CN108727293A - 1,2,8- oxo diazacyclo nonyl- 9- ketone derivatives and its synthetic method - Google Patents

1,2,8- oxo diazacyclo nonyl- 9- ketone derivatives and its synthetic method Download PDF

Info

Publication number
CN108727293A
CN108727293A CN201810654336.8A CN201810654336A CN108727293A CN 108727293 A CN108727293 A CN 108727293A CN 201810654336 A CN201810654336 A CN 201810654336A CN 108727293 A CN108727293 A CN 108727293A
Authority
CN
China
Prior art keywords
indicate
unsubstituted
alkyl
synthetic method
perfluoroalkyl
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
Application number
CN201810654336.8A
Other languages
Chinese (zh)
Other versions
CN108727293B (en
Inventor
莫冬亮
邹宁
陈春华
冯钰�
苏桂发
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.)
Guangxi Normal University
Original Assignee
Guangxi Normal University
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 Guangxi Normal University filed Critical Guangxi Normal University
Priority to CN201810654336.8A priority Critical patent/CN108727293B/en
Publication of CN108727293A publication Critical patent/CN108727293A/en
Application granted granted Critical
Publication of CN108727293B publication Critical patent/CN108727293B/en
Active legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D273/00—Heterocyclic compounds containing rings having nitrogen and oxygen atoms as the only ring hetero atoms, not provided for by groups C07D261/00 - C07D271/00
    • C07D273/02—Heterocyclic compounds containing rings having nitrogen and oxygen atoms as the only ring hetero atoms, not provided for by groups C07D261/00 - C07D271/00 having two nitrogen atoms and only one oxygen atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/07—Optical isomers

Abstract

The invention discloses a kind of 1,2,8- oxo diazacyclo nonyl- 9- ketone derivatives and its synthetic methods.Shown in the structure of derivative of the present invention such as following formula (I), synthetic method is：It takes compound shown in compound and formula (III) as shown in following formula (II) to be placed in organic solvent, reacts in the presence of oxygen, object crude product is made.The method of the invention is simple and easy to control, and the period is short, is not required to anhydrous and oxygen-free condition.The compound difference of structure shown in the formula (I), formula (II) and formula (III) is as follows：R6N=C=X (III)；Wherein：R1Indicate 4- nitrobenzophenones；R2Indicate phenyl；R3Indicate methyl；R4Indicate methyl；R5Indicate hydrogen atom；R6Indicate 4- aminomethyl phenyls；X indicates oxygen atom.

Description

1,2,8- oxo diazacyclo nonyl- 9- ketone derivatives and its synthetic method
The application is the divisional application of " 1- oxygen -2,8- diazacyclo nonane derivatives and its synthetic method ", original application The applying date is：On September 18th, 2016, application No. is：201610826407.9 entitled：1- oxygen -2,8- diazacyclo nonyls Alkane derivatives and its synthetic method.
Technical field
The present invention relates to pharmaceutical technology fields, and in particular to a kind of 1- oxygen -2,8- diazacyclo nonane derivatives and its conjunction At method.
Background technology
Diazacyclo nonane skeleton is core skeleton important in natural products and drug molecule, is important physiological activity Unit has important application in antitumor, anticancer etc..Since diaza nine-atomic ring skeleton is always in organic synthesis Difficult point and challenge so that the application of this kind of compound is limited by very large.The plan of this nine circle heterocyclic rings skeleton is synthesized at present Slightly can by the cascade reaction of palladium chtalyst (R.Shintani, K.Ikehata, T.Hayashi, J.Org.Chem.2011,76, 4776-4780), multi-component cascade reaction (A.F.De la Torre, D.G.Rivera, O.Concepci ó n, R.Echemendia, A.G.Correa, M.W.Paixao, J.Org.Chem.2016,81,803-809) etc., but these methods are all The deficiencies of it is limited that there are substrates, and functional group compatibility is poor, and more complex using raw material.
Invention content
The technical problem to be solved in the present invention is to provide a series of 1- oxygen -2,8- diazacyclo nonanes of structure novels derivatives Object and their synthetic method.
The present invention relates to compound shown in lower formula (I) or its pharmaceutically acceptable salts：
Wherein：
R1Indicate hydrogen, C1~4Alkyl, C1~4Alkoxy, C1~4Perfluoroalkyl or halogen atom or unsubstituted, single The unsubstituted furyl of phenyl or the unsubstituted thiophene of substitution, two substitutions, three substitutions, four substitutions or five substitutions Pheno base or unsubstituted naphthalene；Wherein, substituent group C1~4Alkoxy, C1~4Perfluoroalkyl, C1~4Alkyl, cyanogen Base or halogen atom；
R2Indicate hydrogen, C1~4Alkyl, C1~4Alkoxy, C1~4Perfluoroalkyl or halogen atom or unsubstituted, single The unsubstituted furyl of phenyl or the unsubstituted thiophene of substitution, two substitutions, three substitutions, four substitutions or five substitutions Pheno base or unsubstituted naphthalene；Wherein, substituent group C1~4Alkoxy, C1~4Perfluoroalkyl, C1~4Alkyl, cyanogen Base or halogen atom；
R3Indicate hydrogen, C1~8Alkyl, C1~6Alkoxy or C1~4Perfluoroalkyl or it is unsubstituted, monosubstituted or Disubstituted phenyl；Wherein, substituent group C1~4Alkoxy, C1~4Perfluoroalkyl, C1~6Alkyl or halogen atom；
R4Indicate hydrogen, C1~8Alkyl, C1~6Alkoxy or C1~4Perfluoroalkyl or it is unsubstituted, monosubstituted or Disubstituted phenyl；Wherein, substituent group C1~4Alkoxy, C1~4Perfluoroalkyl, C1~6Alkyl or halogen atom；
R5Indicate hydrogen, C1~8Alkyl, C1~6Alkoxy or C1~4Perfluoroalkyl or it is unsubstituted, monosubstituted or Disubstituted phenyl；Wherein, substituent group C1~4Alkoxy, C1~4Perfluoroalkyl, C1~6Alkyl or halogen atom；
R6Indicate hydrogen, C1~12Alkyl, C1~4Alkoxy, C1~4Perfluoroalkyl or halogen atom or unsubstituted, single Substitution, two substitutions, three substitutions or the unsubstituted furyl of quaternary phenyl or unsubstituted thienyl, or Person is unsubstituted naphthalene；Wherein, substituent group C1~4Alkoxy, C1~4Perfluoroalkyl, C1~4Alkyl, cyano or halogen it is former Son；
X indicates oxygen or sulphur atom.
In above compound：
R1Further preferably hydrogen or C1~4Alkyl or unsubstituted, monosubstituted or disubstituted phenyl；
R2Further preferably hydrogen or C1~4Alkyl or unsubstituted, monosubstituted or disubstituted phenyl；
R3Further preferably hydrogen or C1~4Alkyl or unsubstituted, monosubstituted or disubstituted phenyl；
R4Further preferably hydrogen or C1~4Alkyl or unsubstituted, monosubstituted or disubstituted phenyl；
R5Further preferably hydrogen or C1~4Alkyl or unsubstituted, monosubstituted or disubstituted phenyl；
R6Further preferably hydrogen or C1~12Alkyl or unsubstituted, monosubstituted or disubstituted phenyl.
The synthetic method of compound, mainly includes the following steps that shown in above-mentioned formula (I)：Take the compound as shown in following formula (II) It with compound shown in formula (III), is placed in organic solvent, reacts in the presence of oxygen, object crude product is made；
Wherein：
R1Indicate hydrogen, C1~4Alkyl, C1~4Alkoxy, C1~4Perfluoroalkyl or halogen atom or unsubstituted, single The unsubstituted furyl of phenyl or the unsubstituted thiophene of substitution, two substitutions, three substitutions, four substitutions or five substitutions Pheno base or unsubstituted naphthalene；Wherein, substituent group C1~4Alkoxy, C1~4Perfluoroalkyl, C1~4Alkyl, cyanogen Base or halogen atom；
R2Indicate hydrogen, C1~4Alkyl, C1~4Alkoxy, C1~4Perfluoroalkyl or halogen atom or unsubstituted, single The unsubstituted furyl of phenyl or the unsubstituted thiophene of substitution, two substitutions, three substitutions, four substitutions or five substitutions Pheno base or unsubstituted naphthalene；Wherein, substituent group C1~4Alkoxy, C1~4Perfluoroalkyl, C1~4Alkyl, cyanogen Base or halogen atom；
R3Indicate hydrogen, C1~8Alkyl, C1~6Alkoxy or C1~4Perfluoroalkyl or it is unsubstituted, monosubstituted or Disubstituted phenyl；Wherein, substituent group C1~4Alkoxy, C1~4Perfluoroalkyl, C1~6Alkyl or halogen atom；
R4Indicate hydrogen, C1~8Alkyl, C1~6Alkoxy or C1~4Perfluoroalkyl or it is unsubstituted, monosubstituted or Disubstituted phenyl；Wherein, substituent group C1~4Alkoxy, C1~4Perfluoroalkyl, C1~6Alkyl or halogen atom；
R5Indicate hydrogen, C1~8Alkyl, C1~6Alkoxy or C1~4Perfluoroalkyl or it is unsubstituted, monosubstituted or Disubstituted phenyl；Wherein, substituent group C1~4Alkoxy, C1~4Perfluoroalkyl, C1~6Alkyl or halogen atom；
R6Indicate hydrogen, C1~12Alkyl, C1~4Alkoxy, C1~4Perfluoroalkyl or halogen atom or unsubstituted, single Substitution, two substitutions, three substitutions or the unsubstituted furyl of quaternary phenyl or unsubstituted thienyl, or Person is unsubstituted naphthalene；Wherein, substituent group C1~4Alkoxy, C1~4Perfluoroalkyl, C1~4Alkyl, cyano or halogen it is former Son；
X indicates oxygen or sulphur atom.
In above-mentioned synthetic method, R1、R2、R3、R4、R5And R6Preferential selection it is as previously described.
In above-mentioned synthetic method, compound shown in formula (II) is N- alkenyl α, β-unsaturation nitrone derivative, be can refer to Existing literature (D.Kontokosta, D.S.Muller, D.L.Mo, W.H.Pace, R.A.Simpon, L.L.Anderson, Beilstein J.Org, Chem.2015,11,2097) synthesized, also can free design synthetic route synthesized, herein No longer it is described in detail.And compound shown in formula (III) is isocyanide ester or isothiocyanate, directly can commercially be obtained (such as Phenyl isonitrile acid, isobutyl group isocyanide ester, benzyl isocyanide ester, phenyl isothiocyanate etc.)
In above-mentioned synthetic method, the organic solvent can be selected from benzene, toluene, hexamethylene, petroleum ether, four chlorinations It is a kind of in carbon, tetrahydrofuran, ethyl acetate, acetonitrile, ether, dichloromethane, acetone, chloroform, n-hexane and dioxane Or two or more combination.When the combination for being selected as the above substance of above two of organic solvent, their proportioning can be Arbitrary proportioning.
In above-mentioned synthetic method, reaction, which is typically chosen under air conditions, to be carried out, and simultaneous reactions are preferably less than 100 DEG C Under conditions of carry out, be further preferred that under conditions of room temperature is to 80 DEG C and carry out, more preferably carried out under conditions of 80 DEG C. Whether reaction can be used TLC tracing detections completely.According to the experience of applicant, when reaction carries out under the conditions of room temperature is to 80 DEG C When, reaction time control is more suitable in 5~20h.
In synthetic method of the present invention, the consumption proportion of each raw material is stoichiometric ratio, in practical operation, formula (II) molar ratio of compound is usually 1.0 shown in compound and formula (III) shown in：1.0~5.0.The use of the organic solvent Amount is advisable with that can dissolve the raw material participated in and reacted, it is generally the case that on the basis of compound shown in the formula (II) of 1mmol, institute There is the raw material for participating in reaction usually to be dissolved with the organic solvent of 1~10mL.
It is the crude product of formula (I) compound made from the above method, existing conventional purification process can be used, it is carried out Purifying is to improve the purity of formula (I) compound.Generally use silica gel thin-layer chromatography or silica gel column chromatography, or recrystallization side Formula is purified, and the eluant, eluent in chromatography is identical with solvent when recrystallization, can be by petroleum ether and ethyl acetate By 10：1~1：The mixed solvent of 1 volume ratio composition can also be by n-hexane and ethyl acetate by 10:1~1:1 volume Than the mixed solvent of composition, can also be by petroleum ether and methanol by 100:1~10:The mixed solvent of 1 volume ratio composition, again Either 100 are pressed by dichloromethane and methanol:1~10:The mixed solvent of 1 volume ratio composition.
The present invention also provides compound or its pharmaceutically acceptable salts shown in above-mentioned formula (I) in the preparation of antitumor drugs Application.
Compared with prior art, the present invention provides a series of 1- oxygen -2,8- diazacyclo nonanes of structure novels derivatives Object and its synthetic method, synthetic method provided by the invention is simple and easy to control, and the period is short, is not required to anhydrous and oxygen-free condition.
Specific implementation mode
With reference to specific embodiment, the present invention is described in further detail, to more fully understand present disclosure, but The present invention is not limited to following embodiments.
N- alkenyl α, β-unsaturation nitrone derivative (i.e. compound shown in formula (II)) ginseng involved in following embodiment It is synthesized according to following synthetic routes：
Wherein,
R1Indicate hydrogen, C1~4Alkyl, C1~4Alkoxy, C1~4Perfluoroalkyl or halogen atom or unsubstituted, single The unsubstituted furyl of phenyl or the unsubstituted thiophene of substitution, two substitutions, three substitutions, four substitutions or five substitutions Pheno base or unsubstituted naphthalene；Wherein, substituent group C1~4Alkoxy, C1~4Perfluoroalkyl, C1~4Alkyl, cyanogen Base or halogen atom；
R2Indicate hydrogen, C1~4Alkyl, C1~4Alkoxy, C1~4Perfluoroalkyl or halogen atom or unsubstituted, single The unsubstituted furyl of phenyl or the unsubstituted thiophene of substitution, two substitutions, three substitutions, four substitutions or five substitutions Pheno base or unsubstituted naphthalene；Wherein, substituent group C1~4Alkoxy, C1~4Perfluoroalkyl, C1~4Alkyl, cyanogen Base or halogen atom；
R3Indicate hydrogen, C1~8Alkyl, C1~6Alkoxy or C1~4Perfluoroalkyl or it is unsubstituted, monosubstituted or Disubstituted phenyl；Wherein, substituent group C1~4Alkoxy, C1~4Perfluoroalkyl, C1~6Alkyl or halogen atom；
R4Indicate hydrogen, C1~8Alkyl, C1~6Alkoxy or C1~4Perfluoroalkyl or it is unsubstituted, monosubstituted or Disubstituted phenyl；Wherein, substituent group C1~4Alkoxy, C1~4Perfluoroalkyl, C1~6Alkyl or halogen atom；
R5Indicate hydrogen, C1~8Alkyl, C1~6Alkoxy or C1~4Perfluoroalkyl or it is unsubstituted, monosubstituted or Disubstituted phenyl；Wherein, substituent group C1~4Alkoxy, C1~4Perfluoroalkyl, C1~6Alkyl or halogen atom.
By Cu (OAc)2(0.3mmol, 54mg), α, β-unsaturated oxime substrate S1 (0.3mmol) and ene boric acid S2 (0.9mmol) is placed in reaction tube, and 3mL1 is added, and pyridine (3mmol, 0.24mL) is added in 2- dichloroethanes at room temperature；At 25 DEG C Lower stirring 12~for 24 hours, water (10mL) is added in gained reactant, extracts (2 × 10mL) with dichloromethane, merges organic phase, with nothing It is filtered after aqueous sodium persulfate drying, solvent is removed under reduced pressure, silica gel column chromatography detaches (petrol ether/ethyl acetate=10 on residue：1~ 1：1, volume ratio), obtain target product 1 (i.e. compound N-alkenyl α shown in formula (II), β-unsaturation nitrone).
Isocyanide ester or isothiocyanate (i.e. compound shown in formula (III)) involved in following embodiment are from city It is directly commercially available on field.
Embodiment 1
1- oxygen -2,8- diazacyclo nonane derivatives of the present invention are synthesized by following synthetic routes.
Wherein,
R1Indicate hydrogen, C1~4Alkyl, C1~4Alkoxy, C1~4Perfluoroalkyl or halogen atom or unsubstituted, single The unsubstituted furyl of phenyl or the unsubstituted thiophene of substitution, two substitutions, three substitutions, four substitutions or five substitutions Pheno base or unsubstituted naphthalene；Wherein, substituent group C1~4Alkoxy, C1~4Perfluoroalkyl, C1~4Alkyl, cyanogen Base or halogen atom；
R2Indicate hydrogen, C1~4Alkyl, C1~4Alkoxy, C1~4Perfluoroalkyl or halogen atom or unsubstituted, single The unsubstituted furyl of phenyl or the unsubstituted thiophene of substitution, two substitutions, three substitutions, four substitutions or five substitutions Pheno base or unsubstituted naphthalene；Wherein, substituent group C1~4Alkoxy, C1~4Perfluoroalkyl, C1~4Alkyl, cyanogen Base or halogen atom；
R3Indicate hydrogen, C1~8Alkyl, C1~6Alkoxy or C1~4Perfluoroalkyl or it is unsubstituted, monosubstituted or Disubstituted phenyl；Wherein, substituent group C1~4Alkoxy, C1~4Perfluoroalkyl, C1~6Alkyl or halogen atom；
R4Indicate hydrogen, C1~8Alkyl, C1~6Alkoxy or C1~4Perfluoroalkyl or it is unsubstituted, monosubstituted or Disubstituted phenyl；Wherein, substituent group C1~4Alkoxy, C1~4Perfluoroalkyl, C1~6Alkyl or halogen atom；
R5Indicate hydrogen, C1~8Alkyl, C1~6Alkoxy or C1~4Perfluoroalkyl or it is unsubstituted, monosubstituted or Disubstituted phenyl；Wherein, substituent group C1~4Alkoxy, C1~4Perfluoroalkyl, C1~6Alkyl or halogen atom；
R6Indicate hydrogen, C1~12Alkyl, C1~4Alkoxy, C1~4Perfluoroalkyl or halogen atom or unsubstituted, single Substitution, two substitutions, three substitutions or the unsubstituted furyl of quaternary phenyl or unsubstituted thienyl, or Person is unsubstituted naphthalene；Wherein, substituent group C1~4Alkoxy, C1~4Perfluoroalkyl, C1~4Alkyl, cyano or halogen it is former Son.
By N- alkenyl α, β-unsaturation nitrone substrate 1 (0.3mmol), isocyanide ester 2 (0.9mmol) are placed in reaction tube, 3mL dimethyl sulfoxide (DMSO)s are added, 5-20h is stirred to react at 80 DEG C, gained reactant is added water (10mL), is extracted with dichloromethane (2 × 10mL) merges organic phase, is filtered after being dried with anhydrous sodium sulfate, and solvent is removed under reduced pressure, and silica gel column chromatography detaches on residue (petrol ether/ethyl acetate=10：1~1：1, volume ratio), obtain target product 3.It different target product and its is characterized as below：
3a:Solid, 66mg, 76%yield；mp 100-102℃.1H NMR(400MHz,CDCl3):δ7.35–7.29 (m, 2H), 7.23 (t, J=6.5Hz, 3H), 7.19-7.07 (m, 7H), 7.01 (d, J=8.3Hz, 2H), 6.40 (q, J= 16.1Hz, 2H), 5.92 (d, J=10.9Hz, 1H), 3.83 (d, J=10.9Hz, 1H), 2.66 (q, J=7.4Hz, 1H), 2.20 (s, 3H), 1.99 (s, 3H), 1.39 (d, J=7.4Hz, 3H)；13C NMR(100MHz,CDCl3):δ177.3,154.1, 143.7,137.2,136.2,135.5,134.5,130.1,128.4,128.4,127.9,127.5,126.8,126.2, 125.6,125.4,124.3,123.3,46.8,44.6,20.1,19.9,13.1；IR(neat):3453,3036,2928, 1731,1634,1509,969,695cm-1；MS(ESI)m/z[M+H]+calcd for[C29H29N2O2]+:437.2229； found:437.2230. its structural formula is as follows：
3b:Solid, 40mg, 40%yield；mp 96-97℃.1H NMR(400MHz,CDCl3):δ7.19–7.08(m, 4H), 7.04 (dd, J=10.7,8.0Hz, 2H), 6.99 (d, J=8.3Hz, 2H), 6.87-6.79 (m, 2H), 6.67 (d, J= 8.8Hz, 2H), 6.35-6.22 (m, 2H), 5.82 (d, J=10.9Hz, 1H), 4.08-3.95 (m, 1H), 3.72 (s, 3H), 3.65 (s, 3H), 2.60 (q, J=7.4Hz, 1H), 2.17 (s, 3H), 1.95 (d, J=4.3Hz, 3H), 1.34 (d, J= 7.4Hz,3H).13C NMR(100MHz,CDCl3):δ160.2,158.6,150.6,150.1,135.9,135.6,134.8, 133.6,130.5,130.1,129.5,129.1,128.2,125.0,124.3,121.4,114.4,114.1,56.7,56.1, 51.7,45.6,21.1,18.4,16.2.IR(neat):3451,3032,2924,2850,1733,1606,1510,968, 635cm-1；MS(ESI)m/z[M+H]+calcd for[C31H33N2O4]+:497.2440；found:497.2470. its structural formula It is as follows：
3c:Solid, 67mg, 59%yield；mp 98-99℃.1H NMR(400MHz,CDCl3):δ 7.60 (d, J= 8.2Hz, 2H), 7.41 (d, J=8.3Hz, 2H), 7.36 (d, J=8.1Hz, 2H), 7.23 (d, J=8.2Hz, 2H), 7.11 (d, J=8.5Hz, 2H), 7.05 (d, J=8.4Hz, 2H), 6.52 (d, J=16.0Hz, 1H), 6.40 (d, J=16.0Hz, 1H), 5.95 (d, J=10.9Hz, 1H), 3.92 (d, J=10.9Hz, 1H), 2.64 (q, J=7.4Hz, 1H), 2.22 (s, 3H), 2.02 (s, 3H), 1.42 (d, J=7.4Hz, 3H)13CNMR(100MHz,CDCl3):δ178.3,155.2,148.6,140.1, 138.9,137.2,136.2,130.5,129.9,129.5,127.8,127.4,126.9,12 6.8 (d, J=15Hz), 125.8 (d, J=15Hz), 47.7,45.9,30.0,21.4,21.2,14.4.IR (neat):3446,3047,2925,1730,1624, 1511,966,685cm-1；MS(ESI)m/z[M+H]+calcd for[C31H27F6N2O2]+:573.1977；found: 573.1963. its structural formula is as follows：
3d:Solid, 72.5mg, 61%yield；mp 153-154℃.1H NMR(500MHz,CDCl3):δ 7.42 (d, J= 8.4Hz, 2H), 7.25 (d, J=8.5Hz, 2H), 7.12-7.03 (m, 4H), 6.98 (m, 4H), 6.38 (d, J=16.0Hz, 1H), 6.27 (d, J=16.0Hz, 1H), 5.84 (d, J=10.9Hz, 1H), 3.76 (d, J=10.9Hz, 1H), 2.70 (q, J= 7.4Hz, 1H), 2.18 (s, 3H), 1.97 (s, 3H), 1.33 (d, J=7.4Hz, 3H)；13C NMR(125MHz,CDCl3):δ 178.7,155.6,144.1,138.9,137.5,136.3,135.9,133.1,132.2,130.8,130.1,129.3, 128.9,128.5,126.4,124.7,122.3,121.7,48.2,45.7,21.8,21.6,14.6.IR(neat):3433, 3022,2919,2858,1722,1632,1486,974,658cm-1；MS(ESI)m/z[M+H]+calcd for [C28H27Br2N2O2]+:593.0439；found:593.0432. its structural formula is as follows：
3e:Solid, 34mg, 52%yield；mp 93-94℃.1H NMR(500MHz,CDCl3):δ7.64–7.50(m, 2H), 7.46-7.31 (m, 3H), 7.14 (s, 4H), 5.10 (d, J=10.8Hz, 1H), 3.18-3.15 (m, 2H), 2.43 (q, J =7.4Hz, 1H), 2.10 (s, 3H), 1.93 (s, 3H), 1.33 (d, J=7.4Hz, 3H)13C NMR(125MHz,CDCl3):δ 156.2,152.3,138.4,136.8,136.0,134.8,132.3,130.5,130.3,130.2,125.5,122.6,36.7, 33.6,22.4,19.9,18.8.IR(neat):3426,3014,2927,2846,1713,1647,1467,989,654cm-1；MS (ESI)m/z[M+H]+calcd for[C21H23N2O2]+:335.1760；found:335.1743. its structural formula is as follows：
3f:Solid, 51mg, 56%yield；mp 165-166℃.1H NMR(400MHz,CDCl3):δ 8.21 (d, J= 8.4Hz, 2H), 7.44 (d, J=8.7Hz, 2H), 7.25-7.23 (m, 2H), 7.17-7.09 (m, 3H), 6.97 (d, J= 8.3Hz, 2H), 6.91 (d, J=8.3Hz, 2H), 5.85 (d, J=10.8Hz, 1H), 4.06 (d, J=10.8Hz, 1H), 2.62 (q, J=7.4Hz, 1H), 2.13 (s, 3H), 2.03 (s, 3H), 1.38 (d, J=7.4Hz, 3H)13C NMR(100MHz, CDCl3):δ178.4,155.3,152.4,147.4,141.4,136.8,136.6,136.0,129.7,128.7,128.7, 127.9,127.4,125.2,125.1,123.8,47.1,46.2,21.5,21.2,14.4.IR(neat):3451,2959, 2925,2859,1740,1640,1513,984,754,693cm-1；MS(ESI)m/z[M+H]+calcd for[C27H26N3O4]+: 456.1923；found:456.1919. its structural formula is as follows：
3g:Solid, 38mg, 54%yield；mp 96-97℃.1H NMR(500MHz,CDCl3):δ7.79–7.64(m, 2H), 7.59-7.43 (m, 3H), 7.32-7.20 (m, 4H), 5.12 (d, J=12.4Hz, 1H), 3.16 (s, 3H), 2.34 (s, 3H), 2.20-1.87 (m, 1H), 1.59-1.32 (m, 1H), 1.08-1.06 (d, J=10.1,3H), 1.05-1.03 (d, J= 10.1,3H)；13C NMR(125MHz,CDCl3):δ157.5,152.3,137.8,136.9,136.5,136.1,132.1, 130.5,130.4,130.1,125.2,45.1,35.9,22.2,19.7,19.1,14.5.IR(neat):3453,2961, 2865,1746,1654,1503,980,694cm-1；MS(ESI)m/z[M+H]+calcd for[C22H25N2O2]+:349.1916； found:349.1925. its structural formula is as follows：
3h:Solid, 37mg, 46%yield；mp 99-100℃.1H NMR(500MHz,CDCl3):δ7.45–7.41(m, 1H), 7.34-7.28 (m, 3H), 7.33 (s, 4H), 5.49 (d, J=12.5Hz, 1H), 2.85 (dd, J=22.2,12.4Hz, 1H), 2.65 (s, 3H), 2.44 (s, 3H), 2.33-2.23 (m, 1H), 1.14 (d, J=12.8Hz, 1H)；13C NMR(125MHz, CDCl3):δ153.3,152.4(,144.4,137.8,133.9,131.6,131.0,128.8,126.1,124.5,122.4, 120.3,111.9,53.1,47.8,23.1,20.5,18.2.IR(neat):3442,2978,2858,1739,1649,1505, 973,691cm-1；MS(ESI)m/z[M+H]+calcd for[C22H22F3N2O2]+:403.1633；found:403.1654. it is tied Structure formula is as follows：
3i:Solid, 63mg, 63%yield；mp 104-105℃.1H NMR(500MHz,CDCl3):δ7.94–7.85(m, 2H), 7.53-7.45 (m, 5H), 7.38-7.26 (m, 6H), 7.26-7.15 (m, 6H), 6.76 (d, J=16Hz, 1H), 6.50 (d, J=16Hz, 1H), 5.51 (d, J=12.5Hz, 1H), 3.85 (d, J=12.5Hz, 1H), 3.53 (q J=7.5Hz, 1H), 2.27 (s, 3H), 1.19 (d, J=13.0Hz, 3H)；13C NMR(125MHz,CDCl3):δ142.9,136.6,136.5, 135.7,135.4,134.5,130.6,130.7,129.8,129.7,129.7,129.2,128.8,128.6,128.5, 128.3,48.3,42.8,21.3,15.2.IR(neat):3458,3048,2930,1754,1623,1521,956,698cm-1； MS(ESI)m/z[M+H]+calcd for[C34H31N2O2]+:499.2386；found:499.2364. its structural formula is as follows：
3j:Solid, 54mg, 58%yield；mp 103-104℃.1H NMR(400MHz,CDCl3):δ7.36–7.25(m, 2H), 7.26-7.18 (m, 2H), 7.15-7.04 (m, 7H), 6.99 (d, J=8.2Hz, 2H), 6.42 (d, J=16Hz, 1H), 6.37 (d, J=16Hz, 1H), 5.96 (d, J=11.0Hz, 1H), 3.74 (d, J=11.0Hz, 1H), 2.56-2.38 (m, 2H), 2.16 (s, 3H), 2.01-1.86 (m, 2H), 1.04 (t, J=7.4Hz, 3H), 0.94 (t, J=7.4Hz, 3H)；13C NMR (100MHz,CDCl3):δ181.6,155.4,144.8,138.1,137.3,136.6,135.6,131.1,129.6,129.4, 128.8,128.5,127.8,127.2,126.7,126.5,125.6,124.5,53.4,46.6,30.6,23.5,20.94, 13.4,10.8.IR(neat):3452,3039,291,1735,1638,152,981,693cm-1；MS(ESI)m/z[M+H]+ calcd for[C27H33N2O2]+:417.2542；found:417.2561. its structural formula is as follows：
3k:Solid, 56mg, 61%yield；mp 81-82℃.1H NMR(400MHz,CDCl3)δ7.32–7.18(m, 5H), 7.17-7.12 (m, 4H), 7.10-7.02 (m, 3H), 6.97 (d, J=8.3Hz, 2H), 6.49 (d, J=16.0Hz, 1H), 6.38 (d, J=16.0Hz, 1H), 6.14 (d, J=11.3Hz, 1H), 4.06 (d, J=11.3Hz, 1H), 2.69-2.66 (m, 1H), 2.61-2.58 (m, 1H), 2.16 (s, 1H), 2.11-1.99 (m, 2H), 1.79 (d, J=13.4Hz, 1H), 1.69 (dd, J =12.7,3.7Hz, 1H), 1.50 (d, J=13.6Hz, 1H), 1.37-1.27 (m, 1H)；13C NMR(100MHz,CDCl3):δ 180.8,156.0,143.4,139.7,137.1,136.8,135.5,131.4,129.7,129.4,128.9,128.7, 128.0,127.7,127.4,126.7,125.2,123.9,55.1,44.8,35.8,30.9,30.2,26.9,21.1.IR (neat):3442,3035,2934,2853,1726,1636,1494,1444,1379,983,692cm-1；MS(ESI)m/z[M+ H]+calcd for[C31H31N2O2]+:462.2307；found:462.2316. its structural formula is as follows：
3l:Solid, 41mg, 50%yield；mp 93-94℃.1H NMR(400MHz,CDCl3):δ7.34–7.30(m, 2H), 7.29-7.24 (m, 3H), 7.24-7.13 (m, 5H), 6.54 (d, J=16.1Hz, 1H), 6.49 (d, J=16.1Hz, 1H), 5.76 (d, J=10.8Hz, 1H), 3.99-3.81 (m, 1H), 3.70 (d, J=10.8Hz, 1H), 3.19-2.94 (m, 1H), 2.64-2.43 (m, 1H), 1.96 (s, 3H), 1.77-1.53 (m, 1H), 1.35 (s, 1H), 1.30 (d, J=7.4Hz, 3H),1.26(s,1H).
13C NMR(100MHz,CDCl3):δ177.4,154.8,1440,137.3,135.4,129.1,128.3,127.7, 127.2,127.0,126.1,125.6,125.5,124.2,46.6,45.1,45.0,28.6,20.3,19.0,12.8, 12.7.IR(neat):3439,3031,2926,2858,1723,1631,1493,1450,1383,972,697cm-1；MS(ESI) m/z[M+H]+calcd for[C26H31N2O2]+:403.2385；found:403.2377. its structural formula is as follows：
3m:Solid, 52mg, 60%yield；mp 89-90℃.1H NMR(500MHz,CDCl3):δ7.38–7.34(m, 2H), 7.30-7.26 (m, 4H), 7.22-7.11 (m, 4H), 7.10-7.04 (m, 3H), 6.63 (d, J=16.1Hz, 1H), 6.54 (d, J=16.1Hz, 1H), 6.42-6.34 (m, 2H), 5.61 (d, J=10.7Hz, 1H), 5.16 (d, J=14.2Hz, 1H), 4.17 (d, J=14.2Hz, 1H), 3.16 (d, J=10.7Hz, 1H), 2.48 (q, J=7.4Hz, 1H), 1.92 (s, 3H), 1.26 (d, J=7.4Hz, 3H)13CNMR(125MHz,CDCl3):δ178.6,156.1,144.3,137.2,136.7,136.4, 130.4,129.9,129.6,128.8,128.7,128.6,128.1,127.8,126.7,126.6,126.6,125.0,49.4, 46.7,45.7,21.3,14.1.IR(neat):3448,3035,2927,2862,1719,1634,1495,973,698cm-1；MS (ESI)m/z[M+H]+calcd for[C29H29N2O2]+:437.2229；found:437.2222. its structural formula is as follows：
3n:Solid, 25mg, 29%yield；mp 67-68℃.1H NMR(500MHz,CDCl3):δ7.46–7.43(m, 2H), 7.42-7.35 (m, 4H), 7.32-7.27 (m, 4H), 6.74 (d, J=16.0Hz, 1H), 6.65 (d, J=16.0Hz, 1H), 5.87 (d, J=10.9Hz, 1H), 3.80-3.78 (m, 1H), 3.38-3.33 (m, 1H), 2.61 (q, J=7.4Hz, 1H), 2.30-2.37 (m, 1H), 2.06 (s, 3H), 1.96 (d, J=6.2Hz, 1H), 1.85-1.80 (m, 3H), 1.59 (d, J= 4.7Hz, 1H), 1.48-1.44 (m, 1H), 1.38 (d, J=7.4Hz, 3H)；13C NMR(125MHz,CDCl3):δ178.2, 155.3,144.9,140.0,136.6,129.4,129.4,128.7,127.9,127.7,127.1,127.0,126.6, 126.6,59.8,48.2,45.4,29.8,29.3,26.4,26.2,25.3,21.3,13.7.IR(neat):3437,3034, 2928,2858,1720,1635,1494,984,696cm-1；MS(ESI)m/z[M+H]+calcd for[C28H33N2O2]+: 429.2542；found:429.25394. its structural formula is as follows：
3o:Solid, 84mg, 76%yield；mp 84-85℃.1H NMR(500MHz,CDCl3):δ7.66–7.62(m, 2H), 7.44-7.41 (M, 3H), 7.37-7.27 (m, 4H), 7.26-7.20 (m, 3H), 7.13 (d, J=8.9Hz, 2H), 6.55 (d, J=16.0Hz, 1H), 6.42 (d, J=16.0Hz, 1H), 6.08 (d, J=11.0Hz, 1H), 3.89 (d, J=11.0Hz, 1H), 2.79 (q, J=7.5Hz, 1H), 2.11 (s, 3H), 1.50 (d, J=7.4Hz, 3H)13C NMR(125MHz,CDCl3):δ 178.53 (s), 154.86 (s), 146.14 (s), 144.35 (s), 139.72 (s), 137.89 (d, J=2.1Hz), 136.20 (s),131.44(s),129.75(s),129.50(s),128.62(s),128.04(s),127.36(s),126.61(s),, 126.15(s),124.85(s),117.29(s),90.09(s),47.91(s),21.13(s),14.10(s).IR(neat): 3450,3029,2939,2868,1719,1634,1515,983,692cm-1；MS(ESI)m/z[M+H]+calcd for [C28H26IN2O2]+:549.1039；found:549.1034. its structural formula is as follows：
3p:Solid, 53mg, 59%yield；mp 96-97℃.1H NMR(500MHz,CDCl3):δ7.58-7.53(dm, 2H), 7.45-7.35 (m, 6H), 7.34-7.25 (m, 2H), 7.20 (t, J=3.0Hz, 1H), 6.83 (t, J=16.5Hz, 3H), 6.55 (d, J=16.0Hz, 1H), 6.42 (d, J=16.0Hz, 1H), 6.46 (d, J=30.2Hz, 1H), 5.51 (d, J= 12.5Hz,1H),3.33(s,3H),3.21-3.13(m,1H),2.30(s,3H),2.25(s,3H)2.20-2.10(m,1H), 1.35 (d, J=13.0Hz, 3H)13C NMR(125MHz,CDCl3):δ151.8,151.1,142.8,139.4,136.9, 135.7,135.3,130.5,129.3,128.9,128.6,128.3,128.2),127.8,126.3,124.3,124.1, 120.8,53.6,47.3,22.5,17.8,16.4.IR(neat):3447,3028,2922,2871,1731,1606,1323, 1265,965,693cm-1；MS(ESI)m/z[M+H]+calcd for[C30H31N2O2]+:451.2386；found:451.2368. Its structural formula is as follows：
3q:Solid, 61mg, 68%yield；mp 102-103℃.1H NMR(400MHz,CDCl3):δ7.61–7.55(m, 2H), 7.46-7.37 (m, 6H), 7.37-7.25 (m, 6H), 6.86 (d, J=16Hz, 1H), 6.58 (d, J=16Hz, 1H), 5.98 (d, J=12.5Hz, 1H), 3.30 (d, J=12.5Hz, 1H), 3.17 (s, 3H), 2.37 (s, 3H), 0.99 (s, 3H), 0.95(s,3H)；13C NMR(100MHz,CDCl3):δ166.3,152.7,142.5,137.6,136.7,136.6,134.5, 132.8,131.9,130.4,129.6,128.9,128.7,128.2,127.4,126.6,125.5,125.2,59.3,45.3, 26.3,22.4,22.1；IR(neat):3456,3032,2921,1742,1638,1501,985,692cm-1；MS(ESI)m/z[M +H]+calcd for[C30H31N2O2]+:451.2386；found:451.2391. its structural formula is as follows：
Embodiment 2：
1- oxygen -2,8- diazacyclo nonane derivatives of the present invention are synthesized by following synthetic routes.
Wherein,
R1Indicate hydrogen, C1~4Alkyl, C1~4Alkoxy, C1~4Perfluoroalkyl or halogen atom or unsubstituted, single The unsubstituted furyl of phenyl or the unsubstituted thiophene of substitution, two substitutions, three substitutions, four substitutions or five substitutions Pheno base or unsubstituted naphthalene；Wherein, substituent group C1~4Alkoxy, C1~4Perfluoroalkyl, C1~4Alkyl, cyanogen Base or halogen atom；
R2Indicate hydrogen, C1~4Alkyl, C1~4Alkoxy, C1~4Perfluoroalkyl or halogen atom or unsubstituted, single The unsubstituted furyl of phenyl or the unsubstituted thiophene of substitution, two substitutions, three substitutions, four substitutions or five substitutions Pheno base or unsubstituted naphthalene；Wherein, substituent group C1~4Alkoxy, C1~4Perfluoroalkyl, C1~4Alkyl, cyanogen Base or halogen atom；
R3Indicate hydrogen, C1~8Alkyl, C1~6Alkoxy or C1~4Perfluoroalkyl or it is unsubstituted, monosubstituted or Disubstituted phenyl；Wherein, substituent group C1~4Alkoxy, C1~4Perfluoroalkyl, C1~6Alkyl or halogen atom；
R4Indicate hydrogen, C1~8Alkyl, C1~6Alkoxy or C1~4Perfluoroalkyl or it is unsubstituted, monosubstituted or Disubstituted phenyl；Wherein, substituent group C1~4Alkoxy, C1~4Perfluoroalkyl, C1~6Alkyl or halogen atom；
R5Indicate hydrogen, C1~8Alkyl, C1~6Alkoxy or C1~4Perfluoroalkyl or it is unsubstituted, monosubstituted or Disubstituted phenyl；Wherein, substituent group C1~4Alkoxy, C1~4Perfluoroalkyl, C1~6Alkyl or halogen atom；
R6Indicate hydrogen, C1~12Alkyl, C1~4Alkoxy, C1~4Perfluoroalkyl or halogen atom or unsubstituted, single Substitution, two substitutions, three substitutions or the unsubstituted furyl of quaternary phenyl or unsubstituted thienyl, or Person is unsubstituted naphthalene；Wherein, substituent group C1~4Alkoxy, C1~4Perfluoroalkyl, C1~4Alkyl, cyano or halogen it is former Son.
By N- alkenyl α, β-unsaturation nitrone substrate 1 (0.3mmol), isothiocyanate 2 (0.9mmol) are placed in reaction tube In, 3mL toluene is added, is stirred to react 5-20h at 60 DEG C, gained reactant is removed under reduced pressure solvent, silica gel column chromatography on residue Detach (petroleum ether/methanol=100：1~10：1, volume ratio), obtain target product 3.Different target products and its characterization are such as Under：
3aa:Solid, 65mg, 72%yield；mp 96-97℃.1H NMR(400MHz,CDCl3):δ7.54–7.45(m, 2H), 7.41-7.27 (m, 3H), 7.27-7.16 (m, 7H), 7.14-7.05 (m, 2H), 6.76 (d, J=16.0Hz, 1H), 6.28 (d, J=16.0Hz, 1H), 5.11 (d, J=12.5Hz, 1H), 3.45 (dd, J=12.3,1.8Hz, 1H), 3.07 (s, 3H), 2.49 (dd, J=13.0,1.8Hz, 1H), 2.28 (s, 3H), 1.07 (d, J=7.5Hz, 3H)13C NMR(100MHz, CDCl3):δ177.6,157.7,142.2,135.3,135.2,135.0,133.1,130.7,130.5,129.2,129.0, 128.5,128.4,128.2,127.9,126.4,124.5,51.4,45.5,20.7,18.1,15.9；IR(neat):3444, 3033,2926,1724,16451508,976,692cm-1；MS(ESI)m/z[M+H]+calcd for[C29H29N2O2]+: 453.2001；found:453.2023. its structural formula is as follows：
3ab:Solid, 79mg, 58%yield；mp 161-162℃.1H NMR(500MHz,CDCl3):δ7.95–7.87 (m,2H),7.78–7.69(m,4H),7.66–7.57(m,2H),7.56-7.54(m,3H),7.45–7.35(m,2H),7.28- 7.26 (m, 2H), 7.19-7.15 (m, 2H), 6,82 (d, J=16.0Hz, 1H), 6.70 (d, J=16.0Hz, 1H), 6.23 (d, J =10.9Hz, 1H), 4.21 (d, J=10.9Hz, 1H), 3.26 (q, J=7.4Hz, 1H), 2.57 (s, 3H), 1.76 (d, J= 7.4Hz,3H)；13C NMR(125MHz,CDCl3):δ178.5,160.3,139.9,135.7,135.5,134.8,133.7, 132.3,131.9,131.3,131.1,130.9,130.7,130.3,129.7,128.9,128.7,125.1,123.3, 121.3,120.1,49.6,47.4,22.2,15.8.IR(neat):3439,3025,2923,2864,1737,1641,1513, 978,687cm-1；MS(ESI)m/z[M+H]+calcd for[C34H28Br2N2OS]+:671.0367；found:671.0346. its Structural formula is as follows：
3ac:Solid, 32mg, 51%yield；mp 92-93℃.1H NMR(400MHz,CDCl3):δ7.85–7.72(m, 2H), 7.68-7.42 (m, 3H), 5.96-5.80 (m, 1H), 5.38-5.08 (m, 2H), 4.85 (tt, J=12.4,2.0Hz, 1H), 3.87 (dt, J=12.4,2.0Hz, 2H), 2.98 (t, J=13.0Hz, 2H), 2.52-2.46 (m, 2H), 2.23 (q, J= 12.8Hz, 2H), 1.68-1.54 (m, 2H), 0.96 (t, J=13.2Hz, 3H)；13C NMR(100MHz,CDCl3):δ183.7, 162.5,138.1,135.7,134.2,131.5,130.4,129.7,116.7,113.6,49.3,36.3,25.65(s), 25.3,22.2,14.55；IR(neat):3435,3035,2936,2854,1748,1650,969,689cm-1；MS(ESI)m/z [M+H]+calcd for[C18H23N2OS]+:315.1531；found:315.1562. its structural formula is as follows：
3ad:Solid, 86mg, 74%yield；mp 107-108℃.1H NMR(500MHz,CDCl3):δ7.95–7.88 (m,2H),7.73–7.63(m,2H),7.56–7.43(m,8H),7.38–7.21(m,9H),7.02-6.96(m,1H),6.81 (t, J=3.0Hz, 1H), 6.65-6.98 (m, 1H), 5.75 (d, J=12.3Hz, 1H), 4.01 (d, J=12.5Hz, 1H), 3.72(s,3H),1.72(s,3H)；13C NMR(125MHz,CDCl3):δ185.6,164.9,161.5,143.1,141.4, 139..7,1375,135.2,134.8,130.7,129.9,129.8,129.7,128.9,128.8,127.3,126.9, 126.7,126.3,125.6,117.7,114.9,60,59.6,57.3,27.8.IR(neat):3447,3030,2941,2856, 1752,1648,967,698cm-1；MS(ESI)m/z[M+H]+calcd for[C38H33N2O2S]+:581.2263；found: 581.2269. its structural formula is as follows：
3af:Solid, 60mg, 60%yield；mp 101-102℃.1H NMR(400MHz,CDCl3):δ7.79–7.70 (m, 2H), 7.63 (d, J=7.5Hz, 2H), 7.59-7.53 (m, 3H), 7.39 (d, J=4.5Hz, 4H), 7.35-7.29 (m, 1H), 7.15 (d, J=7.5Hz, 2H), 5.19 (d, J=6.0Hz, 1H), 3.57 (dd, J=11.9,6.2Hz, 1H), 2.88- 2.82(m,1H),2.53–2.23(m,2H),1.75–1.68(m,2H),1.67–1.57(m,2H),1.56–1.46(m,3H), 1.43–1.34(m,1H)；13C NMR(100MHz,CDCl3):δ185.3,163.1,143.1,142.1,132.3,137.2, 131.09,132.0,130.5,130.2,130.0,129.5,129.4,129.1,128.7,127.2,126.3,124.2, 122.3,53.2,48.3,32.7,29.3,28.9,28.5,27.9.IR(neat):3449,3027,2945,2862,1747, 1654,978,692cm-1；MS(ESI)m/z[M+H]+calcd for[C30H28F3N2OS]+:521.1874；found: 521.1859. its structural formula is as follows：
Experimental example 1：1- oxygen -2,8- diazacyclo nonane derivatives of the present invention press down a variety of human tumour strains in vitro Activity experiment processed：
(1) cell culture：By T24, HepG2, NCI-H460,7702 cell culture in containing 10% (volume ratio) fetal calf serum With the DMEM culture mediums of 1% (volume ratio) dual anti-(containing penicillin and streptomysin), in 37 DEG C of temperature, 5%CO2And 95% air It is cultivated in incubator, changes liquid every other day.It is passed on, is frozen after cell covers with.
(2) plate is planted：The cell in exponential phase is taken, removes old culture medium, is washed twice with PBS, trypsase disappears Change cell, new culture medium is added after cell rounding and terminates cell dissociation and blows and beats suspension cell, individual cells suspension is made. Suitable cell suspension is taken, a certain amount of culture medium dilution is added, is inoculated into 96 orifice plates, per 180 μ L of hole, is per hole cell number 20000-40000。
(3) dosing：Sample to be tested is added in 96 orifice plates that kind has tumour cell, per 20 μ L of hole, makes the final dense of sample Degree is 10 μM, carries out primary dcreening operation.According to being screened as a result, different concentration gradients is arranged to compound for primary dcreening operation, every group of setting 5 A multiple holes.CO is put after adding compound2The MTT solution that 10 μ L are prepared is added per hole, puts CO by incubator culture 48h2Incubator continues Cultivate 4~6h.
(4) it tests：The culture medium abandoned in 96 orifice plates is inhaled, the DMSO of 100 μ L is added, 5~10min of concussion on shaking table is put, makes The first a ceremonial jade-ladle, used in libation of crystallization is completely dissolved.With microplate reader with the absorbing wavelength of 570nm, the reference wavelength dual wavelength of 630nm measures absorbance (OD) value calculates inhibiting rate.Inhibiting rate=(1- sample sets OD values/blank group OD values) × 100%, is calculated separately with SPSS softwares IC of each compound to different tumor cell lines50Value.Test result is as follows for it shown in table 1：
Table 1：

Claims (8)

1. compound or its pharmaceutically acceptable salt shown in lower formula (I)：
Wherein：
R1Indicate 4- nitrobenzophenones；
R2Indicate phenyl；
R3Indicate methyl；
R4Indicate methyl；
R5Indicate hydrogen atom；
R6Indicate 4- aminomethyl phenyls；
X indicates oxygen atom.
2. the synthetic method of compound described in claim 1, it is characterised in that：Take compound and formula as shown in following formula (II) (III) compound shown in, is placed in organic solvent, reacts in the presence of oxygen, and object crude product is made；
Wherein：
R1Indicate 4- nitrobenzophenones；
R2Indicate phenyl；
R3Indicate methyl；
R4Indicate methyl；
R5Indicate hydrogen atom；
R6Indicate 4- aminomethyl phenyls；
X indicates oxygen atom.
3. synthetic method according to claim 2, it is characterised in that：The organic solvent is selected from benzene, toluene, hexamethylene Alkane, petroleum ether, carbon tetrachloride, tetrahydrofuran, ethyl acetate, acetonitrile, ether, dichloromethane, acetone, chloroform, n-hexane With a combination of one or more in dioxane.
4. synthetic method according to claim 2, it is characterised in that：Reaction carries out under conditions of less than 100 DEG C.
5. synthetic method according to claim 2, it is characterised in that：Reaction carries out under conditions of less than 80 DEG C.
6. the synthetic method according to any one of claim 2~5, it is characterised in that：It further include purification step：Specifically Object crude product obtained is subjected to silica gel thin-layer chromatography or silica gel column chromatography, or recrystallization, obtains target after purification Object.
7. synthetic method according to claim 6, it is characterised in that：In silica gel thin-layer chromatography or silica gel column chromatography Eluant, eluent is identical with solvent when recrystallization, specially presses 10 by petroleum ether or n-hexane and ethyl acetate：1~1：1 body The long-pending mixed solvent than composition, or press 100 by petroleum ether or dichloromethane and methanol:1~10:1 volume ratio composition Mixed solvent.
8. compound described in claim 1 or its pharmaceutically acceptable salt application in preparation of anti-tumor drugs.
CN201810654336.8A 2016-09-18 2016-09-18 1,2, 8-oxo diazacyclononane-9-one derivative and synthetic method thereof Active CN108727293B (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN201810654336.8A CN108727293B (en) 2016-09-18 2016-09-18 1,2, 8-oxo diazacyclononane-9-one derivative and synthetic method thereof

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN201810654336.8A CN108727293B (en) 2016-09-18 2016-09-18 1,2, 8-oxo diazacyclononane-9-one derivative and synthetic method thereof
CN201610826407.9A CN106432126B (en) 2016-09-18 2016-09-18 1- oxygen -2,8- diazacyclo nonane derivatives and its synthetic method

Related Parent Applications (1)

Application Number Title Priority Date Filing Date
CN201610826407.9A Division CN106432126B (en) 2016-09-18 2016-09-18 1- oxygen -2,8- diazacyclo nonane derivatives and its synthetic method

Publications (2)

Publication Number Publication Date
CN108727293A true CN108727293A (en) 2018-11-02
CN108727293B CN108727293B (en) 2021-05-11

Family

ID=58167880

Family Applications (4)

Application Number Title Priority Date Filing Date
CN201810751421.6A Active CN108623530B (en) 2016-09-18 2016-09-18 1,2, 8-oxo-diazacyclononane-9-thioketone derivative and synthetic method and application thereof
CN201810654336.8A Active CN108727293B (en) 2016-09-18 2016-09-18 1,2, 8-oxo diazacyclononane-9-one derivative and synthetic method thereof
CN201810652968.0A Active CN108752286B (en) 2016-09-18 2016-09-18 1,2, 8-oxo-diazacyclononane derivative and its synthesis process and application
CN201610826407.9A Active CN106432126B (en) 2016-09-18 2016-09-18 1- oxygen -2,8- diazacyclo nonane derivatives and its synthetic method

Family Applications Before (1)

Application Number Title Priority Date Filing Date
CN201810751421.6A Active CN108623530B (en) 2016-09-18 2016-09-18 1,2, 8-oxo-diazacyclononane-9-thioketone derivative and synthetic method and application thereof

Family Applications After (2)

Application Number Title Priority Date Filing Date
CN201810652968.0A Active CN108752286B (en) 2016-09-18 2016-09-18 1,2, 8-oxo-diazacyclononane derivative and its synthesis process and application
CN201610826407.9A Active CN106432126B (en) 2016-09-18 2016-09-18 1- oxygen -2,8- diazacyclo nonane derivatives and its synthetic method

Country Status (1)

Country Link
CN (4) CN108623530B (en)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN111018885A (en) * 2019-12-11 2020-04-17 广西师范大学 1, 2-dioxycyclohexene [3,4-f ] nitrogen oxo cyclononane derivative and synthetic method and application thereof

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN109467558B (en) * 2018-12-13 2021-03-23 广西师范大学 1-hydropyrrolizine derivative and synthesis method and application thereof
CN109678847A (en) * 2018-12-13 2019-04-26 广西师范大学 Gamma lactone substituted pyridine derivative and its synthetic method and application

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3152145A (en) * 1962-05-23 1964-10-06 American Home Prod 5-aryl-3, 1, 4-benzoxadiazepine-2 (1h)-ones
CN101395143A (en) * 2005-12-29 2009-03-25 安姆弗拉玛法国股份公司 Aza heterocyclics for the treatment of malaria or aids
US20160046590A1 (en) * 2009-04-21 2016-02-18 Massachusetts Institute Of Technology Sonic hedgehog modulators
CN105601582A (en) * 2016-01-26 2016-05-25 兰州大学 Compound extracted from elymus dahuricus and preparation method and application thereof

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0863885A2 (en) * 1995-11-14 1998-09-16 The Du Pont Merck Pharmaceutical Company Novel macrocyclic compounds as metalloprotease inhibitors
BR0314183A (en) * 2002-09-30 2005-08-09 Neurosearch As 1,4-Diazabicycloalkane derivatives, any of their enantiomers or any mixture of their enantiomers, or a pharmaceutically acceptable addition salt or n-oxide thereof, pharmaceutical composition, use of said compound, any of its enantiomers or any mixture of their enantiomers, or a pharmaceutically acceptable addition salt thereof, and, method of treating, preventing or alleviating a disease or disorder or condition of a living animal body
AU2007213669A1 (en) * 2006-02-10 2007-08-16 Neurosearch A/S 3,9-diazabicyclo[3.3.1]nonane derivatives and their use as monoamine neurotransmitter re-uptake inhibitors

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3152145A (en) * 1962-05-23 1964-10-06 American Home Prod 5-aryl-3, 1, 4-benzoxadiazepine-2 (1h)-ones
CN101395143A (en) * 2005-12-29 2009-03-25 安姆弗拉玛法国股份公司 Aza heterocyclics for the treatment of malaria or aids
US20160046590A1 (en) * 2009-04-21 2016-02-18 Massachusetts Institute Of Technology Sonic hedgehog modulators
CN105601582A (en) * 2016-01-26 2016-05-25 兰州大学 Compound extracted from elymus dahuricus and preparation method and application thereof

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
LAN HONG等: "Synthesis and negative inotropic effects evaluation of 7-substituted-4,5-dihydro-[1,2,4]oxadiazolo[4,3-a]quinolin-1-ones", 《ARCH. PHARM. RES.》 *
NING ZOU等: "Diastereoselective Synthesis of Nine-Membered Heterocycles via the Cycloaddition and Sequential Rearrangement of N-Vinyl Nitrones with Isocyanates", 《ADV. SYNTH. CATAL.》 *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN111018885A (en) * 2019-12-11 2020-04-17 广西师范大学 1, 2-dioxycyclohexene [3,4-f ] nitrogen oxo cyclononane derivative and synthetic method and application thereof
CN111018885B (en) * 2019-12-11 2021-08-03 广西师范大学 1, 2-dioxycyclohexene [3,4-f ] nitrogen oxo cyclononane derivative and synthetic method and application thereof

Also Published As

Publication number Publication date
CN108752286B (en) 2021-05-11
CN108623530A (en) 2018-10-09
CN108727293B (en) 2021-05-11
CN108752286A (en) 2018-11-06
CN106432126B (en) 2018-12-28
CN108623530B (en) 2021-05-11
CN106432126A (en) 2017-02-22

Similar Documents

Publication Publication Date Title
CN105934432B (en) The diamine derivative of 2,4 disubstituted benzenes 1,5 and its application and pharmaceutical composition prepared therefrom and Pharmaceutical composition
CN103992336B (en) Oxa-or thia evodiamine anti-tumor derivant and preparation method thereof
CN106432126B (en) 1- oxygen -2,8- diazacyclo nonane derivatives and its synthetic method
JP5583589B2 (en) Phenanthroindolizidine derivative and NFκB inhibitor comprising this as an active ingredient
WO2007082475A1 (en) Novel ent-kaurene diterpene compound and its derivatives, their preparation and their use
CN103265442B (en) Novel pleuromutilin derivatives, as well as preparation method and anti-tumour application thereof
Hingane et al. An efficient new route towards biologically active isocryptolepine and γ-carboline derivatives using an intramolecular thermal electrocyclization strategy
CN108314658B (en) A kind of preparation method of polysubstituted oxazole derivatives
CN111763148A (en) Alkynyl cyclopentene derivative containing trifluoromethyl and preparation method and application thereof
CN111892608B (en) Spiroheterocyclic 2, 3-dihydrobenzofuran compound with optical activity and application thereof
Liu et al. Highly diastereoselective assembly of isoxazole and trifluoromethyl containing spiro [pyrrolidin-oxindoles] from N-2, 2, 2-trifluoroethyl-substituted isatin imines and styrylisoxazoles
CN105646546B (en) The position 20 of camptothecins ester derivant and its antitumor application thereof of acid-sensitive type
CN109666006B (en) Aryl derivative bithiazole compound and preparation method and application thereof
CN105017147B (en) A method of recycling and utilize Bedaquiline three-dimensional chemical isomer
CN110317169B (en) 1-substituted isoquinolone compound and preparation method thereof
CN107266458B (en) 2,3- condensed ring indoline derivative object and its synthetic method and application
CN102432622A (en) 4-amino oxadiazole epipodophyllotoxin derivative and preparation method and application thereof
CN113004294B (en) Tetrahydrofuran-1, 4-dihydroquinoline compound and preparation method and application thereof
CN105820132B (en) N- aryl benzotriazole nitrogen oxygen derivatives and its synthetic method
CN107698648A (en) Containing cholesteric naphthalimide analog derivative and its synthesis and application
CN110054577B (en) Compound containing urea and thiourea structure, synthetic method and application thereof
CN104910090B (en) Dihydro-isoxazole class compound and its synthetic method
CN106432043B (en) 2,3- indole dione -3-N- alkenyl nitrone derivatives and its synthetic method and application
CN114031623B (en) C 14 Amino-substituted tetrandrine derivative and preparation and application thereof
CN106632016A (en) Synthesis method of 2-acetamido-5-bromopyridine

Legal Events

Date Code Title Description
PB01 Publication
PB01 Publication
SE01 Entry into force of request for substantive examination
SE01 Entry into force of request for substantive examination
GR01 Patent grant
GR01 Patent grant