CN103183627B - 1,2-diaryl-5-replaces-1H-azoles and preparation method thereof and application - Google Patents
1,2-diaryl-5-replaces-1H-azoles and preparation method thereof and application Download PDFInfo
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- CN103183627B CN103183627B CN201110453556.2A CN201110453556A CN103183627B CN 103183627 B CN103183627 B CN 103183627B CN 201110453556 A CN201110453556 A CN 201110453556A CN 103183627 B CN103183627 B CN 103183627B
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- trimethoxyphenyl
- pyrroles
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Abstract
The invention belongs to medical art, relate to a kind of 1,2-diaryl-5-replaces-1<i>H</iGreatT.G reaT.GT-azoles and uses thereof, exactly, relate to this compounds and prepare the application in antitumor drug as tumor cell proliferation inhibitor.Compound structure of the present invention as disclosed in the claims.Present invention also offers 1,2-diaryl-5-and replace-1<i>H</iGreatT.G reaT.GT-azoles preparation method, the method simple possible, yield is higher.1,2-diaryl-5-of preparation replaces-1<i>H</iGreatT.G reaT.GT-azoles and has good anti-tumor activity, can be used for preparing antitumor drug.
Description
Technical field
The invention belongs to medical art, relate to a kind of 1,2-diaryl-5-and replace-1
h-azoles and uses thereof, exactly, relates to this compounds and is preparing the application in antitumor drug as tumor cell proliferation inhibitor.
Background technology
Malignant tumour is the serious disease threatening human health and life, is one of main lethal cause of disease in China.Find and find that treatment is the current key subjects faced with the new drug of prophylaxis of tumours.
CombretastatinA-4(CA-4) be from the willow of South Africa, be separated the cis-stilbene class natural product obtained, its chemical name be (
z)-2-methoxyl group-5-(3,4,5-trimethoxy styryl) phenol.CA-4 is tubulin polymerization inhibitor, presents very strong inhibition tumor cell proliferation activity, and its prodrug CA-4 phosphoric acid salt (CA-4P) enters three phase clinical investigation phase in the U.S..With CA-4 for lead compound designs, synthesizes the existing report in a large number of research of new active compound for anti tumor, but most CA-4 analogue exists or activity is not high enough or toxicity is comparatively large or synthesize the shortcomings such as more complicated.Relevant report is see PettitG.R., etal.
experientia,
1989, 45,209; NamN.H.
currentMedicinalCHemistry,
2003, 10,1697; TronG.C., etal.JournalofMedicinalCHemistry,
2006, 49 (11), 3033-3044.
Summary of the invention
The object of the invention is to the analog designed, synthesis has the CombretastatinA-4 of good proliferative activity o f tumor, namely 1,2-diaryl-5-replaces-1
h-azoles; Good result is manifested in the anti-tumor activity test in vivo and in vitro of prepared compound.
Target product possible constructions formula (1) of the present invention represents:
Wherein, X is hydrogen, acyl group, hydroxyalkyl, carboxylic acid group;
When A ring be I ~ IV wherein any one ring system time, B ring is V ~ VII wherein any one ring system;
When B ring be I ~ IV wherein any one ring system time, A ring is V ~ VII wherein any one ring system;
Y in I ~ IV represents any substituting group beyond hydrogen atom;
R
1~ R
13be hydrogen, methoxyl group, hydroxyl, halogen atom, nitro, amino or benzyloxy independently of one another, or adjacent two substituting groups are-OCH
2o-thus form five-ring, or adjacent two substituting groups be-CH=CH-NH-thus formation five-ring;
Its precondition is:
If X is hydrogen, A ring is I, and when B ring is V: R
1~ R
5be asynchronously hydrogen; R
1for methyl, methoxyl group, nitro or chlorine, then R
2~ R
5be asynchronously hydrogen; R
2for methyl, methoxyl group, nitro, ethanoyl, chlorine, bromine or kharophen, then R
1, R
3~ R
5be asynchronously hydrogen; R
3for methyl, methoxyl group, oxyethyl group, nitro, ethanoyl, fluorine, chlorine, bromine, iodine, trifluoromethyl, phenoxy group, dimethylamino, kharophen or 2,4 dichloro benzene oxygen base, R
1, R
2, R
4, R
5be asynchronously hydrogen; R
2, R
3be chlorine or simultaneously for methyl, then R simultaneously
1, R
4, R
5be asynchronously hydrogen; R
2for chlorine, and R
3for fluorine, methyl or to chlorophenoxy, then R
1, R
4, R
5be asynchronously hydrogen; , R
2for nitro, and R
3for methyl, then R
1, R
4, R
5be asynchronously hydrogen; R
1, R
3be methyl, then R simultaneously
2, R
4, R
5be asynchronously hydrogen; R
1for nitro, and R
3for chlorine, then R
2, R
4, R
5be asynchronously hydrogen; R
2, R
4be methyl, then R simultaneously
1, R
3, R
5be asynchronously hydrogen; R
1, R
4be methoxyl group, then R simultaneously
2, R
3, R
5be asynchronously hydrogen; R
1for chlorine, and R
4for methyl, then R
2, R
3, R
5be asynchronously hydrogen; R
1, R
3, R
4be chlorine, then R simultaneously
2, R
5be asynchronously hydrogen; Work as R
2and R
3for-CH
2cH
2cH
2cH
2-and when forming six-ring, then R
1, R
4, R
5be asynchronously hydrogen;
If X is hydrogen, A ring is I, and when B ring is VI: R
6~ R
9be asynchronously hydrogen;
If X is hydrogen, A ring is I, and when B ring is VII: R
10~ R
13be asynchronously hydrogen.
Compound of the present invention also comprises the pharmaceutically acceptable non-toxic salt and hydrate thereof that derivative shown in structure above formed, and these pharmaceutically acceptable non-toxic salt comprise the salt that this derivative is formed with acid.Described acid can be the mineral acid of hydrochloric acid, sulfuric acid, Hydrogen bromide, phosphoric acid or the organic acid being selected from acetic acid, citric acid, oxalic acid, tartrate, phenylformic acid, oxysuccinic acid.The hydration number of described hydrate is any real number in 0 ~ 16.
The present invention's preferred part of compounds structure is as follows:
Compound 1
2-(4-p-methoxy-phenyl)-1-(3,4,5-trimethoxyphenyl)-1
h-pyrroles
Compound 2
2-(4-ethoxyl phenenyl)-1-(3,4,5-trimethoxyphenyl)-1
h-pyrroles
Compound 3
1-(3,4,5-trimethoxyphenyl)-2-(4-chloro-phenyl-)-1
h-pyrroles
Compound 4
1-(3,4,5-trimethoxyphenyl)-2-(4-bromophenyl)-1
h-pyrroles
Compound 5
1-(4-p-methoxy-phenyl)-2-(3,4,5-trimethoxyphenyl)-1
h-pyrroles
Compound 6
1-(3-p-methoxy-phenyl)-2-(3,4,5-trimethoxyphenyl)-1
h-pyrroles
Compound 7
1-(3,4-Dimethoxyphenyl)-2-(3,4,5-trimethoxyphenyl)-1
h-pyrroles
Compound 8
1-(3-hydroxyl-4-p-methoxy-phenyl)-2-(3,4,5-trimethoxyphenyl)-1
h-pyrroles
Compound 9
1-(3-amino-4-methoxyl phenyl)-2-(3,4,5-trimethoxyphenyl)-1
h-pyrroles
Compound 10
1-(2-fluorophenyl)-2-(3,4,5-trimethoxyphenyl)-1
h-pyrroles
Compound 11
1-(3-fluorophenyl)-2-(3,4,5-trimethoxyphenyl)-1
h-pyrroles
Compound 12
1-(4-fluorophenyl)-2-(3,4,5-trimethoxyphenyl)-1
h-pyrroles
Compound 13
1-(3,4-difluorophenyl)-2-(3,4,5-trimethoxyphenyl)-1
h-pyrroles
Compound 14
1-(3,5-difluorophenyl)-2-(3,4,5-trimethoxyphenyl)-1
h-pyrroles
Compound 15
1-(the chloro-4-fluorophenyl of 3-)-2-(3,4,5-trimethoxyphenyl)-1
h-pyrroles
Compound 16
1-(3-chloro-phenyl-)-2-(3,4,5-trimethoxyphenyl)-1
h-pyrroles
Compound 17
1-(4-chloro-phenyl-)-2-(3,4,5-trimethoxyphenyl)-1
h-pyrroles
Compound 18
1-(3,4-dichlorophenyl)-2-(3,4,5-trimethoxyphenyl)-1
h-pyrroles
Compound 19
1-(3,5-dichlorophenyl)-2-(3,4,5-trimethoxyphenyl)-1
h-pyrroles
Compound 20
1-(3-bromophenyl)-2-(3,4,5-trimethoxyphenyl)-1
h-pyrroles
Compound 21
1-(4-bromophenyl)-2-(3,4,5-trimethoxyphenyl)-1
h-pyrroles
Compound 22
1-(the fluoro-4-bromophenyl of 2-)-2-(3,4,5-trimethoxyphenyl)-1
h-pyrroles
Compound 23
1-(the fluoro-2-bromophenyl of 4-)-2-(3,4,5-trimethoxyphenyl)-1
h-pyrroles
Compound 24
1-(2-methyl-4-aminophenyl)-2-(3,4,5-trimethoxyphenyl)-1
h-pyrroles
Compound 25
1-(6-methyl-chloro-phenyl-)-2-(3,4,5-trimethoxyphenyl)-1
h-pyrroles
Compound 26
1-(4-cyanophenyl)-2-(3,4,5-trimethoxyphenyl)-1
h-pyrroles
Compound 27
1-(4-p-methoxy-phenyl)-2-(3,4,5-trimethoxyphenyl)-5-formyl radical-1
h-pyrroles
Compound 28
1-(3,4-Dimethoxyphenyl)-2-(3,4,5-trimethoxyphenyl)-5-formyl radical-1
h-pyrroles
Compound 29
1-(4-fluorophenyl)-2-(3,4,5-trimethoxyphenyl)-5-formyl radical-1
h-pyrroles
Compound 30
1-(3-chloro-phenyl-)-2-(3,4,5-trimethoxyphenyl)-5-formyl radical-1
h-pyrroles
Compound 31
1-(4-p-methoxy-phenyl)-2-(3,4,5-trimethoxyphenyl)-5-hydroxymethyl-1
h-pyrroles
1,2-diaryl-5-hydroxyalkyl-1 of the present invention
hthe synthesis of-pyrrole derivatives is enumerated wherein two classes and is described, and other kind can obtain according to following reaction scheme synthesis equally:
By 1,2-diaryl-5-formyl radical-1 of 1 equivalent
hthe NaBH of-pyrrole derivatives and 1 equivalent
4add in ethanol in proper amount, at controlling 25 DEG C, stirring reaction 2h, after being cooled to 0 DEG C, add appropriate 8%HCl solution, regulate pH to 7, with dichloromethane extraction, organic layer saturated common salt water washing, anhydrous sodium sulfate drying, filtrate reduced in volume, thin-layer chromatography obtains sterling, and yield 85%-95%(relevant report is see Wolfsonetal.
org.Commun, 2009,2 (2), 34-41);
1,2-diaryl-5-formyl radical-1 of the present invention
hthe synthesis of-pyrrole derivatives is enumerated wherein two classes and is described, and other kind can obtain according to following reaction scheme synthesis equally:
Under 0 DEG C of nitrogen atmosphere condition, by the POCl of 1.2 equivalents
3add in appropriate dry DMF, after stirring 15min, add 1,2-diaryl-1 of 1 equivalent
h-pyrrole derivatives, temperature rises to 60 DEG C, after reaction 3h, after question response liquid is down to room temperature, add appropriate saturated sodium bicarbonate solution, regulate pH to 7, with dichloromethane extraction, organic layer saturated common salt water washing, anhydrous sodium sulfate drying, filtrate reduced in volume, thin-layer chromatography obtains sterling, and yield 65%-75%(relevant report is see M.M.M.Raposoetal.
tetrahedron, 2006,62,3493 – 3501);
Wherein, R
1~ R
13in replace-1 containing 1,2-amino diaryl-5-
h-pyrrole derivatives can by corresponding R
1~ R
13in prepare through reduction reaction containing the compound of nitro, reductive agent be zinc powder/acetate system (associated class like report see SunC.M., etal.
bioorganic & MedicinalChemistryLetters,2007,17 (4), 1078 – 1081);
Wherein, R
1~ R
13in containing hydroxyl 1,2-diaryl-5-replace-1
h-pyrrole derivatives can by corresponding R
1~ R
13in compound containing benzyloxy etc. prepare through Deprotection reaction, go the reagent of protecting group to be titanium tetrachloride;
1,2-diaryl-1 of the present invention
hthe synthesis of-pyrrole derivatives is enumerated wherein two classes and is described, and other kind can obtain according to following reaction scheme synthesis equally:
Will
n4-diaryl--4-oxo butyramide analog derivative is dissolved in dry toluene, adds the Lawesson reagent of 1 equivalent, is heated to 110 DEG C, 0.5h is reacted under nitrogen atmosphere, after question response liquid is down to room temperature, after removing solvent under reduced pressure, use dichloromethane extraction, organic layer saturated common salt water washing, anhydrous sodium sulfate drying, filtrate reduced in volume, thin-layer chromatography obtains sterling, yield 50%-60%; (associated class like report see M.M.M.Raposoetal.
synthesis2005,2,199 – 210); Hydroxyl deprotection, nitroreduction process are with identical above.
Intermediate involved in the present invention
n, 4-diaryl--the synthesis of 4-oxo butyramide analog derivative is enumerated two classes and is described, and other kind can obtain according to following reaction scheme synthesis equally:
Will containing substituent 4-aryl--4-ketobutyric acid (associated class of its preparation method like report see N.J.Lawrenceetal.
bioorg.Med.Chem.Lett, 2006,16,5844 – 5848) be dissolved in methylene dichloride, add the arylamine of 1 equivalent, the DCC of 2 equivalents, the DMAP of 0.2 equivalent under normal temperature, after stirring 0.5h, remove solvent under reduced pressure, dichloromethane extraction, organic layer brine It, anhydrous sodium sulfate drying, filtrate reduced in volume, thin plate chromatography obtains sterling, yield 75%-85%(associated class like report see M.M.M.Raposoetal.
synthesis2005,2,199 – 210); Hydroxyl deprotection, nitroreduction process are with identical above.
1,2-diaryl-5-provided by the present invention replaces-1
h-azoles preparation method simple possible, yield is higher.
1,2-diaryl-5-replaces-1
h-azoles all has the effect for the treatment of tumor disease preferably, can be used for preparing antitumor drug.
Embodiment
To contribute to understanding the present invention by following example, but content of the present invention is not limited to example.
Agents useful for same of the present invention is commercially available, and nuclear magnetic resonance spectrum is measured by AVANCE-400, BrukerARX-300 fourier transform NMR spectrometer, and mass spectrum is measured by BrukeeEsqure2000, ShimadzuGCMS-QP5050A type mass spectrograph.
embodiment 1:2-(4-p-methoxy-phenyl)-1-(3,4,5-trimethoxyphenyl)-1
hthe preparation of-pyrroles (compound 1):
By 4-(4-p-methoxy-phenyl)-4-ketobutyric acid (0.1g, 0.48mmol) be dissolved in 10mL methylene dichloride, add 3 of 1 equivalent, 4,5-trimethoxy-aniline (0.088g, 0.48mmol), the DCC (0.20g of 2 equivalents, 0.96mmol), the DMAP (0.012g, 0.096mmol) of 0.2 equivalent, after stirring 0.5h under normal temperature, remove solvent under reduced pressure, dichloromethane extraction, organic layer brine It, anhydrous sodium sulfate drying, filtrate reduced in volume, thin plate chromatography obtains intermediate
n-(3,4,5-trimethoxyphenyl)-4-(4-p-methoxy-phenyl)-4-oxo butyramide, yield 80.3%;
Get above-mentioned intermediate (0.1g, 0.27mmol) to be dissolved in 7mL dry toluene, add the Lawesson reagent (0.11g of 1 equivalent, 0.27mmol), be heated to 110 DEG C, under nitrogen atmosphere, react 0.5h, after question response liquid is down to room temperature, dichloromethane extraction is used after removing solvent under reduced pressure, organic layer saturated common salt water washing, anhydrous sodium sulfate drying, filtrate reduced in volume, thin-layer chromatography obtains compound 1, yield 58.7%; The structural formula of compound 1,
1h-NMR and MS data are listed in the table below in-1.
embodiment 2:2-(4-ethoxyl phenenyl)-1-(3,4,5-trimethoxyphenyl)-1
hthe preparation of-pyrroles (compound 2):
Except using corresponding raw material, prepare compound 2 with the method that embodiment 1 is identical, yield is 57.8%; The structural formula of compound 2,
1h-NMR and MS data are listed in the table below in-1.
embodiment 3:1-(3,4,5-trimethoxyphenyl)-2-(4-chloro-phenyl-)-1
hthe preparation of-pyrroles (compound 3):
Except using corresponding raw material, prepare compound 3 with the method that embodiment 1 is identical, yield is 56.4%; The structural formula of compound 3,
1h-NMR and MS data are listed in the table below in-1.
embodiment 4:1-(3,4,5-trimethoxyphenyl)-2-(4-bromophenyl)-1
hthe preparation of-pyrroles (compound 4):
Except using corresponding raw material, prepare compound 4 with the method that embodiment 1 is identical, yield is 59.8%; The structural formula of compound 4,
1h-NMR and MS data are listed in the table below in-1.
embodiment 5:1-(4-p-methoxy-phenyl)-2-(3,4,5-trimethoxyphenyl)-1
hthe preparation of-pyrroles (compound 5):
Except using corresponding raw material, prepare compound 5 with the method that embodiment 1 is identical, yield is 55.3%; The structural formula of compound 5,
1h-NMR and MS data are listed in the table below in-1.
embodiment 6:1-(3-p-methoxy-phenyl)-2-(3,4,5-trimethoxyphenyl)-1
hthe preparation of-pyrroles (compound 6):
Except using corresponding raw material, prepare compound 6 with the method that embodiment 1 is identical, yield is 55.0%; The structural formula of compound 6,
1h-NMR and MS data are listed in the table below in-1.
embodiment 7:1-(3,4-Dimethoxyphenyl)-2-(3,4,5-trimethoxyphenyl)-1
hthe preparation of-pyrroles (compound 7):
Except using corresponding raw material, prepare compound 7 with the method that embodiment 1 is identical, yield is 59.6%; The structural formula of compound 7,
1h-NMR and MS data are listed in the table below in-1.
embodiment 8: 1-(3-hydroxyl-4-p-methoxy-phenyl)-2-(3,4,5-trimethoxyphenyl)-1
hthe preparation of-pyrroles (compound 8):
Except using corresponding raw material, prepare compound 8 with the method that embodiment 1 is identical, yield is 57.5%; The structural formula of compound 8,
1h-NMR and MS data are listed in the table below in-1.
embodiment 9:2-(4-ethoxyl phenenyl)-1-(3,4,5-trimethoxyphenyl)-1
hthe preparation of-pyrroles (compound 9):
Except using corresponding raw material, prepare compound 2 with the method that embodiment 1 is identical, yield is 57.8%; The structural formula of compound 9,
1h-NMR and MS data are listed in the table below in-1.
embodiment 10:1-(2-fluorophenyl)-2-(3,4,5-trimethoxyphenyl)-1
hthe preparation of-pyrroles (compound 10):
Except using corresponding raw material, prepare compound 10 with the method that embodiment 1 is identical, yield is 59.6%; The structural formula of compound 10,
1h-NMR and MS data are listed in the table below in-1.
embodiment 11:1-(3-fluorophenyl)-2-(3,4,5-trimethoxyphenyl)-1
hthe preparation of-pyrroles (compound 11):
Except using corresponding raw material, prepare compound 11 with the method that embodiment 1 is identical, yield is 57.5%; The structural formula of compound 11,1H-NMR and MS data are listed in the table below in-1.
embodiment 12:1-(4-fluorophenyl)-2-(3,4,5-trimethoxyphenyl)-1
hthe preparation of-pyrroles (compound 12):
Except using corresponding raw material, prepare compound 12 with the method that embodiment 1 is identical, yield is 56.9%; The structural formula of compound 12,1H-NMR and MS data are listed in the table below in-1.
embodiment 13:1-(3,4-difluorophenyl)-2-(3,4,5-trimethoxyphenyl)-1
hthe preparation of-pyrroles (compound 13):
Except using corresponding raw material, prepare compound 13 with the method that embodiment 1 is identical, yield is 55.2%; The structural formula of compound 13,
1h-NMR and MS data are listed in the table below in-1.
embodiment 14:1-(3,5-difluorophenyl)-2-(3,4,5-trimethoxyphenyl)-1
hthe preparation of-pyrroles (compound 14):
Except using corresponding raw material, prepare compound 14 with the method that embodiment 1 is identical, yield is 57.5%; The structural formula of compound 14,
1h-NMR and MS data are listed in the table below in-1.
embodiment 15:1-(the chloro-4-fluorophenyl of 3-)-2-(3,4,5-trimethoxyphenyl)-1
hthe preparation of-pyrroles (compound 15):
Except using corresponding raw material, prepare compound 15 with the method that embodiment 1 is identical, yield is 58.4%; The structural formula of compound 15,
1h-NMR and MS data are listed in the table below in-1.
embodiment 16:1-(3-chloro-phenyl-)-2-(3,4,5-trimethoxyphenyl)-1
hthe preparation of-pyrroles (compound 16):
Except using corresponding raw material, prepare compound 16 with the method that embodiment 1 is identical, yield is 57.1%; The structural formula of compound 16,
1h-NMR and MS data are listed in the table below in-1.
embodiment 17:1-(4-chloro-phenyl-)-2-(3,4,5-trimethoxyphenyl)-1
hthe preparation of-pyrroles (compound 17):
Except using corresponding raw material, prepare compound 17 with the method that embodiment 1 is identical, yield is 55.5%; The structural formula of compound 17,
1h-NMR and MS data are listed in the table below in-1.
embodiment 18:1-(3,4-dichlorophenyl)-2-(3,4,5-trimethoxyphenyl)-1
hthe preparation of-pyrroles (compound 18):
Except using corresponding raw material, prepare compound 18 with the method that embodiment 1 is identical, yield is 59.7%; The structural formula of compound 18,
1h-NMR and MS data are listed in the table below in-1.
embodiment 19:1-(3,5-dichlorophenyl)-2-(3,4,5-trimethoxyphenyl)-1
hthe preparation of-pyrroles (compound 19):
Except using corresponding raw material, prepare compound 19 with the method that embodiment 1 is identical, yield is 56.5%; The structural formula of compound 19,
1h-NMR and MS data are listed in the table below in-1.
embodiment 20:1-(3-bromophenyl)-2-(3,4,5-trimethoxyphenyl)-1
hthe preparation of-pyrroles (compound 20):
Except using corresponding raw material, prepare compound 20 with the method that embodiment 1 is identical, yield is 55.6%; The structural formula of compound 20,
1h-NMR and MS data are listed in the table below in-1.
embodiment 21:1-(4-bromophenyl)-2-(3,4,5-trimethoxyphenyl)-1
hthe preparation of-pyrroles (compound 21):
Except using corresponding raw material, prepare compound 21 with the method that embodiment 1 is identical, yield is 58.2%; The structural formula of compound 21,
1h-NMR and MS data are listed in the table below in-1.
embodiment 22:1-(the fluoro-4-bromophenyl of 2-)-2-(3,4,5-trimethoxyphenyl)-1
hthe preparation of-pyrroles (compound 22):
Except using corresponding raw material, prepare compound 22 with the method that embodiment 1 is identical, yield is 55.8%; The structural formula of compound 22,
1h-NMR and MS data are listed in the table below in-1.
embodiment 23:1-(the fluoro-2-bromophenyl of 4-)-2-(3,4,5-trimethoxyphenyl)-1
hthe preparation of-pyrroles (compound 23):
Except using corresponding raw material, prepare compound 23 with the method that embodiment 1 is identical, yield is 55.1%; The structural formula of compound 23,
1h-NMR and MS data are listed in the table below in-1.
embodiment 24:1-(2-methyl-4-aminophenyl)-2-(3,4,5-trimethoxyphenyl)-1
hthe preparation of-pyrroles (compound 24):
Except using corresponding raw material, prepare compound 24 with the method that embodiment 1 is identical, yield is 57.7%; The structural formula of compound 24,
1h-NMR and MS data are listed in the table below in-1.
embodiment 25:1-(6-methyl-chloro-phenyl-)-2-(3,4,5-trimethoxyphenyl)-1
hthe preparation of-pyrroles (compound 25):
Except using corresponding raw material, prepare compound 25 with the method that embodiment 1 is identical, yield is 58.5%; The structural formula of compound 25,
1h-NMR and MS data are listed in the table below in-1.
embodiment 26:1-(4-cyanophenyl)-2-(3,4,5-trimethoxyphenyl)-1
hthe preparation of-pyrroles (compound 26):
Except using corresponding raw material, prepare compound 26 with the method that embodiment 1 is identical, yield is 59.3%; The structural formula of compound 26,
1h-NMR and MS data are listed in the table below in-1.
embodiment 27:1-(4-p-methoxy-phenyl)-2-(3,4,5-trimethoxyphenyl)-5-formyl radical-1
hthe preparation of-pyrroles (compound 27):
Under 0 DEG C of nitrogen atmosphere condition, by the POCl of 1.2 equivalents
3(0.054g, 0.35mmol) adds in appropriate 3mL dry DMF, after stirring 15min, adds intermediate 1-(4-the p-methoxy-phenyl)-2-(3,4,5-trimethoxyphenyl)-1 of preparation in embodiment 5
h-pyrroles (0.1g, 0.29mmol), temperature rises to 60 DEG C, after reaction 3h, after question response liquid is down to room temperature, add appropriate saturated sodium bicarbonate solution, regulate pH to 7, with dichloromethane extraction, organic layer saturated common salt water washing, anhydrous sodium sulfate drying, filtrate reduced in volume, thin-layer chromatography obtains sterling, yield 72.4%; The structural formula of compound 27,
1h-NMR and MS data are listed in the table below in-1.
embodiment 28:1-(3,4-Dimethoxyphenyl)-2-(3,4,5-trimethoxyphenyl)-5-formyl radical-1
hthe preparation of-pyrroles (compound 28):
Except using corresponding raw material, prepare compound 28 with the method that embodiment 27 is identical, yield is 68.3%; The structural formula of compound 28,
1h-NMR and MS data are listed in the table below in-1.
embodiment 29:1-(4-fluorophenyl)-2-(3,4,5-trimethoxyphenyl)-5-formyl radical-1
hthe preparation of-pyrroles (compound 29):
Except using corresponding raw material, prepare compound 29 with the method that embodiment 27 is identical, yield is 73.7%; The structural formula of compound 29,
1h-NMR and MS data are listed in the table below in-1.
embodiment 30:1-(3-chloro-phenyl-)-2-(3,4,5-trimethoxyphenyl)-5-formyl radical-1
hthe preparation of-pyrroles (compound 30):
Except using corresponding raw material, prepare compound 30 with the method that embodiment 27 is identical, yield is 70.6%; The structural formula of compound 30,
1h-NMR and MS data are listed in the table below in-1.
embodiment 31:1-(4-p-methoxy-phenyl)-2-(3,4,5-trimethoxyphenyl)-5-hydroxymethyl-1
hthe preparation of-pyrroles (compound 31):
Intermediate 1-(4-p-methoxy-phenyl)-2-(3,4,5-trimethoxyphenyl)-5-formyl radical-1 prepared by Example 27
hthe NaBH of-pyrroles (0.1g, 0.27mmol) and 1 equivalent
4(0.010g, 0.27mmol) adds in 10ml ethanol, and temperature control is at 25 DEG C, stirring reaction 2h, after question response liquid is down to 0 DEG C, add appropriate 8%HCl solution, regulate pH to 7, with dichloromethane extraction, organic layer saturated common salt water washing, anhydrous sodium sulfate drying, filtrate reduced in volume, thin-layer chromatography obtains sterling, yield 94.7%; The structural formula of compound 31,
1h-NMR and MS data are listed in the table below in-1.
embodiment 32:the anti tumor activity in vitro test of compound of the present invention
External activity testing method and result as follows:
Wherein, clinical conventional antitumor drug Zorubicin (ADM) is positive control experiment group.
Anti-tumor activity body outer screening test-1
Screening method: tetrazolium (micoculturetetrozolium, MTT) reduction method
Cell strain: BGC823 cell line SGC-7901cellline
Action time: 72h
Half-inhibition concentration (the IC of each compound on tumor growth
50, μM) in Table-2.
Anti-tumor activity body outer screening test-2
Screening method: tetrazolium (micoculturetetrozolium, MTT) reduction method
Cell strain: human oral cavity epithelial JEG-3 KBcellline
Action time: 72h
Half-inhibition concentration (the IC of each compound on tumor growth
50, μM) in Table-2.
Anti-tumor activity body outer screening test 3
Screening method: tetrazolium (micoculturetetrozolium, MTT) reduction method
Cell strain: human fibrosarcoma cell's strain HT-1080cellline
Action time: 72h
Half-inhibition concentration (the IC of each compound on tumor growth
50, μM) in Table-2.
Table-1
| Compound | Chemical structure | 1H-NMR(solvent is CDCl 3） | MS |
| 1 | 3.67(6H,s), 3.77(3H,s), 3.84(3H,s), 6.35(4H,m), 6.77(2H,dd,J=2.01,J=6.80), 6.92(1H,m), 7.08(2H,dd,J=2.01,J=6.80) | 339 | |
| 2 | 1.39(3H,t,J=6.95), 3.66(6H,s), 3.84(3H,s), 3.99(2H,J=6.92), 6.35(4H,m), 6.75(2H,dd,J=1.81,J=6.40), 6.90(1H,m), 7.06(2H,dd,J=1.81,J=6.40) | 353 | |
| 3 | 3.69(6H,s), 3.86(3H,s), 6.35(3H,m), 6.43(1H,m), 6.94(1H,m), 7.09(2H,dd,J=2.22,J=6.86), 7.20(2H,dd,J=2.22,J=6.86) | 343 | |
| 4 | 3.69(6H,s), 3.86(3H,s), 6.35(3H,m), 6.44(1H,m), 6.94(1H,m), 7.02(2H,dd,J=1.95,J=6.70), 7.35(2H,dd,J=1.95,J=6.70) | 387 | |
| 5 | 3.63(6H,s), 3.81(6H,s), 6.33(3H,m), 6.41(1H,m), 6.87(3H,m), 7.12(2H,dd,J=2.13,J=6.86) | 339 | |
| 6 | 3.64(6H,s), 3.70(3H,s), 3.82(3H,s), 6.35(3H,m), 6.43(1H,m), 6.72(1H,m), 6.81(2H,m), 6.94(1H,m), 7.23(1H,m) | 339 | |
| 7 | 3.64(6H,s), 3.71(3H,s), 3.82(3H,s), 3.88(3H,s), 6.33(1H,m), 6.38(2H,s), 6.42(1H,m), 6.69(1H,m), 6.79(1H,m), 6.83(1H,m), 6.92(1H,m) | 369 | |
| 8 | 3.65(6H,s),3.82(3H,s),3.90(3H,s),6.31(1H,t,J=3.0), 6.37(2H,s),6.39(1H,m),6.64(1H,q,J=2.28), 6.78(1H,d,J=8.63),6.87(2H,m) | 355 | |
| 9 | 3.65(6H,s), 3.82(3H,s), 3.85(3H,s), 6.29(1H,t,J=2.83), 6.39(3H,m), 6.54(1H,m), 6.57(1H,d,J=2.52), 6.71(1H,d,J=8.18),6.86(1H,m) | 354 | |
| 10 | 3.62(6H,s), 3.81(3H,s), 6.34(2H,s), 6.39(1H,m), 6.45(1H,m), 6.89(2H,m), 7.15(3H,m) | 327 | |
| 11 | 3.65(6H,s), 3.83(3H,s), 6.33(2H,s), 6.36(1H,m), 6.42(1H,m), 6.95(4H,m), 7.31(1H,m) | 327 | |
| 12 | 3.64(6H,s),3.82(3H,s),6.31(2H,s),6.35(1H,m), 6.42(1H,m),6.89(1H,m),7.04(2H,m),7.17(2H,m) | 327 | |
| 13 | 3.67(6H,s), 3.83(3H,s), 6.32(2H,s), 6.35(1H,m), 6.41(1H,m), 6.88(1H,m), 6.92(1H,m), 7.05(1H,m), 7.14(1H,q,J=9.01) | 345 | |
| 14 | 3.69(6H,s), 3.84(3H,s), 6.36(3H,m), 6.41(1H,m), 6.74(3H,m), 6.91(1H,m) | 345 | |
| 15 | 3.67(6H,s), 3.83(3H,s), 6.32(2H,s), 6.35(1H,m), 6.41(1H,m), 6.88(1H,m), 7.02(1H,m), 7.10(1H,t,J=8.43), 7.32(1H,q,J=2.68) | 361 | |
| 16 | 3.65(6H,s),3.83(3H,s),6.32(2H,s),6.36(1H,m), 6.43(1H,m),,6.92(1H,m),7.03(1H,m),7.26(3H,m) | 343 | |
| 17 | 3.65(6H,s), 3.83(3H,s), 6.31(2H,s), 6.36(1H,t,J=3.06), 6.42(1H,m), 6.90(1H,m), 7.12(2H,dd,J=2.11,J=6.64), 7.32(2H,dd,J=2.11,J=6.64) | 343 | |
| 18 | 3.68(6H,s), 3.84(3H,s), 6.33(2H,s), 6.36(1H,m), 6.41(1H,m), 6.89(1H,m), 6.97(1H,m), 7.38(2H,m) | 377 | |
| 19 | 3.70(6H,s),3.84(3H,s),6.34(2H,s),6.36(1H,t,J=3.17), 6.42(1H,m),6.90(1H,m),7.09(2H,d,J=1.55),7.28(1H,m) | 377 | |
| 20 | 3.65(6H,s), 3.83(3H,s), 6.32(2H,s), 6.36(1H,t,J=2.96), 6.42(1H,m), 6.91(1H,m), 7.07(1H,m), 7.19(1H,t,J=7.73), 7.41(2H,m) | 387 | |
| 21 | 3.65(6H,s), 3.83(3H,s), 6.31(2H,s), 6.36(1H,m), 6.42(1H,m), 6.90(1H,m), 7.07(2H,d,J=8.63), 7.47(2H,d,J=8.63) | 387 | |
| 22 | 3.66(6H,s), 3.82(3H,s), 6.32(2H,s), 6.39(1H,m), 6.44(1H,m), 6.85(1H,m), 7.09(1H,t,J=8.09), 7.32(2H,m) | 405 | |
| 23 | 3.66(6H,s), 3.80(3H,s), 6.32(2H,s), 6.38(1H,t,J=2.92), 6.45(1H,m), 6.78(1H,m), 7.04(1H,m), 7.22(1H,q,J=5.74), 7.41(1H,q,J=2.72) | 405 | |
| 24 | 1.80(3H,s), 3.63(6H,s), 3.80(3H,s), 6.33(1H,t,J=3.15), 6.38(2H,s), 6.46(1H,m), 6.62(2H,m), 6.74(1H,m), 6.99(1H,t,J=2.45,J=5.95) | 338 | |
| 25 | 1.88(3H,s), 3.63(6H,s), 3.79(3H,s), 6.36(2H,s), 6.42(1H,t,J=2.96), 6.49(1H,m), 6.67(2H,m), 7.11(1H,m), 7.21(2H,m) | 357 | |
| 26 | 3.66(6H,s), 3.84(3H,s), 6.30(2H,s), 6.41(1H,m), 6.45(1H,m), 6.96(1H,m), 7.29(2H,m), 7.64(2H,d,J=8.35) | 334 | |
| 27 | 3.64(6H,s), 3.82(3H,s), 3.83(3H,s), 6.35(2H,s), 6.53(1H,d,J=4.19), 6.92(2H,dd,J=1.96,J=6.63), 7.19(3H,m), 9.47(1H,s) | 367 | |
| 28 | 3.64(6H,s), 3.76(3H,s), 3.82(3H,s), 3.91(3H,s), 6.38(2H,s), 6.53(1H,d,J=4.22), 6.76(1H,m), 6.87(2H,m), 7.19(1H,d,J=4.30),9.48(1H,s) | 397 | |
| 29 | 3.64(6H,s), 3.82(3H,s), 6.31(2H,s), 6.53(1H,d,J=3.96), 7.10(2H,t,J=8.31), 7.17(1H,d,J=4.22), 7.24(2H,t,J=8.31), 9.50(1H,s) | 355 | |
| 30 | 3.65(6H,s), 3.91(3H,s), 6.33(2H,s), 6.53(1H,d,J=3.96), 7.17(1H,m), 7.34(4H,m), 9.50(1H,s) | 371 | |
| 31 | 3.64(6H,s), 3.82(3H,s), 3.83(3H,s), 4.65(2H,s),6.37(2H,s), 6.53(1H,d,J=4.31), 6.92(2H,dd,J=2.02,J=6.62), 7.08(3H,m), | 369 |
Table-2
Claims (2)
1.1,2-diaryl-5-replaces-1
h-azoles, is selected from:
2-(4-p-methoxy-phenyl)-1-(3,4,5-trimethoxyphenyl)-1
h-pyrroles;
2-(4-ethoxyl phenenyl)-1-(3,4,5-trimethoxyphenyl)-1
h-pyrroles;
1-(3,4,5-trimethoxyphenyl)-2-(4-chloro-phenyl-)-1
h-pyrroles;
1-(3,4,5-trimethoxyphenyl)-2-(4-bromophenyl)-1
h-pyrroles;
1-(4-p-methoxy-phenyl)-2-(3,4,5-trimethoxyphenyl)-1
h-pyrroles;
1-(3-p-methoxy-phenyl)-2-(3,4,5-trimethoxyphenyl)-1
h-pyrroles;
1-(3,4-Dimethoxyphenyl)-2-(3,4,5-trimethoxyphenyl)-1
h-pyrroles;
1-(3-hydroxyl-4-p-methoxy-phenyl)-2-(3,4,5-trimethoxyphenyl)-1
h-pyrroles;
1-(3-amino-4-methoxyl phenyl)-2-(3,4,5-trimethoxyphenyl)-1
h-pyrroles;
1-(2-fluorophenyl)-2-(3,4,5-trimethoxyphenyl)-1
h-pyrroles;
1-(3-fluorophenyl)-2-(3,4,5-trimethoxyphenyl)-1
h-pyrroles;
1-(4-fluorophenyl)-2-(3,4,5-trimethoxyphenyl)-1
h-pyrroles;
1-(3,4-difluorophenyl)-2-(3,4,5-trimethoxyphenyl)-1
h-pyrroles;
1-(3,5-difluorophenyl)-2-(3,4,5-trimethoxyphenyl)-1
h-pyrroles;
1-(the chloro-4-fluorophenyl of 3-)-2-(3,4,5-trimethoxyphenyl)-1
h-pyrroles;
1-(3-chloro-phenyl-)-2-(3,4,5-trimethoxyphenyl)-1
h-pyrroles;
1-(4-chloro-phenyl-)-2-(3,4,5-trimethoxyphenyl)-1
h-pyrroles;
1-(3,4-dichlorophenyl)-2-(3,4,5-trimethoxyphenyl)-1
h-pyrroles;
1-(3,5-dichlorophenyl)-2-(3,4,5-trimethoxyphenyl)-1
h-pyrroles;
1-(3-bromophenyl)-2-(3,4,5-trimethoxyphenyl)-1
h-pyrroles;
1-(4-bromophenyl)-2-(3,4,5-trimethoxyphenyl)-1
h-pyrroles;
1-(the fluoro-4-bromophenyl of 2-)-2-(3,4,5-trimethoxyphenyl)-1
h-pyrroles;
1-(the fluoro-2-bromophenyl of 4-)-2-(3,4,5-trimethoxyphenyl)-1
h-pyrroles;
1-(2-methyl-4-aminophenyl)-2-(3,4,5-trimethoxyphenyl)-1
h-pyrroles;
1-(6-methyl-chloro-phenyl-)-2-(3,4,5-trimethoxyphenyl)-1
h-pyrroles;
1-(4-cyanophenyl)-2-(3,4,5-trimethoxyphenyl)-1
h-pyrroles;
1-(4-p-methoxy-phenyl)-2-(3,4,5-trimethoxyphenyl)-5-formyl radical-1
h-pyrroles;
1-(3,4-Dimethoxyphenyl)-2-(3,4,5-trimethoxyphenyl)-5-formyl radical-1
h-pyrroles;
1-(4-fluorophenyl)-2-(3,4,5-trimethoxyphenyl)-5-formyl radical-1
h-pyrroles;
1-(3-chloro-phenyl-)-2-(3,4,5-trimethoxyphenyl)-5-formyl radical-1
h-pyrroles;
1-(4-p-methoxy-phenyl)-2-(3,4,5-trimethoxyphenyl)-5-hydroxymethyl-1
h-pyrroles.
2. 1,2-diaryl-5-according to claim 1 replaces-1
h-azoles is preparing the application in antitumor drug.
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| WO2008014821A1 (en) * | 2006-08-03 | 2008-02-07 | Rottapharm S.P.A. | 3-substituted-1,5-diarly-2-alkyl-pyrroles highly selective and orally effective cox-2 inhibitors |
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| WO2008014821A1 (en) * | 2006-08-03 | 2008-02-07 | Rottapharm S.P.A. | 3-substituted-1,5-diarly-2-alkyl-pyrroles highly selective and orally effective cox-2 inhibitors |
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