phenyl urethan (SH-023-4)
Figure 196572DEST_PATH_IMAGE034
Adopt the method for embodiment 5, with 4-(4-amino-3-chlorophenoxy)-N-picoline acid amides, replace 4-(4-amino-benzene oxygen)-N-picoline acid amides, obtain target compound, white solid.Fusing point: 138.2～140.0 ℃.
1H?NMR?(CDCl 3)?δ?(ppm):?8.38?~?8.36?(d,?1H,?pyridine- H),?8.04?(s,?1H,?N HCO),?7.69?~?7.68?(d,?1H,?pyridine- H),?7.46?~?7.44?(d,?2H,?Ar- H)，?7.34?~?7.32?(m,?3H,?Ar- H),?7.04?~?7.02?(m,?2H,?Ar- H),?6.97?(s,?1H,?N HCO),?6.95?~?6.94?(m,?1H,?pyridine- H),?5.23?(s,?2H,?C H 2),?3.00?~?2.99?(d,?3H,?C H 3)。
ESI-MS m/z:446 (M+1) +, calculated value: 446.
Embodiment 9: styroyl-4-(2-(methylamino formyl) pyridine-4-oxygen base) phenyl urethan (SH-024)
Figure DEST_PATH_IMAGE035
The method that adopts embodiment 5, replaces chlorobenzyl alcohol with phenylethyl alcohol, obtains target compound, white solid.Fusing point: 170.1～171.4 ℃.
1H?NMR?(CDCl 3)?δ?(ppm):?8.37?~?8.36?(d,?1H,?pyridine- H),?8.04?(s,?1H,?N HCO),?7.71?~?7.70?(d,?1H,?pyridine- H),?7.41?(s,?2H,?Ar- H),?7.34?~?7.31?(m,?2H,?Ar- H),?7.25?(m,?3H,?Ar- H),?7.04?~?7.02?(m,?2H,?Ar- H),?6.95?~?6.93?(m,?1H,?pyridine- H),?6.60?(s,?1H,?N HCO),?4.43?~?4.40?(t,?2H,?C H 2),?3.03?~?3.00?(m,?5H,?C H 2,?C H 3)。
ESI-MS m/z:392 (M+1) +, calculated value: 392.
Embodiment 10: phenmethyl-4-(2-(methylamino formyl) pyridine-4-oxygen base) aminotoluene carbamate (SH-025)
Figure 2011103098417100002DEST_PATH_IMAGE037
Adopt the method for embodiment 1, with 4-(4-methylamino phenoxy group)-N-picoline acid amides, replace 4-(4-amino-benzene oxygen)-N-picoline acid amides, obtain target compound, rose pink solid.Fusing point: 94.3～95.5 ℃.
1H?NMR?(CDCl 3)?δ?(ppm):?8.37?~?8.36?(d,?1H,?pyridine- H),?8.00?(s,?1H,?N HCO),?7.98?(s,?1H,?N HCO),7.68?~?7.67?(d,?1H,?pyridine- H),?7.37?~?7.30?(m,?7H,?Ar- H),?7.05?~?7.03?(d,?2H,?Ar- H),?6.95?~?6.94?(m,?1H,?pyridine- H),?5.15?(s,?2H,?C H 2),?4.40?~?4.39?(d,?2H,?C H 2),?3.01?~?2.99?(d,?3H,?C H 3)。
ESI-MS m/z:392 (M+1) +, calculated value: 392.
Embodiment 11:3-trifluoromethyl-4-(2-(methylamino formyl) pyridine-4-oxygen base) aminotoluene carbamate (SH-027)
Figure DEST_PATH_IMAGE039
Adopt the method for embodiment 1, with 4-(4-methylamino phenoxy group)-N-picoline acid amides, replace 4-(4-amino-benzene oxygen)-N-picoline acid amides, chloroformic acid m-trifluoromethyl phenyl ester replaces chloroformic acid benzyl ester, obtains target compound, obtains white solid.Fusing point: 125.8～129.4 ℃.
1H?NMR?(CDCl 3)?δ?(ppm):?8.41?~?8.39?(d,?1H,?pyridine- H),?8.01?(s,?1H,?N HCO),?7.70?~?7.69?(d,?1H,?pyridine- H),?7.49?~?7.41?(m,?6H,?Ar- H),?7.38?(s,?1H,?N HCO),?7.11?~?7.09?(d,?2H,?Ar- H),?7.02?~?7.00?(m,?1H,?pyridine- H),?4.49?(s,?2H,?C H 2),?3.01?~?3.00?(s,?3H,?C H 3)。
ESI-MS m/z:446 (M+1) +, calculated value: 446.
Embodiment 12:3-trifluoromethyl-2-methyl-4-(2-(methylamino formyl) pyridine-4-oxygen base) aminotoluene carbamate (SH-027-2)
Adopt the method for embodiment 1, with 4-(4-methylamino-3-methylphenoxy)-N-picoline acid amides, replace 4-(4-amino-benzene oxygen)-N-picoline acid amides, chloroformic acid m-trifluoromethyl phenyl ester replaces chloroformic acid benzyl ester, obtains target compound, white solid.Fusing point: 145.3～146.7 ℃.
1H?NMR?(CDCl 3)?δ?(ppm):?8.40?~?8.30?(d,?1H,?pyridine- H),?8.00?(s,?1H,?N HCO),?7.68?~?7.67?(d,?1H,?pyridine- H),?7.45?~?7.43?(m,?5H,?Ar- H),?7.35?(s,?1H,?N HCO),?7.10?~?7.09?(d,?2H,?Ar- H),?7.02?~?7.01?(m,?1H,?pyridine- H),?4.45?(s,?2H,?C H 2),?3.01?~?3.00?(s,?3H,?C H 3),?2.25?(s,?3H,?C H 3)。
ESI-MS m/z:460 (M+1) +, calculated value: 460.
The fluoro-4-of embodiment 13:3-trifluoromethyl-2-(2-(methylamino formyl) pyridine-4-oxygen base) aminotoluene carbamate (SH-027-3)
Figure DEST_PATH_IMAGE043
Adopt the method for embodiment 1, with 4-(4-methylamino-3-fluorophenoxy)-N-picoline acid amides, replace 4-(4-amino-benzene oxygen)-N-picoline acid amides, chloroformic acid m-trifluoromethyl phenyl ester replaces chloroformic acid benzyl ester, obtains target compound, white solid.Fusing point: 153.7～155.0 ℃.
1H?NMR?(CDCl 3)?δ?(ppm):?8.43?~?8.41?(d,?1H,?pyridine- H),?8.02?(s,?1H,?N HCO),?7.72?~?7.70?(d,?1H,?pyridine- H),?7.49?~?7.47?(m,?5H,?Ar- H),?7.40?(s,?1H,?N HCO),?7.15?~?7.13?(d,?2H,?Ar- H),?7.05?~?7.03?(m,?1H,?pyridine- H),?4.52?(s,?2H,?C H 2),?3.01?~?3.00?(s,?3H,?C H 3)。
ESI-MS m/z:464 (M+1) +, calculated value: 464.
The chloro-4-of embodiment 14:3-trifluoromethyl-2-(2-(methylamino formyl) pyridine-4-oxygen base) aminotoluene carbamate (SH-027-4)
Figure DEST_PATH_IMAGE045
With 4-(4-methylamino-3-chlorophenoxy)-N-picoline acid amides, replace 4-(4-amino-benzene oxygen)-N-picoline acid amides, chloroformic acid m-trifluoromethyl phenyl ester replaces chloroformic acid benzyl ester, the method that adopts embodiment 1, obtains target compound, white solid.Fusing point: 147.6～149.4 ℃.
1H?NMR?(CDCl 3)?δ?(ppm):?8.42?~?8.40?(d,?1H,?pyridine- H),?8.02?(s,?1H,?N HCO),?7.73?~?7.72?(d,?1H,?pyridine- H),?7.50?~?7.48?(m,?5H,?Ar- H),?7.38?(s,?1H,?N HCO),?7.14?~?7.12?(d,?2H,?Ar- H),?7.04?~?7.02?(m,?1H,?pyridine- H),?4.50?(s,?2H,?C H 2),?3.01?~?3.00?(s,?3H,?C H 3)。
ESI-MS m/z:480 (M+1) +, calculated value: 480.
The chloro-3-trifluoromethyl of embodiment 15:4-phenmethyl-4-(2-(methylamino formyl) pyridine-4-oxygen base) phenyl urethan (SH-028)
Figure DEST_PATH_IMAGE047
Adopt the method for embodiment 5, the chloro-3-trifluoromethyl-benzyl-alcohol of 4-is replaced to chlorobenzyl alcohol, obtain target compound, white solid.Fusing point: 147.3～148.7 ℃.
1H?NMR?(CDCl 3)?δ?(ppm):?8.37?~?8.36?(d,?1H,?pyridine- H),?8.02?(s,?1H,?N HCO),?7.73?(s,?1H,?Ar- H),?7.69?~?7.68?(d,?1H,?pyridine- H),?7.53?~?7.52?(d,?2H,?Ar- H)，?7.46?~?7.44?(d,?2H,?Ar- H),?7.07~?7.04?(m,?2H,?Ar- H),?6.96?~?6.94?(m,?1H,?pyridine- H),?6.79?(s,?1H,?N HCO),?5.22?(s,?2H,?C H 2),?3.00?~?2.99?(d,?3H,?C H 3)。
ESI-MS m/z:480 (M+1) +, calculated value: 480.
The chloro-3-trifluoromethyl phenmethyl-2-of embodiment 16:4-methyl-4-(2-(methylamino formyl) pyridine-4-oxygen base) phenyl urethan (SH-028-2)
Figure DEST_PATH_IMAGE049
Adopt the method for embodiment 5, the chloro-3-trifluoromethyl-benzyl-alcohol of 4-is replaced to chlorobenzyl alcohol, with 4-(4-amino-3-methylphenoxy)-N-picoline acid amides, replace, with 4-(4-amino-benzene oxygen)-N-picoline acid amides, obtaining target compound, white solid.Fusing point: 137.4～138.9 ℃.
1H?NMR?(CDCl 3)?δ?(ppm):?8.37?~?8.36?(d,?1H,?pyridine- H),?8.00?(s,?1H,?N HCO),?7.72?(s,?1H,?Ar- H),?7.70?~?7.68?(d,?1H,?pyridine- H),?7.52?~?7.50?(d,?2H,?Ar- H)，?7.45?~?7.43?(d,?2H,?Ar- H),?7.05~?7.03?(m,?1H,?Ar- H),?6.97?~?6.95?(m,?1H,?pyridine- H),?6.77?(s,?1H,?N HCO),?5.21?(s,?2H,?C H 2),?3.00?~?2.99?(d,?3H,?C H 3),?2.23?(s,?3H,?C H 3)。
ESI-MS m/z:494 (M+1) +, calculated value: 494.
The fluoro-4-of the chloro-3-trifluoromethyl of embodiment 17:4-phenmethyl-2-(2-(methylamino formyl) pyridine-4-oxygen base) phenyl urethan (SH-028-3)
Figure DEST_PATH_IMAGE051
Adopt the method for embodiment 5, the chloro-3-trifluoromethyl-benzyl-alcohol of 4-is replaced to chlorobenzyl alcohol, with 4-(4-amino-3-fluorophenoxy)-N-picoline acid amides, replace, with 4-(4-amino-benzene oxygen)-N-picoline acid amides, obtaining target compound, white solid.Fusing point: 157.6～159.4 ℃.
1H?NMR?(CDCl 3)?δ?(ppm):?8.39?~?8.37?(d,?1H,?pyridine- H),?8.03?(s,?1H,?N HCO),?7.74?(s,?1H,?Ar- H),?7.72?~?7.70?(d,?1H,?pyridine- H),?7.52?~?7.50?(d,?2H,?Ar- H)，?7.47?~?7.45?(d,?2H,?Ar- H),?7.07~?7.06?(m,?1H,?Ar- H),?6.99?~?6.97?(m,?1H,?pyridine- H),?6.78?(s,?1H,?N HCO),?5.23?(s,?2H,?C H 2),?3.00?~?2.99?(d,?3H,?C H 3)。
ESI-MS m/z:498 (M+1) +, calculated value: 498.
The chloro-4-of the chloro-3-trifluoromethyl of embodiment 18:4-phenmethyl-2-(2-(methylamino formyl) pyridine-4-oxygen base) phenyl urethan (SH-028-4)
Figure DEST_PATH_IMAGE053
Adopt the method for embodiment 5, the chloro-3-trifluoromethyl-benzyl-alcohol of 4-is replaced to chlorobenzyl alcohol, with 4-(4-amino-3-chlorophenoxy)-N-picoline acid amides, replace, with 4-(4-amino-benzene oxygen)-N-picoline acid amides, obtaining target compound, white solid.Fusing point: 157.6～159.4 ℃.
1H?NMR?(CDCl 3)?δ?(ppm):?8.38?~?8.37?(d,?1H,?pyridine- H),?8.02?(s,?1H,?N HCO),?7.74?(s,?1H,?Ar- H),?7.70?~?6.69?(d,?1H,?pyridine- H),?7.53?~?7.52?(d,?2H,?Ar- H)，?7.48?~?7.47?(d,?2H,?Ar- H),?7.07~?7.05?(m,?1H,?Ar- H),?6.98?~?6.96?(m,?1H,?pyridine- H),?6.78?(s,?1H,?N HCO),?5.22?(s,?2H,?C H 2),?3.00?~?2.99?(d,?3H,?C H 3)。
ESI-MS m/z:4514 (M+1) +, calculated value: 514.
Embodiment 19:2-chlorophenylmethyl-4-(2-(methylamino formyl) pyridine-4-oxygen base) phenyl urethan (SH-032)
Adopt the method for embodiment 5, adjacent chlorobenzyl alcohol is replaced to chlorobenzyl alcohol, obtain target compound, yellow solid.Fusing point: 46.7～49.5 ℃
1H?NMR?(CDCl 3)?δ?(ppm):?8.38?~?8.37?(d,?1H,?pyridine- H),?8.23?(s,?1H,?N HCO),?7.73?(s,?1H,?pyridine- H),?7.49?~?7.46?(m,?3H,?Ar- H),?7.43?~?7.41?(m,?1H,?Ar- H),?7.31?~?7.29?(m,?2H,?Ar- H),?7.06~?7.05?(m,?2H,?Ar- H),?6.98?~?6.97?(m,?1H,?pyridine- H),?6.75?(s,?1H,?N HCO),?5.34?(s,?2H,?C H 2),?3.02?~?3.00?(d,?3H,?C H 3)。
ESI-MS m/z:412 (M+1) +, calculated value: 412.
The chloro-3-fluorobenzene of embodiment 20:4-methyl-4-(2-(methylamino formyl) pyridine-4-oxygen base) phenyl urethan (SH-034)
Figure DEST_PATH_IMAGE057
Adopt the method for embodiment 5, the chloro-3-fluoro benzyl alcohol of 4-is replaced to chlorobenzyl alcohol, obtain target compound, white solid.Fusing point: 135.6～137.2 ℃.
1H?NMR?(CDCl 3)?δ?(ppm):?8.36?~?8.35?(d,?1H,?pyridine- H),?8.03?(s,?1H,?N HCO),?7.65?~?7.64?(d,?1H,?pyridine- H),?7.48?~?7.46?(d,?2H,?Ar- H),?7.40?(s,?1H,?N HCO),?7.38?~?7.35?(t,?1H,?Ar- H),?7.15?~?7.07?(m,?2H,?Ar- H),?7.01?~?6.98?(d,?2H,?Ar- H),?6.96?~?6.94?(m,?1H,?pyridine- H),?5.12?(s,?2H,?C H 2),?3.00?~?2.99?(d,?3H,?C H 3)。
ESI-MS m/z:430 (M+1) +, calculated value: 430.
The chloro-3-fluorobenzene methyl-2-of embodiment 21:4-methyl-4-(2-(methylamino formyl) pyridine-4-oxygen base) phenyl urethan (SH-034-2)
Figure DEST_PATH_IMAGE059
Adopt the method for embodiment 5, the chloro-3-fluoro benzyl alcohol of 4-is replaced to chlorobenzyl alcohol, 4-(4-amino-3-methylphenoxy)-N-picoline acid amides replaces, with 4-(4-amino-benzene oxygen)-N-picoline acid amides, obtaining target compound, white solid.Fusing point: 133.2～135.2 ℃.
1H?NMR?(CDCl 3)?δ?(ppm):?8.35?~?8.33?(d,?1H,?pyridine- H),?8.00?(s,?1H,?N HCO),?7.65?~?7.63?(d,?1H,?pyridine- H),?7.46?~?7.44?(d,?2H,?Ar- H),?7.38?(s,?1H,?N HCO),?7.35?~?7.33?(t,?1H,?Ar- H),?7.14?~?7.07?(m,?2H,?Ar- H),?7.00?~?6.98?(d,?1H,?Ar- H),?6.96?~?6.94?(m,?1H,?pyridine- H),?5.12?(s,?2H,?C H 2),?3.00?~?2.99?(d,?3H,?C H 3),?2.22?(s,?3H,?C H 3)。
ESI-MS m/z:444 (M+1) +, calculated value: 444.
The fluoro-4-of the chloro-3-fluorobenzene of embodiment 22:4-methyl-2-(2-(methylamino formyl) pyridine-4-oxygen base) phenyl urethan (SH-039)
Figure 593705DEST_PATH_IMAGE060
Adopt the method for embodiment 5, the chloro-3-fluoro benzyl alcohol of 4-is replaced to chlorobenzyl alcohol, 4-(4-amino-3-fluorophenoxy)-N-picoline acid amides replaces, with 4-(4-amino-benzene oxygen)-N-picoline acid amides, obtaining target compound, white solid.Fusing point: 144.5～147.0 ℃.
1H?NMR?(CDCl 3)?δ?(ppm):?8.41?~?8.40?(d,?1H,?pyridine- H),?8.14?(s,?1H,?N HCO),?8.07?(s,?1H,?N HCO),?7.71?~?7.70?(d,?1H,?pyridine- H),?7.43?~?7.40?(t,?1H,?Ar- H),?7.23?~?7.21?(d,?1H,?Ar- H),?7.15?~?7.14?(d,?1H,?Ar- H),?6.99~?6.97?(m,?1H,?pyridine- H),?6.91?~?6.87?(m,?3H,?Ar- H),?5.19?(s,?2H,?C H 2),?3.00?~?2.99?(d,?3H,?C H 3)。
ESI-MS m/z:448 (M+1) +, calculated value: 448.
The chloro-4-of the chloro-3-fluorobenzene of embodiment 23:4-methyl-2-(2-(methylamino formyl) pyridine-4-oxygen base) phenyl urethan (SH-034-4)
Figure 365090DEST_PATH_IMAGE062
Adopt the method for embodiment 5, the chloro-3-fluoro benzyl alcohol of 4-is replaced to chlorobenzyl alcohol, 4-(4-amino-3-chlorophenoxy)-N-picoline acid amides replaces, with 4-(4-amino-benzene oxygen)-N-picoline acid amides, obtaining target compound, yellow solid.Fusing point: 158.7～159.9 ℃.
1H?NMR?(CDCl 3)?δ?(ppm):?8.38?~?8.36?(d,?1H,?pyridine- H),?8.02?(s,?1H,?N HCO),?7.68?~?7.67?(d,?1H,?pyridine- H),?7.48?~?7.47?(d,?2H,?Ar- H),?7.39?(s,?1H,?N HCO),?7.38?~?7.36?(t,?1H,?Ar- H),?7.15?~?7.08?(m,?2H,?Ar- H),?6.98?~?6.97?(d,?1H,?Ar- H),?6.96?~?6.94?(m,?1H,?pyridine- H),?5.17?(s,?2H,?C H 2),?3.00?~?2.99?(d,?3H,?C H 3)。
ESI-MS m/z:464 (M+1) +, calculated value: 464.
The chloro-3-trifluoromethyl of embodiment 24:4-phenmethyl-4-(2-(methylamino formyl) pyridine-4-oxygen base) aminotoluene carbamate (SH-036)
Figure 31695DEST_PATH_IMAGE064
Adopt the method for embodiment 5, the chloro-3-fluoro benzyl alcohol of 4-is replaced to chlorobenzyl alcohol, 4-(4-methylamino-3-chlorophenoxy)-N-picoline acid amides replaces, with 4-(4-amino-benzene oxygen)-N-picoline acid amides, obtaining target compound, white solid.Fusing point: 139.8～141.1 ℃.
1H?NMR?(CDCl 3)?δ?(ppm):?8.39?~?8.38?(d,?1H,?pyridine- H),?8.00?(s,?1H,?N HCO),?7.69?(s,?1H,?Ar- H),?7.67?~?7.66?(d,?1H,?pyridine- H),?7.49?(d,?2H,?Ar- H),?7.35?~?7.34?(d,?2H,?Ar- H),?7.06?~?7.05?(d,?2H,?Ar- H),?6.98?~?6.97?(m,?1H,?pyridine- H),?6.84?(s,?1H,?N HCO),?5.16?(s,?2H,?C H 2),?4.41?~?4.40?(d,?2H,?C H 2),?3.00?~?2.99?(d,?3H,?C H 3)。
ESI-MS m/z:494 (M+1) +, calculated value: 494.
Embodiment 25:4-fluorobenzene methyl-4-(2-(methylamino formyl) pyridine-4-oxygen base) phenyl urethan (SH-037)
Figure DEST_PATH_IMAGE065
Adopt the method for embodiment 5,4-fluoro benzyl alcohol is replaced to chlorobenzyl alcohol, obtain target compound, white solid.Fusing point: 139.8～141.1 ℃.
1H?NMR?(CDCl 3)?δ?(ppm):?8.37?~?8.36?(d,?1H,?pyridine- H),?8.01?(s,?1H,?N HCO),?7.69?~?7.68?(d,?1H,?pyridine- H),?7.46?~?7.45?(d,?2H,?Ar- H),?7.41?~?7.36?(m,?2H,?Ar- H),?7.08?~?7.02?(m,?4H,?Ar- H),?6.95~?6.94?(m,?1H,?pyridine- H),?6.75?(s,?1H,?N HCO),?5.12?(s,?2H,?C H 2),?3.00?~?2.99?(d,?3H,?C H 3)。
ESI-MS m/z:396 (M+1) +, calculated value: 396.
Embodiment 26:4-fluorobenzene methyl-2-methyl-4-(2-(methylamino formyl) pyridine-4-oxygen base) phenyl urethan (SH-037-2)
Adopt the method for embodiment 5,4-fluoro benzyl alcohol is replaced to chlorobenzyl alcohol, 4-(4-amino-3-methylphenoxy)-N-picoline acid amides replaces, with 4-(4-amino-benzene oxygen)-N-picoline acid amides, obtaining target compound, white solid.Fusing point: 125.5～127.2 ℃.
1H?NMR?(CDCl 3)?δ?(ppm):?8.35?~?8.34?(d,?1H,?pyridine- H),?8.00?(s,?1H,?N HCO),?7.67?~?7.66?(d,?1H,?pyridine- H),?7.45?~?7.43?(d,?2H,?Ar- H),?7.39?~?7.36?(m,?2H,?Ar- H),?7.06?~?7.02?(m,?3H,?Ar- H),?6.93~?6.92?(m,?1H,?pyridine- H),?6.75?(s,?1H,?N HCO),?5.10?(s,?2H,?C H 2),?3.00?~?2.99?(d,?3H,?C H 3),?2.30?(s,?3H,?C H 3)。
ESI-MS m/z:410 (M+1) +, calculated value: 410.
The fluoro-4-of embodiment 27:4-fluorobenzene methyl-2-(2-(methylamino formyl) pyridine-4-oxygen base) phenyl urethan (SH-040)
Figure DEST_PATH_IMAGE067
Adopt the method for embodiment 5,4-fluoro benzyl alcohol is replaced to chlorobenzyl alcohol, 4-(4-amino-3-fluorophenoxy)-N-picoline acid amides replaces, with 4-(4-amino-benzene oxygen)-N-picoline acid amides, obtaining target compound, yellow solid.Fusing point: 136.1～138.5 ℃.
1H?NMR?(CDCl 3)?δ?(ppm):?8.40?~?8.39?(d,?1H,?pyridine- H),?8.14?(s,?1H,?N HCO),?7.98?(s,?1H,?N HCO),?6.69?~?6.68?(d,?1H,?pyridine- H),?7.42?~?7.39?(t,?2H,?Ar- H),?7.10?~?7.06?(t,?2H,?Ar- H),?6.96~?6.95?(m,?1H,?pyridine- H),?6.90?~?6.85?(m,?3H,?Ar- H),?5.20?(s,?2H,?C H 2),?3.01?~?3.00?(d,?3H,?C H 3)。
ESI-MS m/z:414 (M+1) +, calculated value: 414.
The chloro-4-(2-(methylamino of embodiment 28:4-fluorobenzene methyl-2-formyl) pyridine-4-oxygen base) phenyl urethan (SH-037-4)
Figure DEST_PATH_IMAGE069
Adopt the method for embodiment 5,4-fluoro benzyl alcohol is replaced to chlorobenzyl alcohol, 4-(4-amino-3-chlorophenoxy)-N-picoline acid amides replaces, with 4-(4-amino-benzene oxygen)-N-picoline acid amides, obtaining target compound, white solid.Fusing point: 143.2～145.0 ℃.
1H?NMR?(CDCl 3)?δ?(ppm):?8.37?~?8.36?(d,?1H,?pyridine- H),?8.02?(s,?1H,?N HCO),?7.69?~?7.65?(d,?1H,?pyridine- H),?7.46?~?7.44?(d,?2H,?Ar- H),?7.41?~?7.39?(m,?2H,?Ar- H),?7.07?~?7.03?(m,?3H,?Ar- H),?6.96~?6.94?(m,?1H,?pyridine- H),?6.78?(s,?1H,?N HCO),?5.17?(s,?2H,?C H 2),?3.00?~?2.99?(d,?3H,?C H 3)。
ESI-MS m/z:430 (M+1) +, calculated value: 430.
Embodiment 29:4-trifluoromethyl phenmethyl-4-(2-(methylamino formyl) pyridine-4-oxygen base) phenyl urethan (SH-038)
Figure DEST_PATH_IMAGE071
Adopt the method for embodiment 5,4-trifluoromethyl-benzyl-alcohol is replaced to chlorobenzyl alcohol, obtain target compound, white solid.Fusing point: 143.2～144.6 ℃.
1H?NMR?(CDCl 3)?δ?(ppm):?8.37?~?8.36?(d,?1H,?pyridine- H),?8.00?(s,?1H,?N HCO),?7.68?~?7.67?(d,?1H,?pyridine- H),?7.65?~?7.63?(d,?2H,?Ar- H,?pyridine- H),?7.52?~?7.50?(d,?2H,?Ar- H),?7.46?~?7.44?(d,?2H,?Ar- H),?7.05?~?7.03?(d,?2H,?Ar- H),?6.96~?6.94?(m,?1H,?pyridine- H),?6.84?(s,?1H,?N HCO),?5.27?(s,?2H,?C H 2),?3.00?~?2.99?(d,?3H,?C H 3)。
ESI-MS m/z:446 (M+1) +, calculated value: 446.
Embodiment 30:4-trifluoromethyl phenmethyl-2-methyl-4-(2-(methylamino formyl) pyridine-4-oxygen base) phenyl urethan (SH-038-2)
Figure DEST_PATH_IMAGE073
Adopt the method for embodiment 5,4-trifluoromethyl-benzyl-alcohol is replaced to chlorobenzyl alcohol, 4-(4-amino-3-methylphenoxy)-N-picoline acid amides replaces, with 4-(4-amino-benzene oxygen)-N-picoline acid amides, obtaining target compound, white solid.Fusing point: 128.6～130.6 ℃.
1H?NMR?(CDCl 3)?δ?(ppm):?8.35?~?8.34?(d,?1H,?pyridine- H),?8.00?(s,?1H,?N HCO),?7.68?~?7.67?(d,?1H,?pyridine- H),?7.65?~?7.63?(d,?1H,?Ar- H),?7.50?~?7.48?(d,?2H,?Ar- H),?7.45?~?7.44?(d,?2H,?Ar- H),?7.04?~?7.02?(d,?2H,?Ar- H),?6.95~?6.93?(m,?1H,?pyridine- H),?6.82?(s,?1H,?N HCO),?5.15?(s,?2H,?C H 2),?3.00?~?2.99?(d,?3H,?C H 3),?2.22?(s,?3H,?C H 3)
ESI-MS m/z:460 (M+1) +, calculated value: 460.
The fluoro-4-of embodiment 31:4-trifluoromethyl phenmethyl-2-(2-(methylamino formyl) pyridine-4-oxygen base) phenyl urethan (SH-038-3)
Adopt the method for embodiment 5,4-trifluoromethyl-benzyl-alcohol is replaced to chlorobenzyl alcohol, 4-(4-amino-3-fluorophenoxy)-N-picoline acid amides replaces, with 4-(4-amino-benzene oxygen)-N-picoline acid amides, obtaining target compound, white solid.Fusing point: 165.4～167.3 ℃.
1H?NMR?(CDCl 3)?δ?(ppm):?8.38?~?8.36?(d,?1H,?pyridine- H),?8.02?(s,?1H,?N HCO),?7.70?~?7.68?(d,?1H,?pyridine- H),?7.68?~?7.67?(d,?1H,?Ar- H),?7.55?~?7.53?(d,?2H,?Ar- H),?7.49?~?7.48?(d,?2H,?Ar- H),?7.06?~?7.04?(d,?2H,?Ar- H),?6.98~?6.97?(m,?1H,?pyridine- H),?6.86?(s,?1H,?N HCO),?5.27?(s,?2H,?C H 2),?3.00?~?2.99?(d,?3H,?C H 3)。
ESI-MS m/z:464 (M+1) +, calculated value: 464.
The chloro-4-of embodiment 32:4-trifluoromethyl phenmethyl-2-(2-(methylamino formyl) pyridine-4-oxygen base) phenyl urethan (SH-038-4)
Adopt the method for embodiment 5,4-trifluoromethyl-benzyl-alcohol is replaced to chlorobenzyl alcohol, 4-(4-amino-3-chlorophenoxy)-N-picoline acid amides replaces, with 4-(4-amino-benzene oxygen)-N-picoline acid amides, obtaining target compound, white solid.Fusing point: 158.7～160.6 ℃.
1H?NMR?(CDCl 3)?δ?(ppm):?8.39?~?8.37?(d,?1H,?pyridine- H),?8.01?(s,?1H,?N HCO),?7.68?~?7.67?(d,?1H,?pyridine- H),?7.65?~?7.64?(d,?1H,?Ar- H),?7.56?~?7.54?(d,?2H,?Ar- H),?7.47?~?7.45?(d,?2H,?Ar- H),?7.04?~?7.03?(d,?2H,?Ar- H),?6.95~?6.93?(m,?1H,?pyridine- H),?6.85?(s,?1H,?N HCO),?5.25?(s,?2H,?C H 2),?3.00?~?2.99?(d,?3H,?C H 3)。
ESI-MS m/z:464 (M+1) +, calculated value: 464.
Embodiment 33:4-trifluoromethyl phenmethyl-4-(2-(methylamino formyl) pyridine-4-oxygen base) aminotoluene carbamate (SH-043)
Figure 109951DEST_PATH_IMAGE078
Adopt the method for embodiment 5,4-trifluoromethyl-benzyl-alcohol is replaced to chlorobenzyl alcohol, with 4-(4-methylamino phenoxy group)-N-picoline acid amides, replace 4-(4-amino-benzene oxygen)-N-picoline acid amides, obtain target compound, white solid.Fusing point: 137.9～139.3 ℃.
1H?NMR?(CDCl 3)?δ?(ppm):?8.91?(s,?1H,?N HCO),?8.45?~?8.44?(d,?1H,?pyridine- H),?7.84?~?7.83?(d,?1H,?pyridine- H),?6.63?~?6.61?(d,?2H,?Ar- H),?7.49?~?7.47?(d,?2H,?Ar- H),?7.42?~?7.40?(d,?2H,?Ar- H),?7.17~?7.15?(m,?1H,?pyridine- H),?7.10?~?7.08?(d,?2H,?Ar- H),?6.87?(s,?1H,?N HCO),?5.21?(s,?2H,?C H 2),?4.43?(s,?2H,?C H 2),?3.04?~?3.03?(d,?3H,?C H 3)。
ESI-MS m/z:460 (M+1) +, calculated value: 460.
The chloro-3-fluorobenzene methyl-4-(2-(of embodiment 34:4-methylamino formyl) pyridine-4-oxygen base) aminotoluene carbamate (SH-044)
Adopt the method for embodiment 5, the fluoro-3-chlorobenzyl alcohol of 4-is replaced to chlorobenzyl alcohol, 4-(4-methylamino phenoxy group)-N-picoline acid amides replaces 4-(4-amino-benzene oxygen)-N-picoline acid amides, obtains this target compound, white solid.Fusing point: 137.9～139.3 ℃.
1H?NMR?(CDCl 3)?δ?(ppm):?8.40?~?8.39?(d,?1H,?pyridine- H),?8.01?(s,?1H,?N HCO),?7.67?~?7.66?(d,?1H,?pyridine- H),?7.39?~?7.39?(d,?3H,?Ar- H),?7.18?~?7.16?(m,?1H,?Ar- H),?7.05?~?7.02?(d,?3H,?Ar- H),?6.98?~?6.97?(d,?1H,?pyridine- H),?6.83?(s,?1H,?N HCO),?5.10?(s,?2H,?C H 2),?4.41?~?4.40?(s,?2H,?C H 2),?3.04?~?3.03?(d,?3H,?C H 3)。
ESI-MS m/z:444 (M+1) +, calculated value: 444.
Embodiment 35: the test of part of compounds anti tumor activity in vitro
Cell dissociation, to count, make concentration be 5 * 10 4the cell suspension of individual/ml, in 96 orifice plates, every hole adds 100 μ L cell suspension (every holes 5 * 10 3individual cell); 96 orifice plates are placed in 37 ℃, 5%CO 2in incubator, cultivate 24 hours; With perfect medium dilution medicine, to desired concn, every hole adds the corresponding pastille substratum of 100 μ L, sets up negative control group, solvent control group, positive controls simultaneously; 96 orifice plates are placed in 37 ℃, 5% CO 2in incubator, cultivate 72 hours; 96 orifice plates are carried out to MTT dyeing, and λ=490nm, measures OD value.Measuring method is that every hole adds 20 μ L MTT(5mg/ml), at incubator, continue to cultivate 4 hours; Discard substratum, every hole adds 150 μ L DMSO to dissolve, and shaking table mixes for 10 minutes gently; λ=490nm, microplate reader is read the OD value in every hole, calculates inhibiting rate.Record result, calculate anti-tumor activity.Experimental result sees the following form
The amino formate compounds external activity test result of kinases inhibitor
Figure 769920DEST_PATH_IMAGE082
Embodiment 37: anti-tumor in vivo active testing
It is model that mouse source sarcoma is take in this experiment, take BAY 43-9006 as contrast, and tested medicine comprises:
First group: model: physiological saline (administration every day 1 time)
Second group: BAY 43-9006 80 mg/kg(administration every day 1 time)
The 3rd group: SH-007 high dose group 80 mg/kg(administration every day 1 time)
The 4th group: SH-007 low dose group 40 mg/kg(administration every day 1 time)
Animal: source, germline, strain: ICR, is provided by Shanghai Si Laike Experimental Animal Center.7 week age, body weight 24-28 g, male.
Experimental technique:
Aseptic extraction mouse ascites, is prepared into 1.0*10 6/ ml cell suspension, is inoculated in ICR mouse oxter with 0.1 mL.Animal random packet, is divided into 4 groups, 10 every group.Administration in the 3rd day after inoculation, administration 7 days, oral administration gavage administration.Dynamically observe the antineoplastic effect of tested thing.After administration the 8th day, mouse was put to death, and operation strips knurl piece and weighs.
The result weighing according to tumor weight is calculated tumor control rate (antitumor ratio): negative group of average knurl weight of (m-mt)/m(m, mt is the average knurl weight for the treatment of group).
Statistical procedures: application SPSS10.0 statistical software carries out statistical study to data.
Experimental result sees the following form:
Grouping BAY 43-9006 Low dosage High dosage
Tumour inhibiting rate 54.1% 45.9% 57.9%

Claims (9)

1. compound or pharmaceutically acceptable salt thereof shown in general formula (I):
Figure FDA0000436910670000011
Wherein:
R 1and R 2independently selected from hydrogen, halogen, C 1-6alkyl, C 3-8cycloalkyl, C 5-8nonaro-maticity heterocyclic radical, OR 3, nitro, NR 4r 5or cyano group;
Aforementioned R 3, R 4and R 5independently selected from hydrogen, C 1-6alkyl;
Abovementioned alkyl, cycloalkyl or nonaro-maticity heterocyclic radical can be by one or more independently selected from halogen, C 1-6alkyl, OH, nitro, NH 2or the substituting group of cyano group replaces;
Wherein a, m and n are independently selected from 0,1,2,3,4 or 5;
B is independently selected from 0,1,2,3 or 4.
2. compound or pharmaceutically acceptable salt thereof shown in general formula according to claim 1 (I), wherein: n be 0,1 or 2, m be 0 or 1.
3. compound or pharmaceutically acceptable salt thereof shown in general formula according to claim 1 and 2 (I), wherein: R 1and R 2independently selected from hydrogen, fluorine, chlorine, bromine, methyl, ethyl, trifluoromethyl, methoxyl group, trifluoromethoxy, hydroxyl, nitro, amino, dimethylin, diethylin or cyano group.
4. compound or pharmaceutically acceptable salt thereof shown in general formula according to claim 3 (I), wherein: R 2independently selected from hydrogen, fluorine, chlorine, bromine, methyl, nitro, amino or cyano group.
5. compound or pharmaceutically acceptable salt thereof shown in general formula according to claim 1 (I), wherein said general formula (I) compound is selected from:
Phenmethyl-4-(2-(methylamino formyl) pyridine-4-oxygen base) phenyl urethan;
Phenmethyl-2-methyl-4-(2-(methylamino formyl) pyridine-4-oxygen base) phenyl urethan;
The chloro-4-(2-(methylamino of phenmethyl-2-formyl) pyridine-4-oxygen base) phenyl urethan;
The fluoro-4-(2-(methylamino of phenmethyl-2-formyl) pyridine-4-oxygen base) phenyl urethan;
4-chlorophenylmethyl-4-(2-(methylamino formyl) pyridine-4-oxygen base) phenyl urethan;
4-chlorophenylmethyl-2-methyl-4-(2-(methylamino formyl) pyridine-4-oxygen base) phenyl urethan;
The fluoro-4-(2-(methylamino of 4-chlorophenylmethyl-2-formyl) pyridine-4-oxygen base) phenyl urethan;
The chloro-4-(2-(methylamino of 4-chlorophenylmethyl-2-formyl) pyridine-4-oxygen base) phenyl urethan;
Styroyl-4-(2-(methylamino formyl) pyridine-4-oxygen base) phenyl urethan;
Phenmethyl-4-(2-(methylamino formyl) pyridine-4-oxygen base) aminotoluene carbamate;
3-trifluoromethyl-4-(2-(methylamino formyl) pyridine-4-oxygen base) aminotoluene carbamate;
3-trifluoromethyl-2-methyl-4-(2-(methylamino formyl) pyridine-4-oxygen base) aminotoluene carbamate;
The fluoro-4-(2-(methylamino of 3-trifluoromethyl-2-formyl) pyridine-4-oxygen base) aminotoluene carbamate;
The chloro-4-(2-(methylamino of 3-trifluoromethyl-2-formyl) pyridine-4-oxygen base) aminotoluene carbamate;
The chloro-3-trifluoromethyl phenmethyl-4-(2-(of 4-methylamino formyl) pyridine-4-oxygen base) phenyl urethan;
The chloro-3-trifluoromethyl phenmethyl-2-of 4-methyl-4-(2-(methylamino formyl) pyridine-4-oxygen base) phenyl urethan;
The fluoro-4-(2-(methylamino of the chloro-3-trifluoromethyl of 4-phenmethyl-2-formyl) pyridine-4-oxygen base) phenyl urethan;
The chloro-4-(2-(methylamino of the chloro-3-trifluoromethyl of 4-phenmethyl-2-formyl) pyridine-4-oxygen base) phenyl urethan;
2-chlorophenylmethyl-4-(2-(methylamino formyl) pyridine-4-oxygen base) phenyl urethan;
The chloro-3-fluorobenzene methyl-4-(2-(of 4-methylamino formyl) pyridine-4-oxygen base) phenyl urethan;
The chloro-3-fluorobenzene methyl-2-of 4-methyl-4-(2-(methylamino formyl) pyridine-4-oxygen base) phenyl urethan;
The fluoro-4-(2-(methylamino of the chloro-3-fluorobenzene of 4-methyl-2-formyl) pyridine-4-oxygen base) phenyl urethan;
The chloro-4-(2-(methylamino of the chloro-3-fluorobenzene of 4-methyl-2-formyl) pyridine-4-oxygen base) phenyl urethan;
The chloro-3-trifluoromethyl phenmethyl-4-(2-(of 4-methylamino formyl) pyridine-4-oxygen base) aminotoluene carbamate;
4-fluorobenzene methyl-4-(2-(methylamino formyl) pyridine-4-oxygen base) phenyl urethan;
4-fluorobenzene methyl-2-methyl-4-(2-(methylamino formyl) pyridine-4-oxygen base) phenyl urethan;
The fluoro-4-(2-(methylamino of 4-fluorobenzene methyl-2-formyl) pyridine-4-oxygen base) phenyl urethan;
The chloro-4-(2-(methylamino of 4-fluorobenzene methyl-2-formyl) pyridine-4-oxygen base) phenyl urethan;
4-trifluoromethyl phenmethyl-4-(2-(methylamino formyl) pyridine-4-oxygen base) phenyl urethan;
4-trifluoromethyl phenmethyl-2-methyl-4-(2-(methylamino formyl) pyridine-4-oxygen base) phenyl urethan;
The fluoro-4-(2-(methylamino of 4-trifluoromethyl phenmethyl-2-formyl) pyridine-4-oxygen base) phenyl urethan;
The chloro-4-(2-(methylamino of 4-trifluoromethyl phenmethyl-2-formyl) pyridine-4-oxygen base) phenyl urethan;
4-trifluoromethyl phenmethyl-4-(2-(methylamino formyl) pyridine-4-oxygen base) aminotoluene carbamate;
The chloro-3-fluorobenzene methyl-4-(2-(of 4-methylamino formyl) pyridine-4-oxygen base) aminotoluene carbamate.
6. according to compound and pharmaceutical salts thereof shown in the general formula described in any one in claim 1 to 5 (I), it is characterized in that described pharmaceutical salts is to be formed with the acid that is selected from sulfuric acid, hydrochloric acid, Hydrogen bromide, phosphoric acid, phenylformic acid, toluylic acid, Phenylsulfonic acid, methylsulfonic acid, tosic acid, trifluoromethanesulfonic acid, acetic acid, trifluoroacetic acid, tartrate, oxysuccinic acid, citric acid, lactic acid, oxalic acid, fumaric acid, toxilic acid, Whitfield's ointment, tussol, succsinic acid by the compound with logical formula I.
7. a method of preparing the compound or pharmaceutically acceptable salt thereof described in any one in claim 1 to 6, is characterized in that comprising:
The preparation of compound shown in general formula (I):
1) take N-methyl-4-Chloro-2-Pyridyle methane amide is raw material, with the ether of formula (II) compound formation formula (III), then reacts and obtains target compound with formula (IV) compound:
Figure FDA0000436910670000031
Or
2) take N-methyl-4-Chloro-2-Pyridyle methane amide is raw material, with the ether of formula (II) compound formation formula (III), then reacts and obtains target compound with formula V compound in the medium that has dicarbapentaborane imidazoles (CDI):
The preparation of pharmaceutical salts:
Optionally, by aforesaid method 1) or 2) product that obtains prepares its pharmacy acceptable salt with corresponding acid-respons.
8. the application in the pharmaceutical composition that in claim 1 to 6, compound or pharmaceutically acceptable salt thereof shown in the logical formula I described in any one is prepared treatment or prophylaxis of tumours as medicine or the conduct of preparation treatment or prophylaxis of tumours.
9. application according to claim 8, described tumour is cancer of the stomach, liver cancer, lung cancer, the esophageal carcinoma, cervical cancer, mammary cancer, colorectal carcinoma, the rectum cancer, nasopharyngeal carcinoma, ovarian cancer, kidney, bladder cancer, thyroid carcinoma, skin carcinoma, myosarcoma, fibrosarcoma, liposarcoma, osteosarcoma, chondrosarcoma, angiosarcoma, lymphosarcoma, leukemia, melanoma, retinocytoma, withered Bo Shi knurl, Ewing' s tumor, malignant hemangioendothelioma, lymphatic cancer, bladder cancer, prostate cancer, uterus carcinoma, ovarian cancer, hysteromyoma and/or oral carcinoma.
CN201110309841.7A 2011-10-13 2011-10-13 Carbamate compound and application thereof in antitumor drug Expired - Fee Related CN102898363B (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN201110309841.7A CN102898363B (en) 2011-10-13 2011-10-13 Carbamate compound and application thereof in antitumor drug

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CN201110309841.7A CN102898363B (en) 2011-10-13 2011-10-13 Carbamate compound and application thereof in antitumor drug

Publications (2)

Publication Number Publication Date
CN102898363A CN102898363A (en) 2013-01-30
CN102898363B true CN102898363B (en) 2014-04-09

Family

ID=47570886

Family Applications (1)

Application Number Title Priority Date Filing Date
CN201110309841.7A Expired - Fee Related CN102898363B (en) 2011-10-13 2011-10-13 Carbamate compound and application thereof in antitumor drug

Country Status (1)

Country Link
CN (1) CN102898363B (en)

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103087054B (en) * 2013-02-27 2015-12-23 山东大学 4-pyridine phenyl ether compounds and preparation method thereof and application

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101711154A (en) * 2007-02-26 2010-05-19 科森生物科学公司 carbamate compounds
CN101830899A (en) * 2004-12-23 2010-09-15 霍夫曼-拉罗奇有限公司 Heterocyclic carbamate derivatives, their manufacture and use as pharmaceutical agents

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101830899A (en) * 2004-12-23 2010-09-15 霍夫曼-拉罗奇有限公司 Heterocyclic carbamate derivatives, their manufacture and use as pharmaceutical agents
CN101711154A (en) * 2007-02-26 2010-05-19 科森生物科学公司 carbamate compounds

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
刘健颖,等.索拉非尼研究进展.《海峡药学》.2010,第22卷(第4期),9-11.
张庆文，等.一锅法制备抗肿瘤药对甲苯磺酸索拉非尼.《中国药物化学杂志》.2010,第20卷(第5期),358-361. *
索拉非尼研究进展;刘健颖,等;《海峡药学》;20101231;第22卷(第4期);9-11 *

Also Published As

Publication number Publication date
CN102898363A (en) 2013-01-30

Similar Documents

Publication Publication Date Title
TW202012404A (en) Combination product of bcl-2 inhibitor and chemotherapeutic agent and use thereof in the prevention and/or treatment of diseases
CN106565686B (en) Antitubulin
US20160031890A1 (en) Novel methods, compounds, and compositions for inhibition of ros
CN105985342A (en) Pyrimido pyrimidine dione derivative as EGFR inhibitor and application thereof
CN104230952B (en) Compound containing pyrimidine skeleton, and preparation method and use of compound
TR201815685T4 (en) Combinations of act and mec inhibitory compounds for the treatment of cancer.
CN106831812B (en) Simultaneously pyrimidine or pyrazine compounds and its application of the heterocycle of the amide structure containing biaryl
TW201915004A (en) Thienopyridine compound, and preparing method, pharmaceutical composition and application thereof for preparing a medicament capable of preventing or treating tumor growth and metastasis
CN102898363B (en) Carbamate compound and application thereof in antitumor drug
CN106822904B (en) The pharmaceutical composition and its application of inhibitor containing AKT and IRE1 inhibitor
WO2021143927A1 (en) Compound acting as bcr-abl inhibitor
CN113444075B (en) Indoline derivative, preparation method thereof, pharmaceutical composition and application thereof
CN105476996A (en) Application of curcumin and afatinib for combined treatment of non-small cell lung cancer
CN104829613A (en) Diaryl-substituted pyrazolo ring derivative and preparation method thereof, and applications of diaryl-substituted pyrazolo ring derivative in medicine field
CN103159741B (en) The preparation of one class tyrosine kinase inhibitor and purposes
CN111039915B (en) Raf kinase inhibitor, preparation method, pharmaceutical composition and application thereof
CN104402861A (en) Benzene sulfonamide derivatives, preparation method, and treatment application
CN104884061A (en) Compounds for treating Rac-GTPase mediated disorder
CN102552300B (en) Application of monensin as STAT 3 signal specific inhibitor
CN106749338A (en) 1,3- bis- substitution 1H- pyrrolo- [3,2-c] pyridine compounds and application thereof
CN113444074A (en) Compound with EGFR (epidermal growth factor receptor) and Wnt dual inhibition effects as well as preparation method and application thereof
CN115448906B (en) 2-anilinopyrimidine derivative and preparation method and application thereof
CN104402875A (en) Synthesis method and application N-(2-aminoethyl)-N'-(6-substituted-2-benzothiazolyl)urea and salt compounds thereof
CN103965202B (en) Bicyclic-fused heterogeneous ring compound, Preparation Method And The Use
CN113135938B (en) Substituted macrocyclic tyrosine kinase inhibitors and uses thereof

Legal Events

Date Code Title Description
C06 Publication
PB01 Publication
C10 Entry into substantive examination
SE01 Entry into force of request for substantive examination
C14 Grant of patent or utility model
GR01 Patent grant
C56 Change in the name or address of the patentee
CP03 Change of name, title or address

Address after: 210018 No. 9 Zhong Hui Road, Nanjing economic and Technological Development Zone, Nanjing, Jiangsu

Patentee after: NANJING SANHOME PHARMACEUTICAL Co.,Ltd.

Address before: 210018, Jiangsu, Zhujianglu Road 222 Nanjing long hair science and technology building, 16 floor

Patentee before: NANJING SANHOME PHARMACEUTICAL Co.,Ltd.

CF01 Termination of patent right due to non-payment of annual fee
CF01 Termination of patent right due to non-payment of annual fee

Granted publication date: 20140409