CN1793148A - Poly-substituted flavan zothia dizoline kind compound and preparation process and use thereof - Google Patents
Poly-substituted flavan zothia dizoline kind compound and preparation process and use thereof Download PDFInfo
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- CN1793148A CN1793148A CN 200510097012 CN200510097012A CN1793148A CN 1793148 A CN1793148 A CN 1793148A CN 200510097012 CN200510097012 CN 200510097012 CN 200510097012 A CN200510097012 A CN 200510097012A CN 1793148 A CN1793148 A CN 1793148A
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- flavanone
- thiadiazoline
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Abstract
The invention relates to poly-substitution flavane thiadiazoles class compound that uses neighbor hydroxy benzenes diketone and aromaticacid as raw material, taking concentrating and cyclization to gain flavanone class compounding that would react with substituted benzene to gain flavanone-4-phenylhydrazone, phenylhydrazone would cyclizating with thionyl chloride to form poly-substitution flavane thiadiazoles class compound. The invention has restraining function to kinds of tumor cell, and could be used in manufacturing anticancer medicine.
Description
Technical field
The invention belongs to the synthetic method of organic compound, relate to the synthetic method of M-stage kinesin inhibitor, relate in particular to polysubstituted flavane and Thiadiazoline compounds and preparation method, and the application in the preparation antitumor drug.
Background technology
Flavanone derivative has antitumor action.Calendar year 2001 C.Pouget etc. has reported a series of flavanone derivatives with antitumor action, 7-methoxyl group flavanone wherein, and 5-methoxyl group flavanone and 5,7-dimethoxy flavanone is effective to breast cancer cell MCF-7, its IC
50Value is respectively 35.7,35.7 and 36.0 μ M.The structure of the flavanone derivative that this article provided is comparatively common, do not have on the aromatic ring and replace or only contain oxygen functional group (hydroxyl and methoxyl group) replacement, the author has only carried out the discussion of preliminary activity and structure activity relationship to these compounds simultaneously, but the mechanism of its antitumor action is not done further further investigation.The a series of natural flavanone compound of report such as C.T.T.Blatt in 2002 is also inhibited to various tumor cell strains, and wherein compound (-)-Isoglabrachromene is to the IC of KB tumor cell line
50Value only is 1.8 μ M.People such as C.H.Park in 2005 have reported that flavanone has the effect that suppresses stomach cancer cell AGS propagation, and find that molecular mechanism is for suppressing the Tcf activity.
In addition, much contain the segmental compound of thiadiazoles and have antitumor toxicity.People such as Z.Zhang had reported 4 in 2003, and 5-two amido thiadiazoles derivatives have antiproliferative effect, wherein acted on the strongest compound 4-amido carbonyl-5-anilino 1,2, the IC of 3-thiadiazoles
50Value only is 1 μ M.
Summary of the invention
The purpose of this invention is to provide polysubstituted flavane and Thiadiazoline compounds, is the flavanone derivative that contains the Thiadiazoline ring: 2-aryl flavane [4,3-d]-Δ
1,9b-1,2,3-Thiadiazoline compounds has following general structure:
Wherein
The A ring can be not have and replaces, single replacement or polysubstituted, R
1Be H, Cl, CH
3O-, CH
3-;
The B ring can be not have and replaces, single replacement or polysubstituted, R
2Be H, Cl, CH
3O-, CH
3-,-OCH
2O-;
R
3Be NO
2-, CH
3SO
2-, CH
3CONH-;
R
4Be CH
3-, CH
3CH
2-, CH
3CH
2CH
2-, (CH
3)
2CH-;
Another object of the present invention provides polysubstituted flavane and Thiadiazoline compounds (2-aryl flavane [4,3-d]-Δ
1,9b-1,2,3-Thiadiazoline compounds) preparation method, realize by following steps:
Synthetic route of the present invention:
(1) above-mentioned reaction formula is to be used to prepare target compound VI (2-(4-nitro-2-chloro-phenyl-)-3a, 4-dialkoxy flavane [4,3-d]-Δ
1,9b-1,2, the 3-Thiadiazoline) (R
3=NO
2), target compound VII (2-(4-methylsulfonyl-2-chloro-phenyl-)-3a, 4-dialkoxy flavane [4,3-d]-Δ
1,9b-1,2, the 3-Thiadiazoline) (R
3=SO
2CH
3) and target compound VIII (2-(4-acetamido-2-chloro-phenyl-)-3a, 4-dialkoxy flavane [4,3-d]-Δ
1,9b-1,2, the 3-Thiadiazoline) (R
3=NHCOCH
3) reaction formula.Compound I a (2-hydroxy acetophenone) (R wherein
1'=H) can directly be bought, compounds ib (2-hydroxyl-4-methoxyacetophenone) (R
1'=4-methoxyl group) and Compound I c (2-hydroxyl-4,6-dimethoxy) (R
1'=4, the 6-dimethoxy) can be by literature method (K.C.Gulatiet al, Org Synth, Coll.Vol.II, 522﹠amp; K.Y.T.Juntend et al EP0292576) makes, Compound I I (chalcone compound) and compound III (flavanone compound) can by literature method (Xiaoyong Bu et al, Synthesis, 1997,11,1246-1248) make.
(2) compound III (flavanone compound) is in protic solvent, condensation obtains corresponding compounds IV (flavanone-4-oil of mirbane hydrazone compounds) or compound V (flavanone-4-methylsulfonyl phenyl hydrazones compound) with paranitrophenylhydrazine or to the methylsulfonyl phenylhydrazine in the presence of acetic acid, used protic solvent is a methyl alcohol, ethanol etc., temperature of reaction is generally at 30-80 ℃, and the product that obtains can be directly used in next step reaction.
(3) compound IV (flavanone-4-oil of mirbane hydrazone compounds) or compound V (flavanone-4-methylsulfonyl phenyl hydrazones compound) under nitrogen protection with SOCl
2Cyclization, temperature of reaction is generally 60-80 ℃, also can be at ultrasonic radiation (power 250W, frequency 25kHz, room temperature) carry out under, the reaction times is 30 minutes, and the gained intermediate product can obtain target compound VI (2-(4-nitro-2-chloro-phenyl-)-3a with the alcohol reaction again, 4-dialkoxy flavane [4,3-d]-Δ
1,9b-1,2,3-Thiadiazoline compounds) or compound VI I (2-(4-methylsulfonyl-2-chloro-phenyl-)-3a, 4-dialkoxy flavane [4,3-d]-Δ
1,9b-1,2,3-Thiadiazoline compounds), be reflected at 30-80 ℃ and carry out, or (room temperature) carries out under ultrasonic radiation, and the reaction times is 30 minutes, and used alcohol can be methyl alcohol, ethanol, propyl alcohol, Virahol etc., products therefrom is through column chromatography (eluent: sherwood oil: ethyl acetate) can get pure product.
(4) can get R after the compound VI hydrogenation
3Be the intermediate of amino, need not to separate directly behind acetic anhydride acylation, to get target compound VIII (2-(4-acetamido-2-chloro-phenyl-)-3a, 4-dialkoxy flavane [4,3-d]-Δ
1,9b-1,2, the 3-Thiadiazoline).Hydrogenation can be used palladium carbon (Pd-C), Raney's nickel (Raney-Ni) catalysis.Acetylize generally adopts diacetyl oxide or Acetyl Chloride 98Min. as acylating reagent, uses pyridine catalysis, carries out at ambient temperature, and products therefrom is through column chromatography (eluent: sherwood oil: ethyl acetate) can get pure product.
Another purpose of the present invention is polysubstituted flavane and the application of Thiadiazoline compounds in the preparation antitumor drug.Preliminary in-vitro screening finds that they to various tumor cell strains, comprise Bel-7402, ECA-2, and PC-3, HL-60, MCF-7, A549 etc. all have the inhibition proliferation function, 2-(4-methylsulfonyl-2-chloro-phenyl-)-3a wherein, 4-diethoxy-4 '-chlorine flavane [4,3-d]-Δ
1,9b-1,2,3-Thiadiazoline (compound VI Ia), 2-(4-methylsulfonyl-2-chloro-phenyl-)-8-methyl-4 '-methoxyl group-3a, 4-diethoxy flavane [4,3-d]-Δ
1,9b-1,2,3-Thiadiazoline (compound VIII b) and 2-(4-methylsulfonyl-2-chloro-phenyl-)-8-methyl-3a, 4-diethoxy-4 '-chlorine flavane [4,3-d]-Δ
1,9b-1,2,3-Thiadiazoline (compound VI Ie) is all more remarkable to the restraining effect of 6 kinds of tumor cell lines, and its anti-tumor activity is greater than the parent compound flavanone.In vivo test is the result show, compound VI Ia can obviously suppress mouse S180 solid tumor growth (P＜0.01), has significant therapeutic action.Mechanism Study to compound VI Ia anti-tumor activity shows that it can inducing apoptosis of tumour cell.
Characteristics of the present invention are to be lead compound to have active flavanone, go up 3,4 of flavanone parent nucleus and introduce 1,2,3-Thiadiazoline ring.This is the brand-new compound of a class formation, and preliminary pharmacological activity screening experiment shows that most compounds have the vitro inhibition effect to tumour cell, and part of compounds has significant inhibition proliferation function.Compare with the parent compound flavanone, anti-tumor activity obviously improves, and the anti-tumor activity of this heterocyclic introducing can enhancing flavanone is described.Wherein representation compound VIIa has the anti-tumor in vivo activity, and its mechanism is inducing apoptosis of tumour cell.
Description of drawings
Fig. 1 acts on the flow cytometry result of HL-60 cell for compound VI Ia.
Fig. 2 analyzes HL-60 scalariform DNA for agarose gel electrophoresis.
Embodiment
The present invention is further described with accompanying drawing in conjunction with the embodiments.Following embodiment is that explanation is of the present invention, rather than limits the present invention by any way.
Embodiment 1: (compound IV preparation a) of flavanone-4-(4-nitrophenyl) hydrazone
Flavanone 0.448g (2mmol), 4-nitrophenyl hydrazine 0.306g (2mmol), ethanol 20mL and acetate 0.02mL are added in the reaction flask, and backflow 6hr separates out yellow solid again after the solid dissolving.Cooling, suction filtration, filter cake is washed with small amount of ethanol, drying under reduced pressure, (compound IV is 0.626g a), yield 87.2% to obtain yellow solid.Fusing point: 249-250 ℃.
1H NMR(δ，DMSO-d
6)：2.77-2.84(m，1H)，3.35-3.40(m，1H)，5.25(dd，1H，J＝12.0Hz，3.2Hz)，6.96(d，1H，J＝8.4Hz)，7.03(t，1H，J＝8.0，16.0Hz)，7.27(t，1H，J＝8.0，16.0Hz)，7.35(m，2H)，7.38(d，1H，J＝7.2Hz)，7.44(t，2H，J＝7.2，14.4Hz)，7.56(d，2H，J＝7.2Hz)，8.07(d，1H，J＝8.0Hz)，8.11(d，2H，J＝8.8Hz)，10.31(s，1H)。
The preparation of embodiment 2:4 '-methoxyl group flavanone-4-(4-nitrophenyl) hydrazone (compound IV b)
Operating process and embodiment 1 with, just with 4 '-methoxyl group flavanone replacement flavanone.Obtain golden yellow solid (compound IV b), yield 93.2%.Fusing point: 237-238 ℃.
1H NMR(δ，DMSO-d
6)：2.80-2.87(m，1H)，3.29-3.34(m，1H)，3.75(s，3H)，5.18(dd，1H，J＝12.0Hz，2.8Hz)，6.93(d，1H，J＝8.0Hz)，6.98(d，2H，J＝8.8Hz)，7.27(t，1H，J＝8.0，16.0Hz)，7.32(m，2H)，7.47(d，2H，J＝8.8Hz)，7.56(d，2H，J＝7.2Hz)，8.06(d，1H，J＝7.6Hz)，8.11(d，2H，J＝7.6Hz)，10.31(s，1H)。
Embodiment 3:5, the preparation of 7-dimethoxy flavanone-4-(4-nitrophenyl) hydrazone (compound IV c)
Operating process and embodiment 1 are with 5 together, and 7-dimethoxy flavanone replaces flavanone.Obtain orange red solid (compound IV c), yield 89.3%.Fusing point: 214-216 ℃.
1H NMR(δ，DMSO-d
6)：2.73-2.80(m，1H)，3.30-3.35(m，1H)，3.77(s，3H)，3.92(s，3H)，5.18(dd，1H，J＝12.0Hz，3.2Hz)，6.23(d，1H，J＝2.4Hz)，6.30(d，1H，J＝2.4Hz)，7.29(d，2H，J＝2.4Hz)，7.39(t，1H，J＝7.2，14.4Hz)，7.46(t，2H，J＝7.2，14.4Hz)，7.56(d，2H，J＝8.0Hz)，8.13(d，2H，J＝8.0Hz)，10.12(s，1H)。
Embodiment 4:5,7-dimethoxy-2 '-preparation of chlorine flavanone-4-(4-nitrophenyl) hydrazone (compound IV d)
Operating process and embodiment 1 are with 5 together, 7-dimethoxy-2 '-chloro flavanone replacement flavanone.Obtain yellow solid (compound IV d), yield 85.3%.Fusing point: 185-187 ℃.
1H NMR(δ，DMSO-d
6)：2.67-2.74(m，1H)，3.31-3.36(m，1H)，3.75(s，3H)，3.90(s，3H)，5.37(dd，1H，J＝12.0Hz，2.4Hz)，6.22(d，1H，J＝2.4Hz)，6.31(d，1H，J＝2.4Hz)，7.27(brs，2H)，7.40-7.54(m，3H)，7.74(d，1H，J＝8.0Hz)，8.10(d，2H，J＝8.8Hz)，10.10(s，1H)。
Embodiment 5:4 '-methyl-5, the preparation of 7-dimethoxy flavanone-4-(4-nitrophenyl) hydrazone (compound IV e)
Operating process and embodiment 1 with, just with 4 '-methyl-5,7-dimethoxy flavanone replacement flavanone.Obtain red solid (compound IV e), yield 89.7%.Fusing point: 208-210 ℃.
1H NMR(δ，DMSO-d
6)：2.31(s，3H)，2.69-2.76(m，1H)，3.23-3.28(m，1H)，3.74(s，3H)，3.88(s，3H)，5.10(dd，1H，J＝12.0Hz，3.2Hz)，6.19(d，J＝2.0Hz)，6.26(d，J＝2.0Hz)，7.22-7.35(m，4H)，7.41(d，2H，J＝8.0Hz)，8.10(d，2H，J＝9.2Hz)，10.11(s，1H)。
Embodiment 6:4 ', 5, the preparation of 7-trimethoxy flavanone-4-(4-nitrophenyl) hydrazone (compound IV f)
Operating process and embodiment 1 with, just with 4 ', 5,7-trimethoxy flavanone replacement flavanone.Obtain dark red solid (compound IV f), yield 89.7%.Fusing point: 208-210 ℃.
1H NMR(δ，DMSO-d
6)：2.72-2.79(m，1H)，3.21-3.26(m，1H)，3.73(s，3H)，3.75(s，3H)，3.88(s，3H)，5.08(dd，1H，J＝12.0Hz，2.8Hz)，6.18(d，1H，J＝2.4Hz)，6.24(d，1H，J＝2.4Hz)，6.97(d，2H，J＝8.4Hz)，7.27(brs，2H)，7.45(d，2H，J＝8.4Hz)，8.10(d，2H，J＝9.2Hz)，10.12(s，1H)。
Embodiment 7:3 ', 5, the preparation of 7-trimethoxy flavanone-4-(4-nitrophenyl) hydrazone (compound IV g)
Operating process and embodiment 1 with, just with 3 ', 5,7-trimethoxy flavanone replacement flavanone.Obtain red solid (compound IV g), yield 86.7%.Fusing point: 188-189 ℃.
1H NMR(δ，DMSO-d
6)：2.78-2.85(m，1H)，3.31-3.36(m，1H)，3.79(s，3H)，3.92(s，3H)，4.03(s，3H)，5.57(dd，1H，J＝12.0Hz，3.2Hz)，6.22(d，1H，J＝2.0Hz)，6.30(d，1H，J＝2.0Hz)，6.78(d，1H，J＝1.6Hz)，6.86(dd，1H，J＝8.4Hz，1.6Hz)，6.92(d，J＝8.4Hz)，7.35(d，2H，J＝8.0Hz)，8.10(d，2H，J＝8.0Hz)，11.30(s，1H)。
Embodiment 8:3 ', 4 ', 5, the preparation of 7-trimethoxy flavanone-4-(4-nitrophenyl) hydrazone (compound IV h)
Operating process and embodiment 1 with, just with 3 ', 4 ', 5,7-trimethoxy flavanone replacement flavanone.Obtain red solid (compound IV h), yield 90.4%.Fusing point: 204-205 ℃.
1H NMR(δ，DMSO-d
6)：2.81-2.88(m，1H)，3.22-3.27(m，1H)，3.77(s，3H)，3.81(s，3H)，4.02(s，3H)，4.04(s，3H)，6.08-6.12(m，1H)，6.21(d，1H，J＝2.0Hz)，6.30(d，1H，J＝2.0Hz)，7.01(d，1H，J＝8.4Hz)，7.08(dd，1H，J＝8.4Hz，2.0Hz)，7.14(d，1H，J＝2.0Hz)，7.29(brs，2H)，8.15(d，2H，J＝8.8Hz)，10.16(s，1H)。
The preparation of embodiment 9:6-methyl flavanone-4-(4-nitrophenyl) hydrazone (compound IV i)
Operating process and embodiment 1 just replace flavanone with 6-methyl flavanone together.Obtain orange/yellow solid (compound IV i), yield 85.3%.Fusing point＞250 ℃.
1H NMR(δ，DMSO-d
6)：2.32(s，3H)，2.76-2.83(m，1H)，3.35-3.40(m，1H)，5.22(dd，J＝12.0Hz，2.4Hz，1H)，6.88(d，1H，J＝8.0Hz)，7.11(dd，1H，J＝8.0，1.2Hz)，7.35(d，2H，J＝7.2Hz)，7.40(d，1H，J＝7.2Hz)，7.45(t，2H，J＝7.2，14.4Hz)，7.57(d，2H，J＝7.6Hz)，7.89(d，1H，J＝1.2Hz)，8.14(d，2H，J＝7.6Hz)，10.29(s，1H)。
Embodiment 10:6-methyl-3 ', 4 '-preparation of dioxy methylene radical flavanone-4-(4-nitrophenyl) hydrazone (compound IV j)
Operating process and embodiment 1 with, just with 6-methyl-3 ', 4 '-dioxy methylene radical flavanone replaces flavanone.Obtain orange red solid (compound IV j), yield 93.4%.Fusing point:＞250 ℃.
1H NMR(δ，DMSO-d
6)：2.29(s，3H)，2.74-2.81(m，1H)，3.27-3.32(m，1H)，5.10(dd，1H，J＝12.0Hz，2.8Hz)，6.02(s，2H)，6.83(d，1H，J＝8.0Hz)，6.94(d，1H，J＝8.0Hz)，7.01(d，1H，J＝9.2Hz)，7.08(d，1H，J＝8.0Hz)，7.14(s，1H)，7.33(d，2H，J＝8.4Hz)，7.84(s，1H)，8.12(d，2H，J＝8.4Hz)，10.26(s，1H)。
Embodiment 11:6-methyl-3 ', 4 '-preparation of dimethoxy flavanone-4-(4-nitrophenyl) hydrazone (compound IV k)
Operating process and embodiment 1 with, just with 6-methyl-3 ', 4 '-the dimethoxy flavanone replaces flavanone.Obtain orange red solid (compound IV k), yield 89.6%.Fusing point:＞250 ℃.
1H NMR(δ，DMSO-d
6)：2.29(s，3H)，2.82-2.89(m，1H)，3.27-3.33(m，1H)，3.74(s，3H)，3.76(s，3H)，5.10(dd，1H，J＝10.0Hz，2.4Hz)，6.84(d，2H，J＝8.4Hz)，6.97(d，2H，J＝8.4Hz)，7.04-7.09(m，2H)，7.16(s，1H)，7.33(d，2H，J＝8.8Hz)，7.85(s，1H)，8.11(d，2H，J＝8.8Hz)，10.27(s，1H)。
Embodiment 12:6-methyl-4 '-preparation of methoxyl group flavanone-4-(4-nitrophenyl) hydrazone (compound IV l)
Operating process and embodiment 1 with, just with 6-methyl-4 '-the methoxyl group flavanone replaces flavanone.Obtain orange red solid (compound IV l), yield 89.5%.Fusing point:＞250 ℃.
1H NMR(δ，DMSO-d
6)：2.31(s，3H)，2.78-2.85(m，1H)，3.29-3.34(m，1H)，3.78(s，3H)，5.15(dd，J＝12.0Hz，2.4Hz，1H)，6.85(d，1H，J＝8.4Hz)，7.00(d，2H，J＝8.0Hz)，7.10(dd，1H，J＝8.4Hz，1.6Hz)，7.35(d，2H，J＝8.0Hz)，7.49(d，2H，J＝8.8Hz)，7.88(d，1H，J＝1.6Hz)，8.14(d，2H，J＝8.8Hz)，10.30(s，1H)。
Embodiment 13: the preparation of flavanone-4-(4-methylsulfonyl phenyl) hydrazone (compound Va)
Flavanone 0.448g (2mmol), 4-methylsulfonyl phenylhydrazine checking computations salt 0.445g (2mmol), ethanol 20mL and acetate 0.02mL are added in the reaction flask, and backflow 6hr separates out white solid again after the solid dissolving.Cooling, suction filtration, filter cake is washed with small amount of ethanol, and drying under reduced pressure obtains white cotton-shaped solid (compound Va) 0.699g, yield 89.4%.Fusing point: 249-250 ℃.
1H NMR(δ，DMSO-d
6)：2.73-2.80(m，1H)，3.08(s，3H)，3.29-3.34(m，1H)，5.23(dd，1H，J＝12.0Hz，2.8Hz)，6.95(d，1H，J＝8.0Hz)，7.02(t，1H，J＝8.0，16.0Hz)，7.25(t，1H，J＝8.0Hz)，7.34-7.45(m，5H)，7.56(d，2H，J＝8.8Hz)，7.70(d，2H，J＝8.8Hz)，8.05(dd，1H，J＝8.0Hz，2.0Hz)，9.99(s，H)。
Embodiment 14:6-methyl-4 '-preparation of methoxyl group flavanone-4-(4-methylsulfonyl phenyl) hydrazone (compound Vb)
Operating process and embodiment 13 with, just with 6-methyl-4 '-the methoxyl group flavanone replaces flavanone.Obtain white solid (compound Vb), yield 92.1%.Fusing point:＞250 ℃.
1H NMR(δ，DMSO-d
6)：2.31(s，3H)，2.75-2.82(m，1H)，3.11(s，3H)，3.27-3.32(m，1H)，3.78(s，3H)，5.13(dd，J＝12.0Hz，2.4Hz，1H)，6.84(d，1H，J＝8.4Hz)，7.00(d，2H，J＝8.0Hz)，7.07(dd，1H，J＝8.4Hz，1.6Hz)，7.38(d，2H，J＝8.4Hz)，7.49(d，2H，J＝8.0Hz)，7.73(d，2H，J＝8.4Hz)，7.86(d，1H，J＝1.6Hz)，9.97(s，1H)。
The preparation of embodiment 15:4 '-methoxyl group flavanone-4-(4-methylsulfonyl phenyl) hydrazone (compound Vc)
Operating process and embodiment 13 with, just with 4 '-methoxyl group flavanone replacement flavanone.Obtain white solid (compound Vc), yield 93.4%.Fusing point:＞250 ℃.
2.76-2.83(m，1H)，3.08(s，3H)，3.28-3.33(m，1H)，3.75(s，3H)，5.16(dd，1H，J＝12.0Hz，3.2Hz)，6.92(d，1H，J＝8.0Hz)，6.98(d，2H，J＝8.8Hz)，7.24(t，1H，J＝8.0，16.0Hz)，7.35(d，2H，J＝8.8Hz)，7.47(d，2H，J＝8.8Hz)，8.05(d，1H，J＝8.0Hz)，9.98(s，1H)。
Embodiment 16:5, the preparation of 7-dimethoxy flavanone-4-(4-methylsulfonyl phenyl) hydrazone (compound Vd)
Operating process and embodiment 13 are with 5 together, and 7-dimethoxy flavanone replaces flavanone.Obtain white solid (compound Vd), yield 85.3%.Fusing point: 225-227 ℃.
1H NMR(δ，DMSO-d
6)：2.74-2.81(m，1H)，3.04(s，3H)，3.25-3.30(m，1H)，3.71(s，3H)，3.76(s，3H)，5.49(dd，1H，J＝10.0Hz，2.8Hz)，6.13(d，1H，J＝2.0Hz)，6.93(d，2H，J＝8.8Hz)，7.23-7.39(m，5H)，7.65(d，1H，J＝8.8Hz)，11.42(s，1H)。
The preparation of embodiment 17:6-methoxyl group flavanone-4-(4-methylsulfonyl phenyl) hydrazone (compound Ve)
Operating process and embodiment 13 just replace flavanone with 6-methoxyl group flavanone together.Obtain light yellow solid (compound Ve), yield 86.3%.Fusing point:＞250 ℃.
1H NMR(δ，DMSO-d
6)：2.29(s，3H)，2.70-2.77(m，1H)，3.08(s，3H)，3.31-3.36(m，1H)，5.18(dd，J＝12.0Hz，2.8Hz)，6.84(d，1H，J＝8.4Hz)，7.06(d，1H，J＝8.8Hz)，7.36(t，2H，J＝8.8Hz)，7.43(t，2H，J＝8.4Hz)，7.54(d，2H，J＝8.8Hz)，7.70(d，2H，J＝8.8Hz)，7.84(s，1H)，9.94(s，1H)。
Embodiment 18:2-(4-nitro-2-chloro-phenyl-)-3a, 4-diethoxy-4 '-chlorine flavane [4,3-d]-Δ
1,9b-1,2, (compound VI preparation a) of 3-Thiadiazoline
Flavanone-4-(4-nitrophenyl) hydrazone (IVa) 0.72g (2mmol) is added to SOCl in batches
2Among the 16mL (0.22mol), reflux 30min under the nitrogen protection, SOCl is removed in decompression
2, add dehydrated alcohol 16mL, reflux 30min, cooling, decompression recycling ethanol adds water 20mL dilution, dichloromethane extraction (10mL * 3), merge organic layer, saturated nacl aqueous solution is washed (10mL * 2), anhydrous sodium sulfate drying, the reclaim under reduced pressure methylene dichloride, the gained crude product through column chromatography (eluent: sherwood oil: ethyl acetate=100mL: 20mL) separate orange red solid (compound VI a), yield 58.3%, fusing point: 192-194 ℃.
1H NMR(δ，CDCl
3)：0.80(t，3H，J＝7.2，14.4Hz)，0.88(t，3H，J＝7.2Hz，)，2.86-2.90(m，1H)，3.08-3.12(m，1H)，3.26-3.30(m，1H)，3.37-3.41(m，1H)，7.24-7.31(m，2H)，7.57(d，3H，J＝8.8Hz)，7.65(d，2H，J＝8.8Hz)，7.74(d，1H，J＝9.2Hz)，8.09(dd，1H，J＝8.0Hz，1.6Hz)，8.21(dd，1H，J＝9.2Hz，2.8Hz)，8.42(d，1H，J＝2.8Hz)。IR：2921，1609cm
-1。
Embodiment 19:2-(4-nitro-2-chloro-phenyl-)-4 '-methoxyl group-3a, 4-diethoxy flavane [4,3-d]-Δ
1,9b-1,2, the preparation of 3-Thiadiazoline (compound VI b)
Operating process and embodiment 18 with, just with 4 '-methoxyl group flavanone-4-(4-nitrophenyl) hydrazone (IVb) replacement flavanone 4-(4-nitrophenyl) hydrazone, obtain orange red solid (compound VI b).Yield 58.3%, decomposition point: 170 ℃.
1H NMR(δ，CDCl
3)：0.80(t，3H，J＝7.2Hz)，0.88(t，3H，J＝7.2Hz)，2.86-2.90(m，1H，)，3.08-3.12(m，1H)，3.26-3.30(m，1H)，3.37-3.41(m，1H)，3.96(s，3H)，6.93(d，2H，J＝8.8Hz)，7.24-7.31(m，2H)，7.57(d，1H，J＝8.8Hz)，7.61(d，2H，J＝8.8Hz)，7.71(d，1H，J＝9.2Hz)，8.09(dd，1H，J＝8.0Hz，1.6Hz)，8.19(dd，1H，J＝9.2Hz，2.8Hz)，8.29(d，1H，J＝2.8Hz)。IR：2921，1609cm
-1。
Embodiment 20:2-(4-nitro-2-chloro-phenyl-)-7,9-dimethoxy-3a, 4-diethoxy-4 ', 6-dichloro flavane [4,3-d]-Δ
1,9b-1,2, the preparation of 3-Thiadiazoline (compound VI c)
Operating process and embodiment 18 are with 5 together, and 7-dimethoxy flavanone-4-(4-nitrophenyl) hydrazone (IVc) replaces flavanone 4-(4-nitrophenyl) hydrazone, obtains orange red solid (compound VI c).Yield 53.1%, decomposition point: 219 ℃.
1H NMR(δ，DMSO-d
6)：0.88(t，3H，J＝7.2，14.4Hz)，0.97(t，3H，J＝7.2，14.4Hz)，2.84-2.91(m，1H)，3.15-3.22(m，1H)，3.33-3.40(m，1H)，3.44-3.51(m，1H)，4.03(s，3H)，4.06(s，3H)，6.39(s，1H)，7.41(d，2H，J＝8.0Hz)，7.68(d，3H，J＝8.0Hz)，8.10(dd，1H，J＝8.8Hz，2.4Hz)，8.30(d，1H，J＝2.4Hz)。IR：2924，1601cm
-1。
Embodiment 21:2-(4-nitro-2-chloro-phenyl-)-7,9-dimethoxy-3a, 4-diethoxy-2 ', 6-dichloro flavane [4,3-d]-Δ
1,9b-1,2, the preparation of 3-Thiadiazoline (compound VI d)
Operating process and embodiment 18 are with 5 together, 7-dimethoxy-2 '-chlorine flavanone-4-(4-nitrophenyl) hydrazone (IVd) replacement flavanone 4-(4-nitrophenyl) hydrazone, obtain orange red solid (compound VI d).Yield 45.3%, fusing point: 221-224 ℃.
1H NMR(δ，DMSO-d
6)：0.91(t，3H，J＝7.2，14.4Hz)，1.01(t，3H，J＝7.2，14.4Hz)，2.87-2.95(m，1H)，3.22-3.29(m，1H)，3.45-3.61(m，2H)，4.03(s，3H)，4.05(s，3H)，6.39(s，1H)，7.30-7.35(m，2H)，7.42-7.44(m，1H)，7.71(d，1H，J＝9.2Hz)，7.87-7.69(m，1H)，8.10(d，1H，J＝9.2)，8.29(s，1H)。IR：2972，1603cm
-1。
Embodiment 22:2-(4-nitro-2-chloro-phenyl-)-4 '-methyl-7,9-dimethoxy-3a, 4-diethoxy-6-dichloro flavane [4,3-d]-Δ
1,9b-1,2, the preparation of 3-Thiadiazoline (compound VI e)
Operating process and embodiment 18 with, just with 4 '-methyl-5,7-dimethoxy flavanone-4-(4-nitrophenyl) hydrazone (IVe) replacement flavanone 4-(4-nitrophenyl) hydrazone obtains orange red solid (compound VI e).Yield 58.3%, decomposition point: 130 ℃.
1H NMR(δ，DMSO-d
6)：0.82(t，3H，J＝7.2，14.4Hz)，0.90(t，3H，J＝7.2，14.4Hz)，2.43(s，3H)，2.86-2.90(m，1H)，3.08-3.12(m，1H)，3.26-3.30(m，1H)，3.37-3.41(m，1H)，6.41(s，1H)，7.03(d，2H，J＝8.8Hz)，7.22(d，2H，J＝8.8Hz)，7.75(d，1H，J＝9.2Hz)，8.19(dd，1H，J＝9.2Hz，2.8Hz)，8.39(d，1H，J＝2.8Hz)。IR：2927，1598cm
-1。
Embodiment 23:2-(4-nitro-2-chloro-phenyl-)-4 ', 7,9-trimethoxy-3a, 4-diethoxy-6-chlorine flavane [4,3-d]-Δ
1,9b-1,2, the preparation of 3-Thiadiazoline (compound VI f)
Operating process and embodiment 18 with, just with 4 ', 5,7-trimethoxy flavanone-4-(4-nitrophenyl) hydrazone (IVf) replacement flavanone 4-(4-nitrophenyl) hydrazone obtains orange red solid (compound VI f).Yield 40.1%, fusing point: 171-173 ℃.
1H NMR(δ，CDCl
3)：0.88(t，3H，J＝7.2，14.4Hz)，1.00(t，3H，J＝7.2，14.4Hz)，2.84-2.92(m，1H)，3.19-3.26(m，1H)，3.34-3.42(m，1H)，3.48-3.56(m，1H)，3.85(s，3H)，3.98(s，3H)，4.02(s，3H)，6.61(s，1H)，6.94(d，2H，J＝8.8Hz)，7.60(d，2H，J＝8.8Hz)，7.69(d，1H，J＝9.2Hz)，8.08(dd，1H，J＝9.2Hz，1.6Hz)，8.30(d，1H，J＝1.6Hz)。IR：2927，1583cm
-1。
Embodiment 24:2-(4-nitro-2-chloro-phenyl-)-4 ', 5 ', 7,9-tetramethoxy-3a, 4-diethoxy-2 ', 6-dichloro flavane [4,3-d]-Δ
1,9b-1,2, the preparation of 3-Thiadiazoline (compound VI g)
With 5,7,3 ', 4 '-tetramethoxy flavanone-4-(4-nitrophenyl) hydrazone (IVg) 0.95g (2mmol) adds to SOCl
2Among the 16mL (0.43mol), 30min is reacted in ultrasonic radiation down under the nitrogen protection, and SOCl is removed in decompression
2Add dehydrated alcohol 16mL, continue ultrasonic radiation reaction 30min down, decompression recycling ethanol adds water 20mL dilution, dichloromethane extraction (10mL * 3), saturated nacl aqueous solution is washed (10mL * 2), anhydrous sodium sulfate drying, the reclaim under reduced pressure methylene dichloride, the gained crude product is through column chromatography for separation (eluent: sherwood oil: ethyl acetate=100mL: 20mL) obtain orange red solid (compound VI g).Yield 45.7%, fusing point: 207-208 ℃.
1H NMR(δ，DMSO-d
6)：0.83(t，3H，J＝7.2，14.4Hz)，0.96(t，3H，J＝7.2，14.4Hz)，2.78-2.86(m，1H)，3.07-3.15(m，1H)，3.35-3.42(m，1H)，3.51-3.59(m，1H)，3.77(s，3H)，3.83(s，3H)，4.03(s，3H)，4.05(s，3H)，6.72(s，1H)，7.03(s，1H)，7.28(s，2H)，7.68(d，1H，J＝9.2Hz)，8.24(dd，1H，J＝9.2Hz，2.8Hz)，8.42(d，1H，J＝2.8Hz)。IR：2923，1589cm
-1。
Embodiment 25:2-(4-nitro-2-chloro-phenyl-)-3 ', 7,9-trimethoxy-3a, 4-diethoxy-4 ', 6-dichloro flavane [4,3-d]-Δ
1,9b-1,2, the preparation of 3-Thiadiazoline (compound VI h)
Operating process and embodiment 18 with, just with 3 ', 5,7-trimethoxy flavanone-4-(4-nitrophenyl) hydrazone (compound IV h) replacement flavanone 4-(4-nitrophenyl) hydrazone obtains orange red solid (compound VI h).Yield 53.4%, decomposition point: 111 ℃.
1H NMR(δ，CDCl
3)：0.95(t，3H，J＝7.2，14.4Hz)，1.01(t，3H，J＝7.2，14.4Hz)，2.87-2.95(m，1H)，3.24-3.32(m，1H)，3.47-3.63(m，2H)，3.92(s，3H)，4.03(s，3H)，4.06(s，3H)，6.40(s，1H)，6.96-7.00(m，1H)，7.10-7.14(m，1H)，7.43(s，1H)，7.71(d，1H，J＝8.8Hz)，8.10(dd，1H，J＝8.8Hz，2.4Hz)，8.29(d，1H，J＝2.4Hz)。IR：2938，1602cm
-1。
Embodiment 26:2-(4-nitro-2-chloro-phenyl-)-8-methyl-3a, 4-diethoxy-4 '-chlorine flavane [4,3-d]-Δ
1,9b-1,2, the preparation of 3-Thiadiazoline (compound VI i)
Operating process and embodiment 18 just replace flavanone 4-(4-nitrophenyl) hydrazone with 6-methyl flavanone-4-(4-nitrophenyl) hydrazone (compound IV i) together, obtain orange red solid (compound VI i).Yield 76.5%, decomposition point: 171 ℃
1H NMR(δ，DMSO-d
6)：0.80(t，3H，J＝7.2，14.4Hz)，0.89(t，3H，J＝7.2，14.4Hz)，2.38(s，3H)，2.86-2.90(m，1H)，3.07-3.11(m，1H)，3.24-3.28(m，1H)，3.35-3.39(m，1H)，7.18(d，1H，J＝8.4Hz)，7.38(dd，1H，J＝8.4Hz，1.6Hz)，7.56(d，2H，J＝8.8Hz)，7.64(d，2H，J＝8.8Hz)，7.74(d，1H，J＝9.2Hz)，7.89(d，1H，J＝1.6Hz)，8.21(dd，1H，J＝9.2Hz，2.8Hz)，8.42(d，1H，J＝2.8Hz)。IR：2977，1582cm
-1。
Embodiment 27:2-(4-nitro-2-chloro-phenyl-)-8-methyl-3a, 4-diethoxy-4 ', 5 '-dioxy methylene radical-2 '-chlorine flavane [4,3-d]-Δ
1,9b-1,2, the preparation of 3-Thiadiazoline (compound VI j)
Operating process and embodiment 24 with, just with 6-methyl-3 ', 4 '-dioxy methylene radical flavanone-4-(4-nitrophenyl) hydrazone (compound IV j) replaces 5,7,3 ', 4 '-tetramethoxy flavanone-4-(4-nitrophenyl) hydrazone, obtain orange/yellow solid (compound VI j).Yield 37.2%, fusing point: 104-106 ℃.
1H NMR(δ，CDCl
3)：0.85(t，3H，J＝7.2，14.4Hz)，0.92(t，3H，J＝7.2，14.4Hz)，2.85-2.93(m，1H)，3.11-3.19(m，1H)，3.36-3.50(m，2H)，6.14(d，1H，J＝1.2Hz)，6.17(d，1H，J＝1.2Hz)，7.10(s，1H)，7.13(d，1H，J＝8.0Hz)，7.22(s，1H)，7.37(dd，1H，J＝8.0Hz，1.6Hz)，7.75(d，1H，J＝9.2Hz)，7.87(d，1H，J＝1.6Hz)，9.19(dd，1H，J＝9.2Hz，2.4Hz)，8.41(d，1H，J＝2.4Hz)。IR：2977，2870，1582，926cm
-1。
Embodiment 28:2-(4-nitro-2-chloro-phenyl-)-8-methyl-4 ', 5 '-dimethoxy-3a, 4-diethoxy-2 '-chlorine flavane [4,3-d]-Δ
1,9b-1,2, the preparation of 3-Thiadiazoline (compound VI k)
Operating process and embodiment 24 with, just with 6-methyl-3 ', 4 '-dimethoxy flavanone-4-(4-nitrophenyl) hydrazone (compound IV k) replaces 5,7,3 ', 4 '-tetramethoxy flavanone-4-(4-nitrophenyl) hydrazone, obtain orange/yellow solid (compound VI k).Yield 53.2%, fusing point: 105-107 ℃.
1H NMR(δ，CDCl
3)：0.81(t，3H，J＝7.2，14.4Hz)，0.89(t，3H，J＝7.2，14.4Hz)，2.37(s，3H)，2.80-2.87(m，1H)，3.05-3.12(m，1H)，3.31-3.37(m，1H)，3.41-3.48(m，1H)，3.73(s，3H)，3.78(s，3H)，6.97(s，1H)，7.10(d，1H，J＝8.4Hz)，7.21(s，1H)，7.32(dd，1H，J＝8.0Hz，1.6Hz)，7.71(d，1H，J＝9.2Hz)，7.31(dd，1H，J＝8.4Hz，1.6Hz)，7.83(d，1H，J＝1.6Hz)，8.15(dd，1H，J＝9.2Hz，2.4Hz)，8.28(d，1H，J＝2.4Hz)。IR：2927，1587cm
-1。
Embodiment 29:2-(4-nitro-2-chloro-phenyl-)-8-methyl-4 '-methoxyl group-3a, 4-diethoxy flavane [4,3-d]-Δ
1,9b-1,2, the preparation of 3-Thiadiazoline (compound VI l)
Operating process and embodiment 18 with, just with 6-methyl-4 '-methoxyl group flavanone-4-(4-nitrophenyl) hydrazone (IVI) replaces flavanone-4-(4-nitrophenyl) hydrazone, obtains orange red solid (compound VI l).Yield 53.2%, fusing point: 221-224 ℃.
1H NMR(δ，CDCl
3)：0.89(t，3H，J＝7.2，14.4Hz)，0.99(t，3H，J＝7.2，14.4Hz)，2.85-2.93(m，1H)，3.21-3.27(m，1H)，3.43-3.60(m，2H)，3.92(s，3H)，6.93(d，2H，J＝8.8Hz)，7.18(d，1H，J＝8.4Hz)，7.38(dd，1H，J＝8.4Hz，1.6Hz)，7.61(d，2H，J＝8.8Hz)，7.73(d，1H，J＝9.2Hz)，7.89(d，1H，J＝1.6Hz)，8.10(d，1H，J＝9.2Hz)，8.29(s，1H)。IR：2927，1589cm
-1。
Embodiment 30:2-(4-nitro-2-chloro-phenyl-)-3a, 4,7,9-tetramethoxy-4 ', 6-dichloro flavane [4,3-d]-Δ
1,9b-1,2, the preparation of 3-Thiadiazoline (VIm)
Operating process and embodiment 18 with, just with 6-methyl-4 '-methoxyl group flavanone-4-(4-nitrophenyl) hydrazone (IVc) replaces flavanone-4-(4-nitrophenyl) hydrazone, replaces ethanol with methyl alcohol, obtains orange red solid (compound VI m).Yield 52.4%, fusing point: 107-108 ℃.
1H NMR(δ，CDCl
3)：2.90(s，3H)，3.13(s，3H)，4.03(s，3H)，4.06(s，3H)，6.41(s，1H)，7.43(d，2H，J＝8.4Hz)，7.57-7.72(m，3H)，8.10(d，1H，J＝9.6Hz)，8.30(s，1H)。IR：2980，1597cm
-1。
Embodiment 31:2-(4-nitro-2-chloro-phenyl-)-7,9-tetramethoxy-3a, 4-dipropoxy-4 ', 6-dichloro flavane [4,3-d]-Δ
1,9b-1,2, the preparation of 3-Thiadiazoline (VIn)
Operating process and embodiment 18 with, just with 6-methyl-4 '-methoxyl group flavanone-4-(4-nitrophenyl) hydrazone (IVc) replaces flavanone-4-(4-nitrophenyl) hydrazone, replaces ethanol with propyl alcohol, obtains orange red solid (compound VI n).Yield 34.5%, fusing point: 203-204 ℃.
1H NMR(δ，CDCl
3)：0.53(t，3H，J＝7.2，14.4Hz)，0.64(t，3H，J＝7.2，14.4Hz)，1.23-1.39(m，4H)，2.74-2.79(m，1H)，3.12-3.18(m，1H)，3.24-3.29(m，1H，)，3.35-3.40(m，1H)，4.03(s，3H)，4.05(s，3H)，6.39(s，1H)，7.40(d，2H，J＝8.4Hz)，7.66-7.69(m，3H)，8.10(dd，1H，J＝8.8Hz，2.4Hz)，8.30(d，1H，J＝2.4Hz)。IR：2925，1605cm
-1。
Embodiment 32:2-(4-nitro-2-chloro-phenyl-)-7,9-tetramethoxy-3a, 4-diisopropoxy-4 ', 6-dichloro flavane [4,3-d]-Δ
1,9b-1,2, the preparation of 3-Thiadiazoline (VIo)
Operating process and embodiment 18 with, just with 6-methyl-4 '-methoxyl group flavanone-4-(4-nitrophenyl) hydrazone (IVc) replaces flavanone-4-(4-nitrophenyl) hydrazone, replaces ethanol with Virahol, obtains orange red solid (compound VI o).Yield 33.0%, fusing point 240-241 ℃.
1H NMR(δ，CDCl
3)：0.69(d，J＝6.4Hz，6H)，0.81(d，3H，J＝6.0Hz)，1.03(d，3H，J＝6.0Hz)，3.42-3.48(m，1H)，3.92-3.98(m，1H)，4.03(s，3H)，4.05(s，3H)，6.37(s，1H)，7.39(d，2H，J＝8.8Hz)，7.68(d，1H，J＝9.2Hz)，7.73(d，2H，J＝8.8Hz)，8.11(dd，1H，J＝9.2Hz，2.4Hz)，8.31(d，1H，J＝2.4Hz)。IR：2927，1590cm
-1。
Embodiment 33:2-(4-methylsulfonyl-2-chloro-phenyl-)-3a, 4-diethoxy-4 '-chlorine flavane [4,3-d]-Δ
1,9b-1,2, the preparation of 3-Thiadiazoline (VIIa)
Operating process and embodiment 18 just replace flavanone-4-(4-nitrophenyl) hydrazone with flavanone-4-(4-methylsulfonyl phenyl) hydrazone (Va) together, replace ethanol with Virahol, obtain light yellow solid (compound VI Ia).Yield 72.3%, fusing point 112-114 ℃.
1H NMR(δ，CDCl3)：0.90(t，3H，J＝7.2，14.4Hz)，0.95(t，3H，J＝7.2，14.4Hz)，2.91-2.95(m，1H)，3.08(s，3H)，3.27-3.46(m，3H)，7.14-7.18(m，2H)，7.39(d，2H，J＝8.4Hz)，7.48(m，1H)，7.63-7.66(m，3H)，7.79(dd，1H，J＝8.8Hz，2.0Hz)，7.98(d，1H，J＝2.0Hz)，8.05(dd，1H，J＝8.0Hz，1.6Hz)。IR：2954，1608，1585cm
-1。
Embodiment 34:2-(4-methylsulfonyl-2-chloro-phenyl-)-8-methyl-4 '-methoxyl group-3a, 4-diethoxy flavane [4,3-d]-Δ
1,9b-1,2, the preparation of 3-Thiadiazoline (VIIb)
Operating process and embodiment 18 with, just with 6-methyl-4 '-methoxyl group flavanone-4-(4-methylsulfonyl phenyl) hydrazone (Vb) replaces flavanone-4-(4-nitrophenyl) hydrazone, replaces ethanol with Virahol, obtains light yellow solid (compound VI Ib).Yield 69.4%, 131 ℃ of decomposition points.
1H NMR(δ，CDCl3)：0.90(t，3H，J＝7.2，14.4Hz)，0.95(t，3H，J＝7.2，14.4Hz)，2.39(s，3H)，3.07(s，3H)，2.89-2.96(m，1H)，3.22-3.45(m，3H)，6.95(d，2H，J＝8.8Hz)，7.06(d，1H，J＝8.4Hz)，7.25(dd，1H，J＝8.4Hz，2.0Hz)，，7.60(d，2H，J＝8.8Hz)，7.66(d，1H，J＝8.4Hz)，7.78(dd，1H，J＝8.4Hz，2.4Hz)，7.85(d，1H，J＝2.0Hz)，7.97(d，1H，J＝2.4Hz)。IR：2936，1608，1585cm
-1。
Embodiment 35:2-(4-methylsulfonyl-2-chloro-phenyl-)-4 '-methoxyl group-3a, 4-diethoxy flavane [4,3-d]-Δ
1,9b-1,2, the preparation of 3-Thiadiazoline (VIIc)
Operating process and embodiment 18 with, just with 4 '-methoxyl group flavanone-4-(4-methylsulfonyl phenyl) hydrazone (Vc) replacement flavanone-4-(4-nitrophenyl) hydrazone, replace ethanol with Virahol, obtain yellow solid (compound VI Ic).Yield 65.7%, 195 ℃ of decomposition points
1H NMR(δ，CDCl
3)：0.88(t，3H，J＝7.2，14.4Hz)，0.93(t，3H，J＝7.2Hz)，2.89-2.96(m，1H)，3.07(s，3H)，3.24-3.45(m，3H)，6.92(d，2H，J＝8.8Hz)，7.14-7.18(m，2H)，7.60(d，2H，J＝8.8Hz)，7.66(d，1H，J＝8.4Hz)，7.78(dd，1H，J＝8.4Hz，2.4Hz)，7.97(d，1H，J＝2.4Hz)，8.05(dd，1H，J＝8.0Hz，1.6Hz)。IR：2936，1608，1585cm
-1。
Embodiment 36:2-(4-methylsulfonyl-2-chloro-phenyl-)-7,9-dimethoxy-3a, 4-diethoxy-4 ', 6-dichloro flavane [4,3-d]-Δ
1,9b-1,2, the preparation of 3-Thiadiazoline (VIId)
Operating process and embodiment 18 with, just with 4 '-methoxyl group flavanone-4-(4-methylsulfonyl phenyl) hydrazone (Vd) replacement flavanone-4-(4-nitrophenyl) hydrazone, replace ethanol with Virahol, obtain yellow solid (compound VI Id).Yield 59.5%, fusing point 112-114 ℃.
1H NMR(δ，CDCl
3)：0.87(t，3H，J＝7.2，14.4Hz)，0.96(t，3H，J＝7.2，14.4Hz)，2.84-2.90(m，1H)，3.07(s，3H)，3.18-3.25(m，1H)，3.32-3.40(m，1H)，3.43-3.51(m，1H)，4.03(s，3H)，4.04(s，3H)，6.39(s，1H)，7.40(d，2H，J＝8.4Hz)，7.6-7.69(m，3H)，7.77(dd，1H，J＝8.4Hz，2.4Hz)，7.86(d，1H，J＝2.4Hz)。IR：2927，1608，1577cm
-1。
Embodiment 37:2-(4-methylsulfonyl-2-chloro-phenyl-)-8-methyl-3a, 4-diethoxy-4 '-chlorine flavane [4,3-d]-Δ
1,9b-1,2, the preparation of 3-Thiadiazoline (VIIe)
Operating process and embodiment 18 just replace flavanone-4-(4-nitrophenyl) hydrazone with 8-methyl flavanone-4-(4-methylsulfonyl phenyl) hydrazone (Ve) together, replace ethanol with Virahol, obtain yellow solid (compound VI Ie).Yield 72.1%, 130 ℃ of decomposition points.
1H NMR(δ，CDCl
3)：0.90(t，3H，J＝7.2，14.4Hz)，0.95(t，3H，J＝7.2，14.4 Hz)，2.40(s，3H)，2.89-2.96(m，1H)，3.06(s，3H)，3.25-3.46(m，3H)，7.06(d，1H，J＝8.4Hz)，7.25(dd，1H，J＝8.4，2.0Hz)，7.38(d，2H，J＝8.8Hz)，7.63(d，2H，J＝8.8Hz)，7.66(d，1H，J＝8.4Hz)，7.78(dd，1H，J＝8.42.4Hz)，7.84(d，1H，J＝2.0Hz)，7.98(d，1H，J＝2.4Hz)。IR：2979，1609，1592cm
-1。
Embodiment 38:2-(4-acetamido-2-chloro-phenyl-)-3a, 4-diethoxy-4 '-chlorine flavane [4,3-d]-Δ
1,9b-1,2, the preparation of 3-Thiadiazoline (VIIIa)
Get 2-(4-nitro-2-chloro-phenyl-)-3a, 4-diethoxy-4 '-chlorine flavane [4,3-d]-Δ
1,9b-1,2,3-Thiadiazoline (VIa) 0.54g (1mmol) adds in the 10mL round-bottomed bottle, adds Raney-Ni1.0g (weight in wet base), EtOH 6mL, at ambient temperature, logical hydrogen reaction 6hr, suction filtration is removed Raney-Ni, mother liquor reclaim soup compound, drying under reduced pressure.In soup compound, add pyridine 0.34mL, diacetyl oxide 0.34mL, stirring at room 12hr, add water 30mL dilution, dichloromethane extraction (10mL * 3), organic layer washing (10mL * 3), saturated common salt washing (10mL * 2), anhydrous sodium sulfate drying, reclaim methylene dichloride, get soup compound, (eluent: sherwood oil: ethyl acetate=100mL: (compound VIII is 0.50g a) 40mL) to get orange red solid for column chromatography for separation, yield 89.8%, 150 ℃ of decomposition points.
1H NMR(δ，CDCl
3)：＝0.82(t，3H，J＝7.2，14.4Hz)，0.90(t，3H，J＝7.2，14.4Hz)，2.16(s，3H)，2.86-2.90(m，1H)，3.08-3.12(m，1H)，3.26-3.30(m，1H)，3.37-3.41(m，1H)，7.24-7.31(m，2H)，7.35-7.42(brs，4H)，7.59(m，2H)，7.62(d，2H，J＝8.0Hz)，8.07(dd，1H，J＝8.0，1.6Hz)。IR：3413，2980，1703，1681，1597cm
-1。
Embodiment 39:2-(4-acetamido-2-chloro-phenyl-)-8-methyl-3a, 4-diethoxy-4 '-chlorine flavane [4,3-d]-Δ
1,9b-1,2, the preparation of 3-Thiadiazoline (VIIIb)
Operating process and embodiment 38 just use 2-(4-nitro-2-chloro-phenyl-)-8-methyl-3a together, 4-diethoxy-4 '-chlorine flavane [4,3-d]-Δ
1,9b-1,2,3-Thiadiazoline (VIi) replaces compound VI a, obtains orange red solid (compound VIII b).Yield 85.4%, decomposition point: 187 ℃.
1HNMR(δ，CDCl
3)：＝0.89(t，3H，J＝7.2，14.4Hz)，0.97(t，3H，J＝7.2，14.4Hz)，2.18(s，3H)，2.38(s，3H)，2.92-2.99(m，1H)，3.29-4.44(m，3H)，7.04(d，1H，J＝8.4Hz)，7.19-7.22(m，1H)，7.31-7.37(m，4H)，7.62(d，2H，J＝8.0Hz)，7.69(s，1H)，7.82(d，1H J＝2.0Hz)。IR：3417，2979，1698，1595cm
-1。
Embodiment 40:2-(4-acetamido-2-chloro-phenyl-)-4 ', 5 ', 7,9-tetramethoxy-3a, 4-diethoxy-2 ', 6-dichloro flavane [4,3-d]-Δ
1,9b-1,2, the preparation of 3-Thiadiazoline (VIIIc)
Operating process and embodiment 38 just use 2-(4-nitro-2-chloro-phenyl-)-4 ' together, 5 ', 7,9-tetramethoxy-3a, 4-diethoxy-2 ', 6-dichloro flavane [4,3-d]-Δ
1,9b-1,2,3-Thiadiazoline (VIg) replaces compound VI a, obtains orange red solid (compound VIII c).Yield 84.1%, decomposition point: 238 ℃.
1H NMR(δ，CDCl
3)：0.92(t，3H，J＝7.2，14.4Hz)，1.03(t，3H，J＝7.2，14.4Hz)，2.14(s，3H)，3.32-3.40(m，1H)，3.45-3.61(m，2H)，3.70-3.75(m，1H)，3.91(s，3H)，4.00(s，3H)，4.02(s，3H)，6.38(s，1H)，7.03(s，1H)，7.28(s，2H)，7.45(s，2H)，7.57(s，1H)。IR：2923，1589cm
-1。
Embodiment 41:2-(4-acetamido-2-chloro-phenyl-)-3 ', 7,9-trimethoxy-3a, 4-diethoxy-4 ', 6-dichloro flavane [4,3-d]-Δ
1,9b-1,2, the preparation of 3-Thiadiazoline (VIIId)
Operating process and embodiment 38 just use 2-(4-nitro-2-chloro-phenyl-)-3 ' together, and 7,9-tetramethoxy-3a, 4-diethoxy-4 ', 6-dichloro flavane [4,3-d]-Δ
1,9b-1,2,3-Thiadiazoline (VIh) replaces compound VI a, obtains orange red solid (compound VIII d).Yield 87.2%, decomposition point: 207 ℃.
1H NMR(δ，CDCl
3)：0.92(t，3H，J＝7.2，14.4Hz)，1.03(t，3H，J＝7.2，14.4Hz)，2.14(s，3H)，2.91-2.99(m，1H)，3.32-3.40(m，1H)，3.46-3.61(m，2H)，3.91(s，3H)，4.00(s，3H)，4.01(s，3H)，6.38(s，1H)，7.33-7.38(m，2H)，7.41(s，1H)，7.43-7.50(m，2H)，7.57(s，1H)。IR：3417，2985，1687，1595cm
-1。
Embodiment 42:2-aryl flavane [4,3-d]-Δ
1,9b-1,2, the 3-M-stage kinesin inhibitor is to the vitro inhibition effect of different tumour cells
1. experiment material
Cell strain: promyelocytic leukemia HL-60 cell, people's lung cancer A549 cell, people's liver cancer Bel-7402 cell, people's esophagus cancer ECA-109 cell, human breast carcinoma MCF-7 cell, human prostata cancer PC-3 cell.
Substratum: the RPMI1640 substratum contains 10% calf serum.
Medicine and preparation: medicine is the above-mentioned synthetic compound VI of institute, VII and VIII, and medicine is dissolved in DMSO.
2. experimental technique
With the above-mentioned tumour cell that is in logarithmic phase, with 2 * 10
4Individual/ml is inoculated in 96 well culture plates, and every hole adds cell suspension 200 μ l, after cultivating 24h, adds flavanone derivative (0.08-50 μ g/ml) the 2 μ l of 5 kinds of concentration respectively, and each concentration is established 3 multiple holes.Cell is at 37 ℃, 5%CO
2After hatching 72 hours in the incubator, adding concentration is the MTT solution 10 μ l of 5mg/ml, continues to cultivate 4 hours.Supernatant liquor is removed in suction, adds 100 μ l DMSO and shakes up, and with the OD value in microplate reader each hole of mensuration under the 570nm wavelength, the calculation formula of cell inhibitory rate is:
Cell inhibitory rate %=(control group OD value-medication group OD value)/control cells OD value * 100% usefulness Bliss method is obtained IC
50
3. experimental result
2-aryl flavane [4,3-d]-Δ
1,9b-1,2, the effect of 3-M-stage kinesin inhibitor was measured IC respectively after 72 hours
50Value.The result shows, most compounds all have in various degree vitro inhibition effect, wherein IC to 6 kinds of tumour cells
50Value has less than 10 μ g/ml: compound VI a, VIb, VIc, VIm, VIIa, VIId, VIIe and VIIIc are to HL-60 leukemia cell; VIb and VIIe are to the Bel-7402 human liver cancer cell; Compound VI a, VIb, VIe, VIm, VIIa, VIIb, VIIc, VIIIb are to the ECA-109 esophageal cancer cell; Compound VI a, VIb, VIm, VIIa, VIIe, VIIIa, VIIIb are to the PC-3 prostate cancer cell; Compound VI m, VIIa, VIIe are to the MCF-7 breast cancer cell; Compound VIII a, VIIe, VIIId are to the A549 non-small cell lung cancer cell.They to the vitro inhibition exercising result of tumour cell referring to table 1,2.
This compounds of integration test is to the vitro inhibition effect of different tumour cells, compound VI Ia, VIIe and VIIIb are more remarkable to the restraining effect of 6 kinds of tumor cell lines, antitumor spectra is wider, and its anti-tumor activity is obviously greater than parent compound flavanone and hydrazone (IVc).
Table 1 2-aryl flavane [4,3-d]-Δ
1,9b-1,2, the 3-M-stage kinesin inhibitor effect vitro inhibition effect to tumour cell in 72 hours
| Compound | IC50 and 95% fiducial limit (μ g/ml) | ||
| Bel-7402 | ECA-109 | PC-3 | |
| VIa VIb VIc VId VIe VIf VIi VIJ VIk VIl VIm VIIa VIIb VIIc VIId VIIe VIIIa VIIIb VIIIc VIIId flavanones IVc | 12.31(8.23-18.41) 8.00(6.45-9.91) ＞50 ＞50 ＞50 ＞50 14.37(11.91-17.33) ＞50 ＞50 20.87(17.89-24.34) 51.24(37.72-69.62) 10.14(7.72-13.32) 30.50(17.16-54.22 35.91(27.29-47.25) 24.52(21.57-27.86) 8.01(6.79-9.44) 21.50(17.94-25.78) 10.95(9.58-12.51) 27.29(23.28-23.99) 44.15 ＞50 ＞50 | 6.44(4.14-10.02) 9.19(7.16-11.78) ＞50 ＞50 6.63(5.21-8.44) ＞50 15.4(11.36-20.87) ＞50 ＞50 ＞50 9.29(6.68-12.91) 8.71(7.37-10.39) 1.98(1.17-3.37) 6.45(3.98-10.47) 26.35(21.70-32.00) 5.11(3.79-6.89) 6.62(4.86-9.03) 3.44(2.49-4.75) 11.32(9.23-13.89) ＞50 28.25(24.34-32.78) ＞50 | 3.64(2.72-4.88) 5.88(4.68-7.39) 13.53(8.08-22.65) ＞50 11.19(8.62-14.52) 28.42(14.63-55.20) ＞50 ＞50 ＞50 ＞50 4.80(3.80-6.06) 4.99(3.86-6.46) 11.74(6.79-18.28) 23.75(12.92-43.66) ＞50 2.31(1.69-3.17) 2.93(1.96-4.39) 1.59(1.33-1.91) 12.44(8.45-18.32) ＞50 12.9(11.09-14.99) ＞50 |
Table 2 2-aryl flavane [4,3-d]-Δ
1,9b-1,2, the 3-M-stage kinesin inhibitor effect vitro inhibition effect to tumour cell in 72 hours
| The medicine name | IC50 and 95% fiducial limit (μ g/ml) | ||
| MCF-7 | HL-60 | A549 | |
| VIa VIb VIc VId VIe VIf VIi VIJ VIk VIl VIm VIIa VIIb VIIc VIId VIIe VIIIa VIIIb VIIIc VIIId flavanones IVc | 15.38(12.82-18.45) 22.05(19.06-25.50) ＞25 ＞25 ＞25 ＞25 ＞25 ＞25 ＞25 ＞25 5.54(4.55-6.74) 3.89(3.42-4.42) ＞25 25.66(19.887-33.13) 10.82(8.21-14.26) 3.37(3.04-3.74) 17.69(15.68-19.96) 19.83(10.68-36.84) ＞25 ＞25 27.24(20.59-36.04) ＞25 | 1.81(1.47-2.23) 1.32(0.93-1.87) 6.75(5.68-8.03) ＞25 16.82(14.02-20.17) 23.17(20.13-26.67) ＞25 ＞25 ＞25 ＞25 5.14(4.21-6.29) 1.19(0.99-1.43) 11.15(9.89-12.58) 13.23(11.17-15.68) 5.41(4.67-6.26) 1.57(1.10-2.25) 10.23(9.19-11.38) 12.58(11.24-13.41) 9.59(8.73-10.53) 19.97(15.83-25.19) 20.42(16.43-25.37) ＞25 | 11.75(10.38-13.29) 16.08(14.28-18.10) ＞50 ＞50 ＞50 19.08(17.15-21.24) 22.91(20.77-25.26) ＞50 ＞50 ＞50 10.93(8.55-13.99) 10.58(9.42-11.88) 14.50(12.46-16.88) 26.99(19.66-37.06) 19.71(13.00-29.87) 4.93(3.91-6.23) 7.81(7.06-8.63) 9.90(8.94-10.98) 30.18(23.20-39.28) 5.26(3.87-7.14) 25.06(22.20-28.28) ＞50 |
Embodiment 43: compound VI Ia is to the therapeutic action of lotus S180 sarcoma mouse
1. experiment material
Knurl strain: mouse S180 sarcoma.
Animal: the ICR mouse, female, body weight 18-22g.
Medicine and preparation: compound VI Ia is synthetic by this teaching and research room, the medicine anhydrous alcohol solution, and with cremphor el hydrotropy, the physiological saline dilution is corresponding administration concentration.
2. experimental technique
Choose 40 of ICR kind female mices, oxter injection S180 cell suspension 0.2ml/ only (2.5 * 10
6Cell) makes solid tumor models; Inoculation is divided into 3 groups at random with animal next day, and wherein the solvent control group is 20, and all the other respectively organize 10 every group.Press the different concns administration, solvent control group intraperitoneal injection of saline; Administration group abdominal injection compound VI Ia 80mg/kg.Above-mentioned each group is all by the administration volume administration of 0.2ml/10g body weight.Once a day, continuous 7 days.Tail vein injection Docetaxel 10mg/kg next day of positive controls presses the administration volume administration of 0.1ml/10g body weight.Behind the last administration 24hr, mouse is put to death in cervical vertebra dislocation, gets the knurl piece back of weighing and calculates the inhibiting rate (tumour inhibiting rate) of tumor growth by following formula.
Tumour inhibiting rate %=(control group knurl weight-treatment group knurl is heavy)/control group knurl heavy * 100%
3. experimental result
| Group | Dosage (mg/kg) | Route of administration and number of times | Number of animals (only) | The weight of animals (g) | Knurl heavy (g) | Tumour inhibiting rate (%) | ||
| Beginning | Finish | Beginning | Finish | |||||
| Solvent control | - | ipx7 | 20 | 20 | 19±1 | 26±1 | 1.21±0.33 | - |
| VIIa | 80 | ipx7 | 10 | 10 | 19±1 | 21±2 | 0.63±0.23 | 48.2 *** |
| Docetaxel | 10 | ivx4 | 10 | 9 | 19±1 | 17±2 | 0.32±0.15 | 73.4 *** |
Annotate:
* *VIIa VS solvent control, Docetaxel VS solvent control
The result shows that compound VI Ia can obviously suppress mouse S180 solid tumor growth (P＜0.01), and tumour inhibiting rate has significant therapeutic action more than 30%.
Embodiment 44: the effect of compound VI Ia inducing apoptosis of tumour cell
1. experiment material
Cell strain: promyelocytic leukemia HL-60 cell.
Substratum: RPMI 1640 substratum contain 10% calf serum.
Medicine and preparation: compound VI Ia is synthetic by this teaching and research room, and medicine is dissolved in DMSO.
2. flow cytometry compound VI Ia is to the influence in apoptosis of tumor cells and cycle
Get the HL-60 cell inoculation of an amount of logarithmic phase, add compound VI Ia after 24 hours, making final concentration is 0.5 μ g/ml, 1.0 μ g/ml, 2.0 μ g/ml, DMSO is a solvent control, dosing is collecting cell after 48 hours, and D-Hank ' s liquid washes twice, fixedly spends the night for 4 ℃ with 70% ice ethanol.After the PBS washing, the centrifugal 10min of 1000r/min adds 37 ℃ of digestion of RNase A (0.5mg/ml) 30min, PI (50mg/ml) dyeing, room temperature lucifuge 15min, the formation of FACScan analyzing DNA hypodiploid and the variation of cell cycle.
Referring to Fig. 1, the result shows, compound VI Ia 0.5 μ g/ml effect can induce HL-60 leukemia cell the distinctive hypodiploid of apoptosis peak to occur in 48 hours, and increase along with concentration, apoptosis rate increases progressively gradually, and compound VI Ia 0.5 μ g/ml, 1.0 μ g/ml, 2.0 μ g/ml cause that the apoptosis rate of HL-60 cell is respectively 3.93%, 25.29% and 68.34%; Compound VI Ia cell cycle does not have obvious influence.A, B, C, D represent DMSO and compound VI Ia 0.5 μ g/ml, 1.0 μ g/ml, 2.0 μ g/ml effects pair cell dna content and influence in cycle after 48 hours respectively among the figure.
3.DNA the situation of Ladder detection compound VIIa inducing apoptosis of tumour cell
Harvested cell (1 * 10
6), add 0.5ml DNA extract, 1%SDS and Rnase A (5mg/ml), 56 ℃ of Proteinase Ks (2.5mg/ml) spend the night.Add the 0.5ml balance phenol, the 0.5ml chloroform, the centrifugal 10min of 12000r/min gets supernatant, adds chloroform: Virahol (480 μ l: 20ul), the centrifugal 10min of 12000r/min.Add the cold dehydrated alcohol deposit D NA of 1/10 volume 3M sodium-acetate and 2.5 times of volumes ,-20 ℃ are spent the night.The centrifugal 10min of 12000r/min will precipitate with 70% ethanol at last and wash twice, dry.Be dissolved in the TE damping fluid, add the DNA sample loading buffer, 2% agarose gel electrophoresis, EB dyeing is also taken a picture.
The DNA electrophoresis result is referring to Fig. 2, and swimming lane A, B, C, D, E represent DMSO respectively, compound VI Ia (0.5 μ g/ml, 1.0 μ g/ml, 2.0 μ g/ml) and positive control.The result shows that compound VI Ia can induce the HL-60 cell to go out to represent features of apoptosis DNA Ladder.
Need not further to elaborate, believe and adopt the disclosed content in front, those skilled in the art can use the present invention to greatest extent.Therefore, the preferred specific embodiments of front is interpreted as only illustrating, but not limits the scope of the invention by any way.
Claims (9)
1. polysubstituted flavane and Thiadiazoline compounds is characterized in that having following general structure:
Wherein
The A ring can be not have and replaces, single replacement or polysubstituted, R
1Be H, Cl, CH
3O-, CH
3-;
The B ring can be not have and replaces, single replacement or polysubstituted, R
2Be H, Cl, CH
3O-, CH
3-,-OCH
2O-;
R
3Be NO
2-, CH
3SO
2-, CH
3CONH-;
R
4Be CH
3-, CH
3CH
2-, CH
3CH
2CH
2-, (CH
3)
2CH-.
2. polysubstituted flavane according to claim 1 and Thiadiazoline compounds is characterized in that: target compound VI is 2-(4-nitro-2-chloro-phenyl-)-3a, 4-dialkoxy flavane [4,3-d]-Δ
1,9b-1,2,3-Thiadiazoline compounds.
3. polysubstituted flavane according to claim 1 and Thiadiazoline compounds is characterized in that: target compound VII is 2-(4-methylsulfonyl-2-chloro-phenyl-)-3a, 4-dialkoxy flavane [4,3-d]-Δ
1,9b-1,2,3-Thiadiazoline compounds.
4. polysubstituted flavane according to claim 1 and Thiadiazoline compounds is characterized in that: target compound VIII is 2-(4-acetamido-2-chloro-phenyl-)-3a, 4-dialkoxy flavane [4,3-d]-Δ
1,9b-1,2,3-Thiadiazoline compounds.
5. according to the preparation method of arbitrary described polysubstituted flavane of claim 1-4 and Thiadiazoline compounds, it is characterized in that realizing by following steps:
(1) o-hydroxyacetophenone and the aromatic aldehyde that replaces with Compound I is raw material, obtain the compound III flavanone compound through condensation with after two steps of cyclization, compound III is in protic solvent, condensation obtains compound IV flavanone-4-oil of mirbane hydrazone compounds or compound V flavanone-4-methylsulfonyl phenyl hydrazones compound with paranitrophenylhydrazine or to the methylsulfonyl phenylhydrazine in the presence of acetic acid, temperature of reaction is generally at 30-80 ℃, and the reaction times is 2-6 hour;
(2) compound IV or compound V under nitrogen protection with SOCl
2Cyclization, temperature of reaction are generally 60-80 ℃, also can carry out power 250W under ultrasonic radiation, frequency 25kHz, room temperature, the reaction times is 30 minutes, the gained intermediate product can obtain target compound VI 2-(4-nitro-2-chloro-phenyl-)-3a, 4-dialkoxy flavane [4,3-d]-Δ with the alcohol reaction again
1,9b-1,2,3-Thiadiazoline compounds or target compound VII 2-(4-methylsulfonyl-2-chloro-phenyl-)-3a, 4-dialkoxy flavane [4,3-d]-Δ
1,9b-1,2,3-Thiadiazoline compounds is reflected at 30-80 ℃ and carries out, or room temperature is carried out under ultrasonic radiation, and the reaction times is 30 minutes;
(3) can get R after the compound VI hydrogenation
3Be the intermediate of amino, need not to separate directly behind acetic anhydride acylation, to get target compound VIII 2-(4-acetamido-2-chloro-phenyl-)-3a, 4-dialkoxy flavane [4,3-d]-Δ
1,9b-1,2,3-Thiadiazoline compounds, acetylize generally adopts diacetyl oxide or Acetyl Chloride 98Min. as acylating reagent, uses pyridine catalysis, carries out at ambient temperature, and products therefrom can get pure product through column chromatography, and elution requirement is an eluent: sherwood oil: ethyl acetate.
6. the preparation method of polysubstituted flavane according to claim 5 and Thiadiazoline compounds is characterized in that: used protic solvent is selected methyl alcohol or ethanol for use in the step (1).
7. the preparation method of polysubstituted flavane according to claim 5 and Thiadiazoline compounds, it is characterized in that: used alcohol is selected in methyl alcohol, ethanol, propyl alcohol, the Virahol any for use in the step (2), products therefrom is through column chromatography, and eluent: sherwood oil: ethyl acetate gets pure product.
8. the preparation method of polysubstituted flavane according to claim 5 and Thiadiazoline compounds is characterized in that: hydrogenation is selected palladium carbon or raney ni catalysis for use in the step (3).
9. the application in the preparation antitumor drug of polysubstituted flavane according to claim 1 and Thiadiazoline compounds.
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| CN102391272B (en) * | 2011-09-30 | 2014-07-02 | 浙江工业大学 | 1,4-disubstituent-1,4-dihydrobenzopranyl [4,3-c] pyrazole compounds |
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