CN108484587A - 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 PDFInfo
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- CN108484587A CN108484587A CN201810560177.5A CN201810560177A CN108484587A CN 108484587 A CN108484587 A CN 108484587A CN 201810560177 A CN201810560177 A CN 201810560177A CN 108484587 A CN108484587 A CN 108484587A
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- IPCSVZSSVZVIGE-UHFFFAOYSA-M hexadecanoate Chemical compound CCCCCCCCCCCCCCCC([O-])=O IPCSVZSSVZVIGE-UHFFFAOYSA-M 0.000 description 1
- FUZZWVXGSFPDMH-UHFFFAOYSA-M hexanoate Chemical compound CCCCCC([O-])=O FUZZWVXGSFPDMH-UHFFFAOYSA-M 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-M hydroxide Chemical compound [OH-] XLYOFNOQVPJJNP-UHFFFAOYSA-M 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 238000005342 ion exchange Methods 0.000 description 1
- SUMDYPCJJOFFON-UHFFFAOYSA-N isethionic acid Chemical class OCCS(O)(=O)=O SUMDYPCJJOFFON-UHFFFAOYSA-N 0.000 description 1
- 238000000021 kinase assay Methods 0.000 description 1
- 229940043355 kinase inhibitor Drugs 0.000 description 1
- 229940099584 lactobionate Drugs 0.000 description 1
- JYTUSYBCFIZPBE-AMTLMPIISA-N lactobionic acid Chemical compound OC(=O)[C@H](O)[C@@H](O)[C@@H]([C@H](O)CO)O[C@@H]1O[C@H](CO)[C@H](O)[C@H](O)[C@H]1O JYTUSYBCFIZPBE-AMTLMPIISA-N 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- 238000004020 luminiscence type Methods 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 229910001629 magnesium chloride Inorganic materials 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000000155 melt Substances 0.000 description 1
- 239000000178 monomer Substances 0.000 description 1
- KVBGVZZKJNLNJU-UHFFFAOYSA-N naphthalene-2-sulfonic acid Chemical class C1=CC=CC2=CC(S(=O)(=O)O)=CC=C21 KVBGVZZKJNLNJU-UHFFFAOYSA-N 0.000 description 1
- 235000001968 nicotinic acid Nutrition 0.000 description 1
- 239000011664 nicotinic acid Substances 0.000 description 1
- 150000002829 nitrogen Chemical class 0.000 description 1
- 235000015097 nutrients Nutrition 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- 229940049964 oleate Drugs 0.000 description 1
- ZQPPMHVWECSIRJ-KTKRTIGZSA-N oleic acid Chemical compound CCCCCCCC\C=C/CCCCCCCC(O)=O ZQPPMHVWECSIRJ-KTKRTIGZSA-N 0.000 description 1
- 150000003891 oxalate salts Chemical class 0.000 description 1
- 230000001575 pathological effect Effects 0.000 description 1
- VLTRZXGMWDSKGL-UHFFFAOYSA-M perchlorate Inorganic materials [O-]Cl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-M 0.000 description 1
- VLTRZXGMWDSKGL-UHFFFAOYSA-N perchloric acid Chemical compound OCl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-N 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-N phosphoric acid Substances OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 1
- 239000003757 phosphotransferase inhibitor Substances 0.000 description 1
- 229940075930 picrate Drugs 0.000 description 1
- OXNIZHLAWKMVMX-UHFFFAOYSA-M picrate anion Chemical compound [O-]C1=C([N+]([O-])=O)C=C([N+]([O-])=O)C=C1[N+]([O-])=O OXNIZHLAWKMVMX-UHFFFAOYSA-M 0.000 description 1
- 229950010765 pivalate Drugs 0.000 description 1
- IUGYQRQAERSCNH-UHFFFAOYSA-N pivalic acid Chemical compound CC(C)(C)C(O)=O IUGYQRQAERSCNH-UHFFFAOYSA-N 0.000 description 1
- 238000007747 plating Methods 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 235000011056 potassium acetate Nutrition 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- FGIUAXJPYTZDNR-UHFFFAOYSA-N potassium nitrate Chemical compound [K+].[O-][N+]([O-])=O FGIUAXJPYTZDNR-UHFFFAOYSA-N 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 238000005956 quaternization reaction Methods 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 238000006722 reduction reaction Methods 0.000 description 1
- 208000019465 refractory cytopenia of childhood Diseases 0.000 description 1
- 201000010174 renal carcinoma Diseases 0.000 description 1
- 230000019491 signal transduction Effects 0.000 description 1
- AWUCVROLDVIAJX-GSVOUGTGSA-N sn-glycerol 3-phosphate Chemical compound OC[C@@H](O)COP(O)(O)=O AWUCVROLDVIAJX-GSVOUGTGSA-N 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 235000010288 sodium nitrite Nutrition 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
- BDHFUVZGWQCTTF-UHFFFAOYSA-M sulfonate Chemical compound [O-]S(=O)=O BDHFUVZGWQCTTF-UHFFFAOYSA-M 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 229950004288 tosilate Drugs 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 238000002054 transplantation Methods 0.000 description 1
- GPRLSGONYQIRFK-MNYXATJNSA-N triton Chemical compound [3H+] GPRLSGONYQIRFK-MNYXATJNSA-N 0.000 description 1
- 229940070710 valerate Drugs 0.000 description 1
- NQPDZGIKBAWPEJ-UHFFFAOYSA-N valeric acid Chemical compound CCCCC(O)=O NQPDZGIKBAWPEJ-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- 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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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Oncology (AREA)
- Hematology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
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, F, CH3Or OCH3.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
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, F, CH3
Or OCH3.Further, R1Selected from H or CH3, R2Selected from H or F, R3Selected from H or OCH3.The invention further relates to the Formulas I
Pharmaceutically acceptable salt 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-6004, RY-6006, RY-6007 minimum inhibitory concentration are 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 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：N- (Cyclohexylamino) -5- ((2,3- dihydrobenzos [b] thiophene -5- bases) diazenyl) furans -2-
The synthesis of formamide
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].
1-4, N- (Cyclohexylamino) -5- ((2,3- dihydrobenzos [b] thiophene -5- bases) 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), 2,3- dihydrobenzos [b] thiophene (6.00mmol), stirring make solid dissolve, and ice salt bath is cooled to -2 DEG C, add in batches
Enter 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, is stirred
Reaction 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 big
Khaki solid is measured, is filtered, filter cake is with water washing (to filtrate pH=4~5), dry crude product.It is recrystallized, is obtained with alcohol-water
Yellow orange solid N- (Cyclohexylamino) -5- ((2,3- dihydrobenzos [b] thiophene -5- bases) diazenyl) furans -2- formamides,
1.70g, yield 79%.1H-NMR(400MHz,CDCl3)δ:1.20-1.37(m,5H),1.62(m,1H),1.84(m,2H),
2.19(m,2H),3.23(t,2H),3.61(t,2H),4.95(m,1H),6.19(s,1H),6.58(d,1H),7.44(d,1H),
7.56(d,1H),7.71(dd,1H),7.78(d,1H).13C-NMR(125MHz,CDCl3)δ:24.73,25.92,33.63,
35.63,38.23,50.21,100.91,114.67,120.18,121.08,121.89,140.87,144.64,145.97,
147.63,150.14,161.37.LC-MS(ESI,pos,ion)m/z:356[M+H]。
Embodiment 2：N- (Cyclohexylamino) -5- ((6- methyl -2,3- dihydrobenzos [b] thiophene -5- bases) diazenyl)
The synthesis of furans -2- formamides
In 100mL reaction bulbs, NaOH (0.40g, 10.00mmol), Na is added2CO3(0.77g, 7.28mmol), water
(7.75mL), 6- methyl -2,3- dihydrobenzo [b] thiophene (6.00mmol), stirring make solid dissolve, and ice salt bath is cooled to -2
DEG C, diazonium salt solution compound 5 (2.22g, 6.05mmol) is added portionwise.It finishes, adds a small amount of NaHCO3, it is adjusted to reaction solution pH
=8, it is stirred to react 3~4 hours.Reaction solution is poured into the mixed liquor being made by 37% hydrochloric acid (2.35mL) and ice (about 2.35g)
In, a large amount of khaki solids are precipitated, filter, filter cake is with water washing (to filtrate pH=4~5), dry crude product.With alcohol-water
Recrystallization, obtains yellow orange solid N- (Cyclohexylamino) -5- ((6- methyl -2,3- dihydrobenzo [b] thiophene -5- bases) diazene
Base) furans -2- formamides, 1.90g, yield 85%.LC-MS(ESI,pos,ion)m/z:370[M+H].
Embodiment 3：N- (Cyclohexylamino) -5- ((4- methoxyl group -2,3- dihydrobenzos [b] thiophene -5- bases) diazene
Base) furans -2- formamides synthesis
In 100mL reaction bulbs, NaOH (0.40g, 10.00mmol), Na is added2CO3(0.77g, 7.28mmol), water
(7.75mL), 4- methoxyl groups -2,3- dihydrobenzo [b] thiophene (6.00mmol), stirring make solid dissolve, and ice salt bath is cooled to -2
DEG C, diazonium salt solution compound 5 (2.22g, 6.05mmol) is added portionwise.It finishes, adds a small amount of NaHCO3, it is adjusted to reaction solution pH
=8, it is stirred to react 3~4 hours.Reaction solution is poured into the mixed liquor being made by 37% hydrochloric acid (2.35mL) and ice (about 2.35g)
In, a large amount of khaki solids are precipitated, filter, filter cake is with water washing (to filtrate pH=4~5), dry crude product.With alcohol-water
Recrystallization, obtains yellow orange solid N- (Cyclohexylamino) -5- ((4- methoxyl groups -2,3- dihydrobenzo [b] thiophene -5- bases) phenodiazines
Alkenyl) furans -2- formamides, 1.91g, yield 82%.LC-MS(ESI,pos,ion)m/z:386[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-6001 | 0.56 |
| RY-6002 | 0.52 |
| RY-6003 | 0.60 |
| RY-6004 | 0.52 |
| RY-6005 | 0.47 |
| RY-6006 | 0.41 |
| RY-6007 | 0.54 |
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 T3luminescence values in drug-treated hole, and DMSO handles the average value in hole
The average value that the T3luminescence values in hole are handled for 6 DMSO on every block of plate, using 5.0 softwares of GraphPad Prism,
S types dosage-POC curves are drawn using nonlinear regression model (NLRM) and calculate 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, F, CH3Or
OCH3。
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 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 (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1283192A (en) * | 1997-12-22 | 2001-02-07 | 拜尔有限公司 | Inhibition of raf kinase using aryl and hetroaryl substituted heterocyclic ureas |
| CN1471523A (en) * | 2000-09-21 | 2004-01-28 | ʷ | Imidazole derivatives as Raf kinase inhibitors |
| CN1764645A (en) * | 2003-03-24 | 2006-04-26 | 默克专利有限公司 | Oxamide derivatives useful as raf-kinase inhibitors. |
| CN1805748A (en) * | 2003-06-13 | 2006-07-19 | 诺瓦提斯公司 | 2-aminopyrimidine derivatives as RAF kinase inhibitors |
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2018
- 2018-06-03 CN CN201810560177.5A patent/CN108484587A/en active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1283192A (en) * | 1997-12-22 | 2001-02-07 | 拜尔有限公司 | Inhibition of raf kinase using aryl and hetroaryl substituted heterocyclic ureas |
| CN1471523A (en) * | 2000-09-21 | 2004-01-28 | ʷ | Imidazole derivatives as Raf kinase inhibitors |
| CN1764645A (en) * | 2003-03-24 | 2006-04-26 | 默克专利有限公司 | Oxamide derivatives useful as raf-kinase inhibitors. |
| CN1805748A (en) * | 2003-06-13 | 2006-07-19 | 诺瓦提斯公司 | 2-aminopyrimidine derivatives as RAF kinase inhibitors |
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| Title |
|---|
| 李鹃利等: "小分子RAF激酶抑制剂的临床研究进展", 《广东化工》 * |
| 杨涛等: "Raf激酶抑制剂研究进展", 《西北药学杂志》 * |
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