CN107522695B - A kind of hydrochloride and its preparation method and application of PIM kinase inhibitors - Google Patents
A kind of hydrochloride and its preparation method and application of PIM kinase inhibitors Download PDFInfo
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Abstract
The present invention relates to a kind of hydrochlorides and its preparation method and application of PIM kinase inhibitors, wherein shown in the hydrochloride structure such as formula (II) of the PIM kinase inhibitors.The hydrochloride has higher solubility, good stability, higher bioavilability, very low hygroscopicity, and has good inhibitory activity to PIM kinases.
Description
Technical field
The invention belongs to organic compound synthesis and medical applications technical field, and in particular to a kind of PIM kinase inhibitors
Hydrochloride and its preparation method and application.
Background technology
Antitumor drug research is challenge to be rich in current life science and significant field.In recent years, with
The basic process of further investigation to tumour pathogenic mechanism, the changes of Signal transduction in tumour cell is gradually explained
It is bright.Using the Key kinases in some intracellular signal transduction pathway as drug screening target spot, find efficient, less toxic, high specificity
Novel targeted drug has become one of the effective way of current antitumor drug research.Currently, in all pharmacological targets,
The target for being estimated to exceed 1/4 is protein kinase, and 75%, wherein PIM (Provirus are more up in antitumor field
Integration site for Moloney leukemia) kinases is attention rate is high in recent years one of research target.
PIM genes are gained the name as the proviral integration site of moloney murine leukemia virus earliest, and PIM kinases is more
Highly conserved in the evolutionary process of cell tissue, there are three hypotypes for it, are PIM-1, PIM-2 and PIM-3 respectively, belong to ammonia
Acid/Serineprotein kinase.Each hypotype of PIM kinases over-expresses in a variety of human tumor cells, is influenced by number of mechanisms
The proliferation of tumour cell and survival：PIM kinases and transcription factor synergy promote tumor cell proliferation；PIM kinases can also lead to
Peroxophosphoric acid apoptotic proteins BAD and ASK1 increases cell survival；PIM kinases is adjusted by adjusting various kinds of cell periodicity factor
Cell cycle, the proliferation of inducing cell；PIM kinases enhances cell viability measurement by adjusting cell-signaling pathways；PIM kinases
By directly affecting the phosphorylation and other protein substrates such as MYC, Histone H3, p21, p27, CDC25A of Bcl-2,
The factors such as CDC25C and CXR4 adjust the proliferation and apoptosis of cell, and cell cycle regulation and control and the occurrence and development of tumour rise emphatically
It acts on.
PIM kinase inhibitors have following features：
(1) expression is wide：PIM kinases apoptosis capable of inhibiting cell, closely related with the generation of tumour, plurality of liquid and solid are swollen
Find that PIM kinases has overexpression in tumor, therefore preclinical and clinical research report, PIM kinase inhibitors are equal to kinds of tumors
There is significant curative effect.
(2) toxicity is low：It is different from common protein kinase target spot, inhibit PIM kinases that can lead to the apoptosis of tumour cell,
But the other functions of animal are not influenced.Therefore PIM kinase inhibitors are developed into antitumor drug, toxicity may be much smaller than existing
Kinase inhibitor.
(3) it is applicable in wide：It can be used alone, can also be shared with other antineoplastics and carry out treating cancer.
Overexpression of the PIM kinases in tumour works to the survival of cancer cell with diffusion.So inhibiting mistake in tumour
Degree expression PIM kinases is the effective ways for treating tumour.Other than treating tumour, PIM kinase inhibitors can also be used for treating
The immune response (Immunology, 116,82-88,2005) of auto-immune disease, allergy and organ transplant.
CN201210271738.2 describes a kind of kinase inhibitor and preparation method thereof and the application in pharmacy.It is logical
Formula compound includes a big substance, is prepared for 63 compounds in embodiment, and disclose the change in all embodiment 1-63
Close object all has apparent inhibiting effect to the activity of PIM kinases, wherein it is preferred that 50 multiple compounds, but these compounds are herein
Its free form has been only exemplified by patent.
Pharmaceutically, other than activity, solubility, stabilization of the drug in processing, manufacture, storage as therapeutic agent
Property, hygroscopicity and bioavilability etc. it is all most important to medicament research and development, be suitble to medicinal compound and its medicine so finding
It is particularly important with salt form.
Invention content
The object of the present invention is to provide a kind of solubility height, stability is good, hygroscopicity is low, bioavilability is higher, and
There is 5- amino-N- (4- (azepan -4- oxygroups) pyrimidine -5-) -2- (2,6- difluorobenzenes of excellent activity to PIM kinases
Base) thiazole -4-carboxamide (as shown in formula (I)) acceptable salt and contain pharmaceutical composition of the pharmaceutical salts as active ingredient
Object, and provide the method for preparing the pharmaceutical salts and be used in the pharmaceutical salts or the pharmaceutical composition and prepare treatment because PIM swashs
Enzyme over-expresses and the purposes of the drug of the disease of initiation.
It is described that technical scheme is as follows：
On the one hand, the present invention provides the hydrochlorides of compound shown in a kind of formula (I), shown in structure such as formula (II)：
Wherein, the formula (I) is 5- amino-N- (4- (azepan -4- oxygroups) pyrimidine -5-) -2- (2,6- difluorobenzenes
Base) thiazole -4-carboxamide.
Preferably, the hydrochloride is crystal.
Preferably, the X ray diffracting spectrum of the hydrochloric acid salt crystal includes the diffraction maximum that the angles following 2 θ indicate：5.5±
0.2°、8.5±0.2°、9.8±0.2°、17.2±0.2°、23.1±0.2°、25.5±0.2°、27.8±0.2°。
Preferably, further include the diffraction maximum of the angles following 2 θ expression in the X ray diffracting spectrum of the hydrochloric acid salt crystal：13.6
±0.2°、20.9±0.2°、26.7±0.2°、30.0±0.2°、34.2±0.2°。
Preferably, the X ray diffracting spectrum of the hydrochloric acid salt crystal is as shown in Figure 3.
2 angles θ are that the main peak for selecting relative intensity strong in X ray diffracting spectrum obtains above, and crystalline texture may not be only
It is limited by these values, you can to contain peak in addition to this.In addition, generally by X-ray analysis measure crystallize when, peak by
It is possible to generate some evaluated errors in the presence etc. of determining instrument, determination condition, attachment solvent.Such as 2 the angles θ be possible to generate
± 0.2 ° or so of evaluated error, thus when identification crystal structure, it should be taken into account that some errors, by substantial and above-mentioned same
The crystallization that the X-ray spectrogram of sample assigns feature is within.
On the other hand, the present invention provides a kind of method for the hydrochloride preparing above-mentioned formula (I) compound, the method packets
Include following steps：Compound shown in formula (I) is dissolved in solvent, controlling reaction temperature, hydrogen chloride methanol solution is added, heat preservation is anti-
It answers 0~24 hour, solid is precipitated in reaction solution, filters, vacuum drying.
Preferably, in the above preparation method, controlling reaction temperature is 0~30 DEG C, preferably 0 DEG C or 20~30 DEG C；
Preferably, in the above preparation method, after hydrogen chloride methanol solution being added, insulation reaction 30 minutes to 24 hours,
It is preferred that insulation reaction 30 minutes；
Preferably, in the above preparation method, vacuum drying temperature is 50 DEG C.
Preferably, the preparation method includes：Formula (I) compound represented is dissolved in solvent, it is 50 to be heated to temperature
Hydrogen chloride methanol solution, insulation reaction 0~24 hour at 50~100 DEG C, cooling is added in~200 DEG C, preferably 50~100 DEG C
To 20~30 DEG C, solid is precipitated in reaction solution, filters, vacuum drying.
Preferably, in the above preparation method, formula (I) compound represented is dissolved in solvent, it is 50 to be heated to temperature
~60 DEG C；
Preferably, in the above preparation method, be added hydrogen chloride methanol solution after, at 50~60 DEG C insulation reaction 0~
It 24 hours, preferably reacts 5-10 hours, more preferably reaction 5 hours；
Preferably, in the above preparation method, vacuum drying temperature is 50 DEG C.
Preferably, the solvent is selected from methanol, dichloromethane, dimethyl sulfoxide (DMSO) (DMSO), tetrahydrofuran, dimethyl formyl
Amine (DMF), acetone, ethyl alcohol, acetonitrile, propyl alcohol, butanol, N-Methyl pyrrolidone (NMP), ethyl acetate and one kind or more in water
Kind；It is highly preferred that the solvent be selected from methanol, dichloromethane, dimethyl sulfoxide (DMSO), tetrahydrofuran, dimethylformamide, acetone,
It is one or more in ethyl alcohol, acetonitrile, N-Methyl pyrrolidone, ethyl acetate and water；It is further preferred that the solvent is first
Alcohol and dichloromethane, dimethyl sulfoxide (DMSO) and tetrahydrofuran, dimethylformamide and acetone, ethyl alcohol and acetonitrile, N- crassitudes
Ketone and ethyl acetate, N-Methyl pyrrolidone and water or N-Methyl pyrrolidone；Most preferably, the solvent is DMF and third
Ketone；
Preferably, in the above preparation method, a concentration of 0.25mol/L~2mol/L of the hydrogen chloride methanol solution,
It is preferred that 0.5mol/L~1mol/L；
Preferably, in the above preparation method, the hydrogen chloride methanol solution and the molar ratio of compound shown in formula (I) are
0.1~10：1, preferably 1~1.5：1.
In another aspect, the present invention also provides a kind of pharmaceutical composition, described pharmaceutical composition contains shown in above-mentioned formula (I)
The hydrochloride of compound is as active ingredient；
Preferably, described pharmaceutical composition includes pharmaceutically acceptable carrier or excipient；
Preferably, described pharmaceutical composition is tablet, capsule, pill, granule, powder, suppository, injection, solution
Agent, suspension, paste, patch, lotion, drops, liniment or spray.
Another aspect the present invention also provides the hydrochloride of compound shown in above-mentioned formula (I) or above-mentioned contains the hydrochloride
Pharmaceutical composition as active ingredient is being prepared for treating in the drug of the disease caused because PIM kinases over-expresses
Purposes；
Preferably, the disease includes tumour, autoimmune disease, allergic reaction disease, atherosclerosis disease
Rejection disease caused by disease and organ transplant.
Finally, applicant believes that, those skilled in the art with different inorganic acids or can have on the basis of the present invention
Machine acid replaces hydrogen chloride, and the difference of formula (I) compound is prepared in method using the present invention or the method similar with the present invention
Acid-addition salts, still, the hydrochloride of formula (I) compound provided by the invention has significant skill compared with other acid-addition salts
Art advantage.
(1) the hydrochloride salt degree of formula (I) compound of the present invention is high, wherein solubility about 1.5mg/ in water
Ml, conducive to preparation preparation and its absorbed in vivo.
(2) the hydrochloride low in hygroscopicity of formula (I) compound of the present invention, it is moist according to drawing for Chinese Pharmacopoeia regulation progress
In experiment, it is only 0.46% to draw wet weightening；And stability is high, to heat, light, high humidity stabilization, according to Chinese Pharmacopoeia provide into
Capable stability test measures the content in relation to substance, having in the hydrochloride of formula (I) compound of the present invention after 10 days
Close content amplification≤0.13% of substance.
(3) hydrochloride of formula (I) compound of the present invention has higher life compared to other salt form in animal body
Object availability.
(4) three kinds of PIM kinases of hydrochloride pair of formula (I) compound of the present invention all have very high inhibitory activity,
Be suitable for use in prepare treatment because PIM kinases over-expresses cause such as tumour, autoimmune disease, allergy and organ transplant
The diseases such as immune response drug.
Description of the drawings
Hereinafter, carry out the embodiment that the present invention will be described in detail in conjunction with attached drawing, wherein：
Fig. 1 is formula (I) compound hydrochloride that embodiment 2 obtains1HNMR collection of illustrative plates；
Fig. 2 is the mass spectrogram of formula (I) compound hydrochloride that embodiment 2 obtains；
Fig. 3 is the X-ray powder diffraction pattern of formula (I) compound hydrochloride that embodiment 2 obtains.
Specific implementation mode
Present invention will be further explained below with reference to specific examples.It should be understood that these embodiments are merely to illustrate the present invention
Rather than it limits the scope of the invention.In the following examples, the experimental methods for specific conditions are not specified, usually according to conventional strip
Part or according to the normal condition proposed by manufacturer.
Unless otherwise defined, all professional and scientific terms used in text and meaning known to one skilled in the art
Justice is identical.In addition, any method and material similar or impartial to described content can be applied to the method for the present invention.Wen Zhong
The preferred implement methods and materials are for illustrative purposes only.
The synthesis of 1 formula of embodiment (I) compound
1) preparation of 4- (5- amidino-pyridine -4- hydroxyls)-azepan -1- t-butyl formates (SM-3)
Under the conditions of room temperature (25 DEG C), the tertiary fourth of 4- hydroxy-azepane -1- formic acid is added in NaH (71mg, 2.94mmol)
Then it is phonetic that 4- bromines are added in THF (tetrahydrofuran) (10mL) solution ＆ stir of ester (SM-2) (574mg, 2.67mmol) 1 hour
Pyridine -5- amine (SM-1) (348mg, 2.67mmol).Reactant is heated to 100 DEG C under nitrogen protection, in room temperature after stirring 4 hours
Vacuum rotating concentrates under (20-30 DEG C).Residue by silica gel chromatography column purification (eluent after concentration：10-30% ethyl acetate/
Petroleum ether) obtain product 4- (5- amidino-pyridine -4- hydroxyls)-azepan -1- t-butyl formates (SM-3) (370mg,
1.2mmol)。
2) 4- (5- (5- amino -2- (2,6- difluorophenyls) thiazole -4-carboxamide) pyrimidine -4- oxygroups) azepan -
The preparation of 1- t-butyl formates (SM-5)
Compound (SM-3) (52mg, 0.169mmol), compound 5- amino -2- (2,6- difluorophenyl)-thiazole -4- first
Sour (1E) (SM-4) (40mg, 0.169mmol), HATU (77mg, 0.203mmol) and DIEA (93 μ L, 0.507mmol) are in DMF
Mixture in (5mL) stirs 1 hour at 50 DEG C.It is diluted with ethyl acetate (50mL) after cooling, then is washed with saturated common salt
It washs.Organic phase is through Na2SO4Vacuum rotating concentrates under room temperature (20-30 DEG C) after drying.Residue by silica gel chromatography column after concentration
(eluent after purification：10-30% ethyl acetate/petroleum ethers) obtain product 4- (5- (5- amino -2- (2,6- difluorophenyls) thiophenes
Azoles -4- formamides) pyrimidine -4- oxygroups) azepan -1- t-butyl formates (SM-5) (32mg, 0.0585mmol).
3) 5- amino-N- (4- (azepan -4- oxygroups) pyrimidine -5-) -2- (2,6- difluorophenyls) thiazole -4- formyls
The preparation of amine (structural formula I)
Under the conditions of room temperature (25 DEG C), by TFA (trifluoracetic acid) (0.5mL) be added compound (SM-5) (21mg,
CH 0.0384mmol)2Cl2(1mL) solution stirs 10 minutes, under room temperature (25 DEG C) after vacuum rotating concentration, by residue
It is dissolved in CH2Cl2(10mL), solution are washed with the sodium hydroxide (5mL) of 1 equivalent and saturated salt solution (5mL) respectively, organic phase warp
Na2SO4Product 5- amino-N- (4- (azepan -4- oxygroups) are made in vacuum rotating concentration under room temperature (25 DEG C) after drying
Pyrimidine -5-) -2- (2,6- difluorophenyl) thiazole -4-carboxamide (structural formula I) (11mg, 0.0246mmol).
1H NMR (400MHz, CD3OD)：δ ppm 1.55-1.65 (m, 1H), 1.83-1.96 (m, 1H), 2.03-2.13
(m, 4H), 2.76-2.79 (m, 1H), 2.81-2.85 (m, 2H), 2.90-2.96 (m, 1H), 5.44-5.50 (m, 1H), 7.02-
7.06 (m, 2H), 7.31-7.38 (m, 1H), 8.31 (s, 1H), 9.36 (s, 1H).
MS(ESI)447m/z(M+H)+。
The preparation of 2 formula of embodiment (I) compound hydrochloride
Formula (I) compound (0.11mmol), 2ml methanol and 8ml dichloromethane prepared by 50mg embodiments 1 are added to anti-
It answers in bottle, 20~30 DEG C of stirring clarifications are added at one time 165ul1N hydrogen chloride methanol solutions (0.165mmol), solution slowly becomes
Muddiness, 20~30 DEG C of insulated and stirred half an hour, filtering, 50 DEG C of filter cake are dried in vacuo to obtain 38mg off-white powders, yield：
52.7%, mp：232.3~235.4 DEG C.
Wherein1HNMR (400MHz, DMSO-d6) spectrogram is as shown in Figure 1；Mass spectrogram is as shown in Figure 2, wherein m/z：447.9
[(M-HCl)+H]+, 446.9 [M-HCl]+.
Formula (I) compound hydrochloride being prepared is crystal, and the X ray diffracting spectrum of crystal is as shown in figure 3, specific
Testing conditions are as follows, and testing result refers to table 1：
Detecting instrument：Bruker D8AdvanceX light ray diffractometers
Testing conditions：Target=Cu copper starts 2 θ scannings=3.000, terminates 2 θ and scans=40.000, voltage 40KV, electricity
Flow 40mA, Ka1=1.54060, Ka2=1.54439, Ka2/Ka1 ratios=0.5, Ka=1.54186.
The X-ray diffractogram modal data of 1 formula of table (I) compound hydrochloride crystal
The preparation of 3 formula of embodiment (I) compound hydrobromate
Formula (I) compound (0.11mmol), 2ml methanol and 8ml dichloromethane prepared by 50mg embodiments 1 are added to anti-
It answers in bottle, 20~30 DEG C of stirring clarifications are added at one time the mixing of 30%44mg hydrobromic acids (0.163mmol) and 0.5ml methanol
Solution, solution slowly become cloudy, 20~30 DEG C of insulated and stirred half an hour, and filtering, 50 DEG C of filter cake is dried in vacuo to obtain 28mg off-white colors
Solid, yield：48.2%, mp：221.2~223.5 DEG C, m/z：447.9 [(M-HBr)+H]+, 446.9 [M-HBr]+.
The preparation of 4 formula of embodiment (I) compound maleate
Formula (I) compound (0.11mmol), 2ml methanol and 8ml dichloromethane prepared by 50mg embodiments 1 are added to anti-
It answers in bottle, 20~30 DEG C of stirring clarifications are added at one time the mixed solution of 19mg maleic acids (0.164mmol) and 0.5ml methanol,
Solution slowly becomes cloudy, 20~30 DEG C of insulated and stirred half an hour, and filtering, 50 DEG C of filter cake is dried in vacuo to obtain 45mg off-white powders,
Yield：72.7%, mp：231.2~234.3 DEG C, m/z：447.9[(M-C4H4O4)+H]+, 446.9 [M-C4H4O4]+。
The phosphatic preparation of 5 formula of embodiment (I) compound
Formula (I) compound (0.11mmol), 2ml methanol and 8ml dichloromethane prepared by 50mg embodiments 1 are added to anti-
It answers in bottle, 20~30 DEG C of stirring clarifications are added at one time the mixed solution of 5mg phosphoric acid (0.051mmol) and 0.5ml methanol, molten
Liquid slowly becomes cloudy, 20~30 DEG C of insulated and stirred half an hour, and filtering, 50 DEG C of filter cake is dried in vacuo to obtain 45mg off-white powders, receives
Rate：85.4%, mp：218.3~220.8 DEG C, m/z：447.9[(M-H3PO4)+H]+, 446.9 [M-H3PO4]+。
The preparation of 6 formula of embodiment (I) compound succinate
Formula (I) compound (0.11mmol), 2ml methanol and 8ml dichloromethane prepared by 50mg embodiments 1 are added to anti-
It answers in bottle, 20~30 DEG C of stirring clarifications are added at one time the mixed solution of 19mg succinic acid (0.161mmol) and 0.5ml methanol,
Solution slowly becomes cloudy, 20~30 DEG C of insulated and stirred half an hour, and filtering, 50 DEG C of filter cake is dried in vacuo to obtain 47mg off-white powders,
Yield：75.6%, mp：224.1~230.2 DEG C, m/z：447.9[(M-C4H6O4)+H]+, 446.9 [M-C4H6O4]+。
The preparation of 7 formula of embodiment (I) compound sulfate
Formula (I) compound (0.11mmol), 2ml methanol and 8ml dichloromethane prepared by 50mg embodiments 1 are added to anti-
It answers in bottle, 20~30 DEG C of stirring clarifications are added at one time the mixed solution of 8mg sulfuric acid (0.081mmol) and 0.5ml methanol, molten
Liquid slowly becomes cloudy, 20~30 DEG C of insulated and stirred half an hour, and filtering, 50 DEG C of filter cake is dried in vacuo to obtain 55mg off-white powders, receives
Rate：91.8%, mp：228.5~231.7 DEG C, m/z：447.9[(M-H2SO4)+H]+, 446.9 [M-H2SO4]+。
The preparation of 8 formula of embodiment (I) compound citrate
Formula (I) compound (0.11mmol), 2ml methanol and 8ml dichloromethane prepared by 50mg embodiments 1 are added to anti-
It answers in bottle, 20~30 DEG C of stirring clarifications are added at one time the mixed solution of 32mg citric acids (0.167mmol) and 0.5ml methanol,
Solution slowly becomes cloudy, 20~30 DEG C of insulated and stirred half an hour, and filtering, 50 DEG C of filter cake is dried in vacuo to obtain 50mg off-white powders,
Yield：71.2%, mp：240.1~244.7 DEG C, m/z：447.9[(M-C6H8O7)+H]+, 446.9 [M-C6H8O7]+。
The preparation of 9 formula of embodiment (I) compounds benzoic acid salt
Formula (I) compound (0.11mmol), 2ml methanol and 8ml dichloromethane prepared by 50mg embodiments 1 are added to anti-
It answers in bottle, 20~30 DEG C of stirring clarifications are added at one time the mixed solution of 20mg benzoic acid (0.164mmol) and 0.5ml methanol,
Solution is clarified, 20~30 DEG C of insulated and stirred half an hour, 50 DEG C of evaporated under reduced pressure solvents, and 20~30 DEG C of stirrings of 10ml dichloromethane are added
Half an hour, filtering, 50 DEG C of filter cake are dried in vacuo to obtain 41mg off-white powders, yield：65.5%, mp：243.3~250.1 DEG C, m/
z：447.9[(M-C7H6O2)+H]+, 446.9 [M-C7H6O2]+。
The preparation of 10 formula of embodiment (I) compound methanesulfonic acid salt
Formula (I) compound (0.11mmol), 2ml methanol and 8ml dichloromethane prepared by 50mg embodiments 1 are added to anti-
It answers in bottle, 20~30 DEG C of stirring clarifications are added at one time the mixed solution of 16mg methanesulfonic acids (0.166mmol) and 0.5ml methanol,
Solution is clarified, 20~30 DEG C of insulated and stirred half an hour, 50 DEG C of evaporated under reduced pressure solvents, and 20~30 DEG C of stirrings of 10ml dichloromethane are added
Half an hour, filtering, 50 DEG C of filter cake are dried in vacuo to obtain 41mg off-white powders, yield：68.7%, mp：238.1~241.7 DEG C, m/
z：447.9[(M-CH4O3S)+H]+, 446.9 [M-CH4O3S]+。
The preparation of 11 formula of embodiment (I) compound lactate
Formula (I) compound (0.11mmol), 2ml methanol and 8ml dichloromethane prepared by 50mg embodiments 1 are added to anti-
It answers in bottle, 20~30 DEG C of stirring clarifications are added at one time the mixed solution of 15mg lactic acid (0.167mmol) and 0.5ml methanol, molten
Liquid is clarified, 20~30 DEG C of insulated and stirred half an hour, 50 DEG C of evaporated under reduced pressure solvents, and 20~30 DEG C of stirrings of 10ml dichloromethane half are added
Hour, filtering, 50 DEG C of filter cake is dried in vacuo to obtain 40mg off-white powders, yield：67.8%, mp：208.2~211.5 DEG C, m/z：
447.9[(M-C3H6O3)+H]+, 446.9 [M-C3H6O3]+。
The preparation of 12 formula of embodiment (I) compound acetate
Formula (I) compound (0.11mmol), 2ml methanol and 8ml dichloromethane prepared by 50mg embodiments 1 are added to anti-
It answers in bottle, 20~30 DEG C of stirring clarifications are added at one time the mixed solution of 10mg acetic acid (0.167mmol) and 0.5ml methanol, molten
Liquid is clarified, 20~30 DEG C of insulated and stirred half an hour, 50 DEG C of evaporated under reduced pressure solvents, and 20~30 DEG C of stirrings of 10ml dichloromethane half are added
Hour, filtering, 50 DEG C of filter cake is dried in vacuo to obtain 35mg off-white powders, yield：62.8%, mp：230.2~235.7 DEG C, m/z：
447.9[(M-CH3COOH)+H]+, 446.9 [M-CH3COOH]+。
The preparation of 13 formula of embodiment (I) compound tosilate
Formula (I) compound (0.11mmol), 2ml methanol and 8ml dichloromethane prepared by 50mg embodiments 1 are added to anti-
It answers in bottle, 20~30 DEG C of stirring clarifications are added at one time the mixing of 28mg p-methyl benzenesulfonic acid (0.163mmol) and 0.5ml methanol
Solution, solution clarification, 20~30 DEG C of insulated and stirred half an hour, 10ml dichloromethane 20~30 is added in 50 DEG C of evaporated under reduced pressure solvents
DEG C stirring half an hour, filtering, 50 DEG C of filter cake is dried in vacuo to obtain 34mg off-white powders, yield：50%, mp：235.3~237.3
DEG C, m/z：447.9[(M-C7H8O3S)+H]+, 446.9 [M-C7H8O3S]+。
The preparation of 14 formula of embodiment (I) compound palmitate
Formula (I) compound (0.11mmol), 2ml methanol and 8ml dichloromethane prepared by 50mg embodiments 1 are added to anti-
It answers in bottle, 20~30 DEG C of stirring clarifications are added at one time the mixed solution of 42mg palmitic acids (0.164mmol) and 0.5ml methanol,
Solution is clarified, 20~30 DEG C of insulated and stirred half an hour, and 1ml dichloromethane and 10ml n-hexanes is added in 50 DEG C of evaporated under reduced pressure solvents
20~30 DEG C of stirring half an hour, filtering, 50 DEG C of filter cake are dried in vacuo to obtain 65mg off-white powders, yield：84%, mp：240.3~
244.5 DEG C, m/z：447.9[(M-C16H32O2)+H]+, 446.9 [M-C16H32O2]+。
The preparation of 15 formula of embodiment (I) compound fumarate
Formula (I) compound (0.11mmol), 2ml methanol and 8ml dichloromethane prepared by 50mg embodiments 1 are added to anti-
It answers in bottle, 20~30 DEG C of stirring clarifications are added at one time the mixing of 19mg fumaric acid (0.164mmol) and 0.5ml methanol
Solution, solution slowly become cloudy, 20~30 DEG C of insulated and stirred half an hour, and filtering, 50 DEG C of filter cake is dried in vacuo to obtain 50mg off-white colors
Solid, yield：80.8%, mp：233.1~237.5 DEG C, m/z：447.9[(M-C4H4O4)+H]+, 446.9 [M-C4H4O4]+。
The preparation of 16 formula of embodiment (I) compound L-tartrate
Formula (I) compound (0.11mmol), 2ml methanol and 8ml dichloromethane prepared by 50mg embodiments 1 are added to anti-
It answers in bottle, 20~30 DEG C of stirring clarifications, the mixing for being added at one time 25mgL- tartaric acid (0.167mmol) and 0.5ml methanol is molten
Liquid, solution slowly become cloudy, 20~30 DEG C of insulated and stirred half an hour, filtering, 50 DEG C of filter cake be dried in vacuo 52mg off-white colors are solid
Body, yield：60.9%, mp：24 0.1~243.1 DEG C, m/z：447.9[(M-C4H6O6)+H]+, 446.9 [M-C4H6O6]+。
The preparation of 17 formula of embodiment (I) compound ascorbate
Formula (I) compound (0.11mmol), 2ml methanol and 8ml dichloromethane prepared by 50mg embodiments 1 are added to anti-
It answers in bottle, 20~30 DEG C of stirring clarifications, the mixing for being added at one time 29mg ascorbic acid (0.165mmol) and 0.5ml methanol is molten
Liquid, solution clarification, 20~30 DEG C of insulated and stirred half an hour, 10ml dichloromethane and 10ml is being added just in 50 DEG C of evaporated under reduced pressure solvents
20~30 DEG C of stirring half an hour of hexane, filtering, 50 DEG C of filter cake are dried in vacuo to obtain 53mg off-white powders, yield：77.4%, mp：
232.3~235.4 DEG C, m/z：447.9[(M-C6H8O6)+H]+, 446.9 [M-C6H8O6]+。
The preparation of 18 formula of embodiment (I) compound hydrochloride
Formula (I) compound (0.11mmol) prepared by 50mg embodiments 1,2mlDMSO and 8ml tetrahydrofurans are added to anti-
It answers in bottle, 20~30 DEG C of stirring clarifications are added at one time 230ul0.5N hydrogen chloride methanol solutions (0.165mmol), solution is slowly
It becomes cloudy, 20~30 DEG C of insulated and stirred half an hour, filters, 50 DEG C of filter cake is dried in vacuo to obtain 32mg off-white powders, yield：
59.2%, mp：232.3~235.4 DEG C.m/z：447.9 [(M-HCl)+H]+, 446.9 [M-HCl]+.
The compound wherein, being prepared its mass spectrogram,1HNMR (400MHz, DMSO-d6) spectrogram, X ray diffracting spectrum
Corresponding collection of illustrative plates is similar to embodiment 2.
The preparation of 19 formula of embodiment (I) compound hydrochloride
Formula (I) compound (0.11mmol) prepared by 50mg embodiments 1,2mlDMF and 8ml acetone are added to reaction bulb
In, 20~30 DEG C of stirring clarifications are added at one time 230ul0.5N hydrogen chloride methanol solutions (0.165mmol), solution slowly becomes muddy
It is turbid, it 20~30 DEG C of insulated and stirred half an hour, filters, 50 DEG C of filter cake is dried in vacuo to obtain 40mg off-white powders, yield：74%, mp：
232.3~235.4 DEG C, m/z：447.9 [(M-HCl)+H]+, 446.9 [M-HCl]+.
The compound wherein, being prepared its mass spectrogram,1HNMR (400MHz, DMSO-d6) spectrogram, X ray diffracting spectrum
Corresponding collection of illustrative plates is similar to embodiment 2.
The preparation of 20 formula of embodiment (I) compound hydrochloride
Formula (I) compound (0.11mmol), 2ml ethyl alcohol and 8ml acetonitriles prepared by 50mg embodiments 1 are added to reaction bulb
In, 50~60 DEG C are heated to, 230ul0.5N hydrogen chloride methanol solutions (0.165mmol) are added at one time, solution slowly becomes muddy
It is turbid, 50~60 DEG C of insulated and stirreds 5 hours, after be cooled to 20~30 DEG C of stirring half an hour filterings, 50 DEG C of filter cake is dried in vacuo
20mg off-white powders, yield：37%, mp：232.3~235.4 DEG C, m/z：447.9 [(M-HCl)+H]+, 446.9 [M-HCl]
+。
The compound wherein, being prepared its mass spectrogram,1HNMR (400MHz, DMSO-d6) spectrogram, X ray diffracting spectrum
Corresponding collection of illustrative plates is similar to embodiment 2.
The preparation of 21 formula of embodiment (I) compound hydrochloride
Formula (I) compound (0.11mmol), 2ml propyl alcohol and 4ml butanol prepared by 50mg embodiments 1 are added to reaction bulb
In, 70~80 DEG C are heated to, 44ul0.25N hydrogen chloride methanol solutions (0.011mmol) are added at one time, solution slowly becomes muddy
It is turbid, 70~80 DEG C of insulated and stirreds 10 hours, after be cooled to 20~30 DEG C of stirring half an hour filterings, 50 DEG C of filter cake is dried in vacuo
2mg off-white powders, yield：3.7%, mp：232.3~235.4 DEG C, m/z：447.9 [(M-HCl)+H]+, 446.9 [M-HCl]
+。
The compound wherein, being prepared its mass spectrogram,1HNMR (400MHz, DMSO-d6) spectrogram, X ray diffracting spectrum
Corresponding collection of illustrative plates is similar to embodiment 2.
The preparation of 22 formula of embodiment (I) compound hydrochloride
Formula (I) compound (0.11mmol) prepared by 50mg embodiments 1,2mlNMP and 4ml ethyl acetate are added to anti-
It answers in bottle, 20~30 DEG C of stirring clarifications are added at one time 550ul2N hydrogen chloride methanol solutions (1.1mmol), solution slowly becomes muddy
Turbid, 20~30 DEG C of insulated and stirreds 24 hours, filtering, 50 DEG C of filter cake is dried in vacuo to obtain 25mg off-white powders, yield：46.2%,
mp：232.3~235.4 DEG C, m/z：447.9 [(M-HCl)+H]+, 446.9 [M-HCl]+.
The compound wherein, being prepared its mass spectrogram,1HNMR (400MHz, DMSO-d6) spectrogram, X ray diffracting spectrum
Corresponding collection of illustrative plates is similar to embodiment 2.
The preparation of 23 formula of embodiment (I) compound hydrochloride
Formula (I) compound (0.11mmol) prepared by 50mg embodiments 1,8mlNMP and 1ml water are added into reaction bulb,
20~30 DEG C of stirring clarifications, are added at one time 367ul1.5N hydrogen chloride methanol solutions (0.55mmol), and solution slowly becomes cloudy,
20~30 DEG C of insulated and stirreds 24 hours, filtering, 50 DEG C of filter cake are dried in vacuo to obtain 15mg off-white powders, yield：27.7%, mp：
232.3~235.4 DEG C, m/z：447.9 [(M-HCl)+H]+, 446.9 [M-HCl]+.
The compound wherein, being prepared its mass spectrogram,1HNMR (400MHz, DMSO-d6) spectrogram, X ray diffracting spectrum
Corresponding collection of illustrative plates is similar to embodiment 2.
The preparation of 24 formula of embodiment (I) compound hydrochloride
Formula (I) compound (0.11mmol) and 8mlNMP prepared by 50mg embodiments 1 are added into reaction bulb, stirred,
200 DEG C are heated to, 367ul1.5N hydrogen chloride methanol solutions (0.55mmol) are added at one time, 90~100 DEG C of insulated and stirreds 2 are small
When, it is then cooled to 20~30 DEG C of stirrings and filters for 1 hour, 50 DEG C of filter cake is dried in vacuo to obtain 10mg off-white powders, yield：
18.5%, mp：232.3~235.4 DEG C, m/z：447.9 [(M-HCl)+H]+, 446.9 [M-HCl]+.
The compound wherein, being prepared its mass spectrogram,1HNMR (400MHz, DMSO-d6) spectrogram, X ray diffracting spectrum
Corresponding collection of illustrative plates is similar to embodiment 2.
The preparation of 25 formula of embodiment (I) compound hydrochloride
Formula (I) compound (0.11mmol) and 20mlNMP prepared by 50mg embodiments 1 are added into reaction bulb, stirred,
Ice bath is cooled to 0 DEG C, is added at one time 110ul1N hydrogen chloride methanol solutions (0.11mmol), 0 DEG C of insulated and stirred 2 hours, mistake
Filter, 50 DEG C of filter cake are dried in vacuo to obtain 13mg off-white powders, yield：24%, mp：232.3~235.4 DEG C.m/z：447.9[(M-
HCl)+H]+, 446.9 [M-HCl]+.
The compound wherein, being prepared its mass spectrogram,1HNMR (400MHz, DMSO-d6) spectrogram, X ray diffracting spectrum
Corresponding collection of illustrative plates is similar to embodiment 2.
The preparation of 26 formula of embodiment (I) compound hydrochloride
Formula (I) compound (0.11mmol) prepared by 50mg embodiments 1,2mlDMF and 8ml acetone are added to reaction bulb
In, 20~30 DEG C of stirring clarifications are added at one time 55ul1N hydrogen chloride methanol solutions (0.055mmol), and solution slowly becomes cloudy,
20~30 DEG C of insulated and stirred half an hour, filtering, 50 DEG C of filter cake are dried in vacuo to obtain 18mg off-white powders, yield：33.3%, mp：
236.1~239.4 DEG C, m/z：446.9[(M-HCl)+H]+.
Wherein, formula (I) compound hydrochloride being prepared be crystal, mass spectrogram,1HNMR (400MHz, DMSO-d6)
Corresponding collection of illustrative plates is similar to X ray diffracting spectrum to embodiment 2 for spectrogram.
The preparation of 27 formula of embodiment (I) compound hydrochloride
Formula (I) compound (0.11mmol) prepared by 50mg embodiments 1,2mlDMF and 8ml acetone are added to reaction bulb
In, 50~60 DEG C are heated to, 110ul1N hydrogen chloride methanol solutions (0.11mmol) are added at one time, solution slowly becomes cloudy, and 50
~60 DEG C of insulated and stirreds 5 hours, after be cooled to 20~30 DEG C of stirring half an hour filterings, 50 DEG C of filter cake be dried in vacuo 38mg classes are white
Color solid, yield：70.3%, mp：236.1~239.4 DEG C, m/z：446.9[(M-HCl)+H]+.
Wherein, formula (I) compound hydrochloride being prepared be crystal, mass spectrogram,1HNMR (400MHz, DMSO-d6)
Corresponding collection of illustrative plates is similar to X ray diffracting spectrum to embodiment 2 for spectrogram.
The preparation of 28 formula of embodiment (I) compound hydrochloride
Formula (I) compound (0.11mmol) and 2mlDMF and 8ml acetone prepared by 50mg embodiments 1 are added to reaction bulb
In, stirring, ice bath is cooled to 0 DEG C, is added at one time 230ul0.5N hydrogen chloride methanol solutions (0.165mmol), and 0 DEG C of heat preservation is stirred
It mixes 2 hours, filters, 50 DEG C of filter cake is dried in vacuo to obtain 22mg off-white powders, yield：40.7%, mp：236.1~239.4 DEG C,
m/z：446.9[(M-HCl)+H]+.
Wherein, formula (I) compound hydrochloride being prepared be crystal, mass spectrogram,1HNMR (400MHz, DMSO-d6)
Corresponding collection of illustrative plates is similar to X ray diffracting spectrum to embodiment 2 for spectrogram.
1 solubility experiment of experimental example
It weighs and prepares formula (I) compound and its appropriate salt in embodiment 1-17, be suspended in 3ml water, each parallel laboratory test 2
Part, it sets in constant temperature oscillator, for 24 hours, 0.22 μm of hydrophylic filter membranes is crossed in sampling to 37 DEG C of constant temperature oscillations, and drug concentration, meter are measured with HPLC
Calculate solubility.
Wherein, chromatographic condition is as follows：
HPLC：Waters 2695UV detectors
Chromatographic column：C18
Column temperature：25℃
Detection wavelength：301nm
Sampling volume：10μl
Mobile phase A：0.1%TFA-water
Mobile phase B：0.1%TFA-CAN
Gradient elution program is as shown in table 2, formula (I) compound that is prepared in embodiment 1-17 and its various salt form
Solubility is as shown in table 3：
2 gradient elution program of table
3 formula of table (I) compound and its various salt form solubility experiment results
The result shows that the hydrochloride salt degree of formula (I) compound is significantly higher than other salt form, there is excellent solubility.
2 draws moist test of experimental example
According to《Chinese Pharmacopoeia》The two annex XIX J's of version in 2010《Drug draws moist test guideline》It is tried
It tests, calculate separately sample (formula (I) compound and its various salt form that embodiment 1-17 is prepared) draws wet weightening, as a result such as
Shown in table 4.
4 formula of table (I) compound and its each salt form hygroscopicity test result
The result shows that the hydrochloride of formula (I) compound draws moist substantially less than other salt form.
3 stability test of experimental example
According to《Chinese Pharmacopoeia》The two annex XIX C's of version in 2010《Bulk pharmaceutical chemicals are instructed with pharmaceutical preparation stability test
Principle》It is tested, measures the solution of formula (I) compound and its various salt form that embodiment 1-17 is prepared in high temperature (60
DEG C), the increase situation of related substance under illumination (illumination be 45001x ± 500lx), assess its stability.
Wherein, related substance-measuring method is as follows：
HPLC：Waters 2695UV detectors
(2) 5 μm of chromatographic column Diamonsil C18,150 × 4.6mm
Detection wavelength：301nm
Column temperature：30℃
Sampling volume：10μl
Mobile phase A：Methanol
Mobile phase B：Buffer salt (900ml water+10ml triethylamine+5ml phosphoric acid, 1000ml is settled to water)
Gradient elution program is as shown in table 5：
5 gradient elution program of table
Test sample uses acetonitrile-water (1:1) solution is prepared, a concentration of 10-100 μ g/ml, respectively in high temperature (60 DEG C), light
According to being investigated 10 days under (illumination is 45001x ± 500lx), measures 0 day and 10 days related amount of substance and (normalized using peak area
Method calculates), the results are shown in Table 6.
6 Stability Determination result of table
The result shows that the hydrochloric acid salt-stable of formula (I) compound is significantly higher than other salt form.
4 pharmacokinetic trial of experimental example
Three kinds of high salt of formula (I) compound and its solubility that selection example is prepared (i.e. make by embodiment 2,10,12
Standby obtained hydrochloride, mesylate and acetate) carry out Pharmacokinetic experiments.
SD rats 48, male, weight 200-220g are randomly divided into 8 groups, and every group 6, gavage and intravenous injection respectively is given
Give formula (I) compound, the hydrochloride of formula (I) compound, the acetate of formula (I) compound and formula (I) compound mesylate,
Specific arrangement is as shown in table 7：
7 experimental program of table
Gastric infusion：2%HPMC
Intravenously administrable：20%PEG400 is configured to solution
Fasting 12h, free water before experiment；2h is unified after administration feeds.
Blood sampling time point：5min (only intravenously administrable) after administration, 0.25min, 0.5min, 1.0min, 2.0min,
4.0min, 6.0min, 8.0min and for 24 hours；
Sample treatment：In the above setting time point through rat eye rear vein beard extracting vein blood 0.3ml, heparinised tubes are set
In, 11000rpm centrifuges 5min, and separated plasma freezes in -20 DEG C of refrigerators.
Sample test and data analysis：
The concentration of original shape drug in rat plasma is measured using LC/MS/MS methods.
The medicine generation after administration is calculated using the non-compartment model of 5.3 softwares of WinNonlin (Pharsight companies of the U.S.)
Kinetic parameter calculates absolute bioavailability, and calculation formula is as follows, and the results are shown in Table 8：
F=(AUCGavage×DVein)/(AUCVein×DGavage) × 100%
Wherein, F：Absolute bioavailability；AUC：Area under the drug-time curve；D：Medication dose
8 Absolute oral of table utilizes result
The result shows that the hydrochloride bioavilability of formula (I) compound is significantly higher than other salt form.
Experimental example 5PIM kinase activities measure
It entrusts the Shanghai bio tech ltd Run Nuo to carry out the dose-response experiments of PIM1, PIM2 and PIM3, sets altogether
6 concentration gradients are set, initial concentration 30nM, 200nM and 30nM, then gradient dilution successively, verification compound is to PIM enzymes
Inhibiting effect, the results are shown in Table 9.
9 compound of table is to PIM kinase activity test results
The result shows that the hydrochloride of formula (I) compound has very high PIM kinase inhibiting activities.
Claims (24)
1. the hydrochloride of compound shown in a kind of formula (I), shown in structure such as formula (II)：
2. hydrochloride according to claim 1, which is characterized in that the hydrochloride is crystal.
3. hydrochloride according to claim 2, which is characterized in that wrapped in the X ray diffracting spectrum of the hydrochloric acid salt crystal
Include the diffraction maximum of the angles following 2 θ expression：5.5±0.2°、8.5±0.2°、9.8±0.2°、17.2±0.2°、23.1±0.2°、
25.5±0.2°、27.8±0.2°。
4. hydrochloride according to claim 3, which is characterized in that in the X ray diffracting spectrum of the hydrochloric acid salt crystal also
The diffraction maximum indicated including the angles following 2 θ：13.6±0.2°、20.9±0.2°、26.7±0.2°、30.0±0.2°、34.2±
0.2°。
5. hydrochloride according to claim 3, which is characterized in that X ray diffracting spectrum such as Fig. 3 of the hydrochloric acid salt crystal
It is shown.
6. the method for the hydrochloride of compound, feature shown in a kind of formula (I) prepared described in any one of claim 1 to 5
It is, the described method comprises the following steps：Compound shown in formula (I) is dissolved in solvent, controlling reaction temperature, hydrogen chloride is added
Solid is precipitated in methanol solution, insulation reaction 0~24 hour, reaction solution, filters, vacuum drying.
7. according to the method described in claim 6, it is characterized in that, controlling reaction temperature is 0~30 DEG C.
8. the method according to the description of claim 7 is characterized in that controlling reaction temperature is 0 DEG C or 20~30 DEG C.
9. according to the method described in claim 6, it is characterized in that, be added hydrogen chloride methanol solution after, insulation reaction 30 minutes
To 24 hours.
10. according to the method described in claim 9, it is characterized in that, after hydrogen chloride methanol solution is added, insulation reaction 30 is divided
Clock.
11. according to the method described in claim 6, it is characterized in that, vacuum drying temperature is 50 DEG C.
12. the method according to any one of claim 6 to 11, which is characterized in that the solvent is selected from methanol, dichloromethane
Alkane, dimethyl sulfoxide (DMSO), tetrahydrofuran, dimethylformamide, acetone, ethyl alcohol, acetonitrile, propyl alcohol, butanol, N-Methyl pyrrolidone,
It is one or more in ethyl acetate and water.
13. according to the method for claim 12, which is characterized in that it is sub- that the solvent is selected from methanol, dichloromethane, dimethyl
One kind in sulfone, tetrahydrofuran, dimethylformamide, acetone, ethyl alcohol, acetonitrile, N-Methyl pyrrolidone, ethyl acetate and water or
It is a variety of.
14. according to the method for claim 12, which is characterized in that the solvent is methanol and dichloromethane, and dimethyl is sub-
Sulfone and tetrahydrofuran, dimethylformamide and acetone, ethyl alcohol and acetonitrile, N-Methyl pyrrolidone and ethyl acetate, N- methyl pyrroles
Pyrrolidone and water or N-Methyl pyrrolidone.
15. according to the method for claim 12, which is characterized in that the solvent is dimethylformamide and acetone.
16. according to the method described in claim 6, it is characterized in that, a concentration of 0.25mol/L of the hydrogen chloride methanol solution
~2mol/L.
17. according to the method for claim 16, which is characterized in that a concentration of 0.5mol/L of the hydrogen chloride methanol solution
~1mol/L.
18. according to the method described in claim 6, it is characterized in that, the hydrogen chloride methanol solution and compound shown in formula (I)
Molar ratio be 0.1~10：1.
19. according to the method for claim 17, which is characterized in that the hydrogen chloride methanol solution and chemical combination shown in formula (I)
The molar ratio of object is 1~1.5：1.
20. a kind of pharmaceutical composition, which is characterized in that described pharmaceutical composition contains described in any one of claim 1 to 5
The hydrochloride of compound is as active ingredient shown in formula (I).
21. pharmaceutical composition according to claim 20, which is characterized in that described pharmaceutical composition includes that can pharmaceutically connect
The carrier or excipient received.
22. pharmaceutical composition according to claim 20, described pharmaceutical composition is tablet, capsule, pill, particle
Agent, powder, suppository, injection, solution, suspension, paste, patch, lotion, drops, liniment or spray.
23. any one of the hydrochloride of formula (I) compound described in any one of claim 1 to 5 or claim 20 to 22
The pharmaceutical composition is being prepared for the purposes in treating the drug of the disease caused because PIM kinases over-expresses.
24. purposes according to claim 23, which is characterized in that the disease includes tumour, autoimmune disease, mistake
Rejection disease caused by quick property reaction disease, atherosclerosis disease and organ transplant.
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| CN102203079A (en) * | 2008-09-02 | 2011-09-28 | 诺瓦提斯公司 | Picolinamide derivatives as kinase inhibitors |
| CN102924446A (en) * | 2011-08-11 | 2013-02-13 | 上海吉铠医药科技有限公司 | PIM kinase inhibitor, preparation method thereof, and application thereof in pharmacy |
| WO2014033631A1 (en) * | 2012-08-31 | 2014-03-06 | Novartis Ag | N-(3-pyridyl) biarylamides as kinase inhibitors |
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| CN102203079A (en) * | 2008-09-02 | 2011-09-28 | 诺瓦提斯公司 | Picolinamide derivatives as kinase inhibitors |
| CN102924446A (en) * | 2011-08-11 | 2013-02-13 | 上海吉铠医药科技有限公司 | PIM kinase inhibitor, preparation method thereof, and application thereof in pharmacy |
| WO2014033631A1 (en) * | 2012-08-31 | 2014-03-06 | Novartis Ag | N-(3-pyridyl) biarylamides as kinase inhibitors |
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