CN108586439A - A kind of Raf kinase and its application in treatment of cancer - Google Patents

A kind of Raf kinase and its application in treatment of cancer Download PDF

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CN108586439A
CN108586439A CN201810560174.1A CN201810560174A CN108586439A CN 108586439 A CN108586439 A CN 108586439A CN 201810560174 A CN201810560174 A CN 201810560174A CN 108586439 A CN108586439 A CN 108586439A
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刘思良
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    • 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
    • C07D405/12—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 linked by a chain containing hetero atoms as chain links
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    • A61P35/00—Antineoplastic agents
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia

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Abstract

The invention discloses a kind of Raf kinase formula I and its application in treatment of cancer,Wherein：R1、R2、R3、R4It is independently selected from H, CH3Or COOCH3.External pharmacological evaluation confirms inhibitory activity of the compounds of this invention formula I with 1 kinases of Raf, can inhibit A498, HT 29,205 activity of COLO.Cancer related with Raf kinase can be melanoma, liver cancer, kidney, acute leukemia, non-small cell lung cancer, prostate cancer, thyroid cancer, cutaneum carcinoma, colorectal cancer, cancer of pancreas, oophoroma, breast cancer, myelodysplastic syndrome, the cancer of the esophagus, gastric cancer or celiothelioma etc..

Description

A kind of Raf kinase and its application in treatment of cancer
Technical field
The invention belongs to chemical medicines, are related to a kind of Raf kinase formula I and its answering in treatment of cancer With.
Background technology
With the development of molecular biology technology, be gradually concerned by people using Raf-1 as the oncotherapy of target spot and Approve.Due to Raf-1 kinases played in terms of the adjusting of signal path and the pathologic, physiologic phenomenon regulation and control of many complexity it is important Effect, also plays an important role in terms of oncotherapy, using Raf-1 as the Therapy study of target spot in preclinical phase and It is applied in different clinical tests, and has the characteristics that small toxicity and high specificity compared with traditional embolic chemotherapy, therefore with Raf-1, which is the treatment of target spot, sizable application prospect.Studies have shown that in most of eukaryocyte, there are Ras/Raf/ MEK/ERK signal paths, the research with people to Ras/Raf/MEK/ERK signal transduction pathways, using Raf-1 as the swollen of target spot Tumor treatment foreground will gradually extend.Enter clinical treatment from clinical research, for later oncotherapy provide more means with Method.
Sorafenib (Sorafenib, BAY43-9006) is first Raf inhibitor by clinical test.It is preclinical Experiment display, in tumor cell line and the heteroplastic transplantation model of Ras kinases dependent form tumours, Sorafenib can significantly inhibit The activity of Raf-1 and B-Raf.Further study showed that Sorafenib can be used for treating advanced renal cell carcinoma (renal cell Carcinoma, RCC) and primary carcinoma of liver (hepatocellular carcinoma, HCC).However, Sorafenib monomer Or it is not to manage very much that drug combination, which especially carries melanoma the clinical therapeutic efficacy of the malignant mela noma of B-Raf mutation, Think.Sorafenib is developed as a species specific Raf-1 kinase inhibitors, although it cannot be abundant to the B-Raf of mutation Inhibit, but it spreads out to vascular endothelial growth factor (vascularendothelial growth factor, VEGF) and blood platelet Raw growth factor (platelet derived growth factor, PDGF) receptor kinase has height depression effect.
Invention content
The invention discloses a kind of Formula I, structure is：
Wherein：R1、R2、R3、R4It is independently selected from H, CH3Or COOCH3.Further, R1、R4Be independently selected from H or CH3, R2、R3It is independently selected from H or-COOCH3.The invention further relates to the pharmaceutically acceptable salts of the Formula I Or solvate.
Further, Formula I described in some preferred schemes is
The synthetic route that another object of the present invention discloses the Formula I is：
Specifically synthetic method is：
1) at suitable temperature, compound 1 occurs condensation reaction with cyclo-hexylamine (compound 2) and generates N- (cyclohexyl ammonia Base) -5- nitrofuran -2- formamides (compound 3)；
2) under the action of Pd-C catalyst is as catalyst reduction reaction occurs for compound 3, is given birth to by pillar layer separation At 5- amino-N- (Cyclohexylamino) furans -2- formamides (compound 4)；
3) compound 4 and NaNO2Diazol 5- ((Cyclohexylamino) carbamoyl) furans -2- weights are made in/HCl reactions Nitrogen salt (compound 5)；
4) under alkaline condition, compound 5 is coupled with corresponding conjugated compound final product is made again.
Further, the range of reaction temperature of the step 1) is 0~10 DEG C, preferably 3~5 DEG C.
Further, the solvent in the step 2) used in pillar layer separation can be ethyl acetate：Methanol=1：1, Ethyl acetate：Glacial acetic acid=4: 1, ethyl acetate：Methanol=1：1.
Further, the alkali in the step 4) can be sodium carbonate, potassium carbonate, potassium acetate, preferably sodium carbonate.
Another object of the present invention discloses the Formula I and carries out drug development as Raf kinase, with The related cancer of Raf kinase can be melanoma, liver cancer, kidney, acute leukemia, non-small cell lung cancer, forefront Gland cancer, thyroid cancer, cutaneum carcinoma, colorectal cancer, cancer of pancreas, oophoroma, breast cancer, myelodysplastic syndrome, oesophagus Cancer, gastric cancer or celiothelioma etc..
The compounds of this invention Raf kinase inhibiting activities and to the external inhibitory activity of different tumour cells in test example part It is disclosed in detail.It is real that the inhibitory activity to mycobacterium tuberculosis in vitro has also been carried out in the experiment of the compounds of this invention pharmacological effect It tests, is summarized as follows：
It is carried out in 96 orifice plates, test-compound is dissolved in appropriate DMSO, is made into the solution of a concentration of 12.8mg/ml, so After be added in 7H9-OADC culture solutions, be made into the storing liquid of final concentration of 128 μ g/ml, then reality is diluted to fluid nutrient medium Test required concentration.Tested drug final concentration setting is as follows：128、64、32、16、8、4、2、1、0.5、0.25、0.125μg/ Ml, totally 11 concentration gradients.When detection, respectively take 100 μ L of said medicine solution in 96 orifice plates, same drug dilution degree setting three Group parallel control.Mycobacterium tuberculosis type strain H37Rv is added in culture hole, and test-compound pair is observed in 37 DEG C of cultures after a week The minimum inhibitory concentration of mycobacterium tuberculosis, wherein RY-5002, RY-5004, RY-5005, RY-5007 minimum inhibitory concentration are small In 15 μM.
Pharmaceutically acceptable salt of the present invention refers to the organic salt and inorganic salts of the compounds of this invention.Pharmaceutically may be used The salt that the nontoxic acid received is formed includes, but is not limited to, inorganic acid salt, such as hydrochloride, hydrobromate, phosphate, sulfuric acid Salt, perchlorate；Acylate, such as acetate, oxalates, maleate, tartrate, citrate, succinate, the third two Hydrochlorate；Or these salt are obtained by other methods described in the books or literature such as ion-exchange.Other can pharmaceutically connect The salt received includes adipate, alginates, ascorbate, aspartate, benzene sulfonate, benzoate, bisulphate, Borate, butyrate, camphor hydrochlorate, camsilate, cyclopentyl propionate, digluconate, lauryl sulfate, second Sulfonate, formates, fumarate, gluceptate, glycerophosphate, gluconate, Hemisulphate, enanthate, Caproate, hydriodate, 2- hydroxy-ethanesulfonate salts, lactobionate, lactate, laruate, lauryl sulfate, apple Hydrochlorate, mesylate, 2- naphthalene sulfonates, nicotinate, nitrate, oleate, palmitate, pamoate, pectate, persulfuric acid Salt, 3- phenylpropionic acid salt, picrate, pivalate, propionate, stearate, rhodanate, tosilate, 11 Hydrochlorate, valerate, etc..By including alkali metal, alkaline-earth metal, ammonium and N+ (C1-4 alkane with alkali appropriate salt obtained by the reaction Base) 4 salt.Water-soluble or oil-soluble or dispersion product can be obtained by quaternization.Can with the alkali metal of forming salt or Alkaline-earth metal includes sodium, lithium, potassium, calcium, magnesium, etc..Pharmaceutically acceptable salt further comprises appropriate, nontoxic ammonium, season The amine cation that ammonium salt and gegenions are formed, such as halide, hydroxide, carboxylate, hydrosulphate, phosphoric acid compound, nitre Acidulants, C1-8 azochlorosulfonate acid compounds and aromatic sulphonic acid compound.
Solvate of the present invention refers to that one or more solvent molecules are formed by with the compound of the present invention and form Close object.The solvent for forming solvate includes, but is not limited to, water, isopropanol, ethyl alcohol, methanol, dimethyl sulfoxide, ethyl acetate, Acetic acid and ethylaminoethanol.
Specific implementation mode
Embodiment 1：The synthesis of N- (Cyclohexylamino) -5- ((pyridyl group -4) diazenyl) furans -2- formamides
The synthesis of 1-1, N- (Cyclohexylamino) -5- nitrofuran -2- formamides
Water (40mL), NaOH (1.13g, 28.25mmol), cyclo-hexylamine (compound 2) (1.40g, 14.13mmol) are added Enter into 100mL reaction bulbs, and is stirred at room temperature to dissolving.After ice bath is cooled to 3~5 DEG C, 5- nitrofurans-are added portionwise 2- phosgenes (compound 1) (2.00g, 11.39mmol) after adding, continue stirring 1 hour, it is small to be then stirred at room temperature 2 When, obtain light yellow-green solution.Above-mentioned solution is poured into the mixing being made of 37% concentrated hydrochloric acid (54.3mL) and ice (about 20.0g) It in object, precipitates crystal, filters, filter cake is washed with water, acetone respectively, and light yellow solid N- (Cyclohexylamino) -5- is obtained after dry Nitrofuran -2- formamides (compound 3), 2.49g, yield 92%.1H-NMR(400MHz,CDCl3)δ:1.20-1.37(m, 5H),1.62(m,1H),1.84(m,2H),2.19(m,2H),4.95(m,1H),6.26(s,1H),7.79(d,1H),7.99(d, 1H).13C-NMR(125MHz,CDCl3)δ:24.73,25.92,33.63,50.21,111.99,114.67,150.14, 152.40,161.37.LC-MS(ESI,pos,ion)m/z:239[M+H].
The synthesis of 1-2,5- amino-N- (Cyclohexylamino) furans -2- formamides
In 100mL hydrogenation reaction cauldrons, compound 3 (2.49g, 10.48mmol), ethyl alcohol (20mL), 5%Pd-C is added and urges Agent (0.31g), is passed through H2, normal pressure, 5~6 hours of reaction are stirred at room temperature, and (reaction process TLC is into line trace, expansion used Agent is ethyl acetate：Methanol=1：1).After reaction, it filters, filtrate is concentrated under reduced pressure, then pours into ether under ice cooling, 4 In (about 70.0mL), there is crystallization to be precipitated.It filters, filter cake is washed with ether, obtains white solid 5- amino-N- (cyclohexyl ammonia Base) furans -2- formamides (compound 4), 1.61g, yield 74%.1H-NMR(400MHz,CDCl3)δ:1.20-1.35(m, 5H),1.66(m,1H),1.84(m,2H),2.19(m,2H),4.95(m,1H),6.16(s,1H),7.20(d,1H),7.44(d, 1H),8.52(s,2H).13C-NMR(125MHz,CDCl3)δ:24.05,25.87,33.53,50.21,86.35,114.17, 143.55,155.00,161.58.LC-MS(ESI,pos,ion)m/z:209[M+H].
The synthesis of 1-3,5- ((Cyclohexylamino) carbamoyl) furans -2- diazols
In 100mL reaction bulbs, be added compound 4 (1.61g, 7.75mmol), 37% hydrochloric acid (2.06mL, 24.63mmol), water (17.0mL), stirring make solid dissolve, and ice salt bath is cooled to -5 DEG C, and the sodium nitrite of precooling is added dropwise The solution that (7.85molmol) and water (3.43mL) are made into.Drop finishes, and maintains ice bath (about -5~0 DEG C) and is stirred to react 3 hours, obtains Diazonium salt solution 5- ((Cyclohexylamino) carbamoyl) furans -2- diazols (compound 5) are directly used in anti-in next step It answers.LC-MS(ESI,pos,ion)m/z:257[M+H].
The synthesis of 1-4, N- (Cyclohexylamino) -5- ((pyridyl group -4) diazenyl) furans -2- formamides
In 100mL reaction bulbs, NaOH (0.40g, 10.00mmol), Na is added2CO3(0.77g, 7.28mmol), water (7.75mL), pyridine (6.00mmol), stirring make solid dissolve, and ice salt bath is cooled to -2 DEG C, and diazonium salt solution is added portionwise Close object 5 (2.22g, 6.05mmol).It finishes, adds a small amount of NaHCO3, it is adjusted to reaction solution pH=8, is stirred to react 3~4 hours.It will Reaction solution is poured into the mixed liquor being made by 37% hydrochloric acid (2.35mL) and ice (about 2.35g), and a large amount of khaki solids are precipitated, and is taken out Filter, filter cake is with water washing (to filtrate pH=4~5), dry crude product.It is recrystallized with alcohol-water, obtains yellow orange solid N- (rings Hexylamino) -5- ((pyridyl group -4) diazenyl) furans -2- formamides, 1.50g, yield 83%.1H-NMR(400MHz, CDCl3)δ:1.19-1.21(m,4H),1.41-1.54(m,2H),1.70-1.77(m,4H),3.82(m,1H),5.67(s, 1H),6.58(d,1H),7.44(d,1H),7.82(d,2H),8.63(d,2H).13C-NMR(125MHz,CDCl3)δ:24.73, 25.92,33.63,50.21,100.91,114.37,114.67,145.97,150.04,150.14,158.51,161.37.LC- MS(ESI,pos,ion)m/z:299[M+H]。
Embodiment 2：N- (Cyclohexylamino) -5- ((2- methyl formates base-pyridyl group -4) diazenyl) furans -2- formyls The synthesis of amine
In 100mL reaction bulbs, NaOH (0.40g, 10.00mmol), Na is added2CO3(0.77g, 7.28mmol), water (7.75mL), 2- methyl formates yl pyridines (6.00mmol), stirring make solid dissolve, and ice salt bath is cooled to -2 DEG C, is added portionwise Diazonium salt solution compound 5 (2.22g, 6.05mmol).It finishes, adds a small amount of NaHCO3, it is adjusted to reaction solution pH=8, stirring is anti- It answers 3~4 hours.Reaction solution is poured into the mixed liquor being made by 37% hydrochloric acid (2.35mL) and ice (about 2.35g), is precipitated a large amount of Khaki solid filters, and filter cake is with water washing (to filtrate pH=4~5), dry crude product.It is recrystallized with alcohol-water, obtains tangerine Yellow solid N- (Cyclohexylamino) -5- ((2- methyl formates base-pyridyl group -4) diazenyl) furans -2- formamides, 1.92g, yield 89%.LC-MS(ESI,pos,ion)m/z:357[M+H].
Embodiment 3：N- (Cyclohexylamino) -5- ((3- methvl-pyridinium -4- bases) diazenyl) furans -2- formamides Synthesis
In 100mL reaction bulbs, NaOH (0.40g, 10.00mmol), Na is added2CO3(0.77g, 7.28mmol), water (7.75mL), 3- picolines (6.00mmol), stirring make solid dissolve, and ice salt bath is cooled to -2 DEG C, and diazol is added portionwise Solution compound 5 (2.22g, 6.05mmol).It finishes, adds a small amount of NaHCO3, it is adjusted to reaction solution pH=8, is stirred to react 3~4 Hour.Reaction solution is poured into the mixed liquor being made by 37% hydrochloric acid (2.35mL) and ice (about 2.35g), a large amount of khakis are precipitated Solid filters, and filter cake is with water washing (to filtrate pH=4~5), dry crude product.It is recrystallized with alcohol-water, it is solid to obtain orange colour Body N- (Cyclohexylamino) -5- ((3- methvl-pyridinium -4- bases) diazenyl) furans -2- formamides, 1.53g, yield 81%. LC-MS(ESI,pos,ion)m/z:313[M+H]。
Test example 1：The inhibitory activity of Raf-1 kinases is tested
ADP Glo patterns are used for testing the inhibitory activity of Raf-1.Test process is as follows.The ingredient of buffer solution is 25mM HEPES, 10mM MgCl2, 0.01%Triton X-100,100 μ g/mL BSA, 2.5mM DTT, pH=7.4.It will delay Fliud flushing, enzyme, substrate, ATP and determinand are blended on the cell plates in the holes 384-, and total volume is 10 μ L.Then, cell plates are at 30 DEG C It is lower to be incubated 1 hour, then ADP Glo reagents are added into reaction mixture with the dosage in 10 holes μ L/, then 40 points are incubated at 27 DEG C Clock.Then detection reagent (20 holes μ l/), then into detection plate is added, and is incubated 30 minutes at 27 DEG C, last reading.In addition, Hotspot kinase assays also are used for testing the inhibitory activity (IC of compound50), compound is dripped with suitable kinase concentration It is fixed.
Inhibitory activity of the table 1 to Raf-1 kinases
Compound number IC50(μM)
RY-5001 0.35
RY-5002 0.25
RY-5003 0.29
RY-5004 0.19
RY-5005 0.21
RY-5006 0.26
RY-5007 0.29
As shown in Table 1, compound of the present invention have Raf-1 kinase inhibiting activities, can with Raf-1 kinases phases Determine that indication carries out more deep pharmacology activity research in the disease of pass.
Test example 2：CellTiter-Glo method test cell inhibitory activity
1, cell strain：
Human renal carcinoma cell strain A498；Human colon cancer cell strain HT-29；Human colon cancer cell strain COLO-205.
2, plating cells：
It collects the cell in exponential phase of growth and carries out viable count with Vi-Cell XR cell counters.With culture Cell suspension is adjusted to concentration appropriate by base, adds 90 μ l cell suspensions in 96- porocyte culture plates per hole.The cell completed is set In 37 DEG C, 5%CO2Incubator culture 24 hours.
3, compound is handled：
To being set as compound processing board, every plant of cell per well adds 10 × change of the corresponding 3 times of gradient dilutions of 10 μ l respectively Polymer solution (20 μM or 10 μM of final initial concentration), each each 3 multiple holes of drug concentration.
Read T3：After drug-treated 72 hours, 50 μ l are added per hole and melts in advance and equilibrates to the CTG solution of room temperature, use is micro- Orifice plate oscillator mixing 2 minutes uses Envision2104 plate readers to measure luminescence letters after ten minutes in being placed at room temperature for Number.
4, data analysis：
POC(percent ofcontrol：With the percentage compareed) calculation formula：
Compound handles the average value * 100% in the value/DMSO processing hole in hole
The value in wherein compound processing hole is the T3 luminescence values in drug-treated hole, and the processing holes DMSO are averaged Value handles the average value of the T3 luminescence values in hole for 6 DMSO on every block of plate, soft using GraphPad Prism 5.0 Part draws S types dosage-POC curves using nonlinear regression model (NLRM) and calculates IC50Value.
5, experimental result：
Inhibitory activity (IC of the table 2 to different tumour cells50Value)
As shown in Table 2, compound according to the present invention has external inhibitory activity to A498, HT-29 and COLO-205. Disease related with Raf kinase can be melanoma, liver cancer, kidney, acute leukemia, non-small cell lung cancer, preceding Row gland cancer, thyroid cancer, cutaneum carcinoma, colorectal cancer, cancer of pancreas, oophoroma, breast cancer, myelodysplastic syndrome, food Pipe cancer, gastric cancer or celiothelioma etc..

Claims (5)

1. a kind of general formula structure is the compound and its pharmaceutically acceptable salt or solvate of formula I
Wherein：R1、R2、R3、R4It is independently selected from H, CH3Or COOCH3。
2. Formula I as described in claim 1, characterized in that be selected from following compound：
3. application of the Formula I as claimed in claim 1 or 2 as Raf kinase.
4. application of the Formula I as claimed in claim 1 or 2 in preparing treating cancer drug.
5. application as claimed in claim 4, the cancer is selected from melanoma, liver cancer, kidney, acute leukemia, non-small Cell lung cancer, prostate cancer, thyroid cancer, cutaneum carcinoma, colorectal cancer, cancer of pancreas, oophoroma, breast cancer, myelosis are different Normal syndrome, the cancer of the esophagus, gastric cancer or celiothelioma etc..
CN201810560174.1A 2018-06-03 2018-06-03 A kind of Raf kinase and its application in treatment of cancer Pending CN108586439A (en)

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Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1805748A (en) * 2003-06-13 2006-07-19 诺瓦提斯公司 2-aminopyrimidine derivatives as RAF kinase inhibitors
CN101048388A (en) * 2004-08-31 2007-10-03 阿斯利康(瑞典)有限公司 Quinazolinone derivatives and their use as B-Raf inhibitors
CN102317293A (en) * 2008-12-05 2012-01-11 艾科尔公司 RAF inhibitors and their uses
CN102884060A (en) * 2010-03-24 2013-01-16 阿米泰克治疗方案公司 Heterocyclic compounds useful for kinase inhibition
CN107801378A (en) * 2015-05-22 2018-03-13 普莱希科公司 For treating the PLX 8394 or PLX 7904 of the related diseases of BRAF V600

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1805748A (en) * 2003-06-13 2006-07-19 诺瓦提斯公司 2-aminopyrimidine derivatives as RAF kinase inhibitors
CN101048388A (en) * 2004-08-31 2007-10-03 阿斯利康(瑞典)有限公司 Quinazolinone derivatives and their use as B-Raf inhibitors
CN102317293A (en) * 2008-12-05 2012-01-11 艾科尔公司 RAF inhibitors and their uses
CN102884060A (en) * 2010-03-24 2013-01-16 阿米泰克治疗方案公司 Heterocyclic compounds useful for kinase inhibition
CN107801378A (en) * 2015-05-22 2018-03-13 普莱希科公司 For treating the PLX 8394 or PLX 7904 of the related diseases of BRAF V600

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