CN103709122B - Antitumor and the antifungal compound being used for the treatment of - Google Patents

Antitumor and the antifungal compound being used for the treatment of Download PDF

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CN103709122B
CN103709122B CN201310633520.1A CN201310633520A CN103709122B CN 103709122 B CN103709122 B CN 103709122B CN 201310633520 A CN201310633520 A CN 201310633520A CN 103709122 B CN103709122 B CN 103709122B
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cancer
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antitumor
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CN103709122A (en
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陈亿
刘捷
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Sichuan University
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    • C07D279/18—[b, e]-condensed with two six-membered rings
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    • C07D279/18—[b, e]-condensed with two six-membered rings
    • C07D279/22—[b, e]-condensed with two six-membered rings with carbon atoms directly attached to the ring nitrogen atom
    • C07D279/24—[b, e]-condensed with two six-membered rings with carbon atoms directly attached to the ring nitrogen atom with hydrocarbon radicals, substituted by amino radicals, attached to the ring nitrogen atom
    • C07D279/28—[b, e]-condensed with two six-membered rings with carbon atoms directly attached to the ring nitrogen atom with hydrocarbon radicals, substituted by amino radicals, attached to the ring nitrogen atom with other substituents attached to the ring system
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    • C07D279/14—1,4-Thiazines; Hydrogenated 1,4-thiazines condensed with carbocyclic rings or ring systems
    • C07D279/18—[b, e]-condensed with two six-membered rings
    • C07D279/22—[b, e]-condensed with two six-membered rings with carbon atoms directly attached to the ring nitrogen atom
    • C07D279/30—[b, e]-condensed with two six-membered rings with carbon atoms directly attached to the ring nitrogen atom with acyl radicals attached to the ring nitrogen atom
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    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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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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    • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
    • C07D513/04—Ortho-condensed systems

Abstract

The present invention relates to medical technical field, preparation technology and the antitumor and antimycotic medical usage thereof that a class has antitumor activity and Antifungal Compounds, particularly, to cancer of the stomach, various metastatic hepatic carcinoma, breast cancer, lung cancer, colon cancer, the Several Kinds of Malignancies such as melanoma have obvious curative effects.

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 of the antitumor and antifungal compound fused tricyclic that is used for the treatment of of a class and it is anti-swollenKnurl and antimycotic medical usage.
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 four points of total death tollOne of. Cancer of the stomach is the modal a kind of malignant tumour of China, and its death rate accounts for the first place of various malignant tumours. Liver cancer is China's second cancer" killer ", the position that leapt to the first in part High Phc Incidence Area, accounts for 45% of whole world PLC mortality number. Breast cancer is harm WomanHealthMajor malignant tumor, the whole world approximately has 1,200,000 women that breast cancer occurs every year. The existing cancer patient's death rate of China exceedes 30% at present,Become the second largest factor of China's death. Medicine treatment has become a kind of methods for the treatment of that malignant tumour effectively and is generally used.Within 2010, global antineoplastic sales volume is about 60,000,000,000 dollars. The antineoplastic of application is of a great variety clinically, wherein chemotherapeutic ownerThere is the antibiotic of alkylating agent molybdenum complex antineoplastic, anthracene ring antitumor medicinal, destruction DNA etc. In addition natural antitumor medicine,The research of thing also occupies sizable ratio, has camptothecine, vincristine, taxol etc. as commonly used clinically at present some medicines. But,Existing antineoplastic exists the selectively problem such as poor, toxic and side effect, drug resistance. The antineoplastic of finding high-efficiency low-toxicity is still sectionThe important topic that scholar faces. The invention provides the fused tricyclic class medicines structure with antitumor activity, have before important Application and DevelopmentScape. In recent years, antifungal drug research has obtained compared with much progress, but also comes with some shortcomings for clinical medicine at present, as: Fluconazole pairAspergillus effect is poor, and antibody-resistant bacterium constantly produces; Special more poor to saccharomycete effect than naphthalene fen; Itraconazole is difficult for seeing through blood-brain barrier, and poison is secondaryEffect 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, fused tricyclic compounds or its pharmaceutically acceptable salt effectively suppress some cancerThe growth of cell, this compounds has obvious inhibitory action to cancer of the stomach, liver cancer, breast cancer cell, in addition, this fused tricyclic compounds orIts pharmaceutically acceptable salt of person also has inhibition to conk.
Its structural formula is as follows:
X is selected from S, O, N-R ', C=O
R1And R ' be selected from be respectively hydrogen, alkyl,R2、R3、R4And R5Being selected from respectively monosubstituted and polysubstituted is hydrogen, alkyl, cycloalkyl, alkoxyl, aryl, hydroxyl, carboxylicBase, halogen, itrile group, nitro.
A subset of this fused tricyclic compounds has following chemical formula:
Described compound exists with the form of hydrate or salt. Salt is inorganic salts or organic salt, example hydrochloric acid salt, sulfate, fumarate, firstSulfonate, sulfonate etc.
Further say R1From hydrogen, alkyl, benzyl, select R2、R3、R4And R5Be respectively monosubstituted;
Further say R2、R3、R4And R5Be respectively hydrogen, bromine, methoxyl group, chlorine, hydroxyl, carboxyl, itrile group.
Here term " alkyl " refers to the straight or branched-chain hydrocarbons 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 ring with 3 to 12 carbon of partShape alkyl. The example of cycloalkyl includes but not limited to cyclopropyl, cyclobutyl, cyclopenta plinth, cyclohexyl, cyclic vinyl, suberyl plinth and ringOctyl group. Refer to-O-of term " alkoxyl " alkyl. Term " aryl " refers to 6 carbon monocycles, 10 carbon dicyclos, and the aromatic ring system that 14 carbon three encircle, wherein everyIndividual ring can have 1 to 4 substituting group. The example of aromatic ring includes but not limited to phenyl, naphthyl and anthryl. Alkyl, virtue as mentioned hereinBase, cycloalkyl, aryl, alkoxyl comprise replacement and unsubstituted part.
Represent some examples of fused tricyclic heterocycles compound of the present invention below
Represent some other example of compound of the present invention below:
Above-mentioned fused tricyclic compounds suppresses cancer cell and conk. Therefore, on the other hand, feature of the present invention is also to treat cancerThe method of disease and fungi. The method comprises needs one of effective above-claimed cpd of its curer.
Detailed description of the invention
1: compound 1 synthetic
Concrete synthesis step is: will（0.5mmol），CuI（0.1mmol），L-proline(0.2mmol),andK2CO3 (2.5mmol) adds in reactor, substitutes Ar gas three times. Add(0.55mmol) He 2.0MLDMSO, stirs 48h at 90 DEG C, continues to be heated to 110 DEG C of reaction 48h, with TLC monitoring reaction. Pressure reducing and steaming solvent, residueBe dissolved in 20mL ethyl acetate. Organic phase waterside three times, salt washing 1 time, anhydrous sodium sulfate drying. After concentrated, after column chromatography purification, must produceThing 1.1HNMR(400MHz,DMSO-d6):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);13CNMR(100MHz,DMSO-d6)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
Concrete synthesis step is:
2-iodo phenol 1.0mmol and 1-F-2-nitrobenzene 1.0mmol and 2mmol potash are dissolved in 10mLDMSO, under 100 degreeHeat 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。1HNMR(400MHz,CDCl3):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).13CNMR(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 acetic anhydride are mixed, stirred overnight at room temperature, mixture adds the water-soluble of sodium carbonateLiquid, is extracted with ethyl acetate, organic phase anhydrous sodium sulfate drying, and concentrated rear column chromatography obtains product N-(2-(2-iodophenoxy)phenyl)acetamid.1HNMR(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).13CNMR(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 potash are added in reactor, under argon shield, by noteEmitter adds DMEDA0.1mmol and toluene 1mL. Stir 24 hours at 135 degree, reactant liquor is cooled to after room temperature and dissolves with carrene,Filter, concentrated solution, obtains compound 19 by column chromatography.1HNMR(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)。13CNMR(100MHz,CDCl3):δ=169.0,150.8,129.3,126.7,125.0,123.2,116.7,23.0.
3: compound 25 synthetic
2mmol,2.0mmol,CuI0.2mmol,0.4mmol,Cs2CO3The mixture of 4.0mmol is dissolved in the DMF of 5mL, N2Under gas protection, be heated to 120 degree 24 hours. After reactant liquor cool to room temperature, use secondAcetoacetic ester dissolves, and filters, and with ethyl acetate washing, after filtrate concentrate drying, column chromatography purification obtains compound 25.
4: compound 37 synthetic
By 0.15mmol'sThe CuI of 20mol% is dissolved in 0.4mLDMSO and 0.4mLIn the mixed liquor of chlorobenzene, 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 37.1HNMR(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,);13CNMR(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;MSm/z276[M+1]+
Fused tricyclic of the present invention is the active compound for anti tumor of a class high-efficiency low-toxicity, to various metastatic hepatic carcinomas, Vipoma and melanoma etc.Several Kinds of Malignancy has obvious curative effects. Its main pharmacodynamics result of the test is as follows:
1. test method
By one group of tumor cell line, i.e. SK-Hep-1(liver cancer), HepG2(hepatocellular carcinoma), MKN-45(cancer of the stomach) and, MDA-MB-231(breast cancer cell), A549(non-small cell lung cancer), OVCAR-3(oophoroma), A498(kidney), HCT-116(knotIntestinal cancer), 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 preserveIn plastic ware in the PRMI medium that is full of 5% hyclone. In 96 orifice plates, inoculating final densities is 10000 cell/mL'sTumour cell. Utilize test compound process cell (at least 5 variable concentrations), every concentration is all made 6 parallel holes, separately establish blank well andControl wells during drug effect, with the growing state of inverted phase contrast microscope observation of cell, is cultivated 72 hours in 37 degree CO2 incubatorsAfter, every hole adds the MTT20 μ L of 5g/L, cultivates 4h, abandons supernatant, adds DMSO approximately 100 μ L/ holes, and vibration 10min, makesPurple crystal thing fully dissolves, and measures the absorbance at 490nm place with ELIASA. According to the cell toxicant of the value representation test compound of IC50Property. The mean value of 6 Duplicate Samples of above-mentioned value representation.
All effectively suppressing at all compounds of the compound 1-48 of above-mentioned test is SK-Hep-1, HepG2, MKN-45, MDA-MB-231, A549, the growth of OVCAR-3, A498, HCT-116, M4 cell. Unexpectedly, in them, great majority are all shownThe IC50 value illustrating is less than 1mM, and some are even less than 100nM.
2. drug sensitive experiment
Before experiment, picking neogenesis cryptococcus, candida albicans and Candida parapsilosis etc. the SDA culture medium of preserving from 4 degree with inoculation circleBe seeded to 1mLYEPD nutrient solution, in 35 degree, with 250r/min shaken cultivation, activation 16h, makes fungi in exponential phase of growthLater stage. Get this bacterium liquid to 1mLYEPD nutrient solution, again activate with said method, after 16h, with blood cell counting plate counting, withRPMI1640 nutrient solution is adjusted bacterial concentration to 1 × 103－5×103Individual/mL.
Compound 1-48 is made into 6.4mg/mL solution with DMSO respectively. Get aseptic 96 orifice plates, add RPMI1640100 in No. 1 hole of every rowμ L makes 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 2μ 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
Candida albicans, neogenesis cryptococcus are cultivated after 72h respectively at 35 degree, survey each hole OD value with enzyme micro-plate reader in 630nm. With positive controlBoring ratio, the drug concentration in the least concentration hole declining more than 80% taking OD value is as MIC80(medicine when conk 80% is suppressed is denseDegree).

Claims (7)

1. the compound shown in formula I or its pharmaceutically acceptable salt are for the preparation of antitumor and purposes antifungal drug, describedTumour is cancer of the stomach, liver cancer, oophoroma, kidney, colon cancer or melanoma, and described fungi is neogenesis cryptococcus or closely level and smoothCandida albicans, the structure of described formula I compound is as follows:
Wherein R2、R3、R4For monosubstituted or polysubstituted, be selected from hydrogen, halogen, alkaneOxygen base, alkyl, hydroxyl, carboxyl, itrile group, refer to-O-of described alkoxyl alkyl, described alkyl is chosen as methyl, secondBase, n-propyl group, i-propyl group, n-butyl, i-butyl, t-butyl.
2. purposes according to claim 1, is characterized in that R2、R3、R4Be selected from hydrogen, bromine, methoxyl group, chlorine, hydroxyl,Carboxyl, itrile group.
3. purposes according to claim 1, is characterized in that the compound that described formula I compound is following structure
4. purposes according to claim 1, is characterized in that R2、R3、R4For monosubstituted.
5. purposes according to claim 1, is characterized in that described salt is inorganic salts or organic salt.
6. purposes according to claim 1, is characterized in that described salt is hydrochloride, sulfate, fumarate or sulfonic acidSalt.
7. purposes according to claim 1, is characterized in that described salt is mesylate.
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KR20190025920A (en) * 2016-06-23 2019-03-12 바이오이믹스 아베 Anti-infective heterocyclic compounds and uses thereof
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