CN104557711B - The preparation and application of the pyrazoles oxime compound of the structure containing FTS - Google Patents
The preparation and application of the pyrazoles oxime compound of the structure containing FTS Download PDFInfo
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- CN104557711B CN104557711B CN201410831451.XA CN201410831451A CN104557711B CN 104557711 B CN104557711 B CN 104557711B CN 201410831451 A CN201410831451 A CN 201410831451A CN 104557711 B CN104557711 B CN 104557711B
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- 0 CC(C)*(C1)([C@]1C#C)C(C)=CCCC(C)=CCCC(C)=CCSc1ccccc1C(C)=O Chemical compound CC(C)*(C1)([C@]1C#C)C(C)=CCCC(C)=CCCC(C)=CCSc1ccccc1C(C)=O 0.000 description 1
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
- C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
- C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D231/18—One oxygen or sulfur atom
- C07D231/20—One oxygen atom attached in position 3 or 5
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Abstract
The present invention relates to the preparation and application of a kind of pyrazoles oxime compound (I) of structure containing FTS.It is condensed to yield with the oxime of hydroxyl containing pyrazoles (II) and farnesyl thiosalicylic isoxazolecarboxylic acid (III).The pyrazoles oxime compound I of the structure containing FTS has effective prevention effect to tumour cell HCT116 and Hep G2, and the compound can be used for the antineoplastic for preparing the field such as medical.
Description
Technical field
The invention belongs to field of medicaments, and in particular to pyrazoles oxime compound of a kind of structure containing FTS and preparation method thereof
And medical usage.
Background technology
The preventing and treating of tumour is the core realm of medical science research all the time, and anti-tumor agents are widely used so that more
Number tumour cell has obtained effective treatment.But with the continuous expansion of medical anti-tumor agents application scale, conventional medicament kind
Resistance problems increasingly highlight, plus the emergence of new tumor disease so that newtype drug continues to research and develop
As inevitable choice.
Pyrazoles 9 oxime derivate is a kind of important nitrogen-containing heterocycle compound, is played an important role in anti-tumor aspect, such as
Compound A~D of the discoveries such as Park shows cytotoxicity to tumor line, wherein, compound A and compound B are to people's Colon and rectum
Adenocarcinoma cell HCT15 IC50Value is respectively 0.10 and 1.83 μ g/mL；Compound A and compound B are to human A549 cell lines
IC50Value is respectively 0.13 and 0.39 μ g/mL；ICs of the compound C and compound D to Proliferation of Human Ovarian Cell Skov-350Value difference
For 9.06 and 0.28 μ g/mL；ICs of the compound C and compound D to people's central nerve neuroma XF49850Value is respectively 3.87
With 0.02 μ g/mL (Bioorg.Med.Chem.Lett., 2005,15,3307-3312).
In addition, farnesyl thiosalicylic acid (FTS) is a kind of important Ras protein inhibitors, being capable of competitive substitution F-
Ras and F-Ras mutains are combined with Galectins, suppress to trigger downstream signaling pathway (including Raf and P13K signals by Ras
Path, so as to promote apoptosis of tumor cells, suppress the growth of tumour cell.Result of the test shows that FTS is to lung cell A549
IC50It is worth for 40 μM；To breast cancer cell MCF-7 IC50Value is at 75 μM or so；Also have inhibitory action to cancer of pancreas Panc-1, its
IC50It is worth for 35 μM.In view of FTS has good antitumor activity and smaller toxic side effect, study, can control into the clinical II phases
Treat lung cancer and cancer of pancreas (J Med Chem.2009,52,197-205；J Thorac Oncol,2011,6,1435-1437；
Future Oncol,2010,6,885–891)。
Therefore, in order to find and find the lead drug with more high anti-tumor activity, we are spelled using active substructure
The method connect, pyrazoles oxime and FTS activity units are reasonably combined, there is containing for medical value the invention discloses a kind of
The pyrazoles oxime compound of FTS structures.
The content of the invention
It is an object of the invention to provide the pyrazoles oxime compound of one kind structure containing FTS, to meet new type antineoplastic medicine
Treatment need.
It is a further object of the present invention to provide the preparation method of above-claimed cpd.
There is the purposes in terms of antitumor activity it is a still further object of the present invention to provide above-claimed cpd.
The object of the invention can be reached by following measures：
The pyrazoles oxime compound of the structure of the present invention containing FTS, it is characterised in that possess the structure as shown in formula I：
Wherein, the position of substitution represents with 2~4 on phenyl ring；
R is H, Cl, Br, F, I, CH3, OCH3Or OCF3In a kind of group monosubstituted base, or for above-mentioned any two kinds
Group forms disubstituted；
The position of substitution of R on phenyl ring can be in two or three-digit or 4.
The pyrazoles oxime compound preparation method of such structure containing FTS, it is characterised in that the compound shown in formula I is by leading to
Formula II and farnesyl thiosalicylic isoxazolecarboxylic acid (III) are condensed to yield under acid binding agent effect：
Wherein, the position of substitution represents with 2~4 on phenyl ring；
R is H, Cl, Br, F, I, CH3, OCH3Or OCF3In a kind of group monosubstituted base, or for above-mentioned any two kinds
Group forms disubstituted；
The position of substitution of R on phenyl ring can be in two or three-digit or 4.
Wherein acid binding agent is：Pyridine, picoline, triethylamine, diisopropylethylamine (DIEA), 4-N, N- lutidines
(DMAP)。
The dosage of acid binding agent is usually 1.3~10 times of compound mole shown in formula II.
Wherein solvent is：DMF (DMF), DMA (DMA), DMSO, dichloromethane,
Chloroform, toluene, 1,2- dichloroethanes, dioxane, acetonitrile etc..
Wherein the mole of compound III is 0.9~2.0 times of the compound mole of formula II.
The compound reference literature of formula II (Eur.J.Med.Chem., (2013) 60,376-385；
Bioorg.Med.Chem.Lett., 2005 (15), 3307-3312.) method synthesize to obtain；General formula III compound reference literature
The method of (Bioorg.Med.Chem., 2014 (22), 374-380.) synthesizes to obtain.
Compound of Formula I has excellent therapeutic effect to tumour cell, thus the compound of the present invention can be used as preparing
Anti-tumor agents.Described tumour cell has HCT116, Hep G2 etc..
When the compound of the invention represented by formula I is used as antineoplastic, can be used alone, or with antitumor group
The mode of compound uses, i.e., using Formulas I as active component, preparation is made for being administered plus carrier combinations commonly used in the art,
It can be made into oral dosage form such as tablet, granule, capsule etc..
The various formulations of pharmaceutical composition of the present invention can be prepared according to well known method in pharmaceutical field.These medicines
, also can be according to the serious journey of disease with the active component that can contain in preparation with such as 0.05% to 90% weight of carrier combinations
Degree or the different dosages of formulation exceed this dosage range.
The pyrazoles oxime compound of the structure disclosed by the invention containing FTS has excellent therapeutic effect to tumour cell, because
This can be used to prepare the antineoplastic for medicine and other fields.
Embodiment
For the ease of being further appreciated that to the present invention, examples provided below has done more detailed description to it.This
A little embodiments are only not used for limiting the scope of the present invention or implementation principle for narration.
Embodiment 1：
Chemical compounds I a synthesis (R=4-CH3)
Added in reaction bulb pyrazoles oxime intermediate II a 3mmol, farnesyl thiosalicylic isoxazolecarboxylic acid (III) 4.5mmol and
30mL DMF, 9mmol triethylamines are put under stirring thereto, the mixture of gained is stirred at room temperature 16 hours.Stop reaction.Will
Reaction solution is concentrated to dryness, and silica gel mixed sample dress post separation purifies to obtain a of object I.1H NMR(400MHz,CDCl3):δ8.13(s,
1H, CH=N), 7.85 (d, J=8.0Hz, 1H, Ar-H), 7.32-7.41 (m, 2H, Ar-H), 7.12-7.15 (m, 3H, Ar-H),
6.82 (d, J=8.8Hz, 2H, Ar-H), 5.08-5.33 (m, 3H, SCH2CH and 2×CH2CH=CCH3),3.60(s,3H,
N-CH3), 3.56 (d, J=7.2Hz, 2H, SCH 2CH), 2.54 (s, 3H, CH3), 2.31 (s, 3H, Ar-CH3), 1.94-2.11
(m,8H,2×CCH 2CH 2CH), 1.59-1.72 (m, 12H, 4 × CH=CCH 3).
Embodiment 2：
Chemical compounds I b synthesis (reference compound Ia synthesis, wherein R=3-F)
Added in reaction bulb pyrazoles oxime intermediate II b 5mmol, farnesyl thiosalicylic isoxazolecarboxylic acid (III) 7mmol and
25mL dichloromethane, 25mmol pyridines are put under stirring thereto, the mixture of gained is stirred at room temperature 20 hours.Stop anti-
Should.Reaction solution is concentrated to dryness, silica gel mixed sample dress post separation purifies to obtain the b of object I.1H NMR(400MHz,CDCl3):δ
8.09 (s, 1H, CH=N), 7.77~7.79 (m, 1H, Ar-H), 7.20-7.36 (m, 3H, Ar-H), 7.05~7.09 (m, 1H,
), Ar-H 6.75~6.80 (m, 1H, Ar-H), 6.63 (d, J=7.2Hz, 2H, Ar-H), 5.00~5.25 (m, 3H, SCH2CH
and 2×CH2CH=CCH3),3.55(s,3H,N-CH3), 3.49 (d, J=7.2Hz, 2H, SCH 2CH),2.46(s,3H,CH3),
1.86~2.09 (m, 8H, 2 × CCH 2CH 2CH), 1.51~1.65 (m, 12H, 4 × CH=CCH 3).
Embodiment 3：
Chemical compounds I c synthesis (reference compound Ia synthesis, wherein R=4-Cl)
Added in reaction bulb pyrazoles oxime intermediate II c 4mmol, farnesyl thiosalicylic isoxazolecarboxylic acid (III) 5.2mmol and
30mL dichloromethane, 10mmol 4-N, N- lutidines is put under stirring thereto, the mixture of gained is reacted at room temperature 18
Hour, stop reaction.Reaction solution is concentrated to dryness, silica gel mixed sample dress post separation purifies to obtain the c of object I.
1H NMR(400MHz,CDCl3):δ 8.07 (s, 1H, CH=N), 7.77-7.79 (m, 1H, Ar-H), 7.29-7.34
(m,1H,Ar-H),7.22-7.27(m,2H,Ar-H),7.05-7.09(m,1H,Ar-H),6.86-6.99(m,1H,Ar-H),
6.82 (d, J=8.8Hz, 2H, Ar-H), 5.00-5.26 (m, 3H, SCH2CH and 2×CH2CH=CCH3),3.54(s,3H,
N-CH3), 3.49 (d, J=7.6Hz, 2H, SCH 2CH), 2.45 (s, 3H, CH3), 1.86-2.04 (m, 8H, 2 × CCH 2CH 2CH),
1.51-1.60 (m, 12H, 4 × CH=CCH 3).
Embodiment 4：
Chemical compounds I d synthesis (reference compound Ia synthesis, wherein R=4-OCF3)
Added in reaction bulb pyrazoles oxime intermediate II d 3mmol, farnesyl thiosalicylic isoxazolecarboxylic acid (III) 3.9mmol and
30mL acetonitriles, 15mmol diisopropylethylamine (DIEA) is put under stirring thereto, the mixture room temperature reaction 19 of gained is small
When, stop reaction.Reaction solution is concentrated to dryness, silica gel mixed sample dress post separation purifies to obtain the d of object I.1H NMR(400MHz,
CDCl3):δ 8.15 (s, 1H, CH=N), 7.84-7.86 (m, 1H, Ar-H), 7.33-7.43 (m, 2H, Ar-H), 7.21 (d, J=
8.4Hz, 2H, Ar-H), 7.12-7.16 (m, 1H, Ar-H), 6.97 (d, J=9.2Hz, 2H, Ar-H), 5.06-5.33 (m, 3H,
SCH2CH and 2×CH2CH=CCH3),3.63(s,3H,N-CH3), 3.57 (d, J=7.2Hz, 2H, SCH 2CH), 2.52 (s,
3H,CH3), 1.94-2.11 (m, 8H, 2 × CCH 2CH 2CH), 1.59-1.72 (m, 12H, 4 × CH=CCH 3).
Embodiment 5：
Screening active ingredients of the sample to tumour cell
Using tetramethyl nitrogen azoles indigo plant colorimetric method (MTT) antitumor activity in vitro.It is HepG2 cell lines for examination object
With human colon cancer cell HCT116.FTS is selected as positive control drug.Take in exponential phase of growth cell one in good condition
Bottle, 0.25% Trypsin Induced is added, attached cell is come off, be made every milliliter and contain 2 × 104~4 × 104Individual cell hangs
Liquid.Cell suspension inoculation is taken, per the μ L of hole 180, to put constant temperature CO on 96 orifice plates2Cultivated 24 hours in incubator.Change liquid, add by
Trying compound Ia-Id, (compound is diluted with after dmso solution with PBS, and Test compound concentrations are 25 × 10-6), per hole
20 μ L, cultivate 48 hours.MTT is added in 96 orifice plates, per the μ L of hole 20, reacted 4 hours in incubator.Supernatant is sucked, is added
Dimethyl sulfoxide (DMSO), per the μ L of hole 150, shaken 5 minutes on plate shaker.With enzyme-linked immunosorbent assay instrument wavelength be at 570nm determine
Trap per hole, calculate cell inhibitory rate.Experimental result is as shown in table 1.
Cell inhibitory rate=(negative control group OD values-tested material group OD values)/negative control group OD value × 100%.
The inhibiting rate (%) that table 1.Ia-Id breeds to Partial tumors cell
Result of the test is found, when test concentrations are 25 μm of ol/L, chemical compounds Ia- I d to HepG2 cell lines and
Human colon cancer cell HCT116 has different degrees of cytotoxicity, and the wherein d of chemical compounds I b- I are shown to HepG2 and HCT116
Preferable inhibiting rate, chemical compounds I c respectively reach 90.4 and 88.5% to HepG2 and HCT116 inhibiting rate, and drug effect is substantially higher
In positive control drug FTS.Data above shows, is combined by FTS fragments and pyrazoles oxime unit, some mesh of gained
Mark thing shows good inhibition to HepG2 and HCT116.
Claims (5)
1. the pyrazoles oxime compound of a kind of structure containing FTS, it is characterised in that possess the structure as shown in formula I：
Wherein, the position of substitution represents with 2~4 on phenyl ring；
R is H, Cl, Br, F, I, CH3, OCH3Or OCF3In a kind of group monosubstituted base, or be above-mentioned any two kinds of groups
What is formed is disubstituted；
The position of substitution of R on phenyl ring is in two or three-digit or 4.
2. the preparation method of the pyrazoles oxime compound of a kind of structure containing FTS, it is characterised in that the compound shown in formula I is by leading to
Formula II and farnesyl thiosalicylic isoxazolecarboxylic acid (III) are condensed to yield under acid binding agent effect：
Wherein, the position of substitution represents with 2~4 on phenyl ring；
R is H, Cl, Br, F, I, CH3, OCH3Or OCF3In a kind of group monosubstituted base, or be above-mentioned any two kinds of groups
What is formed is disubstituted；
The position of substitution of R on phenyl ring is in two or three-digit or 4.
3. preparation method as claimed in claim 2, wherein acid binding agent are：Pyridine, picoline, triethylamine, diisopropyl second
Amine (DIEA), 4-N, N- lutidines (DMAP)；The dosage of acid binding agent is usually 1.3 of compound mole shown in formula II
~10 times.
4. preparation method as claimed in claim 2, wherein solvent are：DMF (DMF), N, N- dimethyl second
Acid amides (DMA), DMSO, dichloromethane, chloroform, toluene, 1,2- dichloroethanes, dioxane, acetonitrile.
5. the mole of synthetic method as claimed in claim 2, wherein compound III is the 0.9 of the compound mole of formula II
~2.0 times.
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| US5338749A (en) * | 1989-02-10 | 1994-08-16 | Basf Aktiengesellschaft | Diaryl-substituted heterocyclic compounds, their preparation and drigs and cosmetics obtained therefrom |
| WO2003027074A1 (en) * | 2001-09-25 | 2003-04-03 | Bayer Pharmaceuticals Corporation | Pyrazole derivatives useful in the treatment of hyper-proliferative disorders |
| WO2004017961A2 (en) * | 2002-08-21 | 2004-03-04 | Astrazeneca Ab | Derivatives of 3-hydroxy-4-(cyclyl-alkylaminoalkyl)-5-phenyl-1h-pyrazole as antagonists of the gonadotropin releasing hormone (gnrh) for use in the treatment of sex hormone related conditions, such as prostatic of uterine cancer |
| WO2008121861A2 (en) * | 2007-03-28 | 2008-10-09 | Xenon Pharmaceuticals Inc. | Pyrazole and pyrrole compounds useful in treating iron disorders |
| CN103450301A (en) * | 2013-09-09 | 2013-12-18 | 南通大学 | Farnesyl thiosalicylic acid-nucleoside conjugate as well as preparation method and medical application thereof |
| CN103864720A (en) * | 2014-01-23 | 2014-06-18 | 南通大学 | Phenyl acrylic acid farnesyl thiosalicylic acid (FTA) derivative as well as preparation method and application |
-
2014
- 2014-12-26 CN CN201410831451.XA patent/CN104557711B/en active Active
Patent Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5338749A (en) * | 1989-02-10 | 1994-08-16 | Basf Aktiengesellschaft | Diaryl-substituted heterocyclic compounds, their preparation and drigs and cosmetics obtained therefrom |
| WO2003027074A1 (en) * | 2001-09-25 | 2003-04-03 | Bayer Pharmaceuticals Corporation | Pyrazole derivatives useful in the treatment of hyper-proliferative disorders |
| WO2004017961A2 (en) * | 2002-08-21 | 2004-03-04 | Astrazeneca Ab | Derivatives of 3-hydroxy-4-(cyclyl-alkylaminoalkyl)-5-phenyl-1h-pyrazole as antagonists of the gonadotropin releasing hormone (gnrh) for use in the treatment of sex hormone related conditions, such as prostatic of uterine cancer |
| WO2008121861A2 (en) * | 2007-03-28 | 2008-10-09 | Xenon Pharmaceuticals Inc. | Pyrazole and pyrrole compounds useful in treating iron disorders |
| CN103450301A (en) * | 2013-09-09 | 2013-12-18 | 南通大学 | Farnesyl thiosalicylic acid-nucleoside conjugate as well as preparation method and medical application thereof |
| CN103864720A (en) * | 2014-01-23 | 2014-06-18 | 南通大学 | Phenyl acrylic acid farnesyl thiosalicylic acid (FTA) derivative as well as preparation method and application |
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