CN102443005A - Spiroheterocycle compound of chalcone and application of spiroheterocycle compound - Google Patents
Spiroheterocycle compound of chalcone and application of spiroheterocycle compound Download PDFInfo
- Publication number
- CN102443005A CN102443005A CN2011102317239A CN201110231723A CN102443005A CN 102443005 A CN102443005 A CN 102443005A CN 2011102317239 A CN2011102317239 A CN 2011102317239A CN 201110231723 A CN201110231723 A CN 201110231723A CN 102443005 A CN102443005 A CN 102443005A
- Authority
- CN
- China
- Prior art keywords
- alkyl
- cyclic hydrocarbon
- aryl
- heterocyclic radical
- heteroaryl
- 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.)
- Pending
Links
Images
Landscapes
- Indole Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention relates to a spiroheterocycle compound with a general formula (I), stereoisomers, enantiomer, tautomers or mixtures thereof, or pharmaceutically acceptable salts, solvates or predrugs thereof, wherein II, R1, R2, R3, Ar1 and Ar2 are as defined herein. The compound provided by the invention has a better application prospect in the medicine aspect, and the application prospect specifically comprises but is not limited to preparation of anti-tumor medicines, tyrosine kinase inhibitor medicines, medicines for treating diseases caused by oxidative stress and anti-inflammation medicines for treating inflammation-related diseases.
Description
Technical field
The present invention relates to the spiro-heterocycle compound of novel cinnamophenone, comprise this compound compositions and uses thereof.Particularly, the present invention relates to following spiroheterocyclic compound, under the catalyst-free condition, prepare through 1,3 Dipolar Cycloaddition by common cinnamophenone.
Background technology
Chalcone compounds belongs to flavonoid compound, its basic framework 1, and 3-diaryl acrylketone extensively is present in the plants such as Radix Glycyrrhizae, hops, safflower, Herba Oxytropis falcatae.Natural chalcone compounds contains hydroxyl more on phenyl ring; Can show wide biological activity with different receptors bind, like antitumor action, anti-inflammatory action, analgesic activity, antiulcer action, antivirus action, anti-microbial effect, antifungic action, malaria effect etc.But chalcone compounds content natural in the plant is generally lower, and the cost of extraction separation is also bigger.And synthetic cinnamophenone compound also has the BA identical with natural cinnamophenone, thereby Chinese scholars has been carried out more research to the synthetic and activity of chalcone compounds.Up to the present, the report of synthesizing chalcone compounds mainly concentrates on the simple chalcone compounds that is generated by the reaction of aromatic aldehyde ketone generation cross aldol condensation.In addition, also comprise some other structure of modification, mainly contain: acrylketone is five yuan of pyrazoles ring structures, hexa-member heterocycle in the middle of changing; Changing acrylketone is to form title complex with metal again on the heterocyclic basis.Relevant synthesizing chalcone compounds also has certain patent report, domestic have the report have: the patent No. be CN 101485651A patent report chalcone derivative have hypolipidemic activity and hepatoprotective effect; The patent No. be CN 1990446A patent report cinnamophenone have the activity that suppresses beta-secretase, can be used for treating senile dementia.External report has: the patent No. be US 7851654 patent report the acceptable salt of chalcone derivative medicine, preparation method and application; The patent No. be US 2009/0252694A1 patent report novel chalcone derivative preparation method and application.
The natural product of having reported that much has heterocycle structure shows better BA than the compound that does not have heterocycle structure; Therefore the present invention has introduced the spiroheterocyclic structure on the basis of chalcone skeleton structure, synthesizes novel spiro-heterocycle chalcone derivative.Synthetic this compounds is synthetic through the method for " treating different things alike ", belongs to 1,3 Dipolar Cycloaddition of high yield.Simultaneously we also find through previous experiments, and this compounds has some and the quite or better BA of simple chalcone compounds, like anti-inflammatory, anti-oxidant, anti-tumor activity.
Summary of the invention
The object of the present invention is to provide a kind of spiro-heterocycle compound of novel cinnamophenone; Like general formula (1) compound; And comprise its steric isomer, enantiomer, tautomer or its mixture; Or the acceptable salt of its medicine, solvolyte or prodrug, include but not limited to be used for antitumor, be suppressed to bfgf receptor Tyrosylprotein kinase, anti-oxidant and antiphlogistic purposes.
Particularly: the invention provides general formula (I) compound, and comprise its steric isomer, enantiomer, tautomer or its mixture, or the acceptable salt of its medicine, solvolyte or prodrug:
Wherein:
R1 is hydrogen, alkyl, thiazolinyl, alkynyl, haloalkyl, aryl, cyclic hydrocarbon radical, cyclic hydrocarbon radical alkyl, heteroaryl, heterocyclic radical;
Or R1 is the substituted aralkyl of quilt-C (O) N (R6) R7, wherein:
R6 is hydrogen, alkyl, aryl or aralkyl;
And R7 be hydrogen, alkyl, haloalkyl ,-R9-N (R4) R5, aryl, aralkyl, cyclic hydrocarbon radical, cyclic hydrocarbon radical alkyl, heterocyclic radical, heterocyclic radical alkyl, heteroaryl, heteroaralkyl;
Or R6 and R7 and connected nitrogen form heterocyclic radical or heteroaryl together;
And wherein each aryl of R6 and R7, aralkyl, cyclic hydrocarbon radical, cyclic hydrocarbon radical alkyl, heterocyclic radical, heterocyclic radical alkyl, heteroaryl and heteroaryl groups can randomly be replaced by one or more substituting groups that are selected from alkyl, cyclic hydrocarbon radical, aryl, aralkyl, halogen, haloalkyl, heterocyclic radical and heteroaryl;
Or R1 is for randomly being replaced by-C (O) OR5, halogen, haloalkyl, alkyl, nitro, cyanic acid, aryl (optional by cyano replaces), aralkyl (randomly being replaced by one or more alkyl groups), heterocyclic radical or the substituted aralkyl of heteroaryl;
Or R1 be-R9-N (R10) R11 ,-R9-N (R12) C (O) R11, wherein:
Each-R10 is hydrogen, alkyl, aryl or aralkyl;
Each-R11 is hydrogen, alkyl, haloalkyl, cyclic hydrocarbon radical, cyclic hydrocarbon radical alkyl, aryl, aralkyl, heterocyclic radical, heterocyclic radical alkyl, heteroaryl, heteroaralkyl;
R12 is hydrogen, alkyl, aryl, aralkyl;
And wherein each aryl of R10 and R11, aralkyl, cyclic hydrocarbon radical, cyclic hydrocarbon radical alkyl, heterocyclic radical, heterocyclic radical alkyl, heteroaryl and heteroaralkyl group can randomly be replaced by one or more substituting groups that are selected from alkyl, cyclic hydrocarbon radical, aryl, aralkyl, halogen, haloalkyl, nitro, heterocyclic radical and heteroaryl;
Or R1 is heterocyclic radical alkyl or heteroaralkyl, and wherein said heterocyclic radical alkyl or heteroaryl groups are randomly replaced by one or more substituting groups that are selected from alkyl, halogen, haloalkyl, aryl and aralkyl;
Or R1 and R2 and can form the condensed ring that is selected from cyclic hydrocarbon radical, heterocyclic radical, aryl or heteroaryl with its direct-connected nitrogen or carboatomic ring atom, and remaining R1 group such as preceding text define;
R2 be independently selected from hydrogen, alkyl, thiazolinyl, alkynyl, alkoxyl group, halogen, haloalkyl, haloalkenyl group, halogenated alkoxy, cyclic hydrocarbon radical, cyclic hydrocarbon radical alkyl, aryl, aralkyl, aryl alkenyl, heterocyclic radical, heterocyclic radical alkyl, heteroaryl, heteroaralkyl ,-R8-N (R4) R5;
Or R2 and R1 and can form the condensed ring that is selected from cyclic hydrocarbon radical, heterocyclic radical, aryl or heteroaryl with its direct-connected carbon or azo-cycle atom, and remaining R2 group such as preceding text define;
Each R3 all be independently selected from hydrogen, alkyl, thiazolinyl, alkynyl, alkoxyl group, halogen, haloalkyl, haloalkenyl group, halogenated alkoxy, cyclic hydrocarbon radical, cyclic hydrocarbon radical alkyl, aryl, aralkyl, aryl alkenyl, heterocyclic radical, heterocyclic radical alkyl, heteroaryl, heteroaralkyl ,-R8-N (R4) R5;
Or two adjacent R3 groups with its direct-connected condensed hetero-aromatic ring or condensed heterocycle atom can form the condensed ring that is selected from cyclic hydrocarbon radical, aryl, heterocyclic radical and heteroaryl, and if remaining R3 group exist then define like preceding text;
Each R4 and R5 are independently selected from hydrogen, alkyl, thiazolinyl, alkynyl, haloalkyl, alkoxyalkyl, cyclic hydrocarbon radical, cyclic hydrocarbon radical alkyl, aryl, aralkyl, heterocyclic radical and heteroaryl;
Or when R4 and R5 all were connected on the identical nitrogen-atoms, R4 and R5 and connected nitrogen-atoms can form heterocyclic radical or heteroaryl together, and if remaining R4 and R5 group exist then define like preceding text;
And each R8 is the alkylidene chain of valence bond or straight or branched, the alkenylene chain of straight or branched or the alkynylene chain of straight or branched; And each R9 is the alkylidene chain of straight or branched, the alkenylene chain of straight or branched or the alkynylene chain of straight or branched;
Ar
1And Ar
2Can be identical also can be inequality, can be aromatic ring, fragrant heterocycle, replace aromatic ring and replace fragrant heterocycle; Substituting group can for alkyl, thiazolinyl, alkynyl, alkoxyl group, halogen, haloalkyl, haloalkenyl group, halogenated alkoxy, cyclic hydrocarbon radical, cyclic hydrocarbon radical alkyl, aryl, aralkyl, aryl alkenyl, heterocyclic radical, heterocyclic radical alkyl, heteroaryl, heteroaralkyl, amino, substituted amino, carboxyl, aminoacyl, replacement aminoacyl, benzoyl group, substituted benzene acyl group, nicotinoyl, replacement nicotinoyl ,-R
8-N (R
4) R
5Substituting group can replace aromatic ring and fragrant heterocyclic optional position, and is perhaps simultaneously polysubstituted.
The compounds of this invention or the acceptable salt of its medicine can contain one or more asymmetric centers; And therefore can cause enantiomer, diastereomer and other steric isomer; Its according to the absolute stereo chemistry be defined as (R)-or (S)-, or to amino acid be (D)-or (L)-.The present invention expectation comprises the isomer that all these are possible, with and racemize and optically pure form.Optical activity (+) and (-), (R)-with (S)-or (D)-can use chiral synthon or chiral reagent preparation, or use routine techniques such as chromatography and fractional crystallization solution with (L)-isomer.The routine techniques of the single enantiomer of preparation/separation comprises from the chirality of suitable optical purity precursor synthetic; Or for example use chirality HPLC (HPLC) to the fractionation of racemic modification (the perhaps racemic modification of salt or verivate). when the compound described in this paper contains two strong or other how much asymmetric centers of alkene; And unless otherwise, these compound expectations comprise E and Z geometrical isomer.Likewise, also expectation comprises all tautomeric forms.
" steric isomer " is meant by forming through identical valence bond bonded same atoms, but the compound with not interchangeable different three-dimensional structures.Various steric isomers and composition thereof are contained in the present invention's expectation, and comprise " enantiomer ", and it is meant two kinds of steric isomers, and its molecule each other can not the eclipsed mirror image.
" tautomer " is meant that proton is passed to another atom of same molecular from an atom of molecule.The present invention includes the tautomer of any said compound.
General formula (1) compound is to be obtained through 1,3 Dipolar Cycloaddition under the condition that does not add catalyzer by common chalcone compounds.Particularly be exactly 1) acetophenone compounds is dissolved in the ethanol, add the phenyl aldehyde compounds, stir and dropping alkali, react completely under the room temperature, separate and purified product; 2) in methanol solvate, add 1) middle pure compound, isatin and the sarkosine that reacts, reflux.The resulting compound of method purifying through recrystallization and column chromatography.
General formula (1) compound has BA preferably, aspect medical, has certain application prospect, specifically and so includes but not limited to the purposes of following medicine and pharmacology aspect:
Discover through anti tumor activity in vitro on the one hand and can suppress SGC7901 and HepG2 growth of tumour cell (specifically seeing embodiment 2), thereby might develop into new antitumor drug;
Through compound fibroblast growth factor acceptor 1 (FGFR1) Tyrosylprotein kinase is suppressed activity research on the other hand; Find that this compounds can suppress FGFR1 Tyrosylprotein kinase (specifically seeing embodiment 3), thereby might develop into new tyrosine kinase inhibitor medicine;
Find to have anti-oxidant activity (specifically seeing embodiment 4) preferably through the antioxidation activity in vitro experimental study on the other hand, thereby might develop into the medicine of new treatment by the oxidative stress associated diseases;
Discover that through the extracorporeal anti-inflammatory activity experiment inflammatory factor is had better inhibited activity (specifically seeing embodiment 5) on the other hand, thereby might develop into the new treatment and the medicine of inflammation related disease.
Correspondingly, the invention provides pharmaceutical composition, it contains general formula (I) compound of effective dose, and pharmaceutically acceptable carrier.The pharmaceutically acceptable carrier that uses among this paper refers to nontoxic weighting agent, stablizer, thinner, adjuvant or other pharmaceutical adjuncts.For example, thinner, vehicle are like water, saline water etc.; Weighting agent is like starch, sucrose etc.; Tackiness agent is like derivatived cellulose, alginate, gelatin and/or Vinylpyrrolidone polymer; Wetting agent is like glycerine; Disintegrating agent is like agar, lime carbonate and/or sodium hydrogencarbonate; Absorption enhancer is like quaternary ammonium compound; Tensio-active agent is like cetyl alcohol; Absorption carrier is like kaolin and/or soap clay; Lubricant is like talcum powder, calcium stearate/magnesium, polyoxyethylene glycol etc.In addition, pharmaceutical composition of the present invention can also further contain other auxiliary material, like flavouring agent, sweeting agent etc.Known technology according to this area; Can pharmaceutical composition be processed various formulations according to the needs of therapeutic purpose, route of administration; Preferred said composition is a unit dosage form, like freeze-dried, tablet, capsule, pulvis, emulsion agent, aqueous injection or sprays, more preferably this pharmaceutical composition be injection type (as; Lyophilized injectable powder) or oral dosage form (as, tablet, capsule).Wherein, pharmaceutically acceptable carrier mentioned above is meant the pharmaceutical carrier that pharmaceutical field is conventional.
Beneficial effect of the present invention does; Invented spiro-heterocycle compound of one type of novel cinnamophenone and preparation method thereof; Find its have antitumor, suppress FGFR1 Tyrosylprotein kinase, anti-oxidant and anti-inflammatory action, can be used for being prepared into antitumor class, tyrosine kinase inhibitor class, treat disease that oxidative stress causes and with the anti-inflammatory drug of inflammation related disease.
Description of drawings
Fig. 1 mtt assay mensuration compound suppresses active inhibiting rate to the increment of SGC7901 cell
Fig. 2 mtt assay mensuration compound suppresses active inhibiting rate to the increment of HepG2 cell
Fig. 3 20 μ m part of compounds suppress motility rate to the FGFR1 Tyrosylprotein kinase
Fig. 4 part of compounds is to the inhibiting rate of DPPH
The activity of the scavenger cell expressing tumor necrosin (IL-6) that the inhibition of Fig. 5 compound is lipopolysaccharide-induced
The crystalline structure of Fig. 6 compound L 11H23D1 and structure cell accumulation graph (dotted line is represented hydrogen bond)
Embodiment
The present invention further specifies in following embodiment.These embodiment are for illustrative purposes, rather than are used for limiting scope of the present invention.
Embodiment 1 preparation method and part of compounds structure elucidation
The preparation method is following:
1), acetophenone compounds is dissolved in the ethanol, adds the phenyl aldehyde compounds, stir and also drip alkali, react completely under the room temperature, separate and purified product;
2), in methanol solvate, add 1) in the reaction pure compound, isatin and sarkosine, reflux;
3) the carrying out of the close monitoring reaction of TLC, the reaction times was generally 5-24 hour.After finishing, reaction will select the separation and purification condition flexibly for use; Reaction product is generally all water insoluble or be slightly soluble in water; And product solubleness in ethanol is littler than raw material; Go out deposition so generally can directly add elutriation, use the alcohol-water washing precipitation of 5-10% again, perhaps add the acid-alkali accommodation reaction solution earlier and after neutrality, add the suitable quantity of water deposition again.With TLC analyzing and testing purity, impure sample is with the organic solvent recrystallization or carry out purifying with the method for silica gel column chromatography for the solid precipitation of separating out or oily matter.
1 '-methyl-3 '-(3,4,5-Three methyl Benzene acyl group)-4 '-(2, the 4-Dimethoxyphenyl)-spiral shell-[3H-indoles-3,2 '-hydrogenation pyrroles]-2-ketone (L28H16 D1)
Orange red powder, productive rate 56.3%, 166.1～170.1 ℃ of fusing points.
1H-NMR (CDCl
3), δ: 8.132 (d, J=15.6Hz, 1H, H-β), 7.926 (d, J=8.4Hz, 2H, H-2 '; H-6 '), 7.733 (d, J=9.6Hz, 1H, H-6), 7.490 (d, J=15.6Hz, 1H, H-α); 7.431 (d, J=9Hz, 1H, H-3), 7.307 (m, 1H, H-5), 7.302 (m, 1H; H-3), 6.700 (d, J=8.4Hz, 2H, H-3 ', H=5 '), 4.190 (brs, 2H, NH
2-4 ') .IR (cm
-1): 3331,3227 (NH
2), 1650 (C=O), 1469,1560,1580 (Ar), 1609 (C=C) .ESI-MS m/z:533.0 (M+1)
+, calcd for C
30H
32N
2O
7: 532.58
1 '-methyl-3 '-(2,4 ,-dimethoxy benzoyl group)-4 '-(3,4, the 5-Dimethoxyphenyl)-spiral shell-[acenaphthylene-1 (2H), 2 '-hydrogenation pyrroles]-2-ketone (L28H16D2)
Orange-yellow powder, productive rate 74.9%, 77.2～79.6 ℃ of fusing points.
1H-NMR (CDCl
3), δ: 8.132 (d, J=15.6Hz, 1H, H-β), 7.926 (d, J=8.4Hz, 2H, H-2 '; H-6 '), 7.733 (d, J=9.6Hz, 1H, H-6), 7.490 (d, J=15.6Hz, 1H, H-α); 7.431 (d, J=9Hz, 1H, H-3), 7.307 (m, 1H, H-5), 7.302 (m, 1H; H-3), 6.700 (d, J=8.4Hz, 2H, H-3 ', H=5 '), 4.190 (brs, 2H, NH
2-4 ') .IR (cm
-1): 3331,3227 (NH
2), 1650 (C=O), 1469,1560,1580 (Ar), 1609 (C=C) .ESI-MS m/z:568.0 (M+1)
+, calcd for C
34H
33NO
7: 567.23
1 '-methyl-3 '-(2,4 ,-dimethoxy benzoyl group)-4 '-(3,4, the 5-Dimethoxyphenyl)-spiral shell-[3H-indoles-3,2 '-hydrogenation pyrroles]-2-ketone (L11H37 D1)
Orange-yellow powder, productive rate 68.1%, 77.3～82.3 ℃ of fusing points.
1H-NMR (CDCl
3), δ: 8.132 (d, J=15.6Hz, 1H, H-β), 7.926 (d, J=8.4Hz, 2H, H-2 '; H-6 '), 7.733 (d, J=9.6Hz, 1H, H-6), 7.490 (d, J=15.6Hz, 1H, H-α); 7.431 (d, J=9Hz, 1H, H-3), 7.307 (m, 1H, H-5), 7.302 (m, 1H; H-3), 6.700 (d, J=8.4Hz, 2H, H-3 ', H=5 '), 4.190 (brs, 2H, NH
2-4 ') .IR (cm
-1): 3331,3227 (NH
2), 1650 (C=O), 1469,1560,1580 (Ar), 1609 (C=C) .ESI-MS m/z:533.1 (M+1)
+, calcd for C
30H
32N
2O
7: 532.58
1 '-methyl-3 '-(3,4 ,-dimethoxy benzoyl group)-4 '-(3,4, the 5-Dimethoxyphenyl)-spiral shell-[3H-indoles-3,2 '-hydrogenation pyrroles]-2-ketone (L20H37 D1)
Orange red powder, productive rate 58.2%, 138.5～142.7 ℃ of fusing points.
1H-NMR (CDCl
3), δ: 8.132 (d, J=15.6Hz, 1H, H-β), 7.926 (d, J=8.4Hz, 2H, H-2 '; H-6 '), 7.733 (d, J=9.6Hz, 1H, H-6), 7.490 (d, J=15.6Hz, 1H, H-α); 7.431 (d, J=9Hz, 1H, H-3), 7.307 (m, 1H, H-5), 7.302 (m, 1H; H-3), 6.700 (d, J=8.4Hz, 2H, H-3 ', H=5 '), 4.190 (brs, 2H, NH
2-4 ') .IR (cm
-1): 3331,3227 (NH
2), 1650 (C=O), 1469,1560,1580 (Ar), 1609 (C=C) .ESI-MS m/z:519.0 (M+1)
+, calcd for C
29H
30N
2O
7: 518.56
1 '-methyl-3 '-(2,4,5-trimethoxy benzoyl group)-4 '-(3,4, the 5-Dimethoxyphenyl)-spiral shell-[3H-indoles-3,2 '-hydrogenation pyrroles]-2-ketone (L28H37D1)
Orange red powder, productive rate 61.7%, 63.9～68.5 ℃ of fusing points.
1H-NMR (CDCl
3), δ: 8.132 (d, J=15.6Hz, 1H, H-β), 7.926 (d, J=8.4Hz, 2H, H-2 '; H-6 '), 7.733 (d, J=9.6Hz, 1H, H-6), 7.490 (d, J=15.6Hz, 1H, H-α); 7.431 (d, J=9Hz, 1H, H-3), 7.307 (m, 1H, H-5), 7.302 (m, 1H; H-3), 6.700 (d, J=8.4Hz, 2H, H-3 ', H=5 '), 4.190 (brs, 2H, NH
2-4 ') .IR (cm
-1): 3331,3227 (NH
2), 1650 (C=O), 1469,1560,1580 (Ar), 1609 (C=C) .ESI-MS m/z:563.1 (M+1)
+, calcd for C
31H
34N
2O
8: 562.61
1 '-methyl-3 '-(2,3,4-trimethoxy benzoyl group)-4 '-(3-hydroxyl-4-p-methoxy-phenyl)-spiral shell-[3H-indoles-3,2 '-hydrogenation pyrroles]-2-ketone (L28H15 D1)
Orange red powder, productive rate 72.9%, 195.6～201.0 ℃ of fusing points.
1H-NMR (CDCl
3), δ: 8.132 (d, J=15.6Hz, 1H, H-β), 7.926 (d, J=8.4Hz, 2H, H-2 '; H-6 '), 7.733 (d, J=9.6Hz, 1H, H-6), 7.490 (d, J=15.6Hz, 1H, H-α); 7.431 (d, J=9Hz, 1H, H-3), 7.307 (m, 1H, H-5), 7.302 (m, 1H; H-3), 6.700 (d, J=8.4Hz, 2H, H-3 ', H=5 '), 4.190 (brs, 2H, NH
2-4 ') .IR (cm
-1): 3331,3227 (NH
2), 1650 (C=O), 1469,1560,1580 (Ar), 1609 (C=C) .ESI-MS m/z:519.0 (M+1)
+, calcd for C
29H
30N
2O
7: 518.21
1 '-methyl-3 '-(2-fluorobenzene acyl group)-4 '-(3, the 4-dihydroxy phenyl)-spiral shell-[3H-indoles-3,2 '-hydrogenation pyrroles]-2-ketone (L15H23D1)
The red-brown powder, productive rate 72.66%, 121.8～124.4 ℃ of fusing points.
1H-NMR (CDCl
3), δ: 7.750 (dt, J=1.8Hz, 7.8Hz, 1H, Ar-H
6), 7.612～7.649 (m, 1H, Ar-H
4'), 7.371～7.395 (m, 1H, Ar-H
5'), 7.331～7.365 (m, 1H, Ar-H
3'), 7.295 (d, J=8.4Hz, 1H, Ar-H
2"), 7.265 (d, J=8.4Hz, 1H, Ar-H
5"), 7.082～7.135 (m, 2H, Ar-H
3", Ar-H
4"), 6.920 (d, J=2.4Hz, 1H, Ar-H
2), 6.815 (dd, J=2.4Hz, 8.4Hz, 1H, Ar-H
6), 6.755 (d, J=8.4Hz, 1H, Ar-H
5), 4.507 (d, J=9.0Hz, 1H, 3-CH), 4.258 (q, J=9.6Hz, 16.8Hz, 1H, 4-CH), 3.474 (t, J=9.0Hz, 1H, 5-CH
2), 3.302 (t, J=9.0Hz, 1H, 5-CH
2), 2.109 (s, 3H, 1-N-CH
3) .ESI-MS m/z:430.9 (M-1)
-, calcd for C
25H
21FN
2O
4: 432.44.
1 '-methyl-3 '-(2-chlorobenzene acyl group)-4 '-(3, the 4-dihydroxy phenyl)-spiral shell-[3H-indoles-3,2 '-hydrogenation pyrroles]-2-ketone (L16H23D1)
Pale brown toner end, productive rate 60.16%, 188.4～189.55 ℃ of fusing points.
1H-NMR (CDCl
3), δ: 9.321 (s, 1H, N-H), 7.275 (d, J=7.8Hz, 1H, Ar-H
6'), 7.184～7.224 (m, 4H, Ar-H
3', Ar-H
4', Ar-H
5', Ar-H
2"), 7.017～7.050 (m, 4H, Ar-H
2, Ar-H
3", Ar-H
4", Ar-H
5"), 6.832 (d, J=7.2Hz, 1H, Ar-H
6), 6.766 (d, J=7.2Hz, 1H, Ar-H
5), 4.633 (t, J=9.0Hz, 1H, 3-CH), 4.214 (q, J=9.0Hz, 16.8Hz, 1H, 4-CH), 3.434 (t, J=9.0Hz, 1H, 5-CH
2), 3.337～3.373 (m, 1H, 5-CH
2), 3.485～3.501 (m, 1H, 5-CH
2), 2.062 (s, 3H, 1-N-CH
3) .ESI-MS m/z:446.8 (M-1)
-, calcd for C
25H
21ClN
2O
4: 448.9.
1 '-methyl-3 '-(2-chlorobenzene acyl group)-4 '-(3, the 4-Dimethoxyphenyl)-spiral shell-[3H-indoles-3,2 '-hydrogenation pyrroles]-2-ketone (L16H46D1) pale yellow powder, productive rate 38.07%, 123.5～128.9 ℃ of fusing points.
1H-NMR (CDCl
3), δ: 7.460 (d, J=7.8Hz, 1H, Ar-H
6'), 7.351～7.394 (m, 3H, Ar-H
3', Ar-H
4', Ar-H
2"), 7.088～7.187 (m, 5H, Ar-H
2, Ar-H
5', Ar-H
3", Ar-H
4", Ar-H
5"), 6.877 (d, J=7.8Hz, 1H, Ar-H
6), 6.830 (d, J=7.8Hz, 1H, Ar-H
5), 4.676 (t, J=9.0Hz, 1H, 3-CH), 4.405～4.431 (m, 1H, 4-CH), 3.917 (s, 6H, Ar-3-OCH
3, Ar-4-OCH
3), 3.716～3.735 (m, 1H, 5-CH
2), 3.485～3.501 (m, 1H, 5-CH
2), 2.175 (s, 3H, 1-N-CH
3) .ESI-MS m/z:477.0,478.9 (M+1)
+, calcd for C
27H
25ClN
2O
4: 476.95
1 '-methyl-3 '-(3,4-difluoro benzoyl group)-4 '-(3, the 4-dihydroxy phenyl)-spiral shell-[3H-indoles-3,2 '-hydrogenation pyrroles]-2-ketone (L26H23D1)
Yellow powder, productive rate 21.53%, 136 ℃ of carbonizations of fusing point.
1H-NMR (CDCl
3), δ: 9.531 (s, 1H, N-H), 8.018～8.078 (m, 1H, Ar-H
6'), 7.268～7.310 (m, 2H, Ar-H
2', Ar-H
2"), 7.205～7.229 (m, 1H, Ar-H
5'), 6.978～7.033 (m, 3H, Ar-H
3", Ar-H
4", Ar-H
5"), 6.861 (d, J=1.8Hz, 1H, Ar-H
2), 6.802 (dd, J=1.8Hz, 7.8Hz, 1H, Ar-H
6), 7.748 (d, J=7.8Hz, 1H, Ar-H
5), 4.404 (d, J=9.6Hz, 1H, 3-CH), 4.292 (dt, J=9.6Hz, 16.8Hz, 1H, 4-CH), 3.515 (t, J=9.0Hz, 1H, 5-CH
2), 3.335 (t, J=9.0Hz, 1H, 5-CH
2), 2.147 (s, 3H, 1-N-CH
3) .ESI-MS m/z:448.8 (M-1)
-, calcd for C
25H
20F
2N
2O
4: 450.43
The test of embodiment 2 anti tumor activity in vitro
Test their growth in vitro inhibition activity with MTT (tetramethyl-azo azoles salt colourimetry) method, represent the power of their anti tumor activity in vitro with the active inhibiting rate of cell inhibitory effect gastric carcinoma cells (SGC7901), liver cancer cell (HepG2).Material: four Cuo salt (MTT), with the phosphate buffered saline buffer dissolving MTT of 0.01mol/L, final concentration is 5mg/mL, filtration sterilization, 4 ℃ of preservations after the packing; The RMPI-1640 complete culture solution adds green grass or young crops, Streptomycin sulphate (100U/ml, 100 μ g/mL) and the 50ml inactivated fetal bovine serum mixing of 6ml, 4 ℃ of preservations in the RMPI-1640 nutrient solution of 500ml; The deactivation of foetal calf serum, behind 4 ℃ of following thawings of foetal calf serum, 56 ℃ of water-bath deactivation 30min ,-20 ℃ of preservations.Method: 5000 cells/well are inoculated in 96 orifice plates, and every hole adds 200 μ L RMPI-1640 complete culture solutions, 37 ℃, 5%CO
2, cultivated 24 hours under the saturated humidity; Every hole adds 1 μ L test-compound, and the compound final concentration is 20 μ g/mL, continues to cultivate 72h; Every hole adds the MTT 20 μ L of 5mg/mL, hatches 4 hours; As far as possible nutrient solution in the sucking-off hole fully adds DMSO liquid (150 μ L/ hole), and vibrating fully dissolves crystallisate; The OD value in each hole of ELIASA detection (λ=570nm); Draw the cell viability graphic representation, obtain inhibitory rate of cell growth.Inhibitory rate of cell growth=[(the OD value of blank OD value-administration group)/blank OD value] * 100%.All compounds have carried out replication three times.During mensuration with examining not his spit of fland (a kind of analogue of cinnamophenone) as the positive control medicine.The inhibition activity of cell growth is seen illustrated in figures 1 and 2, and test compounds has especially shown the better inhibited tumor cell growth activity to HepG2 to tumour cell.
Embodiment 3 compounds are to fibroblast growth factor acceptor 1 (FGFR1) tyrosine-kinase enzyme inhibition activity
It is active to the inhibition of FGFR1 Tyrosylprotein kinase to have tested part of compounds, and experiment employing method is Caliper Mobility Shift Assay, and promptly the mobility detection technique with the micro-fluid chip technology is the detection method of core.Concrete experimental procedure is: configuration 1.25x kinase reaction damping fluid and kinase reaction stop buffer; In the compound solution of the 5x concentration of 5 μ L, add the FGFR1 kinase solution of the 2.5x of 10 μ L, incubated at room adds the 2.5x peptide substrate solution of 10 μ L again after 10 minutes, adds 25 μ L kinase reaction stop buffers behind the reaction specified time down at 28 ℃; Data are collected in test on Caliper, and to the * 100 of the inhibiting rate of kinase activity=(max-conversion)/(max-min), " max " for not adding the DMSO contrast of compound, " min " is low contrast.The final concentration of test compounds is 20 μ mol/L, is three multiple holes during test at every turn, has carried out replication altogether three times.Compound is seen Fig. 3 to the inhibition activity of FGFR1 Tyrosylprotein kinase.Survey and have 3 compounds to show better inhibited activity in 6 compounds, especially the inhibiting rate of L15H23D1 reaches 46%.
The test of embodiment 4 antioxidation activity in vitro
Measured the antioxidation activity in vitro of compound with the DPPH method.Experimental procedure: use anhydrous alcohol solution DPPH, configuration mother liquor (7.5 * 10
4μ mol/L), keep in Dark Place under 0-4 ℃; Be diluted to 150 μ mol/L with absolute ethyl alcohol before using.Use the DMSO dissolved compound, its starting point concentration 1.0 * 10
4Mg/L keeps in Dark Place under 0-4 ℃; Be diluted to 20mg/L with absolute ethyl alcohol before using; In 96 orifice plates, add DPPH solution and compound solution, mixing in room temperature (25 ℃) held 30min, is designated as solutions i; In 96 orifice plates, add compound solution and absolute ethyl alcohol, mixing in room temperature (25 ℃) held 30min, is designated as solution j; In 96 orifice plates, add DPPH solution and absolute ethyl alcohol, mixing in room temperature (25 ℃) held 30min, is designated as solution c; 517nm measures its absorbancy and is respectively Ai, Aj, Ac on ELIASA.Calculate the inhibiting rate of liquid to be measured according to formula, that is: inhibiting rate (%)=[1-(Ai-Aj)/Ac] * 100% to DPPH; Do contrast with Quercetin and vitamins C (Vc) during test, repeated experiments is measured three times in three multiple holes of the each mensuration of each compound.The DPPH inhibiting rate of compound is as shown in Figure 4, has 4 compounds to show anti-oxidant activity preferably in 6 compounds of test, and the inhibiting rate of DPPH is reached more than 80%, and its activity is near positive control Quercetin and vitamins C (Vc).The structure activity relationship analysis shows that active reservation is necessary to last 3 and 4 of compd A r2 ring to high anti-oxidation for hydroxyl simultaneously, and promptly LnH23D1 has basically shown good active.
Embodiment 5 extracorporeal anti-inflammatory active testings
Cell model through using LPS (LPS) inductive scavenger cell to produce inflammatory factor release has carried out the experiment of anti-inflammatory molecular pharmacological screening to compound.Experimental technique is following: with 3ml scavenger cell density is 4 * 10
5It is the petridish of 3.5mm that the DMEM nutrient solution of individual/ml places diameter, contains 5%CO in 37 ℃
2Cell culture incubator in cultivate and to change fresh nutrient solution after 24 hours; Dissolve tested compounds with DMSO; The solution of tested compounds is added in the above-mentioned petridish; Final concentration is 10 μ M, and pretreatment cell 2 hours adds the LPS (Sigma-Aldrich that 3 μ L contain 0.5mg/mL again; USA) DMEM solution is inflamed with irritation cell and reacts and the generation inflammatory factor, continues to cultivate 22 hours; Behind the co-processing 24 hours, need, collect nutrient solution, gross protein by experiment; Wherein the IL-6 in the nutrient solution detects through ELISA, and total protein concentration detects through protein detection kit, and the inflammatory factor content data of acquisition is calibrated with corresponding total protein content; Only add blank DMSO in the blank, do not add compound and LPS; Add blank DMSO of 3 μ L and 3 μ L LPS solution in the LPS control group, do not add tested compounds; With curcumine as the positive control medicine; Whole experiment repeated test 3-5 time.The extracorporeal anti-inflammatory activity representes that with the relative ratios of the inflammatory factor that relative LPS (being decided to be 100) produces the result is as shown in Figure 5.4 compounds being tested all have anti-inflammatory activity preferably, and especially L26H23D1 and L15H23D1 all reach more than 50% the inhibition activity of inflammatory factor, and two kinds are the compound with certain DEVELOPMENT PROSPECT.
The crystalline structure of embodiment 6 compound L 11H23D1
The L11H23D1 that takes a morsel uses acetone: and water (V: V=2: the dissolving of 1) mixing solutions, place that solvent slowly volatilizees under 4 ℃ of environment, obtain yellow styloid after 6 days.
The crystal of L11H23D1 is carried out structure determination with Bruker SMARTAPEXII-CCD X ray single crystal diffractometer under 293K.(λ=0.71073nm), graphite crystal monochromator under 293K, ° are collected diffraction data (SMART program) with ρ-ω scan mode in 2.3 °＜θ＜28.1 to adopt Mo K alpha-ray.Collect 6423 of point diffractions altogether, 4694 of wherein independent diffraction datas [R (int)=0.022].The crystalline molecular formula is C
27H
28N
2O
7, molecular weight 492.51 belongs to oblique system, and spacer is C2/c, unit cell parameters
β=96.898 (2) °,
Z=8, D
X=1.386Mg m
-3, μ=0.10mm
-1, F (000)=2080.Final discrepancy factor R=0.044, wR=0.137.With of the reduction of data of SAINT program, with making absorption correction after the SADABS program to collecting.Structure elucidation is with direct method (SHELXTL program), and non-hydrogen atom is with the refine of complete matrix method of least squares, and Wasserstoffatoms is confirmed (SHELXTL-97) by Theoretical Calculation.Final discrepancy factor converges on R=0.047.The crystalline structure of L11H23D1 is seen Fig. 6 with brilliant bag accumulation graph.
Claims (9)
1. general formula (I) compound, its steric isomer, enantiomer, tautomer or its mixture, or the acceptable salt of its medicine, solvolyte or prodrug:
Wherein:
R
1Be hydrogen, alkyl, thiazolinyl, alkynyl, haloalkyl, aryl, cyclic hydrocarbon radical, cyclic hydrocarbon radical alkyl, heteroaryl, heterocyclic radical;
Or R
1Be quilt-C (O) N (R
6) R
7Substituted aralkyl, wherein:
R
6Be hydrogen, alkyl, aryl or aralkyl;
And R
7For hydrogen, alkyl, haloalkyl ,-R
9-N (R
4) R
5, aryl, aralkyl, cyclic hydrocarbon radical, cyclic hydrocarbon radical alkyl, heterocyclic radical, heterocyclic radical alkyl, heteroaryl, heteroaralkyl;
Or R
6And R
7And connected nitrogen forms heterocyclic radical or heteroaryl together;
And R wherein
6And R
7Each aryl, aralkyl, cyclic hydrocarbon radical, cyclic hydrocarbon radical alkyl, heterocyclic radical, heterocyclic radical alkyl, heteroaryl and heteroaryl groups can be randomly replaced by one or more substituting groups that are selected from alkyl, cyclic hydrocarbon radical, aryl, aralkyl, halogen, haloalkyl, heterocyclic radical and heteroaryl;
Or R
1For randomly by-C (O) OR
5, halogen, haloalkyl, alkyl, nitro, cyanic acid, aryl (optional by cyano replaces), aralkyl (randomly being replaced by one or more alkyl groups), heterocyclic radical or the substituted aralkyl of heteroaryl replace;
Or R
1For-R
9-N (R
10) R
11,-R
9-N (R
12) C (O) R
11, wherein:
Each-R
10Be hydrogen, alkyl, aryl or aralkyl;
Each-R
11Be hydrogen, alkyl, haloalkyl, cyclic hydrocarbon radical, cyclic hydrocarbon radical alkyl, aryl, aralkyl, heterocyclic radical, heterocyclic radical alkyl, heteroaryl, heteroaralkyl;
R
12Be hydrogen, alkyl, aryl, aralkyl;
And R wherein
10With R
11Each aryl, aralkyl, cyclic hydrocarbon radical, cyclic hydrocarbon radical alkyl, heterocyclic radical, heterocyclic radical alkyl, heteroaryl and heteroaralkyl group can be randomly replaced by one or more substituting groups that are selected from alkyl, cyclic hydrocarbon radical, aryl, aralkyl, halogen, haloalkyl, nitro, heterocyclic radical and heteroaryl;
Or R
1Be heterocyclic radical alkyl or heteroaralkyl, wherein said heterocyclic radical alkyl or heteroaryl groups are randomly replaced by one or more substituting groups that are selected from alkyl, halogen, haloalkyl, aryl and aralkyl;
Or R
1And R
2And can form the condensed ring that is selected from cyclic hydrocarbon radical, heterocyclic radical, aryl or heteroaryl, and remaining R with its direct-connected nitrogen or carboatomic ring atom
1Group such as preceding text define;
R
2Be independently selected from hydrogen, alkyl, thiazolinyl, alkynyl, alkoxyl group, halogen, haloalkyl, haloalkenyl group, halogenated alkoxy, cyclic hydrocarbon radical, cyclic hydrocarbon radical alkyl, aryl, aralkyl, aryl alkenyl, heterocyclic radical, heterocyclic radical alkyl, heteroaryl, heteroaralkyl ,-R
8-N (R
4) R
5
Or R
2And R
1And can form the condensed ring that is selected from cyclic hydrocarbon radical, heterocyclic radical, aryl or heteroaryl, and remaining R with its direct-connected carbon or azo-cycle atom
2Group such as preceding text define;
Each R
3All be independently selected from hydrogen, alkyl, thiazolinyl, alkynyl, alkoxyl group, halogen, haloalkyl, haloalkenyl group, halogenated alkoxy, cyclic hydrocarbon radical, cyclic hydrocarbon radical alkyl, aryl, aralkyl, aryl alkenyl, heterocyclic radical, heterocyclic radical alkyl, heteroaryl, heteroaralkyl ,-R
8-N (R
4) R
5
And each R wherein
2Each cyclic hydrocarbon radical, cyclic hydrocarbon radical alkyl, aryl, aralkyl, aryl alkenyl, heterocyclic radical, heterocyclic radical alkyl, heteroaryl and heteroaralkyl group can be randomly by one or more be selected from alkyl, thiazolinyl, alkynyl, alkoxyl group, halogen, haloalkyl, haloalkenyl group, halogenated alkoxy, cyclic hydrocarbon radical, cyclic hydrocarbon radical alkyl, aryl, aralkyl, aryl alkenyl, heterocyclic radical, heterocyclic radical alkyl, heteroaryl, heteroaralkyl ,-R
8-N (R
4) R
5:
Or two adjacent R
3Group with its direct-connected condensed hetero-aromatic ring or condensed heterocycle atom can form the condensed ring that is selected from cyclic hydrocarbon radical, aryl, heterocyclic radical and heteroaryl, and remaining R
3If group exists then defines like preceding text;
Each R
4And R
5Be independently selected from hydrogen, alkyl, thiazolinyl, alkynyl, haloalkyl, alkoxyalkyl, cyclic hydrocarbon radical, cyclic hydrocarbon radical alkyl, aryl, aralkyl, heterocyclic radical and heteroaryl;
Or work as R
4And R
5When all being connected on the identical nitrogen-atoms, R
4And R
5And connected nitrogen-atoms can form heterocyclic radical or heteroaryl together; And remaining R
4And R
5If group exists then defines like preceding text;
And each R
8Be the alkylidene chain of valence bond or straight or branched, the alkenylene chain of straight or branched or the alkynylene chain of straight or branched; And each R
9Be the alkylidene chain of straight or branched, the alkenylene chain of straight or branched or the alkynylene chain of straight or branched;
Ar
1And Ar
2Can be identical also can be inequality, can be aromatic ring, fragrant heterocycle, replace aromatic ring and replace fragrant heterocycle; Substituting group can for alkyl, thiazolinyl, alkynyl, alkoxyl group, halogen, haloalkyl, haloalkenyl group, halogenated alkoxy, cyclic hydrocarbon radical, cyclic hydrocarbon radical alkyl, aryl, aralkyl, aryl alkenyl, heterocyclic radical, heterocyclic radical alkyl, heteroaryl, heteroaralkyl, amino, substituted amino, carboxyl, aminoacyl, replacement aminoacyl, benzoyl group, substituted benzene acyl group, nicotinoyl, replacement nicotinoyl ,-R
8-N (R
4) R
5Substituting group can replace aromatic ring and fragrant heterocyclic optional position, and is perhaps simultaneously polysubstituted.
2. compound as claimed in claim 1 is selected from following compounds:
1 '-methyl-3 '-(3,4,5-trimethoxy benzoyl group)-4 '-(2, the 4-Dimethoxyphenyl)-spiral shell-[3H-indoles-3,2 '-hydrogenation pyrroles]-2 (1H)-ketone;
1 '-methyl-3 '-(2,4 ,-dimethoxy benzoyl group)-4 '-(3,4, the 5-Dimethoxyphenyl)-spiral shell-[acenaphthylene-1 (2H), 2 '-hydrogenation pyrroles]-2-ketone;
1 '-methyl-3 '-(3,4,5-trimethoxy benzoyl group)-4 '-(3,4, the 5-trimethoxyphenyl)-spiral shell-[3H-indoles-3,2 '-hydrogenation pyrroles]-2 (1H)-ketone;
1 '-methyl-3 '-(2-fluorobenzene acyl group)-4 '-(3,4 ,-dihydroxy phenyl)-spiral shell-[3H-indoles-3,2 '-hydrogenation pyrroles]-2 (1H)-ketone;
1 '-methyl-3 '-(3,4,5-trimethoxy benzoyl group)-4 '-(2, the 4-Dimethoxyphenyl)-spiral shell-[acenaphthylene-1 (2H), 2 '-hydrogenation pyrroles]-2-ketone;
1 '-methyl-3 '-(3,4-difluoro benzoyl group)-4 '-(3,4 ,-dihydroxy phenyl)-spiral shell-[3H-indoles-3,2 '-hydrogenation pyrroles]-2 (1H)-ketone.
3. method for preparing the said compound of claim 1 is characterized in that may further comprise the steps:
1), acetophenone compounds is dissolved in the ethanol, adds the phenyl aldehyde compounds, stir and also drip alkali, react completely under the room temperature, separate and purified product;
2), in methanol solvate, add 1) in pure compound, isatin and sarkosine, reflux;
3) the carrying out of the close monitoring reaction of TLC; Reaction times was generally 5-24 hour, and reaction will be selected the separation and purification condition for use after finishing flexibly, and reaction product is generally all water insoluble or be slightly soluble in water; And product solubleness in ethanol is littler than raw material; Go out deposition so generally can directly add elutriation, use the alcohol-water washing precipitation of 5-10% again, perhaps add the acid-alkali accommodation reaction solution earlier and after neutrality, add the suitable quantity of water deposition again; With TLC analyzing and testing purity, impure sample is with the organic solvent recrystallization or carry out purifying with the method for silica gel column chromatography for the solid precipitation of separating out or oily matter.
4. the spiro-heterocycle compound of the described cinnamophenone of claim 1 is in pharmaceutically related application.
5. the spiro-heterocycle compound of the described cinnamophenone of claim 4 is as the application of fibroblast growth factor acceptor tyrosine kinase inhibitor.
6. the application of the spiro-heterocycle compound conduct of the described cinnamophenone of claim 4 and anti-inflammatory related drugs.
7. the application of the spiro-heterocycle compound conduct of the described cinnamophenone of claim 4 and anti-oxidant related drugs.
8. the application of the spiro-heterocycle compound conduct of the described cinnamophenone of claim 4 and antitumor related drugs.
9. a pharmaceutical composition is characterized in that, comprises the spiro-heterocycle compound and at least a pharmaceutically acceptable carrier as the described cinnamophenone of claim 1 of active ingredient of dose therapeutically effective.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2011102317239A CN102443005A (en) | 2011-08-12 | 2011-08-12 | Spiroheterocycle compound of chalcone and application of spiroheterocycle compound |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2011102317239A CN102443005A (en) | 2011-08-12 | 2011-08-12 | Spiroheterocycle compound of chalcone and application of spiroheterocycle compound |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN102443005A true CN102443005A (en) | 2012-05-09 |
Family
ID=46005982
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN2011102317239A Pending CN102443005A (en) | 2011-08-12 | 2011-08-12 | Spiroheterocycle compound of chalcone and application of spiroheterocycle compound |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN102443005A (en) |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105693732A (en) * | 2016-01-20 | 2016-06-22 | 贵州大学 | Turmerone framework spliced 3-pyrrolespirooxindoles compound as well as preparation method and application of turmerone framework spliced 3-pyrrolespirooxindoles compound |
| CN106478491A (en) * | 2016-10-08 | 2017-03-08 | 贵州大学 | 3 aminomethyl quaternary carbon Oxoindoles splice 3 five yuan of carbocyclic ring volution oxidized indole compounds and preparation method and application |
| CN107056707A (en) * | 2017-01-23 | 2017-08-18 | 温州医科大学 | A kind of 3,4,5 trimethoxy benzene-like compounds and its application in anti-oxidation medicine is prepared |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6114540A (en) * | 1997-09-08 | 2000-09-05 | Arqule, Inc. | Spiro[pyrrolidine-2,3'-oxindole] compounds and methods of use |
| US20090252694A1 (en) * | 2006-04-03 | 2009-10-08 | Industry-Academic Cooperation Foundation Gyeongsang National Universtiy | Novel Chalcone Derivatives, Pharmaceutically Acceptable Salt, Method for Preparation and Uses Thereof |
-
2011
- 2011-08-12 CN CN2011102317239A patent/CN102443005A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6114540A (en) * | 1997-09-08 | 2000-09-05 | Arqule, Inc. | Spiro[pyrrolidine-2,3'-oxindole] compounds and methods of use |
| US20090252694A1 (en) * | 2006-04-03 | 2009-10-08 | Industry-Academic Cooperation Foundation Gyeongsang National Universtiy | Novel Chalcone Derivatives, Pharmaceutically Acceptable Salt, Method for Preparation and Uses Thereof |
Non-Patent Citations (11)
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105693732A (en) * | 2016-01-20 | 2016-06-22 | 贵州大学 | Turmerone framework spliced 3-pyrrolespirooxindoles compound as well as preparation method and application of turmerone framework spliced 3-pyrrolespirooxindoles compound |
| CN105693732B (en) * | 2016-01-20 | 2019-05-24 | 贵州大学 | Turmerone skeleton splices 3- pyrroles's loop coil oxidized indole compounds and preparation method and application |
| CN106478491A (en) * | 2016-10-08 | 2017-03-08 | 贵州大学 | 3 aminomethyl quaternary carbon Oxoindoles splice 3 five yuan of carbocyclic ring volution oxidized indole compounds and preparation method and application |
| CN106478491B (en) * | 2016-10-08 | 2019-10-18 | 贵州大学 | 3- aminomethyl quaternary carbon Oxoindole splices five yuan of carbocyclic ring loop coil oxidized indole compounds of 3- and preparation method and application |
| CN107056707A (en) * | 2017-01-23 | 2017-08-18 | 温州医科大学 | A kind of 3,4,5 trimethoxy benzene-like compounds and its application in anti-oxidation medicine is prepared |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| AU2005266493B2 (en) | Inhibitors of Hsp90 | |
| CN1688535B (en) | Novel bioactive diphenyl ethene compounds and their therapeutic applications | |
| CN102762575A (en) | Multicyclic compounds and methods of use thereof | |
| EA020609B1 (en) | IMIDAZO[1,2-a]PYRIDIN-2-YLPHENYL DERIVATIVES TO BE USED IN CANCER TREATMENT | |
| JP2020537667A (en) | Antagonist of muscarinic acetylcholine receptor M4 | |
| CN103222970B (en) | Asymmetric list carbonyl curcumin analog application in preparation of anti-tumor drugs | |
| WO2022198003A1 (en) | Negative allosteric modulators of metabotropic glutamate receptor 2 | |
| CN113336735B (en) | Urolithin compound, preparation method, pharmaceutical composition and application | |
| CN102443005A (en) | Spiroheterocycle compound of chalcone and application of spiroheterocycle compound | |
| WO2014183673A1 (en) | Anti-tumor use of anagrelide and derivatives thereof | |
| JPS6239564A (en) | Alpha-benzylidene-gamma-butyrolactone or gamma-butyrolactam derivative | |
| CN107652275B (en) | Quinazoline derivative and preparation method and application thereof | |
| CN111217825B (en) | 4-O-aminopropyl earth licorice A derivative and preparation and application thereof | |
| CN113912594A (en) | Nitrothiophene methylamine optical isomer and medical application thereof | |
| CA3088968C (en) | Dihydroindolizinone derivative | |
| CN104844515B (en) | Isolongifolane pyrazole compounds and applications thereof | |
| CN112300145A (en) | Three-aromatic ring compound targeting STAT3 bifunctional phosphorylation site and application thereof | |
| CN111825608A (en) | Tetrahydroquinoline and tetrahydroisoquinoline compounds and application thereof | |
| CN101157628B (en) | Substituted benzoic acid nitrogen-containing derivatives and antineoplastic usage thereof | |
| CN108586341B (en) | Amide compounds and medicinal salts thereof, and preparation method and medicinal application thereof | |
| CN104487425A (en) | New compounds and new use | |
| CN115197236B (en) | Linear type glabra A analogue and preparation and application thereof | |
| CN111217824B (en) | 4-O-arylaminopropyl glycyrrhiza A derivative and preparation and application thereof | |
| CA2011143C (en) | Pyridinecarboxylic acid amide derivatives and pharmaceutical compositions comprising same | |
| WO2003087082A1 (en) | Pyranocoumarin derivatives |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C02 | Deemed withdrawal of patent application after publication (patent law 2001) | ||
| WD01 | Invention patent application deemed withdrawn after publication |
Application publication date: 20120509 |