CN108774161A - The preparation and its application of six kinds of PARP1 inhibitor - Google Patents

The preparation and its application of six kinds of PARP1 inhibitor Download PDF

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CN108774161A
CN108774161A CN201810812259.4A CN201810812259A CN108774161A CN 108774161 A CN108774161 A CN 108774161A CN 201810812259 A CN201810812259 A CN 201810812259A CN 108774161 A CN108774161 A CN 108774161A
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hydrazine
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史大永
王立军
郭传龙
李祥乾
江波
李晓伟
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    • C07—ORGANIC CHEMISTRY
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    • C07C337/00—Derivatives of thiocarbonic acids containing functional groups covered by groups C07C333/00 or C07C335/00 in which at least one nitrogen atom of these functional groups is further bound to another nitrogen atom not being part of a nitro or nitroso group
    • C07C337/06—Compounds containing any of the groups, e.g. thiosemicarbazides
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    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/12—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms
    • C07D295/125—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms with the ring nitrogen atoms and the substituent nitrogen atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
    • C07D295/13—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms with the ring nitrogen atoms and the substituent nitrogen atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain

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Abstract

The present invention relates to the preparation of six kinds of novel PARP1 inhibitor and the combinations of such compound, and the application in antitumor and/or anticancer medicine, and the invention further relates to the preparation method of such compound, the chemical constitution of the compound is as follows：

Description

The preparation and its application of six kinds of PARP1 inhibitor
Technical field
The present invention relates to technical field of pharmaceuticals, specifically six kinds of PARP1 inhibitor and its pharmacological activity and pharmacy is used On the way.The compound and its derivative can be used for preventing and/or treat the diseases such as tumour or cancer caused by various factors.
Background technology
Malignant tumour seriously affects the health of people, has become the second largest cause of disease for leading to human death, only secondary In cardiovascular and cerebrovascular disease.It is counted according to World Health Organization, the tumor patient that the whole world is newly made a definite diagnosis every year is 10,000,000 or more, every year entirely Ball tumor mortality sum is up to 7,000,000 people.With the exacerbation of environmental pollution, cancer morbidity improves year by year, is in multiple situation, Swift and violent growing trend will be presented in 2014 address prediction whole world cases of cancer of World Health Organization, by 14,000,000 people in 2012, pass year by year 19,000,000 people for increasing to 2025,24,000,000 people were up to by 2035, and death toll will also be increased to by annual 6000000 10000000.2012, newly-increased 3,070,000 cancer patients of China simultaneously caused about 2,200,000 people dead, account for the 21.9% of global total amount respectively With 26.8%, cancer has become the first cause of urban and rural residents of China death.Tumour not only seriously threatens the people's Health brings economic loss to patient and patient family, but also can cause white elephant to state and society.It finds Efficiently, the new type antineoplastic medicine of the novel mechanism of low toxicity, alternative killing or inhibition tumour cell has become antitumor The important directions of medicament research and development.
Poly ADP ribose polymerase -1 (PARP-1) participates in DNA reparations and transcriptional control process, can not only adjust Central transcription factor in cell survival and death process or tumour generation and inflammation forming process, has become in recent years The popular target spot of therapeutic field of tumor.The breast cancer and oophoroma of PARP-1 inhibitor for treating BRCA1/BRCA2 mutation have aobvious Curative effect is write, main mechanism is to participate in the function that SSB/DSB is repaired for PARP-1, by inhibiting PARP-1 catalytic activity With PARP-1 is trapped in both mechanisms plays on the DNA of damage antitumor, the rucaparib of Clovis Oncology As first drug being honored in such drug, there are 3 kinds of PARP1 inhibitor as antitumor drug in clinic at present Using.
Marine source bromine phenolic compound is primarily referred to as dynamic from oceans such as marine fungi, seaweed, sponge, ascidian and bryozoans Compound in plant and microorganism containing one or more hydroxyls and bromine atom substituted benzene ring in isolated molecular structure, It is a kind of compound that marine source shows unique characteristics.It is more deep to the screening active ingredients of bromine phenolic compound at present, it obtains Largely there is good biological active guide in anti-oxidant, antibacterial, antitumor, antithrombotic, hypoglycemic, biological food refusal etc. Compound [Mar. Drugs 2011,9 (7), 1273-1292；Bioorganic Chem.2015,60,49-57； Eur.J.Med. Chem.,2012,54,423-428.].Such compound potential application and development valence in terms of antitumor activity Value has also caused the great interest of domestic and international researchers.(thiosemicarbazone) compound has antiviral and antitumor, anti-fiber crops Multiple biological activities, the synthesis and bioactivity research for such compound such as wind disease, treating tuberculosis and anti-malarial become as medicine Research hotspot (the Environ Pollut.2015 Sep of object chemistry；204:81-9, Sep Sci.2017Jan；40(2):514- 523, Bioorg Chem.2015 Jun；60:49-57).
The present invention utilizes drug molecule hybrid design principle, by bromine phenol and thiosemicarbazide compound antitumor activity group Coupling design six kinds of compound 1-6 of synthesis are carried out, in the prior art without six kinds of compound 1-6 provided by the invention and its conduct The report of PARP1 inhibitor is also applied without the analog derivative or its pharmaceutical composition and is caused in preparation or treatment various factors Tumour or the disease medicaments such as cancer in report.
Invention content
The present invention relates to technical field of pharmaceuticals, specifically six kinds of PARP1 inhibitor, preparation method and its pharmacology are lived Property and pharmaceutical use.Such compound and its derivative can be used for preventing and/or treat tumour, cancer caused by various factors Etc. diseases.
To achieve the above object, the technical solution adopted by the present invention is as follows：
Present invention design has synthesized six kinds of PARP1 inhibitor, and chemical constitution is as follows：
Chemical name Chinese is respectively：2,2'- (((butane -1,4- diyls dioxy) two (bromo- 5- methoxyl groups -4- benzene of 3- Base)) dimethylene) two (N- methyl hydrazine -1- thioamides) (1), 2,2'- (((propane -1,3- diyls dioxy) two (bromo- 5- of 3- Methoxyl group -4- phenyl)) dimethylene) two (N- (morpholinyl) hydrazine -1- thioamides) (2), 2,2'- (((butane-Isosorbide-5-Nitrae-two Base dioxy) two (the bromo- 5- methoxyl groups -4- phenyl of 3-)) dimethylene) two (N- (morpholinyl) hydrazine -1- thioamides) (3), 2, 2'- (((hexane -1,6- diyls dioxy) two (the bromo- 5- methoxyl groups -4- phenyl of 3-)) dimethylene) two (N- (morpholinyl) hydrazines - 1- thioamides) (4), 2,2'- (((propane -1,3- diyl dioxy) two (the bromo- 5- methoxyl groups -4- phenyl of 3-)) dimethylenes) Two (hydrazine -1- thioamides) (5), 2,2'- (((butane-Isosorbide-5-Nitrae-diyl dioxy) two (the bromo- 5- methoxyl groups -4- phenyl of 3-)) two Asias Methyl) two (hydrazine -1- thioamides) (6)；
English name is respectively：2,2'-(((butane-1,4-diylbis(oxy)) bis(3-bromo-5- methoxy-4, 1-phenylene))bis(methaneylylidene))bis(N-methylhydrazine-1- Carbothioamide) (1), 2,2'- (((propane-1,3-diylbis (oxy)) bis (3-bromo-5-methoxy-4, 1-phenylene))bis(methaneylylidene)) bis(N-(3-morpholinopropyl)hydrazine-1- Carbothioamide) (2), 2,2'- (((butane-1,4-diylbis (oxy)) bis (3-bromo-5-methoxy-4, 1-phenylene))bis (methaneylylidene))bis(N-(3-morpholinopropyl)hydrazine-1- Carbothioamide) (3), 2,2'- (((hexane-1,6-diylbis (oxy)) bis (3-bromo-5-methoxy-4, 1-phenylene))bis(methaneylylidene))bis(N-(3-morpholinopropyl) hydrazine-1- Carbothioamide) (4), 2,2'- (((propane-1,3-diylbis (oxy)) bis (3-bromo-5-methoxy-4, 1-phenylene)) bis (methaneylylidene)) bis (hydrazine-1-carbothioamide) (5), 2,2'- (((butane-1,4-diylbis(oxy))bis (3-bromo-5-methoxy-4,1-phenylene))bis (methaneylylidene)) bis(hydrazine-1-carbothioamide)(6)
One kind or two or more mixing in six kinds of novel PARP1 inhibitor 1-6 have antitumor activity, herein Signified inhibitor 1-6 can be the chemical equivalents such as the pharmaceutically acceptable salt of inhibitor 1-6 and inhibitor 1-6 itself In one kind, but be not limited to the above chemical equivalent.
Invention also provides six kinds of novel PARP1 inhibitor 1-6 of the present invention to prepare for preventing and/or treating Application in the relevant disease such as tumour caused by various factors and/or cancer.
When six kinds of novel PARP1 inhibitor of the present invention are used as drug, can directly it use, or with the shape of pharmaceutical composition Formula uses.The pharmaceutical composition contains 0.1-99%, and preferably 0.5-90% the compounds of this invention, remaining is pharmaceutically may be used The pharmaceutical carrier and/or excipient of receiving.
The pharmaceutical carrier or excipient is one or more solids, semisolid and liquid diluent, filler and medicine Tetramune adjuvant.The pharmaceutical composition of the present invention is used in the form of per weight dose.The drug of the present invention can be through note Penetrate (intravenous, intramuscular injection), oral and three kinds of form administrations of external application.
It is an object of the present invention to provide six kinds of novel PARP1 inhibitor and preparation method thereof, and the compound and its derivative can To prevent and/or treat the diseases such as tumour caused by various factors and/or cancer, for example, lung cancer, liver cancer, breast cancer, oophoroma, One or two or more kinds in the tumours such as prostate cancer and/or Cancerous disease.
1, the synthesis and structure identification of compound
Steps are as follows for the preparation method of six kinds of novel PARP1 inhibitor 1-6 of the present invention：
Step 1：Prepare intermediate alkoxy dibromophenol benzaldehyde (I-III):
At room temperature, 5- bromines vanillic aldehyde (13.9g, 60mmol) and potassium carbonate (2.8g, 20mmol) are mixed and flask is added In, 20mLDMF dissolvings are added, stirs 10min, 1,3- dibromopropanes or Isosorbide-5-Nitrae-dibromobutane or 1,6- bis- is added dropwise while stirring Bromohexane (2mL, 20mmol), 80 DEG C of heating condensing reflux 10h, is added 500mL water, has white flock precipitate precipitation, will precipitate Filtering is used in combination saturated sodium bicarbonate washing precipitation, ethyl acetate washing to precipitate to obtain intermediate.
Step 2：Prepare compound 1-6:
It weighs midbody compound I or II or III (2mmol) and corresponding thiosemicarbazides (4.4mmol) is blended in 10 0mL In 95% ethyl alcohol, 10min is stirred, 1000 μ L acetic acid are added dropwise while stirring, condensing reflux 12h is heated at 70 DEG C, is precipitated white Color precipitates, and precipitation is filtered, and precipitation is washed with ethyl alcohol, dry compound 1-6.The thiosemicarbazides is 4- methylaminos Sulphur, 4- [3- (4- morpholines) propyl] -3- thiosemicarbazides, thiosemicarbazides are one or more kinds of.
2, six kinds of compound 1-6 of the present invention measure polyadenylic acid diphosphonic acid phosphoribosynltransferase (PARP1) inhibitory activity and walk Suddenly
When experiment each reagent used should all be balanced to room temperature, reagent or sample preparation, it is both needed to mix well, avoids blistering.
(1) it is loaded：Blank well, gauge orifice, sample to be tested hole are set respectively.Blank well adds 100 μ of standard items sample diluting liquid L, remaining hole add 100 μ L of standard items or sample to be tested respectively, and mixing, 37 DEG C are incubated 90 minutes.
(2) liquid is discarded, is dried, 100 μ L of biotinylated antibody working solution are added in each hole, 37 DEG C incubate 1 hour.
(3) discard liquid in hole, dry, board-washing 3 times, impregnate 1-2 minute every time, about 350 μ L/ per hole, drying and It is patted on blotting paper and pats dry liquid in hole.
(4) per 100 μ L of the enzyme conjugate working solution in hole (being prepared in 15 minutes before use), 37 DEG C incubate 30 minutes.
(5) liquid in hole is discarded, is dried, board-washing 5 times, method is the same as step 3.
(6) add 90 μ L of substrate solution (TMB) per hole, 37 DEG C are protected from light incubation 15 minutes or so.
(7) add 50 μ L of terminate liquid per hole, terminate reaction.
(8) use microplate reader in the optical density (OD values) in each hole of 450nm wavelength measurements.
(9) inhibiting rate is calculated according to measurement OD values.
3, six kinds of compound 1-6 of the present invention measure various cytotoxicities
Synthesis of derivatives is detected to the thin of the human tumor cells of in vitro culture using currently used tetrazolium (MTT) method Cellular toxicity.Cell strain selected by anticancer experiment in vitro：Human lung cancer cell A549 and human liver cancer cell HepG2, human normal cell line Strain：Human umbilical vein endothelial cells HUVEC.Assay method：The cell of logarithmic growth phase, by cell suspension inoculation to 96 orifice plates, 37 DEG C, 100% relative humidity, contain 5%CO2, 95% air incubator preculture for 24 hours after, then dosing.In addition, each Concentration sets negative control (isoconcentration DMSO) and blank background (being not added with cell), and each group is all provided with 3 multiple holes.It is continuous again to cultivate for 24 hours, Then MTT solution is added per hole, continues after cultivating 4h, carefully sucking supernatant, (suspension cell is needed first to centrifuge, then sucked Clearly).DMSO is added per hole, sets micro oscillator concussion 5min and is completely dissolved so as to crystallize, microplate reader 492nm Single wavelength colorimetrics, Measure OD values.Inhibiting rate (%)=(one blank group OD mean values of experimental group OD mean values)/(control group OD mean values-blank group OD mean values) X100%, and calculate IC50Value.
The invention has the advantages that：
Compound 1-6 provided by the invention has very strong inhibitory activity to PARP1, various to what is tested through mtt assay Tumor cell line all has stronger inhibitory activity, and relatively low to normal cell Human umbilical vein endothelial cells HUVEC toxicity, card Bright the compounds of this invention all has good antitumor activity, has good application prospect in terms of antitumor drug exploitation. Six kinds of PARP1 inhibitor of the present invention couple have carried out chemical synthesis preparation, and starting material is cheap and easily-available, and manufacturing cost is low, targeted It closes object high income and technological operation is simple, there is good industrialization production foreground.
Specific implementation mode
To better understand the essence of the present invention, will illustrate six kinds of the present invention with the embodiment of the present invention below Preparation method and the pharmacological action of PARP1 inhibitor 1-6 with this embodiment as a result, but do not limit the present invention.
Embodiment 1：2,2'- (((butane -1,4- diyls dioxy) two (the bromo- 5- methoxyl groups -4- phenyl of 3-)) dimethylene) Two (N- methyl hydrazine -1- thioamides) (2,2'- (((butane-1,4-diylbis (oxy)) bis (3-bromo-5- methoxy-4, 1-phenylene))bis(methaneylylidene))bis(N-methylhydrazine-1- Carbothioamide), compound 1) preparation；
(1) it weighs 5- bromines vanillic aldehyde (13.9g, 60mmol) and potassium carbonate (2.8g, 20mmol) is added in 1L flasks, add Enter 20mLDMF dissolvings, stir 10min, Isosorbide-5-Nitrae-dibromobutane (2mL, 20mmol), 80 DEG C of heating condensing refluxes are added dropwise while stirring 10h is added 500mL water, there is white flock precipitate precipitation, will precipitation filtering, saturated sodium bicarbonate washing precipitation is used in combination, with a small amount of Ethyl acetate washing precipitation, is dried to obtain midbody compound II.
(2) 0.2mmol midbody compounds II (100mg) and 0.44mmol 4- methylthiosemicarbazones (46.3mg) are weighed It is placed in 100mL reaction bulbs, the ethyl alcohol of 10mL 95% is added, stir 10 min, 100 μ L acetic acid are then added dropwise, add at 70 DEG C White precipitate is precipitated in hot condensing reflux 12h, filters, precipitation is washed with ethyl alcohol, dry that compound as white solid 1, yield are 85.2%.1H-NMR (500MHz, DMSO-d6) δ：11.52 (s, 2H, CH), 8.54 (m, 2H, NH), 7.93 (s, 2H, NH), 7.68 (s, 2H, ArH), 7.38 (s, 2H, ArH), 4.01 (s, 4H, OCH2), 3.86 (s, 6H, OCH3), 3.01 (d, J= 4.5Hz, 6H, NCH3), 1.90 (s, 4H, CH2)；13C NMR (125MHz, DMSO-d6) δ：178.1,154.0,146.3, 140.5,131.9,123.2,117.9,111.7,72.9,56.8,31.3,26.7.
Embodiment 2：2,2'- (((propane -1,3- diyls dioxy) two (the bromo- 5- methoxyl groups -4- phenyl of 3-)) dimethylene) Two (N- (morpholinyl) hydrazine -1- thioamides) (2,2'- (((propane-1,3-diylbis (oxy)) bis (3-bromo- 5-methoxy-4,1-phenylene))bis(methaneylylidene)) bis(N-(3-morpholinopropyl) ), hydrazine-1-carbothioamide compound 2)
The preparation method of compound 2 is similar to the preparation method of compound 1, and difference from Example 1 is will be former Material Isosorbide-5-Nitrae-dibromobutane is changed to 1,3- dibromopropanes, and midbody compound I is prepared, 4- methylamino sulphur is then changed to 4- [3- (4- morpholines) propyl] -3- thiosemicarbazides, are prepared compound as white solid 2, yield 83.2%.1H-NMR (500MHz, DMSO-d6)δ：11.50 (s, 2H, CH), 8.56 (t, J=6Hz, 2H, NH), 7.94 (s, 2H, NH), 7.68 (s, 2H, ArH), 7.35 (d, J=1.5Hz, 2H, ArH), 4.19 (t, J=6.5Hz, 4H, OCH2), 3.85 (s, 6H, OCH3), 3.59 (dd, 4H, CH2), 3.54 (s, 8H, CH2), 2.31 (m, 10H, CH2), 2.12 (m, 2H, CH2), 1.74 (m, 4H, CH2)；13C NMR (125MHz, DMSO-d6)δ：177.3,153.8,146.3,140.7,131.8,123.0,117.8, 112.1,70.6,66.6,56.8,56.4,53.8,42.6,31.1,26.2.
Embodiment 3：2,2'- (((butane -1,4- diyls dioxy) two (the bromo- 5- methoxyl groups -4- phenyl of 3-)) dimethylene) Two (N- (morpholinyl) hydrazine -1- thioamides) (2,2'- (((butane-1,4-diylbis (oxy)) bis (3-bromo- 5-methoxy-4,1-phenylene))bis(methaneylylidene))bis (N-(3-morpholinopropyl) ), hydrazine-1-carbothioamide compound 3)
The preparation method of compound 3 is similar to the preparation method of compound 1, and method same as Example 1 is prepared Then 4- methylamino sulphur is changed to 4- [3- (4- morpholines) propyl] -3- thiosemicarbazides, is prepared by midbody compound II To compound as white solid 3, yield 84.6%.1H-NMR (500MHz, DMSO-d6)δ：11.49 (s, 2H, CH), 8.55 (t, J =6Hz, 2H, NH), 7.94 (s, 2H, NH), 7.68 (s, 2H, ArH), 7.35 (s, 2H, ArH), 4.02 (s, 4H, OCH2), 3.86 (s, 6H, OCH3), 3.59 (dd, 4H, CH2), 3.54 (s, 6H, CH2), 2.31 (m, 10H, CH2), 1.90 (s, 4H, CH2), 1.74 (m, 4H, CH2)；13C NMR (125MHz, DMSO-d6)δ：177.3,154.0,146.3,140.7,131.8, 122.9,118.0,112.0,72.9,66.6,56.8,56.4,53.8,42.6,26.7,26.2.
Embodiment 4：2,2'- (((hexane -1,6- diyls dioxy) two (the bromo- 5- methoxyl groups -4- phenyl of 3-)) dimethylene) Two (N- (morpholinyl) hydrazine -1- thioamides) (2,2'- (((hexane-1,6-diylbis (oxy)) bis (3-bromo-5- methoxy-4,1-phenylene))bis(methaneylylidene)) bis(N-(3-morpholinopropyl) ), hydrazine-1-carbothioamide compound 4)
The preparation method of compound 4 is similar to the preparation method of compound 1, and difference from Example 1 is will be former Material Isosorbide-5-Nitrae-dibromobutane is changed to 1,6- dibromo-hexanes, and intermediate compound III is prepared, is then changed to 4- methylamino sulphur 4- [3- (4- morpholines) propyl] -3- thiosemicarbazides, are prepared compound as white solid 4, yield 83.2%.1H NMR (DMSO-d6,500MHz,ppm):δ11.48(s, 2H),8.54(overlap,4H),7.94(s,2H),7.67(s,2H), 7.34 (s, 2H), 3.95 (t, 4H, J=6.5 Hz), 3.86 (s, 6H), 3.53-3.61 (overlap, 12H), 2.29-2.33 (overlap,12H), 1.70-1.77(overlap,8H),1.50(m,4H)；13C NMR(DMSO-d6,125MHz,ppm):δ 177.3(2C),154.0(2C),146.5(2C),140.7(2C),131.8(2C),123.0(2C),117.9 (2C),112.0 (2C),73.2(2C),66.6(4C),56.8(2C),56.4(2C),53.8(4C),42.6(2C), 30.0(2C),26.2 (2C),25.6(2C)；
Embodiment 5：2,2'- (((propane -1,3- diyls dioxy) two (the bromo- 5- methoxyl groups -4- phenyl of 3-)) dimethylene) Two (hydrazine -1- thioamides) (2,2'- (((propane-1,3-diylbis (oxy)) bis (3-bromo-5-methoxy-4, 1-phenylene)) bis (methaneylylidene)) bis (hydrazine-1-carbothioamide), compound 5)
The preparation method of compound 5 is similar to the preparation method of compound 1, and difference from Example 1 is will be former Material Isosorbide-5-Nitrae-dibromobutane is changed to 1,3- dibromopropanes, and midbody compound I is prepared, 4- methylamino sulphur is then changed to ammonia Compound as white solid 5, yield 91.0% is prepared in base thiocarbamide.1H-NMR (500MHz, DMSO-d6)δ：11.46 (s, 2H, CH), 8.23 (s, 2H, NH), 8.16 (s, 2H, NH), 7.92 (s, 2H, NH), 7.63 (s, 2H, ArH), 7.47 (s, 2H, ArH), 4.18 (t, J=6.5Hz, 4H, OCH2), 3.84 (s, 6H, OCH3), 2.11 (m, 2H, CH2)；13C NMR (125MHz, DMSO-d6)δ：178.4,153.9,146.4,140.9,131.9,123.9,117.6,111.1,70.6,56.8,31.1.
Embodiment 6：2,2'- (((butane -1,4- diyls dioxy) two (the bromo- 5- methoxyl groups -4- phenyl of 3-)) dimethylene) Two (hydrazine -1- thioamides) (2,2'- (((butane-1,4-diylbis (oxy)) bis (3-bromo-5-methoxy-4, 1-phenylene)) bis (methaneylylidene)) bis (hydrazine-1-carbothioamide), compound 6)
The preparation method of compound 6 is similar to the preparation method of compound 1, and method same as Example 1 is prepared Then 4- methylamino sulphur is changed to thiosemicarbazides, compound as white solid 6, yield is prepared by midbody compound II 90.5%.1H-NMR (500MHz, DMSO-d6)δ：11.45 (s, 2H, CH), 8.22 (s, 2H, NH), 8.16 (s, 2H, NH), 7.92 (s, 2H, NH), 7.60 (s, 2H, ArH), 7.47 (s, 2H, ArH), 4.00 (s, 4H, OCH2), 3.85 (s, 6H, OCH3), 1.98 (s, 4H, CH2)；13C NMR (125MHz, DMSO-d6)δ：：178.4,154.1,146.4,140.9,131.9,123.9, 117.7,111.0,72.9,56.8,26.7.
Embodiment 7：Compound 1-6 measures polyadenylic acid diphosphonic acid phosphoribosynltransferase (PARP1) inhibitory activity
When experiment each reagent used should all be balanced to room temperature, reagent or sample preparation, it is both needed to mix well, avoids blistering.
(1) it is loaded：Blank well, gauge orifice, sample to be tested hole are set respectively.Blank well adds 100 μ of standard items sample diluting liquid L, remaining hole add 100 μ L of standard items or sample to be tested respectively, and mixing, 37 DEG C are incubated 90 minutes.
(2) liquid is discarded, is dried, 100 μ L of biotinylated antibody working solution are added in each hole, 37 DEG C incubate 1 hour.
(3) discard liquid in hole, dry, board-washing 3 times, impregnate 1-2 minute every time, about 350 μ L/ per hole, drying and It is patted on blotting paper and pats dry liquid in hole.
(4) per 100 μ L of the enzyme conjugate working solution in hole (being prepared in 15 minutes before use), 37 DEG C incubate 30 minutes.
(5) liquid in hole is discarded, is dried, board-washing 5 times, method is the same as step 3.
(6) add 90 μ L of substrate solution (TMB) per hole, 37 DEG C are protected from light incubation 15 minutes or so.
(7) add 50 μ L of terminate liquid per hole, terminate reaction.
(8) use microplate reader in the optical density (OD values) in each hole of 450nm wavelength measurements.
(9) standard curve is brought into according to measurement OD values to calculate.
Table 1：Compound 1-6 inhibits PARP activity data tables under 100nM concentration
Compound Inhibiting rate (100%)
1 68.4
2 54.3
3 56.1
4 55.4
5 62.2
6 49.6
Embodiment 8：Compound 1-6 measures tumor cell proliferation inhibition activity
The thin of the human tumor cells of synthesis Compounds in vitro culture is detected using currently used tetrazolium (MTT) method Cellular toxicity.Cell strain selected by anticancer experiment in vitro：Human lung cancer cell A549 and human liver cancer cell HepG2, in human umbilical vein Chrotoplast HUVEC.Assay method：The cell of logarithmic growth phase makes it per hole cell number by cell suspension inoculation to 96 orifice plates It is 3 × 103It is a, 37 DEG C, 100% relative humidity, 5%CO2 containing volume content, 95% air incubator preculture for 24 hours after, Then dosing.In addition, by a concentration of 1.25, the compound 1-6 of 2.5,5.0,10.0,20.0 mcg/mls, each concentration sets the moon Property control (isoconcentration DMSO) and blank background (being not added with cell), each group be all provided with 3 multiple holes.It is continuous again to cultivate for 24 hours, then per hole Be added 20 microlitre of 5 mg/ml MTT solution, continue cultivate 4h after, carefully suck supernatant (suspension cell needs first to centrifuge, Supernatant is sucked again).150 microlitres of DMSO are added per hole, sets micro oscillator concussion 5min and is completely dissolved so as to crystallize, microplate reader 492nm Single wavelength colorimetrics measure OD values.Inhibiting rate (%)=(one blank group OD mean values of experimental group OD mean values)/(control group OD Mean value-blank group OD mean values) x100%, and application SPSS17.0 softwares calculate IC50It is worth (table 2).
Table 2：Compound 1-6 is to tumor cell proliferation inhibition activity tables of data (IC50,ug/mL)
The experimental results showed that compound 1-6 provided by the invention has very strong inhibition under 100nM concentration to PARP1 Activity, compound 1-6 have good antitumor activity, have stronger suppression to the external of various tumor cell lines tested System activity, relatively low to normal Human umbilical vein endothelial cells HUVEC toxicity, the compounds of this invention can be used for preventing and/or treat Caused by various factors with tumour or the relevant disease of cancer and symptom.
Comparative example 9：
Using determination of experimental method identical with compound 1-6, it to PARP1 inhibitory activity and swells compound as follows Tumor cell proliferation inhibitory activity, experimental result find that control compounds show that very weak inhibition is lived under 100nM concentration to PARP1 Property (5.2%), to surveyed tumor cell line unrestraint proliferation activity.
Embodiment 10：The preparation of compound injection liquid
By compound 1-6, with a small amount of DMSO, (weight ratio is respectively：1：0.1-1：0.5, it is herein 1：0.4) after dissolving, Routinely plus water for injection (weight ratio 1:20-1:200, it is herein 1:200) injection is made in, refined filtration, embedding sterilizing.
Embodiment 11：The preparation of compound powder injection
By compound 1-6, with a small amount of DMSO, (weight ratio is respectively：1：0.1-1：0.5, it is herein 1：0.5) after dissolving, Being dissolved in sterile water for injection, (weight ratio is：1：20-1：60, it is herein 1:60) it in, is stirred to dissolve, with sterile suction filtration Funnel filters, then sterile refined filtration, is sub-packed in ampoule, sterile after frozen drying to seal to obtain powder-injection.
Embodiment 12：The preparation of compound pulvis
It is 9 that compound 1-6 is pressed to it respectively with excipient weight ratio:Excipient (Tween 80 is added in 1 ratio:The third two Alcohol:Cyclodextrin:Lactose=1:2:4:12) pulvis, is made.
Embodiment 13：The preparation of compound tablet
Compound 1-6 is pressed into itself and excipient (hypromellose E5 respectively：Microcrystalline cellulose MCC102:Stearic acid Magnesium:(8% PVP K30)=15:15:2:0.1) weight ratio is 5:Excipient, pelletizing press sheet is added in 1 ratio.
Embodiment 14：The preparation of compound oral solution
Compound 1-6 is added separately in the distilled water containing 20% simple syrup of mass concentration and 0.1% sodium benzoate, is pressed A concentration of 15 μ g/mL oral solutions are made in traditional oral liquid preparation method.
Embodiment 15：The preparation of compound capsule formulation
Compound 1-6 is pressed into itself and excipient (medical starch respectively:Glucose:Gelatin hydrolysate:Glycine=30:10:1: 1) weight ratio is 5:1 ratio mixing, is made capsule.
Embodiment 16：The preparation of compound capsule formulation
Compound 1-6 is pressed into itself and excipient (medical starch respectively:Glucose:Gelatin hydrolysate:Glycine=30:10:1: 1) weight ratio is 3:1 ratio mixing, is made capsule.

Claims (8)

1.PARP1 inhibitor, it is characterized in that：It is with one or two or more kinds of for active ingredient in following six kinds of compounds, and six Kind structural formula of compound is as follows：
2. PARP1 inhibitor described in accordance with the claim 1, it is characterized in that：Chemical name Chinese is respectively：2,2'- (((fourths Alkane -1,4- diyls dioxy) two (the bromo- 5- methoxyl groups -4- phenyl of 3-)) dimethylene) two (N- methyl hydrazine -1- thioamides) (1), 2,2'- (((propane -1,3- diyls dioxy) two (the bromo- 5- methoxyl groups -4- phenyl of 3-)) dimethylene) two (N- (morpholinyl) Hydrazine -1- thioamides) (2), 2,2'- (((butane-Isosorbide-5-Nitrae-diyl dioxy) two (the bromo- 5- methoxyl groups -4- phenyl of 3-)) two methylenes Base) two (N- (morpholinyl) hydrazine -1- thioamides) (3), 2,2'- (((hexane -1,6- diyl dioxy) two (bromo- 5- methoxies of 3- Base -4- phenyl)) dimethylene) two (N- (morpholinyl) hydrazine -1- thioamides) (4), 2,2'- (((propane -1,3- diyls two Oxygen) two (the bromo- 5- methoxyl groups -4- phenyl of 3-)) dimethylene) two (hydrazine -1- thioamides) (5), 2,2'- (((butane-Isosorbide-5-Nitrae-two Base dioxy) two (the bromo- 5- methoxyl groups -4- phenyl of 3-)) dimethylene) two (hydrazine -1- thioamides) (6)；
English name is respectively：2,2'-(((butane-1,4-diylbis(oxy))bis(3-bromo-5-methoxy-4,1- Phenylene)) bis (methaneylylidene)) bis (N-meth ylhydrazine-1-carbothioamide) (1), 2,2'-(((propane-1,3-diylbis(oxy))bis(3-bromo-5-methoxy-4,1-phenylene))bis (methaneylylidene)) (N- (3-morpholinopropyl) hydrazine-1-carbothioamide) (2) bis, 2,2'-(((butane-1,4-diylbis(oxy))bis(3-bromo-5-methoxy-4,1-phenylene))bis (methaneylylidene)) (N- (3-morpholinopropyl) hydrazine-1-carbothioamide) (3) bis, 2,2'-(((hexane-1,6-diylbis(oxy))bis(3-bromo-5-methoxy-4,1-phenylene))bis (methaneylylidene)) (N- (3-morpholinopropyl) hydrazine-1-carbothioamide) (4) bis, 2,2'-(((propane-1,3-diylbis(oxy))bis(3-bromo-5-methoxy-4,1-phenylene))bis (methaneylylidene)) (hydrazine-1-carbothioamide) (5) bis, 2,2'- (((butane-1,4- diylbis(oxy))bis(3-bromo-5-methoxy-4,1-phenylene))bis(methaneylylidene))bis (hydrazine-1-carbothioamide)(6)。
3. a kind of antitumor drug, it is characterised in that：
The active constituent of the antitumor drug is the materia medica of six kinds of compounds described in claim 1, six kinds of compounds One or two or more kinds in the chemical equivalent of upper acceptable salt and six kinds of compounds, six kinds of compounds, six kinds of changes One or two or more kinds of mixing in the pharmaceutically acceptable salt of object and the chemical equivalent of six kinds of compounds are closed as work The drug of sexual element is preparing one or two or more kinds of medicines in preventing and/or treating the relevant diseases and symptom such as tumour, cancer Application in object.
4. drug described in accordance with the claim 3, it is characterised in that：
The drug is tablet, capsule, oral solution, granule, pill or injection, but is not limited to the above dosage form.
5. drug described in accordance with the claim 3, it is characterised in that：The relevant diseases such as the prevention and/or treatment tumour, cancer With the one or two or more kinds in symptom, particularly relate to the tumours such as lung cancer, liver cancer, breast cancer, oophoroma, prostate cancer and/ Or the one or two or more kinds in Cancerous disease.
6. one or two or more kinds of drugs in the relevant diseases and symptom such as a kind of prevention and/or treatment tumour, cancer, feature It is：In the chemical equivalent of six kinds of compounds, the pharmaceutically acceptable salt of six kinds of compounds and six kinds of compounds One or two or more kinds can directly use, or in the form of pharmaceutical composition use；The pharmaceutical composition contains 0.1- 99%, preferably 0.5-90% six kinds of compounds, six kinds of compounds pharmaceutically acceptable salt and six kinds of chemical combination One or two or more kinds in the chemical equivalent of object, remaining is pharmaceutically acceptable pharmaceutical carrier and/or excipient.
7. a kind of preparation method of PARP1 inhibitor described in claim 1, it is characterised in that：
Step 1：Prepare intermediate alkoxy dibromophenol benzaldehyde (I-III):
At room temperature, 5- bromines vanillic aldehyde (13.9g, 60mmol) and potassium carbonate (2.8g, 20mmol) are mixed and is added in flask, is added 20mLDMF dissolves, and stirs 10min, 1,3- dibromopropanes or Isosorbide-5-Nitrae-dibromobutane or 1,6- dibromo-hexanes are added dropwise while stirring (2mL, 20mmol), 80 DEG C of heating condensing reflux 10h, is added 500mL water, there is white flock precipitate precipitation, precipitation is filtered, and Precipitation is washed with saturated sodium bicarbonate, ethyl acetate washing precipitates to obtain intermediate, (can provide range accordingly)
Step 2：Prepare compound 1-6:
It weighs midbody compound I or II or III (2mmol) and corresponding thiosemicarbazides (4.4mmol) is blended in 10 0mL 95% Ethyl alcohol in, stir 10min, 1000 μ L acetic acid be added dropwise while stirring, condensing reflux 12h is heated at 70 DEG C, it is heavy that white is precipitated It forms sediment, precipitation is filtered, precipitation is washed with ethyl alcohol, dry compound 1-6.
8. preparation method according to claim 7, it is characterised in that：
The thiosemicarbazides is 4- methylamino sulphur, 4- [3- (4- morpholines) propyl] -3- thiosemicarbazides, thiosemicarbazides one kind Or it is two or more.
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