CN104557870B - A kind of fumarate of pyridinylamine compound - Google Patents
A kind of fumarate of pyridinylamine compound Download PDFInfo
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- CN104557870B CN104557870B CN201310513865.3A CN201310513865A CN104557870B CN 104557870 B CN104557870 B CN 104557870B CN 201310513865 A CN201310513865 A CN 201310513865A CN 104557870 B CN104557870 B CN 104557870B
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- 0 C[C@](c(c(Cl)ccc1F)c1Cl)[U]c1cc(/C(/C=C/CCC2)=C\*2C2CCNCC2)cnc1NC(C)=O Chemical compound C[C@](c(c(Cl)ccc1F)c1Cl)[U]c1cc(/C(/C=C/CCC2)=C\*2C2CCNCC2)cnc1NC(C)=O 0.000 description 1
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- 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 fumarate of pyridinylamine compound and its production and use.The fumarate simplicity of the pyridinylamine compound provided is easy to get, while has good stability and excellent oral administration biaavailability concurrently, is available for preparing the medicine for being used to preventing or treating the positive primary of such as ALK or the tumour of Metastatic Nsclc.
Description
Technical field
The present invention relates to a kind of fumarate of pyridinylamine compound, belongs to organic compound synthesis and medical applications technology
Field.
Background technology
EGFR-TK（Protein Tyrosine Kinases, PTKs）Played in signal transduction pathway in the cell
Extremely important effect.It participate in normal cell regulation, signal transmission and development, also the propagation with tumour cell, break up, move
Move it is closely related with apoptosis, therefore suppress EGFR-TK it is active for suppress and treat tumour play the role of it is positive.Junket
Histidine kinase family has multiple hypotypes, including EGF-R ELISA hypotype（EGFR）, vascular endothelial growth factor receptor
Hypotype（VEGFR）, platelet derived growth factor receptor hypotype（PDGFR）And anaplastic lymphoma kinase（ALK）Deng research hair
Present kinds of tumor cells（Such as non-small cell lung cancer, breast cancer and glioblastoma etc.）The middle abnormal activation that ALK kinases be present
And expression.
(R)-3-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine（Crizotinib, XALKORITM）It is that a kind of anaplastic lymphoma that Pfizer Inc. develops swashs
Enzyme (ALK) oral inhibitor, in August, 2011 first the U.S. listing (Nat.Rev.Drug Discov.10,895-896,
2011).The medicine clinic is mainly used in the positive Locally Advanced of anaplastic lymphoma (ALK) or transfer non-small cell lung cancer
(NSCLC) treatment of patient.Shown in the chemical constitution of (R)-3-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine such as formula (I)：
CN102850328A discloses chemical constitution such as formula（Ⅱ）A kind of shown pyridinylamine compound, it is
Crizotinib analog, there is good inhibiting effect to ALK.
In addition to treating effect, as therapeutic agent medicine processing, manufacture, storage when stability, hygroscopicity and
Bioavilability etc. is all most important to medicament research and development.
The content of the invention
The invention provides a kind of formula（II）The fumarate of compound, its structure such as formula（III）It is shown：
Present invention also offers a kind of formula（III）The method of compound, it comprises the following steps：By formula（II）Chemical combination
Thing is dissolved in organic solvent, and it is 0~80 DEG C to control temperature, under agitation the ethanol solution for the fumaric acid that addition has configured, 0.5~
After 2 hours, reaction solution separates out solid, filters, and vacuum drying, obtains formula（III）Compound.
In some embodiments of the invention, one kind in methanol, ethanol, dichloromethane, acetone of organic solvent or
A variety of mixed solvents.
In some embodiments of the invention, the fumaric acid and formula added（II）The mol ratio of compound be 1.2~
1.5：1.
In some embodiments of the invention, the ethanol solution concentration of the fumaric acid added be 1.0mol/L~
2.0mol/L, preferably 1.0mol/L~1.5mol/L.
In some embodiments of the present invention, preferably carried out at 0~50 DEG C；In some other embodiment, react into one
Step is preferably carried out at 20~50 DEG C.
Inorganic acid or organic acid that can be different replace fumaric acid, and formula is prepared using the method similar with the above method
（II）The different acid-addition salts of compound.
The present invention also provides a kind of pharmaceutical composition, and it includes the formula of therapeutically effective amount（III）Compound and pharmaceutically may be used
The carrier of receiving.Pharmaceutically acceptable carrier can be solid or liquid.Solid carrier may include flavor enhancement, lubricant, increasing
One or more materials in solvent, suspending agent, filler, adhesive, tablet disintegrant or encapsulated materials.Suitable solid
Carrier for example including：Magnesium stearate, talcum, sucrose, lactose, dextrin, starch, gelatin, cellulose, methylcellulose, carboxymethyl
Sodium cellulosate, polyvinylpyrrolidone.Liquid-carrier is used to prepare the compositions such as solution, suspension, emulsion, syrup.For mouth
The suitable liquid-carrier of clothes and parenterai administration includes water, alcohols, oil etc..
Present invention also offers formula（III）Compound is preparing the purposes in being used to prevent or treat the medicine of tumour.This
The formula of invention（III）Compound can be combined individually or with other drugs, for preparing antineoplastic.Described tumour can be with
It is lung cancer, primary positive preferably ALK or Metastatic Nsclc.
Embodiment：
The present invention is described in further detail below by embodiment, but the present invention is not limited to following embodiments.
The formula of embodiment 1（II）The preparation of compound
The preparation of the bromo- 3- of A.N- acetyl group -5- [(1R) -1- (the chloro- 3- fluorophenyls of 2,6- bis-) ethyoxyl] -2- pyridine amine
The bromo- 3- of 500mg5- [(1R) -1- (the chloro- 3- fluorophenyls of 2,6- bis-) ethyoxyl] -2- pyridine amine is dissolved in 15mL dichloros
In methane, 0 DEG C is cooled to, 1mL triethylamines is added and continues after stirring 5 minutes, after the chloroacetic chloride of 1.1 equivalents is added dropwise, be warming up to room
Temperature reaction 5 hours.Water terminating reaction is added, dichloromethane extraction, anhydrous sodium sulfate drying, is filtered, concentration.Crude product acetic acid
Ethyl ester：Petroleum ether=1：4 column chromatographies, obtain white-yellowish solid 400mg, yield 72%.
The bromo- 3- of 5- [(1R) -1- (the chloro- 3- fluorophenyls of 2,6- bis-) ethyoxyl] -2- pyridines amine can be according to Organic
Process Research&Development,2011,15(5):Disclosed in the documents such as 1018-1026 or WO2007066187
Method is prepared.
B.N- acetyl group -3- [(1R) -1- (the chloro- 3- fluorophenyls of 2,6- bis-) ethyoxyl] -5- [1- (4-N-Boc- piperidines
Base) -1H- pyrazoles -4- bases] -2- pyridine amine preparation
By the bromo- 3- of 300mg N- acetyl group -5- [(1R) -1- (the chloro- 3- fluorophenyls of 2,6- bis-) ethyoxyl] -2- pyridines amine and
230mg1- (4-N-Boc- piperidyls) -4- (ring -2- bases of 4,4,5,5- tetramethyls-[1,3,2] dioxy boron penta) -1H- pyrazoles is dissolved in
In 5mL DMF, add in the 1mL aqueous solution of the cesium carbonate containing 300mg, add 20mg Pd with nitrogen displacement air three times
(PPh3)2Cl2, then, reactant mixture is warming up to 75 DEG C and stirred 12 hours with nitrogen displacement air three times.After reaction terminates, it is down to
Room temperature, the dilution of 20mL ethyl acetate is added, diatomite filtering, is washed with ethyl acetate, the ethyl acetate layer of merging is with anhydrous sulphur
Sour sodium concentrates after drying, crude product ethyl acetate:Petroleum ether=1:1 column chromatography purifies, and obtains white foam solid 330mg,
Yield 78%.
C.N- acetyl group -3- [(1R) -1- (the chloro- 3- fluorophenyls of 2,6- bis-) ethyoxyl] -5- [1- (4- piperidyls) -1H- pyrroles
Azoles -4- bases] -2- pyridine amine preparation
By obtained N- acetyl group -3- [(1R) -1- (the chloro- 3- fluorophenyls of 2,6- bis-) ethyoxyl] -5- [1- (4-N-Boc-
Piperidyl) -1H- pyrazoles -4- bases] -2- pyridine amine 100mg is dissolved in a small amount of dichloromethane, in 0 DEG C of stirring, add 4N HCl's
Dioxane solution 2mL, after stirring 20 minutes, removal of solvent under reduced pressure, adds 10mL water, and pH=10 are adjusted with sodium bicarbonate solid,
Dried after being extracted using dichloromethane, concentration, column chromatography obtains white solid 71mg, yield 85%.MS：m/e492(M+1).
The formula of embodiment 2（III）The preparation of compound
Take 0.01mol formula（II）Compound is dissolved in ethanol, and the richness that the concentration configured is 1.2mol/L is added at 20 DEG C
The ethanol solution 10mL of horse acid, after reacting 1 hour, reaction solution separates out solid, and filtering vacuum is dried, and obtains off-white powder, mp：
216.9-218.5℃。
The formula of embodiment 3（III）The preparation of compound
Take 0.01mol formula（II）Compound is dissolved in dichloromethane, and it is 1.2mol/L to add the concentration configured at 30 DEG C
Fumaric acid ethanol solution 10mL, reaction 1 hour after, reaction solution separate out solid, filtering vacuum dry, obtain off-white powder,
mp：215.8-217.3℃.
The formula of embodiment 4（III）The preparation of compound
Take 0.01mol formula（II）Compound is dissolved in acetone, and it is 1.2mol/L that 50 DEG C of stirrings, which add down the concentration configured,
Fumaric acid ethanol solution 10mL, reaction 1 hour after, reaction solution separate out solid, filtering vacuum dry, obtain off-white powder,
mp：216.1-217.7℃.
The formula of embodiment 5（III）The preparation of compound
Take 0.01mol formula（II）Compound is dissolved in methanol, and it is 1.2mol/L that 30 DEG C of stirrings, which add down the concentration configured,
Fumaric acid ethanol solution 10mL, reaction 1 hour after, reaction solution separate out solid, filtering vacuum dry, obtain off-white powder,
mp：216.0-217.2℃.
The formula of reference example 1（II）The preparation of other acid-addition salts of compound
Using the method for embodiment 2, fumaric acid is substituted with different organic acids or inorganic acid, obtains formula（II）Compound
A series of acid-addition salts.
The formula of table 1（II）Other acid-addition salts of compound
The draws moist test of embodiment 6
Formula（II）The formula that compound and embodiment 2, reference example 1 are prepared into（II）The various salt of compound according to《China
Pharmacopeia》The two annex XIX J's of version in 2010《Medicine draws moist test guideline》Tested, calculating sample draws wet respectively
Weightening, as a result as shown in table 2.
The draws moist test result of table 2
| Sample ID | Draw wet weightening（%） |
| Formula（II）Compound | 61.75 |
| Fumarate | 0.80 |
| Hydrochloride | 256.39 |
| Tosilate | 164.27 |
| Mesylate | 232.53 |
| Maleate | 1.15 |
| Malate | 7.83 |
| Succinate | 3.60 |
The formula of embodiment 7（II）The pharmacokinetic trial of the acid-addition salts of compound
The SD male rats 27,200~220g of body weight of health are taken, timing daily is raised is raised with Rat Standard granule
Material, fasting 12h before experiment, 4h recovers, for food, to test equal free water in front and rear and experimentation after administration.9 groups are randomly divided into,
1st group of single dose gastric infusion (R)-3-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine；2nd group of single dose gastric infusion formula（II）Compound；3rd~9 group single respectively
Dosage gastric infusion formula（III）Compound, formula（II）Hydrochloride, tosilate, mesylate, the maleic acid of compound
Salt, malate, succinate；The dosage of 9 groups of rats is 0.11mmol/kg, (0h) and administration before administration
Afterwards 0.5,1,2,4,6,8,10,24h takes blood about 0.2~0.3mL by eyeground vein clump, anticoagulant heparin, centrifugal separation plasma, accurately
0.1mL is measured into EP pipes, adds 1.2mL ethyl acetate, 5min, centrifugation 5min (8000r are mixed at a high speed with turbine mixer
min-1), supernatant is collected, in drying up solvent with nitrogen on 30 DEG C of nitrogen evaporators, the residue μ L of mobile phase 100 dissolve, with vortex
Blender mixes at a high speed 1min, centrifugation 5min (14000rmin-1), 80 μ L of supernatant liquid of transfer to sample injection bottle, the μ L of HPLC sample introductions 10
Detection, record chromatogram.As a result it is as shown in table 3：
Compound oral administration biaavailability result in the rat of table 3
| Compound | Oral administration biaavailability（AUC, ug/mL*h） |
| (R)-3-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine | 15.474 |
| Formula（II）Compound | 17.056 |
| Fumarate | 25.654 |
| Hydrochloride | 19.043 |
| Tosilate | 13.182 |
| Mesylate | 12.866 |
| Maleate | 14.165 |
| Malate | 17.393 |
| Succinate | 10.453 |
HPLC testing conditions are as follows：
Liquid chromatograph：The supper-fast high separating liquid chromatography Prominence UFLC XR of Shimadzu
Analytical column：Shim-pack XR-ODSⅡ(2.0*75mm2.2μm)
Mobile phase：0.1% formic acid solution of the ammonium formate containing 5mM/acetonitrile=80/20 (V/V)
Flow velocity：0.25mL/min column temperatures：40℃
Sampling volume：10 μ L analysis times：10.5min
PDA wave-length coverages：260~275nm detection cell temperature：40℃.
Claims (11)
- A kind of 1. fumarate of formula (II) compound, shown in its structure such as formula (III)：
- A kind of 2. method for preparing formula (III) compound, it is characterised in that comprise the following steps：By formula (II), compound is dissolved in has In solvent, it is 0~80 DEG C to control temperature, adds the ethanol solution of the fumaric acid configured under agitation, after 0.5~2 hour, Reaction solution separates out solid, filters, and vacuum drying, obtains formula (III) compound.
- 3. the method described in claim 2, it is characterised in that used organic solvent is selected from methanol, ethanol, dichloromethane, third One or more mixed solvents in ketone.
- 4. the method described in Claims 2 or 3, it is characterised in that the fumaric acid added and the mol ratio of formula (II) compound are 1.2~1.5：1.
- 5. the method described in Claims 2 or 3, it is characterised in that the ethanol solution concentration of used fumaric acid is 1.0mol/L ~2.0mol/L.
- 6. the method described in claim 4, it is characterised in that the ethanol solution concentration of used fumaric acid be 1.0mol/L~ 2.0mol/L。
- 7. the method described in claim 5, it is characterised in that the ethanol solution concentration of used fumaric acid be 1.0mol/L~ 1.5mol/L。
- 8. a kind of pharmaceutical composition, its include formula (III) compound described in claim 1 of therapeutically effective amount and its pharmaceutically Acceptable pharmaceutical carrier.
- 9. formula (III) compound described in claim 1 is preparing the purposes in being used to prevent or treat the medicine of tumour.
- 10. the purposes described in claim 9, it is characterised in that the tumour is lung cancer.
- 11. the purposes described in claim 10, it is characterised in that the lung cancer is that the positive primary of ALK or metastatic are non-small thin Born of the same parents' lung cancer.
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| RU2684278C1 (en) * | 2015-04-23 | 2019-04-05 | Чиа Тай Тяньцин Фармасьютикал Груп Ко., Лтд | Pyridilamine fumarate and its crystals |
| CN105424831B (en) * | 2015-11-11 | 2017-11-10 | 江苏康缘药业股份有限公司 | The quantitative detecting method of active ingredient in Buddhist nun's bulk drug is replaced in the life of two p-methyl benzenesulfonic acid edge |
| CN113747900B (en) * | 2019-05-22 | 2024-04-02 | 正大天晴药业集团股份有限公司 | Pharmaceutical composition of pyridinamine compound and application of pharmaceutical composition in ROS1 positive non-small cell lung cancer |
| WO2024022282A1 (en) * | 2022-07-25 | 2024-02-01 | 正大天晴药业集团股份有限公司 | Use of pyridylamine compound in specific ros1 gene fusion non-small cell lung cancer |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101372475A (en) * | 2008-03-19 | 2009-02-25 | 南京工业大学 | Aromatic heterocyclic substituted acardite derivative and use thereof |
| CN102850328A (en) * | 2011-07-01 | 2013-01-02 | 中国科学院上海药物研究所 | Pyridine chemical, its preparation method, and pharmaceutical composition containing the chemical and application thereof |
| CN103263416A (en) * | 2013-04-28 | 2013-08-28 | 杭州鸿运华宁生物医药工程有限公司 | Application of pyridylamine compound in preparation of drugs used for treating lung cancer and suitable for oral administration |
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| CN103842353A (en) * | 2011-09-21 | 2014-06-04 | 苏州韬略生物科技有限公司 | Pyridines compounds as inhibitors of kinase |
| CN103121993A (en) * | 2011-11-21 | 2013-05-29 | 上海壹志医药科技有限公司 | Salt of 2,6-dichloro-3-fluorophenyl derivative |
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101372475A (en) * | 2008-03-19 | 2009-02-25 | 南京工业大学 | Aromatic heterocyclic substituted acardite derivative and use thereof |
| CN102850328A (en) * | 2011-07-01 | 2013-01-02 | 中国科学院上海药物研究所 | Pyridine chemical, its preparation method, and pharmaceutical composition containing the chemical and application thereof |
| CN103263416A (en) * | 2013-04-28 | 2013-08-28 | 杭州鸿运华宁生物医药工程有限公司 | Application of pyridylamine compound in preparation of drugs used for treating lung cancer and suitable for oral administration |
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