CN108285460A - A kind of pharmaceutical salts of EGFR kinase inhibitor and preparation method thereof and purposes - Google Patents
A kind of pharmaceutical salts of EGFR kinase inhibitor and preparation method thereof and purposes Download PDFInfo
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- CN108285460A CN108285460A CN201710014187.4A CN201710014187A CN108285460A CN 108285460 A CN108285460 A CN 108285460A CN 201710014187 A CN201710014187 A CN 201710014187A CN 108285460 A CN108285460 A CN 108285460A
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- IQNVEOMHJHBNHC-UHFFFAOYSA-N n-[2-[2-(dimethylamino)ethyl-methylamino]-5-[[4-(1h-indol-3-yl)pyrimidin-2-yl]amino]-4-methoxyphenyl]prop-2-enamide Chemical compound COC1=CC(N(C)CCN(C)C)=C(NC(=O)C=C)C=C1NC1=NC=CC(C=2C3=CC=CC=C3NC=2)=N1 IQNVEOMHJHBNHC-UHFFFAOYSA-N 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
- C07D498/04—Ortho-condensed systems
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The present invention relates to a kind of pharmaceutical salts of EGFR kinase inhibitor.Specifically, the present invention relates to N (2 ((2 (dimethylamino) ethyl) (methyl) amino) 4 methoxyl groups 5 ((4 (3,4 dihydro 1H [1,4] oxazine simultaneously 10 base of [4,3 a] indoles) 5 fluoropyrimidine, 2 base) amino) phenyl) it the mesylate of allyl amide, preparation method and its is used to prepare treatment and/or prevents the application of the drug with drug-resistant tumors.The compound of the present invention has the dissolubility and bioavilability improved, to have better antitumous effect.
Description
Technical field
The present invention relates to a kind of pharmaceutical salts of EGFR kinase inhibitor and preparation method thereof.Specifically, the present invention relates to
(((([1,4] oxazines are simultaneously by 3,4- dihydros -1H- by 4- by 2- ((2- (dimethylamino) ethyl) (methyl) amino) -4- methoxyl groups -5- by N-
[4,3-a] indoles -10- bases) -5-FU -2- bases) amino) phenyl) allyl amide pharmaceutical salts and preparation method thereof and purposes.
Background technology
EGF-R ELISA (EGFR) is the transmembrane protein tyrosine kinase members of erbB receptor families.ErbB receptors
Homologous dimerization and/or heterodimeric lead to the phosphorylation of key tyrosine residue in Intracellular domain, stimulation participate in cell Proliferation and
Many Cellular Signaling Transduction Mediated accesses of existence.The imbalance of erbB families signal transduction promotes proliferation, intrusion, transfer, blood vessel life
It survives at tumour cell, and has been described in many cancers, such as lung cancer, incidence cancer and breast cancer etc..Small point
Sub- EGFR tyrosine kinase inhibitors and ATP competitive bindings to EGFR intracellular region phosphorylation sites, inhibit EGFR from process phosphoric acid
And downstream signaling pathway is blocked, to achieve the purpose that inhibit tumour cell.
Gefitinib, Tarceva are the reversible micromolecular inhibitors of the first generation of EGFR, are mainly used for treating non-small cell
Lung cancer.But clinical research shows that (12-14 months) just generate anti-medicine to many patients to these EGFR micromolecular inhibitors quickly
Property.Research shows that residue T790M mutation of guarding the gate are EGFR gene 20 exon, one catastrophe points, it is the master for causing drug resistance to generate
Want one of mechanism.Second generation irreversible inhibitor, as Afatinib have to the EGFR that L858R and T790M are mutated it is very strong
Inhibiting effect has notable curative effect to the patient that Gefitinib or Tarceva have developed immunity to drugs.However the second generation
EGFR mutant inhibitor similarly has very strong inhibiting effect to Wild type EGFR, so as to cause big in treatment clinical course
Some patientss generate toxic side effect, for example fash, diarrhea.
Therefore third generation EGFR inhibitor should be kept to EGFR firstL858RActivated mutant body, Exon19 lack activated mutant
Body and T790M resistant mutants have stronger inhibiting effect, while should overcome the toxic side effect of second generation inhibitor, that is, reduce
To the inhibiting effect of Wild type EGFR.Compound AZD9291 (also known as N- (the 2- of Astrazeneca AB (AstraZeneca) research and development
{ 2- dimethylaminoethyls-methylamino } -4- methoxyl groups -5- { [4- (1- methyl indol -3- bases) pyrimidine -2-base] amino } phenyl)
Propyl- 2- acrylamides) it is a kind of oral, irreversible EGFR inhibitor, but its metabolin AZ5104 is to Wild type EGFR
Also there is very strong inhibiting effect.Therefore, new E GFR kinase inhibitor of the exploitation with more preferable drug effect is still needed to, while the EGFR swashs
Enzyme inhibitor has better druggability, such as has the advantages that good water solubility, bioavilability are high, hygroscopicity is low etc..
Invention content
The present invention provides a kind of such as following formula (I) compound represented N- (2- ((2- (dimethylamino) ethyl) (methyl)
Amino) -4- methoxyl groups -5- ((4- (3,4- dihydros -1H- [1,4] oxazines simultaneously [4,3-a] indoles -10- bases) -5-FU -2-
Base) amino) phenyl) and allyl amide officinal salt,
Vitro kinase activity detection finds formula (I) compound to mutant egf R kinases, such as EGFRL858R/T790MKinases has
There are good inhibitory activity, IC50Value is less than 1nM, while small on the influence of Wild type EGFR kinases, has preferable selectivity.Body
Outer cell experiment is the result shows that formula (I) compound is preferable to the inhibiting effect of double-mutant cell, and to EGFR wild-type cells
Inhibiting effect is small, and selectivity is good, helps to reduce adverse reaction clinically.
However, in the druggability research process of formula (I) compound, the inventors found that formula (I) compound
Free alkali form water solubility is at a fairly low, and has very high hygroscopicity, these defects are very unfavorable for exploitation drug.This
Inventor to N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -4- methoxyl groups -5- ((4- (3,4- dihydros -1H- [1,
4] oxazine simultaneously [4,3-a] indoles -10- bases) -5-FU -2- bases) amino) phenyl) salt form of allyl amide carried out depth
Enter research.Astoundingly, the inventors found that the mesylate of formula (I) compound compared with free alkali form compared to having
Unexpected advantage is conducive to drug development, and stability first is improved, and in addition water-soluble and bioavilability also obtains
Prodigious raising is suitble to preparation process research, is conducive to patent medicine.
Another aspect of the invention provides N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -4- methoxyl groups -5-
((4- (3,4- dihydros -1H- [1,4] oxazines simultaneously [4,3-a] indoles -10- bases) -5-FU -2- bases) amino) phenyl) acrylyl
The preparation method of amine mesylate includes the steps that free alkali formula (I) compound is reacted into salt with methanesulfonic acid, can be according to ability
It is prepared by the salifying method of domain routine.
Above-mentioned reaction can carry out in organic solvent, wherein the organic solvent is rudimentary organic solvent, described rudimentary have
Solvent is the ketones solvent that alcohols solvent of the carbon atom number less than 6 or carbon atom number are less than 6, preferably methanol, ethyl alcohol, positive third
Alcohol, isopropanol, n-butanol, n-amyl alcohol, n-hexyl alcohol, acetone, methyl ethyl ketone, methyl iso-butyl ketone (MIBK) etc., more preferably isopropanol
Or acetone.
In some embodiments, the preparation method of the mesylate of formula (I) compound according to the present invention, wherein N-
(((([1,4] oxazines are simultaneously by 3,4- dihydros -1H- by 4- by 2- ((2- (dimethylamino) ethyl) (methyl) amino) -4- methoxyl groups -5-
[4,3-a] indoles -10- bases) -5-FU -2- bases) amino) phenyl) molar ratio of allyl amide and methanesulfonic acid is about 1:0.5-
5.In other embodiments, N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -4- methoxyl groups -5- ((4- (3,
4- dihydros -1H- [1,4] oxazine simultaneously [4,3-a] indoles -10- bases) -5-FU -2- bases) amino) phenyl) allyl amide and first
The molar ratio of sulfonic acid is about 1:1-3.In preferred embodiments, N- (2- ((2- (dimethylamino) ethyl) (methyl) ammonia
Base) -4- methoxyl groups -5- ((4- (3,4- dihydros -1H- [1,4] oxazines simultaneously [4,3-a] indoles -10- bases) -5-FU -2- bases)
Amino) phenyl) molar ratio of allyl amide and methanesulfonic acid is about 1:1-2.
In a specific embodiment, N- (2- ((2- (dimethylamino) ethyl) (methyl) ammonia in above-mentioned reaction
Base) -4- methoxyl groups -5- ((4- (3,4- dihydros -1H- [1,4] oxazines simultaneously [4,3-a] indoles -10- bases) -5-FU -2- bases)
Amino) phenyl) molar ratio of allyl amide and methanesulfonic acid is about 1:1.1.In some embodiments, formula according to the present invention
(I) preparation method of compound methanesulfonic acid salt, wherein reaction temperature are about 20 DEG C-about 70 DEG C, the reaction time be about 0.5h- about
6h.In other embodiments, reaction temperature is about 20 DEG C-about 60 DEG C, and the reaction time is about 1h- about 4h.
In a specific embodiment, the preparation method of the mesylate of formula (I) compound according to the present invention,
Middle N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -4- methoxyl groups -5- ((4- (3,4- dihydros -1H- [1,4] oxazines
And [4,3-a] indoles -10- bases) -5-FU -2- bases) amino) phenyl) molar ratio of allyl amide and methanesulfonic acid is about 1:1-
2, reaction temperature is about 50 DEG C-about 60 DEG C, and the reaction time is about 2h- about 4h.
Another aspect of the invention provides a kind of pharmaceutical composition, contains N- (2- ((2- (dimethylamino) ethyl)
(methyl) amino) ((4- (3,4- dihydros -1H- [1,4] oxazines simultaneously [4,3-a] indoles -10- bases) -5- fluorine is phonetic by -4- methoxyl groups -5-
Pyridine -2- bases) amino) phenyl) allyl amide mesylate and pharmaceutically acceptable carrier.
" pharmaceutically acceptable carrier " refers to the carrier for Therapeutic Administration, including various excipient and diluent.It should
Term refers to some such medicament carriers：It themselves is not necessary active constituent, and does not have excessive toxicity after applying.It closes
Suitable carrier is well known to those of ordinary skill in the art.In Remington's Pharmaceutical Sciences
Discussing fully about pharmaceutically acceptable excipient can be found in (Mack Pub.Co., N.J.1991).In the composition
Pharmaceutically acceptable carrier may include liquid, such as water, brine, glycerine, ethyl alcohol.In addition, also may be present in these carriers auxiliary
The substance of helping property, such as diluent, disintegrant, solubilizer and lubricant.
In some preferred embodiments, pharmaceutically acceptable carrier of the present invention includes diluent, disintegration
Agent, solubilizer and lubricant.Wherein diluent is preferably microcrystalline cellulose and at least one other diluents；Lubricant is excellent
Be selected as sodium stearyl fumarate, Compritol 888 ATO it is one or more；Disintegrant is preferably hydroxypropyl cellulose.
Another aspect of the present invention provides N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -4- methoxyl groups -
5- ((4- (3,4- dihydros -1H- [1,4] oxazines simultaneously [4,3-a] indoles -10- bases) -5-FU -2- bases) amino) phenyl) allyl
Amide mesylate or pharmaceutical composition comprising above-mentioned mesylate prepare for treat and/or the drug of pre- preventing tumor in
Application, especially prepare treatment and/or prevent with drug resistance tumour drug in application.It is described that there is drug resistance
Tumour can be the tumour that there is drug resistance to a variety of drugs, the preferred tumour to the anti-medicine of EGFR inhibitor, for example, to first,
Second, third generation EGFR inhibitor, such as there is the tumour of drug resistance to Gefitinib, Tarceva and Lapatinib.It is described
Tumour includes but not limited to solid tumor, preferably lung cancer, head and neck neoplasm, colorectal cancer, carcinoma of urinary bladder, cancer of pancreas, breast cancer, preceding
Row gland cancer, gastric cancer, carcinoma of mouth, liver cancer, oophoroma.It is highly preferred that the tumour is non-small cell lung cancer.In some embodiments
In, the method that the present invention provides tumour of formula (I) compound methanesulfonic acid salt treatment with drug resistance, wherein the tumour carries
EGFR mutators.In one embodiment, the EGFR mutators that the tumour carries are that the 20th exon exists
T790M is mutated.In another embodiment, the EGFR mutators that the tumour carries are that the 21st exon exists
L858R is mutated and/or missing/insertion mutation.In another embodiment, the EGFR mutators of the tumour carrying are
T790M and L858R double mutations.In other embodiments, the present invention is provided to treat the formula (I) of the present invention of tumour
The pharmaceutical composition of compound methanesulfonic acid salt or the present invention, wherein treatment function of tumor shows prominent curative effect, the choosing of height
Selecting property and/or less side effect.In some other embodiments, the present invention provides formula (I) compound methanesulfonic acid of the present invention
The method of the medicine composite for curing tumour of salt or the present invention, the method includes giving to need its bacterium's
The present invention formula (I) compound methanesulfonic acid salt or the present invention pharmaceutical composition, it is generated treatment tumour in terms of effect table
Prominent curative effect now, the selectivity of height and/or less side effect.
Specific implementation mode
The present invention is explained in more detail with reference to embodiments, the embodiment of the present invention is merely to illustrate the technology of the present invention
Scheme, and non-limiting the scope of the present invention.The material used in following embodiment and experimental example is unless specifically indicated quotient
Purchase obtains.
Embodiment 1：N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -4- methoxyl groups -5- ((4- (3,4- bis-
Hydrogen -1H- [1,4] oxazine simultaneously [4,3-a] indoles -10- bases) -5-FU -2- bases) amino) phenyl) allyl amide
The synthesis of step a 2- skatoxyls
In 100ml reaction bulbs, Lithium Aluminium Hydride (902.63mg, 23.78mmol), THF (30ml) are sequentially added, room temperature is stirred
Ice bath after 5min is mixed, indole -2-carboxylic ethyl ester (3g, 15.86mmol) is slowly added to, finishes, is warmed to room temperature reaction 2h.Reaction knot
System is cooled to 0 DEG C by Shu Hou, is then added thereto 20ml THF and 1.7ml20%KOH, is filtered after stirring 10min,
Filter cake is washed with 20ml THF, filtrate is washed once with saturation NaCl (10ml), and anhydrous sodium sulfate drying, filtering is concentrated and dried
Title object 2.3g is directly used in next step.
ESI-Ms m/z:148.1[M+H]。
The step b 3,4- dihydros -1H- [synthesis of 1,4] oxazines simultaneously [4,3-a] indoles
In 500ml reaction bulbs, 2- skatoxyls (300mg, 2.04mmol), KOH obtained by step a are sequentially added
(285.91mg, 5.10mmol) and CH2Cl2(160ml), ice bath are cooled to 0 DEG C or so, and nitrogen protection stirs 10min.By 40mL
Dissolved with diphenyl (vinyl) sulfonium triflate (Diphenyl (vinyl) sulfonium
Trifluoromethanesulfonate) the CH of (888.86mg, 2.45mmol)2Cl2Solution is added dropwise in above-mentioned reaction system,
It finishes, is warmed to room temperature reaction.After TLC monitoring raw materials disappear, after reaction, water quenching is added to go out reaction, ethyl acetate extraction, conjunction
And ethyl acetate layer, anhydrous sodium sulfate drying are filtered, concentration, column chromatography purifies to obtain title object 300mg.
ESI-Ms m/z:174.1[M+H]。
Step c 10- (the chloro- 5-FU -4- bases of 2-) -3,4- dihydros -1H- [conjunctions of 1,4] oxazines simultaneously [4,3-a] indoles
At
In 100mL reaction bulbs, sequentially add alchlor (4.36g, 32.68mmol), glycol dimethyl ether (50mL),
Bis- chloro- 5-FUs (3.21g, 19.61mmol) of 2,4-, step b gains 3,4- dihydros -1H- [1,4] oxazine are simultaneously [4,3-a]
Indoles (2.83g, 16.35mmol), back flow reaction 2h.TLC shows that after reaction, reaction solution is cooled to room temperature, filtering, filter cake
Washing obtains title object after dry.
ESI-Ms m/z:303.1[M+H]。
([1,4] oxazines are simultaneously [4,3-a] by 3,4- dihydros -1H- by step d N- (the fluoro- 2- methoxyl groups -5- nitrobenzophenones of 4-) -4-
Indoles -10- bases) -5-FU -2- amine
In 250ml reaction bulbs, by step c gains 10- (the chloro- 5-FU -4- bases of 2-) -3,4- dihydros -1H- [1,
Simultaneously [4,3-a] indoles (3.03g, 10mmol) and the fluoro- 2- methoxyl groups -5- nitroanilines (2.05g, 11mmol) of 4- are molten for 4] oxazines
In 25mL Isosorbide-5-Nitraes-dioxane, K is then sequentially added3PO4(4.25g, 20mmol), XPhos (0.48g, 1mmol) and Pd2
(dba)3Reaction system is warming up to 120 DEG C and stirred 10 hours, after reaction, is cooled to room temperature, mistake by (0.92g, 1mmol)
Filter, sec-butyl alcohol washing, dry title compound.ESI-Ms m/z:453.1[M+H].
Step e N- (4- ((2- (dimethylamino) ethyl) (methyl) amino) -2- methoxyl group -5- nitrobenzophenones) -4-
The synthesis of (3,4- dihydros -1H- [1,4] oxazines simultaneously [4,3-a] indoles -10- bases) -5-FU -2- amine
In 50ml reaction bulbs, sequentially add step d gains N- (the fluoro- 2- methoxyl groups -5- nitrobenzophenones of 4-) -4- (3,
4- dihydros -1H- [Isosorbide-5-Nitrae] oxazines simultaneously [4,3-a] indoles -10- bases) -5-FU -2- amine (2.72g, 6mmol), N, N, N '-three
Methyl ethylenediamine (1.83g, 18mmol), diisopropylethylamine (2.3g, 18mmol) and 10ml dioxane, 110 DEG C of reflux are anti-
3h is answered, after reaction, concentration, column chromatography purifies to obtain title compound.ESI-Ms m/z:535.2[M+H].
Step f N- (4- ((2- (dimethylamino) ethyl) (methyl) amino) -2- methoxyl group -5- aminophenyls) -4-
The synthesis of (3,4- dihydros -1H- [1,4] oxazines simultaneously [4,3-a] indoles -10- bases) -5-FU -2- amine
In 50ml reaction bulbs, step e gains N- (4- ((2- (dimethylamino) ethyl) (methyl) ammonia is sequentially added
Base) -2- methoxyl group -5- nitrobenzophenones) -4- (3,4- dihydros -1H- [1,4] oxazines simultaneously [4,3-a] indoles -10- bases) -5- fluorine is phonetic
Pyridine -2- amine (2.68g, 5mmol), 10%Pd-C (20mg) and 30ml methanol are depressed, hydrogen reducing 1h, instead in 1 normal atmosphere
After answering, filtering is concentrated to give title compound, is directly used in next step.
ESI-Ms m/z:505.3[M+H]。
Step g N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -4- methoxyl groups -5- ((4- (3,4- dihydros -
1H- [1,4] oxazine simultaneously [4,3-a] indoles -10- bases) -5-FU -2- bases) amino) phenyl) allyl amide synthesis
In 150ml single port bottles, step f gains N- (4- ((2- (dimethylamino) ethyl) (methyl) amino)-are added
2- methoxyl group -5- aminophenyls) -4- (3,4- dihydros -1H- [1,4] oxazines simultaneously [4,3-a] indoles -10- bases) -5-FU -2-
Amine (2.12g, 4.2mmol), diisopropylethylamine (0.53g, 4.2mmol) and 20ml anhydrous methylene chlorides slowly add after dissolving
Enter the dichloromethane solution that 5ml is dissolved with allyl acyl chlorides (0.37g, 4.2mmol), reacts 10min, after reaction, concentration,
Column chromatography purifies to obtain title compound.
1H NMR(400MHz,CDCl3):δ10.09-10.17(m,1H),9.46(s,1H),8.39(d,1H),7.89-
7.94(m,1H),7.55(s,1H),7.34-7.38(m,1H),7.29(s,1H),7.24-7.28(m,1H),6.81(s,1H),
6.26-6.43(m,2H),5.71-5.65(m,1H),5.31(s,2H),4.22-4.27(m,2H),4.20(d,2H),3.90(s,
3H),2.86-2.94(m,2H),2.73(s,3H),2.23-2.33(s,8H)。
ESI-Ms m/z:560.3[M+H]。
Embodiment 2：N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -4- methoxyl groups -5- ((4- (3,4- bis-
Hydrogen -1H- [1,4] oxazine simultaneously [4,3-a] indoles -10- bases) -5-FU -2- bases) amino) phenyl) allyl amide mesylate
It weighs formula (I) compound (156.8mg, 0.28mmol) to be dissolved in the acetone of 1.49mL 95%, solid is molten at 55 DEG C
Clearly, with 1mL acetone dilution methanesulfonic acid (29.11mg, 0.30mmol), the acetone soln of methanesulfonic acid is added into above-mentioned formula at 55 DEG C
(I) it in the acetone soln of compound, is filtered after reacting 2h, acetone washing, at room temperature vacuum drying obtains mesylate 165mg.
Embodiment 3：N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -4- methoxyl groups -5- ((4- (3,4- bis-
Hydrogen
- 1H- [1,4] oxazine simultaneously [4,3-a] indoles -10- bases) -5-FU -2- bases) amino) phenyl) allyl amide breast
Hydrochlorate
It using the method for embodiment 2, is reacted with Pfansteihl with free alkali formula (I) compound, obtains the breast of formula (I) compound
Hydrochlorate.
Embodiment 4：N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -4- methoxyl groups -5- ((4- (3,4- bis-
Hydrogen -1H- [1,4] oxazine simultaneously [4,3-a] indoles -10- bases) -5-FU -2- bases) amino) phenyl) allyl amide maleate
It using the method for embodiment 2, is reacted with maleic acid with free alkali formula (I) compound, obtains the horse of formula (I) compound
Carry out hydrochlorate.
Embodiment 5：N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -4- methoxyl groups -5- ((4- (3,4- bis-
Hydrogen -1H- [1,4] oxazine simultaneously [4,3-a] indoles -10- bases) -5-FU -2- bases) amino) phenyl) allyl amide other salt
Using the method for embodiment 2, with free alkali formula (I) compound and different organic acids or inorganic acid reaction at
The citrate, hydrochloride, hydrobromate, sulfate, nitrate, phosphate, tartrate, amber of formula (I) compound is made in salt
Amber hydrochlorate, acetate, trifluoroacetate, fumarate, Chinese holly edge hydrochlorate, benzene sulfonate, benzoate, naphthalene sulfonate, malic acid
Salt, alpha-ketoglutarate, gluconate, glycollate and oxalates.
Experimental example 1：Formula (I) compound officinal salt relevant nature is studied
Dissolubility：The various officinal salts of formula (I) compound, including mesylate, lactate, horse are detected using conventional method
Come hydrochlorate, citrate, hydrochloride, hydrobromate, sulfate, nitrate, phosphate, tartrate, succinate, acetic acid
Salt, trifluoroacetate, fumarate, Chinese holly edge hydrochlorate, benzene sulfonate, benzoate, naphthalene sulfonate, malate, α -one penta 2
The water solubility of hydrochlorate, gluconate, glycollate and oxalates.
The experimental results showed that the dissolubility of the mesylate of formula (I) compound is changed significantly better than the formula (I) of free alkali form
Close the salt form of object and other acid.
It can be seen that for other pharmaceutical salts of formula (I) compound and formula (I) compound, formula (I) compound
The dissolubility of mesylate significantly increases, and is suitble to medicinal.
Stability：The fusing point of the mesylate of formula (I) compound is significantly larger than free alkali and other medicines of formula (I) compound
Use salt.
The mesylate of formula (I) compound is more stable compared with other pharmaceutical salts of free alkali form and formula (I) compound, places
In under room temperature, purity is not decreased obviously, and hygroscopicity reduces.
Experimental example 2：The oral administration biaavailability of formula (I) compound officinal salt is studied
1 experiment material
1.1 compound
ORAL FORMULATION：Compound prepared by embodiment 1- embodiments 4 is dissolved in citric acid-citric acid of 25mM respectively
Sodium buffer solution (pH2.75), is made 2.7mg/ml clear solutions.
1.2 animal
Male SD rat, weight 180-220g are purchased from Shanghai western Poole-Bi Kai experimental animals Co., Ltd.
2~4 days environment laundering period are given before tested rat experiment, water supply after 2h, 4h is administered in fasting 8-12h before being administered
Food is given afterwards.
1.3 reagent
Methanol (chromatographically pure)：Spectrum companies produce；
Acetonitrile (chromatographically pure)：Spectrum companies produce；
Remaining reagent is that commercially available analysis is pure.
1.4 instrument
The triple level four bars LC-MS instrument of 4500 types of API, are furnished with electric spray ion source (ESI), and LC-30AD double pumps are purchased from
American AB company；
SIL-30AC autosamplers；
CTO-30AC column ovens；
DGU-20A3R degassers；
Analyst QS A01.01 chromatographic work stations；
Milli-Q Superpure water machines (Millipore Inc)；
Qilinbeier Vortex-5 oscillators；
Ⅹ II table-type high-speed refrigerated centrifuges of HITACHI CF16R.
2 experimental methods
1) male SD rat 12, are divided into 4 groups, every group of rat 3, fasting but can free water after 12 hours, when taking 0
Carve blank plasma；
2) 4 groups of rats in step 1) are taken, gavage (intragastric administration, I.G.) is given respectively
Mesylate, lactate, maleate, formula (I) compound 13.5mg/kg (being converted by free alkali number)；
3) 5min, 15min, 30min, 1h, 2h, 4h, 8h, 10h after gavage are set from eyeground vein clump continuous blood sampling for 24 hours
In being distributed in the EP pipes of anticoagulant heparin, upper plasma is taken after 8000rpm/min centrifugations 5min, -20 DEG C freeze, and wait for LC-MS/MS
Analysis；
4) the blood concentration-time data obtained by step 3) are asked using WinNonlin softwares and calculate pharmacokinetics ginseng
Number, experimental result are shown in Table 1：
Table 1：The medicine of formula (I) compound and its mesylate, Pfansteihl salt and maleate is for parametric results
The medicine of the above rat for test result show it is oral give rat Isodose after, the methanesulfonic acid of formula (I) compound
Salt half-life period compared with the Pfansteihl salt of formula (I) compound and relatively good (I) compound of dissolubility, maleic acid obviously prolongs
It is long, it mesylate exposed amount in animal body and increases significantly up to Cmax, mesylate is suitble to medicinal.
Claims (8)
- The mesylate of formula 1. (I) compound,
- 2. a kind of method preparing mesylate as described in claim 1, the method includes by formula (I) compound and methylsulphur The step of acid reaction is at salt.
- 3. preparation method according to claim 2, wherein salt-forming reaction carry out in rudimentary organic solvent, described is rudimentary Organic solvent is the ketones solvent that alcohols solvent of the carbon atom number less than 6 or carbon atom number are less than 6.
- 4. preparation method according to claim 3, wherein the rudimentary organic solvent is isopropanol or acetone.
- 5. according to the preparation method described in claim 2-4 any one, wherein formula (I) compound and the molar ratio of methanesulfonic acid is 1:0.5-5, preferably 1:1-3, more preferably 1:1-2.
- 6. a kind of pharmaceutical composition contains mesylate as described in claim 1 and pharmaceutically acceptable carrier.
- 7. application of the mesylate as described in claim 1 in preparing the drug for the treatment of and/or pre- preventing tumor.
- 8. the use as claimed in claim 7, wherein the tumour is the tumour with drug resistance, it is preferable that the tumour is There is the tumour of drug resistance to EGFR inhibitor.
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| CN107955019A (en) * | 2016-10-17 | 2018-04-24 | 广东众生药业股份有限公司 | A kind of salt form, crystal form and preparation method of EGFR inhibitor |
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| CN101318962A (en) * | 2003-09-17 | 2008-12-10 | 詹森药业有限公司 | Fused heterocyclic compound |
| US20080221090A1 (en) * | 2007-03-05 | 2008-09-11 | Bristol-Myers Squibb Company | HCV NS5B Inhibitors |
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