CN107513057A - One kind pleasure is cut down for the weary oxygen activation prodrug of Buddhist nun and its application - Google Patents
One kind pleasure is cut down for the weary oxygen activation prodrug of Buddhist nun and its application Download PDFInfo
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- CN107513057A CN107513057A CN201710794954.8A CN201710794954A CN107513057A CN 107513057 A CN107513057 A CN 107513057A CN 201710794954 A CN201710794954 A CN 201710794954A CN 107513057 A CN107513057 A CN 107513057A
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- Prior art keywords
- cut down
- buddhist nun
- weary oxygen
- pleasure
- oxygen activation
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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
- C07D405/12—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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- 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
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- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
One kind pleasure is cut down for the weary oxygen activation prodrug of Buddhist nun and its application, and structure meets formula (I)Wherein：R is O, S.Such medicine is stablized under normal operation, and drug effect is weaker.It is unstable under the conditions of weary oxygen, the molecule with stronger drug effect can be produced.Such medicine has good drug effect and security, the preparation available for tumor.
Description
Technical field
The invention belongs to pharmaceutical field, there is provided one kind pleasure is cut down for the weary oxygen activation prodrug of Buddhist nun and its application.
Background technology
Happy cut down for Buddhist nun (Lenvatinib) is a kind of receptor tyrosine kinase (RTK) inhibitor, suppresses vascular endothelial growth
The acceptor VEGFR1 (FLT1) of the kinase activity (VEGF) of the factor, VEGFR2 (KDR), and VEGFR3 (FLT4).Lenvatinib
Also suppression fibroblast growth factor (FGF) acceptor FGFR1,2,3 and 4, in platelet derived growth factor receptor (PDGFR
α), KIT, and RET9.(Int J Cancer.2008,122,664-671) be applied to have local recurrence or transfer, progressivity,
The treatment of radioiodine-intractable differentiated thyroid carcinoma and liver cancer patient.The most common side effects of Lenvatinib have high blood
Pressure, fatigue, diarrhoea, articular muscle are felt sorry (arthralgia/courbature), appetite reduces, are vomitted, hyperproteosis (albuminuria), hand in urine
Slap swelling and pain, hand and/or sole (hand-foot syndrome), change (voice disorder) occurs in stomachache and pronunciation.
Lenvatinib can cause serious side effects, including heart failure, thrombosis (arterial thromboembolism event), hepatic injury (liver poison
Property), injury of kidney (kidney failure and damage), connection, electrocardiographic activity extremely changes (QT between gastrointestinal perforation or stomach or intestines
Interval extends), low blood calcium, with property headache, epileptic attack and visible change (invertibity leukoencephalopathy syndrome), severe haemorrhage
(massive haemorrhage) if, the treatment of patient's gestation occur that be not born youngster's risk and thyrotropic hormone produce and damaging suppression occur
System.(Oncotarget.2016,7:44545-44557.)
With the fast-growth of tumour, Partial tumors tissue is more and more remote from nearest blood vessel, and oxygen is insufficient, causes to swell
The weary oxygen of knurl (Nature review cancer 2002,2:38-47).Traditional antineoplastic has to the tumour of near vessels
Good lethality, but it is limited to the function of tumor in weary oxygen region.Tumor hypoxia activated prodrugs can be specifically weary in tumour
Oxygen region discharge anti-tumor active ingredient, so as to kill weary oxygen region tumour (Chinese Journal of Cancer 2014,
33:80-86).Weary oxygen activation prodrug has tumor-targeting, so as to have more preferable security, joins with traditional antineoplastic
It is outstanding to close antitumous effect when using.Wherein TH302 comes into clinical research, has good treatment to cancer of pancreas etc.
Act on (Journal of Clinical Oncology 2015,33,1475-1482).
The content of the invention
The technical problem of solution：The present invention provides a kind of pleasure and cut down for the weary oxygen activation prodrug of Buddhist nun and its application.Such prodrug
There is less drug effect under normal oxygen conditions, there is stronger drug effect under the conditions of weary oxygen, have excellent antitumaous effect and
Good security, available for the medicine for preparing treatment tumour.
Technical scheme：The happy weary oxygen activation prodrug cut down for Buddhist nun of one kind, structure meet formula (I)
Wherein：R is-O- or-S-.
The happy weary oxygen activation prodrug cut down for Buddhist nun of one kind, structure is as shown in formula 1 or 2：
The application of above-claimed cpd or its pharmaceutically acceptable salt in tumor is prepared.
Tumor, active ingredient are above-claimed cpd or its pharmaceutically acceptable salt.
It has been found that the happy O- demethyls product (3) cut down for Buddhist nun (Lenvatinib) has good external tyrosine
The inhibitory activity of kinases, and corresponding O- benzyls substitutive derivative (4) substantially reduces to the inhibitory activity of external EGFR-TK
(being shown in Table 1), prompt that the inhibitory activity of its EGFR-TK will be reduced in the larger substituent of position introducing.
Using HPLC, investigated target compound under normal operation with the stability under the conditions of weary oxygen, as a result display (see
Table 2), target compound (1,2) has good stability (being shown in Table 2) under normoxic conditions, unstable under the conditions of weary oxygen,
Rapid metabolization is that expection activity metabolin O- demethyls pleasure is cut down for Buddhist nun (being shown in Table 3).But furan nucleus or thiphene ring are changed to phenyl ring
(such as compound 4), more stable under the conditions of normal and weary oxygen, weary oxygen selective is poor.On furan nucleus or thiphene ring side chain
Similar compound (such as compound 5,6) normoxic conditions for obtaining of two methyl missing under lack good stability and (be shown in Table
2).Therefore, the weary oxygen activation of such compound has structural specificity.
Beneficial effect：The pleasure that the present invention obtains is cut down for the weary oxygen activation prodrug of Buddhist nun, is stablized under normal operation, has relatively low
The inhibitory activity of EGFR-TK, therefore the possibility for producing toxic side effect reduces；Under the conditions of weary oxygen, junket can be quickly produced
The stronger molecule of histidine kinase inhibitory activity, produce antitumor action.Sent out therefore, it is possible to the specific tumour to weary oxygen region
Antitumor action is waved, reduces the toxic side effect to its hetero-organization, available for the medicine for preparing treatment tumour.
Brief description of the drawings
Fig. 1 is growth inhibition effect figure of the target compound to people's HCCLM3 subcutaneous transplantation knurls.
Embodiment
The following examples can make those skilled in the art to be fully understood by the present invention, but not limit this in any way
Invention.
Embodiment 1：The synthesis of target compound：
The synthesis of compound 1
0.412g (1.00mmol) O- demethyls pleasure is cut down for Buddhist nun (3), (the 5- nitro furans of 0.28g (3.00mmol) 2- methyl -2
Mutter) ethanol is dissolved in dry methylene chloride (50mL).0 DEG C is cooled to, instills and 0.752mL tributyls phosphorus (3.06mmol) is added dropwise,
Drop finishes, and is stirred at room temperature 48 hours.Solvent is recovered under reduced pressure, silica gel column chromatography obtains target compound (0.035g).1H NMR(DMSO-
d6,δ,ppm,300MHz):8.66 (d, 2H), 8.28 (d, 1H), 7.96 (d, 1H), 7.86 (s, 1H), 7.73 (s, 1H), 7.51
(s, 1H), 7.48 (d, 1H), 7.42 (d, 1H), 7.24 (dd, 1H), 7.19 (d, 1H), 6.71 (d, 1H), 6.53 (t, 1H),
2.66 (s, 1H), 1.77 (s, 6H), 0.66 (q, 2H), 0.41 (s, 2H).
The synthesis of compound 2:
The method of reference target compound 1, (the 5- nitro furans of 2- methyl -2 are replaced with 2- methyl -2 (5- nitro thiophenes phenol) ethanol
Mutter) synthesis.1H NMR(DMSO-d6,δ,ppm,300MHz):8.62 (d, 2H), 8.23 (d, 1H), 7.92 (d, 1H), 7.81 (s,
1H), 7.70 (s, 1H), 7.47 (s, 1H), 7.45 (d, 1H), 7.77 (d, 1H), 7.20 (dd, 1H), 7.16 (d, 1H), 6.95
(d, 1H), 6.48 (t, 1H), 2.62 (s, 1H), 1.83 (s, 6H), 0.62 (q, 2H), 0.38 (s, 2H).
Embodiment 2：The inhibitory activity screening of the external EGFR-TK of target compound
By a series of test-compound of gradient concentrations, the enzyme solutions with certain concentration are incubated jointly at ambient temperature
5min, adds appropriate enzyme reaction substrate, ATP afterwards, starts enzyme reaction process, after 30min, is added into enzyme reaction system suitable
The reaction terminating liquid and detection liquid of amount, after being incubated 1h, on multi-function microplate reader, determine the enzyme activity under specific compound concentration
Power, and the inhibitory activity of the compounds on enzyme activities of various concentrations is calculated, afterwards according to quadruplex parameters, to various concentrations chemical combination
The inhibitory activity of enzyme activity is fitted under thing, calculates IC50 values.
The inhibitory activity (IC50, nM) of the external EGFR-TK of the target compound of table 1
| Compound | VEGFR2(KDR) |
| 1 | 46 |
| 2 | 48 |
| 4 | 51 |
| 3 (O- demethyls pleasure is cut down for Buddhist nun) | 3 |
| Pleasure is cut down for Buddhist nun | 4 |
As a result show, the inhibitory activity of the external EGFR-TK of target compound 1,2 is cut down significantly lower than O- demethyls pleasure
For Buddhist nun (about 15 times).
Embodiment 3：Study on the stability of the target compound in liver homogenate
It is prepared by NADPH activation systems：Precision weighs NADPNa2, G-6-P-Na, G-6-PDH and MgCl2In right amount, it is dissolved in water
And constant volume, system contain 2mmol L-1NADPNa2, 40mmol L-1G-6-P-Na, 4U L-1G-6-PDH, 40mmol L- 1MgCl2, -20 DEG C of preservations.
Sample preparation：Appropriate sample methanol solution is added in EP pipes first, water-bath volatilizes solvent, adds Tris bufferings
Solution, rat liver homogenate, it is vortexed and mixes.37 DEG C of pre-temperatures of constant temperature oscillation tank incubate 5min.Add the μ L of NADPH activation systems 200, whirlpool
Rotation is well mixed to be reacted with starting.Reaction final volume is 400 μ L, containing 1.0mmolL-1 1NADPNa2, 20mmol L-1G-6-P-
Na, 2U L-1G-6-PDH, 20mmol L-1MgCl2, liver homogenate albumen quality concentration is 2.0mg mL-1, Final substrate concentrations 0.5
μmoL L-1.37 DEG C of water-bath temperature are incubated.Acetonitrile 0.4mL terminating reactions are separately added into after temperature incubates 120min.Parallel 5 parts.
Sample treatment：After acetonitrile terminating reaction, it is vortexed and ultrasonic 5min makes to be well mixed, high speed centrifugation (13000r min-1, 20min, 4 DEG C), supernatant is taken, is volatilized under 37 DEG C of water-bath nitrogen streams.Residue is redissolved with 400 μ L methanol, and ultrasound makes dissolving complete,
High speed centrifugation (13 000r min-1, 20min, 4 DEG C), supernatant is analyzed for HPLC, determines target compound concentration.
Study on the stability of the target compound of table 2 in liver homogenate
| Compound number | Proto-drug concentration (μm oLL-1) |
| 1 | 0.45 |
| 2 | 0.45 |
| 4 | 0.45 |
| 5 | 0.2 |
| 6 | 0.1 |
Above experimental result is shown：Target compound 1,2,4 is more stable in liver homogenate, and 5,6 in liver homogenate
It is unstable, be easily metabolized.
Embodiment 4：Study on the stability under target compound anoxia state in liver homogenate
Operate reference implementation example 3, during sample incubation, solution first uses nitrogen treatment 20 minutes before sample is added, and is adding
It is incubated under a nitrogen 120 minutes after entering sample.Centrifugate is cut down dense for Buddhist nun with HPLC measure target compounds and O- demethyls pleasure
Degree.
Study on the stability under the target compound anoxia state of table 3 in liver homogenate
| Compound number | Proto-drug (μm oLL-1) | O- demethyls pleasure is cut down for Buddhist nun (μm oLL-1) |
| 1 | 0.05 | 0.41 |
| 2 | 0.05 | 0.42 |
| 4 | 0.44 | Undetermined |
As a result show, target compound 1,2 under the conditions of weary oxygen can fast transition be O- demethyls pleasure cut down for Buddhist nun.
Embodiment 5：Growth inhibition effect of the target compound to human hepatoma HepG2 cell's subcutaneous transplantation knurl
Take the logarithm the human hepatoma HepG2 cell in growth period, with 5 × 106Individual cell 0.2mL-1Only-1Concentration, inoculation
It is subcutaneous in the right oxter portion of nude mice, into knurl after 20 days.
Dosage regimen:Animal pattern 40, be divided at random negative control group, it is happy cut down for Buddhist nun's group (0.4mg/kg), low dose
Amount group (compound 2,1mg/kg), high dose group (compound 2,4mg/kg), respectively through gastric infusion (1 time/daily), continue 3
In week, with vernier caliper measurement tumour major diameter and minor axis, survey per week is twice.Draw Subcutaneous Tumor Growth curve.
Inhibition, changes of weight are shown in Fig. 1：After administration, each group shows that the significant tumour growth that suppresses acts on, high agent
Amount group shows more preferable therapeutic action.All test group nude mouse body weight do not have a notable difference, but respectively less than control group.
The technical concepts and features of above example only to illustrate the invention, its object is to allow person skilled in the art to be
Present disclosure can be understood and implemented according to this, it is not intended to limit the scope of the present invention.It is all smart according to the present invention
The equivalent transformation or modification that refreshing essence is done, should all be included within the scope of the present invention.
Claims (4)
1. the happy weary oxygen activation prodrug cut down for Buddhist nun of one kind, it is characterised in that structure meets formula (I)
Wherein：R is-O- or-S-.
2. a kind of happy weary oxygen activation prodrug cut down for Buddhist nun according to claim 1, it is characterised in that as shown in formula 1 or 2：
3. any compounds of claim 1-2 or its pharmaceutically acceptable salt answering in tumor is prepared
With.
4. tumor, it is characterised in that active ingredient is any compounds of claim 1-2 or it pharmaceutically may be used
The salt of receiving.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201710794954.8A CN107513057A (en) | 2017-09-06 | 2017-09-06 | One kind pleasure is cut down for the weary oxygen activation prodrug of Buddhist nun and its application |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201710794954.8A CN107513057A (en) | 2017-09-06 | 2017-09-06 | One kind pleasure is cut down for the weary oxygen activation prodrug of Buddhist nun and its application |
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| CN107513057A true CN107513057A (en) | 2017-12-26 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201710794954.8A Pending CN107513057A (en) | 2017-09-06 | 2017-09-06 | One kind pleasure is cut down for the weary oxygen activation prodrug of Buddhist nun and its application |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110437223A (en) * | 2019-08-06 | 2019-11-12 | 江苏千之康生物医药科技有限公司 | Happy Thiazolinone derivative and its application for cutting down ticrynafen |
| WO2021120717A1 (en) | 2019-12-20 | 2021-06-24 | 深圳艾欣达伟医药科技有限公司 | Anticancer compound and medical use thereof |
| CN115215799A (en) * | 2022-08-12 | 2022-10-21 | 上海爱博医药科技有限公司 | Urea multi-target tyrosine kinase inhibitor and various medical applications thereof |
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| CN1791591A (en) * | 2003-03-26 | 2006-06-21 | 安吉奥金尼药品有限公司 | Bioreductively-activated prodrugs |
| CN106279321A (en) * | 2016-08-09 | 2017-01-04 | 南京医科大学 | Gemcitabine ProTide weary oxygen activation prodrug and application thereof |
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| CN1478078A (en) * | 2000-10-20 | 2004-02-25 | ������������ʽ���� | Nitrogen-containing aromatic ring derivatives |
| CN101024627A (en) * | 2000-10-20 | 2007-08-29 | 卫材R&D管理有限公司 | Nitrogen-containing aromatic derivatives |
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Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110437223A (en) * | 2019-08-06 | 2019-11-12 | 江苏千之康生物医药科技有限公司 | Happy Thiazolinone derivative and its application for cutting down ticrynafen |
| WO2021023016A1 (en) * | 2019-08-06 | 2021-02-11 | 江苏千之康生物医药科技有限公司 | Thiazolidone derivative of lovatinib acid and application thereof |
| CN110437223B (en) * | 2019-08-06 | 2022-11-25 | 江苏千之康生物医药科技有限公司 | Thiazolone derivative of lenetinic acid and application thereof |
| WO2021120717A1 (en) | 2019-12-20 | 2021-06-24 | 深圳艾欣达伟医药科技有限公司 | Anticancer compound and medical use thereof |
| CN115215799A (en) * | 2022-08-12 | 2022-10-21 | 上海爱博医药科技有限公司 | Urea multi-target tyrosine kinase inhibitor and various medical applications thereof |
| CN115215799B (en) * | 2022-08-12 | 2024-05-31 | 上海爱博医药科技有限公司 | Urea multi-target tyrosine kinase inhibitor and multiple medical applications thereof |
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Application publication date: 20171226 |