CN102757435B - Trans-3-indolyl-4-pyrroldiazepinecycloheptane-2,5-pyrrolidine-2,5-diketone compound and preparation method thereof - Google Patents
Trans-3-indolyl-4-pyrroldiazepinecycloheptane-2,5-pyrrolidine-2,5-diketone compound and preparation method thereof Download PDFInfo
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- NTEIVXIVZRCPJD-UHFFFAOYSA-N CC(C)(C)OC(N1C[n](cc2)c3c2cccc3CC1)=O Chemical compound CC(C)(C)OC(N1C[n](cc2)c3c2cccc3CC1)=O NTEIVXIVZRCPJD-UHFFFAOYSA-N 0.000 description 1
- SFXPRWVUNDBYDK-UHFFFAOYSA-N CC(C)(C)OC(NCCc1cccc2c1[nH]cc2)=O Chemical compound CC(C)(C)OC(NCCc1cccc2c1[nH]cc2)=O SFXPRWVUNDBYDK-UHFFFAOYSA-N 0.000 description 1
- JRWUXZQPAULKLR-UHFFFAOYSA-N NCCc1cccc2c1[nH]cc2 Chemical compound NCCc1cccc2c1[nH]cc2 JRWUXZQPAULKLR-UHFFFAOYSA-N 0.000 description 1
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Abstract
The invention relates to the field of chemical synthesis of medicaments, in particular to a trans-3-indolyl-4-pyrroldiazepinecycloheptane-2,5-pyrrolidine-2,5-diketone compound and a preparation method thereof. Research trails on the tumor suppression effect of tumor-bearing mice find that the compound has an obvious tumor suppression effect and can be applied to preparation of anti-tumor medicaments.
Description
Technical field
The present invention relates to the synthetic field of pharmaceutical chemistry, be specifically related to a kind of trans-3-indyl-4-indoles diazepine suberane base-2,5-tetramethyleneimine-2,5-dione compounds and preparation method thereof.
Background technology
Cancer (cancer), medical terminology also claims malignant tumour (malignant neoplasm), cancer cells is defined as again heterology cell.Due to factors such as people's environment and lifestyle changes, morbidity and the mortality ratio of cancer constantly raise at present.In fact, tumour replaces cardiovascular and cerebrovascular diseases gradually becomes global No.1 killer, and the sickness rate ascendant trend of China's malignant tumour is especially swift and violent.Show according to investigations, the morbidity of China's cancer increases with annual 3%-5% speed at present, more than annual tumour new cases approximately have 2,200,000 people, and wherein with liver cancer, lung cancer, these three high morbidities of cancer of the stomach are main.
The generation of cancer has many-sided reason, but the method for the treatment of at present cancer is mainly divided into three major types: surgical resection, the chemotherapy (chemotherapy) of local radiation treatment (radiotherapy) and use medicine.In the time that malignant tumour is only confined to a certain organ or tissue of health, can adopts excision or local radiation to treat, but in the time that cancer cells infringement scope is large or long-range transfer occurs cancer cells, just need chemotherapy.
But cancer therapy drug also can suppress Normocellular growth in killing cancer cells, and therefore most medicine has certain side effect.For example,, if novantrone uses excessive meeting to cause cardiac failure; Cisplatin has renal toxicity; Bleomycin can cause pulmonary fibrosis, the cyclophosphamide of the high dosage cystitis that can cause bleeding; Oncovin and taxol taxol have nervus peripheralis toxicity etc.Because these medicines have certain limitation at anti-tumor aspect, therefore novel antitumor class targeting preparation will become the study hotspot in this field.The present invention is a kind of novel antineoplastic target medicine going out based on this type of drug research.
The growth of cell and differentiation are by signal factor control, and when the cell protein of the carrying signal factor is undergone mutation, the growth of cell and differentiation will produce variation, thereby cause the generation of cancer cells.In this process, find the imbalance of receptor tyrosine kinase and the generation of human cancer and developed relevant.So far, c-Met receptor tyrosine kinase is the high-affinity receptor of known unique pHGF (HGF) that is called as scattering factor (scatter factor).C-Met and HGF normally in conjunction with time, signal factor will impel cell normal growth and differentiation, once c-Met and HGF imbalance, signal conduction will be out of control, impels the generation of cancer cells, propagates and diffusion.The compounds of this invention is a kind of orally active small molecules c-Met receptor tyrosine kinase inhibitors, by regulating c-Met receptor tyrosine kinase to reach the effect for the treatment of tumor disease.It is wide that this compound demonstrates antitumor spectrum, determined curative effect, and the feature such as untoward reaction is lighter, and patient tolerability is good, is a kind of novel antineoplastic target medicine.
Summary of the invention
The object of the present invention is to provide the one with pharmaceutical use that a class is new trans-3-indyl-4-indoles diazepine suberane base-2,5-tetramethyleneimine-2,5-dione compounds and preparation method thereof.
The present invention is specifically related to the compound shown in general formula I structure below:
Wherein, R is monose or oligosaccharides.
In the present invention, monose specifically refers to seminose, fructose, ribose, ribodesose, glucose, semi-lactosi, wood sugar, sorbose or pectinose.
Monose specifically refers to D-ribose, D-ribodesose ,-D-Glucose, D-semi-lactosi, D-wood sugar or D-R.
In the present invention, oligosaccharides specifically refers to lactose, sucrose, maltose, raffinose, stachyose, trehalose, melibiose, gentiobiose, cellobiose, gentianose, melizitose, acacia trisaccharide and trisaccharide maltose.
The compound with formula I structure the present invention relates to, wherein preferred compound is:
(3R, 4R)-3-(1H-indol-3-yl)-4-(5-((2R, 3R, 4S, 5S, 6R)-3,4,5-trihydroxy--6-(methylol) tetrahydrochysene-2H-pyrans-2-yl)-4,5,6,7-tetrahydrochysene [1,3] diazepine is [6,7,1-hi] indoles-1-yl also) tetramethyleneimine-2,5-diketone;
(3R, 4R)-3-(5-((2R, 3R, 4R, 5S, 6R)-3,4-dihydroxyl-6-(methylol)-5-(((2S, 3R, 4S, 5S, 6R)-3,4,5-trihydroxy--6-(methylol) tetrahydrochysene-2H-pyrans-2-yl) oxo) tetrahydrochysene-2H-pyrans-2-yl)-4,5,6,7-tetrahydrochysene [1,3] diazepine also [6,7,1-hi] indoles-1-yl)-4-(1H-indol-3-yl) tetramethyleneimine-2,5-diketone;
(3R, 4R)-3-(1H-indol-3-yl)-4-(5-((2R, 3R, 4S, 5S, 6R)-3,4,5-trihydroxy--6-(((2S, 3R, 4S, 5S, 6R)-3,4,5-trihydroxy--6-(methylol) tetrahydrochysene-2H-pyrans-2-yl) oxo) methyl) tetrahydrochysene-2H-pyrans-2-yl)-4,5,6,7-tetrahydrochysene [1,3] diazepine also [6,7,1-hi] indoles-1-yl) tetramethyleneimine-2,5-diketone;
(3R, 4R)-3-(5-((2R, 3R, 4R, 5S, 6R)-5-(((2S, 3R, 4R, 5S, 6R)-3,4-dihydroxyl-6-(methylol)-5-(((2S, 3R, 4S, 5S, 6R)-3,4,5-trihydroxy--6-(methylol) tetrahydrochysene-2H-pyrans-2-yl) oxo) tetrahydrochysene-2H-pyrans-2-yl) oxo)-3,4-dihydroxyl-6-(methylol) tetrahydrochysene-2H-pyrans-2-yl)-4,5,6,7-tetrahydrochysene [1,3] diazepine also [6,7,1-hi] indoles-1-yl)-4-(1H-indol-3-yl) tetramethyleneimine-2,5-diketone.
Another object of the present invention is to disclose a kind of trans-3-indyl-4-indoles diazepine suberane base-2,5-tetramethyleneimine-2, the preparation method of 5-dione compounds:
Preparation process specifically comprises the following steps:
(1) 7-formyl indole and diethyl phosphorocyanidate are dissolved in tetrahydrofuran (THF), ether, methylene dichloride or toluene equal solvent; add the lithium salts such as lithium cyanide, lithium chloride or the lithiumbromide of catalytic amount; after having reacted; add again the alcoholic solvent such as Virahol or the trimethyl carbinol; finally by mixed solution under-5 ~ 10 ° of C, be slowly added drop-wise in tetrahydrofuran (THF), ether, methylene dichloride or the toluene solvant of means of samarium iodide and obtain intermediate 2.
(2) intermediate 2 is under the catalysis such as Raney's nickel or palladium carbon, and in alcoholic solvent, under 30 ~ 80psi hydrogen pressure, 0 ~ 30 ° of C reaction obtains intermediate 3.
(3) intermediate 3 is dissolved in dry tetrahydrofuran (THF), acetonitrile or methylene dichloride equal solvent, then add triethylamine, the alkali such as diisopropyl ethyl amine or sodium hydroxide, finally add tert-Butyl dicarbonate (11.7g, 52.5mmol) be dissolved in the mixed solution of tetrahydrofuran (THF), acetonitrile or methylene dichloride equal solvent, 0 ~ 30 ° of C reaction obtains intermediate 4.
(4) intermediate 4 and paraformaldehyde, in dry toluene, dimethylbenzene, DMF or DMSO solvent, are heated to 100 ~ 150 ° of C stirrings and within 10 ~ 20 hours, obtain intermediate 5.
(5) under-5 ~ 10 ° of C, intermediate 5 and oxalyl chloride are mixed in anhydrous tetrahydro furan, ether, methylene dichloride or toluene equal solvent, then add the alkali alcosols such as sodium methylate, sodium ethylate or sodium tert-butoxide, 0 ~ 30 ° of C reaction obtains intermediate 6.
(6) intermediate 6 and indole-3-acetamide (intermediate 7) are in anhydrous tetrahydro furan ether, methylene dichloride or toluene equal solvent, and with organic bases processing such as potassium tert.-butoxide, sodium methylate, sodium ethylate or sodium tert-butoxides, 0 ~ 25 ° of C reaction obtains intermediate 8.
(7) by magnesium chips and intermediate 8 in the alcoholic solvents such as dehydrated alcohol, reflux 2 ~ 5 hours, obtains racemoid intermediate 9.
(8) use
the chiral columns such as (Daicel, U.S.A.) 20mm × 250mm, with supercritical fluid chromatography preparation, obtain trans-compound intermediate 10.
(9) under-5 ~ 10 ° of C, the solution forming in alcoholic solvent to intermediate 10 passes into dry hydrogen chloride gas, obtains intermediate 11 after 3 ~ 8 hours.
(10) intermediate 11 and a kind of monose or oligosaccharides are dissolved in alcoholic solvent, within reflux 20-48 hour, obtain Compound I.
The present invention is by the research trial of tumor-bearing mice tumor-inhibiting action is found, the compounds of this invention tumor killing effect is remarkable, can be used as the purposes of preparation treatment antitumor drug.
Embodiment
Below in conjunction with embodiment, the present invention is described in further detail, but limitation of the present invention not, all any this areas of doing according to the disclosure of invention be equal to replacement, all belong to protection scope of the present invention.
In embodiment, room temperature refers to the envrionment temperature of 10 to 25 ℃.
Embodiment 1 intermediate 2-(1H-indoles-7-yl) preparation of acetonitrile
In dry there-necked flask, add 7-formyl indole (14.8g, 100mmol) and dry tetrahydrofuran (THF) (300ml), then add successively lithium cyanide (350mg; 10mmol) and diethyl phosphorocyanidate (19.7ml; 130mmol), finish stirred overnight at room temperature.After TLC detection reaction completes, add the trimethyl carbinol (10.0ml, 100mmol) to stir 30 minutes.Under room temperature, mixed solution is slowly added drop-wise in the means of samarium iodide tetrahydrofuran solution of 0.1M (3.0L, 300mmol).Finish, continue to stir 30 minutes.By this mixed solution evaporated under reduced pressure, add after 2 liters of ethyl acetate are diluted and proceed to separating funnel, with the dilute hydrochloric acid (500ml × 3) of 1N, saturated sodium bicarbonate (500ml × 2) and saturated aqueous common salt (500ml) washing.Anhydrous magnesium sulfate drying, filter, be spin-dried for.Residue is purified with silica gel chromatographic column, obtains off-white color solid 2-(1H-indoles-7-yl with ethyl acetate/hexane (1:1) wash-out) acetonitrile (8.7g, 56%).
1H-NMR(400MHz,DMSO-d
6)δ：10.07(brs,1H),7.51(d,J＝7.5Hz,1H),7.28(d,J＝3Hz,1H),7.09(d,J＝7.5Hz,1H),6.99(dd,J＝7.5Hz,7.5Hz,1H),6.43(d,J＝3Hz,1H),4.58(s,2H)。
Embodiment 2 intermediate 2-(1H-indoles-7-yls) preparation of ethamine
To the 2-(1H-indoles-7-yl that adds embodiment 1 to prepare in 1 liter of autoclave) acetonitrile (8.5g, 53.8mmol), methyl alcohol (300ml) solution of Raney's nickel (8.5g) and ammonia (3.6g).Pass into hydrogen, keeping pressure is 340 kPas (50psi), stirred overnight at room temperature.After having reacted, remove by filter Raney's nickel, evaporated under reduced pressure, debris, with ethyl acetate/water (1:1,500ml) dilution, stirs separatory after 15 minutes.Organic layer is with saturated aqueous common salt (100ml × 2) washing, anhydrous sodium sulfate drying, filters, is spin-dried for and to obtain light yellow oily 2-(1H-indoles-7-yl) ethamine (8.1g, 94%).LCMS（M+H）=161。Embodiment 3 intermediate 2-(1H-indoles-7-yls) preparation of the ethyl carbamic acid tert-butyl ester
Under nitrogen protection; to the 2-(1H-indoles-7-yl that adds embodiment 2 to prepare in dry there-necked flask) ethamine (8.4g; 52.5mmol), dry tetrahydrofuran (THF) (200ml) and triethylamine (13.4g; 131.2mmol); under stirring; slowly dropping tert-Butyl dicarbonate (11.7g, 52.5mmol) is dissolved in the mixed solution of tetrahydrofuran (THF) (100ml).Finish stirring at room temperature 6 hours.After TLC detection reaction completes, by this mixed solution evaporated under reduced pressure, add after 300ml ethyl acetate is diluted and proceed to separating funnel, with saturated sodium bicarbonate (100ml × 2) and saturated aqueous common salt (100ml) washing.Anhydrous sodium sulfate drying, filter, be spin-dried for and to obtain white solid 2-(1H-indoles-7-yl) the ethyl carbamic acid tert-butyl ester (12.4g, 91%).LCMS（M+H）=261。
Embodiment 4 intermediates 6,7-dihydro-[1,3] diazepine is the preparation of [6,7,1-hi] indoles-5 (4H) t-butyl formate also
Under nitrogen protection, to the 2-(1H-indoles-7-yl that adds embodiment 3 to prepare in dry there-necked flask) the ethyl carbamic acid tert-butyl ester (11.7g, 45.3mmol) and dry toluene (100ml).After stirring, add paraformaldehyde (1.4g, 45.3mmol), be heated to 110 ° of C and stir 15 hours.After TLC detection reaction completes, by this mixed solution evaporated under reduced pressure, residual solids obtains white needles solid 6 with ether-hexane recrystallization, and 7-dihydro-[1,3] diazepine is [6,7,1-hi] indoles-5 (4H) t-butyl formate (10.0g, 81%) also.LCMS（M+H）=273。
Embodiment 5 intermediate 7-methoxy methyl acyl group-6,7-dihydro-[1,3] diazepine is the preparation of [6,7,1-hi] indoles-5 (4H) t-butyl formate also
Under 0 ° of C, prepare to embodiment 46,7-dihydro-[1,3] also [6,7,1-hi] indoles-5 (4H) t-butyl formate (9.7g of diazepine, in anhydrous tetrahydro furan (200ml) solution 35.6mmol), slowly add oxalyl chloride (12.6ml, 142.4mmol).0 ° of C stirs until raw material disappears, and then this mixture is cooled to-78 ° of C, slowly adds the methanol solution (0.5M) of sodium methylate (215.0ml).Finish, mixed solution rises to stirring at room temperature.Evaporated under reduced pressure solvent after 1 hour, debris is diluted with ethyl acetate (200ml) and is used saturated aqueous common salt (50ml × 2) to wash.Organic layer is with anhydrous sodium sulfate drying, filtration, evaporate to dryness.Residue is purified with silica gel chromatographic column, obtains light yellow solid 7-methoxy methyl acyl group-6 with ethyl acetate/hexane (1:1) wash-out, and 7-dihydro-[1,3] diazepine is [6,7,1-hi] indoles-5 (4H) t-butyl formate (9.1g, 72%) also.LCMS（M+H）=359。
Embodiment 6 intermediate 7-[4-(1H-indol-3-yls)-2,5-dioxo-2,5-dihydro-1H-pyrroles-3-yl]-6,7-dihydro-[1,3] diazepine is the preparation of [6,7,1-hi] indoles-5 (4H) t-butyl formate also
Under 0 ° of C; 7-methoxy methyl acyl group-6 of preparing to embodiment 5; 7-dihydro-[1; 3] diazepine also [6; 7,1-hi] indoles-5 (4H) t-butyl formates (8.6g, 24.0mmol) and indole-3-acetamide (4.7g; in anhydrous tetrahydro furan (250ml) solution 26.4mmol), slowly add potassium tert.-butoxide (8.5g, 72.0mmol).0 ° of C stirs after 3 hours and adds concentrated hydrochloric acid (20.0ml), and this mixture at room temperature stirs evaporated under reduced pressure after 2 hours.Residue dilutes with ethyl acetate (250ml) and uses saturated aqueous common salt (100ml) to wash.Organic layer is with anhydrous sodium sulfate drying, filtration, evaporate to dryness.Residue is purified with silica gel chromatographic column, obtain carmetta solid 7-[4-(1H-indol-3-yl with ethyl acetate/hexane (1:1) wash-out)-2,5-dioxo-2,5-dihydro-1H-pyrroles-3-yl]-6,7-dihydro-[1,3] diazepine also [6,7,1-hi] indoles-5 (4H) t-butyl formates (11.5g, 78%).
1H-NMR(400MHz,DMSO-d
6)δ：11.67(d,J＝2.4Hz,1H),10.94(s,1H),7.69-7.75(m,2H),7.19-7.38(m,3H),6.73-6.89(m,2H),6.60-6.69(m,2H),5.11-5.68(m,2H),4.12(m,2H),2.95(m,2H),1.42(s,9H)。
Embodiment 7 intermediates (±)-trans-7-[4-(1H-indol-3-yl)-2,5-dioxo-2,5-dihydro-1H-pyrrolidin-3-yl]-6,7-dihydro-[1,3] diazepine is the preparation of [6,7,1-hi] indoles-5 (4H) t-butyl formate also
Under nitrogen protection; by magnesium chips (0.9g; 36.0mmol) join 7-[4-(1H-indol-3-yl prepared by embodiment 6)-2,5-dioxo-2,5-dihydro-1H-pyrroles-3-yl]-6; 7-dihydro-[1; 3] also [6,7,1-hi] indoles-5 (4H) t-butyl formate (8.7g of diazepine; in anhydrous methanol (100ml) solution 18.0mmol), reflux 2 hours.After cool to room temperature, solvent evaporated, residue is to dilute with ethyl acetate (300ml) and to use 1M hydrochloric acid (100ml × 2) and salt solution (100ml) to wash.Organic layer is with anhydrous sodium sulfate drying, filtration, evaporate to dryness.Residue is purified with silica gel chromatographic column, obtain the white solid of class (±)-trans-7-[4-(1H-indol-3-yl with ethyl acetate/hexane (2:1) wash-out)-2,5-dioxo-2,5-dihydro-1H-pyrrolidin-3-yl]-6,7-dihydro-[1,3] diazepine also [6,7,1-hi] indoles-5 (4H) t-butyl formates (7.0g, 80.6%).LCMS（M+H）=485。
Embodiment 8(3R, 4R)-7-[4-(1H-indol-3-yl)-2,5-dioxo-2,5-dihydro-1H-pyrrolidin-3-yl]-6,7-dihydro-[1,3] diazepine also [6,7,1-hi] indoles-5 (4H) t-butyl formate and (3S, 4S)-7-[4-(1H-indol-3-yl)-2,5-dioxo-2,5-dihydro-1H-pyrrolidin-3-yl]-6,7-dihydro-[1,3] diazepine also [6,7,1-hi] chromatographic separation of indoles-5 (4H) t-butyl formate
By (±)-trans-7-[4-(1H-indol-3-yl)-2,5-dioxo-2,5-dihydro-1H-pyrrolidin-3-yl]-6,7-dihydro-[1,3] diazepine also [6,7,1-hi] indoles-5 (4H) t-butyl formates (7.0g) are dissolved in acetonitrile (20ml), mixture with
the preparation of post (Daicel, U.S.A.) 20mm × 250mm supercritical fluid chromatography, with 45% methyl alcohol/CO
2with the flow velocity wash-out of 4.0mL/ minute.Obtained very fast elution peak at 5.05 minutes, there is the trans-isomer(ide) (3.1g) of negative rotation luminosity, for (-)-(3R, 4R)-7-[4-(1H-indol-3-yl)-2,5-dioxo-2,5-dihydro-1H-pyrrolidin-3-yl]-6,7-dihydro-[1,3] also [6,7,1-hi] indoles-5 (4H) t-butyl formate of diazepine; Obtained slower elution peak at 6.25 minutes, there is the trans-isomer(ide) (3.4g) of dextrorotation luminosity, for (+)-(3S, 4S)-7-[4-(1H-indol-3-yl)-2,5-dioxo-2,5-dihydro-1H-pyrrolidin-3-yl]-6,7-dihydro-[1,3] also [6,7,1-hi] indoles-5 (4H) t-butyl formate of diazepine.The only relative retention time based on related compound of absolute stereo chemistry ownership, and may be contrary.The measurement of all specific rotatioies is to carry out in 25 ° of C, 589nm and chloroform.
Embodiment 9 intermediate (3R, 4R)-7-[4-(1H-indol-3-yls)-4-(4,5,6,7-tetrahydrochysene [1,3] diazepine is [6,7,1-hi] indoles-1-yl also) and tetramethyleneimine-2, the preparation of 5-diketone
Under 0 ° of C, to (3R, 4R)-7-[4-(1H-indol-3-yl)-2,5-dioxo-2,5-dihydro-1H-pyrrolidin-3-yl]-6,7-dihydro-[1,3] also [6,7,1-hi] indoles-5 (4H) t-butyl formate (3.1g of diazepine, in methyl alcohol (65ml) solution 6.4mmol), pass into dry hydrogen chloride gas, evaporated under reduced pressure solvent after 5 hours.Residue joins on 50gDowex 50W H+ type cation exchange resin column after with a small amount of water dissolution, first with pure water wash-out, after effluent liquid is neutrality, elute product with methyl alcohol/ammoniacal liquor (1:1) again, be spin-dried for solvent and obtain white powder (3R, 4R)-7-[4-(1H-indol-3-yl)-4-(4,5,6,7-tetrahydrochysene [1,3] diazepine also [6,7,1-hi] indoles-1-yl) tetramethyleneimine-2,5-diketone (2.3g, 94%).LCMS（M+H）=385。
Embodiment 10 compound (3R, 4R)-3-(1H-indol-3-yls)-4-(5-((2R, 3R, 4S, 5S, 6R)-3,4,5-trihydroxy--6-(methylol) tetrahydrochysene-2H-pyrans-2-yl)-4,5,6,7-tetrahydrochysene [1,3] diazepine also [6,7,1-hi] indoles-1-yl) tetramethyleneimine-2, the preparation of 5-diketone (Ia)
To (3R, 4R)-7-[4-(1H-indol-3-yl)-4-(4,5,6,7-tetrahydrochysene [1,3] diazepine is [6,7,1-hi] indoles-1-yl also) tetramethyleneimine-2, in methyl alcohol (4ml) solution of 5-diketone (159 milli g, 0.41mmol), add alpha-D-glucose, reflux 22 hours.React rear solvent evaporated, purified with silica gel column chromatography, obtained orange solid (3R with methyl alcohol/chloroform (1:7) wash-out, 4R)-3-(1H-indol-3-yl)-4-(5-((2R, 3R, 4S, 5S, 6R)-3,4,5-trihydroxy--6-(methylol) tetrahydrochysene-2H-pyrans-2-yl)-4,5,6,7-tetrahydrochysene [1,3] diazepine also [6,7,1-hi] indoles-1-yl) tetramethyleneimine-2,5-diketone (183 milli g, 82%).
1H-NMR(400MHz,DMSO-d
6)δ：11.69(d，J＝2.4Hz，1H),10.97(s,1H),7.69-7.75(m,2H),7.20-7.39(m,3H),6.77-6.89(m,2H),6.63-6.71(m,2H),6.28(d,J=8.8Hz,1H),6.01(t,J=4.0Hz,1H),5.11-5.68(m,4H),4.92(d,J=5.3Hz,1H,),4.49(dd,J＝7.2Hz,20Hz,2H),4.15(m,2H),2.95(m,2H),4.06-4.10(m,2H),3.95-4.01(m,2H),3.81-3.84(m,1H),3.54-3.59(m,1H)。
Embodiment 11 compound (3R, 4R)-3-(5-((2R, 3R, 4R, 5S, 6R)-3,4-dihydroxyl-6-(methylol)-5-(((2S, 3R, 4S, 5S, 6R)-3,4,5-trihydroxy--6-(methylol) tetrahydrochysene-2H-pyrans-2-yl) oxo) tetrahydrochysene-2H-pyrans-2-yl)-4,5,6,7-tetrahydrochysene [1,3] diazepine also [6,7,1-hi] indoles-1-yl)-4-(1H-indol-3-yl) tetramethyleneimine-2, the preparation of 5-diketone (Ib)
Make (3R according to embodiment 1 ~ 9 method, 4R)-7-[4-(1H-indol-3-yl)-4-(4, 5, 6, 7-tetrahydrochysene [1, 3] diazepine also [6, 7, 1-hi] indoles-1-yl) tetramethyleneimine-2, 5-diketone, according to the step of embodiment 10, replace D-Glucose preparation (3R with D-Maltose, 4R)-3-(5-((2R, 3R, 4R, 5S, 6R)-3, 4-dihydroxyl-6-(methylol)-5-(((2S, 3R, 4S, 5S, 6R)-3, 4, 5-trihydroxy--6-(methylol) tetrahydrochysene-2H-pyrans-2-yl) oxo) tetrahydrochysene-2H-pyrans-2-yl)-4, 5, 6, 7-tetrahydrochysene [1, 3] diazepine also [6, 7, 1-hi] indoles-1-yl)-4-(1H-indol-3-yl) tetramethyleneimine-2, 5-diketone.
1H-NMR(400MHz,DMSO-d
6)δ：11.65(d，J＝2.4Hz，1H),10.91(s,1H),7.69-7.76(m,2H),7.19-7.39(m,3H),6.74-6.879(m,2H),6.60-6.69(m,2H),6.36(d,J=9.0Hz,1H),6.04(bs,1H),5.72(bs,1H),5.11-5.68(m,7H),4.69(bs,1H),4.51(dd,J＝7.2Hz,20Hz,2H),4.26(bd,J=9.6Hz,1H,),4.16-4.21(m,2H),4.12(m,2H),3.92(t,J=8.4Hz,1H),3.84(bd,J=10.7Hz,1H),3.78(d,J=11.0Hz,1H),3.66-3.69(m,1H),3.55-3.63(m,3H),3.50(t,J=9.1Hz,1H),3.34-3.36(m,1H),3.15(t,J=9.4Hz,1H),2.95(m,2H)。
Embodiment 12 compound (3R, 4R)-3-(1H-indol-3-yls)-4-(5-((2R, 3R, 4S, 5S, 6R)-3,4,5-trihydroxy--6-(((2S, 3R, 4S, 5S, 6R)-3,4,5-trihydroxy--6-(methylol) tetrahydrochysene-2H-pyrans-2-yl) oxo) methyl) tetrahydrochysene-2H-pyrans-2-yl)-4,5,6,7-tetrahydrochysene [1,3] diazepine also [6,7,1-hi] indoles-1-yl) tetramethyleneimine-2, the preparation of 5-diketone (Ic)
Make (3R according to embodiment 1 ~ 9 method, 4R)-7-[4-(1H-indol-3-yl)-4-(4, 5, 6, 7-tetrahydrochysene [1, 3] diazepine also [6, 7, 1-hi] indoles-1-yl) tetramethyleneimine-2, 5-diketone, according to the step of embodiment 10, replace D-Glucose preparation (3R with D-melibiose, 4R)-3-(1H-indol-3-yl)-4-(5-((2R, 3R, 4S, 5S, 6R)-3, 4, 5-trihydroxy--6-(((2S, 3R, 4S, 5S, 6R)-3, 4, 5-trihydroxy--6-(methylol) tetrahydrochysene-2H-pyrans-2-yl) oxo) methyl) tetrahydrochysene-2H-pyrans-2-yl)-4, 5, 6, 7-tetrahydrochysene [1, 3] diazepine also [6, 7, 1-hi] indoles-1-yl) tetramethyleneimine-2, 5-diketone.
1H-NMR(400MHz,DMSO-d
6)δ：11.66(d，J＝2.4Hz，1H),10.90(s,1H),7.72-7.78(m,2H),7.20-7.39(m,3H),6.70-6.88(m,2H),6.63-6.72(m,2H),6.36(d,J=8.5Hz,1H),5.13-5.69(m,2H),4.87(bs,1H),4.47(dd,J=7.2Hz,20Hz,2H),4.15-4.18(m,3H),4.09(dd,J=11.5Hz,4.7Hz,1H),4.05(bt,J=8.8Hz,1H),3.94(dd,J=11.5Hz,2.2Hz,1H),3.84-3.86(m,2H),3.79-3.81(m,2H),3.69(bd,J=1.4Hz,2H),3.57(dd,J=11.1Hz,5.6Hz,1H),3.50(dd,J=11.1Hz,5.8Hz,1H),3.24(s,3H),2.90(m,2H)。
Embodiment 13_ compound (3R, 4R)-3-(5-((2R, 3R, 4R, 5S, 6R)-5-(((2S, 3R, 4R, 5S, 6R)-3, 4-dihydroxyl-6-(methylol)-5-(((2S, 3R, 4S, 5S, 6R)-3, 4, 5-trihydroxy--6-(methylol) tetrahydrochysene-2H-pyrans-2-yl) oxo) tetrahydrochysene-2H-pyrans-2-yl) oxo)-3, 4-dihydroxyl-6-(methylol) tetrahydrochysene-2H-pyrans-2-yl)-4, 5, 6, 7-tetrahydrochysene [1, 3] diazepine also [6, 7, 1-hi] indoles-1-yl)-4-(1H-indol-3-yl) tetramethyleneimine-2, the preparation of 5-diketone (Id)
Make (3R according to embodiment 1 ~ 9, 4R)-7-[4-(1H-indol-3-yl)-4-(4, 5, 6, 7-tetrahydrochysene [1, 3] diazepine also [6, 7, 1-hi] indoles-1-yl) tetramethyleneimine-2, 5-diketone, according to the step of embodiment 10, replace D-Glucose preparation (3R with D-trisaccharide maltose, 4R)-3-(5-((2R, 3R, 4R, 5S, 6R)-5-(((2S, 3R, 4R, 5S, 6R)-3, 4-dihydroxyl-6-(methylol)-5-(((2S, 3R, 4S, 5S, 6R)-3, 4, 5-trihydroxy--6-(methylol) tetrahydrochysene-2H-pyrans-2-yl) oxo) tetrahydrochysene-2H-pyrans-2-yl) oxo)-3, 4-dihydroxyl-6-(methylol) tetrahydrochysene-2H-pyrans-2-yl)-4, 5, 6, 7-tetrahydrochysene [1, 3] diazepine also [6, 7, 1-hi] indoles-1-yl)-4-(1H-indol-3-yl) tetramethyleneimine-2, 5-diketone.
1H-NMR(400MHz,DMSO-d
6)δ：11.65(d，J＝2.4Hz，1H),10.89(s,1H),7.66-7.70(m,2H),7.17-7.39(m,3H),6.70-6.859(m,2H),6.60-6.67(m,2H),6.33(d,J=9.1Hz,1H),6.06(t,J=3.8Hz,1H),5.70(d,J=3.6Hz,1H),5.12-5.67(m,6H),5.09(d,J=5.7Hz,1H),5.05(d,J=3.7Hz,1H),4.93(d,J=6.1Hz,1H),4.91(d,J=6.1Hz,1H),4.68(t,J=5.5Hz,1H),4.55(t,J=5.6Hz,1H),4.48(dd,J＝7.2Hz,20Hz,2H),4.15-4.20(m,3H),4.13(m,2H),3.90(td,J=8.3Hz,3.3Hz,1H),3.64-3.84(m,7H),3.59(ddd,J=14.7Hz,9.0Hz,5.7Hz,1H),3.36-3.54(m,3H),3.24-3.29(m,2H),3.20(s,3H),3.09(ddd,J=14.9Hz,9.2Hz,5.7Hz,1H),2.93(m,2H)。
The research of test example to tumor-bearing mice tumor-inhibiting action
One, laboratory animal and knurl strain
Kunming mouse, female, weight 18-22g, is provided by plant of laboratory animal special commission of Sichuan Province.S
180and H
22knurl strain is provided by Ai Yan bio tech ltd, Shanghai.
Two, experimental technique
Belly inoculation S is got respectively in the foundation of bearing mouse model
180and H
22the kind mouse of knurl strain 7d, de-neck is put to death, and under aseptic condition, extracts ascites, and after washed twice, adjusting oncocyte concentration by stroke-physiological saline solution is 1 × 10
7cells/ml.
Grouping and administration (1) are got 60 mouse in right oxter inoculation S
180after oncocyte liquid 0.1ml, be divided at random 6 groups, 10 every group.Be respectively lotus knurl control group, embodiment 10,11,12,13 compound groups and positive control drug endoxan (CTX) group.Administration next day after inoculation oncocyte liquid, lotus knurl control group gavage equivalent physiological saline; The not oral 20mg/kg of embodiment 10,11,12,13 compound component; Positive controls (CTX ip 100mg/kg).Each group administration every day 1 time, successive administration 14d;
(2) get 60 mouse in right oxter inoculation H
22after oncocyte liquid 0.1ml, be divided at random 6 groups, 10 every group.Be respectively lotus knurl control group, embodiment 10,11,12,13 compound groups and positive control drug endoxan (CTX) group.Administration next day after inoculation oncocyte liquid, lotus knurl control group gavage equivalent physiological saline; The not oral 20mg/kg of embodiment 10,11,12,13 compound component; Positive controls (CTX ip 100mg/kg).Each group administration every day 1 time, successive administration 14d.
Tumour inhibiting rate and body weight have a net increase of length
The administration of each group mouse last is put to death next day, accurately weighs Mouse Weight, completely peels off tumour and claims knurl weight, calculates each group of tumour inhibiting rate, the scale of construction have a net increase of Changke number by formula.
The average knurl of tumour inhibiting rate (%)=(the average knurl weight of the average knurl weight-administration of model group group)/model group heavy × 100%
Body weight has a net increase of front body weight (the g)-tumor weight (g) of rear body weight (the g)-experiment of long (g)=experiment
Three, experimental result
To S
180the impact of tumor-bearing mice tumor growth and body weight
With control group comparison, heavy obviously reduce (P<0.05) of embodiment 10,11,12,13 compound group knurls, tumour inhibiting rate is between 41.32% ~ 47.93%; Body weight has a net increase of long significantly (P<0.05); Endoxan positive controls tumor suppression is remarkable, and tumour inhibiting rate is 36.36%, but body weight gain is few.
Table 1 is to S
180tumor-bearing mice tumor growth restraining effect
| Group | Number of animals | Knurl heavy (g) | Tumour inhibiting rate (%) | Body weight has a net increase of long (g) |
| Lotus knurl control group | 10 | 121±036 | / | 2.17±0.45 |
| Embodiment 10 compounds | 10 | 0.64±0.23 a | 47.11 | 4.76±1.53 a |
| Embodiment 11 compounds | 10 | 0.71±0.29 a | 41.32 | 4.22±1.87 a |
| Embodiment 12 compounds | 10 | 0.69±0.31 a | 42.98 | 4.55±1.32 a |
| Embodiment 13 compounds | 10 | 0.63±0.25 a | 47.93 | 5.01±2.52 a |
| Endoxan group | 10 | 0.77±0.17 a | 36.36 | 1.43±0.11 |
A:P < 0.05, with the comparison of physiological saline group.
To H
22the impact of tumor-bearing mice tumor growth and body weight
With control group comparison, heavy obviously reduce (P<0.05) of embodiment 10,11,12,13 compound group knurls, tumour inhibiting rate is between 30.56% ~ 37.96%; Body weight has a net increase of long significantly (P<0.05); Endoxan positive controls tumor suppression is remarkable, and tumour inhibiting rate is 25%, but body weight gain is few.
Table 2 is to H
22tumor-bearing mice tumor growth restraining effect
| Group | Number of animals | Knurl heavy (g) | Tumour inhibiting rate (%) | Body weight has a net increase of long (g) |
| Lotus knurl control group | 10 | 1.08±0.12 | / | 0.63±0.07 |
| Embodiment 10 compounds | 10 | 0.71±0.23 a | 34.26 | 2.14±0.45 a |
| Embodiment 11 compounds | 10 | 0.68±0.31 a | 37.04 | 1.98±0.24 a |
| Embodiment 12 compounds | 10 | 0.75±0.28 a | 30.56 | 2.47±0.76 a |
| Embodiment 13 compounds | 10 | 0.67±0.22 a | 37.96 | 1.87±0.53 a |
| Endoxan group | 10 | 0.81±0.34 a | 25.00 | 0.23±0.03 b |
A:P < 0.05, with the comparison of lotus knurl control group; B:P < 0.05, with the comparison of lotus knurl control group.
Claims (2)
1. compound as follows:
(3R, 4R)-3-(1H-indol-3-yl)-4-(5-((2R, 3R, 4S, 5S, 6R)-3,4,5-trihydroxy--6-(methylol) tetrahydrochysene-2H-pyrans-2-yl)-4,5,6,7-tetrahydrochysene [1,3] diazepine is [6,7,1-hi] indoles-1-yl also) tetramethyleneimine-2,5-diketone;
(3R, 4R)-3-(5-((2R, 3R, 4R, 5S, 6R)-3,4-dihydroxyl-6-(methylol)-5-(((2S, 3R, 4S, 5S, 6R)-3,4,5-trihydroxy--6-(methylol) tetrahydrochysene-2H-pyrans-2-yl) oxo) tetrahydrochysene-2H-pyrans-2-yl)-4,5,6,7-tetrahydrochysene [1,3] diazepine also [6,7,1-hi] indoles-1-yl)-4-(1H-indol-3-yl) tetramethyleneimine-2,5-diketone;
(3R, 4R)-3-(1H-indol-3-yl)-4-(5-((2R, 3R, 4S, 5S, 6R)-3,4,5-trihydroxy--6-(((2S, 3R, 4S, 5S, 6R)-3,4,5-trihydroxy--6-(methylol) tetrahydrochysene-2H-pyrans-2-yl) oxo) methyl) tetrahydrochysene-2H-pyrans-2-yl)-4,5,6,7-tetrahydrochysene [1,3] diazepine also [6,7,1-hi] indoles-1-yl) tetramethyleneimine-2,5-diketone;
(3R, 4R)-3-(5-((2R, 3R, 4R, 5S, 6R)-5-(((2S, 3R, 4R, 5S, 6R)-3,4-dihydroxyl-6-(methylol)-5-(((2S, 3R, 4S, 5S, 6R)-3,4,5-trihydroxy--6-(methylol) tetrahydrochysene-2H-pyrans-2-yl) oxo) tetrahydrochysene-2H-pyrans-2-yl) oxo)-3,4-dihydroxyl-6-(methylol) tetrahydrochysene-2H-pyrans-2-yl)-4,5,6,7-tetrahydrochysene [1,3] diazepine also [6,7,1-hi] indoles-1-yl)-4-(1H-indol-3-yl) tetramethyleneimine-2,5-diketone.
2. the purposes of compound in preparation treatment antitumor drug described in claim 1.
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