CN105418623B - Camptothecine sulphonyl amidine compound and its preparation method and application - Google Patents
Camptothecine sulphonyl amidine compound and its preparation method and application Download PDFInfo
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- CN105418623B CN105418623B CN201510766116.0A CN201510766116A CN105418623B CN 105418623 B CN105418623 B CN 105418623B CN 201510766116 A CN201510766116 A CN 201510766116A CN 105418623 B CN105418623 B CN 105418623B
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- camptothecine
- piperazine
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/22—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains four or more hetero rings
Abstract
The present invention discloses a kind of camptothecine compounds and its preparation method and application.The camptothecine sulphonyl amidine compound of the present invention is that formula 1 such as is shown, in formula：R1For methyl, ethyl, rubigan, to nitreAny one in base phenyl, p-methylphenyl, p-fluorophenyl, phenyl, thienyl, pyridyl group or naphthalene；R2For any one in hydrogen, fluorine or methoxyl group.The preparation method of camptothecine compounds of the present invention is：7 benzyl diethylenediamine camptothecine trifluoroacetates are dissolved in dichloromethane, it adds in catalyst of triethylamine and stirring clarifies solution, sequentially add sulfonyl azide compound and alkynes, it is eventually adding cuprous iodide catalysis reaction, after, the crude product that solvent obtains target product is removed after reaction is quenched with dichloromethane.The camptothecine sulphonyl amidine compound of the present invention can be applied in the medicine for treating various cancers is prepared.
Description
Technical field
The present invention relates to the preparation method of medicinal compound and the purposes of prepared drug, and exactly the present invention is a kind of
New camptothecine compounds and the preparation method of this compound and its purposes in antitumor drug is prepared.
Background technology
Camptothecine is that Wall is equal to 1966 first from the distinctive Nyssaceae plant camptotheca acuminata of China
(Camptothecaacuminata) isolated a kind of quinoline alkaloid with notable cytotoxic activity in
(J.Nat.Prod.2004,67,129-135), shows the Several Kinds of Malignancy such as osteocarcinoma, liver cancer, carcinoma of urinary bladder and leukaemia
Good inhibiting effect, but found in Clinical practice, camptothecine can be generated when playing its antitumor activity bone marrow suppression,
Vomiting and the more serious side effect such as diarrhea, at the same due to the special alkalinity of nitrogen on quinoline ring in its molecular structure it is water-soluble compared with
Difference, it is impossible to direct human body parenterai administration.Further to improve its water solubility and reducing its toxic side effect, the 1970s
Initial stage has carried out clinical trial phase to the water-soluble sodium salt of camptothecine, although observed certain active anticancer and carry significantly
The high water solubility of such drug, but because its is serious and unpredictalbe toxic side effect causes further clinical test to interrupt.
In recent years, domestic and international researcher has carried out system in-depth study to camptothecine, wherein using it as guide's derivative synthesis
Multiple reactive compounds for example Irinotecan, topotecan, 9-aminocamptothecin, 9-nitrocamptothecin, DX-8951f,
GG211, BNP-1350, ST-1481 and CKD-602 etc. ratify listing or in clinical investigation phase by FDA
(Bioorg.Med.Chem.2004,12,1585-1604；Phytochem.2004,65,2735-2749).According to existing at present
The structure activity study (SAR researchs) to camptothecine, it is found that carry out modification substitution in C-7, camptothecine B rings and produce
Raw compound has higher active anticancer compared with camptothecine, this may be since the substituent group of these derivatives is usual
With the interaction for increasing fat-soluble, participation CPT and I-DNA of Topo and stablize a variety of specific functions such as E ring hydroxy-lactone rings
Result.Therefore, to B rings C-7 modified and be transformed, to improve the activity of such compound object, and pass through raising
Ratio of the lactone ring form in human plasma so as to improve the activity of such compound and reduce toxicity indirectly, at present
One of Main Topics as research and development camptothecine.
In order to improve the druggability of camptothecine, using the structure activity study of existing camptothecine as guidance, consider camptothecine 7
It is modified and is transformed in position, it would be possible to improved its activity and enhance lactonic ring stability, so as to obtain active higher, toxicity
Lower camptothecin derivative.
Invention content
A kind of camptothecine sulphonyl amidine compound that can be overcome the shortage of prior art of offer of the present invention, meanwhile, the present invention
The preparation method and its purposes in antitumor drug that this kind of new compound is provided.
The camptothecine sulphonyl amidine compound of the present invention is that formula 1 such as shows camptothecine sulphonyl amidine compound,
In formula：R1 is methyl, ethyl, rubigan, p-nitrophenyl, p-methylphenyl, p-fluorophenyl, phenyl, thiophene
Any one in base, pyridyl group or naphthalene；R2 is any one in hydrogen, fluorine or methoxyl group.
The preparation method of camptothecine compounds of the present invention is：7- piperazine methyls-camptothecine trifluoroacetate is dissolved in
In dichloromethane, add in catalyst of triethylamine and stirring clarifies solution, sequentially add sulfonyl azide compound and alkynes, institute
The alkynes stated for phenylacetylene, to Methoxy-phenylacetylene, to any one in fluorobenzene acetylene, after treating that more than reagent adds in, most
Cuprous iodide catalysis reaction is added in afterwards, and removing solvent after being stirred to react at normal temperatures, after reaction is quenched with dichloromethane obtains
The crude product of target product, the sulfonyl azide compound is sulfonyloxy methyl nitrine, ethyl sulfonyl azide, phenylSulphon are folded
Nitrogen, p-methylphenyl sulfonyl azide, p-nitrophenyl sulfonyl azide, p-fluorophenyl sulfonyl azide, rubigan sulfonyl azide,
Any one in 2- thienyl sulphonyls nitrine, 3- pyridyl groups sulfonyl azide and 2- naphthalene sulfonyl azides, referring to formula 2.
The product prepared through aforementioned preparation process can be again through column chromatography purification process.
In the preparation method of the camptothecine compounds of the present invention, during the crude by column chromatography purification process of target product
It is with volume ratio:70:1~100:1 chloroform-methanol elution；The column chromatography that 200~300 mesh can be used in silica gel for chromatography column is used
Silica gel.
It is by 0.2mmol 7- piperazine methyls-camptothecine in the specific preparation method of the camptothecine compounds of the present invention
Trifluoroacetate is dissolved in 10mL dichloromethane, and sulfonyl azide compound and alkynes solution addition be respectively 0.22~
0.44mmol, the addition of cuprous iodide is 0.01mmol.
Preferred sulfonyl azide compound and alkynes solution usage point in the preparation method of the camptothecine compounds of the present invention
It Wei not 0.24mmol.
Raw material used in the present invention, 7- benzyl diethylenediamines-camptothecine, preparation method referring to literature methodJ.Am.Chem.Soc.2013,135,9412-9419）.
The present invention uses " diversity synthesis " this thought, by common active function groups on sulphonyl amidine this drug molecule
With 7- benzyl diethylenediamines-camptothecine
By way of multi-component reaction with reference to and synthesized 18 novel camptothecin derivatives as shown in formula 3 to formula 21
Compound, to seek the camptothecin derivative with more druggability.
Show that this kind of camptothecine compounds of the invention can be in the medicine for treating various cancers be prepared through related experiment
Using showing that the compound of Formulas I is thin to human lung adenocarcinoma cell (A549), human breast carcinoma through anti tumor activity in vitro the selection result
Born of the same parents' strain (MDA-MB-231), human mouth epidermoid carcinoma cell (KB), human mouth epidermoid carcinoma cells resistance strain (KBvin) and people
Breast cancer cell (MCF-7) shows stronger inhibitory activity, and some compounds are higher than current clinical medicine Irinotecan,
Therefore, the compound of the present invention can be used for preparing anti-tumor drug.Camptothecine compounds structure of the present invention is new
Grain husk, synthesis technology is simple, product purity is high, and stronger inhibiting effect is shown to tumour cell, before having excellent application
Scape.
Specific embodiment
Prepare embodiment
Embodiment 1：The synthesis of target compound Ia
The synthesis of raw material 7- benzyl diethylenediamines-camptothecine：2.5 grams of camptothecine is taken to add in 60mL75%'s in round-bottomed flask
Sulfuric acid solution makes its stirring and dissolving, then under condition of ice bath, adds in 3.125 grams of ferrous sulfate heptahydrates, stirs 5min, still
Under condition of ice bath, the chloroacetaldehyde solution of 40mL40% is added dropwise with constant pressure funnel, 5min is stirred after being added dropwise, still in ice bath
Under the conditions of, with constant pressure funnel add in 12.5mL, hydrogen peroxide.Half an hour recession is reacted under condition of ice bath and removes ice bath.Normal temperature condition
Reaction is subjected to ice bath after lower reaction 10h, appropriate ice water is then added in, there are a large amount of yellow solids to be precipitated, filter, rushed with ice water
Filter wash cake is multiple, then multiple with the solution flushing filter cake of chloroform/n-hexane=7/3, and filter cake is put into drying tower drying, spare,
Obtain 7- benzyl chlorides-camptothecine (compound 2).By 7- benzyl chlorides -1.5 grams of camptothecine in round-bottomed flask, it is dissolved in suitable dry DMF
In, then 1.6 grams of Boc piperazines are added in thereto, 10hr is stirred at room temperature, is concentrated under reduced pressure, column chromatography (chloroform-methanol) obtains 7-
Benzyl Boc piperazines-camptothecine (compound 3).7- benzyls Boc piperazines -1 gram of camptothecine is taken in round-bottomed flask, adds in CH2Cl2
With each 4mL of TFA, 10hr is stirred at room temperature, is concentrated under reduced pressure into drying regime, addition ether is appropriate, and compound, mistake are scraped from bottle wall
Filter obtains compound as yellow powder (compound 4), reacts referring to formula 4.
The synthesis of Ia：0.2mmol 7- piperazine methyls-camptothecine trifluoroacetate is taken to be dissolved in 10mL dichloromethane, is added in
Appropriate triethylamine clarifies solution, sequentially adds 0.22mmol sulfonyloxy methyls nitrine and 0.22mmol phenylacetylene solution.Treat with
After upper reagent adds in, it is eventually adding the catalysis reaction of 0.01mmol cuprous iodides；It is stirred to react 30-60min at normal temperatures.
After reaction, reaction is quenched with 2mL dichloromethane, then removes solvent under reduced pressure, crude by column chromatography purifying, with chloroform-
Methanol elutes, and obtains target product, reacts referring to formula 5.
Yield:66%；Fusing point：
239-242℃；1HNMR(DMSO-d6,400MHz)δ:8.40 (d, 1H, J=8Hz, C9-H), 8.16 (d, 1H, J=
8Hz, C12-H), 7.84 (t, 1H, J=8Hz, C10-H), 7.70 (t, 1H, J=8Hz, C11-H), 7.36-7.33 (m, 3H,
Ar-H,C14-H),7.27-7.24(m,3H,Ar-H),6.54(s,1H,C20-OH),5. 43(s,2H,C17-H),5.31(s,
2H,C5-H),4.38(s,2H,-CH 2-Ar),4.05 (s,2H,-CH 2-piperazine),3.68(s,2H,piperazine-
H),3.30 (s,2H,piperazine-H),2.94(s,3H,Ms-CH 3),2.54(s,2H,piperazine-H),2.30(s,
2H, piperazine-H), 1.92-1.81 (m, 2H, C 19-H), 0.88 (t, 3H, J=8Hz, C18-H)；MS-ESIm/z:
664.3[M+Na]+.。
Embodiment 2：The synthesis of target compound Ib
It is same with embodiment 1, sulfonyloxy methyl nitrine is only replaced with ethyl sulfonyl azide.React products therefrom detection data such as
Under：Yield:67%；Fusing point： 233-238℃；1HNMR(DMSO-d6,400MHz)δ:8.40 (d, 1H, J=8Hz, C9-H),
8.15 (d, 1H, J=8Hz, C12-H), 7.84 (t, 1H, J=8Hz, C10-H), 7.70 (t, 1H, J=8Hz, C11-H),
7.36-7.31(m,3H,Ar-H,C14-H),7.28-7.24(m,3H,Ar-H),6.54(s,1H,C20-OH),5. 43(s,2H,
C17-H), 5.31 (s, 2H, C5-H), 4.39 (s, 2H ,-CH 2-Ar),4.05 (s,2H,-CH 2-piperazine),3.67(s,
2H, piperazine-H), 3.31 (s, 2H, piperazine-H), 3.00-2.92 (m, 2H ,-SO2-CH 2-),2.54(s,2H,
piperazine-H),2.28(s,2H,piperazine-H),1.92-1.80(m,2H, C19-H),1.26-1.14(m,3H,-
SO2-CH2-CH 3), 0.88 (t, 3H, J=8Hz, C18-H)；MS-ESIm/z:678.3[M+Na]+.。
Embodiment 3：The synthesis of target compound Ic
It is same with embodiment 1, sulfonyloxy methyl nitrine is only replaced with phenylSulphon nitrine.React products therefrom detection data such as
Under：Yield:65%；Fusing point： 209-212℃；1HNMR(DMSO-d6,400MHz)δ:8.39 (d, 1H, J=8Hz, C9-H),
8.15 (d, 1H, J=8Hz, C12-H), 7.86-7.79 (m, 3H, C10-H, Ar-H), 7.69 (t, 1H, J=8Hz, C11-H),
7.57-7.47(m,3H,Ar-H),7.33-7.21(m,6H,C14-H,Ar-H),6.53(s,1H,C20-O H),5.43(s,2H,
C17-H),5.30(s,2H,C5-H),4.44(s,2H,-CH 2-Ar),4.04 (s,2H,-CH 2-piperazine),3.67(s,
2H,piperazine-H),3.29 (s,2H,piperazine-H),2.54(s,2H,piperazine-H),2.29(s,2H,
), piperazine-H 1.90-1.81 (m, 2H, C19-H), 0.87 (t, 3H, J=8 Hz, C18-H)；MS-ESIm/z:726.3
[M+Na]+.。
Embodiment 4：The synthesis of target compound Id
It is same with embodiment 1, sulfonyloxy methyl nitrine is only replaced with 2- thiophenesulfonyls nitrine.React products therefrom detection data such as
Under：Yield:53%；Fusing point： 222-226℃；1HNMR(DMSO-d6,400MHz)δ:8.39 (d, 1H, J=8Hz, C9-H),
8.15 (d, 1H, J=8Hz, C12-H), 7.86-7.79 (m, 2H, C10-H, thiophene-H), 7.69 (t, 1H, J=8Hz,
C11-H),7.52-7.49(m,1H,Ar-H),7.34-7.30(m,3H,Ar-H,C14-H),7.26-7.23 (m,1H,Ar-H),
7.20-7.15(m,2H,thiophene-H),7.08-7.04(m,1H,thiophene-H),6.54(s,1H,C20-OH),
5.43(s,2H,C17- H),5.30(s,2H,C5-H),4.43(s,2H,-CH 2-Ar),4.05(s,2H,-CH 2-
), piperazine 3.73 (s, 2H, piperazine-H), 3.35 (s, 2H, piperazine-H), 2.55 (t, 2H, J=
4Hz, piperazine-H), 2.30 (t, 2H, J=4Hz, piperazine-H), 1.92-1.81 (m, 2H, C19-H), 0.88
(t, 3H, J=8Hz, C18-H)；MS-ESIm/z:732.2[M+Na]+.。
Embodiment 5：The synthesis of target compound Ie
It is same with embodiment 1, only to replace sulfonyloxy methyl nitrine to chlorobenzenesulfonyl nitrine.React products therefrom detection data such as
Under：Yield:61%；Fusing point:209-210℃；1HNMR(DMSO-d6,400MHz)δ:8.39 (d, 1H, J=8Hz, C9-H),
8.15 (d, 1H, J=8Hz, C12-H), 7.86-7.77 (m, 3H, C10-H, Ar-H), 7.69 (t, 1H, J=8Hz, C11-H),
7.55-7.52(m,2H,Ar-H),7.33-7.22(m,4H,Ar-H,C14-H),7.20-7.16(m, 2H,Ar-H),6.54(s,
1H,C20-OH),5.43(s,2H,C17-H),5.30(s,2H,C5-H),4.42(s,2H,-CH 2-Ar),4.05 (s,2H,-CH 2-piperazine),3.68(s,2H,piperazine-H),3.29 (s,2H,piperazine-H),2.54(s,2H,
), piperazine-H 2.31 (s, 2H, piperazine-H), 1.92-1.81 (m, 2H, C19-H), 0.88 (t, 3H, J=8
Hz,C18-H)；MS-ESIm/z:760.2[M+Na]+.。
Embodiment 6：The synthesis of target compound If
It is same with embodiment 1, sulfonyloxy methyl nitrine is only replaced with 3- pyridine sulfonyl sulfonyls nitrine.React products therefrom detection data such as
Under：Yield:63%；m.p.227-230℃；1HNMR(DMSO-d6,400MHz)δ:8.94(s,1H,pyridine-H),8.72-
8.70 (m, 1H, pyridine-H), 8.4 0 (d, 1H, J=8Hz, C9-H), 8.20-8.14 (m, 2H, C12-H, pyridine-
), H 7.84 (t, 1H, J=8Hz, C10-H), 7.70 (t, 1H, J=8Hz, C11-H), 7. 54-7.50 (m, 1H, pyridine-
H),7.34-7.18(m,6H,Ar-H,C14-H),6.54(s,1H,C20-OH),5.43(s,2H,C17-H),5.31(s,2H,C5
-H),4.45(s,2H,-CH 2-Ar),4.06(s,2H,-CH 2- piperazine), 3.70 (d, 2H, J=8Hz, piperazine-
), H 3.37 (s, 2H, piperazine-H), 2.54 (t, 2H, J=4Hz, piperazine-H), 2.33 (t, 2H, J=4Hz,
), piperazine-H 1.92-1.81 (m, 2H, C19-H), 0.87 (t, 3H, J=8Hz, C18-H)；MS-ESIm/z:727.6
[M+Na]+.。
Embodiment 7：The synthesis of target compound Ig
It is same with embodiment 1, sulfonyloxy methyl nitrine is only replaced with 3- pyridine sulfonyl sulfonyls nitrine.React products therefrom detection data such as
Under：Yield:72%；Fusing point： 195-197℃；1HNMR(DMSO-d6,400MHz)δ:8.40-8.38(m,2H,C9-H,
naphthalene-H),8.16-7.98(m,4H,C12-H,naph thalene-H),7.85-7.82(m,2H,C10-H,
naphthalene-H),7.71-7.60(m,3H,C11-H,naphthalene-H),7.32-7.17(m,6H,Ar -H,C14-
H), 6.53 (s, 1H, C20-OH), 5.43 (s, 2H, C17-H), 5.30 (s, 2H, C5-H), 4.47 (s, 2H ,-CH 2-Ar),4.03
(s, 2H ,-CH 2-piperazine),3.69(s,2H,piperazine-H),3.31 (s,2H,piperazine-H),2.58
(d, 2H, J=8Hz, piperazine-H), 2.29 (s, 2H, piperazine-H), 1.91-1.82 (m, 2H, C19-H), 0.86
(t, 3H, J=8Hz, C18-H)；MS-ESIm/z:776.7[M+Na]+.。
Embodiment 8：The synthesis of target compound Ih
It is same with embodiment 2, only to replace phenylacetylene to Methoxy-phenylacetylene.It is as follows to react products therefrom detection data：Production
Rate:63%；Fusing point： 230-234℃；1HNMR(DMSO-d6,400MHz)δ:8.40 (d, 1H, J=8Hz, C9-H), 8.16 (d,
1H, J=8Hz, C12-H), 7.84 (t, 1H, J=8Hz, C10-H), 7.70 (t, 1H, J=8Hz, C11-H), 7.33 (s, 1H,
), C14-H 7.20 (d, 2H, J=8Hz, Ar-H), 6.91-6.89 (m, 2H, Ar-H), 6.54 (s, 1H, C20-OH), 5.43 (s,
2H,C17-H),5.32(s,2H,C5-H),4.30(s,2H,-CH 2-Ar),4.07 (s,2H,-CH 2-piperazine),3.73
(s,3H,CH 3-O-Ar),3.65(s,2H,piperazine-H),3.31 (s,2H,piperazine-H),2.97(q,2H,J
=8Hz, CH3-CH 2-SO2-),2.55(s,2H,piperazine-H),2.31(s,2H,piperazine-H),1.9 2-1.81
(m,2H,C19-H),1.26-1.16(m,3H,-SO2-CH2-CH 3), 0.88 (t, 3H, J=8Hz, C18-H)；MS-ESIm/z:
708.4[M+Na]+.。
Embodiment 9：The synthesis of target compound Ii
It is same with embodiment 8, only to replace ethyl sulfonyl azide to Methyl benzenesulfonyl nitrine.React products therefrom detection data
It is as follows：Yield:70%；Fusing point：
208-210℃；1HNMR(DMSO-d6,400MHz)δ:8.38 (d, 1H, J=8Hz, C9-H), 8.14 (d, 1H, J=
8Hz, C12-H), 7.83 (t, 1H, J=8Hz, C10-H), 7.70-7.64 (m, 3H, C11-H, Ar-H), 7.31-7.27 (m,
3H, Ar-H, C14-H), 7.09 (d, 2H, J=8Hz, Ar-H), 6.85 (d, 2H, J=8H z, Ar-H), 6.53 (s, 1H, C20-
OH),5.42(s,2H,C17-H),5.30(s,2H,C5-H),4.31(s,2H,-CH 2-Ar),4.04 (s,2H,-CH 2-
piperazine),3.72(s,3H,CH3-O-Ar),3.63(s,2H,piperazine-H),3.33 (s,2H,
piperazine-H),2.65(s,2H,piperazine-H),2.39-2.25(m,5H,piperazine-H,CH3-Ts),
1.88-1.83 (m, 2H, C19-H), 0.86 (t, 3H, J=8Hz, C18-H)；MS-ESIm/z:770.8[M+Na]+.。
Embodiment 10：The synthesis of target compound Ij
It is same with embodiment 8, ethyl sulfonyl azide is only replaced with p-nitrophenyl sulfonyl azide.React products therefrom detection data
It is as follows：Yield:65%；Fusing point：
210-215℃；1HNMR(DMSO-d6,400MHz)δ:8.41 (d, 1H, J=8Hz, C9-H), 8.27 (d, 2H, J=
8Hz, Ar-H), 8.16 (d, 1H, J=8Hz, C12-H), 8.02 (d, 2H, J=8Hz, Ar-H), 7.85 (t, 1H, J=8Hz,
), C10-H 7.70 (t, 1H, J=8, C11-H), 7.33 (s, 1H, C14-H), 7.08 (d, 2H, J=8Hz, Ar-H), 6.85 (d,
2H, J=8Hz, Ar-H), 6.54 (s, 1H, C20-OH), 5.43 (s, 2H, C17-H), 5.32 (s, 2H, C5-H), 4.35 (s,
2H,-CH 2-Ar),4.08 (s,2H,-CH 2-piperazine),3.71(s,5H,CH3-O-Ar,piperazine-H),3.38
(s,2H,piperazine-H),2.54(s,2H,piperazine-H) ,2.37(s,2H,piperazine-H),1.90-
1.83 (m, 2H, C19-H), 0.88 (t, 3H, J=8Hz, C18-H)；MS-ESIm/z:789.3[M+Na]+.。
Embodiment 11：The synthesis of target compound Ik
It is same with embodiment 6, only to replace phenylacetylene to Methoxy-phenylacetylene.It is as follows to react products therefrom detection data：Production
Rate:61%；Fusing point:238-242℃；1HNMR(DMSO-d6,400MHz)δ:8.98 (d, 1H, J=8Hz, pyridine-H),
8.74 (s, 1H, pyridine-H), 8.41 (d, 1H, J=8Hz, C9-H), 8.20-8.15 (m, 2H, C12-H, pyridine-
), H 7.85 (t, 1H, J=8Hz, C10-H), 7.70 (t, 1H, J=8Hz, C11-H), 7.55-7.5 2 (m, 1H, pyridine-
), H 7.33 (s, 1H, C14-H), 7.13 (d, 2H, J=8Hz, Ar-H), 6.88 (d, 2H, J=8Hz, Ar-H), 6.54 (s, 1H,
C20-OH),5. 44(s,2H,C17-H),5.32(s,2H,C5-H),4.37(s,2H,-CH 2-Ar),4.08 (s,2H,-CH 2-
piperazine),3.74(s,3H,CH3-O-Ar), 3.69 (d, 2H, J=8Hz, piperazine-H), 3.39 (d, 2H, J=
8Hz, piperazine- H), 2.54 (s, 2H, piperazine-H), 2.36 (t, 2H, J=4Hz, piperazine-H),
1.91-1.83 (m, 2H, C19-H), 0.88 (t, 3H, J=8Hz, C18-H)； MS-ESIm/z:757.1[M+Na]+.。
Embodiment 12：The synthesis of target compound Il
It is same with embodiment 7, only to replace phenylacetylene to Methoxy-phenylacetylene.It is as follows to react products therefrom detection data：Production
Rate:72%；Fusing point： 210-214℃；1HNMR(DMSO-d6,400MHz)δ:8.40-8.37(m,2H,C9-H,
), naphthalene-H 8.15 (d, 1H, J=8Hz, C12-H), 8. 08 (d, 1H, J=8Hz, naphthalene-H), 8.01
(dd, 2H, J=8,16Hz, naphthalene-H), 7.85-7.81 (m, 2H, C10-H, naphthalene-H), 7.71-
7.60 (m, 3H, C11-H, naphthalene-H), 7.32 (s, 1H, C14-H), 7.10 (d, 2H, J=8Hz, Ar-H), 6,80
(d, 2H, J=8Hz, Ar-H), 6. 53 (s, 1H, C20-OH), 5.43 (s, 2H, C17-H), 5.31 (s, 2H, C5-H), 4.38
(s, 2H ,-CH 2- Ar), 4.06 (s, 2H ,-CH 2-piperazine),3.68(s,5H,piperazine-H,CH3-O-Ar),
3.33 (s,2H,piperazine-H),2.56(s,2H,piperazine-H),2.33(s,2H,piperazine-H),
1.91-1.81 (m, 2H, C19-H), 0.87 (t, 3H, J=8 Hz, C18-H)；MS-ESIm/z:806.6[M+Na]+.。
Embodiment 13：The synthesis of target compound Im
It is same with embodiment 2, only to replace phenylacetylene to fluorobenzene acetylene.It is as follows to react products therefrom detection data：Yield:
63%；Fusing point： 239-243℃；1HNMR(DMSO-d6,400MHz)δ:8.41 (d, 1H, J=8Hz, C9-H), 8.17 (d, 1H, J
=8Hz, C12-H), 7.87 (t, 1H, J=8Hz, C10-H), 7.71 (t, 1H, J=8Hz, C11-H), 7.34-7.29 (m, 3H,
Ar-H,C14-H),7.21-7.16(m,2H,Ar-H),6.54(s,1H,C20-OH),5. 44(s,2H,C17-H),5.33(s,
2H, C5-H), 4.37 (s, 2H ,-CH 2-Ar),4.07 (s,2H,-CH 2-piperazine),3.64(s,2H,piperazine-
H), 3.31 (s, 2H, piperazine-H), 2.99 (q, 2H, J=8Hz ,-SO2-CH 2-),2.54(s,2H,piperazine-
), H 2.32 (s, 2H, piperazine-H), 1.91-1.82 (m, 2H, C19-H), 1.25 (t, 3H, J=8Hz ,-SO2-CH2-CH 3), 0.88 (t, 3H, J=8Hz, C18-H)；MS-ESIm/z:696.7[M+Na]+.。
Embodiment 14：The synthesis of target compound In
It is same with embodiment 9, only to replace fluorobenzene acetylene to Methoxy-phenylacetylene.React products therefrom detection data such as
Under：Yield:70%；Fusing point： 216-219℃；1HNMR(DMSO-d6,400MHz)δ:8.40 (d, 1H, J=8Hz, C9-H),
8.16 (d, 1H, J=8Hz, C12-H), 7.84 (t, 1H, J=8Hz, C10-H), 7.71-7.66 (m, 3H, C11-H, Ar-H),
7.32-7.28(m,3H,Ar-H,C14-H),7.24-7.21(m,2H,Ar-H),7.17-7.12(m,2H, Ar-H),6.53(s,
1H,C20-OH),5.43(s,2H,C17-H),5.31(s,2H,C5-H),4.39(s,2H,-CH 2-Ar),4.06 (s,2H,-CH 2-piperazine),3.65(s,2H,piperazine-H),3.31 (s,2H,piperazine-H),2.58(s,2H,
piperazine-H),2.34(s,5H,piperazine-H,CH 3-Ts),1.90-1.83(m,2H,C19-H),0.87(t,
3H, J=8Hz, C18-H)；MS-ESIm/z:758.7[M+Na]+.。
Embodiment 15：The synthesis of target compound Io
It is same with embodiment 6, only to replace phenylacetylene to fluorobenzene acetylene.It is as follows to react products therefrom detection data：Yield:
58%；Fusing point： 245-248℃；1HNMR(DMSO-d6,400MHz)δ:8.99(s,1H,pyridine-H),8.77(s,1H,
), pyridine-H 8.41 (d, 1H, J=8Hz, C9- H), 8.20-8.15 (m, 2H, C12-H, pyridine-H), 7.84 (t,
1H, J=8Hz, C10-H), 7.70 (t, 1H, J=8Hz, C11-H), 7.54 (d, 1H, J=4Hz, p yridine-H), 7.33
(s, 1H, C14-H), 7.24 (dd, 2H, J=4,8Hz, Ar-H), 7.17-7.11 (m, 2H, Ar-H), 6.54 (s, 1H, C20-
OH),5.43(s,2H, C17-H),5.32(s,2H,C5-H),4.43(s,2H,-CH 2-Ar),4.07 (s,2H,-CH 2-
), piperazine 3.69 (d, 2H, J=8Hz, piperazine-H), 3.39 (s, 2H, piperazine-H), 2.54 (d,
2H, J=4Hz, piperazine-H), 2.37 (d, 2H, J=4Hz, piperazine-H), 1.92-1.81 (m, 2H, C19-H)
, 0.88 (t, 3H, J=8Hz, C18-H)；MS-ESIm/z:745.1[M+Na]+.。
Embodiment 16：The synthesis of target compound Ip
It is same with embodiment 10, only to replace fluorobenzene acetylene to Methoxy-phenylacetylene.React products therefrom detection data such as
Under：Yield:65%；Fusing point： 212-215℃；1HNMR(DMSO-d6,400MHz)δ:8.40 (d, 1H, J=8Hz, C9-H),
8.29 (d, 2H, J=8Hz, Ar-H), 8.15 (d, 1H, J=8Hz, C12-H), 8.04 (d, 2H, J=8Hz, Ar-H), 7.85
(t, 1H, J=8Hz, C10-H), 7.71 (t, 1H, J=8, C11-H), 7.33 (s, 1H, C14-H), 7.24-7.07 (m, 4H,
Ar-H),6.54(s,1H,C20-OH),5.43(s,2H,C17-H),5.33(s,2H,C5-H),4.42(s,2H,-CH 2-Ar),
4.09 (s,2H,-CH 2-piperazine),3.70(s,2H,piperazine-H),3.40 (s,2H,piperazine-H),
2.55(s,2H,piperazine-H),2.38(s,2H,piperazine-H),1.90-1.83(m,2H,C19-H),0.86(t,
3H, J=8 Hz, C18-H)；MS-ESIm/z:801.6[M+Na]+.。
Embodiment 17：The synthesis of target compound Iq
It is same with embodiment 13, only to replace ethyl sulfonyl azide to fluorobenzene sulfonyl azide.React products therefrom detection data
It is as follows：Yield:65%；Fusing point： 218-219℃；1HNMR(DMSO-d6,400MHz)δ:8.40 (d, 1H, J=8Hz, C9-H),
8.16 (d, 1H, J=8Hz, C12-H), 7.96 (m, 2H, Ar-H), 7.84 (t, 1H, J=8Hz, C10-H), 7.70 (t, 1H, J
=8, C11-H), 7.45 (m, 2H, Ar-H), 7.31 (s, 1H, C14-H), 7.24-7.08 (m, 4H, Ar-H), 6. 53 (s, 1H,
C20-OH),5.43(s,2H,C17-H),5.32(s,2H,C5-H),4.41(s,2H,-CH 2-Ar),4.07 (s,2H,-CH 2-
piperazine),3.67(s,2H,piperazine-H),3.31 (s,2H,piperazine-H),2.53(s,2H,
), piperazine-H 2.35 (s, 2H, piperazine-H), 1.92-1.82 (m, 2H, C19-H), 0.88 (t, 3H, J=8
Hz,C18-H)；MS-ESIm/z:762.4[M+Na]+.。
Embodiment 18：The synthesis of target compound Ir
It is same with embodiment 7, only to replace phenylacetylene to fluorobenzene acetylene.It is as follows to react products therefrom detection data：Yield:
72%；Fusing point： 200-203℃；1HNMR(DMSO-d6,400MHz)δ:8.41-8.39(m,2H,C9-H,naphthalene-
H),8.17-7.98(m,4H,C12-H,naph thalene-H),7.86-7.82(m,2H,C10-H,naphthalene-H),
7.71-7.62 (m, 3H, C11-H, naphthalene-H), 7.32 (s, 1H, C14-H), 7.23 (t, 2H, J=8Hz, Ar-H),
7.09 (t, 2H, J=8Hz, Ar-H), 6.54 (s, 1H, C20-OH), 5.43 (s, 2H, C17-H), 5.31 (s, 2H, C5-H),
4.45 (s, 2H ,-CH 2- Ar), 4.06 (s, 2H ,-CH 2-piperazine),3.69(s,2H,piperazine-H),3.31
(s,2H,piperazine-H),2.56(s,2H,piperazine-H),2.34(s,2H,piperazine-H),1.90-1.85
(m, 2H, C19-H), 0.87 (t, 3H, J=8 Hz, C18-H)；MS-ESIm/z:794.2[M+Na]+.。
The test method and result of the antitumor activity of compound a-r
The pharmacological evaluation of the present invention uses Sulforhodamine B (sulforhodamineB, SRB) colorimetric method.Tumour cell is trained
The RPMI-1640 culture mediums for selecting 10% fetal calf serum (FBS) are supported, by tumor cell inoculation in 96 orifice plates, 3- is cultivated in each hole
5 × 103 cells add in the solution title compound to be tested of various concentration.After culture 72 hours, precooling is added in per hole
Solution of trichloroacetic acid (50%, w/v) fixes cell, and 30 minutes are fixed in refrigerator.After 96 orifice plates dry at room temperature, add per hole
Enter the SRB dye liquors (1% peracetic acid formulation, purchased from SigmaChemical companies) of 0.04% (w/v), dyeing is outwelled after 30 minutes
Dye liquor is rinsed 4 times with acetic acid, removes unbonded dyestuff, room temperature is dried.It is dissolved with the non-buffered Tris-base lye of 100 μ L
The dyestuff combined with cell protein is vibrated 20 minutes on horizontal shaker, absorbs light microplate reader (U.S. Bio-Tek using ELx800
Company produces, and operates software Gen5) measure absorption value at 515nm.All experiments set 3 parallel groups or in triplicate.Compound
The cytotoxic activity test result of a-r is shown in Table 1.
The cytotoxic activity result of the test of 1 compound Ia-r of table
Note：(1) screening technique：Sulforhodamine B colorimetric methods；(2) action time：48 hours (3) compound numbersIaPoint
Not Wei previous embodiment 1 to 18 products therefrom of embodiment.
Five kinds of tumour cell in vitro cytotoxic effect test results are shown, the compound synthesized by the present invention is shown
Good poisoning human lung adenocarcinoma cell (A549), Breast cancer lines (MDA-MB-231), human mouth epidermoid carcinoma cell
(KB), the activity of the tumour cells such as human mouth epidermoid carcinoma cells resistance strain (KBvin) and human breast cancer cell (MCF-7), and
Some compounds show the in vitro cytotoxic effect higher than camptothecine clinical medicine Irinotecan.In all derivatives, chemical combination
Object a, c, d, e, m, p, r all show higher activity to five kinds of tested cells, and activity is higher by Irinotecan 10~20
Times, show preferable application prospect.
Claims (9)
1. a kind of camptothecine sulphonyl amidine compound, structure are as shown in Equation 1：
In formula：R1 is methyl, ethyl, rubigan, p-nitrophenyl, p-methylphenyl, p-fluorophenyl, phenyl, thienyl, pyrrole
Any one in piperidinyl or naphthalene；R2 is any one in hydrogen, fluorine or methoxyl group.
2. the preparation method of camptothecine sulphonyl amidine compound according to claim 1, it is characterised in that by 7- piperazine first
Base camptothecine trifluoroacetate is dissolved in dichloromethane, adds in catalyst of triethylamine and stirring clarifies solution, sequentially add
Sulfonyl azide compound and alkynes, the alkynes for phenylacetylene, to Methoxy-phenylacetylene, to any one in fluorobenzene acetylene, treat
After more than reagent adds in, cuprous iodide catalysis reaction is eventually adding, after being stirred to react at normal temperatures, uses dichloromethane
The crude product that solvent obtains target product is removed after reaction is quenched, the sulfonyl azide compound is sulfonyloxy methyl nitrine, ethyl
Sulfonyl azide, phenylSulphon nitrine, p-methylphenyl sulfonyl azide, p-nitrophenyl sulfonyl azide, p-fluorophenyl sulfonyl azide,
It is any one in rubigan sulfonyl azide, 2- thienyl sulphonyls nitrine, 3- pyridyl groups sulfonyl azide and 2- naphthalene sulfonyl azides
It is a.
3. the preparation method of camptothecine sulphonyl amidine compound according to claim 2, it is characterised in that will be obtained
The crude by column chromatography purification process of target product.
4. the preparation method of camptothecine sulphonyl amidine compound according to claim 3, which is characterized in that target product
It is with volume ratio during crude by column chromatography purification process:70:1~100:1 chloroform-methanol elution.
5. the preparation method of camptothecine sulphonyl amidine compound according to claim 4, it is characterised in that silica gel for chromatography
Column uses the column chromatography silica gel of 200~300 mesh.
6. the preparation method of the camptothecine sulphonyl amidine compound according to Claims 2 or 3 or 4 or 5, which is characterized in that
0.2mmol7- piperazine methyls-camptothecine trifluoroacetate is dissolved in 10mL dichloromethane, sulfonyl azide compound and alkynes solution
Addition is respectively 0.22~0.44mmol, and the addition of cuprous iodide is 0.01mmol.
7. the preparation method of the camptothecine sulphonyl amidine compound according to Claims 2 or 3 or 4 or 5, it is characterised in that sulphur
Acylazide and alkynes solution usage are respectively 0.24mmol.
8. the preparation method of camptothecine sulphonyl amidine compound according to claim 6, it is characterised in that sulfonyl azide
It is respectively 0.24mmol that object, which is closed, with alkynes solution usage.
9. a kind of camptothecine sulphonyl amidine compound described in claim 1 is preparing treatment adenocarcinoma of lung, human breast carcinoma or population
Application in the drug of chamber epidermoid carcinoma.
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| Design and synthesis of new 7-(N-substituted-methyl)-camptothecin derivatives as potent cytotoxic agents;Xiao-Bo Zhao et al.;《Bioorganic & Medicinal Chemistry Letters》;20140627;第24卷(第16期);第3850-3853页，摘要，第3851页 Scheme 1，化合物9a-9s，第3852页Table 1 * |
| 鬼臼毒素和喜树碱脒类衍生物的设计、合成及杀虫活性研究;赵永龙;《中国优秀硕士学位论文全文数据库 医药卫生科技辑》;20141215;第E057-25页 * |
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