CN104892580B - A kind of novel benzimidazole pyrimidinamine derivatives and its application - Google Patents
A kind of novel benzimidazole pyrimidinamine derivatives and its application Download PDFInfo
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- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
Abstract
The invention provides a kind of deuterated benzimidazole pyrimidinamine derivatives, and it is formula (I)Shown compound or its pharmaceutically acceptable salt, monocrystalline or polymorph and its application in the medicine for treating cancer is prepared, additionally provide a kind of pharmaceutical composition comprising the compound；Wherein, R1、R2、R3、R4、R5、R6、R7、R8、R9、R10、R11、R12、R13、R14、R15、R16Hydrogen or deuterium are each independently, and at least contains 1 deuterium altogether.Deuterated benzimidazole pyrimidinamine derivatives mesylate provided by the invention adds the half-life period of medicine, extends the time that medicine is detained in human body, while improves the concentration of medicine in blood, so as to can reach more preferable curative effect.
Description
Technical field
The invention belongs to heterocyclic drug field, more particularly to a kind of new benzimidazole-pyrimidinamine derivatives and its should
With.
Background technology
At present, the incidence of disease of American Women's breast cancer and the death rate do not occupy the 2nd and the 3rd；And it is in China, breast cancer
The women incidence of disease the 1st, the malignant tumour of the death rate the 4th, and also its incidence of disease raises year by year, it is estimated that, Chinese city breast cancer
The incidence of disease 53.87/10 ten thousand were up in 2015, the rural area incidence of disease is up to 40.14/10 ten thousand, i.e., 2015, Chinese mammary gland
The estimated neopathy number of cases of cancer is 560,000-75 ten thousand, and this is a huge quantity, also implies that needs are more, more effectively controls
Treat the treatment that medicine is used for breast cancer.
With going deep into breast cancer research, according to the expression of the species specificity acceptor of breast cancer three (ER, PR,
HER2), breast cancer distinguishes three kinds of different types at present, i.e.,：Luminal types (ER and/or PR are positive, and HER2 is negative), HER2
Positive breast cancer (HER2 is positive, and ER and PR are negative), " basal cell type breast cancer " (ER, PR, HER2 acceptor are feminine gender), its
Middle Luminal types breast cancer is most commonly seen, accounts for the 50%-60% of all breast cancer.Compared to the breast cancer of other 2 types,
The speed of growth of Luminal type breast cancer is relatively slow, and its invasion is relatively low, and short-term prognosis is best, but compares other classes
The breast cancer of type, its long term survival have no advantage.The medical treatment of Luminal type breast cancer include chemotherapy, endocrine therapy and
Targeted therapy.Compared to chemotherapy, for targeted therapy because its specificity is stronger, toxicity is smaller, receives increasing attention, also gets over
Received come more patient, still, the breast cancer positive compared to HER2, the targeted therapy means of Luminal type breast cancer are less,
Only rapamycin inhibitor Yi Weimosi is used for the Luminial types that joint Exemestane is used for endocrine therapy failure at present
The treatment of advanced breast cancer, therefore, the new drug for studying the targeted therapy of Luminal type breast cancer seem very urgent.
LY2835219, its structural formula are：
It is a kind of cell-cycle kinases suppression
Preparation (cyclin-dependent kinase), can be by suppressing Retinoblastoma Protein mainly for CDK4/6
The phosphorylation of (Retinoblastoma, RB), keeps the activity of RB albumen, and arresting cell cycle is played by the conversion of G1-S phases
Suppress the effect of tumor cell proliferation, the medicine observed the effect of good in the patient with breast cancer of Luminal types.But
Due to its toxicity, as the incidence of haematics toxicity is higher (leucocyte, neutrophil leucocyte and blood platelet decline, anaemia), and
Diarrhoea, Nausea and vomiting and fatigue, decline wherein III degree neutrophil leucocyte occurs for about 30% patient, III occurs for 8% patient
Degree diarrhoea and fatigue.Therefore, it is necessary to the molecular structure by optimizing LY2835219, to reduce the toxicity of medicine, improves medicine
Tolerance.
The content of the invention
The present invention is intended to provide a kind of new change with cell-cycle kinases inhibitory activity and more preferable pharmacodynamics performance
Compound and its application.
In a first aspect, the invention provides a kind of deuterated benzo imidazol-pyrimidine amine derivative, it is chemical combination shown in formula (I)
Thing or its pharmaceutically acceptable salt, monocrystalline or polymorph,
Wherein, R1、R2、R3、R4、R5、R6、R7、R8、R9、R10、R11、R12、R13、R14、R15、R16Be each independently hydrogen or
Deuterium, and at least contain 1 deuterium altogether.
Preferably, compound provided by the invention or its pharmaceutically acceptable salt, monocrystalline or polymorph, its feature exist
In R1、R2、R3、R4、R5、R6、R7、R8、R9、R10、R11、R12、R13、R14、R15、R16In a total of 2~16 deuteriums.
Preferably, compound provided by the invention or its pharmaceutically acceptable salt, monocrystalline or polymorph, its feature exist
In R1、R2、R3、R4、R5It is deuterium, and R6、R7、R8、R9、R10、R11、R12、R13、R14、R15、R16It is hydrogen, specially formula (II)
Shown compound：
It is further preferred that compound provided by the invention or its pharmaceutically acceptable salt, monocrystalline or polymorph, its
In, the pharmaceutically acceptable salt is the salt that the compound is formed with inorganic acid or organic acid.The inorganic acid be selected from
Lower one or more：Hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid, hydrogen sulfide；The organic acid is selected from following a kind of or more
Kind：P-methyl benzenesulfonic acid, salicylic acid, tartaric acid, winestone hydracid, ascorbic acid, maleic acid, benzene sulfonic acid, fumaric acid, gluconic acid,
Glucose wake up acid, formic acid, acetic acid, glutamic acid, methanesulfonic acid, ethyl sulfonic acid, benzene sulfonic acid, lactic acid, oxalic acid, to bromo-benzene sulfonic acid, carbonic acid, lemon
Lemon acid, benzoic acid, malic acid.
Still more preferably methanesulfonic acid, i.e., using the compound provided by the invention as shown in formula (I) and methanesulfonic acid forming salt,
Compound specially shown in formula (III)：
It is further preferred that compound provided by the invention or its pharmaceutically acceptable salt, monocrystalline or polymorph,
Wherein, the pharmaceutically acceptable salt is the salt that compound shown in formula (II) is formed with methanesulfonic acid, specially shown in formula (IV)
Compound：
Second aspect, the invention provides any of the above-described kind of compound or its pharmaceutically acceptable salt, monocrystalline or polycrystalline
Application of the type thing in the medicine for treating cancer is prepared, wherein, the cancer is selected from：Oophoroma, cervical carcinoma, colorectum
Cancer, breast cancer, film gland cancer, glioma, glioblastoma, melanoma, prostate cancer, leukaemia, leaching knurl, non-Hodgkin's
Leaching knurl, stomach cancer, lung cancer, hepatocellular carcinoma, intestines and stomach ask matter knurl (GIST), thyroid cancer, cholangiocarcinoma, carcinoma of endometrium, kidney,
Anaplastic large cell drenches knurl, acute myelocytic leukemia (AML), Huppert's disease, melanoma, celiothelioma；Preferably
For breast cancer.
The third aspect, the invention provides a kind of pharmaceutical composition, it is characterised in that including any of the above-described kind of compound or
Its pharmaceutically acceptable salt, monocrystalline or polymorph and pharmaceutically acceptable carrier or excipient, such as can pharmaceutically connect
Auxiliary material received etc..The pharmaceutical composition can also include the crystalline hydrate of any of the above-described kind of compound, solvate even medicine
Thing prodrug.
Pharmaceutical composition of the present invention can be administered orally with any acceptable peroral dosage form, including
But it is not limited to：Capsule, tablet, water suspension or solution.
Pharmaceutical composition of the present invention, if the selection of its peroral dosage form is tablet, preferably active component is crystal.This
Invention described pharmaceutical composition can be administered alone, or with other pharmaceutically acceptable compound administering drug combinations.
Vitro Experimental Results confirm, deuterated benzo imidazol-pyrimidine amine derivative mesylate provided by the invention with
The Bioactivity of LY2835219 mesylates is suitable；Pharmacokinetic studies confirm deuterated benzo miaow provided by the invention
Azoles-pyrimidinamine derivatives add the half-life period of medicine, extend the time that medicine is detained in human body, while improve blood Chinese medicine
The concentration of thing, so as to reach the effect of more preferable；And it is more stable in vivo, reduces it in enteron aisle inwall and in liver
First-pass metabolism, the bad metabolism of medicine is reduced, drug toxicity and other side effects can be reduced.
Unless otherwise indicated, the deuterated benzimidazole provided by the invention as shown in formula (I), (II), (III), (IV)-
Pyrimidinamine derivatives and its all pharmaceutically acceptable salts, crystalline hydrate, solvate, prodrug, monocrystalline or polycrystalline
Type thing belongs to the scope of the present invention.
The present invention prepares deuterated benzo imidazol-pyrimidine amine derivative and its medicine as shown in formula (I), (II), (III), (IV)
Each chemical combination used in acceptable salt, crystalline hydrate, solvate, prodrug, monocrystalline or polymorph on
Thing can prepare according to preparation method provided by the invention, but be not limited to preparation method provided by the invention.
Embodiment
The present inventor has found a kind of new benzimidazole-pyrimidinamine derivatives and its pharmaceutically acceptable by research
Salt compared with LY2835219, there is significantly superior different pharmacokinetics and/or pharmacodynamics performance, therefore be more suitable for
Suppress the compound of cell-cycle kinases, and then the more applicable medicine for preparing treating cancer and relevant disease.
In a first aspect, the invention provides a kind of deuterated benzo imidazol-pyrimidine amine derivative, it is chemical combination shown in formula (I)
Thing or its pharmaceutically acceptable salt, monocrystalline or polymorph,
Wherein, R1、R2、R3、R4、R5、R6、R7、R8、R9、R10、R11、R12、R13、R14、R15、R16Be each independently hydrogen or
Deuterium, and at least contain 1 deuterium altogether.
In a preferred embodiment, compound provided by the invention or its pharmaceutically acceptable salt, monocrystalline or polycrystalline
Type thing, it is characterised in that R1、R2、R3、R4、R5、R6、R7、R8、R9、R10、R11、R12、R13、R14、R15、R16In a total of 2~16
Individual deuterium.
In a preferred embodiment, compound provided by the invention or its pharmaceutically acceptable salt, monocrystalline or polycrystalline
Type thing, it is characterised in that R1、R2、R3、R4、R5It is deuterium, and R6、R7、R8、R9、R10、R11、R12、R13、R14、R15、R16It is hydrogen,
Compound specially shown in formula (II)：
In a further preferred embodiment, compound provided by the invention or its pharmaceutically acceptable salt, list
Brilliant or polymorph, wherein, the pharmaceutically acceptable salt is the salt that the compound is formed with inorganic acid or organic acid.Institute
State inorganic acid and be selected from one or more of：Hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid, hydrogen sulfide；The organic acid choosing
From one or more of：P-methyl benzenesulfonic acid, salicylic acid, tartaric acid, winestone hydracid, ascorbic acid, maleic acid, benzene sulfonic acid, richness
Horse acid, gluconic acid, glucose wake up acid, formic acid, acetic acid, glutamic acid, methanesulfonic acid, ethyl sulfonic acid, benzene sulfonic acid, lactic acid, oxalic acid, to bromine
Benzene sulfonic acid, carbonic acid, citric acid, benzoic acid, malic acid.
In an embodiment still more preferably, the compound provided by the invention as shown in formula (I) and first sulphur are used
Compound shown in sour forming salt, specially formula (III)：
In an embodiment still more preferably, compound provided by the invention or its pharmaceutically acceptable salt,
Monocrystalline or polymorph, wherein, the pharmaceutically acceptable salt is the salt that compound shown in formula (II) is formed with methanesulfonic acid, is had
Body is compound shown in formula (IV)：
Second aspect, the invention provides any of the above-described kind of compound or its pharmaceutically acceptable salt, monocrystalline or polycrystalline
Application of the type thing in the medicine for treating cancer is prepared, wherein, the cancer is selected from：Oophoroma, cervical carcinoma, colorectum
Cancer, breast cancer, film gland cancer, glioma, glioblastoma, melanoma, prostate cancer, leukaemia, leaching knurl, non-Hodgkin's
Leaching knurl, stomach cancer, lung cancer, hepatocellular carcinoma, intestines and stomach ask matter knurl (GIST), thyroid cancer, cholangiocarcinoma, carcinoma of endometrium, kidney,
Anaplastic large cell drenches knurl, acute myelocytic leukemia (AML), Huppert's disease, melanoma, celiothelioma；Preferably
For breast cancer.
The third aspect, the invention provides a kind of pharmaceutical composition, it is characterised in that including any of the above-described kind of compound or
Its pharmaceutically acceptable salt, monocrystalline or polymorph and pharmaceutically acceptable carrier or excipient, such as can pharmaceutically connect
Auxiliary material received etc..The pharmaceutical composition can also include the crystalline hydrate of any of the above-described kind of compound, solvate even medicine
Thing prodrug.
Pharmaceutical composition of the present invention can be administered orally with any acceptable peroral dosage form, including
But it is not limited to：Capsule, tablet, water suspension or solution.
Pharmaceutical composition of the present invention, if the selection of its peroral dosage form is tablet, preferably active component is crystal.This
Invention described pharmaceutical composition can be administered alone, or with other pharmaceutically acceptable compound administering drug combinations.
Reagent and raw material used in embodiment provided by the invention and test can be bought by market, with reference to specific
The present invention is further elaborated for embodiment, but the present invention is not limited to implementation below.
Synthetic route 1
As shown in synthetic route 1, by can be with commercially available pyrimidine radicals-benzimidazole chloride (B) and pyridine radicals amine (A)
Coupling reaction occurs under palladium chtalyst effect, is made such as formula (I) compound；The R in formula (I) in said synthesis route 1 is deuterium
For ethyl.
Synthetic route 2
As shown in synthetic route 2, the commercially available bromo- pyridine -3- formaldehyde of 6- and five deuterated ethyl piperazidines of 1- are coupled,
Then bromine is replaced with amine, pyridine radicals amine (A) is made.
Embodiment 1a
Prepare [5- (the deuterated ethyl-piperazin -1- ylmethyls of 4- five)-pyridine -2- bases]-[the fluoro- 4- of 5- (fluoro- 3- isopropyls of 7-
Base -2- methyl -3H- benzimidazole -5- bases)-pyrimidine -2-base]-amine
N2Under atmosphere, in the fluoro- 1- isopropyls -2- methyl isophthalic acids H- benzimidazoles of 6- (the fluoro- pyrimidine-4-yls of the chloro- 5- of 2-) -4-
In the Isosorbide-5-Nitrae-dioxanes (20mL) of (1.5g), 5- (the deuterated ethyl-piperazin -1- ylmethyls of 4- five)-pyridine -2- bases amine (1.1g),
Cesium carbonate (3.0g), three (dibenzalacetone) two palladium (0.2g), and double (the benzoylthio) -9,9- diformazans of 4,5- are added portionwise
Base xanthene (0.2g).By mixture in 110 DEG C of heating responses 2 hours, react and monitored through TLC.Room temperature is cooled to, is stirred lower by instead
Liquid is answered to pour into frozen water (50mL).This system extracts through dichloromethane (30mL X 3).Merge organic phase, and with salt water washing
(20mL X 2), after anhydrous sodium sulfate drying, be concentrated under reduced pressure to obtain 1.8g viscous brown crude products.The crude product is through silica gel column chromatography
Purification obtains off-white powder title compound.
MS(ES+)：M/z=512.2 (M+H).
Embodiment 1b
Prepare [5- (the deuterated ethyl-piperazin -1- ylmethyls of 4- five)-pyridine -2- bases]-[the fluoro- 4- of 5- (fluoro- 3- isopropyls of 7-
Base -2- methyl -3H- benzimidazole -5- bases)-pyrimidine -2-base]-amine mesylate
N2Under atmosphere, at [5- (the deuterated ethyl-piperazin -1- ylmethyls of 4- five)-pyridine -2- bases]-[(7- is fluoro- by the fluoro- 4- of 5-
3- isopropyl -2- methyl -3H- benzimidazole -5- bases)-pyrimidine -2-base]-amine (0.7g) dichloromethane (1OmL) and methanol
In the solution of (1OmL), methanesulfonic acid (10mL) is added.Solution is stirred at room temperature 1 hour, removes solvent.Washed with methyl tertiary butyl ether
Repeatedly, that is, 0.9g title compounds are obtained.
1H-NMR(CD3OD-d4) δ 8.58 (b, 1H), 8.32 (s, 1H), 8.26 (b, 2H), 7.87-7,78 (m, 2H),
4.98-4.92(m,1H),3.67(brs,2H),3.50-3.42(m,2H),3.22-3.09(m,6H),2.71(d,6H),1.72
(d,6H)。
Prepare intermediate 5- (the deuterated ethyl-piperazin -1- ylmethyls of 4- five)-pyridine -2- base amine
N2Under atmosphere, in the deuterated ethyl-piperazins (1.0g) of 1- (the bromo- pyridin-3-yl methyl of 6-) -4- five, cuprous oxide
Liquefied ammonia (5.0g) is added in the degased mixture of (0.01g) and methanol (5mL).The mixture is heated overnight at 70 DEG C, reaction
Monitored through TLC.Room temperature is cooled to, through diatomaceous earth plug, and solvent is removed in vacuum.Add dichloromethane (5mL).It is organic
Mutually washed with 1N sodium hydrate aqueous solutions (5mL) and salt solution (5mL X2), after anhydrous sodium sulfate drying, be concentrated under reduced pressure slightly
Product.The crude product purifies to obtain title compound (0.3g) through silica gel column chromatography.
MS(ES+):M/z=226 (M+H)+。
Prepare five deuterated ethyl-piperazins of intermediate 1- (the bromo- pyridin-3-yl methyl of 6-) -4-
N2Under atmosphere, the deuterated ethyl piperazidines (1.2mL) of 1- five are added to the bromo- pyridine -3- formaldehyde (1.5g) of 6- and dichloro
In the mixed solution of methane (5mL).Then sodium triacetoxy borohydride (1.6g) is added, 12-16 is stirred at room temperature in reaction
Hour, react and monitored through TLC.With dichloromethane (5mL) and 2N sodium hydrate aqueous solutions (5mL) terminating reaction.Use dichloromethane
(5mL) aqueous layer extracted is twice.Organic phase washs (5mL X2) with saturated brine, after anhydrous sodium sulfate drying, is concentrated under reduced pressure
Crude product.The crude product purifies to obtain title compound (2.1g) through silica gel column chromatography.
MS(ES+):M/z=290 (M+H)+。
Prepare the fluoro- 1- isopropyls -2- methyl isophthalic acids H- benzimidazoles of intermediate 6- (the fluoro- pyrimidine-4-yls of the chloro- 5- of 2-) -4-
N2Under atmosphere, the commercially available fluoro- pyrimidines of chloro- 5- (6.3g) of 2,4- bis- are dissolved in 1,2- dimethoxy-ethanes
In (60mL).Then double (triphenylphosphine) palladium bichlorides (II) (2.5g) and 2M aqueous sodium carbonates (50mL) are added.Mixed solution
4- fluoro- 1- isopropyls -2- methyl -6- (4,4,5,5- tetramethyls-[1,3,2] dioxaborolan alkane -2- are added dropwise at 80 DEG C
Base) -1H- benzimidazoles (10g) 1,2- dimethoxy-ethanes (50mL) solution.Reaction is stirred 1 hour at 84 DEG C, reaction warp
TLC is monitored.Room temperature is cooled to, gained mixture is extracted with EtOAc (40mL X 3), merges organic phase and is washed with saturated salt
Wash (40mL X 3).After anhydrous sodium sulfate drying, be concentrated under reduced pressure to obtain crude product.The crude product purifies through silica gel column chromatography to be marked
Inscribe compound (5g).
MS(ES+):M/z=323 (M+H)+。
Embodiment 2a
Preparation [5- (4- (tri- deuterated ethyls of 2,2,2-)-piperazine -1- ylmethyls)-pyridine -2- bases]-[(7- is fluoro- by the fluoro- 4- of 5-
3- isopropyl -2- methyl -3H- benzimidazole -5- bases)-pyrimidine -2-base]-amine
Prepared according to the method described in embodiment 1, difference is：Replaced with 1- (tri- deuterated ethyls of 2,2,2-) piperazine
Five deuterated ethyl piperazidines of 1-, so as to which target product be made.
MS(ES+)：M/z=510.2 (M+H).
Embodiment 2b
Preparation [5- (4- (tri- deuterated ethyls of 2,2,2-)-piperazine -1- ylmethyls)-pyridine -2- bases]-[(7- is fluoro- by the fluoro- 4- of 5-
3- isopropyl -2- methyl -3H- benzimidazole -5- bases)-pyrimidine -2-base]-amine mesylate
Prepared according to the method described in embodiment 1, difference is：Replaced with 1- (tri- deuterated ethyls of 2,2,2-) piperazine
Five deuterated ethyl piperazidines of 1-, so as to which target product be made.
Embodiment 3a
Prepare [5- (4- (bis- deuterated ethyls of 1,1-)-piperazine -1- ylmethyls)-pyridine -2- bases]-[the fluoro- 4- of 5- (fluoro- 3- of 7-
Isopropyl -2- methyl -3H- benzimidazole -5- bases)-pyrimidine -2-base]-amine
Prepared according to the method described in embodiment 1, difference is：1- is replaced with 1- (bis- deuterated ethyls of 1,1-) piperazine
Five deuterated ethyl piperazidines, so as to which target product be made.
MS(ES+)：M/z=509.2 (M+H).
Embodiment 3b
Prepare [5- (4- (bis- deuterated ethyls of 1,1-)-piperazine -1- ylmethyls)-pyridine -2- bases]-[the fluoro- 4- of 5- (fluoro- 3- of 7-
Isopropyl -2- methyl -3H- benzimidazole -5- bases)-pyrimidine -2-base]-amine mesylate
Prepared according to the method described in embodiment 1, difference is：1- is replaced with 1- (bis- deuterated ethyls of 1,1-) piperazine
Five deuterated ethyl piperazidines, so as to which target product be made.
Test 1 cell in vitro strain MKN28 and cell line MCF-7 killing experiments
The embodiment compound that Example 1b is prepared, it is thin to colon cancer cell line MKN28 and breast cancer to investigate it
Born of the same parents' strain MCF-7 lethal effect, using LY2835219 as positive control, PBS is as blank control.
Respectively by each 20000 of 2 kinds of cells of MKN28 and MCF-7 cell lines, 7 75cm are inoculated into2Tissue Culture Flask, enter
Row cell culture.Passage is incubated at 37 DEG C, 5% CO2gas incubator, counted, 1000rpm is centrifuged 5 minutes, with training
Support the whole cell density of keynote, according to 2000/100ul/ holes, the inoculating cell in 96 orifice plates.Second day, difference agent-feeding treatment,
500,100,30,10,3,1,0.3,0.1,0.03,0.01nmol, according to above-mentioned cell doubling time, respectively to dosing after
MKN28 and MCF-7 cells cultivate within 3 days.Day is being detected, 100 μ L CCK8 reagent (days are added into each cell culture well
This colleague chemistry), it is put into incubator and stands 1 hour, is determined with Beijing Pu Lang companies ELIASA (model DNM9602) in 450nm
Light absorption value, using GraphPad softwares, IC50 is calculated, testing sample is to MKN28 and MCF-7 cell line lethal effect testing results
It is shown in Table 1, table 2：
Table 1
Table 2
Compound Y：LY2835219
Compound X：Embodiment 1b compounds
As known from Table 1, experimental group and positive controls testing sample are to the killing of MKN28 and MCF-7 cell line cells, raw
Long half-inhibition concentration IC50 is suitable, and difference is not notable, (P ＞ 0.05), but is substantially better than MKN28 to MCF-7 inhibition level.
Illustrate that the embodiment compound that the embodiment of the present invention 1 prepares is suitable with the LY2835219 lethal effect to cancer cell,
Change LY2835219 structure, its Bioactivity will not be changed.
Test 2 Pharmacokinetic Evaluations
The embodiment compound that Example 1b is prepared, pharmacokinetic studies are carried out to it, with LY2835219 first
Sulfonate is as positive control, and PBS is as blank control.
Animal subject is：Male CD1 mouse, body weight 18-22g, animal center provides as tested by the medicine of Shanghai, using perhaps
Can the number of card SYXK (Shanghai) 2010-0049.Animal subject should carry out adaptability raising in 3-7 days a few days ago in experiment in test site, male
Property CD1 mouse, are randomly divided into 2 groups, gavage is given by test agent respectively, fasting 12 hours before experiment, free water.It is small to be administered 2
When after unified feed.Single oral gavage gives the testing sample of 25mg/kg dosage, and the testing sample of experimental group and positive controls is equal
With 0.5%w/v HPMC, 0.25,0.5,1.0,2.0,3.0,5.0,8.0,10 and 24h is sampled upon administration respectively；Per time point 3
Mouse, through eyeball of mouse rear vein beard extracting vein blood 0.3mL after above setting time point Animal Anesthesia, puts heparinised tubes
In, 11000g is centrifuged 5 minutes, separated plasma, is freezed in -20 DEG C of refrigerators.During sample detection, plasma sample is through methanol extraction egg
The concentration of compound L Y2835219 mesylates and embodiment compound in blood plasma is determined using LC-MS/MS methods after white, linearly
Scope is 30.0-30000ng/mL.
Main pharmacokinetic parameters (T after mouse stomach administration is calculated using the softwares of WinNonlin 6.3max, Cmax, AUC,
MRT and t1/2).Wherein, up to Cmax CmaxWith peak time TmaxFor measured value.
Lower area of blood concentration-time curve AUC0-tValue：Calculated using trapezoidal method.
AUC0-∞=AUC0-t+Ct/ke,
Ct is the blood concentration that last can measure time point, and ke is elimination rate constant；
Eliminate half-life period t1/2=0.693/ke；
Mean residence time MRT=AUMC/AUC.
The mouse of table 3 difference gavage 25mg/kg compounds X (embodiment compound) and Y (LY2835219) original shape medicines afterwards
Pharmacokinetic parameters
From table 2 it was found from experimental data, the C of embodiment compound that preparation method that embodiment 1b is provided preparesmax
It is 1.34 times of LY mesylates；Its exposed amount (AUC0-t) it is 1.44 times of LY2835219 mesylates；It eliminates half-life period
t1/2It is 1.35 times of LY2835219 mesylates, that is, extends 35%, illustrates the preparation method that 1b of the embodiment of the present invention is provided
The embodiment compound prepared, compared to LY2835219 mesylates, significantly improve blood concentration, extend medicine half
Decline the phase, significant difference.
Embodiment compound provided by the invention considerably increases the half-life period of medicine, and it is stagnant in body to extend medicine
The time stayed；The concentration of medicine in blood is improved simultaneously, so as to reach the effect of more preferable.Meanwhile it can reasonably release and compare
LY2835219 mesylates, the dosage of embodiment compound provided by the invention is smaller, and then can further eliminate medicine
Bad metabolic problems, reduce drug toxicity and other side effects.
The specific embodiment of the present invention is described in detail above, but it is intended only as example, it is of the invention and unlimited
It is formed on particular embodiments described above.To those skilled in the art, it is any to the equivalent modifications that carry out of the present invention and
Substitute also all among scope of the invention.Therefore, the impartial conversion made without departing from the spirit and scope of the invention and
Modification, all should be contained within the scope of the invention.
Claims (7)
1. compound or its pharmaceutically acceptable salt shown in a kind of formula (II)：
2. compound according to claim 1 or its pharmaceutically acceptable salt, it is characterised in that described pharmaceutically to connect
The salt received is the salt that the compound is formed with inorganic acid or organic acid.
3. compound according to claim 2 or its pharmaceutically acceptable salt, it is characterised in that the inorganic acid is selected from
One or more of：Hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid, hydrogen sulfide；The organic acid be selected from it is following a kind of or
It is a variety of：P-methyl benzenesulfonic acid, salicylic acid, tartaric acid, winestone hydracid, ascorbic acid, maleic acid, benzene sulfonic acid, fumaric acid, glucose
Acid, glucose wake up acid, formic acid, acetic acid, glutamic acid, methanesulfonic acid, ethyl sulfonic acid, benzene sulfonic acid, lactic acid, oxalic acid, to bromo-benzene sulfonic acid, carbon
Acid, citric acid, benzoic acid, malic acid.
4. compound according to claim 1 or its pharmaceutically acceptable salt, it is characterised in that described pharmaceutically to connect
The salt that the salt received is the compound and methanesulfonic acid is formed, compound specially shown in formula (IV)：
5. the compound or its pharmaceutically acceptable salt as any one of above-mentioned claim are being prepared for treating cancer
Application in the medicine of disease, wherein, the cancer is selected from：Oophoroma, cervical carcinoma, colorectal cancer, breast cancer, film gland cancer, glue
Matter knurl, glioblastoma, melanoma, prostate cancer, NHL, stomach cancer, lung cancer, hepatocellular carcinoma, intestines and stomach
Mesenchymoma (GIST), thyroid cancer, cholangiocarcinoma, carcinoma of endometrium, kidney, primary cutaneous type, acute myeloid are white
Blood disease (AML), Huppert's disease, melanoma, celiothelioma.
6. application according to claim 5, it is characterised in that the cancer is breast cancer.
7. a kind of pharmaceutical composition, it is characterised in that including the compound as any one of Claims 1-4 or its medicine
Acceptable salt and pharmaceutically acceptable carrier or excipient on.
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