CN111148747B - Salt form and crystal form of pyridopyrimidine compound and preparation method thereof - Google Patents
Salt form and crystal form of pyridopyrimidine compound and preparation method thereof Download PDFInfo
- Publication number
- CN111148747B CN111148747B CN201880061016.XA CN201880061016A CN111148747B CN 111148747 B CN111148747 B CN 111148747B CN 201880061016 A CN201880061016 A CN 201880061016A CN 111148747 B CN111148747 B CN 111148747B
- Authority
- CN
- China
- Prior art keywords
- degrees
- crystalline form
- ray powder
- diffraction pattern
- 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
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
- A61K31/5375—1,4-Oxazines, e.g. morpholine
- A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
- A61K31/5375—1,4-Oxazines, e.g. morpholine
- A61K31/5386—1,4-Oxazines, e.g. morpholine spiro-condensed or forming part of bridged ring systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
Abstract
The salt form and the crystal form of the pyridopyrimidine compound and preparation methods thereof are provided, and particularly discloses free alkali and sulfate of the compound shown in the formula (I), the crystal form and the preparation method thereof, and application of the salt form and the crystal form in preparation of medicines for treating diseases or symptoms caused by dysfunction of a PI3K-Akt-mTOR signaling pathway.
Description
Technical Field
The invention relates to a salt form and a crystal form of a pyridopyrimidine compound and a preparation method thereof, and particularly discloses free alkali and sulfate of the compound shown in formula (I), a crystal form and a preparation method thereof, and application of the salt form and the crystal form in preparation of a medicament for treating diseases or symptoms caused by dysfunction of a PI3K-Akt-mTOR signaling pathway.
Background
In recent years, researches show that the PI3K-Akt-mTOR signal pathway plays a key role in growth, proliferation, invasion and metastasis of tumor cells, and the blocking of the PI3K-Akt-mTOR signal pathway in the cells can inhibit the proliferation of the tumor cells and even promote the apoptosis of the tumor cells. In various human tumors, multiple key node proteins in a PI3K-Akt-mTOR signaling pathway are over-activated due to mutation or amplification of coding genes, such as mutation and amplification of upstream receptor type tyrosine kinase, PIK3CA genes coding for p110 alpha catalytic subunits are mutated and amplified in various tumors, over-activation of Akt and PDK1 and universal deletion of negative regulator PTEN.
Mammalian target of rapamycin (mTOR) is one of the important substrates for Akt, a non-classical serine/threonine protein kinase belonging to the phosphatidylinositol-3-kinase related kinase (PIKK) family. The mTOR signaling pathway is a key pathway for regulating cell growth and proliferation, and integrates signals from nutritional molecules, energy states, and growth factors, enabling regulation of a large number of life processes. Abnormal activation of the mTOR signaling pathway is a commonality of the development and progression of a variety of tumors and has thus become a hotspot in the development of anti-tumor inhibitors.
However, mTOR was found to exist in at least two functional complexes, mTORC1 and mTORC2, which mediate both associative and independent bio-signaling functions. Clinically used rapamycin drugs (including rapamycin and its analogs) bind to the FKBP12 protein binding site (FRB) near the catalytic site of mTORC1 through allosterism, and exert a partial inhibition effect on mTOR protein. These compounds do not directly inhibit mTORC2 nor completely block all signals mediated by mTORC 1. Although rapamycin drugs have shown some clinical efficacy in some tumor spectra, the mode of action of these drugs does not fully exploit the potential of mTOR targeting to antitumor drugs. In particular, in some major solid tumors, mTORC 2-mediated hyperphosphorylation (activation) of AKT is critical for tumor maintenance and growth, but mTORC2 cannot be inhibited by rapamycin.
The development of ATP-competitive and specific mTOR small molecule inhibitors opens the possibility for a variety of cancer treatments. Some of the recently reported competitive inhibitors of ATP have shown stronger inhibitory effects on tumor cell growth and survival, protein synthesis, bioenergy metabolism, etc., compared to rapamycin analogues. In animal experiments, the medicine has strong single-drug antitumor activity on MDA361 breast cancer, U87MG glioma, A549 and H1975 lung cancer, and A498 and 786-O kidney cancer.
In summary, given that mTOR signaling pathways are involved in a variety of tumor profiles, the development of more effective mTOR inhibitors provides new ideas and strategies for novel broad-spectrum antitumor drugs. At present, a plurality of mTOR inhibitors enter clinical research stages, which indicates that ATP competitive mTOR inhibitors are likely to become a new generation of antitumor drugs to enter clinical use.
The inventors of the present invention have determined that mTOR inhibitors are ATP competitive inhibitors and thus their mechanism of action is a non-rapamycin like compound. In addition, the inventor obtains a novel pyridopyrimidine or pyrimidopyrimidine compound through reasonable design and comprehensive consideration of factors such as water solubility, metabolic stability and the like of the compound on the basis of the previously reported compound. The compound can show better mTOR inhibition activity on enzyme and cell levels. After further optimization and screening, the compound is expected to be developed into an antitumor drug with simple preparation and higher activity.
Disclosure of Invention
In a first aspect of the invention, the invention provides a crystalline form I of the compound of formula (I) having an X-ray powder diffraction pattern (preferably measured using Cu-ka) having characteristic diffraction peaks at the following 2 Θ angles: 7.600 + -0.2 deg., 9.374 + -0.2 deg., 13.838 + -0.2 deg., 14.179 + -0.2 deg., 15.218 + -0.2 deg., 17.659 + -0.2 deg., 21.018 + -0.2 deg., 21.700 + -0.2 deg..
In one embodiment, form I has an X-ray powder diffraction pattern (preferably, measured using Cu-k α) having characteristic diffraction peaks at nine or more, ten or more, eleven or more, twelve or more, or thirteen or more 2 θ angles selected from the group consisting of: 7.600 + -0.2 deg., 9.374 + -0.2 deg., 13.838 + -0.2 deg., 14.179 + -0.2 deg., 15.218 + -0.2 deg., 17.162 + -0.2 deg., 17.659 + -0.2 deg., 18.663 + -0.2 deg., 19.521 + -0.2 deg., 20.160 + -0.2 deg., 21.018 + -0.2 deg., 21.700 + -0.2 deg., 22.939 + -0.2 deg., 23.478 + -0.2 deg..
In another embodiment, form I has an X-ray powder diffraction pattern (preferably, measured using Cu-k α) as shown in figure 1.
In another embodiment, X-ray powder diffraction pattern analysis data (preferably, measured using Cu-k α) for form I is shown in table 1.
TABLE 1X-ray powder diffraction Pattern analysis data of form I
In another embodiment, the differential scanning calorimetry curve of form I has an endothermic peak at 238.1 ± 3 ℃.
In another embodiment, the differential scanning calorimetry curve of form I is shown in figure 2.
In another embodiment, the thermogravimetric analysis curve of form I has a weight loss of about 0.224% at 150 ± 3 ℃.
In another embodiment, the thermogravimetric analysis curve of form I is shown in figure 3.
In another embodiment, the present invention also provides a method for preparing form I, comprising:
a) Mixing the compound of formula (I), isopropanol and ethyl acetate, heating and stirring;
b) Adjusting the temperature to 0-10 ℃, stirring, and slowly cooling for crystallization;
c) Filtering, washing and drying.
In a second aspect of the invention, the invention provides a sulphate salt of a compound of formula (I).
In one embodiment, the present invention provides a crystalline form II of the sulfate salt of the compound of formula (I) having an X-ray powder diffraction pattern with characteristic diffraction peaks at the following 2 Θ angles: 6.889 + -0.2 deg., 8.523 + -0.2 deg., 17.306 + -0.2 deg., 18.668 + -0.2 deg., 20.443 + -0.2 deg., 21.196 + -0.2 deg., 23.684 + -0.2 deg..
In another embodiment, form II has characteristic diffraction peaks at eight or more, nine or more, ten or more, eleven or more, twelve or more, or thirteen or more 2 Θ angles selected from the group consisting of: 6.889 + -0.2 deg., 8.523 + -0.2 deg., 9.295 + -0.2 deg., 12.554 + -0.2 deg., 12.886 + -0.2 deg., 13.797 + -0.2 deg., 15.758 + -0.2 deg., 16.634 + -0.2 deg., 17.306 + -0.2 deg., 18.668 + -0.2 deg., 20.443 + -0.2 deg., 21.196 + -0.2 deg., 23.186 + -0.2 deg., 23.684 + -0.2 deg..
In another embodiment, form II has an X-ray powder diffraction pattern as shown in figure 4.
In another embodiment, the X-ray powder diffraction pattern analysis data for form II is shown in table 2.
TABLE 2X-ray powder diffraction Pattern analysis data of Crystal form II
In another embodiment, the differential scanning calorimetry curve for form II has an endothermic peak at 318.6 ± 3 ℃.
In another embodiment, the differential scanning calorimetry curve for form II is shown in figure 5.
In another embodiment, the thermogravimetric analysis curve of form II has a weight loss of about 0.447% at 150 ± 3 ℃.
In another embodiment, the thermogravimetric analysis curve of form II is as shown in figure 6.
In another embodiment, the present invention also provides a method for preparing crystalline form II, comprising:
a) Mixing the compound of formula (I) and methanol, heating and stirring;
b) Adding a sulfuric acid solution while stirring, and stirring under a heating condition;
c) Blowing the solution to dryness, adding acetonitrile, and stirring under a heating condition;
d) Filtering and drying.
In a third aspect of the invention, the invention provides the use of any one of the salt forms and crystal forms described above in the preparation of a medicament for the treatment of a disease or condition caused by dysfunction of the PI3K-Akt-mTOR signaling pathway.
Drawings
Figure 1 shows the X-ray powder diffraction pattern of form I.
Figure 2 shows the differential scanning calorimetry curve for form I.
Figure 3 shows the thermogravimetric analysis curve of form I.
Figure 4 shows an X-ray powder diffraction pattern of form II.
Fig. 5 shows a differential scanning calorimetry curve for form II.
Figure 6 shows a thermogravimetric analysis curve of form II.
Figure 7 shows the results of dynamic vapor sorption analysis of form I, wherein the solid diamond line represents the sorption curve and the solid square line represents the desorption curve.
Detailed Description
The invention is further described below with reference to the figures and examples. It should be understood, however, that these examples are for the purpose of illustrating the invention in more detail, and are not to be construed as limiting the invention in any way.
The reagents and methods employed in the examples of the invention are conventional in the art. It will be clear to those skilled in the art that, unless otherwise specified, temperatures are expressed in degrees Celsius (C.) and operating temperatures are carried out at ambient temperature, which is 10 deg.C to 30 deg.C, preferably 20 deg.C to 25 deg.C; the allowable error of the melting point is +/-1%; the yield is mass percent.
Experimental methods
5363X-ray powder diffraction (XRPD) 1.X
XRPD data for each crystal form was determined by Macro XRPD using an XRD-6000 instrument from Shimadzu corporation (Shimadzu) and the diffraction parameters were as follows:
x-ray: the concentration of Cu, k alpha,
1.54056
x-ray light pipe setting: 40kV,30mA
Divergent slit: automatic
A monochromator: is free of
Scanning mode: continuous
Scan range (° 2 Theta): 5-50 degree
Scan speed (°/min): 5
2. Differential Scanning Calorimetry (DSC)
The DSC data for the individual crystal forms were determined by a Diamond differential scanning calorimeter from perkin elmer (PerkinElmer) with the following thermal analysis parameters:
temperature range (. Degree. C.): 30-300
Scanning rate (. Degree. C./min): 20
Protective gas: nitrogen gas
3. Thermogravimetric analysis (TGA)
TGA data for each crystal form was determined by a Pyris 1 instrument from perkin elmer with the following thermal analysis parameters:
temperature range (. Degree. C.): 30-350 deg.C
Scanning rate (. Degree. C./min): 20
Protective gas: nitrogen gas
Technical effects
The crystal form has the advantages of high solubility, high stability, low hygroscopicity/hygroscopicity and the like, and has good application prospect.
Examples
The following examples are intended to illustrate specific embodiments of the present invention, but are not intended to limit the invention in any way.
Example 1 preparation of a Compound of formula (I)
3-Acetylbenzoic acid (200 g) was dissolved in 2L of methanol (or ethanol, propanol) and 128ml of concentrated sulfuric acid was slowly added at room temperature. The mixture was heated to reflux and reacted overnight. After the completion of the detection reaction, methanol was removed by concentration under reduced pressure. The remaining oil was dissolved in 2L of ethyl acetate, washed 1 time with 1L of water, 2 times with 1L of saturated sodium bicarbonate, and 1 time with 0.5L of saturated brine, respectively. The organic phase was dried over anhydrous sodium sulfate, and ethyl acetate was then removed by concentration under reduced pressure to give a red oil, which was cooled to room temperature to precipitate 189g of a yellow solid (intermediate (1)). The yield thereof was found to be 87%.
Intermediate (1) (195 g) was dissolved in toluene (1L), DMF-DMA (195 ml) was added, and the solution was heated to reflux. The reaction was carried out for 6 hours. After the completion of the reaction was detected, the solvent was removed by concentration under reduced pressure to give a brown oil. 400ml of methyl t-butyl ether was added, filtered and dried under reduced pressure to obtain 191g of a yellow solid (intermediate (2)). The yield thereof was found to be 75%.
6-aminouracil (109 g) was dissolved in 2.5L of acetic acid, and intermediate (2) (167 g) was added to the system in portions, and heated to 100 ℃ with stirring. The reaction was carried out for 12 hours. Detecting the reaction is complete, and removing the mixed solvent under reduced pressure. pH =7 was adjusted with 2N aqueous potassium hydroxide solution and filtered. The solid was stirred in 400ml of saturated aqueous citric acid (1.5L) for 1 hour, filtered and the filter cake was washed with water to neutrality to give 204g of a yellow powder (intermediate (3)). Yield: 95.8 percent.
Intermediate (3) (200 g) was dissolved in 3L of phosphorus oxychloride and heated to 120 ℃ under reflux for 18 h. After completion of the reaction was checked, the solvent was evaporated to dryness, ethyl acetate (2L) was added and slurried, followed by suction filtration and removal of the residual solvent under reduced pressure to obtain 202g of a flocculent solid (intermediate (4)). Yield: 90.9 percent.
Intermediate (4) (100 g) was dissolved in tetrahydrofuran (4L), and bridged morpholine hydrochloride (53.7 g), and DIEA (152 ml) were added and stirred at room temperature for 3 hours. To examine the completion of the reaction, the reaction solution was evaporated to dryness to give a red solid, ethyl acetate (2L) was added and slurried, suction filtered, and the residual solvent was removed under reduced pressure to give 113g of a reddish solid (intermediate (5)). Yield: 91.5 percent.
Intermediate (5) (50 g) was dissolved in 1.5L DMF and DIEA (31.5 g) and 3-S-methylmorpholine (18.5 g) were added sequentially and heated to reflux at 140 ℃ for 24 hours. And cooling to room temperature. The solvent was removed by concentration under reduced pressure, and 3L of ethyl acetate was added to dissolve the crude product, which was washed 2 times with 2000ml of water, 1 time with 1000ml of saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a yellow solid crude product. The crude product was slurried with 300ml ethyl acetate, filtered off with suction and dried under reduced pressure to give 41g of intermediate (6). Yield: 70.7 percent.
The intermediate (6) (40 g) was dissolved in 30% methylamine alcohol solution (1100 ml) and reacted at 40-45 ℃ for 22 hours. After completion of the reaction was checked, the solvent was removed by concentration under reduced pressure, and the residue was added to 2L of methylene chloride, washed 3 times with 500ml of water, 1 time with 500ml of saturated saline, and the organic layer was dried over anhydrous sodium sulfate. Concentrating under reduced pressure. The solid was slurried with 400ml of ethyl acetate, filtered and dried. 36g of compound of formula (I) are obtained.
Example 2 preparation of form I
10g (21.07 mmol) of the compound of formula (I) and isopropanol (7.8g, 10mL,0.78X, 1V) were put into a 500ml three-necked flask, ethyl acetate (90g, 100mL,9.0X, 10V) was added, then the temperature was raised to 70 to 80 ℃, the mixture was stirred at 70 to 80 ℃ for 1 to 2 hours, the temperature was adjusted to 0 to 10 ℃, the mixture was stirred at 0 to 10 ℃ for 2 to 3 hours, and crystallization was carried out by slow cooling. The mixture was filtered, and the filter cake was washed with ethyl acetate (9g, 10mL,0.9X, 1V), and dried at 50-55 ℃ for 10-15 hours to obtain 9.2g of crystalline form I as a pale yellow solid.
Example 3 preparation of form II
About 200mg of the compound of formula (I) is weighed into a glass vial, 2ml of methanol is added and heated to 50-60 ℃ and stirred for about 10 minutes, the sample being a clear solution. 0.25mol/L H is added dropwise with stirring 2 SO 4 3ml of the solution (molar ratio 1: 1.8) was stirred at 50-60 ℃ for 1 hour to give a clear solution. The solution was blow-dried with nitrogen at room temperature and 2ml acetonitrile was added and stirred at 50-60 ℃ for 2 hours. Filtering the suspension, and drying the solid at 40-50 ℃ overnight to obtain the crystal form II.
Example 4 solubility test
In order to examine the solubility of different salt forms and crystal forms in different pH buffer solutions, the solubility of artificial gastric juice and intestinal juice is simulated. About 3mg of solid is precisely weighed into a liquid phase sampling bottle and 1ml of different solvents is added and sonicated for 10 minutes. After dispersing it uniformly, shaking at 200rpm at 25 ℃ for 20 hours, taking out, centrifuging at 15000rpm for 15 minutes, taking up the supernatant and diluting it by a certain multiple using a corresponding solvent, measuring the concentration using HPLC, and measuring the pH. The HPLC conditions are shown in Table 3. The results of the solubility measurements are shown in Table 4.
TABLE 3 HPLC conditions
TABLE 4 solubility test results
Abbreviations:
SGF: artificial Gastric juice (strained Gastric Fluid)
FaSSIF: fasted artificial Intestinal Fluid (stimulated Small Intestinal Fluid under fast state)
FeSSIF: satiety state artificial Intestinal Fluid (stimulated Small Intestinal Fluid under Fed state)
From the solubility experiment results, the solubility of the crystal form I is pH-dependent, the solubility is better under an acidic condition, the solubility in 0.IN HCL is more than 3mg/ml, the solubility is reduced under an alkaline condition, and the solubility is reduced to 0.01mg/ml under a pH6.8 condition. Form II can significantly improve solubility, particularly in water and alkaline solutions. The solubility of form II in water may be greater than 3mg/ml.
EXAMPLE 5 solution stability test
Based on the solubility test, a sample solution of 0.1N HCl, 0.05M acetate buffer pH4.5, 0.05M phosphate buffer pH6.8 and water was prepared at a concentration in the range of 100-500. Mu.g/ml. The sample solution was placed at 40 ℃ for 0 hour and 24 hours and sampled for detection of the substance concerned. The experimental results are shown in table 5, which indicates that each crystal form has good stability under the above conditions.
TABLE 5 solution stability test results
Example 6 dynamic vapor sorption analysis (DVS) of form I
The DVS data for form I was determined by the DVS inrinsic instrument from SMS corporation with the following test parameters:
temperature (. Degree. C.): 25
Initial humidity (% RH): 0
End point humidity (% RH): 95
Humidity gradient (% RH): 5
Cycle number: 1
As shown in fig. 7, form I has low hygroscopicity, and the hygroscopic gain is less than 0.25% at a relative humidity of 95%.
Example 7 hygroscopicity analysis of form II
The test is carried out according to the guiding principle of the moisture absorption test of the medicines in the second appendix XIX J of the 2010 version of Chinese pharmacopoeia. Appropriate amounts of three batches of crystal form II samples are respectively taken and spread in a weighing bottle which is saturated in a constant temperature dryer at 25 +/-1 ℃ one day before the test (saturated ammonium chloride solution is placed at the lower part, the relative humidity is 80%), the thickness is about 1mm, and the samples are precisely weighed. And placing the weighing bottle in the constant-temperature and constant-humidity dryer after the bottle is opened, and precisely weighing the bottle after the bottle is placed for 24 hours. The results are shown in Table 6, which shows that the product has no hygroscopicity (Chinese pharmacopoeia 2010 edition appendix XIX J medicament hygroscopicity test guiding principle: less than 0.2% of hygroscopicity weight gain indicates no or almost no hygroscopicity).
TABLE 6 hygroscopicity results for form II
It should be understood that the above examples are for illustrative purposes only and are not intended to limit the scope of the present invention, and that various insubstantial modifications and adaptations of the invention may be made by those skilled in the art in light of the above teachings.
Claims (9)
1. Crystalline form II of the sulphate salt of the compound of formula (I) having an X-ray powder diffraction pattern with characteristic diffraction peaks at the following 2 Θ angles: 6.889 +/-0.2 degrees, 8.523 +/-0.2 degrees, 17.306 +/-0.2 degrees, 18.668 +/-0.2 degrees, 20.443 +/-0.2 degrees, 21.196 +/-0.2 degrees, 23.684 +/-0.2 degrees;
and has an X-ray powder diffraction pattern having characteristic diffraction peaks at eight or more 2-theta angles selected from the group consisting of: 6.889 + -0.2 deg., 8.523 + -0.2 deg., 9.295 + -0.2 deg., 12.554 + -0.2 deg., 12.886 + -0.2 deg., 13.797 + -0.2 deg., 15.758 + -0.2 deg., 16.634 + -0.2 deg., 17.306 + -0.2 deg., 18.668 + -0.2 deg., 20.443 + -0.2 deg., 21.196 + -0.2 deg., 23.186 + -0.2 deg., 23.684 + -0.2 deg..
2. The crystalline form of claim 1 having an X-ray powder diffraction pattern having characteristic diffraction peaks at nine or more 2 θ angles selected from the group consisting of: 6.889 + -0.2 deg., 8.523 + -0.2 deg., 9.295 + -0.2 deg.,
12.554±0.2°，12.886±0.2°，13.797±0.2°，15.758±0.2°，16.634±0.2°，17.306±0.2°，18.668±0.2°，20.443±0.2°，21.196±0.2°，23.186±0.2°，23.684±0.2°。
3. the crystalline form of claim 1 having an X-ray powder diffraction pattern having characteristic diffraction peaks at ten or more 2 θ angles selected from the group consisting of: 6.889 + -0.2 deg., 8.523 + -0.2 deg., 9.295 + -0.2 deg.,
12.554±0.2°，12.886±0.2°，13.797±0.2°，15.758±0.2°，16.634±0.2°，17.306±0.2°，18.668±0.2°，20.443±0.2°，21.196±0.2°，23.186±0.2°，23.684±0.2°。
4. the crystalline form of claim 1 having an X-ray powder diffraction pattern with characteristic diffraction peaks at eleven or more 2 θ angles selected from the group consisting of: 6.889 +/-0.2 degrees, 8.523 +/-0.2 degrees, 9.295 +/-0.2 degrees,
12.554±0.2°，12.886±0.2°，13.797±0.2°，15.758±0.2°，16.634±0.2°，17.306±0.2°，18.668±0.2°，20.443±0.2°，21.196±0.2°，23.186±0.2°，23.684±0.2°。
5. the crystalline form of claim 1 having an X-ray powder diffraction pattern with characteristic diffraction peaks at twelve or more 2 θ angles selected from the group consisting of: 6.889 + -0.2 deg., 8.523 + -0.2 deg., 9.295 + -0.2 deg.,
12.554±0.2°，12.886±0.2°，13.797±0.2°，15.758±0.2°，16.634±0.2°，17.306±0.2°，18.668±0.2°，20.443±0.2°，21.196±0.2°，23.186±0.2°，23.684±0.2°。
6. the crystalline form of claim 1 having an X-ray powder diffraction pattern having characteristic diffraction peaks at thirteen or more 2-theta angles selected from the group consisting of: 6.889 + -0.2 deg., 8.523 + -0.2 deg., 9.295 + -0.2 deg.,
12.554±0.2°，12.886±0.2°，13.797±0.2°，15.758±0.2°，16.634±0.2°，17.306±0.2°，18.668±0.2°，20.443±0.2°，21.196±0.2°，23.186±0.2°，23.684±0.2°。
7. the crystalline form of claim 1 having an X-ray powder diffraction pattern as shown in figure 4.
8. The crystalline form of claim 1 having a differential scanning calorimetry curve with an endothermic peak at 318.6 ± 3 ℃ and/or a thermogravimetric analysis curve with a weight loss of about 0.447% at 150 ± 3 ℃.
9. A process for preparing a crystalline form of a salt of a compound of formula (I), said crystalline form being as claimed in any one of claims 1 to 8, and said process comprising the steps of:
a) Mixing the compound of formula (I) and methanol, heating and stirring;
b) Adding an acid solution while stirring, and stirring under a heating condition;
c) Blowing the solution to dryness, adding acetonitrile, and stirring under a heating condition; and
d) Filtering and drying.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201711085175 | 2017-11-07 | ||
| CN2017110851757 | 2017-11-07 | ||
| PCT/CN2018/114354 WO2019091400A1 (en) | 2017-11-07 | 2018-11-07 | Salt form and crystal form of pyridopyrimidine compound and preparation method thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN111148747A CN111148747A (en) | 2020-05-12 |
| CN111148747B true CN111148747B (en) | 2023-04-04 |
Family
ID=66438202
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201880061016.XA Active CN111148747B (en) | 2017-11-07 | 2018-11-07 | Salt form and crystal form of pyridopyrimidine compound and preparation method thereof |
Country Status (2)
| Country | Link |
|---|---|
| CN (1) | CN111148747B (en) |
| WO (1) | WO2019091400A1 (en) |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102887895A (en) * | 2011-07-22 | 2013-01-23 | 山东轩竹医药科技有限公司 | Pyridopyrimidine mammalian target of rapamycin (mTOR) inhibitor |
| CN103588792A (en) * | 2013-03-04 | 2014-02-19 | 中国科学院上海药物研究所 | Pyrazolopyrimidine or pyrimidinopyrimidine compounds, preparation method therefor, pharmaceutical compositions thereof and applications thereof |
| WO2016150396A1 (en) * | 2015-03-25 | 2016-09-29 | 中国科学院上海药物研究所 | Process of synthesizing substituted pyridine and pyrimidine compound |
-
2018
- 2018-11-07 WO PCT/CN2018/114354 patent/WO2019091400A1/en active Application Filing
- 2018-11-07 CN CN201880061016.XA patent/CN111148747B/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102887895A (en) * | 2011-07-22 | 2013-01-23 | 山东轩竹医药科技有限公司 | Pyridopyrimidine mammalian target of rapamycin (mTOR) inhibitor |
| CN103588792A (en) * | 2013-03-04 | 2014-02-19 | 中国科学院上海药物研究所 | Pyrazolopyrimidine or pyrimidinopyrimidine compounds, preparation method therefor, pharmaceutical compositions thereof and applications thereof |
| WO2016150396A1 (en) * | 2015-03-25 | 2016-09-29 | 中国科学院上海药物研究所 | Process of synthesizing substituted pyridine and pyrimidine compound |
Non-Patent Citations (2)
| Title |
|---|
| A.John Blacker et al..Salt Screening and Selection.《Pharmaceutical Process Development Current Chemical and Engineering Challenges》.The Royal Society of Chemistry,2011,第300页. * |
| 赵桂森等主编.药物的化学结构与生物活性的关系.《新药设计与开发基础》.山东大学出版社,2015,第93-94页. * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN111148747A (en) | 2020-05-12 |
| WO2019091400A1 (en) | 2019-05-16 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN107955019B (en) | Salt form and crystal form of EGFR inhibitor and preparation method thereof | |
| CN112912380B (en) | Crystal form and amorphous form of MEK inhibitor and application thereof | |
| CN110483485A (en) | Pyrimidines, preparation method and medical usage | |
| WO2018028591A1 (en) | Quinoline derivative and use thereof | |
| CN112424202B (en) | Crystal forms of active compounds inhibiting CDK4/6 and uses thereof | |
| CN109053592B (en) | 1- (2, 5-dimethoxyphenyl) -3- (substituted pyrimidine-4-yl) urea compound and preparation and application thereof | |
| CN111479809A (en) | Crystal form and salt form of TGF- β RI inhibitor and preparation method thereof | |
| JP2023536491A (en) | Solid form of compound | |
| CN111148747B (en) | Salt form and crystal form of pyridopyrimidine compound and preparation method thereof | |
| CN109053594B (en) | 1- (3, 5-dimethoxyphenyl) -3- (substituted pyrimidine-4-yl) urea compound and preparation and application thereof | |
| CN109369620B (en) | Pyridine compound, preparation method thereof and application thereof in resisting gastric cancer | |
| WO2023174400A1 (en) | Salt of substituted amino six-membered nitric heterocyclic compound, crystal form thereof, method for preparing same, and use thereof | |
| CN116987066A (en) | Pyrimidine compound and preparation method and application thereof | |
| CN112028880A (en) | Oxitinib dimer, preparation method and application thereof | |
| JP7101781B2 (en) | Salt morphology as an Akt inhibitor and its crystalline morphology | |
| WO2022063229A1 (en) | Salt of arylaminoquinazoline-containing compound, and preparation method therefor and use thereof | |
| TWI793207B (en) | Salt form, crystal form as fgfr4 inhibitor compound and preparation method thereof | |
| EP3632912B1 (en) | Pyridoquinazoline derivatives useful as protein kinase inhibitors | |
| CN112110864A (en) | 4-amide substituted pyrimidine targeted DDR1 inhibitor, preparation method thereof and application of inhibitor in antitumor activity | |
| CN115340502B (en) | BCL-XL inhibitor and preparation method and application thereof | |
| CN113784971B (en) | Crystal form of EGFR inhibitor and preparation method thereof | |
| CN115340499B (en) | BCL-XL inhibitors and uses thereof | |
| CN114907342A (en) | Polymorph of free base of nitrogen-containing fused heterocyclic compound and preparation method and application thereof | |
| TWI826013B (en) | Crystal forms of imidazolinone derivatives | |
| CN110117275B (en) | Aminopyrimidine compound and application thereof in anti-cancer drugs |
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 |