CN109705090B - Tartaric acid addition salts of 3, 4-disubstituted 1H-pyrazole compounds and crystalline forms thereof - Google Patents
Tartaric acid addition salts of 3, 4-disubstituted 1H-pyrazole compounds and crystalline forms thereof Download PDFInfo
- Publication number
- CN109705090B CN109705090B CN201811079167.6A CN201811079167A CN109705090B CN 109705090 B CN109705090 B CN 109705090B CN 201811079167 A CN201811079167 A CN 201811079167A CN 109705090 B CN109705090 B CN 109705090B
- Authority
- CN
- China
- Prior art keywords
- addition salt
- tartaric acid
- acid addition
- solvent
- powder diffraction
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
Images
Abstract
The present invention provides pharmaceutical compositions of one or more 4- (2, 6-dichloro-benzoylamino) -1H-pyrazole-3-carboxylic acid piperidin-4-yl-tartaric acid addition salts, crystalline forms of the tartaric acid addition salts, and the use of compositions comprising the crystalline forms of the tartaric acid addition salts in the prevention and treatment of diseases or disorders mediated by cyclin dependent kinases.
Description
Technical Field
The present invention relates to tartaric acid addition salts of 4- (2, 6-dichloro-benzoylamino) -1H-pyrazole-3-carboxylic acid piperidin-4-ylamide and crystalline forms thereof, methods of preparing the acid addition salts and crystalline forms thereof.
Background
Cyclin-dependent kinases (cyclin dependent kinase, CDKs) are key kinases for cell cycle regulation and are involved in physiological processes such as cell proliferation, transcription, survival, etc. Modulation of the expression levels, degradation rates and activation levels of the various CDKs and cyclin throughout the cell cycle results in the cyclic formation of a series of CDK/cyclin complexes, the formation of which is passaged through discrete cell cycle checkpoints, thereby enabling the process of cell division to continue. CDK functions can be largely divided into two major classes. One class of CDKs is involved in cell cycle regulation, mainly including CDK1, CDK2, CDK4, CDK6, and the like. Retinoblastoma protein (retinoblastoma protein, RB) binds to and inhibits the activity of transcription factor E2F without external signal stimulation, inhibits proliferation, and puts the cells in G0 phase. Under the stimulation of external mitosis signals, the cells enter the G1 phase, the synthesis of cyclin D is increased, the cyclin D is combined with CDK4/6, RB is phosphorylated, the inhibition of E2F is partially released, and the expression of proteins cyclin E and the like required by cycle progression is increased. In the late G1 phase, cyclin E binds to CDK2, further phosphorylating RB, and E2F activity is fully released, and the cell passes through the G1/S restriction site and enters the S phase. At this time, cyclin A replaces cyclin E to bind CDK2 and participate in DNA replication. In the S later stage, cyclin A forms a complex with CDK1, drives mitosis to proceed, promotes cells to pass through the M stage, and finally completes the mitosis process of the cells.
Another broad class of CDKs are involved in transcriptional regulation, including predominantly CDK7, CDK8, CDK9, CDK10, CDK11, and the like. CDK7/cyclin H, CDK8/cyclin C, CDk9/cyclin T regulate transcription by modulating RNA polymerase II phosphorylation. Wherein CDK7/cyclin H also comprises CDK-activated kinase (CDK activating kinase, CAK) which modulates CDK activity. CDK3/cyclin C can regulate RB phosphorylation, participate in G0/G1 transition, and can also phosphorylate activated replication factor 1 (activating transcription factor, ATF 1) to improve the level of activation. CDK10/cyclin M regulates transcription by phosphorylating transcription factor Ets.
In addition, CDK2 is a very critical cyclin-dependent kinase that completes the G1 phase into the S phase, CDK2 binds to cyclin E and activates, maintaining phosphorylation of pr b in the G1 later phase, ensuring that cells pass smoothly through the G1 phase and into the S phase. In the early stages of S phase CDK2 binds to cyclin a to inactivate the E2F transcription factor, whereas inactivation of E2F is a prerequisite for completion of S phase, and the duration of E2F activity will lead to apoptosis. Thus, selective inhibition of CD-view/cyclin a may lead to an increase in E2F concentration, which in turn leads to arrest or apoptosis of the S phase of the cell. Whereas CDK5 differs from CDK in the traditional sense in that its regulatory subunits are not cyclin, but p35 and p39, studies now show that CDK5 is also involved in many processes such as tumor development and expansion-related proliferation, survival and epithelial mesenchymal transition.
In mammalian cells, CDK monomers are inactive and only bind to the corresponding regulatory subunit cyclin to become active in a stable conformation. Intracellular CDK expression is generally constant, but cyclin is expressed and degraded periodically at different stages of the cell cycle, and this pattern of cyclin expression determines the ordered activation of different CDKs. Cyclin regulates subcellular localization of CDKs and recognizes specific substrates through specific anchor sites, functioning as phosphorylations.
In tumor cells, cyclin overexpression or overactivation, CDK1 activity is inhibited, upstream division signals are continuously activated, etc. all cause the CDK activity to change. Deregulation of CDK activity directly or indirectly causes uncontrolled cell proliferation, genomic instability (increased DNA mutations, chromosomal deletions, etc.), chromosomal instability (variation in chromosome number), etc., and is involved in the development of tumors. Since CDK activity is essential for cell division, there is often an increase in CDK activity in tumors. CDK inhibitors currently undergoing clinical or preclinical studies can be broadly classified into ATP-competitive and non-competitive inhibitors, depending on the mechanism of action.
Among them, the compound 4- (2, 6-dichloro-benzoylamino) -1H-pyrazole-3-carboxylic acid piperidin-4-ylamide (original name AT7519, hereinafter referred to as AT 7519) according to the present invention is disclosed for the first time in International patent application No. PCT/GB2004/003179 (publication No. WO 2005/012356), which discloses that the compound has an inhibitory activity against cyclin dependent kinase (CDK kinase). Which can inhibit CDK1, CDK2, CDK4 and CDK9. And, the compound also has activity against glycogen synthase kinase-3 (GSK-3).
In International application PCT/GB 2006/000207 (publication No. WO 2006/077426), the mesylate salt of this compound and its crystalline form are disclosed, and it is claimed that the mesylate salt has better solubility, more stable properties and the like.
Disclosure of Invention
The object of the present invention is to provide pharmaceutical compositions of one or more 4- (2, 6-dichloro-benzoylamino) -1H-pyrazole-3-carboxylic acid piperidin-4-yl-tartaric acid addition salts, crystalline forms of the tartaric acid addition salts, and the use of tartaric acid addition salt compositions comprising the crystalline forms in the prevention and treatment of diseases or disorders mediated by cyclin dependent kinases. The 4- (2, 6-dichloro-benzoylamino) -1H-pyrazole-3-carboxylic acid piperidin-4-yl-tartaric acid addition salt is prepared by the present inventors by reacting 4- (2, 6-dichloro-benzoylamino) -1H-pyrazole-3-carboxylic acid piperidin-4-yl-acyl free base with tartaric acid, hereinafter referred to as "tartaric acid addition salt".
In a first aspect of the invention, there is provided a tartaric acid addition salt of 4- (2, 6-dichloro-benzoylamino) -1H-pyrazole-3-carboxylic acid piperidin-4-yl acyl.
As a preferred embodiment, the tartaric acid addition salt is in crystalline form.
In some embodiments, the crystalline Form of the tartaric acid addition salt is Form I crystals.
The Form I crystals have characteristic peaks in terms of 2θ (°) in X-ray powder diffraction (XRD) spectra using Cu-ka radiation of about 17.7±0.2, 19.1±0.2 and 26.2±0.2.
As a preferred mode, the Form I crystals have an X-ray powder diffraction (XRD) spectrum expressed in terms of 2 theta (°) using Cu-K alpha radiation with characteristic peaks at about one, two or three of 12.7 + -0.2, 13.02 + -0.2 or 16.4 + -0.2.
As a preferred mode, the Form I crystals have an X-ray powder diffraction (XRD) spectrum expressed in terms of 2 theta (°) using Cu-K alpha radiation with characteristic peaks at about one, two or three of 20.4 + -0.2, 21.6 + -0.2 or 24.5 + -0.2.
As a preferred mode, the Form I crystals have characteristic peaks in terms of 2 theta (°) at about 12.7.+ -. 0.2, 13.3.+ -. 0.2, 16.4.+ -. 0.2, 17.7.+ -. 0.2, 19.1.+ -. 0.2, 20.4.+ -. 0.2, 21.6.+ -. 0.2, 24.5.+ -. 0.2 and 26.2.+ -. 0.2 by X-ray powder diffraction (XRD) spectrum using Cu-K alpha radiation.
As a preferred mode, the Form I crystal has an X-ray powder diffraction (XRD) spectrum in terms of 2θ (°) using Cu-ka radiation, having an X-ray powder diffraction pattern as shown in fig. 1.
As a preferred mode, the Form I crystals have a DSC endotherm transition from about 194 to about 200deg.C.
In other embodiments, the crystalline tartaric acid addition salt is Form II crystals.
As a preferred mode, the Form II crystals have characteristic peaks in terms of 2 theta (°) at about 7.0.+ -. 0.2, 10.5.+ -. 0.2 and 21.8.+ -. 0.2 of the X-ray powder diffraction (XRD) spectrum using Cu-K alpha radiation.
As a preferred mode, the Form II crystals have an X-ray powder diffraction (XRD) spectrum expressed in terms of 2 theta (°) using Cu-K alpha radiation with characteristic peaks at about one, two or three of 13.0.+ -. 0.2, 17.4.+ -. 0.2 or 14.0.+ -. 0.2.
As a preferred mode, the Form II crystals have an X-ray powder diffraction (XRD) spectrum expressed in terms of 2 theta (°) using Cu-K alpha radiation with characteristic peaks at about one, two or three of 23.5 + -0.2, 18.6 + -0.2 or 24.8 + -0.2.
As a preferred mode, the Form II crystals have characteristic peaks in terms of 2 theta (°) at about 7.0.+ -. 0.2, 10.5.+ -. 0.2, 21.8.+ -. 0.2, 13.0.+ -. 0.2, 17.4.+ -. 0.2, 14.0.+ -. 0.2, 23.5.+ -. 0.2, 18.6.+ -. 0.2 and 24.8.+ -. 0.2 in X-ray powder diffraction (XRD) spectrum using Cu-K alpha radiation.
As a preferred mode, the Form II crystal has an X-ray powder diffraction (XRD) spectrum in terms of 2θ (°) using Cu-ka radiation, having an X-ray powder diffraction pattern as shown in fig. 4.
As a preferred mode, the Form II crystals have a DSC endotherm transition of about 107-127 ℃.
In other embodiments, the crystalline tartaric acid addition salt is Form III crystals.
In a preferred Form, the Form III crystals have characteristic peaks in terms of 2 theta (°) in the X-ray powder diffraction (XRD) spectrum of about 11.0.+ -. 0.2, 14.4.+ -. 0.2, 22.6.+ -. 0.2 using Cu-K alpha radiation.
As a preferred mode, the Form III crystals have an X-ray powder diffraction (XRD) spectrum expressed in terms of 2 theta (°) using Cu-K alpha radiation with characteristic peaks at about one, two or three of 15.8 + -0.2, 18.4 + -0.2, 23.2 + -0.2.
As a preferred mode, the Form III crystals have an X-ray powder diffraction (XRD) spectrum expressed in terms of 2 theta (°) using Cu-K alpha radiation with characteristic peaks at about one or two or three of 16.2 + -0.2, 26.5 + -0.2, 28.2 + -0.2.
As a preferred mode, the Form III crystals have characteristic peaks in terms of 2 theta (°) at about 11.0.+ -. 0.2, 14.4.+ -. 0.2, 22.6.+ -. 0.2, 15.8.+ -. 0.2, 18.4.+ -. 0.2, 16.2.+ -. 0.2, 23.2.+ -. 0.2, 26.5.+ -. 0.2, 28.2.+ -. 0.2 by X-ray powder diffraction (XRD) spectrum using Cu-K alpha radiation.
As a preferred mode, the Form III crystal has an X-ray powder diffraction (XRD) spectrum in terms of 2θ (°) using cu—kα radiation, having an X-ray powder diffraction pattern as shown in fig. 7.
As a preferred mode, the Form III crystals have a DSC endotherm transition of about 116-135 ℃.
In another aspect of the invention, a process for preparing the tartaric acid addition salt forms is provided.
As a preferred embodiment, the process for preparing Form I of the tartaric acid addition salt comprises adding the tartaric acid addition salt to a quantity of a suitable solvent and centrifuging with stirring to obtain a solid.
Preferably, the solvent is selected from alcohols, nitriles, ketones, esters, ethers, aromatics, halogenated hydrocarbons, or alkane solvents.
In some embodiments, the alcoholic solvents are methanol, ethanol, and propanol; the nitrile solvent is acetonitrile; the ketone solvent is acetone and methyl isobutyl ketone; the esters are ethyl acetate and isopropyl acetate; the ethers are methyl tertiary butyl ether, tetrahydrofuran and 1, 4-dioxane; the aromatic is toluene; the halohydrocarbon is dichloromethane and chloroform; the alkane is n-heptane.
Preferably, the solvent is a mixture of one or more of the above solvents in any ratio.
Preferably, the reaction temperature is-20 to 60 ℃.
In some embodiments, the temperature is preferably 25 ℃.
As a preferred scheme, the preparation method of the Form II crystal Form of the tartaric acid addition salt comprises the following steps:
the method comprises the following steps: dissolving the tartaric acid addition salt in a certain amount of proper solvent, filtering, and volatilizing at a certain temperature to obtain a solid.
Preferably, the suitable solvent is preferably methanol; the temperature is preferably 50 ℃.
The second method is as follows: stirring the tartaric acid addition salt in a proper solvent at high temperature, and centrifuging to obtain a solid.
Preferably, the temperature is 80 ℃; the solvent is selected from acetylacetone, benzonitrile or a mixture of the acetylacetone and the benzonitrile in any proportion.
In another aspect of the invention, a pharmaceutical composition is provided comprising a therapeutically effective amount of the tartaric acid addition salt.
As a preferred mode, the pharmaceutical composition is an injection.
As a preferred mode, the content of the tartaric acid addition salt in the pharmaceutical composition is 0.001% -0.1%, preferably 0.01% -0.05%.
As a preferred mode, the pharmaceutical composition further comprises a pharmaceutically acceptable excipient, wherein the excipient is cyclodextrin or a derivative thereof, and the cyclodextrin or the derivative thereof is selected from hydroxypropyl-beta-cyclodextrin, dihydroxyl-beta-cyclodextrin, hydroxyethyl-beta-cyclodextrin, 2-hydroxypropyl-beta-cyclodextrin, 3-hydroxypropyl-beta-cyclodextrin, 2, 3-dihydroxypropyl-beta-cyclodextrin, 2,3, 6-trihydroxypropyl-beta-cyclodextrin or sodium sulfobutyl-beta-cyclodextrin. Sodium sulfobutyl-beta-cyclodextrin is preferred.
As a preferred mode, when the pharmaceutical composition is prepared into injection, the auxiliary materials also comprise water and additives, and the additives are not limited to one or more of pH regulator, antibacterial agent, antioxidant, cosolvent, osmotic pressure regulator, emulsifier, stabilizer and suspending agent. The pH regulator is one or more of sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate and potassium bicarbonate, preferably sodium hydroxide.
In another aspect the invention provides a product comprising preparing an aqueous solution of the tartaric acid addition salt and a pharmaceutically-acceptable additive.
In another aspect, the invention provides a use of the composition, or the product, in a medicament for the prophylaxis or treatment of a disease or condition mediated by cyclin dependent kinase.
As a preferred mode, the composition, or the product, is for use in the prevention or treatment of cancer.
As a preferred mode, the cancer is selected from bladder cancer, breast cancer, colon cancer, kidney cancer, epidermoid cancer, liver cancer, lung cancer, esophageal cancer, gall bladder cancer, ovarian cancer, pancreatic cancer, stomach cancer, cervical cancer, thyroid cancer, prostate cancer or skin cancer; hematopoietic tumors of lymphoid lineage; hematopoietic tumors of myeloid lineage; thyroid follicular carcinoma; a tumor of interstitial origin; tumors of the central or peripheral nervous system; melanoma; seminoma; teratocarcinoma; osteosarcoma; xeroderma pigmentosum; keratoacanthoma; thyroid follicular carcinoma; or kaposi's sarcoma.
Preferably, the cancer is selected from the group consisting of leukemia, acute lymphoblastic leukemia, B-cell lymphoma, T-cell lymphoma, hodgkin's lymphoma, non-Hodgkin's lymphoma, hairy cell lymphoma, burkett's lymphoma, acute and chronic myelogenous leukemia, myelodysplastic syndrome, and promyelocytic leukemia.
As a preferred mode, the cancer is selected from the group consisting of breast cancer, ovarian cancer, colon cancer, prostate cancer, esophageal cancer, squamous cell carcinoma, and non-small cell lung cancer.
Detailed Description
The present inventors have found unexpectedly for the first time through extensive and intensive studies. The present invention has been completed on the basis of this finding.
Drawings
FIG. 1 is an X-ray powder diffraction pattern of the tartaric acid addition salt Form I.
FIG. 2 is a DSC scan of the tartaric acid addition salt Form I.
FIG. 3 is a TGA plot of the tartaric acid addition salt Form I.
FIG. 4 is an X-ray powder diffraction pattern of the tartaric acid addition salt Form II.
FIG. 5 is a DSC scan of the tartaric acid addition salt Form II.
FIG. 6 is a TGA plot of the tartaric acid addition salt Form II.
FIG. 7 is an X-ray powder diffraction pattern of the Form III of the tartaric acid addition salt.
FIG. 8 is a DSC scan of Form III of the tartaric acid addition salt.
FIG. 9 is a TGA plot of the Form III of the tartaric acid addition salt.
FIG. 10 is a DVS diagram of the Form I of the tartaric acid addition salt.
FIG. 11 is a DVS of the Form II of the tartaric acid addition salt.
FIG. 12 is a DVS diagram of the Form III of the tartaric acid addition salt.
Fig. 13 is a DVS diagram of mesylate.
FIG. 14 is a graph showing the stability of Form I of the tartaric acid addition salt.
FIG. 15 is a graph showing the stability of Form II of the tartaric acid addition salt.
FIG. 16 is a graph showing the stability of Form III of the tartaric acid addition salt.
FIG. 17 is a graph of the stability of the mesylate salt.
FIG. 18 is a PSD plot of the Form I of the tartaric acid addition salt.
FIG. 19 is a PSD of the Form II of the tartaric acid addition salt.
FIG. 20 is a PSD of the Form III of the tartaric acid addition salt.
FIG. 21 is a PSD plot of mesylate.
FIG. 22 is a graph of MCF-7 cell proliferation assay.
The invention has the main advantages that:
the crystalline form of the tartaric acid addition salt of the present invention has, as compared to other salts or free bases:
better solubility, which allows for better intra-menstrual administration;
better stability and convenient storage;
better moisture permeability;
the particle size distribution is better, the requirements of large-scale production are met, the post-treatment process of the preparation process is simplified, and the quality control is improved;
better physicochemical properties;
can improve the biological activity of anticancer and has better therapeutic index.
It is understood that within the scope of the present invention, the above-described technical features of the present invention and technical features specifically described below (e.g., in the examples) may be combined with each other to constitute new or preferred technical solutions. And are limited to a space, and are not described in detail herein.
The invention will be further illustrated with reference to specific examples. The experimental methods, in which specific conditions are not noted in the following examples, are generally conducted under conventional conditions or under conditions recommended by the manufacturer. Percentages and parts are by weight unless otherwise indicated.
The instrument and the method for collecting data are as follows:
the X-ray powder diffraction pattern of the invention was collected on a Panalytical Empyrean X ray powder diffractometer. The X-ray powder diffraction method parameters of the invention are as follows:
x-ray reflection parameters: cu, K alpha
Kα2/kα1 intensity ratio: 0.50
Voltage: 45 KV (kV)
Current flow: 40 milliamperes (mA)
Scanning range: from 3.0 to 40.0 DEG
Differential thermal analysis (DSC) data were obtained from TA Instruments Q2000MDSC, instrument control software Thermal Advantage and analysis software Universal Analysis. Typically 1 to 10mg of the sample is placed in a capped (unless otherwise specified) aluminum crucible and the sample is warmed from room temperature to 300 ℃ under the protection of dry N2 at a ramp rate of 10 ℃/min, while TA software records the thermal change of the sample during the warming. In this application, melting point is reported as the onset temperature.
Thermogravimetric analysis (TGA) data were taken from TA Instruments Q500TGA, instrument control software Thermal AdVantage and analysis software Universal Analysis. Usually, 5-15 mg of sample is placed in a platinum crucible, the temperature of the sample is raised from room temperature to 250 ℃ or 300 ℃ under the protection of 50mL/min dry N2 at a heating rate of 10 ℃/min by adopting a sectional high-resolution detection mode, and meanwhile, the TA software records the weight change of the sample in the heating process. The water content of the crystalline form of the present invention is calculated based on the TGA weight loss, which is a reference to the water content of the crystalline form, as known to those skilled in the art, but is not an absolute representation of the number of water molecules contained in the crystalline form.
Differential Scanning Calorimetric (DSC) plots as described herein were taken on TA Q2000. The method parameters of differential scanning calorimetric analysis (DSC) are as follows:
scanning rate: 10 ℃/min
Protective gas: nitrogen gas
Thermogravimetric analysis (TGA) patterns according to the present invention were collected on TA Q500. The method parameters of thermogravimetric analysis (TGA) according to the present invention are as follows:
scanning rate: 10 ℃/min
Protective gas: nitrogen gas
Other instrument parameters used the following examples were run at room temperature unless specifically stated.
Example 14 preparation of- (2, 6-dichloro-benzoylamino) -1H-pyrazole-3-carboxylic acid piperidin-4-yl-tartaric acid
A. Synthetic intermediate 1
To a 100L reaction vessel, 6.31kg of raw material, N-dimethylformamide (45L), carbodiimide (6.59 kg), 1-hydroxybenzotriazole (4.65 kg) were added, the reaction was stirred for 0.5h, the ice-water bath was cooled to 0 to 10℃and the starting material 1 (4.5 kg) was added in portions, then the temperature was raised to 20 to 25℃and the reaction was stirred for 16h, the reaction solution was added to 270L of water, solids were precipitated, suction filtration, washing, liquid-separated extraction, the organic phases were combined and dried.
B. Synthesis of intermediate 2:
adding the intermediate 1 (2.5 kg) and tetrahydrofuran (44 kg) into a 100L reaction kettle, stirring, heating to 45-50 ℃ to dissolve, adding 250g of 10% Pd/C catalyst, heating to 45-50 ℃ to react for 16h; filtering, pumping, adding dichloromethane (60.65 kg) into the residue, stirring for 10-15min, filtering, washing filter cake, and concentrating the filtrate under reduced pressure to obtain crude product of intermediate 2.
C. Synthetic intermediate 3:
compound intermediate 2 (2.05 kg), dichloromethane (15.41 kg) and triethylamine (0.81 kg) are added into a reaction kettle, the temperature is reduced to 0-5 ℃, a dichloromethane solution of 2, 6-dichlorobenzoyl chloride (1.46 kg dissolved in 0.5kg of dichloromethane) is dripped into the reaction kettle, and after the dripping is finished, the reaction is carried out at room temperature under stirring for 3 hours; 54.53kg of methylene chloride was added to the reaction mixture, followed by washing with 5% HCl (12.3 kg. Times.2), saturated aqueous sodium hydrogencarbonate (18.16 kg. Times.1), saturated brine (19.82 kg. Times.1), drying the organic phase with anhydrous sodium sulfate (1 kg), filtering, and concentrating the filtrate under reduced pressure to dryness; to the residue were added absolute ethanol (4.85 kg) and n-heptane (20.91 kg), stirred at room temperature for 1h, filtered, the filter cake rinsed with n-heptane (1 kg) and the filter cake dried to give intermediate 3.
D. Synthetic intermediate 4:
42.11kg of dichloromethane and 2.8kg of intermediate 3 are added into a 100L reaction kettle, stirring is carried out, trifluoroacetic acid (6.86 kg) is added into the reaction liquid drop, and after the drop is finished, the mixture is stirred for 3-5 hours under heat preservation; the reaction solution was concentrated to dryness under reduced pressure, isopropanol (11 kg) was added to the residue, filtration was carried out, the cake was rinsed with isopropanol (1 kg), the cake was dried, absolute ethanol (6.5 kg) was added to the crude product, the temperature was lowered to 40 to 45 ℃ after warming and dissolution, about half of the solvent was distilled off by concentrating under reduced pressure, the temperature was lowered to 20 to 25 ℃, filtration was carried out, the cake was rinsed with absolute ethanol (0.5 kg), and 2.55kg of intermediate 4 was obtained by drying.
E. Synthesis of tartrate:
(1) 43.89kg of dichloromethane, 26.14kg of absolute ethanol and 4 (1.65 kg) of intermediate are added into a reaction kettle, 0.08kg of active carbon is added after stirring and dissolving, the temperature is raised to 35-40 ℃ for continuous stirring for 15 minutes, and then the temperature is reduced to 20-25 ℃; filtering, concentrating the filtrate under reduced pressure, adding 13.04kg of methanol into the residue, and stirring and dispersing for later use;
(2) Dissolving 0.78kg of L- (+) tartaric acid in 2.61kg of methanol, adding 0.04kg of active carbon, heating to 35-40 ℃ and continuously stirring for 15 minutes, and then cooling to 20-25 ℃; filtering, and keeping filtrate for later use;
(3) Heating the reaction solution in the step (1) to 50-55 ℃, dripping the L- (+) tartaric acid methanol solution in the step 2, and keeping stirring for 4.5 hours at 50-55 ℃ after dripping; cooling the reaction solution to 20-25 ℃, stirring overnight, filtering, leaching the filter cake with 0.53kg of absolute methanol, and vacuum drying overnight to obtain tartrate, wherein the yield is 81.3%.
1 H-NMR(DMSO-D 6 ,400MHz)δ10.15(s,1H),8.63-8.61(d,1H),8.35(s,1H),7.60-7.50(m,3H),4.00(m,1H),3.30-3.27(d,2H),2.95-2.89(m,2H),4.88-4.99(m,2H),2.58(br s,1H),2.09(m,1H),1.61(d,J＝8.0,3H),1.91-1.76(m,4H)。
EXAMPLE 2 preparation of the Form I tartrate addition salt
601.7mg of the tartaric acid addition salt was weighed, 10mL of methylene chloride was added, stirred at 25℃and then the solid was collected by centrifugation and dried to give a solid. The crystal form was characterized by the X-ray imaging method described above.
The crystal form has characteristic peaks at the 2 theta value of 17.7 degrees+/-0.2 degrees, 19.1 degrees+/-0.2 degrees, 26.2 degrees+/-0.2 degrees, 13.3 degrees+/-0.2 degrees, 12.7 degrees+/-0.2 degrees, 16.4 degrees+/-0.2 degrees, 21.6 degrees+/-0.2 degrees, 20.4 degrees+/-0.2 degrees and 24.5 degrees+/-0.2 degrees according to detection. The X-ray powder diffraction data are shown in fig. 1 and table 1.
TABLE 1
Then, the Form I of the tartaric acid addition salt was measured using a TA Instruments Q2000MDSC enthusiasm analyzer, starting with a first endotherm at about 81℃and a second endotherm at about 194℃and referring specifically to FIG. 2.
The TGA of this crystalline form, as shown in figure 3, has a mass loss gradient of about 1.9% when heated to 150 ℃.
EXAMPLE 3 preparation of the Form I of the tartaric acid addition salt
The same procedure as in example 2 was followed using the conditions shown in Table 2 below to obtain a solid, which was measured.
TABLE 2
| Sequence number | Raw material quality (mg) | Solvent(s) | Volume (mL) | T(℃) | The obtained |
| 1 | 10.6 | Methanol | 0.5 | 4 | Form I |
| 2 | 11 | Ethanol | 0.5 | 50 | Form I |
| 3 | 10.5 | Isopropyl alcohol | 0.5 | 25 | Form I |
| 4 | 11.1 | Acetonitrile | 0.5 | 25 | Form I |
| 5 | 10.8 | Acetone (acetone) | 0.5 | 25 | Form I |
| 6 | 11.5 | Methyl isobutyl ketone | 0.5 | 25 | Form I |
| 7 | 11.4 | Acetic acid ethyl ester | 0.5 | 25 | Form I |
| 8 | 10.0 | Acetic acid isopropyl ester | 0.5 | 25 | Form I |
| 9 | 10.2 | Methyl tert-butyl ether | 0.5 | 25 | Form I |
| 10 | 10.7 | Tetrahydrofuran (THF) | 0.5 | 25 | Form I |
| 11 | 10.9 | 2-methyltetrahydrofuran | 0.5 | 25 | Form I |
| 12 | 10.2 | 1, 4-Dioxahexacyclic ring | 0.5 | 25 | Form I |
| 13 | 10.2 | Dichloromethane (dichloromethane) | 0.5 | 25 | Form I |
| 14 | 11.0 | Chloroform (chloroform) | 0.5 | 25 | Form I |
| 15 | 10.3 | Methanol/toluene 2:1 | 0.5 | 25 | Form I |
| 16 | 10.2 | Toluene/n-heptane 1:1 | 0.5 | 25 | Form I |
Form I was obtained by X-powder diffraction, DSC and TGA.
EXAMPLE 4 preparation of the Form II tartrate addition salt
About 200mg of the tartaric acid addition salt solid was weighed, dissolved in 80mL of methanol, filtered and quickly evaporated at 50℃to give a solid.
The sample has characteristic peaks at 2 theta values of 7.0 DEG + -0.2 DEG, 10.5 DEG + -0.2 DEG, 21.8 DEG + -0.2 DEG, 13.0 DEG + -0.2 DEG, 17.4 DEG + -0.2 DEG, 14.0 DEG + -0.2 DEG, 23.5 DEG + -0.2 DEG, 18.6 DEG + -0.2 DEG, 24.8 DEG + -0.2 DEG, as detected by XRPD. The X-ray powder diffraction data are shown in fig. 4 and table 3.
TABLE 3 Table 3
Then, form II of the tartaric acid addition salt was measured using a TA Instruments Q2000MDSC enthusiasm analyzer, starting with a first endotherm at about 56 ℃, a second endotherm at about 107 ℃, and a third endotherm at about 162 ℃, see in particular fig. 5.
The TGA of this crystalline form, as shown in figure 6, has a mass loss gradient of about 3.1% when heated to 77 ℃. Continuing to heat to 150 ℃, there was a mass loss gradient of about 3.0%.
EXAMPLE 5 preparation of the Form II tartrate addition salt
The same procedure as in example 2 was followed using the conditions shown in Table 4 below to obtain a solid, which was measured.
TABLE 4 Table 4
| Sequence number | Raw material quality (mg) | Solvent(s) | Volume (mL) | The obtained |
| 1 | 10.9 | Acetylacetone (acetylacetone) | 0.3 | Form II |
| 2 | 10.5 | Benzonitrile | 0.3 | Form II |
Form II was obtained by X-powder diffraction, DSC and TGA.
EXAMPLE 6 preparation of the Form III of the tartaric acid addition salt
Weighing a certain amount of tartaric acid addition salt solid, placing the solid in a certain amount of solvent described in table 5, stirring, centrifuging to collect solid, and drying. The detection shows that the crystal forms are all tartaric acid addition salt crystal forms Form III.
TABLE 5
| Sequence number | Raw material quality (mg) | Solvent(s) | Volume (mL) | The obtained |
| 1 | 582.7 | Water and its |
20 | Form III |
| 2 | 10.5 | Tetrahydrofuran/water 9:1 | 0.5 | Form III |
XRPD detection shows that the composition has characteristic peaks at values of θ of 11.0°±0.2°,14.4°±0.2°,22.6°±0.2°,15.8°±0.2°,18.4°±0.2°,16.2°±0.2°,23.2°±0.2°,26.5°±0.2°, and 28.2°±0.2°. The X-ray powder diffraction data are shown in fig. 7 and table 6.
TABLE 6
Then, the Form III of the tartaric acid addition salt was measured using a TA Instruments Q2000MDSC enthusiasm analyzer, and a first endotherm was initiated at about 60℃and a second endotherm was initiated at about 116℃with DSC of the Form as shown in FIG. 8.
The TGA of this crystalline form, as shown in figure 9, has a mass loss gradient of about 5.2% when heated to 84 ℃. Continuing to heat to 131 ℃, there was a mass loss gradient of about 2.0%.
EXAMPLE 7 determination of hygroscopicity of Form I of the tartaric acid addition salt
About 10mg of the Form I of the tartaric acid addition salt of the present invention was taken and tested for hygroscopicity by a dynamic moisture sorption (DVS) instrument. The experimental results are shown in table 7. The DVS diagram of the Form I crystal Form hygroscopicity test is shown in FIG. 10.
TABLE 7
The results show that the crystal Form I of the tartaric acid addition salt of the invention has 0.45 percent of weight gain after being balanced under the humidity of 80 percent, and belongs to slightly moisture absorption according to the definition standard of moisture absorption weight gain.
Example 8 hygroscopicity test of Form II tartrate crystals:
about 10mg of the Form II of the tartaric acid addition salt of the present invention was taken and tested for hygroscopicity by a dynamic moisture sorption (DVS) instrument. The experimental results are shown in table 8. The DVS diagram of the Form II crystal Form hygroscopicity test is shown in FIG. 11.
TABLE 8
The results show that the crystal Form II of the tartaric acid addition salt of the invention has 0.35 percent of weight gain after being balanced at 80 percent of humidity, and belongs to slightly moisture permeability according to the definition standard of moisture permeability weight gain.
Example 9 hygroscopicity test of Form III of the tartaric acid addition salt:
about 10mg of the Form III of the tartaric acid addition salt of the present invention was taken and tested for hygroscopicity by a dynamic moisture sorption (DVS) instrument. The experimental results are shown in table 9. The DVS diagram of the Form III crystal Form hygroscopicity test is shown in FIG. 12.
TABLE 9
The results show that the crystal Form III of the tartaric acid addition salt of the invention has 0.29 percent of weight gain after being balanced at 80 percent of humidity, and belongs to slightly moisture absorption according to the definition standard of moisture absorption weight gain.
Example 10 hygroscopicity test of methanesulfonic acid salt:
the mesylate salt was prepared using the method disclosed in chinese patent CN101146791, and the solids detected were consistent with the data in this patent.
About 10mg of the above methanesulfonate was used for the moisture absorption by a dynamic moisture adsorption (DVS) instrument. The experimental results are shown in table 10. The DVS diagram of the hygroscopicity test of the mesylate salt is shown in FIG. 13.
Table 10
The weight of the mesylate is increased by 0.62% after the mesylate is balanced under the humidity of 80%, and the mesylate belongs to slightly moisture permeability according to the definition standard of moisture permeability weight increase. The results show that the hygroscopicity of the mesylate salt is slightly higher than that of the tartaric acid addition salt of the invention, namely the Form I, the Form II and the Form III.
Definition of hygroscopicity characterization and weight gain (guidelines for drug hygroscopicity test in the 2015 edition of Chinese pharmacopoeia, rule 9103, experimental conditions: 25 ℃ ± 1 ℃,80% relative humidity): deliquescence: absorb sufficient moisture to form a liquid
The moisture absorption performance is very good: the weight gain of the wet-induced hair is not less than 15 percent
Moisture permeability: the weight gain of the wet-induced weight is less than 15 percent but not less than 2 percent
Slightly hygroscopic: the weight gain of the wet-drawing is less than 2 percent but not less than 0.2 percent
No or little hygroscopicity: the weight gain of the wet-induced weight is less than 0.2 percent
Example 11 stability test of the tartaric acid addition salt Form I:
three samples of the Form I of the tartaric acid addition salt were taken and placed in open temperature and humidity chambers at 25℃/60% RH and 40℃/75% RH for 1 week and at 80℃ for 1 day, respectively, and were sampled for purity and XRPD. The XRPD comparison results are shown in fig. 14 (XRPD patterns of the tartrate addition salt Form I starting sample, placed at 25 ℃/60% rh and 40 ℃/75% rh for 1 week and 80 ℃ for 1 day in order from top to bottom), and the results are shown in table 11.
TABLE 11
| Initial crystal form | Conditions of placement | Purity% | Crystal modification |
| Form I | 25℃/60％RH | 99.75 | Unchanged |
| Form I | 40℃/75％RH | 99.71 | Unchanged |
| Form I | 80℃ | 99.34 | Unchanged |
The tartaric acid addition salt Form I was left at 25 ℃/60% rh and 40 ℃/75% rh for 1 week and at 80 ℃ for 1 day, the Form remained unchanged and the purity did not change significantly. The results show that the Form I crystal Form of the tartaric acid addition salt has good stability.
Example 12 stability test of tartrate addition salt Form II:
three samples of the Form II of the tartaric acid addition salt were taken and placed in open temperature and humidity chambers at 25℃/60% RH and 40℃/75% RH for 1 week and at 80℃ for 1 day, respectively, and were sampled for purity and XRPD. The XRPD comparison results are shown in fig. 15 (XRPD patterns of the tartrate addition salt form ii starting sample, placed at 25 ℃/60% rh and 40 ℃/75% rh for 1 week and 80 ℃ for 1 day in order from top to bottom), and the results are shown in table 12.
Table 12
| Initial crystal form | Conditions of placement | Purity% | Crystal |
| Form II | |||
| 25℃/60％RH | 99.77 | Unchanged | |
| Form II | 40℃/75％RH | 99.72 | Unchanged |
| Form II | 80℃ | 99.30 | Unchanged |
The tartaric acid addition salt Form II crystalline Form was left at 25 ℃/60% rh and 40 ℃/75% rh for 1 week and at 80 ℃ for 1 day, the crystalline Form remained unchanged and the purity did not change significantly. The results show that the Form II of the tartaric acid addition salt has good stability.
Example 13 stability test of tartrate addition salt Form III:
three samples of the Form III of the tartaric acid addition salt were taken and placed in open temperature and humidity chambers at 25℃/60% RH and 40℃/75% RH for 1 week and at 80℃ for 1 day, respectively, and were sampled for purity and XRPD. The XRPD comparison results are shown in fig. 16 (XRPD patterns of the tartrate addition salt Form III starting sample, placed at 25 ℃/60% rh and 40 ℃/75% rh for 1 week and 80 ℃ for 1 day in order from top to bottom), and the results are shown in table 13.
TABLE 13
The tartaric acid addition salt Form III was left at 25℃/60% RH and 40℃/75% RH for 1 week and at 80℃ for 1 day, the Form remained unchanged and the purity did not change significantly. The results show that the Form III of the tartaric acid addition salt has good stability.
Example 14 stability test of mesylate:
three mesylate samples prepared according to the method disclosed in chinese patent CN101146791 were taken and placed in open-ended thermostatted humidity chambers at 25 ℃/60% rh and 40 ℃/75% rh for 1 week and at 80 ℃ for 1 day, respectively, and sampled for purity and XRPD. The XRPD comparison results are shown in fig. 17 (XRPD patterns of mesylate starting samples in order from top to bottom, XRPD patterns of 1 week under 25 ℃/60% rh and 40 ℃/75% rh conditions, and 1 day under 80 ℃) and are shown in table 14.
TABLE 14
| Initial crystal form | Conditions of placement | Purity% | Crystal |
| Methanesulfonate salt | |||
| 25℃/60％RH | 99.93 | | |
| Methanesulfonate salt | |||
| 40℃/75％RH | 99.92 | | |
| Methanesulfonate salt | |||
| 80℃ | 99.97 | Unchanged |
The mesylate salt was left at 25 ℃/60% rh and 40 ℃/75% rh for 1 week and at 80 ℃ for 1 day, the crystalline form remained unchanged and no significant changes in purity were seen. The results show that the stability of the mesylate salt is equivalent to the Form I, form II and Form III of the tartaric acid addition salt of the invention.
Example 15 particle size distribution and morphology study test:
the tartrate addition salt forms Form I, form II, form III and the mesylate salt of the present invention were tested for particle size distribution and the results are shown in table 15.
TABLE 15
| Crystal form | MV(μm) | SD | D10(μm) | D50(μm) | D90μm) |
| Form I crystal Form | 12.28 | 11.34 | 0.842 | 6389 | 30.92 |
| Form II crystal Form | 66.64 | 46.02 | 13.64 | 51.89 | 140.30 |
| Form III crystal Form | 348.90 | 236.0 | 70.65 | 317.2 | 655.10 |
| Methanesulfonate salt | 386.7 | 407.3 | 6.80 | 240.3 | 821.4 |
MV: average particle size by volume
D10: represents the particle size corresponding to 10% of the particle size distribution (volume distribution)
D50: representing the particle size corresponding to 50% of the particle size distribution (volume distribution), also called median diameter
D90: represents the particle size corresponding to 90% of the particle size distribution (volume distribution)
The experimental results show that:
the PSD plot for Form I is shown in FIG. 18, with a volume average particle size of 12.28 microns.
The PSD of Form II is shown in FIG. 19, and the volume average particle size of Form II is 66.64. Mu.m. And the particle size distribution is narrower, almost shows a normal distribution, and the particle size distribution is uniform.
The PSD of Form III is shown in FIG. 20, and the volume average particle size of Form III is 348.90. Mu.m. And the particle size distribution is narrower, almost shows a normal distribution, and the particle size distribution is uniform.
PSD for the mesylate salt is shown in FIG. 21, with a volume average particle size of 386.7 microns. The particle size is larger, the particle size distribution is wider, and the particle size distribution is uneven.
Example 16 solubility test study:
the tartaric acid addition salt crystal Form I, crystal Form II and crystal Form III samples are respectively prepared into saturated solutions by using pH6.5FaSSIF (artificial intestinal juice in a fasting state) and pure water, and the content of the samples in the saturated solutions is measured by a High Performance Liquid Chromatography (HPLC) method after 1 hour, 4 hours and 24 hours. The solubility data of the tartaric acid addition salt forms I, II and III are shown in Table 16.
Table 16
The results show that the tartaric acid addition salt crystal forms I, II and III all show good stability.
EXAMPLE 17 pharmaceutical formulation
Parenteral compositions for injection are prepared as follows: sodium sulfobutylbetacyclodextrin is dissolved in water for injection and then the tartrate salt (e.g., form I) is added to provide a tartrate salt concentration of 0.8 to 1.5% by weight. The solution was then filtered off, sterilized, filled in an ampoule, and sealed.
Example 18 Activity test
The proliferation inhibition activity of the tartaric acid addition salt of the present invention on the human breast cancer cell line MCF-7 was determined by the following method.
The measuring method comprises the following steps: MCF-7 cells (purchased from ATCC) were first prepared according to 1X 10 4 cells/well were plated in 96-well plates and incubated overnight (37 ℃,7% co 2).
4- (2, 6-dichloro-benzoylamino) -1H-pyrazole-3-carboxylic acid piperidin-4-ylamide in the form of different salts was diluted at an initial concentration of 100. Mu.M, 3-fold concentration gradient.
The 96-well plate was removed, the supernatant was removed, and different salt forms of 4- (2, 6-dichloro-benzoylamino) -1H-pyrazole-3-carboxylic acid piperidin-4-ylamide diluted in different concentrations were added and incubated in an incubator for 72H (37 ℃,7% CO 2). Taking out the 96-well plate, adding CCK-8 color reagent, incubating for 30min at 37 ℃, reading the plate by an enzyme label reader, and measuring the OD value at 450 nm. The data are shown in Table 17:
TABLE 17
| Salt type | Tartaric acid addition salts | Methanesulfonate salt | Hydrochloride salt |
| EC50(nM) | 446.6 | ～1086 | 898.2 |
All documents mentioned in this application are incorporated by reference as if each were individually incorporated by reference. Further, it will be appreciated that various changes and modifications may be made by those skilled in the art after reading the above teachings, and such equivalents are intended to fall within the scope of the claims appended hereto.
Claims (24)
1. A tartaric acid addition salt of crystalline 4- (2, 6-dichloro-benzoylamino) -1H-pyrazole-3-carboxylic acid piperidin-4-ylamide, characterized by characteristic peaks in the X-ray powder diffraction spectrum expressed in 2Θ (°) using Cu-ka radiation at 12.7±0.2, 13.3±0.2, 16.4±0.2, 17.7±0.2, 19.1±0.2, 20.4±0.2, 21.6±0.2, 24.5±0.2 and 26.2±0.2.
2. The tartaric acid addition salt according to claim 1, characterized in that its X-ray powder diffraction spectrum in terms of 2Θ (°) using Cu-ka radiation has the X-ray powder diffraction pattern as shown in figure 1.
3. The tartaric acid addition salt according to claim 1, wherein the DSC endotherm has a transition from about 194 ℃ to about 200 ℃.
4. A tartaric acid addition salt of crystalline 4- (2, 6-dichloro-benzoylamino) -1H-pyrazole-3-carboxylic acid piperidin-4-ylamide, characterized by characteristic peaks in the X-ray powder diffraction spectrum expressed in 2Θ (°) using Cu-ka radiation at 7.0±0.2, 10.5±0.2, 21.8±0.2, 13.0±0.2, 17.4±0.2, 14.0±0.2, 23.5±0.2, 18.6±0.2 and 24.8±0.2.
5. The tartaric acid addition salt according to claim 4, characterized in that its X-ray powder diffraction (XRD) spectrum in terms of 2Θ (°) using Cu-ka radiation has the X-ray powder diffraction pattern as shown in figure 4.
6. The tartaric acid addition salt of claim 4, wherein the DSC endotherm has a transition from about 107 ℃ to about 127 ℃.
7. A tartaric acid addition salt of crystalline piperidin-4-ylamide 4- (2, 6-dichloro-benzoylamino) -1H-pyrazole-3-carboxylic acid, characterized by characteristic peaks in the X-ray powder diffraction spectrum expressed in 2Θ (°) using Cu-ka radiation at 11.0±0.2, 14.4±0.2, 22.6±0.2, 15.8±0.2, 18.4±0.2, 16.2±0.2, 23.2±0.2, 26.5±0.2, 28.2±0.2.
8. The tartaric acid addition salt according to claim 7, characterized in that its X-ray powder diffraction spectrum in terms of 2Θ (°) using Cu-ka radiation has an X-ray powder diffraction pattern as shown in figure 7.
9. The tartaric acid addition salt of claim 7, wherein the DSC endotherm has a transition at about 116 ℃ to about 135 ℃.
10. A process for the preparation of the crystalline form of the piperidin-4-ylamide tartrate addition salt of 4- (2, 6-dichloro-benzoylamino) -1H-pyrazole-3-carboxylic acid as defined in any one of claims 1 to 3, comprising adding the tartrate addition salt to a quantity of solvent, and centrifuging under agitation to give a solid; wherein the solvent is alcohols, nitriles, ketones, esters, ethers, aromatics, halogenated hydrocarbons, or alkane solvents; the heating temperature is-20-60 ℃; wherein:
the alcohol solvent is methanol, ethanol and propanol;
the nitrile solvent is acetonitrile;
the ketone solvent is acetone and methyl isobutyl ketone;
the ester solvent is ethyl acetate and isopropyl acetate;
the ether solvent is methyl tertiary butyl ether, tetrahydrofuran and 1, 4-dioxane;
the aromatic solvent is toluene;
the halogenated hydrocarbon solvent is dichloromethane and chloroform;
the alkane solvent is n-heptane.
11. The method of claim 10, wherein the heating temperature is 25 ℃.
12. A process for preparing the crystalline form of the piperidin-4-ylamide tartrate addition salt of 4- (2, 6-dichloro-benzoylamino) -1H-pyrazole-3-carboxylic acid as defined in any one of claims 4 to 6, comprising the steps of:
the method comprises the following steps: dissolving the tartaric acid addition salt in a certain amount of methanol, filtering, and volatilizing at 50 ℃ to obtain a solid;
the second method is as follows: the tartaric acid addition salt was stirred in acetylacetone or benzonitrile solvent at 80 ℃ and centrifuged to give a solid.
13. A process for preparing the crystalline form of the piperidin-4-ylamide tartrate addition salt of 4- (2, 6-dichloro-benzoylamino) -1H-pyrazole-3-carboxylic acid according to any one of claims 7 to 9, comprising placing the tartrate addition salt in an amount of solvent, and stirring to obtain a solid; wherein the solvent is water or a mixed solvent system formed by ethers and water.
14. The method of claim 13, wherein the mixed solvent system is a tetrahydrofuran/water system.
15. A composition comprising a therapeutically effective amount of the tartaric acid addition salt of any one of claims 1-9.
16. The composition of claim 15, wherein the composition is an injection.
17. The composition of claim 16, wherein the tartaric acid addition salt is present in an amount of 0.5 to 2.0 weight/mL.
18. The composition of claim 17 wherein the tartaric acid addition salt is present in an amount of 0.8 to 1.5 weight/mL.
19. The composition of claim 17, further comprising a pharmaceutically acceptable excipient which is cyclodextrin or a derivative thereof.
20. The composition of claim 19, wherein the excipient is hydroxypropyl- β -cyclodextrin, dihydroxy- β -cyclodextrin, hydroxyethyl- β -cyclodextrin, 2-hydroxypropyl- β -cyclodextrin, 3-hydroxypropyl- β -cyclodextrin, 2, 3-dihydroxypropyl- β -cyclodextrin, 2,3, 6-trihydroxypropyl- β -cyclodextrin, or sodium sulfobutyl- β -cyclodextrin.
21. The composition of claim 20, wherein the excipient is sodium sulfobutyl- β -cyclodextrin.
22. A product comprising an aqueous solution prepared from the tartaric acid addition salt of any one of claims 1-9 and a pharmaceutically-acceptable additive.
23. Use of a tartaric acid addition salt according to any one of claims 1 to 9, a composition according to any one of claims 15 to 21 or a product according to claim 22 in the manufacture of a medicament for the prevention or treatment of a disease or condition mediated by a cyclin dependent kinase.
24. The use of claim 23, wherein the disease or condition mediated by cyclin dependent kinase is cancer.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2017110149622 | 2017-10-25 | ||
| CN201711014962 | 2017-10-25 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN109705090A CN109705090A (en) | 2019-05-03 |
| CN109705090B true CN109705090B (en) | 2023-06-20 |
Family
ID=66253856
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201811079167.6A Active CN109705090B (en) | 2017-10-25 | 2018-09-17 | Tartaric acid addition salts of 3, 4-disubstituted 1H-pyrazole compounds and crystalline forms thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN109705090B (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113289587B (en) * | 2021-05-10 | 2023-11-28 | 苏州君盟生物医药科技有限公司 | Sulfhydryl modified magnetic nano microsphere and preparation method and application thereof |
Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2005012256A1 (en) * | 2003-07-22 | 2005-02-10 | Astex Therapeutics Limited | 3, 4-disubstituted 1h-pyrazole compounds and their use as cyclin dependent kinases (cdk) and glycogen synthase kinase-3 (gsk-3) modulators |
| WO2008009954A1 (en) * | 2006-07-21 | 2008-01-24 | Astex Therapeutics Limited | Medical use of cyclin dependent kinases inhibitors |
| CN101146791A (en) * | 2005-01-21 | 2008-03-19 | 阿斯泰克斯治疗有限公司 | 4-(2,6-dichlorobenzoylamino)-1H-pyrazole-3-carboxylic acid piperidin-4-ylamid acid addition salts as kinase inhibitors |
| CN101484439A (en) * | 2006-05-05 | 2009-07-15 | 阿斯泰克斯治疗有限公司 | 4- (2,6-dichloro-benzoylamino) -1h-pyrazole-3-carboxylic acid (1-methanesulphonyl-piperidin-4-yl) -amide for the treatment of cancer |
| CN105878244A (en) * | 2014-11-12 | 2016-08-24 | 中国药科大学 | CDK2 inhibitor and applications thereof |
-
2018
- 2018-09-17 CN CN201811079167.6A patent/CN109705090B/en active Active
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2005012256A1 (en) * | 2003-07-22 | 2005-02-10 | Astex Therapeutics Limited | 3, 4-disubstituted 1h-pyrazole compounds and their use as cyclin dependent kinases (cdk) and glycogen synthase kinase-3 (gsk-3) modulators |
| CN101146791A (en) * | 2005-01-21 | 2008-03-19 | 阿斯泰克斯治疗有限公司 | 4-(2,6-dichlorobenzoylamino)-1H-pyrazole-3-carboxylic acid piperidin-4-ylamid acid addition salts as kinase inhibitors |
| CN101484439A (en) * | 2006-05-05 | 2009-07-15 | 阿斯泰克斯治疗有限公司 | 4- (2,6-dichloro-benzoylamino) -1h-pyrazole-3-carboxylic acid (1-methanesulphonyl-piperidin-4-yl) -amide for the treatment of cancer |
| WO2008009954A1 (en) * | 2006-07-21 | 2008-01-24 | Astex Therapeutics Limited | Medical use of cyclin dependent kinases inhibitors |
| CN105878244A (en) * | 2014-11-12 | 2016-08-24 | 中国药科大学 | CDK2 inhibitor and applications thereof |
Non-Patent Citations (1)
| Title |
|---|
| STN.STN.《STN》.2022, * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN109705090A (en) | 2019-05-03 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| EP3191469B1 (en) | 2-h-indazole derivatives as cyclin-dependent kinase (cdk) inhibitors and therapeutic uses thereof | |
| US11040979B2 (en) | Substituted pyrrolo[1,2-b]pyridazines for treating disorders related to KIT and PDGFR | |
| TW202043212A (en) | Shp2 inhibitor and application thereof | |
| EP3746072B1 (en) | 2h-indazole derivatives as cdk4 and cdk6 inhibitors and therapeutic uses thereof | |
| TWI706951B (en) | Isethionate and crystalline form of cyclin-dependent kinase inhibitor and preparation methods thereof | |
| CN107698603B (en) | Thienopyrimidine compound, preparation method thereof, medicinal composition and application thereof | |
| CN111187253A (en) | Novel crystalline form of axitinib | |
| EA031059B1 (en) | Crystalline form alpha of afatinib di-maleate | |
| JP6937322B2 (en) | Salt of substituted piperidine compound | |
| CN113840604A (en) | Crystalline forms of a JAK2 inhibitor | |
| EP3176173B1 (en) | Crystalline free bases of c-met inhibitor or crystalline acid salts thereof, and preparation methods and uses thereof | |
| US9884856B2 (en) | Crystal form of Dabrafenib mesylate and preparation method thereof | |
| EP3805229B1 (en) | Salt of fused ring pyrimidine compound, crystal form thereof and preparation method therefor and use thereof | |
| TW201638090A (en) | A crystalline form of cyclin-dependent protein kinase inhibitor and preparation methods thereof | |
| JP6676626B2 (en) | Crystal of mesylate salt of acylthiourea compound and method for producing the same | |
| JP2018135268A (en) | Novel heteroaryl amino-3-pyrazole derivative and pharmacologically acceptable salt thereof | |
| BR112020026052A2 (en) | crystal form of the compound for the inhibition of cdk4 / 6 activity and its use | |
| CN109705090B (en) | Tartaric acid addition salts of 3, 4-disubstituted 1H-pyrazole compounds and crystalline forms thereof | |
| WO2020061996A1 (en) | Novel crystal forms of deuterated azd9291 compound and use thereof | |
| CN110283162B (en) | Epidermal growth factor receptor inhibitor and application thereof | |
| CN110520425A (en) | EOC315 Mod.I crystal-form compound and preparation method thereof | |
| WO2020172906A1 (en) | New-type pan-raf kinase inhibitor and use thereof | |
| EP4095139A1 (en) | Salt of arylaminopurine derivative, preparation method therefor and use thereof | |
| CN111601791B (en) | EZH2 inhibitors, pharmaceutically acceptable salts and polymorphs thereof, and uses thereof | |
| CN110407839B (en) | Preparation and application of triazole heterocyclic compound containing heteroaryl amide structure |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |