CN107987063A - A kind of HSP90 inhibitor and its application in antitumor drug - Google Patents

A kind of HSP90 inhibitor and its application in antitumor drug Download PDF

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Publication number
CN107987063A
CN107987063A CN201711494337.2A CN201711494337A CN107987063A CN 107987063 A CN107987063 A CN 107987063A CN 201711494337 A CN201711494337 A CN 201711494337A CN 107987063 A CN107987063 A CN 107987063A
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compound
pharmaceutically acceptable
acceptable salt
amides compound
reaction
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窦玉玲
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings

Abstract

The invention discloses the amides compound or its pharmaceutically acceptable salt shown in a kind of formula I,Wherein, R1Selected from CH3Or CF3, R2Selected from CH3Or

Description

A kind of HSP90 inhibitor and its application in antitumor drug
Technical field
The invention belongs to chemicals synthesis and pharmacological activity field, it is related to a kind of HSP90 inhibitor and its antitumor The application of medicine.
Background technology
Heat shock protein（Heat shock proteins, HSPs）It is body stress（Viral infection, anoxic, ultraviolet Irradiation etc.）The histone matter molecule synthesized under state, therefore also known as stress protein.HSPs is initially in 1962 by geneticist Ritossa has found that it is egg that is a kind of highly conserved during biological evolution and being widely present in protokaryon and eucaryote White matter.Heat shock protein is both the biomarker of cellular stress, and intracellular important molecular chaperone protein.HSPs Major function is to participate in maintaining the correct folding of its client protein in body so that albumen being capable of structure needed for physiology function As so as to play a significant role in regulatory protein synthesis is positioned with the balance and albumen degraded.
According to degree of homology and molecular size range, heat shock protein is broadly divided into 5 families：HSP90 families（83~ 90kD）, HSP70 families（66~78kD）, HSP60 families, small molecule HSP families（15~30kD）, exist in addition with molecular weight The macromolecular HSPs of 100~110kD.They have different positioning in cell, thus exercise different cell functions.Wherein HSP90 families are the hot spots of current research, obtain extensive concern.
It was found that HSP90 is mostly in the state of activation in tumour cell, otherwise static shape is mostly in normal cell State.In the state of activation, HSP90 forms compound with substrate or client protein and auxiliary molecular chaperones etc., protects substrate or client Albumen cannot be easily degraded by proteases.The effect that HSP90 can be played is dependency ATP, and ATP/ADP binding sites carry conception and turn The effect of changing, adjusts formation and assembling that HSP90 participates in the molecular chaperones compound of influence.Some researches show that HSP90 and many originals Oncogene forms complex, such as p210bcr/ in proto-oncogene pp60v-src, p53, chronic myeloid leukemia cel l line k562 Abl and p23 etc., shows that existence of the HSP90 to tumour has important influence, its performer in oncogenic pathways is important Role.
It is well known that the most important feature of tumour cell is escape of the upper reconciliation to apoptosis to growth signals.HSP90 pairs The stability of growth of tumour cell Regulate signal function has material impact.And the oncogene that the interference of HSP90 inhibitor is complicated Path, has more obvious advantage compared with the tumor suppressor gene path of selectivity.But limited by the prior art, it is existing HSP90 inhibitor is difficult equally to give out more hope and challenge in front also there are many deficiencies.As scientific level is into one Step development, the discovery of the more perfect HSP90 inhibitor of structure will more efficiently suppress the occurrence and development of tumour cell.
The content of the invention
It is an object of the invention to provide the amides compound or its pharmaceutically acceptable salt shown in a kind of formula I,
Wherein, R1Selected from CH3Or CF3, R2Selected from CH3OrOr。
The structure and its corresponding numbering of 1 the compounds of this invention formula I of table
Numbering Structure Numbering Structure
Ⅰ-1 Ⅰ-4
Ⅰ-2 Ⅰ-5
Ⅰ-3 Ⅰ-6
Another object of the present invention is to provide a kind of synthetic route of formula I：
Further, each step synthetic method is in the synthetic route：
1) in glacial acetic acid, the ammonolysis of 5- amidos furans -2- carboxylic acids and the annular anhydride compound progress acid anhydrides with substituent Reaction, generates substituted furancarboxylic acid compound, is extracted after the completion of reaction with organic solvents such as dichloromethane, then mutually washed with water Organic phase, solvent evaporated after drying, sterling is obtained with acetone and ethyl alcohol recrystallization；
2) chlorination under carboxylic acid derivates low temperature under nitrogen protection, is generated into chloride compounds with thionyl chloride；
3) reacted, extracted after solvent evaporated with organic solvent, water under low temperature in acetonitrile with the primary amino-compound and acyl chlorides of substitution It is dry after washing, flash chromatography post separation after solvent evaporated, the amide compound substituted.
Further, the extraction agent that can be selected after the completion of reaction in the step 1) includes ethyl acetate, dichloromethane Alkane etc., preferably dichloromethane；The inorganic salt solution of washing is selected from saturated sodium bicarbonate solution and saturated nacl aqueous solution.
Further, the ratio of acetone and ethanol is 1 during recrystallization in the step 1):1 to 1:4, preferably 1:3.
Further, the reaction condition described in the step 2) is 0-10 DEG C, and half an hour, temperature was no more than before reaction 10 DEG C, preferably more than 5 DEG C.
Further, the organic solvent of extraction includes but not limited to ethyl acetate, dichloromethane, stone in the step 3) Oily ether, methyl tertiary butyl ether(MTBE) etc., ethyl acetate and dichloromethane.
Another object of the present invention is to provide amides compound or its pharmaceutically acceptable salt conduct of a kind of formula I Application of the HSP90 inhibitor in preventing and/or treating disease.
Another object of the present invention is to provide a kind of formula I amides compound or its pharmaceutically acceptable salt pre- Application in anti-and/or treating cancer.
Obviously, the above according to the present invention, according to the ordinary technical knowledge and means of this area, is not departing from this hair Under the premise of bright above-mentioned basic fundamental thought, the modification, replacement or change of other diversified forms can also be made.
Embodiment
Embodiment 1：N- furans -2- bases -5- (2,5- dioxy -3- trifluoromethyl -2,5- dihydro -1H- pyrroles -1- bases) furan Mutter the synthesis of -2- formamides
Synthetic route is as follows：
Step 1)：The synthesis of 5- (2,5- dioxy -3- trifluoromethyl -2,5- dihydro -1H- pyrroles -1- bases) furans -2- formic acid
5- amido furans -2- carboxylic acids (10 mmol) are added in the reaction vessel for filling 25 ml glacial acetic acids, add 3- trifluoros Methylfuran base -2,5- diketone (11 mmol), mixing is refluxed overnight, and is subsequently cooled to<50 DEG C, solvent is shifted in a vacuum, it is residual Excess dissolving, obtained solution water (50 ml × 2), saturation NaHCO in dichloromethane (50 ml)3Aqueous solution (50 ml × 2) wash with saturated salt solution (50 ml × 2), and dried with anhydrous sodium sulfate.It is evaporated in vacuo solvent, residue is with 15 Ml acetone solutions, then 30 ml ethanol crystallizations are added dropwise, are filtered, 50 DEG C of vacuum drying, obtain 2.2 grams of off-white color 5- (2,5- dioxies- 3- trifluoromethyl -2,5- dihydro -1H- pyrroles -1- bases) furans -2- formic acid solids, yield 80%.1H-NMR (400 MHz, CDCl3) δ: 7.33(d, 1H), 7.48(d, 1H), 7.75(s, 1H), 13.15(br, 1H).LC-MS(ESI, pos, ion) m/z: 276[M+1]。
Step 2)：The conjunction of 5- (2,5- dioxy -3- trifluoromethyl -2,5- dihydro -1H- pyrroles -1- bases) furans -2- formyl chlorides Into
Under nitrogen protection, by thionyl chloride (15 mmol) and 5- (2,5- dioxy -3- trifluoromethyl -2,5- dihydro -1H- pyrroles Cough up -1- bases) furans -2- formic acid (10 mmol) is dissolved in tetrahydrofuran under 5 DEG C of the following conditions of ice-water bath, half an hour is reacted, after Recovery be stirred at room temperature 20 it is small when, evaporated under reduced pressure solvent, petroleum ether is beaten to obtain 1.8 g yellow 5- (2,5- dioxy -3- fluoroforms Base -2,5- dihydro -1H- pyrroles -1- bases) furans -2- formyl chloride powder, yield 75%.1H-NMR (400 MHz, CDCl3) δ: 7.39(d, 1H), 7.74-7.75(m, 2H).LC-MS(ESI, pos, ion) m/z: 294[M+1]。
Step 3)：N- furans -2- bases -5- (2,5- dioxy -3- trifluoromethyl -2,5- dihydro -1H- pyrroles -1- bases) furans - The synthesis of 2- formamides
5- (2,5- dioxy -3- trifluoromethyl -2,5- dihydro -1H- pyrroles -1- bases) furans -2- formyl chlorides (10 mmol) is molten Under the conditions of acetonitrile, 0-5 DEG C, by 2- amido furans（12mmol）Acetonitrile solution dropwise enter in above-mentioned system, during dropwise addition Internal temperature is not higher than 10 °C, after being added dropwise, is stirred overnight at room temperature, then solvent evaporated.Use dichloromethane（100ml）Dissolving Residue, uses water（100ml X 2）Wash organic phase, organic phase anhydrous Na2SO4It is dry, after solvent evaporated, flash column chromatography Separation, obtains 2.8 g off-white color N- furans -2- bases -5- (2,5- dioxy -3- trifluoromethyl -2,5- dihydro -1H- pyrroles -1- bases) Furans -2- formamide solids, yield 95%.1H-NMR (400 MHz, CDCl3) δ: 6.68(t, 1H), 7.00(dd, 1H), 7.20(d, 1H), 7.44(d, 1H), 7.78(s, 1H), 7.88(d, 1H).13C-NMR(75 MHz, CDCl3) δ: 97.51, 98.21, 108.09, 116.4, 118.69, 133.17, 134.15, 137.34, 140.62, 146.73, 148.63, 157.27, 169.73, 172.82.LC-MS(ESI, pos, ion) m/z: 341[M+1]。
Embodiment 2：N- methyl -5- (2,5- dioxy -3- trifluoromethyl -2,5- dihydro -1H- pyrroles -1- bases) furans -2- first The synthesis of acid amides
Step 1) and step 2) are identical with the step 1) and step 2) of embodiment 1, and synthetic product is identical.
Step 3)：N- methyl -5- (2,5- dioxy -3- trifluoromethyl -2,5- dihydro -1H- pyrroles -1- bases) furans -2- first The synthesis of acid amides
5- (2,5- dioxy -3- trifluoromethyl -2,5- dihydro -1H- pyrroles -1- bases) furans -2- formyl chlorides (10 mmol) are dissolved in Acetonitrile, under the conditions of 0-5 DEG C, by methylamine（12mmol）Methanol solution be added dropwise in above-mentioned system, internal temperature during dropwise addition Not higher than 10 DEG C, after being added dropwise, it is stirred overnight at room temperature, then solvent evaporated.Use dichloromethane（100ml）Dissolve residue, Use water（100ml X 2）Wash organic phase, organic phase anhydrous Na2SO4Dry, after solvent evaporated, flash column chromatography separation, obtains 2.7 g off-white color N- methyl -5- (2,5- dioxy -3- trifluoromethyl -2,5- dihydro -1H- pyrroles -1- bases) furans -2- formamides Solid, yield 94%.1H-NMR (400 MHz, CDCl3) δ: 2.85(s, 3H), 5.98(s, 1H), 7.20(d, 1H), 7.44(d, 1H), 7.74(s, 1H).13C-NMR(75 MHz, CDCl3) δ: 26.07, 97.51, 118.55, 118.69, 133.17, 134.15, 140.62, 142.9, 160.75, 169.73, 172.82.LC-MS(ESI, pos, ion) m/z: 289[M+1]。
Embodiment 3：N- (2- picoline -4- bases) -5- (2,5- dioxy -3- trifluoromethyl -2,5- dihydro -1H- pyrroles - 1- yls) furans -2- formamides synthesis
Step 1) and step 2) are identical with the step 1) and step 2) of embodiment 1, and synthetic product is identical.
Step 3)：N- (2- picoline -4- bases) -5- (2,5- dioxy -3- trifluoromethyl -2,5- dihydro -1H- pyrroles -1- Base) furans -2- formamides synthesis
5- (2,5- dioxy -3- trifluoromethyl -2,5- dihydro -1H- pyrroles -1- bases) furans -2- formyl chlorides (10 mmol) are dissolved in Acetonitrile, under the conditions of 0-5 DEG C, by 2- picoline -4- amine（12mmol）Methanol solution be added dropwise in above-mentioned system, be added dropwise process Middle internal temperature is not higher than 10 DEG C, after being added dropwise, is stirred overnight at room temperature, then solvent evaporated.Use dichloromethane（100ml）It is molten Residue is solved, uses water（100ml X 2）Wash organic phase, organic phase anhydrous Na2SO4It is dry, after solvent evaporated, quick column color Spectrum separation, obtains 3.4 g off-white colors N- (2- picoline -4- bases) -5- (2,5- dioxy -3- trifluoromethyl -2,5- dihydros -1H- Pyrroles -1- bases) furans -2- formamide solids, yield 93%.1H-NMR (400 MHz, CDCl3) δ: 2.22(s, 3H), 7.20(d, 1H), 7.41-7.49(m, 3H), 7.75(s, 1H), 8.55(d, 1H), 9.04(s, 1H).13C-NMR (75 MHz, CDCl3) δ: 23.38, 97.51, 113.33, 116.77, 118.22, 118.69, 133.17, 134.15, 140.62, 143.52, 146.62, 150.33, 157.04, 161.81, 169.73, 172.82.LC-MS (ESI, pos, ion) m/z: 366[M+1]。
Test example 1：Compound enzyme level determination of activity
The Screening Platform of people's HSP90- alpha inhibitors is built, using fluorescence polarization（FP）Method, based on principle be to pass through detection Fluorescein-labeled small molecule and the change of molecular weight before and after other interactions of molecules, calculated level direction and vertical direction Fluorescence polarization value makees correlation analysis.After if the combination balance being fluorescently labeled between small molecule and macromolecular is established, it is excited Moved slowly during hair, the fluorescence polarization light value measured can increase.If the combination between fluorescent marker small molecule and macromolecular is by it The substitution of his aglucon, it is rotated or turned over speed and can accelerate under free state, and transmitting light is put down relative to exciting light.
Fluorescent marker small molecule applied in the present invention is GM-BODIPY（With reference to BMCL, 2003,13,3975-3978 The synthetic method synthesis）.Reaction carries out in 384 hole blackboards, reaction hydrophobin HFB buffer solutions used：50mM KCl, 5mM MgCl2, 20mM Na2MoO4, 0.01% NP40,0.1mg/ml BGG, 2mM DTT, pH7.3.Reaction system volume 50mL, wherein including 5nM GM-BODIPY（Geldanamycin）, 30nM HSP90 and test compound or DMSO, DMSO's contains Amount is 2 ‰.It is another to do the two groups holes added with HFB buffer solutions as blank control and 5nM GM-BODIPY as negative control.4 When reaction 12-16 is small at DEG C, detected under Biotek microplate reader, excitation wavelength 485nm, launch wavelength 530nm, measures mP Value.Inhibiting rate is calculated using equation below：
（It is not added with compound mP- and adds compound mP）/（It is not added with compound mP- negative controls mP）*100%
After the inhibiting rate for calculating the compound of various concentrations, the IC of the compound is calculated50, the IC of compound50Value is shown in Table 2：This IC of the invention Formula I to people HSP90- α50
Compound IC50（μM） Compound IC50（μM）
Ⅰ-1 0.424 Ⅰ-4 0.108
Ⅰ-2 0.360 Ⅰ-5 0.038
Ⅰ-3 0.301 Ⅰ-6 0.014
Test example 2：Mtt assay measures inhibitory action of the compounds of this invention to different tumour cells
First, cell line
Human lung cancer cell A549, Human hepatoma cell line Bel-7402, human large cell lung cancer cell NCI-H460, human gastric adenocarcinoma BGC-823, human breast cancer cell line Bcap-37.
2nd, experimental procedure：
1. the cell in growth period of taking the logarithm, Trypsin Induced, 1640 cell culture fluid tune concentration of cell suspension of RPMI for 6 × 104A/mL.Add 100 μ L of cell suspension per hole in 96 well culture plates, put 37 DEG C, 5% CO224h, cell patch are cultivated in incubator Wall.
2. medicine group to be measured：1640 cell culture fluids of RPMI are removed, add the RPMI of the medicine to be measured of concentration gradient 1640 cell culture fluid, 100 μ L, each concentration set 6 parallel holes.96 orifice plates after dosing are placed in 37 DEG C, 5% CO2Incubator Middle culture 48h, the action effect of medicine is observed under inverted microscope.
Control group：Compared with medicine group to be measured, the medicine to be measured for adding concentration gradient is changed to add the RPMI of not drug containing 1640 cell culture fluids, other step all sames.
Blank group：Compared with control group, cell is not added with, other step all sames.
Nutrient solution is discarded after the centrifugation of 3.96 orifice plates, after carefully being rushed 2 ~ 3 times with PBS, adds the RPMI containing 0.5% MTT 1640 cell culture fluid, 100 μ L, continue to cultivate 4h.
4. removing supernatant, 150 μ L dimethyl sulfoxide (DMSO)s are added per hole, low-speed oscillation 10min on shaking table is put, ties formazan Brilliant fully dissolving.
5. the optical density in each hole is measured at enzyme-linked immunosorbent assay instrument 490nm（OD values）.
6. parallel hole OD values are represented with mean ± SD, inhibiting rate formula is calculated：[(ODControl group-ODBlank group)-(ODMedicine group to be measured- ODBlank group)]/(ODControl group-ODBlank group)*100%。
7. using 5 data processing softwares of GraphPad Prism, by drawing amount effect curve calculation of half inhibitory concentration （IC50）.
3rd, experimental result
1 the compounds of this invention of table is to different human tumor cells IC50Value
From above-mentioned test example, amides compound of the present invention has the obvious activity for suppressing HSP90.HSP90 is cell One of interior most active molecular chaperone protein, plays an important role in the generation and evolution of tumour, amide-type of the present invention Compound has good inhibitory activity to different human tumor cells, can be carried out as the anti-cancer agent with Prospect of R ＆ D More deep research and development, to supplement existing antitumor drug market.

Claims (9)

1. amides compound or its pharmaceutically acceptable salt shown in a kind of formula I,
Wherein, R1Selected from CH3Or CF3, R2Selected from CH3Or。
2. amides compound as claimed in claim 1 or its pharmaceutically acceptable salt, its synthetic route are：
。
3. amides compound as claimed in claim 2 or its pharmaceutically acceptable salt, each step in the synthetic route Synthetic method is：
1) in glacial acetic acid, the ammonolysis of 5- amidos furans -2- carboxylic acids and the annular anhydride compound progress acid anhydrides with substituent Reaction, generates substituted furancarboxylic acid compound, is extracted after the completion of reaction with organic solvents such as dichloromethane, then mutually washed with water Organic phase, solvent evaporated after drying, sterling is obtained with acetone and ethyl alcohol recrystallization；
2) chlorination under carboxylic acid derivates low temperature under nitrogen protection, is generated into chloride compounds with thionyl chloride；
3) reacted, extracted after solvent evaporated with organic solvent, water under low temperature in acetonitrile with the primary amino-compound and acyl chlorides of substitution It is dry after washing, flash chromatography post separation after solvent evaporated, the amide compound substituted.
4. amides compound as claimed in claim 3 or its pharmaceutically acceptable salt, the middle reaction of the step 1) is completed The extraction agent that can be selected afterwards includes ethyl acetate, dichloromethane etc., preferably dichloromethane.
5. amides compound as claimed in claim 3 or its pharmaceutically acceptable salt, in the step 1) during recrystallization The ratio of acetone and ethanol is 1:1 to 1:4, preferably 1:3.
6. amides compound as claimed in claim 3 or its pharmaceutically acceptable salt, described in the step 2) Reaction condition is 0-10 DEG C, and half an hour temperature is no more than 10 DEG C, preferably more than 5 DEG C before reaction.
7. amides compound as claimed in claim 3 or its pharmaceutically acceptable salt, extraction in the step 3) Organic solvent includes but not limited to ethyl acetate, dichloromethane, petroleum ether, methyl tertiary butyl ether(MTBE) etc., ethyl acetate and two Chloromethanes.
8. amides compound as claimed in claim 1 or its pharmaceutically acceptable salt are preventing as HSP90 inhibitor And/or the application in treatment disease.
9. amides compound as claimed in claim 1 or its pharmaceutically acceptable salt are in prevention and/or treating cancer Application.
CN201711494337.2A 2017-12-31 2017-12-31 A kind of HSP90 inhibitor and its application in antitumor drug Withdrawn CN107987063A (en)

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Citations (4)

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CN101410387A (en) * 2006-03-27 2009-04-15 内尔维阿诺医学科学有限公司 Pyridyl- and pyrimidinyl-substituted pyrrole-, thiophene- and furane-derivatives as kinase inhibitors
CN107438603A (en) * 2015-04-22 2017-12-05 里格尔药品股份有限公司 Pyrazole compound and preparation and the method using the compound

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1662236A (en) * 2002-04-27 2005-08-31 阿斯特拉曾尼卡有限公司 Inhibitors of histone deacetylase
CN101006052A (en) * 2004-07-30 2007-07-25 埃克塞利希斯股份有限公司 Pyrrole derivatives as pharmaceutical agents
CN101410387A (en) * 2006-03-27 2009-04-15 内尔维阿诺医学科学有限公司 Pyridyl- and pyrimidinyl-substituted pyrrole-, thiophene- and furane-derivatives as kinase inhibitors
CN107438603A (en) * 2015-04-22 2017-12-05 里格尔药品股份有限公司 Pyrazole compound and preparation and the method using the compound

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Title
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Application publication date: 20180504