CN105418623A - Camptothecin sulfonyl amidine compound and preparation method and application thereof - Google Patents
Camptothecin sulfonyl amidine compound and preparation method and application thereof Download PDFInfo
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- CN105418623A CN105418623A CN201510766116.0A CN201510766116A CN105418623A CN 105418623 A CN105418623 A CN 105418623A CN 201510766116 A CN201510766116 A CN 201510766116A CN 105418623 A CN105418623 A CN 105418623A
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- piperazine
- sulfonyl azide
- camptothecine
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- 0 CC[C@@](C)C=C(C)CCC(C(C)C)C1*CC(C[C@](C)*2*[C@@](C)C2)C1 Chemical compound CC[C@@](C)C=C(C)CCC(C(C)C)C1*CC(C[C@](C)*2*[C@@](C)C2)C1 0.000 description 4
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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 invention discloses a camptothecin sulfonyl amidine compound and a preparation method and application thereof. The camptothecin sulfonyl amidine compound is shown in the formula 1, wherein in the formula, R1 is any one of methyl, ethyl, p-chlorophenyl, p-nitrophenyl, p-methylphenyl, p-fluorophenyl, phenyl, thienyl, pyridyl and naphthyl; R2 is any one of hydrogen, fluorine and methoxy. The preparation method of the camptothecin sulfonyl amidine compound includes the steps that 7-benzylpiperazine-camptothecin trifluoroacetate is dissolved into methylene dichloride, a catalyst (triethylamine) is added for stirring to clarify a solvent, then a sulfonyl azide and alkyne are sequentially added, finally, copper iodide is added for a catalytic reaction, after completion, methylene dichloride is used for a quenching reaction, then the solvent is removed, and a crude product of the target product is obtained. The camptothecin sulfonyl amidine compound can be applied to preparation of medicine for treating all kinds of cancers.
Description
Technical field
The present invention relates to the preparation method of medicinal compound and the purposes of prepared medicine, the present invention is exactly a kind of new camptothecine compounds, and the preparation method of this compound is preparing the purposes in antitumor drug with it.
Background technology
Camptothecine be Wall equal 1966 first from the distinctive Nyssaceae plant camptotheca acuminata of China (
camptothecaacuminata) in be separated quinoline alkaloid that obtain a kind of have a remarkable cytotoxic activity (
j.Nat.Prod.2004,67,129-135), good restraining effect is shown to Several Kinds of Malignancies such as osteocarcinoma, liver cancer, bladder cancer and leukemia, but find when Clinical practice, camptothecine can produce the comparatively severe side effect such as bone marrow depression, vomiting and diarrhoea when playing its anti-tumor activity, simultaneously water-soluble poor because of the special alkalescence of nitrogen on quinoline ring in its molecular structure, can not direct human body parenterai administration.For improving its water-soluble and its toxic side effect of reduction further, phase early 1970s has carried out the water-soluble sodium salt of camptothecine
clinical trial phase, although observed certain antitumour activity and substantially increase the water-soluble of such medicine, because its serious and unpredictalbe toxic side effect makes further clinical trial interrupt.In recent years, domestic and international investigator has carried out the deep research of system to camptothecine, wherein with its be guide's derivative synthesis multiple active compounds as irinotecan, topotecan, 9-aminocamptothecin, 9-nitrocamptothecin, DX-8951f, GG211, BNP-1350, ST-1481 and CKD-602 etc. by FDA approval listing or be in clinical investigation phase (
bioorg.Med.Chem.2004,12,1585-1604;
phytochem.2004,65,2735-2749).According to the existing structure activity study to camptothecine (SAR research) at present, can find, carry out in camptothecine B ring C-7 position modifying and replace and the compound of generation has higher antitumour activity compared with camptothecine, this may be because the substituting group of these derivatives has the result increasing the multiple specific functions such as fat-soluble, to participate in CPT and Topo I-DNA interaction and stable E ring hydroxy-lactone ring usually.Therefore, B ring C-7 position is modified and transformed, to improving the activity of this compounds thing, and by improving the ratio of lactone ring form in human plasma thus indirectly improving the activity of this compounds and reduce toxicity, become one of Main Topics of research and development camptothecine at present.
In order to improve the druggability of camptothecine, with the structure activity study of existing camptothecine for instructing, consider camptothecine 7 to carry out modifying and transforming, likely will improve its activity and strengthen lactonic ring stability, thus obtaining the camptothecin derivative that activity is higher, toxicity is lower.
Summary of the invention
The camptothecine sulphonyl amidine compound providing a class can overcome prior art deficiency of the present invention, meanwhile, the invention provides the preparation method of this class novel cpd and the purposes in antitumor drug thereof.
Camptothecine sulphonyl amidine compound of the present invention shows camptothecine sulphonyl amidine compound such as formula 1,
In formula: R1 be methyl, ethyl, rubigan, p-nitrophenyl, p-methylphenyl, to any one in fluorophenyl, phenyl, thienyl, pyridyl or naphthyl; R2 is any one in hydrogen, fluorine or methoxyl group.
The preparation method of camptothecine compounds of the present invention is: be dissolved in methylene dichloride by 7-benzyl diethylenediamine-camptothecine trifluoroacetate, adding catalyst of triethylamine and stirring makes solution clarify, add sulfonyl azide compound and alkynes successively again, described alkynes is phenylacetylene, to Methoxy-phenylacetylene, to any one in fluorobenzene acetylene, after treating that above reagent adds, finally add cuprous iodide catalyzed reaction, after stirring reaction terminates at normal temperatures, the crude product that desolventizing obtains target product is removed with after methylene dichloride cancellation reaction, described sulfonyl azide compound is sulfonyloxy methyl nitrine, ethyl sulfonyl azide, phenylSulphon nitrine, p-methylphenyl sulfonyl azide, p-nitrophenyl sulfonyl azide, to fluorophenyl sulfonyl azide, rubigan sulfonyl azide, 2-thienyl sulphonyl nitrine, any one in 3-pyridyl sulfonyl azide and 2-naphthyl sulfonyl azide, see formula 2.
The product prepared through aforementioned preparation process can again through column chromatography purification process.
In the preparation method of camptothecine compounds of the present invention, during the crude by column chromatography purification process of target product, volume ratio is: the chloroform-methanol wash-out of 70:1 ~ 100:1; Silica gel for chromatography post can adopt 200 ~ 300 object column chromatography silica gel.
That 0.2mmol7-benzyl diethylenediamine-camptothecine trifluoroacetate is dissolved in 10mL methylene dichloride in the concrete preparation method of camptothecine compounds of the present invention, sulfonyl azide compound and alkynes solution add-on are respectively 0.22 ~ 0.44mmol, and the add-on of cuprous iodide is 0.01mmol.
In the preparation method of camptothecine compounds of the present invention, preferred sulfonyl azide compound and alkynes solution usage are respectively 0.24mmol.
The raw material that the present invention is used, 7-benzyl diethylenediamine-camptothecine, preparation method see literature method (
j.Am.Chem.Soc.2013,135,9,412 9419).
The present invention uses " diversity synthesis " this thought, active function groups conventional on this drug molecule of sulphonyl amidine is combined by the mode of multi-component reaction with 7-benzyl diethylenediamine-camptothecine and has synthesized such as formula 18 novel camptothecin derivatives compounds shown in 3 to formula 21, to seek the camptothecin derivative having more druggability.
Show through related experiment, this kind of camptothecine compounds of the present invention can be applied in the medicine of the various cancer of preparation treatment, shows, formula through anti tumor activity in vitro the selection result
icompound stronger inhibit activities is shown to human lung adenocarcinoma cell (A549), Breast cancer lines (MDA-MB-231), human oral epidermoid carcinoma cell (KB), human oral epidermoid carcinoma cells resistance strain (KBvin) and human breast cancer cell (MCF-7), and some compounds are higher than current clinical medicine irinotecan, therefore, compound of the present invention can be used for preparing anti-tumor drug.Camptothecine compounds novel structure of the present invention, synthesis technique is simple, product purity is high, shows stronger restraining effect to tumour cell, has excellent application prospect.
Embodiment
Preparation embodiment
Embodiment 1: the synthesis of target compound Ia
The synthesis of raw material 7-benzyl diethylenediamine-camptothecine: get camptothecine 2.5 grams in round-bottomed flask, the sulphuric acid soln adding 60mL75% makes its stirring and dissolving, subsequently under condition of ice bath, add 3.125 grams of iron vitriols, stir 5min, still under condition of ice bath, drip the monochloroacetaldehyde solution of 40mL40% by constant pressure funnel, dropwise rear stirring 5min, still under condition of ice bath, add 12.5mL by constant pressure funnel, hydrogen peroxide.Deicing bath of dropping back half an hour is reacted under condition of ice bath.After reacting 10h under normal temperature condition, ice bath is carried out in reaction, then appropriate frozen water is added, a large amount of yellow solid is had to separate out, suction filtration, with frozen water flush cake repeatedly, then the solution flush cake using chloroform/normal hexane=7/3 is repeatedly, filter cake is put into drying tower drying, for subsequent use, obtain the chloro-camptothecine of 7-benzyl (compound 2).By chloro-for 7-benzyl camptothecine 1.5 grams in round-bottomed flask, be dissolved in appropriate dry DMF, then add the Boc piperazine of 1.6 grams wherein, stirring at room temperature 10hr, concentrating under reduced pressure, column chromatography (chloroform-methanol) obtains 7-benzyl Boc piperazine-camptothecine (compound 3).Get 7-benzyl Boc piperazine-camptothecine 1 gram in round-bottomed flask, add each 4mL of CH2Cl2 and TFA, stirring at room temperature 10hr, be evaporated to drying regime, add ether in right amount, scrape compound from bottle wall, filter, obtaining compound is yellow powder (compound 4).
It reacts see formula 4,
The synthesis of Ia: get 0.2mmol7-benzyl diethylenediamine-camptothecine trifluoroacetate and be dissolved in 10mL methylene dichloride, add appropriate triethylamine and solution is clarified, then add 0.22mmol sulfonyloxy methyl nitrine and 0.22mmol phenylacetylene solution successively.After treating that above reagent adds, finally add 0.01mmol cuprous iodide catalyzed reaction; Stirring reaction 30-60min at normal temperatures.After reaction terminates, with 2mL methylene dichloride cancellation reaction, then remove solvent under reduced pressure, crude by column chromatography purifying, use chloroform-methanol wash-out, obtain target product.
It reacts see formula 5,
Productive rate: 66%; Fusing point: 239-242
oc;
1hNMR (DMSO
-d 6 , 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, C19-H), 0.88 (t, 3H,
j=8Hz, C18-H); MS-ESIm/z:664.3 [M+Na]
+..
Embodiment 2: the synthesis of target compound Ib
Same with embodiment 1, only replace sulfonyloxy methyl nitrine with ethyl sulfonyl azide.It is as follows that reaction products therefrom detects data: productive rate: 67%; Fusing point: 233-238
oc;
1hNMR (DMSO
-d 6 , 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 ,-SO
2-
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 ,-SO
2-CH
2-
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
Same with embodiment 1, only replace sulfonyloxy methyl nitrine with phenylSulphon nitrine.It is as follows that reaction products therefrom detects data: productive rate: 65%; Fusing point: 209-212
oc;
1hNMR (DMSO
-d 6 , 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-OH), 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=8Hz, C18-H); MS-ESIm/z:726.3 [M+Na]
+..
Embodiment 4: the synthesis of target compound Id
Same with embodiment 1, only replace sulfonyloxy methyl nitrine with 2-thiophenesulfonyl nitrine.It is as follows that reaction products therefrom detects data: productive rate: 53%; Fusing point: 222-226
oc;
1hNMR (DMSO
-d 6 , 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
Same with embodiment 1, only to replace sulfonyloxy methyl nitrine to chlorobenzenesulfonyl nitrine.It is as follows that reaction products therefrom detects data: productive rate: 61%; Fusing point: 209-210
oc;
1hNMR (DMSO
-d 6 , 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=8Hz, C18-H); MS-ESIm/z:760.2 [M+Na]
+..
Embodiment 6: the synthesis of target compound If
Same with embodiment 1, only replace sulfonyloxy methyl nitrine with 3-pyridine sulfonyl sulfonyl nitrine.It is as follows that reaction products therefrom detects data: productive rate: 63%; M.p.227-230
oc;
1hNMR (DMSO
-d 6 , 400MHz)
δ: 8.94 (s, 1H, pyridine-H), 8.72-8.70 (m, 1H, pyridine-H), 8.40 (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
Same with embodiment 1, only replace sulfonyloxy methyl nitrine with 3-pyridine sulfonyl sulfonyl nitrine.It is as follows that reaction products therefrom detects data: productive rate: 72%; Fusing point: 195-197
oc;
1hNMR (DMSO
-d 6 , 400MHz)
δ: 8.40-8.38 (m, 2H, C9-H, naphthalene-H), (8.16-7.98 m, 4H, C12-H, naphthalene-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
Same with embodiment 2, only to replace phenylacetylene to Methoxy-phenylacetylene.It is as follows that reaction products therefrom detects data: productive rate: 63%; Fusing point: 230-234
oc;
1hNMR (DMSO
-d 6 , 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, CH
3-
cH 2-SO
2-), 2.55 (s, 2H, piperazine-H), 2.31 (s, 2H, piperazine-H), 1.92-1.81 (m, 2H, C19-H), 1.26-1.16 (m, 3H ,-SO
2-CH
2-
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
Same with embodiment 8, only to replace ethyl sulfonyl azide to Methyl benzenesulfonyl nitrine.It is as follows that reaction products therefrom detects data: productive rate: 70%; Fusing point: 208-210
oc;
1hNMR (DMSO
-d 6 , 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=8Hz, 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
Same with embodiment 8, only replace ethyl sulfonyl azide with p-nitrophenyl sulfonyl azide.It is as follows that reaction products therefrom detects data: productive rate: 65%; Fusing point: 210-215
oc;
1hNMR (DMSO
-d 6 , 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
Same with embodiment 6, only to replace phenylacetylene to Methoxy-phenylacetylene.It is as follows that reaction products therefrom detects data: productive rate: 61%; Fusing point: 238-242
oc;
1hNMR (DMSO
-d 6 , 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), 7.55-7.52 (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
Same with embodiment 7, only to replace phenylacetylene to Methoxy-phenylacetylene.It is as follows that reaction products therefrom detects data: productive rate: 72%; Fusing point: 210-214
oc;
1hNMR (DMSO
-d 6 , 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=8Hz, C18-H); MS-ESIm/z:806.6 [M+Na]
+..
Embodiment 13: the synthesis of target compound Im
Same with embodiment 2, only to replace phenylacetylene to fluorobenzene acetylene.It is as follows that reaction products therefrom detects data: productive rate: 63%; Fusing point: 239-243
oc;
1hNMR (DMSO
-d 6 , 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 ,-SO
2-
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 ,-SO
2-CH
2-
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
Same with embodiment 9, only to replace Methoxy-phenylacetylene fluorobenzene acetylene.It is as follows that reaction products therefrom detects data: productive rate: 70%; Fusing point: 216-219
oc;
1hNMR (DMSO
-d 6 , 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
Same with embodiment 6, only to replace phenylacetylene to fluorobenzene acetylene.It is as follows that reaction products therefrom detects data: productive rate: 58%; Fusing point: 245-248
oc;
1hNMR (DMSO
-d 6 , 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, pyridine-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
Same with embodiment 10, only to replace Methoxy-phenylacetylene fluorobenzene acetylene.It is as follows that reaction products therefrom detects data: productive rate: 65%; Fusing point: 212-215
oc;
1hNMR (DMSO
-d 6 , 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=8Hz, C18-H); MS-ESIm/z:801.6 [M+Na]
+..
Embodiment 17: the synthesis of target compound Iq
Same with embodiment 13, only to replace ethyl sulfonyl azide to fluorobenzene sulfonyl azide.It is as follows that reaction products therefrom detects data: productive rate: 65%; Fusing point: 218-219
oc;
1hNMR (DMSO
-d 6 , 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=8Hz, C18-H); MS-ESIm/z:762.4 [M+Na]
+..
Embodiment 18: the synthesis of target compound Ir
Same with embodiment 7, only to replace phenylacetylene to fluorobenzene acetylene.It is as follows that reaction products therefrom detects data: productive rate: 72%; Fusing point: 200-203
oc;
1hNMR (DMSO
-d 6 , 400MHz)
δ: 8.41-8.39 (m, 2H, C9-H, naphthalene-H), (8.17-7.98 m, 4H, C12-H, naphthalene-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=8Hz, C18-H); MS-ESIm/z:794.2 [M+Na]
+..
Compound
the test method of the anti-tumor activity of a-r and result
Pharmacological evaluation of the present invention adopts Sulforhodamine B(sulforhodamineB, SRB) colorimetry.Tumor cell culture selects the RPMI-1640 substratum of 10% foetal calf serum (FBS), and by tumor cell inoculation in 96 orifice plates, 3-5 × 103 cell is cultivated in each hole, adds the solution title compound to be tested of different concns.Cultivate after 72 hours, every hole adds solution of trichloroacetic acid (50%, the w/v) fixed cell of precooling, fixes 30 minutes in refrigerator.After drying under 96 orifice plate room temperatures, every hole adds 0.04%(w/v) SRB dye liquor (peracetic acid formulation of 1%, purchased from SigmaChemical company), dye and outwell dye liquor after 30 minutes, rinse 4 times with acetic acid, remove unconjugated dyestuff, room temperature is dried.Dissolve with 100 μ L non-buffered Tris-base alkali lye the dyestuff be combined with cell protein, horizontal shaker vibrates 20 minutes, adopt ELx800 absorb light microplate reader (Bio-Tek company of the U.S. produces, function software Gen5) to measure 515nm place absorption value.All tests establish 3 parallel group or in triplicate.Compound
a- rcytotoxic activity test result in table 1.
To five kinds of tumour cell in vitro cytotoxic effect test result displays, compound synthesized by the present invention all shows the activity of the tumour cells such as good poisoning human lung adenocarcinoma cell (A549), Breast cancer lines (MDA-MB-231), human oral epidermoid carcinoma cell (KB), human oral epidermoid carcinoma cells resistance strain (KBvin) and human breast cancer cell (MCF-7), and some compounds exhibit go out the in vitro cytotoxic effect higher than camptothecine clinical medicine irinotecan.In all derivatives, compound
a, c, d, e, m, p, rall demonstrate higher activity to tested five kinds of cells, its activity exceeds irinotecan 10 ~ 20 times, shows good application prospect.
Claims (9)
1. as formula I shows camptothecine sulphonyl amidine compound, in formula: R1 be methyl, ethyl, rubigan, p-nitrophenyl, p-methylphenyl,
to any one in fluorophenyl, phenyl, thienyl, pyridyl or naphthyl; R2 is any one in hydrogen, fluorine or methoxyl group.
2. the preparation method of camptothecine compounds according to claim 1, 7-benzyl diethylenediamine-camptothecine trifluoroacetate is it is characterized in that to be dissolved in methylene dichloride, adding catalyst of triethylamine and stirring makes solution clarify, add sulfonyl azide compound and alkynes successively again, described alkynes is phenylacetylene, to Methoxy-phenylacetylene, to any one in fluorobenzene acetylene, after treating that above reagent adds, finally add cuprous iodide catalyzed reaction, after stirring reaction terminates at normal temperatures, the crude product that desolventizing obtains target product is removed with after methylene dichloride cancellation reaction, described sulfonyl azide compound is sulfonyloxy methyl nitrine, ethyl sulfonyl azide, phenylSulphon nitrine, p-methylphenyl sulfonyl azide, p-nitrophenyl sulfonyl azide, to fluorophenyl sulfonyl azide, rubigan sulfonyl azide, 2-thienyl sulphonyl nitrine, any one in 3-pyridyl sulfonyl azide and 2-naphthyl sulfonyl azide.
3. the preparation method of camptothecine compounds according to claim 1, is characterized in that the crude by column chromatography purification process of obtained target product.
4. the preparation method of camptothecine compounds according to claim 3, is characterized in that, during the crude by column chromatography purification process of target product, volume ratio is: the chloroform-methanol wash-out of 70:1 ~ 100:1.
5. method according to claim 4, is characterized in that silica gel for chromatography post adopts 200 ~ 300 object column chromatography silica gel.
6. the preparation method of the camptothecine compounds according to Claims 2 or 3 or 4 or 5, it is characterized in that, 0.2mmol7-benzyl diethylenediamine-camptothecine trifluoroacetate is dissolved in 10mL methylene dichloride, sulfonyl azide compound and alkynes solution add-on are respectively 0.22 ~ 0.44mmol, and the add-on of cuprous iodide is 0.01mmol.
7. the preparation method of the camptothecine compounds according to Claims 2 or 3 or 4 or 5, is characterized in that sulfonyl azide compound and alkynes solution usage are respectively 0.24mmol.
8. a kind of camptothecine compounds according to claim 1 is applied in the medicine of the various cancer of preparation treatment.
9. purposes according to claim 8, is characterized in that described cancer cell is lung adenocarcinoma cell (A549), Breast cancer lines (MDA-MB-231), human oral epidermoid carcinoma cell (KB), human oral epidermoid carcinoma cells resistance strain (KBvin) or human breast cancer cell (MCF-7).
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| XIAO-BO ZHAO ET AL.: "Design and synthesis of new 7-(N-substituted-methyl)-camptothecin derivatives as potent cytotoxic agents", 《BIOORGANIC & MEDICINAL CHEMISTRY LETTERS》 * |
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