CN108864060A - A kind of diazonium analog derivative and its application in cancer treatment - Google Patents
A kind of diazonium analog derivative and its application in cancer treatment Download PDFInfo
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Abstract
The invention discloses a kind of diazonium analog derivative formula I and its application in cancer treatment,Wherein：R1、R2、R3、R4It is independently selected from H, CH3Or-COOCH3.External pharmacological evaluation confirms that diazonium analog derivative formula I of the present invention has the inhibitory activity of Raf-1 kinases, and A498, HT-29, COLO-205 can be inhibited active.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
Technical field
The invention belongs to chemical medicine, it is related to a kind of diazonium analog derivative formula I and its application in cancer treatment.
Background technique
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 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 is that the treatment of target spot has sizable application prospect.Studies have shown that in most of eukaryocyte, there are Ras/Raf/
MEK/ERK signal path, the research with people to Ras/Raf/MEK/ERK signal transduction pathway, using Raf-1 as the swollen of target spot
Tumor treatment prospect 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 for passing through clinical test.It is preclinical
Test display, in tumor cell line and the heteroplastic transplantation model of Ras kinases dependent form tumour, Sorafenib can be significantly inhibited
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 inhibitor, 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.
Summary of the invention
The invention discloses a kind of diazonium analog derivative formula I, structure is：
Wherein：R1、R2、R3、R4It is independently selected from H, CH3Or-COOCH3.Further, R1、R4It is independently selected from H
Or CH3, R2、R3It is independently selected from H or-COOCH3.The invention further relates to pharmaceutically may be used for the diazonium analog derivative formula I
The salt or solvate of receiving.
Further, diazonium analog derivative formula I described in some preferred schemes is
The synthetic route that another object of the present invention discloses the diazonium analog derivative formula I is：
Specifically synthetic method is：
1) at suitable temperature, compound 1 and 4- (diethylamino) phenyl amine (compound 2) occur condensation reaction and generate
N- (4- (diethylamino) phenyl) -5- nitrofuran -2- formamide (compound 3)；
2) under the action of Pd-C catalyst is as catalyst reduction reaction occurs for compound 3, raw by pillar layer separation
At 5- amino-N- (4- (diethylamino) phenyl) furans -2- formamide (compound 4)；
3) compound 4 and NaNO2/ HCl, which reacts, is made diazonium salt 5- ((4- (diethylamino) phenyl) carbamoyl)
Furans -2- diazonium 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, solvent used in pillar layer separation can be ethyl acetate in the step 2)：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 diazonium analog derivative formula I and opens as Raf kinase progress drug
Hair, 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..
The compounds of this invention Raf kinase inhibiting activity and to the external inhibitory activity of different tumour cells in test example part
It is disclosed in detail.It has also been carried out in the experiment of the compounds of this invention pharmacological effect real to the inhibitory activity of mycobacterium tuberculosis in vitro
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 that concentration is 12.8mg/ml, so
After be added in 7H9-OADC culture solution, 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-2004~RY-2007 minimum inhibitory concentration is less than 10 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 salt, lactobionate, lactate, laruate, lauryl sulfate, apple
Hydrochlorate, mesylate, 2- naphthalene sulfonate, nicotinate, nitrate, oleate, palmitate, pamoate, pectate, persulfuric acid
Salt, 3- phenylpropionic acid salt, picrate, pivalate, propionate, stearate, rhodanate, tosilate, 11
Hydrochlorate, valerate, etc..It include alkali metal, alkaline-earth metal, ammonium and N+ (C1-4 alkane by the salt reacted with alkali appropriate
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 sulphonic acid compound 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 forms
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 embodiment
Embodiment 1：N- (4- (diethylamino) phenyl) -5- ((pyridyl group -4) diazenyl) furans -2- formamide
Synthesize the synthesis of 1-1, N- (4- (diethylamino) phenyl) -5- nitrofuran -2- formamide
By water (40mL), NaOH (1.13g, 28.25mmol), 4- (diethylamino) phenyl amine (compound 2) (2.34g,
It 14.13mmol) is added in 100mL reaction flask, and is stirred at room temperature to dissolution.After ice bath is cooled to 3~5 DEG C, in batches plus
Enter 5- nitrofuran -2- phosgene (compound 1) (2.00g, 11.39mmol), after adding, continues stirring 1 hour, then exist
It stirs 2 hours at room temperature, obtains light yellow-green solution.Above-mentioned solution is poured by 37% concentrated hydrochloric acid (54.3mL) and ice (about
It 20.0g) in the mixture formed, precipitates crystal, filters, filter cake uses water, acetone washing respectively, obtains light yellow solid N- after dry
(4- (diethylamino) phenyl) -5- nitrofuran -2- formamide (compound 3), 2.89g, yield 83.7%.1H-NMR
(400MHz,CDCl3)δ:1.12(t,6H),3.40(q,4H),6.90(d,2H),7.34(d,2H),7.79(d,1H),7.99
(d,1H),9.08(s,1H).13C-NMR(125MHz,CDCl3)δ:12.99,46.42,111.99,115.94,117.00,
124.04,124.93,145.55,148.63,152.40,161.81.LC-MS(ESI,pos,ion)m/z:304[M+H].
The synthesis of 1-2,5- amino-N- (4- (diethylamino) phenyl) furans -2- formamide
In 100mL hydrogenation reaction cauldron, addition compound 3 (2.89g, 9.53mmol), ethyl alcohol (20mL), 5%Pd-C are urged
Agent (0.31g), is passed through H2, normal pressure, 5~6 hours of reaction are stirred at room temperature, and (reaction process is tracked with TLC, 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- (4- (diethyl
Amino) phenyl) furans -2- formamide (compound 4), 1.98g, yield 76.2%.1H-NMR(400MHz,CDCl3)δ:1.12
(t,6H),3.40(q,4H),6.90(d,2H),7.20(d,1H),7.34(d,2H),7.44(d,1H),8.94(s,1H).13C-
NMR(125MHz,CDCl3)δ:12.99,46.42,86.35,114.69,117.00,124.04,124.93,143.85,
145.55,155.00,161.81.LC-MS(ESI,pos,ion)m/z:274[M+H].
The synthesis of 1-3,5- ((4- (diethylamino) phenyl) carbamoyl) furans -2- diazonium salt
In 100mL reaction flask, be added compound 4 (1.98g, 7.24mmol), 37% hydrochloric acid (2.06mL,
24.63mmol), water (17.0mL), stirring dissolve solid, and ice salt bath is cooled to -5 DEG C, and the sodium nitrite of pre-cooling is added dropwise
The solution that (0.50g, 7.30molmol) and water (3.43mL) are made into.Drop finishes, and maintains ice bath (about -5~0 DEG C) and is stirred to react 3
Hour, diazonium salt solution 5- ((4- (diethylamino) phenyl) carbamoyl) furans -2- diazonium salt (compound 5) is obtained, directly
It connects for reacting in next step.1H-NMR(400MHz,CDCl3)δ:1.12(t,6H),3.40(q,4H),6.90(d,2H),7.20
(d,1H),7.34(d,2H),7.44(d,1H),8.94(s,1H).13C-NMR(125MHz,CDCl3)δ:12.99,46.42,
86.35,114.69,117.00,124.04,124.93,143.85,145.55,155.00,161.81.LC-MS(ESI,pos,
ion)m/z:321[M+H].
The synthesis of 1-4, N- (4- (diethylamino) phenyl) -5- ((pyridyl group -4) diazenyl) furans -2- formamide
In 100mL reaction flask, NaOH (0.40g, 10.00mmol), Na is added2CO3(0.77g, 7.28mmol), water
(7.75mL), pyridine (6.00mmol), stirring dissolve solid, and ice salt bath is cooled to -2 DEG C, and diazonium salt solution is added portionwise
It closes object 5 (1.91g, 5.95mmol).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- (4-
(diethylamino) phenyl) -5- ((pyridyl group -4) diazenyl) furans -2- formamide, 1.77g, yield 82%.1H-NMR
(400MHz,CDCl3)δ:1.12(t,6H),3.40(q,4H),6.58(d,1H),6.90(d,2H),7.34(d,2H),7.44
(d,1H),7.81(d,2H),8.63(d,2H),9.20(s,1H).13C-NMR(125MHz,CDCl3)δ:12.99,46.42,
100.91,114.37,115.94,117,124.04,124.93,145.55,148.63,148.72,150.04,155.71,
161.81.LC-MS(ESI,pos,ion)m/z:364[M+H]。
Embodiment 2：N- (4- (diethylamino) phenyl) -5- ((2- methyl formate base-pyridyl group -4) diazenyl) furan
It mutters the synthesis of -2- formamide
In 100mL reaction flask, NaOH (0.40g, 10.00mmol), Na is added2CO3(0.77g, 7.28mmol), water
(7.75mL), 2- methyl formate yl pyridines (6.00mmol), stirring dissolve solid, and ice salt bath is cooled to -2 DEG C, is added portionwise
Diazonium salt solution compound 5 (1.91g, 5.95mmol).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- (4- (diethylamino) phenyl) -5- ((2- methyl formate base-pyridyl group -4) diazenyl) furans -2- formyl
Amine, 1.86g, yield 74%.LC-MS(ESI,pos,ion)m/z:422[M+H].
Embodiment 3：N- (4- (diethylamino) phenyl) -5- ((3- methyl-pyridinyl -4) diazenyl) furans -2- first
The synthesis of amide
In 100mL reaction flask, NaOH (0.40g, 10.00mmol), Na is added2CO3(0.77g, 7.28mmol), water
(7.75mL), 3- picoline (6.00mmol), stirring dissolve solid, and ice salt bath is cooled to -2 DEG C, and diazonium salt is added portionwise
Solution compound 5 (1.91g, 5.95mmol).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- (4- (diethylamino) phenyl) -5- ((3- methyl-pyridinyl -4) diazenyl) furans -2- formamide, 1.80g are produced
Rate 80%.LC-MS(ESI,pos,ion)m/z:378[M+H].
Test example 1：The inhibitory activity of Raf-1 kinases is tested
ADP Glo mode is used to test the inhibitory activity of Raf-1.Test process is as follows.The ingredient of buffer 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 hole 384-, and total volume is 10 μ L.Then, cell plates are at 30 DEG C
It is lower to be incubated for 1 hour, then ADP Glo reagent is added into reaction mixture with the dosage in 10 holes μ L/, then be incubated for 40 points at 27 DEG C
Clock.Then detection reagent (20 hole μ l/), then into detection plate is added, and is incubated for 30 minutes at 27 DEG C, last reading.In addition,
Hotspot kinase assay also is used to test 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-2001 | 0.19 |
| RY-2002 | 0.10 |
| RY-2003 | 0.27 |
| RY-2004 | 0.18 |
| RY-2005 | 0.24 |
| RY-2006 | 0.15 |
| RY-2007 | 0.26 |
As shown in Table 1, compound of the present invention have Raf-1 kinase inhibiting activity, can with Raf-1 kinases phase
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 counter.With culture
Cell suspension is adjusted to concentration appropriate by base, and every hole adds 90 μ l cell suspensions in 96- porocyte culture plates.The cell completed is set
In 37 DEG C, 5%CO2Incubator culture 24 hours.
3, compound is handled：
To compound processing board is set as, 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, every hole is added 50 μ l and melts in advance and equilibrate to the CTG solution of room temperature, and use is micro-
Orifice plate oscillator mixes 2 minutes, is believed after ten minutes with Envision2104 plate reader measurement luminescence in being placed at room temperature for
Number.
4, data are analyzed：
POC(percent of control：With the percentage compareed) calculation formula：
Compound handles value/DMSO processing hole average value * 100% in hole
Wherein the value in compound processing hole is the T3 luminescence value in drug-treated hole, and the processing hole DMSO is averaged
Value handles the average value of the T3 luminescence value in hole for 6 DMSO on every block of plate, soft using GraphPad Prism 5.0
Part draws S type dosage-POC curve using nonlinear regression model (NLRM) and calculates IC50Value.
5, experimental result：
Inhibitory activity (the IC of 2 pairs of table 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
Column 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 diazonium analog derivative and its pharmaceutically acceptable salt or solvate of formula I
Wherein：R1、R2、R3、R4It is independently selected from H, CH3Or-COOCH3。
2. diazonium analog derivative formula I as described in claim 1, characterized in that be selected from following compound：
3. application of the diazonium analog derivative formula as claimed in claim 1 or 2 I as Raf kinase.
4. application of the diazonium analog derivative formula I as claimed in claim 1 or 2 in treating cancer.
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..
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Citations (5)
| 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 |
-
2018
- 2018-06-03 CN CN201810560075.3A patent/CN108864060A/en active Pending
Patent Citations (5)
| 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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