CN103709122A - Antitumor and antifungal compound for treatment - Google Patents

Antitumor and antifungal compound for treatment Download PDF

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CN103709122A
CN103709122A CN201310633520.1A CN201310633520A CN103709122A CN 103709122 A CN103709122 A CN 103709122A CN 201310633520 A CN201310633520 A CN 201310633520A CN 103709122 A CN103709122 A CN 103709122A
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compound
cancer
salt
antitumor
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CN103709122B (en
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陈亿
刘捷
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Sichuan University
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    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
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    • C07D513/04—Ortho-condensed systems

Abstract

The invention relates to the technical field of medicines, in particular to a preparation technology of a compound with antitumor activity and antifungal activity and antitumor and antifungal medicinal use of the compound. The compound especially has obvious therapeutic effects on gastric cancer, various metastatic liver cancer, breast cancer, lung cancer, colon cancer, melanomas and multiple malignant tumors.

Description

Antitumor and the antifungal compound being used for the treatment of
Technical field
The present invention relates to medical technical field, is its method for making and its antitumor and antimycotic medicinal use of the antitumor and antifungal compound fused tricyclic that is used for the treatment of of a class.
Background technology
The malignant tumour serious threat mankind's life and health, the annual whole world approximately has 7,000,000 people to die from cancer, accounts for 1/4th of total death toll.Cancer of the stomach is the modal a kind of malignant tumour of China, and its mortality ratio accounts for the first place of various malignant tumours.Liver cancer is China's second cancer " killer ", and the position that leapt to the first in part High Phc Incidence Area, accounts for 45% of whole world PLC mortality number.Mammary cancer is the major malignant tumor of harm WomanHealth, and the whole world approximately has 1,200,000 women that mammary cancer occurs every year.The existing cancer patients's mortality ratio of China exceedes 30% at present, has become the second largest factor of China's death.Pharmacological agent has become a kind of methods for the treatment of that malignant tumour effectively and is generally used.Within 2010, global antitumor drug sales volume is about 60,000,000,000 dollars.The antitumor drug of application is of a great variety clinically, and wherein chemotherapeutics mainly contains the microbiotic of alkylating agent molybdenum complex antitumor drug, anthracene ring antitumor medicinal, destruction DNA etc.In addition, the research of natural antitumor medicine also occupies sizable ratio, as commonly used clinically at present some medicines, has camptothecine, vincristine(VCR), taxol etc.Yet existing antitumor drug exists the problems such as selectivity is poor, toxic side effect, resistance.The antitumor drug of finding high-efficiency low-toxicity is still the important topic that scientist faces.The invention provides the fused tricyclic class medicines structure with anti-tumor activity, there is important development prospect.In recent years, antifungal drug research has obtained compared with much progress, but for clinical medicine, also comes with some shortcomings at present, as: fluconazole is poor to aspergillus tubigensis effect, and Resistant strain constantly produces; Special more poor to yeast effect than naphthalene fen; Itraconazole is difficult for seeing through hemato encephalic barrier, and toxic side effect incidence is higher.Therefore, find efficient, low toxicity, broad-spectrum antifungal medicine is still a worldwide important topic.
Summary of the invention
The present invention is based on a wonderful discovery, it is the growth that fused tricyclic compounds or its pharmacy acceptable salt effectively suppress some cancer cells, this compounds has obvious restraining effect to cancer of the stomach, liver cancer, breast cancer cell, in addition, this fused tricyclic compounds or its pharmacy acceptable salt also have inhibition to fungal growth.
Its structural formula is as follows:
Figure BDA0000426185350000021
X is selected from S, O, N-R ', C=O
R 1and R ' be selected from be respectively hydrogen, alkyl,
Figure BDA0000426185350000022
R 2, R 3, R 4and R 5being selected from respectively monosubstituted and polysubstituted is hydrogen, alkyl, cycloalkyl, alkoxyl group, aryl, hydroxyl, carboxyl, halogen, itrile group, nitro.
A subset of this fused tricyclic compounds has following chemical formula:
Figure BDA0000426185350000023
Described compound exists with the form of hydrate or salt.Salt is inorganic salt or organic salt, example hydrochloric acid salt, vitriol, fumarate, mesylate, sulfonate etc.
Further say R 1from hydrogen, alkyl, benzyl, select R 2, R 3, R 4and R 5be respectively monosubstituted;
Further say R 2, R 3, R 4and R 5be respectively hydrogen, bromine, methoxyl group, chlorine, hydroxyl, carboxyl, itrile group.
Here term " alkyl " refers to the straight or branched-chain hydrocarbon that contains 1-10 carbon atom.The example of alkyl includes but not limited to methyl, ethyl, n-propyl group, i-propyl group, n-butyl, i-butyl, t-butyl.Term " cycloalkyl " refers to the saturated and unsaturated cyclic hydrocarbon group with 3 to 12 carbon of part.The example of cycloalkyl includes but not limited to cyclopropyl, cyclobutyl, cyclopentyl plinth, cyclohexyl, cyclic vinyl, suberyl plinth and ring octyl group.Refer to-O-of term " alkoxyl group " alkyl.Term " aryl " refers to 6 carbon monocycles, 10 carbon dicyclos, and the aromatic ring system of 14 carbon three rings, wherein each ring can have 1 to 4 substituting group.The example of aromatic ring includes but not limited to phenyl, naphthyl and anthryl.Alkyl, aryl, cycloalkyl, aryl, alkoxyl group comprise replacement and unsubstituted part as mentioned herein.
Some examples that represent fused tricyclic heterocycles compound of the present invention below
Figure BDA0000426185350000051
The some other example that represents compound of the present invention below:
Figure BDA0000426185350000071
Figure BDA0000426185350000081
Figure BDA0000426185350000091
Figure BDA0000426185350000101
Above-mentioned fused tricyclic compounds suppresses cancer cell and fungal growth.Therefore, on the other hand, feature of the present invention is also to treat the method for cancer and fungi.The method comprises needs one of effective above-claimed cpd of its curer.
Embodiment
1: compound 1 synthetic
Figure DEST_PATH_GDA0000464551510000102
Concrete synthesis step is: will
Figure DEST_PATH_GDA0000464551510000111
(0.5mmol), CuI(0.1mmol), L-proline (0.2mmol), andK2CO3 (2.5mmol) adds in reactor, substitutes Ar gas three times.Add
Figure DEST_PATH_GDA0000464551510000112
(0.55mmol) and 2.0mLDMSO, stir 48h at 90 ℃, continue to be heated to 110 ℃ of reaction 48h, with TLC monitoring reaction.Pressure reducing and steaming solvent, residue is dissolved in 20mL ethyl acetate.Organic phase waterside three times, salt washing 1 time, anhydrous sodium sulfate drying.After concentrated, after column chromatography purification, obtain product 1. 1H?NMR(400MHz,DMSO-d 6):8.35(s,1H),7.14(dd,J=2.0,10.4Hz,1H),6.91(s,1H),6.65(s,1H),6.55(s,1H),2.10(s,3H),2.09(s,3H); 13C?NMR(100MHz,DMSO-d 6)d148.9(J=243.8Hz),140.0,136.4,134.0,129.1(J=13.5Hz),124.7,123.8(J=9.4Hz),121.4(J=2.5Hz),120.7(J=3.2Hz),114.4(J=22.6Hz),114.1,111.8,20.5,19.1.MS(EI)m/z279(M)+。
2: compound 19 synthetic
Figure DEST_PATH_GDA0000464551510000113
Concrete synthesis step is:
2-iodo phenol 1.0mmol and 1-F-2-oil of mirbane 1.0mmol and 2mmol salt of wormwood are dissolved in 10mLDMSO, the lower heating of 100 degree 15 hours.Be cooled to after room temperature, add large water gaging, be extracted with ethyl acetate three times.After organic phase is washed three times, concentrate drying obtains 2-(2-iodophenoxy) aniline. 1H?NMR(400MHz,CDCl 3):7.85(dd,J=1.5,7.8Hz,1H),7.30(dt,J=1.5Hz,J=7.8Hz,1H),6.92-6.82(m,3H),6.67(d,J=8.1Hz,2H),6.53(dd,J=1.5Hz,J=7.5Hz,1H),4.89(s,2H).? 13C?NMR(100MHz,CDCl3):157.3,142.6,140.8,140.2,130.7,126.0,125.5,120.5,117.5,117.3,116.7,88.7。
2-(2-iodophenoxy) aniline1mmol and 5mmol diacetyl oxide are mixed, stirred overnight at room temperature, mixture adds the aqueous solution of sodium carbonate, be extracted with ethyl acetate, organic phase anhydrous sodium sulfate drying, concentrated rear column chromatography obtains product N-(2-(2-iodophenoxy) phenyl) acetamid. 1h NMR (400MHz, CDCl3): 8.36 (d, J=7.9Hz, 1H), 7.94 (s, 1H), 7.79 (d, J=8.0Hz, 1H), 7.23 (t, J=7.7Hz, 1H), 7.04 (t, J=7.7Hz, 1H), 6.94 (d, J=7.7Hz, 1H), 6.84 (t, J=7.4Hz, 1H), 6.70 (d, J=8.1Hz, 1H), 2.11 (s, 3H). 13c NMR (100MHz, CDCl3): δ=168.1,155.1,144.9,139.5,129.6,129.1,125.6,123.9,123.6,121.1,118.8,116.9,88.2,24.5. (EI): m/z=353[M]+
N-(2-(2-iodophenoxy) phenyl) acetamid1mmol and 2mmol salt of wormwood are added in reactor, under argon shield, by syringe, add DMEDA0.1mmol and toluene 1mL.At 135 degree, stir 24 hours, reaction solution dissolves with methylene dichloride after being cooled to room temperature, filters, and concentrated solution, obtains compound 19 by column chromatography. 1H?NMR(400MHz,CDCl3):δ=7.50-7.45(m,2H),7.22-7.16(m,2H),7.15-7.10(m,4H),2.33(s,3H)。 13C?NMR(100MHz,CDCl3):δ=169.0,150.8,129.3,126.7,125.0,123.2,116.7,23.0.
3: compound 25 synthetic
Figure DEST_PATH_GDA0000464551510000121
2mmol, 2.0mmol, CuI0.2mmol,
Figure DEST_PATH_GDA0000464551510000124
0.4mmol, Cs 2cO 3the mixture of 4.0mmol is dissolved in the DMF of 5mL, N 2under gas protection, be heated to 120 degree 24 hours.After reaction solution cool to room temperature, with acetic acid ethyl dissolution, filter, with ethyl acetate washing, after filtrate concentrate drying, column chromatography purification obtains compound 25.
4: compound 37 synthetic
Figure BDA0000426185350000125
By 0.15mmol's
Figure BDA0000426185350000131
the CuI of 20mol% is dissolved in the mixed solution of 0.4mLDMSO and 0.4mL chlorobenzene, and 140 degree are lower to be stirred 48 hours.Use TLC monitoring reaction course.After having reacted, with acetic acid ethyl dissolution, after concentrate drying, column chromatography purification obtains compound 37. 1H?NMR(400MHz,DMSO):δ6.05(s,2H),7.66(s,1H),7.93-8.01(m,2H),8.26-8.57(m,5H),8.87-8.95(m,2H),10.78(brs,1H,); 13C?NMR(100MHz,DMSO):54.34,122.60,123.18,125.43,125.72,126.36,130.05,131.23,134.00,135.72,138.19,138.72,145.57,146.03,181.82;MS?m/z276[M+1] +
Fused tricyclic of the present invention is the active compound for anti tumor of a class high-efficiency low-toxicity, and the Several Kinds of Malignancies such as various secondary liver cancers, Vipoma and melanoma are had to obvious curative effects.Its main pharmacodynamics test-results is as follows:
1. test method
With one group of tumor cell line, be SK-Hep-1(liver cancer), HepG2(hepatocellular carcinoma), MKN-45(cancer of the stomach), MDA-MB-231(breast cancer cell), A549(nonsmall-cell lung cancer), OVCAR-3(ovarian cancer), A498(kidney), HCT-116(colorectal carcinoma), M4(melanoma) detect the anti tumor activity in vitro of above-mentioned fused tricyclic compounds.
By SK-Hep-1, HepG2, MKN-45, MDA-MB-231, A549, OVCAR-3, A498, HCT-116, M4 are kept in the plastic ware in the PRMI medium that is full of 5% foetal calf serum.In 96 orifice plates, inoculate the tumour cell that final densities is 10000 cell/mL.Utilize test compound to process cell (at least 5 different concns), every concentration is all made 6 parallel holes, separately establishes blank well and control wells, during drug effect, with the growing state of inverted phase contrast microscope observation of cell, in 37 degree CO2 incubators, to cultivate after 72 hours, every hole adds the MTT20 μ L of 5g/L, cultivate 4h, abandon supernatant liquor, add DMSO approximately 100 μ L/ holes, vibration 10min, purple crystal thing is fully dissolved, by microplate reader, measure the absorbancy at 490nm place.According to the cytotoxicity of the value representation test compound of IC50.The mean value of 6 Duplicate Samples of above-mentioned value representation.
At all compounds of the compound 1-48 of above-mentioned test, all effectively suppressing is SK-Hep-1, HepG2, MKN-45, MDA-MB-231, A549, the growth of OVCAR-3, A498, HCT-116, M4 cell.Unexpectedly, the IC50 value that in them, great majority are all expressed is less than 1mM, and some are even less than 100nM.
Figure BDA0000426185350000141
Figure BDA0000426185350000161
Figure BDA0000426185350000171
2. drug sensitive experiment
Before experiment, the SDA substratum of preserving from 4 degree with inoculation circle, picking cryptococcus neoformans, Candida albicans and Candida parapsilosis etc. are seeded to 1mL YEPD nutrient solution, and in 35 degree, with 250r/min shaking culture, activation 16h, makes fungi in later stage exponential phase of growth.Get this bacterium liquid to 1mL YEPD nutrient solution, with aforesaid method, again activate, after 16h, with blood cell counting plate counting, with RPMI1640 nutrient solution, adjust bacterial concentration to 1 * 10 3-5 * 10 3individual/mL.
Compound 1-48 is made into 6.4mg/mL solution with DMSO respectively.Get aseptic 96 orifice plates, in No. 1 hole of every row, add RPMI1640100 μ L and make blank; 3-12 hole respectively adds freshly prepared bacterium liquid 100 μ L; No. 2 hole adds respectively bacterium liquid 200 μ L and test-compound solution 2 μ L; 10 grades, 2-11 hole doubling dilution, No. 12 holes are not containing medicine; Make positive control.Each drug sensitive plate is cultivated in 35 degree.
MIC value is judged
Candidiasis, cryptococcus neoformans are cultivated after 72h respectively at 35 degree, with enzyme micro-plate reader, in 630nm, survey each hole OD value.With positive control boring ratio, the drug level in the minimum concentration hole that the OD value of take declines more than 80% is MIC 80(drug level when fungal growth 80% is suppressed).
Figure BDA0000426185350000181
Figure BDA0000426185350000191
Figure BDA0000426185350000201

Claims (6)

1. compound or its pharmacy acceptable salt, is characterized in that the structural formula of compound is
Figure FDA0000426185340000011
X is selected from S, O, N-R ', C=O;
R 1and R ' be selected from be respectively hydrogen, alkyl,
R 2, R 3, R 4and R 5being selected from respectively monosubstituted and polysubstituted is hydrogen, alkyl, cycloalkyl, alkoxyl group, aryl, hydroxyl, carboxyl, halogen, itrile group, nitro.
2. compound as claimed in claim 1 or its pharmacy acceptable salt, it is specifically selected from following structure:
Figure FDA0000426185340000013
3. compound as claimed in claim 1 or 2 or its pharmacy acceptable salt, is characterized in that: R 1from hydrogen, alkyl, benzyl, select R 2, R 3, R 4and R 5be respectively monosubstituted.
4. compound or its pharmacy acceptable salt as described in claim 1-3 any one, is characterized in that: R 2, R 3, R 4and R 5be respectively hydrogen, bromine, methoxyl group, chlorine, hydroxyl, carboxyl, itrile group.
5. compound or its pharmacy acceptable salt as described in claim 1-4 any one, its feature is that form with hydrate or salt exists at it, salt is inorganic salt or organic salt, is specifically selected from hydrochloride, vitriol, fumarate, mesylate, sulfonate.
6. the compound described in claim 1-5 or its pharmacy acceptable salt are for the preparation of the purposes of antitumor or antifungal drug.
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CN104356142A (en) * 2014-10-22 2015-02-18 爱医生技股份有限公司 Dehydrothiamine [2,3-c] quinoline-12-ketone derivatives, and preparation method and application thereof
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CN110818706A (en) * 2018-08-09 2020-02-21 苏州东南药业股份有限公司 Four-condensed ring quinoxaline derivative and preparation method thereof
CN113004216A (en) * 2019-12-20 2021-06-22 湖南超亟化学科技有限公司 Preparation method and application of novel benzoxazine hypochlorous acid fluorescent molecular probe
CN113004216B (en) * 2019-12-20 2023-10-03 湖南超亟检测技术有限责任公司 Preparation method and application of benzoxazine hypochlorous acid fluorescent molecular probe
CN115557890A (en) * 2022-09-01 2023-01-03 宁波大学 Polysubstituted acridone alkyl derivative and preparation method and application thereof

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