CN117915919A - Polymorphs, pharmaceutical compositions and uses of azaaromatic ring compounds and pharmaceutically acceptable salts thereof - Google Patents

Polymorphs, pharmaceutical compositions and uses of azaaromatic ring compounds and pharmaceutically acceptable salts thereof Download PDF

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Publication number
CN117915919A
CN117915919A CN202280060100.6A CN202280060100A CN117915919A CN 117915919 A CN117915919 A CN 117915919A CN 202280060100 A CN202280060100 A CN 202280060100A CN 117915919 A CN117915919 A CN 117915919A
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ray powder
diffraction pattern
powder diffraction
compound
free base
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赵双妮
王吉标
陶涛
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Yangtze River Pharmaceutical Group Co Ltd
Shanghai Haiyan Pharmaceutical Technology Co Ltd
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Yangtze River Pharmaceutical Group Co Ltd
Shanghai Haiyan Pharmaceutical Technology Co Ltd
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    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders

Abstract

Polymorphs of an azaaromatic ring compound and pharmaceutically acceptable salts thereof, pharmaceutical compositions containing the same, methods for preparing the same, and use of the polymorphs or pharmaceutical compositions containing the same in preparing medicaments for preventing or treating cancers or immune related diseases mediated by adenosine A2A receptors and/or adenosine a 2B receptors.

Description

Polymorphs, pharmaceutical compositions and uses of azaaromatic ring compounds and pharmaceutically acceptable salts thereof
RELATED APPLICATIONS
The present application claims priority from chinese patent application No.202111080394.2 entitled "polymorphs of azaaromatic ring compounds and pharmaceutically acceptable salts thereof, pharmaceutical compositions and uses", filed on 9/15/2021, the entire contents of which are incorporated herein by reference.
Technical Field
The application relates to the technical field of medicines, in particular to a polymorph of an azaaromatic ring compound 3- (4-amino-6- (1- ((1-ethyl-1H-pyrazol-3-yl) methyl) -1H-1,2, 3-triazole-4-yl) -5-fluoropyrimidine-2-yl) -2-methylbenzonitrile or pharmaceutically acceptable salt thereof, a pharmaceutical composition containing the polymorph, a preparation method of the polymorph and application of the pharmaceutical composition.
Background
Adenosine (Adenosine) is an endogenous nucleoside that is spread throughout the cells of the human body, consisting of adenine and ribose, which are widely distributed both inside and outside the cells. Adenosine is involved in a variety of physiological and biochemical functions in the body, for example, adenosine can directly enter the myocardium, phosphorylate to form adenosine triphosphate (Adenosine triphosphate, ATP), and participate in the energy metabolism of the myocardium. In the central nervous system (Central Nervous System, CNS), adenosine controls neurotransmitter release and postsynaptic neuron responses, and acts to regulate motor, protect neurons, influence important life processes such as sleep and wakefulness. In pathological conditions, extracellular adenosine concentrations can increase significantly under tumor or hypoxic conditions. Adenosine can play an important role in tumor immunosuppression by promoting tumor angiogenesis, proliferation, progression, and tumor migration.
Adenosine receptors (Adenosine Receptor, AR) belong to the family of G protein-coupled receptors (Guanosine-binding Protein Coupled Receptor, gpcrs), the endogenous ligand of which is adenosine. The adenosine receptor currently known consists of four subtypes a 1、A 2A、A 2B and a 3. Wherein binding of adenosine to the a 1 or a 3 receptor inhibits cyclic adenosine monophosphate (cAMP) production; and the binding with the A 2A or A 2B receptor can activate the adenosine activating enzyme, so as to up-regulate the level of cAMP and play a further physiological regulation role.
Both a 1 and a 3 receptors are mainly expressed in the central nervous system, whereas both a 2A and a 2B adenosine receptors are expressed in both the central nervous system and the peripheral system. In the tumor microenvironment, two adenosine receptors A 2A and A 2B are widely expressed in immune cells, and have a very strong immunosuppressive function. An increase in extracellular adenosine concentration is one of the important mechanisms of immune escape of tumor cells, and its concentration level is determined by the level of ATP and the expression levels of CD39 and CD 73. The increase in extracellular adenosine concentration is associated with cell death or hypoxia release of large amounts of ATP in the tumor microenvironment, which can be up to 10-20 times that of normal tissue. Adenosine binds to adenosine receptors in the tumor microenvironment, and can inhibit anti-tumor responses, such as inhibiting cd8+ T cell function, enhancing immunosuppressive regulatory T cell function, inhibiting antigen presenting cell function by dendritic cells, etc. Recent studies have shown that binding to the a 2A receptor can also inhibit the tumor killing effect of natural killer cells. Further studies have shown that a 2A adenosine receptor antagonists can increase the viability and killing capacity of dendritic antigen presenting cells, T cells, and natural killer cells, inhibit the function of regulatory T cells (T-regs), bone marrow-derived suppressor cells (MDSCs), and tumor-associated macrophages (TAMs), eliminate tumor immune tolerance, promote the occurrence of tumor immune responses, thereby causing tumor growth to be inhibited, and extend the survival of mice. In addition, the a 2B receptor has also been reported to promote tumor migration in murine melanoma and triple negative breast cancer models, and thus a 2B receptor antagonists are also effective cancer therapeutic targets. Blocking the activation of adenosine signaling pathways reduces or relieves immunosuppression, enhancing the anti-tumor function of immune cells, particularly T cells, is therefore considered to be one of the effective means of cancer treatment. The A 2A/A 2B dual receptor antagonist is used for simultaneously blocking the activation of the two receptors, and has profound clinical application value for tumor treatment in terms of mechanism, which is to regulate and control different immune cell groups and comprehensively block the immunosuppression effect brought by adenosine in microenvironment.
In order to better meet the market demand, compounds having a 2A/A 2B receptor antagonistic activity and pharmaceutically acceptable salts and polymorphs thereof have been further developed to facilitate further drug development.
Disclosure of Invention
The application provides a polymorph of an azaaromatic ring compound shown in a formula (X) or pharmaceutically acceptable salt thereof, a pharmaceutical composition containing the polymorph, a preparation method or application thereof,
The pharmaceutically acceptable salt is selected from: hydrochloride, sulfate, citrate, fumarate or succinate salts.
In some embodiments, the polymorphs of the compound of formula X or the polymorphs of the pharmaceutically acceptable salts of the compound of formula X are each independently in anhydrous form, in hydrate form or in solvate form.
Each of the X-ray powder diffraction patterns referred to in the present application can be obtained independently using cu—kα radiation.
In a first aspect of the present application, there is provided form I, i.e. form I of the free base, of the compound of formula (X) having an X-ray powder diffraction pattern with characteristic diffraction peaks at the following 2θ (°) angles: 7.57.+ -. 0.2, 13.41.+ -. 0.2, 14.64.+ -. 0.2, 19.81.+ -. 0.2 and 24.43.+ -. 0.2.
In some embodiments, the X-ray powder diffraction pattern of free base form I further comprises 1 or 2 characteristic diffraction peaks at 2θ (°) angles selected from: 24.87.+ -. 0.2 and 27.46.+ -. 0.2.
In some embodiments, the X-ray powder diffraction pattern of free base form I further comprises 2 or more characteristic diffraction peaks at 2θ (°) angles selected from: 8.56.+ -. 0.2, 15.40.+ -. 0.2, 18.55.+ -. 0.2, 21.25.+ -. 0.2, 23.05.+ -. 0.2, 23.59.+ -. 0.2 and 25.60.+ -. 0.2.
In some embodiments, the X-ray powder diffraction pattern of free base form I has characteristic diffraction peaks ：7.57±0.2、8.56±0.2、10.60±0.2、11.80±0.2、13.41±0.2、14.16±0.2、14.64±0.2、15.40±0.2、16.63±0.2、17.23±0.2、18.55±0.2、19.81±0.2、21.25±0.2、22.18±0.2、22.46±0.2、23.05±0.2、23.59±0.2、24.43±0.2、24.87±0.2、25.60±0.2、26.03±0.2 and 27.46 ±0.2 at the following 2θ (°) angles.
In some embodiments, the X-ray powder diffraction pattern of free base form I has diffraction peaks at 2θ (°) values shown in table 1, with the relative intensities of the diffraction peaks shown in table 1. Wherein the definition of each relative intensity symbol is shown in table 12.
TABLE 1
2θ(°) I/I 0 2θ(°) I/I 0 2θ(°) I/I 0
7.57 VS 16.63 W 23.59 M
8.56 M 17.23 W 24.43 S
10.60 W 18.55 M 24.87 S
11.80 W 19.81 S 25.60 M
13.41 S 21.25 M 26.03 W
14.16 W 22.18 W 27.46 S
14.64 S 22.46 W - -
15.40 M 23.05 M - -
In some embodiments, the X-ray powder diffraction pattern of free base form I is substantially as shown in figure 1.
In some embodiments, the X-ray powder diffraction pattern of free base form I is shown in fig. 1.
In some embodiments, the differential scanning calorimetry curve of the free base form I has an endothermic peak at 179.10 ±3 ℃.
In some embodiments, the differential scanning calorimetry curve of the free base form I has an endotherm at 179.10 ±2 ℃.
In some embodiments, the differential scanning calorimetry curve of the free base form I has an endotherm at 179.10 ±0.5 ℃.
In some embodiments, the differential scanning calorimetry curve of the free base form I is substantially as shown in figure 2.
In some embodiments, the differential scanning calorimetry curve of the free base form I is shown in figure 2.
In a second aspect of the present application, there is provided a process for the preparation of the free base form I comprising the steps of:
mixing a compound of formula (X) with a solvent of I-3, heating to dissolve at a temperature of 45 ℃ to 85 ℃, cooling to 0 ℃ to room temperature, separating to obtain a solid of I-3, and
Drying the I-3 th solid to obtain the free base form I;
Wherein the I-3 solvent is methanol or ethanol.
In some specific embodiments, the process for preparing the free base form I comprises the steps of:
Mixing a compound of formula (X) with a solvent of I-3, heating to dissolve at a temperature of 45 ℃ to 55 ℃, cooling to 0 ℃ to 4 ℃, separating to obtain a solid of I-3, and
Drying the I-3 th solid to obtain the free base form I;
Wherein the I-3 solvent is methanol or ethanol.
In some specific embodiments, the process for preparing the free base form I comprises the steps of:
mixing a compound of formula (X) with a solvent of I-3A, heating to dissolve at a temperature of 70-80 ℃, cooling to room temperature, separating to obtain a solid of I-3, and
Drying the I-3 th solid to obtain the free base form I;
wherein the first solvent I-3A is ethanol.
In some specific embodiments, the process for preparing the free base form I comprises the steps of:
Mixing a compound of formula (X) with a solvent of type I-3B, heating to dissolve at a temperature of 60-70 ℃, cooling to room temperature, separating to obtain a solid of type I-3, and
Drying the I-3 th solid to obtain the free base form I;
Wherein the I-3B solvent is methanol.
In a third aspect of the present application, there is provided form IV of the compound of formula (X), i.e. form IV of the free base, having an X-ray powder diffraction pattern with characteristic diffraction peaks at the following 2θ (°) angles: 11.88.+ -. 0.2, 14.17.+ -. 0.2, 16.96.+ -. 0.2, 22.63.+ -. 0.2, 23.56.+ -. 0.2 and 25.66.+ -. 0.2.
In some embodiments, the X-ray powder diffraction pattern of free base form IV further comprises at least one characteristic diffraction peak at 2θ (°) angle selected from the group consisting of: 15.76.+ -. 0.2 and 26.08.+ -. 0.2.
In some embodiments, the X-ray powder diffraction pattern of free base form IV further comprises at least one characteristic diffraction peak at 2θ (°) angle selected from the group consisting of: 15.76.+ -. 0.2, 26.08.+ -. 0.2 and 37.48.+ -. 0.2.
In some embodiments, the X-ray powder diffraction pattern of free base form IV further comprises 2 or more characteristic diffraction peaks at 2θ (°) angles selected from the group consisting of: 14.89.+ -. 0.2, 21.73.+ -. 0.2, 24.43.+ -. 0.2, 26.65.+ -. 0.2, 27.39.+ -. 0.2, 28.42.+ -. 0.2 and 30.24.+ -. 0.2.
In some embodiments, the X-ray powder diffraction pattern of free base form IV further comprises at least one characteristic diffraction peak at 2θ (°) angle selected from the group consisting of: 8.71.+ -. 0.2, 19.93.+ -. 0.2 and 31.78.+ -. 0.2.
In some embodiments, the X-ray powder diffraction pattern of free base form IV has characteristic diffraction peaks ：8.71±0.2、9.57±0.2、11.88±0.2、14.17±0.2、14.89±0.2、15.76±0.2、16.96±0.2、19.93±0.2、21.73±0.2、22.63±0.2、23.56±0.2、24.43±0.2、25.66±0.2、26.08±0.2、26.65±0.2、27.39±0.2、28.42±0.2、30.24±0.2、31.78±0.2 and 33.15 ±0.2 at the following 2θ (°) angles.
In some embodiments, the X-ray powder diffraction pattern of free base form IV has characteristic diffraction peaks ：8.71±0.2、9.57±0.2、11.88±0.2、14.17±0.2、14.89±0.2、15.76±0.2、16.96±0.2、19.93±0.2、21.73±0.2、22.63±0.2、23.56±0.2、24.43±0.2、25.66±0.2、26.08±0.2、26.65±0.2、27.39±0.2、28.42±0.2、30.24±0.2、31.78±0.2、33.15±0.2 and 37.48 ±0.2 at the following 2θ (°) angles.
In some embodiments, the X-ray powder diffraction pattern of free base form IV has diffraction peaks at 2θ (°) values shown in table 2, with the relative intensities of the diffraction peaks shown in table 2. Wherein the definition of each relative intensity symbol is shown in table 12.
TABLE 2
2θ(°) I/I 0 2θ(°) I/I 0 2θ(°) I/I 0
8.71 M 19.93 M 26.65 M
9.57 W 21.73 M 27.39 M
11.88 VS 22.63 S 28.42 M
14.17 VS 23.56 VS 30.24 M
14.89 M 24.43 M 31.78 M
15.76 S 25.66 VS 33.15 W
16.96 VS 26.08 S 37.48 S
In some embodiments, the X-ray powder diffraction pattern of free base form IV is substantially as shown in figure 4.
In some embodiments, the X-ray powder diffraction pattern of free base form IV is shown in fig. 4.
In some embodiments, the differential scanning calorimetry curve of the free base form IV has an endothermic peak at 170.43 ±3 ℃.
In some embodiments, the differential scanning calorimetry curve of the free base form IV has an endotherm at 170.43 ±2 ℃.
In some embodiments, the differential scanning calorimetry curve of the free base form IV has an endotherm at 170.43 ±0.5 ℃.
In some embodiments, the differential scanning calorimetry curve of the free base form IV is substantially as shown in figure 5.
In some embodiments, the differential scanning calorimetry curve of the free base form IV is shown in figure 5.
In a fourth aspect of the application, there is provided a process for the preparation of form IV of the free base comprising the steps of:
Mixing the free base form I of the first aspect of the application with an IV-1 solvent, suspending and shaking at room temperature for 20 to 30 hours, separating to obtain an IV-1 solid, drying the IV-1 solid to obtain the free base form IV; wherein the IV-1 th solvent is isopropanol; or (b)
Mixing the free base form I of the first aspect of the application with IV-2 solvent, suspending and shaking at room temperature for 160 to 170 hours, separating to obtain IV-2 solid, drying the IV-2 solid to obtain the free base form IV; wherein the IV-2 solvent is isopropanol or water.
In a fifth aspect of the present application, there is provided form V of the compound of formula (X), i.e. form V of the free base, having an X-ray powder diffraction pattern with characteristic diffraction peaks at the following 2θ (°) angles: 11.88.+ -. 0.2, 16.36.+ -. 0.2, 16.99.+ -. 0.2, 22.99.+ -. 0.2, 23.47.+ -. 0.2 and 26.41.+ -. 0.2.
In some embodiments, the X-ray powder diffraction pattern of free base form V has characteristic diffraction peaks at the following 2θ (°) angles: 11.88.+ -. 0.2, 16.36.+ -. 0.2, 16.99.+ -. 0.2, 22.99.+ -. 0.2, 23.47.+ -. 0.2, 26.41.+ -. 0.2 and 37.48.+ -. 0.2.
In some embodiments, the X-ray powder diffraction pattern of free base form V further comprises at least one characteristic diffraction peak at 2θ (°) angle selected from the group consisting of: 7.90.+ -. 0.2, 13.71.+ -. 0.2, 14.14.+ -. 0.2, 15.31.+ -. 0.2, 17.80.+ -. 0.2, 18.76.+ -. 0.2, 21.34.+ -. 0.2, 24.82.+ -. 0.2, 25.51.+ -. 0.2, 27.88.+ -. 0.2 and 30.46.+ -. 0.2.
In some embodiments, the X-ray powder diffraction pattern of free base form V further comprises at least one characteristic diffraction peak ：7.90±0.2、13.71±0.2、14.14±0.2、15.31±0.2、17.80±0.2、18.76±0.2、21.34±0.2、24.82±0.2、25.51±0.2、27.88±0.2、30.46±0.2 and 43.60±0.2 at 2θ (°) angles selected from the group.
In some embodiments, the X-ray powder diffraction pattern of free base form V further comprises 2 or more characteristic diffraction peaks at 2θ (°) angles selected from: 15.77.+ -. 0.2, 20.03.+ -. 0.2, 28.40.+ -. 0.2, 30.85.+ -. 0.2, 32.71.+ -. 0.2, 33.15.+ -. 0.2 and 34.62.+ -. 0.2.
In some embodiments, the X-ray powder diffraction pattern of free base form V has characteristic diffraction peaks ：7.90±0.2、8.62±0.2、9.73±0.2、11.88±0.2、13.71±0.2、14.14±0.2、15.31±0.2、15.77±0.2、16.36±0.2、16.99±0.2、17.80±0.2、18.76±0.2、20.03±0.2、21.34±0.2、22.99±0.2、23.47±0.2、24.82±0.2、25.51±0.2、26.41±0.2、27.88±0.2、28.40±0.2、30.46±0.2、30.85±0.2、32.71±0.2、33.15±0.2 and 34.62±0.2 at the following 2θ (°) angles.
In some embodiments, the X-ray powder diffraction pattern of free base form V has characteristic diffraction peaks ：7.90±0.2、8.62±0.2、9.73±0.2、11.88±0.2、13.71±0.2、14.14±0.2、15.31±0.2、15.77±0.2、16.36±0.2、16.99±0.2、17.80±0.2、18.76±0.2、20.03±0.2、21.34±0.2、22.99±0.2、23.47±0.2、24.82±0.2、25.51±0.2、26.41±0.2、27.88±0.2、28.40±0.2、30.46±0.2、30.85±0.2、32.71±0.2、33.15±0.2、34.62±0.2、37.48±0.2 and 43.60±0.2 at the following 2θ (°) angles.
In some embodiments, the X-ray powder diffraction pattern of free base form V has diffraction peaks at 2θ (°) values shown in table 3, with the relative intensities of the diffraction peaks shown in table 3. Wherein the definition of each relative intensity symbol is shown in table 12.
TABLE 3 Table 3
2θ(°) I/I 0 2θ(°) I/I 0 2θ(°) I/I 0
7.90 S 17.80 S 28.40 M
8.62 W 18.76 S 30.46 S
9.73 W 20.03 M 30.85 M
11.88 VS 21.34 S 32.71 M
13.71 S 22.99 VS 33.15 M
14.14 S 23.47 VS 34.62 M
15.31 S 24.82 S 37.48 VS
15.77 M 25.51 S 43.60 S
16.36 VS 26.41 VS - -
16.99 VS 27.88 S - -
In some embodiments, the X-ray powder diffraction pattern of free base form V is substantially as shown in figure 6.
In some embodiments, the X-ray powder diffraction pattern of free base form V is shown in fig. 6.
In some embodiments, the differential scanning calorimetry curve of the free base form V has an endotherm at 179.02±3 ℃.
In some embodiments, the differential scanning calorimetry curve of the free base form V has an endotherm at 179.02±2 ℃.
In some embodiments, the differential scanning calorimetry curve of the free base form V has an endotherm at 179.02±0.5 ℃.
In some embodiments, the differential scanning calorimetry curve of the free base form V is substantially as shown in figure 7.
In some embodiments, the differential scanning calorimetry curve of the free base form V is shown in figure 7.
In a sixth aspect of the present application, there is provided a process for the preparation of form V of the free base comprising the steps of:
Mixing the free base form I of the first aspect of the application with a V-1 solvent, suspending and shaking at room temperature for 160 to 170 hours, separating to obtain a V-1 solid, drying the V-1 solid to obtain the free base form V; wherein the V-1 solvent is methyl tertiary butyl ether.
Mixing and dissolving the compound of formula (X) according to the first aspect of the application with a V-2 solvent, allowing to stand at room temperature, volatilizing the V-2 solvent to dryness, obtaining the free base crystalline form V; wherein the V-2 solvent is acetone.
In a seventh aspect of the present application, there is provided form VIII, i.e. form VIII of the free base, of the compound of formula (X) having an X-ray powder diffraction pattern with characteristic diffraction peaks at the following 2θ (°) angles: 6.40.+ -. 0.2, 13.12.+ -. 0.2 and 15.91.+ -. 0.2.
In some embodiments, the X-ray powder diffraction pattern of free base form VIII further comprises 1 or 2 characteristic diffraction peaks at 2θ (°) angles selected from the group consisting of: 22.69.+ -. 0.2 and 26.95.+ -. 0.2.
In some embodiments, the X-ray powder diffraction pattern of free base form VIII further comprises at least one characteristic diffraction peak at 2θ (°) angle selected from the group consisting of: 11.62.+ -. 0.2, 12.36.+ -. 0.2, 16.62.+ -. 0.2, 18.34.+ -. 0.2, 18.88.+ -. 0.2, 24.94.+ -. 0.2 and 29.65.+ -. 0.2.
In some embodiments, the X-ray powder diffraction pattern of free base form VIII further comprises at least one characteristic diffraction peak at 2θ (°) angle selected from the group consisting of: 11.62.+ -. 0.2, 12.36.+ -. 0.2, 16.62.+ -. 0.2, 18.34.+ -. 0.2, 18.88.+ -. 0.2, 24.94.+ -. 0.2, 29.65.+ -. 0.2 and 37.48.+ -. 0.2.
In some embodiments, the X-ray powder diffraction pattern of free base form VIII has characteristic diffraction peaks ：6.40±0.2、11.62±0.2、12.36±0.2、13.12±0.2、15.91±0.2、16.62±0.2、18.34±0.2、18.88±0.2、22.69±0.2、24.94±0.2、26.95±0.2 and 29.65±0.2 at the following 2θ (°) angles.
In some embodiments, the X-ray powder diffraction pattern of free base form VIII has characteristic diffraction peaks ：6.40±0.2、11.62±0.2、12.36±0.2、13.12±0.2、15.91±0.2、16.62±0.2、18.34±0.2、18.88±0.2、22.69±0.2、24.94±0.2、26.95±0.2、29.65±0.2 and 37.48 ±0.2 at the following 2θ (°) angles.
In some embodiments, the X-ray powder diffraction pattern of free base form VIII has diffraction peaks at 2θ (°) values shown in table 4, with the relative intensities of the diffraction peaks shown in table 4. Wherein the definition of each relative intensity symbol is shown in table 12.
TABLE 4 Table 4
2θ(°) I/I 0 2θ(°) I/I 0 2θ(°) I/I 0
6.40 VS 16.62 M 26.95 M
11.62 M 18.34 M 29.65 M
12.36 M 18.88 M 37.48 M
13.12 VS 22.69 M - -
15.91 S 24.94 M - -
In some embodiments, the X-ray powder diffraction pattern of free base form VIII is substantially as shown in figure 8.
In some embodiments, the X-ray powder diffraction pattern of free base form VIII is shown in fig. 8.
In some embodiments, the differential scanning calorimetry curve of the free base form VIII has an endothermic peak at 162.93 ±3 ℃.
In some embodiments, the differential scanning calorimetry curve of the free base form VIII has an endothermic peak at 162.93 ±2 ℃.
In some embodiments, the differential scanning calorimetry curve of the free base form VIII has an endotherm at 162.93 ±0.5 ℃.
In some embodiments, the differential scanning calorimetry curve of the free base form VIII is substantially as shown in figure 9.
In some embodiments, the differential scanning calorimetry curve of the free base form VIII is shown in figure 9.
In an eighth aspect of the application, there is provided a process for the preparation of crystalline form VIII of the free base comprising the steps of:
mixing the free base form I, the free base form iv or the free base form V described in the above aspects with a Z 3 -1 solvent, suspending and shaking at room temperature for 70 to 80 hours, separating to obtain a Z 3 -1 solid, and drying the Z 3 -1 solid to obtain the free base form VIII; wherein the Z 3 -1 solvent is acetone or ethanol water solution with the volume fraction of 50%.
In a ninth aspect of the present application, there is provided crystalline form I of the hydrochloride salt of the compound of formula (X) having an X-ray powder diffraction pattern with characteristic diffraction peaks at the following 2Θ (°) angles: 11.95.+ -. 0.2, 24.37.+ -. 0.2, 25.21.+ -. 0.2 and 26.35.+ -. 0.2.
In some embodiments, the X-ray powder diffraction pattern of hydrochloride form I further comprises at least one characteristic diffraction peak at 2θ (°) angle selected from the group consisting of: 8.83.+ -. 0.2, 14.13.+ -. 0.2, 15.33.+ -. 0.2, 15.68.+ -. 0.2, 18.86.+ -. 0.2, 23.64.+ -. 0.2, 27.67.+ -. 0.2 and 28.57.+ -. 0.2.
In some embodiments, the X-ray powder diffraction pattern of hydrochloride form I has characteristic diffraction peaks ：8.83±0.2、11.95±0.2、14.13±0.2、15.33±0.2、15.68±0.2、17.25±0.2、18.86±0.2、23.64±0.2、24.37±0.2、25.21±0.2、26.35±0.2、27.67±0.2 and 28.57±0.2 at the following 2θ (°) angles.
In some embodiments, the X-ray powder diffraction pattern of hydrochloride form I has diffraction peaks at the 2θ (°) values shown in table 5, with the relative intensities of the diffraction peaks shown in table 5. Wherein the definition of each relative intensity symbol is shown in table 12.
TABLE 5
2θ(°) I/I 0 2θ(°) I/I 0 2θ(°) I/I 0
8.83 S 17.25 M 26.35 VS
11.95 VS 18.86 S 27.67 S
14.13 S 23.64 S 28.57 S
15.33 S 24.37 VS - -
15.68 S 25.21 VS - -
In some embodiments, the hydrochloride salt form I has an X-ray powder diffraction pattern substantially as shown in figure 10.
In some embodiments, the hydrochloride salt form I has an X-ray powder diffraction pattern as shown in fig. 10.
In a tenth aspect of the application, there is provided a crystalline sulfate form I of a compound of formula (X),
The X-ray powder diffraction pattern thereof has characteristic diffraction peaks at the following 2θ (°) angles: 8.22.+ -. 0.2, 11.29.+ -. 0.2, 14.14.+ -. 0.2, 16.96.+ -. 0.2, 18.13.+ -. 0.2, 22.27.+ -. 0.2, 23.86.+ -. 0.2 and 27.79.+ -. 0.2.
In some embodiments, the X-ray powder diffraction pattern of sulfate form I further comprises 2 or more characteristic diffraction peaks at 2θ (°) angles selected from the group consisting of: 6.54.+ -. 0.2 and 11.64.+ -. 0.2.
In some embodiments, the X-ray powder diffraction pattern of sulfate form I further comprises 2 or more characteristic diffraction peaks at 2θ (°) angles selected from the group consisting of: 6.54.+ -. 0.2, 11.64.+ -. 0.2 and 37.48.+ -. 0.2.
In some embodiments, the X-ray powder diffraction pattern of sulfate form I has characteristic diffraction peaks at the following 2θ (°) angles: 6.54.+ -. 0.2, 8.22.+ -. 0.2, 11.29.+ -. 0.2, 11.64.+ -. 0.2, 14.14.+ -. 0.2, 16.96.+ -. 0.2, 18.13.+ -. 0.2, 22.27.+ -. 0.2, 23.86.+ -. 0.2 and 27.79.+ -. 0.2.
In some embodiments, the X-ray powder diffraction pattern of sulfate form I has characteristic diffraction peaks at the following 2θ (°) angles: 6.54.+ -. 0.2, 8.22.+ -. 0.2, 11.29.+ -. 0.2, 11.64.+ -. 0.2, 14.14.+ -. 0.2, 16.96.+ -. 0.2, 18.13.+ -. 0.2, 22.27.+ -. 0.2, 23.86.+ -. 0.2, 27.79.+ -. 0.2 and 37.48.+ -. 0.2.
In some embodiments, the X-ray powder diffraction pattern of sulfate form I has diffraction peaks at 2θ (°) values shown in table 6, with the relative intensities of the diffraction peaks shown in table 6. Wherein the definition of each relative intensity symbol is shown in table 12.
TABLE 6
2θ(°) I/I 0 2θ(°) I/I 0 2θ(°) I/I 0
6.54 M 14.14 S 23.86 S
8.22 S 16.96 VS 27.79 S
11.29 S 18.13 S 37.48 M
11.64 M 22.27 S - -
In some embodiments, the X-ray powder diffraction pattern of sulfate form I is substantially as shown in figure 11.
In some embodiments, the X-ray powder diffraction pattern of sulfate form I is shown in fig. 11.
In an eleventh aspect of the present application, there is provided a citrate crystalline form I of a compound of formula (X) having an X-ray powder diffraction pattern with characteristic diffraction peaks at the following 2θ (°) angles: 12.55.+ -. 0.2, 14.50.+ -. 0.2, 21.55.+ -. 0.2 and 22.75.+ -. 0.2.
In some embodiments, the X-ray powder diffraction pattern of citrate form I has characteristic diffraction peaks at the following 2θ (°) angles: 12.55.+ -. 0.2, 14.50.+ -. 0.2, 21.55.+ -. 0.2, 22.75.+ -. 0.2, 37.51.+ -. 0.2 and 43.63.+ -. 0.2.
In some embodiments, the X-ray powder diffraction pattern of citrate form I further comprises at least one characteristic diffraction peak at 2θ (°) angle selected from the group consisting of: 5.38.+ -. 0.2, 9.78.+ -. 0.2 and 13.63.+ -. 0.2.
In some embodiments, the X-ray powder diffraction pattern of citrate form I has characteristic diffraction peaks at the following 2θ (°) angles: 5.38.+ -. 0.2, 9.78.+ -. 0.2, 12.55.+ -. 0.2, 13.63.+ -. 0.2, 14.50.+ -. 0.2, 21.55.+ -. 0.2 and 22.75.+ -. 0.2.
In some embodiments, the X-ray powder diffraction pattern of citrate form I has characteristic diffraction peaks at the following 2θ (°) angles: 5.38.+ -. 0.2, 9.78.+ -. 0.2, 12.55.+ -. 0.2, 13.63.+ -. 0.2, 14.50.+ -. 0.2, 21.55.+ -. 0.2, 22.75.+ -. 0.2, 37.51.+ -. 0.2 and 43.63.+ -. 0.2.
In some embodiments, the X-ray powder diffraction pattern of citrate form I has diffraction peaks at 2θ (°) values shown in table 7, with the relative intensities of the diffraction peaks shown in table 7. Wherein the definition of each relative intensity symbol is shown in table 12.
TABLE 7
2θ(°) I/I 0 2θ(°) I/I 0 2θ(°) I/I 0
5.38 S 13.63 S 22.75 VS
9.78 S 14.50 VS 37.51 VS
12.55 VS 21.55 VS 43.63 VS
In some embodiments, the citrate salt form I has an X-ray powder diffraction pattern substantially as shown in figure 12.
In some embodiments, the citrate salt form I has an X-ray powder diffraction pattern as shown in figure 12.
In a twelfth aspect of the present application, there is provided crystalline fumarate salt form I of a compound of formula (X) having an X-ray powder diffraction pattern with characteristic diffraction peaks at the following 2θ (°) angles: 7.12.+ -. 0.2, 11.71.+ -. 0.2 and 16.90.+ -. 0.2.
In some embodiments, the X-ray powder diffraction pattern of fumarate salt form I further comprises at least one characteristic diffraction peak at 2θ (°) angle selected from the group consisting of: 23.26.+ -. 0.2, 23.65.+ -. 0.2, 24.64.+ -. 0.2 and 25.54.+ -. 0.2.
In some embodiments, the X-ray powder diffraction pattern of fumarate salt form I further comprises at least one characteristic diffraction peak at 2θ (°) angle selected from the group consisting of: 8.02.+ -. 0.2, 15.69.+ -. 0.2, 18.22.+ -. 0.2 and 26.44.+ -. 0.2.
In some embodiments, the X-ray powder diffraction pattern of fumarate salt form I further comprises at least one characteristic diffraction peak at 2θ (°) angle selected from the group consisting of: 8.02.+ -. 0.2, 15.69.+ -. 0.2, 18.22.+ -. 0.2, 26.44.+ -. 0.2 and 37.87.+ -. 0.2.
In some embodiments, the X-ray powder diffraction pattern of fumarate salt form I further comprises 2 or more characteristic diffraction peaks at 2θ (°) angles selected from: 10.48.+ -. 0.2, 13.80.+ -. 0.2, 22.00.+ -. 0.2 and 22.42.+ -. 0.2.
In some embodiments, the X-ray powder diffraction pattern of fumarate salt form I has characteristic diffraction peaks ：7.12±0.2、8.02±0.2、10.48±0.2、11.71±0.2、13.80±0.2、15.69±0.2、16.90±0.2、18.22±0.2、22.00±0.2、22.42±0.2、23.26±0.2、23.65±0.2、24.64±0.2、25.54±0.2 and 26.44±0.2 at the following 2θ (°) angles.
In some embodiments, the X-ray powder diffraction pattern of fumarate salt form I has characteristic diffraction peaks ：7.12±0.2、8.02±0.2、10.48±0.2、11.71±0.2、13.80±0.2、15.69±0.2、16.90±0.2、18.22±0.2、22.00±0.2、22.42±0.2、 23.26±0.2、23.65±0.2、24.64±0.2、25.54±0.2、26.44±0.2 and 37.87 ±0.2 at the following 2θ (°) angles.
In some embodiments, the X-ray powder diffraction pattern of fumarate salt form I has diffraction peaks at 2θ (°) values shown in table 8, with the relative intensities of the diffraction peaks shown in table 8. Wherein the definition of each relative intensity symbol is shown in table 12.
TABLE 8
2θ(°) I/I 0 2θ(°) I/I 0 2θ(°) I/I 0
7.12 VS 16.90 VS 24.64 VS
8.02 S 18.22 S 25.54 VS
10.48 M 22.00 M 26.44 S
11.71 VS 22.42 M 37.87 S
13.80 M 23.26 VS - -
15.69 S 23.65 VS - -
In some embodiments, the fumarate salt form I has an X-ray powder diffraction pattern substantially as shown in figure 13.
In some embodiments, the fumarate salt form I has an X-ray powder diffraction pattern as shown in fig. 13.
In a thirteenth aspect of the present application, there is provided crystalline succinate salt form I of the compound of formula (X) having an X-ray powder diffraction pattern with characteristic diffraction peaks at the following 2Θ (°) angles: 13.78.+ -. 0.2, 14.14.+ -. 0.2 and 22.12.+ -. 0.2.
In some embodiments, the X-ray powder diffraction pattern of succinate form I has characteristic diffraction peaks at the following 2θ (°) angles: 13.78+ -0.2, 14.14+ -0.2, 22.12+ -0.2 and 37.84+ -0.2.
In some embodiments, the X-ray powder diffraction pattern of succinate crystalline form I further comprises at least one characteristic diffraction peak at 2θ (°) angle selected from the group consisting of: 4.87.+ -. 0.2, 9.31.+ -. 0.2, 18.16.+ -. 0.2, 20.71.+ -. 0.2 and 26.83.+ -. 0.2.
In some embodiments, the X-ray powder diffraction pattern of succinate crystalline form I has characteristic diffraction peaks at the following 2θ (°) angles: 4.87.+ -. 0.2, 9.31.+ -. 0.2, 13.78.+ -. 0.2, 14.14.+ -. 0.2, 15.69.+ -. 0.2, 18.16.+ -. 0.2, 20.71.+ -. 0.2, 22.12.+ -. 0.2 and 26.83.+ -. 0.2.
In some embodiments, the X-ray powder diffraction pattern of succinate crystalline form I has characteristic diffraction peaks at the following 2θ (°) angles:
4.87.+ -. 0.2, 9.31.+ -. 0.2, 13.78.+ -. 0.2, 14.14.+ -. 0.2, 15.69.+ -. 0.2, 18.16.+ -. 0.2, 20.71.+ -. 0.2, 22.12.+ -. 0.2, 26.83.+ -. 0.2, 37.84.+ -. 0.2 and 44.07.+ -. 0.2.
In some embodiments, the X-ray powder diffraction pattern of succinate crystalline form I has diffraction peaks at 2θ (°) values shown in table 9, with the relative intensities of the diffraction peaks shown in table 9. Wherein the definition of each relative intensity symbol is shown in table 12.
TABLE 9
2θ(°) I/I 0 2θ(°) I/I 0 2θ(°) I/I 0
4.87 S 15.69 M 26.83 S
9.31 S 18.16 S 37.84 VS
13.78 VS 20.71 S 44.07 M
14.14 VS 22.12 S - -
In some embodiments, the X-ray powder diffraction pattern of the succinate salt form I is substantially as shown in figure 14.
In some embodiments, the X-ray powder diffraction pattern of the succinate salt form I is shown in fig. 14.
In a fourteenth aspect of the present application, there is provided crystalline succinate salt form ii of the compound of formula (X) having an X-ray powder diffraction pattern with characteristic diffraction peaks at the following 2Θ (°) angles: 12.49.+ -. 0.2 and 14.50.+ -. 0.2.
In some embodiments, the X-ray powder diffraction pattern of succinate crystalline form ii further comprises at least one characteristic diffraction peak at 2θ (°) angle selected from the group consisting of: 11.86.+ -. 0.2, 15.22.+ -. 0.2, 16.90.+ -. 0.2, 21.64.+ -. 0.2, 22.87.+ -. 0.2 and 25.75.+ -. 0.2.
In some embodiments, the X-ray powder diffraction pattern of succinate crystalline form ii further comprises at least one characteristic diffraction peak at 2θ (°) angle selected from the group consisting of: 11.86.+ -. 0.2, 15.22.+ -. 0.2, 16.90.+ -. 0.2, 21.64.+ -. 0.2, 22.87.+ -. 0.2, 25.75.+ -. 0.2 and 37.84.+ -. 0.2.
In some embodiments, the X-ray powder diffraction pattern of succinate form ii has characteristic diffraction peaks at the following 2θ (°) angles: 5.35.+ -. 0.2, 11.86.+ -. 0.2, 12.49.+ -. 0.2, 14.50.+ -. 0.2, 15.22.+ -. 0.2, 16.90.+ -. 0.2, 21.64.+ -. 0.2, 22.87.+ -. 0.2 and 25.75.+ -. 0.2.
In some embodiments, the X-ray powder diffraction pattern of succinate form ii has characteristic diffraction peaks at the following 2θ (°) angles: 5.35.+ -. 0.2, 11.86.+ -. 0.2, 12.49.+ -. 0.2, 14.50.+ -. 0.2, 15.22.+ -. 0.2, 16.90.+ -. 0.2, 21.64.+ -. 0.2, 22.87.+ -. 0.2, 25.75.+ -. 0.2 and 37.84.+ -. 0.2.
In some embodiments, the X-ray powder diffraction pattern of succinate form ii has diffraction peaks at 2θ (°) values shown in table 10, with the relative intensities of the diffraction peaks shown in table 10. Wherein the definition of each relative intensity symbol is shown in table 12.
Table 10
2θ(°) I/I 0 2θ(°) I/I 0 2θ(°) I/I 0
5.35 M 15.22 S 25.75 S
11.86 S 16.90 S 37.84 S
12.49 VS 21.64 S - -
14.50 VS 22.87 S - -
In some embodiments, the X-ray powder diffraction pattern of succinate form ii is substantially as shown in figure 15.
In some embodiments, the X-ray powder diffraction pattern of succinate form ii is shown in fig. 15.
In a fifteenth aspect of the present application there is provided a process for the preparation of a polymorph of a pharmaceutically acceptable salt of a compound of formula (X), comprising the steps of:
The compound of formula (X) as described above is mixed with an acid in a molar ratio of acid (hydrogen ions) to compound of formula (X) of 1.1 to 1.5:1, 1 to 3mL of solvent is added, the solution is clarified by ultrasonic heating, the reaction is carried out at 45 to 50 ℃ for 3 to 5 hours, the temperature is lowered or an anti-solvent is added to precipitate a polymorph in solid form.
In some embodiments, the acid is hydrochloric acid, sulfuric acid, citric acid, fumaric acid, or succinic acid.
In some embodiments, the solvent is ethanol, ethyl acetate, or acetone.
In some embodiments, the antisolvent is n-heptane.
In a sixteenth aspect, the present application provides a pharmaceutical composition comprising:
(a) A polymorph of a compound of formula (X) or a pharmaceutically acceptable salt thereof as described above; and (b) a pharmaceutically acceptable carrier.
In a seventeenth aspect of the present application, there is provided the use of free base form I, free base form IV, free base form V, free base form VIII of a compound of formula (X) as described above, or hydrochloride form I, sulfate form I, citrate form I, fumarate form I, succinate form ii thereof, for the preparation of an a 2A receptor or a 2B receptor inhibitor.
In an eighteenth aspect of the application there is provided the use of a polymorph of a compound of formula (X) or a pharmaceutically acceptable salt thereof, as described above, e.g. form I, form IV, form V, form VIII, or a hydrochloride, form I, a sulphate, a citrate, a fumarate, a succinate form ii, or a pharmaceutical composition according to the sixteenth aspect of the application, for the manufacture of a medicament for the prevention or treatment of a disease mediated by the adenosine a 2A receptor and/or the adenosine a 2B receptor.
The present application provides a method for preventing or treating a disease mediated by the adenosine a 2A receptor and/or the adenosine a 2B receptor, comprising administering to a patient in need thereof a therapeutically effective amount of a polymorph of a compound of formula (X) or a pharmaceutically acceptable salt thereof as described in the above embodiments, or a pharmaceutical composition as described in the above embodiments.
The present application provides polymorphs of a compound of formula (X) or a pharmaceutically acceptable salt thereof as described in the above embodiments, or a pharmaceutical composition as described in the above embodiments, for use in the prevention or treatment of diseases mediated by the adenosine a 2A receptor and/or the adenosine a 2B receptor.
In some embodiments, the disease is cancer or an immune related disease.
In some embodiments, the cancer is selected from the group consisting of prostate cancer, colon cancer, rectal cancer, pancreatic cancer, cervical cancer, gastric cancer, endometrial cancer, brain cancer, liver cancer, bladder cancer, ovarian cancer, testicular cancer, head cancer, neck cancer, melanoma, basal carcinoma, mesothelial lining cancer, white blood cell cancer, esophageal cancer, breast cancer, muscle cancer, connective tissue cancer, small cell lung cancer, non-small cell lung cancer, adrenal cancer, thyroid cancer, kidney cancer, and bone cancer; or glioblastoma, mesothelioma, renal cell carcinoma, gastric cancer, sarcoma, choriocarcinoma, basal cell carcinoma of the skin, and testicular seminoma.
In some embodiments, the immune-related disorder is selected from the group consisting of rheumatoid arthritis, renal failure, lupus, asthma, psoriasis, colitis, pancreatitis, allergies, fibrosis, anemic fibromyalgia, alzheimer's disease, congestive heart failure, stroke, aortic stenosis, arteriosclerosis, osteoporosis, parkinson's disease, infection, crohn's disease, ulcerative colitis, allergic contact dermatitis, and other eczemas, systemic sclerosis, and multiple sclerosis.
The compound of formula (X), the polymorph of the compound of formula X, the polymorph of the pharmaceutically acceptable salt of the compound of formula X, or the pharmaceutical composition containing the compound of formula (X), the polymorph of the compound of formula (X) or the polymorph of the pharmaceutically acceptable salt of the compound of formula X has good pharmacological activity for inhibiting A 2A receptors and/or A 2B receptors. In addition, polymorphs of the compound of formula (X) and polymorphs of the pharmaceutically acceptable salts of the compound of formula X have good stability and thus have potential to be developed into medicaments.
It is understood that within the scope of the present application, the above-described technical features of the present application and technical features specifically described below (e.g., in the examples) may be combined with each other to constitute a new technical solution. And are limited to a space, and are not described in detail herein.
Drawings
In order to more clearly illustrate the technical solutions of the embodiments or the conventional techniques of the present application, the drawings required for the descriptions of the embodiments or the conventional techniques will be briefly described below, and it is apparent that the drawings in the following description are only embodiments of the present application, and other drawings may be obtained from the disclosed drawings without inventive effort to those skilled in the art.
FIG. 1 is an XPRD plot (using Cu-K alpha radiation, with an abscissa of angle 2 θ (°), and an ordinate of SQR (counts)) of the free base form I of the compound of formula X, prepared in example 2, where SQR represents the square root of the intensity;
FIG. 2 is a DSC chart (abscissa indicates temperature (. Degree. C.) and ordinate indicates heat flow rate (W/g)) of the free base form I of the compound of formula X prepared in example 2;
FIG. 3 is a TGA spectrum (temperature (. Degree. C.) on the abscissa and weight change (%)) of the free base form I of the compound of formula X prepared in example 2;
FIG. 4 is an XPRD plot (using Cu-K alpha radiation, with an abscissa of angle 2 θ (°), and an ordinate of SQR (counts)) of the free base form IV of the compound of formula X, prepared in example 3, where SQR represents the square root of the intensity;
FIG. 5 is a DSC chart (abscissa indicates temperature (. Degree. C.) and ordinate indicates heat flow rate (W/g)) of the free base form IV of the compound of formula X prepared in example 3;
FIG. 6 is an XPRD plot (using Cu-K alpha radiation, abscissa is angle 2 θ (°), and ordinate is intensity (counts)) of the free base form V of the compound of formula X prepared in example 4;
FIG. 7 is a DSC chart (abscissa indicates temperature (. Degree. C.) and ordinate indicates heat flow rate (W/g)) of the free base form V of the compound of formula X prepared in example 4;
FIG. 8 is an XPRD plot (using Cu-K alpha radiation, abscissa at angle 2 θ (°), and ordinate at intensity (counts)) of the free base form VIII of the compound of formula X prepared in example 5;
FIG. 9 is a DSC chart (abscissa indicates temperature (. Degree. C.) and ordinate indicates heat flow rate (W/g)) of the free base crystalline form VIII of the compound of formula X prepared in example 5;
FIG. 10 is an XPRD chart (using Cu-K alpha radiation, abscissa is angle 2 θ (°), and ordinate is intensity (counts)) of the hydrochloride salt form I of the compound of formula X prepared in example 6;
FIG. 11 is an XPRD graph (using Cu-K alpha radiation, abscissa is angle 2 θ (°), and ordinate is intensity (counts)) of the sulfate form I of the compound of formula X prepared in example 7;
FIG. 12 is an XPRD plot (using Cu-K alpha radiation, abscissa is angle 2 θ (°), and ordinate is intensity (counts)) of crystalline form I of citrate of the compound of formula X prepared in example 8;
FIG. 13 is an XPRD plot (using Cu-K alpha radiation, abscissa is angle 2 θ (°), and ordinate is intensity (counts)) of the fumarate salt form I of the compound of formula X prepared in example 9;
FIG. 14 is an XPRD plot (using Cu-K alpha radiation, abscissa is angle 2 θ (°), and ordinate is intensity (counts)) of crystalline form I of succinate salt of the compound of formula X prepared in example 10;
FIG. 15 is an XPRD plot (using Cu-K alpha radiation, abscissa is angle 2 θ (°), and ordinate is intensity (counts)) of crystalline form II of the succinate salt of the compound of formula X prepared in example 11.
Detailed Description
The polymorphs of the compound of formula (X) and polymorphs of the pharmaceutically acceptable salts of the compound of formula (X), pharmaceutical compositions comprising the polymorphs, processes for preparing the polymorphs and pharmaceutical compositions, and uses thereof of the present application are described in further detail below in conjunction with the specific examples. The present application may be embodied in many different forms and is not limited to the embodiments described herein. Rather, these embodiments are provided so that this disclosure will be thorough and complete.
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this application belongs. The terminology used herein in the description of the application is for the purpose of describing particular embodiments only and is not intended to be limiting of the application.
In the present application, "first aspect," "second aspect," "third aspect," "fourth aspect," "fifth aspect," etc. are for descriptive purposes only and are not to be construed as indicating or implying a relative importance or quantity, nor as implying an importance or quantity of technical features indicated. Also, "first," "second," "third," "fourth," "fifth," etc. are for non-exhaustive list of descriptive purposes only and are not to be construed as limiting the number of closed forms.
In the application, the technical characteristics described in an open mode comprise a closed technical scheme composed of the listed characteristics and also comprise an open technical scheme comprising the listed characteristics.
In the present application, the numerical ranges are referred to as continuous, and include the minimum and maximum values of the ranges, and each value between the minimum and maximum values, unless otherwise specified. Further, when a range refers to an integer, each integer between the minimum and maximum values of the range is included. Further, when multiple range description features or characteristics are provided, the ranges may be combined. In other words, unless otherwise indicated, all ranges disclosed herein are to be understood to include any and all subranges subsumed therein.
The percentage content referred to in the present application refers to mass percentage for both solid-liquid mixing and solid-solid mixing and volume percentage for liquid-liquid mixing unless otherwise specified.
The percentage concentrations referred to in the present application refer to the final concentrations unless otherwise specified. The final concentration refers to the ratio of the additive component in the system after the component is added.
The temperature parameter in the present application is not particularly limited, and may be a constant temperature treatment or a treatment within a predetermined temperature range. The constant temperature process allows the temperature to fluctuate within the accuracy of the instrument control.
Compounds of the application
In the present application, the compound of formula (X) is 3- (4-amino-6- (1- ((1-ethyl-1H-pyrazol-3-yl) methyl) -1H-1,2, 3-triazol-4-yl) -5-fluoropyrimidin-2-yl) -2-methylbenzonitrile, which has high inhibitory activity against adenosine A 2A receptor and/or adenosine A 2B receptor.
In the present application, polymorphs of a compound of formula (X) include polymorphs of the free base of a compound of formula (X), and polymorphs of a pharmaceutically acceptable salt of a compound of formula (X). Wherein the pharmaceutically acceptable salt is selected from hydrochloride, sulfate, citrate, fumarate or succinate. Polymorphs of the compound of formula (X) and pharmaceutically acceptable salts thereof include, but are not limited to, free base form I, free base form iv, free base form v, free base form VIII, hydrochloride form I, sulfate form I, citrate form I, fumarate form I, succinate form I, and succinate form ii of the compound of formula (X).
As used herein, a "therapeutically effective amount" refers to an amount of a compound of the application that will elicit a biological or medical response in an individual, e.g., reduce or inhibit enzyme or protein activity or ameliorate symptoms, alleviate a condition, slow or delay a disease process, or prevent a disease, etc.
As used herein, a "pharmaceutically acceptable carrier" should in principle be non-toxic, inert. The form of the "pharmaceutically acceptable carrier" is not particularly limited and includes, but is not limited to, solid, semi-solid, liquid, and the like. The pharmaceutically acceptable carrier should be compatible with the patient, preferably a mammal, more particularly a human. One of the effects of the pharmaceutically acceptable carrier is to adapt the delivery of the active agent to the target site without stopping the activity of the agent. As used herein, the language "pharmaceutically acceptable carrier" includes buffers compatible with pharmaceutical administration, sterile water for injection, solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like. Each carrier is "pharmaceutically acceptable" in the sense of being compatible with the other ingredients of the formulation and not deleterious to the patient.
As used herein, "patient" refers to an animal, preferably a mammal, more preferably a human. The term "mammal" refers to a warm-blooded vertebrate mammal, including, for example, cats, dogs, rabbits, bears, foxes, wolves, monkeys, deer, mice, pigs, and humans.
As used herein, "treating" refers to alleviating, slowing progression, attenuating, preventing, or maintaining an existing disease or disorder (e.g., cancer). Treatment also includes curing, preventing the development of, or alleviating to some extent, one or more symptoms of the disease or disorder.
In the present application, "using Cu-ka radiation" means that the corresponding spectrum is obtained using ka radiation detection of a Cu target, and when detected by other methods, each diffraction peak may deviate within an acceptable range in the art, and should not be construed as limiting the present application.
Polymorphs
The solid is present either in amorphous form or in crystalline form. In the case of the crystalline form, the molecules are positioned within the three-dimensional lattice sites. When a compound crystallizes from a solution or slurry, it may crystallize in a different spatial lattice arrangement (this property is known as "polymorphism") to form crystals having different crystalline forms, which are known as "polymorphs". Different polymorphs of a given substance may differ from each other in one or more physical properties such as solubility and dissolution rate, true specific gravity, crystal form, stacking means, flowability and/or solid state stability.
Crystallization
The solution may be manipulated such that the solubility limit of the compound is exceeded, thereby completing crystallization on a production scale. This can be accomplished by a variety of methods, for example, dissolving the compound at a relatively high temperature, and then cooling the solution below the saturation limit; or by boiling, atmospheric evaporation, vacuum drying or by some other method; the solubility of the compounds may be reduced by adding an anti-solvent or a mixture of such solvents in which the compounds have low solubility. An alternative is to adjust the pH to reduce the solubility. For a detailed description of crystallization see Crystallization, third edition, J W Mullens, butterworth-heineeman ltd.,1993,ISBN 0750611294.
Identification and Properties of the Crystal form
The present application, after preparing polymorphs of a compound of formula (X), has been studied for its properties in a number of ways and instruments as follows.
X-ray powder diffraction (XRPD)
Methods for determining X-ray powder diffraction of crystalline forms are known in the art. XRPD can detect information such as changes in crystalline form, crystallinity, crystal structure state, etc., and is a common means for identifying crystalline forms. The peak positions of the XRPD patterns are primarily dependent on the structure of the crystalline form, and the measure of 2θ of the XRPD patterns may vary slightly from instrument to instrument, and therefore the value of 2θ cannot be considered absolute. Depending on the instrument conditions used in the test according to the application, the diffraction peaks are allowed to have certain errors (e.g. + -0.2 °). It will be appreciated that the range of errors is not absolute for different test instruments and test conditions. The crystalline form of the compound of formula X of the present application has a particular crystalline form and a particular characteristic peak in the XRPD pattern.
In the present application, the "X-ray powder diffraction pattern has a characteristic diffraction peak at a specific 2θ (°) angle" means that the peak value of the peak is within the indicated numerical range, the indicated numerical point, the vicinity of the indicated numerical range, or the vicinity of the indicated numerical point. The position of a certain peak or peaks in the actual X-ray powder diffraction pattern may be slightly shifted, i.e. may be slightly different from the characteristic peak combination indicated in the present application or from the X-ray powder diffraction pattern due to different measurement factors such as the measuring instrument and the measurement condition, but it is understood that it is possible for a person skilled in the art to identify whether the characteristic peak combination or the X-ray powder diffraction pattern slightly different from each other may substantially constitute the crystal form of the present application. These are therefore considered to be substantially in accordance with the crystalline forms of the application and are considered to be within the scope of the application. For example, the expression "the X-ray powder diffraction pattern has a peak at a diffraction angle of 7.57±0.2" means that the peak of the peak may be located within and in the vicinity of 7.57±0.2 as long as the identification of the crystal form as a whole is not affected. Here, "0.2" indicates only an error in the diffraction angle position of the peak, and is independent of the peak shape and the peak width of the peak.
In the present application, "X-ray powder diffraction pattern" substantially as characterized by a particular pattern "should be understood similarly, and as long as it is possible to identify a certain X-ray powder diffraction pattern as substantially consistent with the X-ray powder diffraction pattern of the present application as a whole, it is considered to fall within the scope of the present application.
It is to be understood that the differential scanning calorimetric curve of the present application and the endothermic peak positions shown therein should be similarly understood to allow slight disagreement with the specific numerical values or specific numerical ranges or specific spectra disclosed herein, but should be considered to fall within the scope of the present application as long as a part or all of the endothermic peak positions in the differential scanning calorimetric curve, or the entire curve, are considered to be substantially consistent with the present application as a whole.
It will be appreciated that other spectra characterizing the type of crystallization may be similarly understood.
Differential scanning calorimeter analysis (DSC)
Also known as "differential calorimetric analysis" is a technique that measures the relationship between the energy difference between the substance being measured and the reference substance and the temperature during heating. The position, shape and number of peaks on a DSC profile are related to the nature of the substance and can therefore be used qualitatively to identify the substance. The method is commonly used in the art to detect various parameters such as the phase transition temperature, the glass transition temperature, the reaction heat and the like of a substance. The peak positions of the DSC spectra may slightly differ from instrument to instrument, and thus the values of the peak positions of the DSC endotherm peaks cannot be regarded as absolute. The experimental error or difference may have a value of 5 ℃ or less, or 4 ℃ or less, or 3 ℃ or less, or 2 ℃ or less, or 1 ℃ or less, depending on the conditions of the apparatus used in the test according to the present application.
Thermogravimetric analysis (TGA)
TGA is a technology for measuring the mass change of a substance along with the temperature under program control, is suitable for checking the loss of a solvent in a crystal or the sublimation and decomposition processes of a sample, and can infer the condition of containing crystal water or a crystallization solvent in the crystal. The quality change exhibited by the TGA profile depends on many factors such as sample preparation and instrumentation; the quality of TGA detection varies slightly from instrument to instrument. Depending on the instrument conditions used in the test according to the application, the error in the mass change is not absolute, allowing for a certain error (e.g. + -0.1%).
If salt formation is desired to occur simultaneously with crystallization, if the salt is less soluble in the reaction medium than the starting material, the addition of an appropriate acid or base can result in direct crystallization of the desired salt. Also, completion of the synthesis reaction may allow direct crystallization of the final product in a medium where the final desired form is less soluble than the reactants.
Optimization of crystallization may include seeding the crystallization medium with crystals of the desired form. In addition, many crystallization methods use a combination of the above strategies. One example is to dissolve the compound of interest in a solvent at an elevated temperature, followed by the addition of an appropriate volume of anti-solvent in a controlled manner to bring the system well below saturation level. At this point, the desired form of seed crystals (and maintaining the integrity of the seed crystals) may be added and the system cooled to complete crystallization.
As used herein, the term "room temperature" generally refers to 4-30 ℃, preferably 20±5 ℃.
Identification and Properties of polymorphs
Powder diffraction by X-rays
Polymorphs of the compound of formula (X) of the present application have specific crystalline forms with specific characteristic peaks in the X-ray powder diffraction pattern (XPRD). XPRD spectra were collected on a Equisox 3000S/N X ray powder diffraction analyzer and XPRD parameters are shown in Table 11 below.
TABLE 11
Parameters (parameters) XPRD
X-ray source Cu K(λ＝1.54056 Angstrom)
Light pipe settings 40 Kv 30 milliamp
Detector for detecting a target object PSD
Scanning range (2 theta degree) 0°～120°
Scanning step length (2 theta degree) 0.03
Scanning rate 1 Second/step
In the X-ray powder diffraction pattern, the position of each peak is determined by 2θ (°). It will be appreciated that different instruments and/or conditions may result in slightly different data being generated, with variations in the location and relative intensities of the peaks. It will be appreciated by those skilled in the art that the low diffraction angle peaks and their intensity, peak shape integrity, etc. are relatively more reference in determining crystalline forms from XRPD patterns. In the present application, the applicant has further studied and found that, when tested using the above-described instrument, strong background peaks of a blank metal disk appear in the vicinity of two positions of the high diffraction angle having 2 θ (°) values of 37 and 44. For example, the peak around 37 ° in fig. 4 is presumed to be a peak generated by a blank metal disc (e.g., a peak at 37.48 ° in table 2), the peak around 37 ° in fig. 6 and a peak around 43 ° are presumed to be a peak generated by a blank metal disc (e.g., a peak at 37.48 ° and 43.60 ° in table 3), the peak around 37 ° in fig. 8 is presumed to be a peak generated by a blank metal disc (e.g., a peak at 37.48 ° in table 4), the peak around 37 ° in fig. 11 is presumed to be a peak generated by a blank metal disc (e.g., a peak at 37.48 ° in table 6), the peak around 37 ° and a peak around 43 ° in fig. 12 are presumed to be a peak generated by a blank metal disc (e.g., a peak at 37.51 ° and 43.63 ° in table 7), the peak around 37 ° in fig. 13 is presumed to be a peak generated by a blank metal disc (e.g., a peak at 37.87 ° in table 8), the peak around 37 ° in fig. 14 and the peak around 43 ° are presumed to be a peak generated by a blank metal disc (e.g., a peak at 37.84 ° and a peak at 37 ° in table 9), and the peak around 43 ° are presumed to be a peak at 37 ° in fig. 15. The intensity division of the peaks reflects only the approximate size of the peak at each location. In the present application, each of the crystal forms was defined as having a diffraction peak with the highest peak height as a base peak and a relative intensity of 100% as I 0, and the other peaks were defined as having a ratio of the peak height to the base peak height as relative intensities I/I 0, and the relative intensities of the peaks were defined as shown in table 12 below.
Table 12
Relative strength I/I 0(％) Definition of the definition
50～100 VS (very strong)
25～50 S (Strong)
10～25 M (Medium)
1～10 W (Weak)
Differential Scanning Calorimeter (DSC)
DSC profiles were collected on a DISCOVERY DSC25 differential scanning calorimeter and the test parameters are shown in table 13 below.
TABLE 13
Parameters (parameters) DSC
Method of Linear temperature rise
Sample tray Aluminum plate and gland
Temperature range 25℃–300℃
Scan rate (. Degree. C./min) 10
Protective gas Nitrogen gas
It will be appreciated that additional values may be obtained using other types of instruments that function the same as the instruments described above or using different test conditions than those used in the present application, and therefore, the values recited should not be considered absolute values.
Those skilled in the art will appreciate that the above parameters used to characterize the physical properties of crystals may vary slightly due to instrument errors or operator differences, and therefore are only used to aid in characterizing the polymorphs provided by the present application and are not to be considered as limiting.
Reagents and apparatus
In the present application, the structure and purity of the compounds are determined by nuclear magnetic resonance (1 HNMR) and/or liquid mass spectrometry (LC-MS). 1 HNMR: brukerAVANCE-400 nuclear magnetic instruments, wherein the internal standard is Tetramethylsilane (TMS). LC-MS: agilent 1200 HPLC System/6140 MS liquid Mass Spectrometry (manufacturer: agilent), column WatersX-Bridge, 150X 4.6mm,3.5 μm.
Starting materials known in the present application may be synthesized using or following methods known in the art or may be purchased from companies such as ABCR GmbH & Co.KG, acros Organics, ALDRICH CHEMICAL Company, shao Yuan chemical technology (Accela ChemBio Inc) and Dary chemical.
As used herein, DCM: dichloromethane, DMF: dimethylformamide, DMSO: dimethyl sulfoxide, THF: tetrahydrofuran, EA: ethyl acetate, PE: petroleum ether, pd (dppf) Cl 2: [1,1' -bis (diphenylphosphino) ferrocene ] Palladium dichloride, pd (PPh 3) 2Cl 2: bis (triphenylphosphine) Palladium (II) chloride, DPPA: diphenylazide phosphate, DBU:1, 8-diazabicyclo undec-7-ene.
Preparation of intermediate V1
2-Methyl-3-bromoxynil (15 g,76.51 mmol), bis-pinacolato borate (23.32 g,91.82 mmol), potassium acetate (15.02 g,153.03 mmol) and Pd (dppf) Cl 2 (2.80 g) were dissolved in a mixed solution of DMSO (20 mL) and dioxane (100 mL) and stirred at 100deg.C under nitrogen for 3.5 hours. The reaction was completed, and the solid product obtained by evaporating the solvent under reduced pressure was separated from the resultant by column chromatography (EA: PE15% -40%) to obtain Compound V1 (21.05 g, purity: 78.0%, yield: 100%). MS (ESI) 244.1[ M+H ] +.
Preparation of intermediates 1-5
Step one:
Compound V2-1 (40 g,198.60 mmol) and triisopropylsilylacethylene (38.03g 208.53mmol) are dissolved in THF (400.00 mL), stirred and cooled to 0℃under argon, cuI (3.78 g,19.86 mmol) and Pd (PPh 3) 2Cl 2 (6.97 g,9.93 mmol) are added sequentially, then Et 3 N (60.17 g,595.79 mmol) is slowly added dropwise, stirring is completed at 0℃for 2 hours, heating to room temperature and stirring is continued for 6 hours, then cooling to 0℃and NH 3/H 2 O (120.00 g,2.61mol,120.00mL,37% purity) is added dropwise, and stirring is carried out at room temperature overnight, LC-MS detection reaction is complete, thus obtaining compound V2-2.MS (ESI) 347 M+H ].
Step two:
The reaction solution in step 1 was added with a large amount of water, extracted with DCM (200 mL. Times.3), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give 40mL of the remaining DCM, and a large amount of solid was precipitated, 60mL of petroleum ether was added with stirring, and the resultant was filtered to give compound V2-3 (31 g), and the remaining mother liquor was purified by column chromatography on silica gel (DCM: PE=30% -80%), to give compound V2-3 (43 g). MS (ESI) 328[ M+H ] +.
Step three:
Compound V2-3 (41 g,125.04 mmol) and compound V1 (42.56 g,175.05 mmol) were dissolved in a mixed solvent of dioxane (400 mL) and water (60 mL), na 2CO 3 (26.51 g,250.08 mmol) and Pd (dppf) 2 Cl (4.57 g,6.25 mmol) were added in this order under stirring argon at room temperature, and then heated to 100deg.C and stirred for 24 hours. The reaction was poured into ice water, extracted with DCM (300 mL. Times.2), dried over anhydrous sodium sulfate, concentrated to dryness under reduced pressure, and purified by silica gel column to give V2-4 as a yellow solid (44 g,107.69mmol,86.12% yield). MS (ESI) 409.2[ M+H ] +.
Step four:
Compound V2-4 (44 g,107.69 mmol) was added to 400mL of methanol, NH 4 F (47.60 g,1.40 mol) was added with stirring at room temperature, then the mixture was stirred under argon for 8 hours at 70℃and the reaction solution was added to a large amount of water with stirring, and a large amount of solid was washed out, and filtered to give brown product V2-5 (27 g,107.04mmol,99.40% yield). MS (ESI) 253.1[ M+H ] +.
Example 1
Preparation of Compounds of formula X
Step one:
Compound 1H-pyrazole-3-carboxylic acid ethyl ester (25 g,178.39 mmol) and cesium carbonate (58.12 g,178.39 mmol) were dissolved in DMF (150 mL), and ethyl iodide (30.61 g,196.23 mmol) was added with stirring at room temperature, followed by heating to 80℃and stirring overnight. The reaction solution was poured into water, extracted with EA (150 ml×2), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column separation (EA: pe=0 to 70%) to give ethyl 1-ethylpyrazole-3-carboxylate (11.5 g,68.37mmol,38.33% yield) as a white solid. MS (ESI) 169[ M+H ] +.
Step two:
The compound ethyl 1-ethylpyrazole-3-carboxylate (11.5 g,68.37 mmol) was dissolved in THF (150 mL), cooled to-10deg.C under argon, liAlH 4 (3.89 g,102.56 mmol) was added in portions, and then stirred at about 0deg.C for 1 hour. 5.0g of sodium sulfate decahydrate was added to the reaction mixture in portions at 0℃and stirred at 0℃for 1 hour, and the mixture was slowly warmed to room temperature and stirred for 1 hour. Filtration and concentration of the filtrate under reduced pressure gave (1-ethylpyrazol-3-yl) methanol (7.8 g,61.83mmol,90.43% yield) as a colorless oil. MS (ESI) 127[ M+H ] +.
Step three:
Compound (1-ethylpyrazol-3-yl) methanol (7.8 g,61.83 mmol) was dissolved in THF (60 mL), DPPA (18.04 g,74.19 mmol) was added under stirring under an argon-shielded ice-bath, DBU (14.12 g,92.74mmol,13.84 mL) was then slowly added dropwise, the temperature was controlled below 15℃and the temperature was raised to 45℃after the addition and stirring was continued overnight. The reaction mixture was stirred with 200mL of water, extracted with methyl tert-butyl ether (100 mL. Times.2), and the organic phases were combined, washed with water (200 mL) and used directly in the next reaction.
Step four:
To the organic phase of step three, a solution of compound V2 (15.52 g,61.52 mmol) in THF (100 mL) and methyl tert-butyl ether (200 mL) was added, and stirred at room temperature under argon, copper sulfate pentahydrate (153.60 mg, 615.21. Mu. Mol) was added sequentially to dissolve in water (20 mL), sodium ascorbate (487.51 mg,2.46 mmol) was dissolved in water (20 mL), and then heated to 60℃and stirred for 16 hours. The reaction solution was poured into water, extracted with dichloromethane (1000 ml×2), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography on silica gel (PE: DCM (containing 2% triethylamine) =30% -100%), to give compound X (19.00 g).
1H NMR(400MHz,DMSO-d 6)δ8.64(s,1H),7.91(d,J＝7.0Hz,1H),7.82(d,J＝7.8Hz,1H),7.67(d,J＝2.2Hz,1H),7.51(s,2H),7.44(t,J＝7.8Hz,1H),6.23(d,J＝2.2Hz,1H),5.60(s,2H),4.06(q,J＝7.3Hz,2H),2.61(s,3H),1.30(t,J＝7.4Hz,3H).
The resulting solid X compound was subjected to XRPD detection and its powder X-ray diffraction pattern had no characteristic peaks, and was in amorphous form.
Test example 1: inhibitory Activity of Compounds of formula X on the A 2A receptor and the A 2B receptor
CHO-K1/ADORA 2A/G.alpha.15 (GenScript, M00246) and CHO-K1/ADORA 2B/G.alpha.15 (GenScript, M00329) cells were cultured in ham's F-12 (Gibco, 31765092) medium. The culture medium contains 10% FBS, 200 μg/mL Zeocin and 100 μg/mL Hygromycin B or 10% FBS, 400 μg/mL G418 and 100 μg/mL Hygromycin B, and the specific culture conditions are shown in the corresponding instruction. The screening steps are as follows:
(1) The cell density was adjusted to 6X 10 5 cells/ml with serum-free medium.
(2) Mu.L of cell fluid, 2.5. Mu.L of NECA (Sigma, 119140-10 MG) and 2.5. Mu.L of compound solution were added to each well of 384 well plates (Greiner Bio-One, 784075) in this order, respectively, the NECA final concentration being 50nM (CHO-K1/ADORA 2A) or 10nM (CHO-K1/ADORA 2B) and the compound final concentration being 3. Mu.M starting 3-fold dilution down.
(3) Placing in a 37 ℃ incubator for static culture for 30mins.
(4) Mu.L of cAMP-d 2 and 5. Mu.L of cAMP-ab (Cisbio, 62AM4 PEB) were added sequentially.
(5) The 384-well plate was left at room temperature in the dark for 1 hour.
(6) The plate was read (Victor X5, perkinElmer), XLfit nonlinear regression analysis data, and IC 50 of the compound was calculated. The results are shown in Table 14 below.
TABLE 14 inhibitory Activity of Compounds of formula X on the A 2A receptor and the A 2B receptor
Numbering of compounds A 2A receptor (IC 50/μM) A 2B receptor (IC 50/μM)
X <0.001 0.001
As can be seen from Table 14, the compounds of formula X according to the examples of the present application have higher inhibitory activity against both the A 2A receptor and the A 2B receptor.
Test example 2: in vivo drug substitution test
The LC/MS method was used to determine the drug concentration at different time points after intravenous administration and intragastric administration of the compound of formula X according to the application in mice, to study the pharmacokinetic behavior of the compound of formula X according to the application in mice and to evaluate its pharmacokinetic profile.
Experimental protocol:
Test animals: healthy adult male ICR mice (25 g-40 g in weight, 12 mice in intravenous injection group were free to drink and eat, and the intragastric administration group was fasted overnight, and were free to drink and eat after 4 hours of administration) provided by Beijing Vetong Lihua laboratory animal technologies Co., ltd;
mode and dosage of administration: animals meeting the experimental requirements are selected before administration, and marked by weighing. ICR mice were given intravenous (2 mg/kg,5%DMSO,pH4.5 20%Captisol) and intragastric (10 mg/kg,5%DMSO,pH4.5 20%Captisol).
Blood sample collection: intravenous administration and intragastric administration were each performed at about 100 μl blood collection via jugular vein at 0.083 hours, 0.25 hours, 0.5 hours, 1 hour, 2 hours, 4 hours, 6 hours, 7.5 hours and 24 hours, respectively, after administration. The blood was transferred to a 1.5mLEP tube, to which EDTA2K had been added in advance, and centrifuged for 4min (8000 rpm,4 ℃) to separate out plasma, and the whole process was completed within 15min after blood collection. All plasma samples were stored in-20 ℃ freezer until the samples were analyzed.
The pharmacokinetic parameters of the compound of formula X of the present application in mice given intravenously are shown in table 15.
TABLE 15 pharmacokinetic parameters under intravenous administration
Numbering of compounds Clearance CLz (mL/min/kg) Area under the curveAUC 0-t(hr·ng/mL)
Compounds of formula X 17.2 1918
The pharmacokinetic parameters of compound X of the present application in mice administered by gavage are shown in table 16.
TABLE 16 pharmacokinetic parameters under gastric administration
Numbering of compounds C max(ng/mL) Area under curve AUClast (hr ng/mL)
Compounds of formula X 7060 8569
Test example 3: in vivo efficacy experiment of the inventive Compound of formula X
Experimental protocol: the test example examines mice with melanoma cell line B16F10-OVA-hPD-L1 subcutaneously transplanted tumor mice, and after administration of the compound of formula X of the present application via the oral route of administration, their in vivo efficacy against melanoma B16F10-OVA-hPD-L1 tumor-bearing mice was tested.
Experimental materials: c57BL/6 mice (females); mouse melanoma B16F10-OVA-hPD-L1 cells (Shanghai university of traffic cell bank) were cultured in vitro in a monolayer under culture conditions of 10% fetal bovine serum in DMEM medium at 37deg.C in a 5% CO 2 incubator. Passaging was performed by conventional digestion with pancreatin-EDTA. When the cells are in the exponential growth phase and the saturation is 80% -90%, collecting the cells and counting.
Compound preparation: the compound of formula X was measured and added to a vehicle (40% sulfobutyl- β -cyclodextrin (captisol) in acetic acid buffer, pH 4.0) to make a sample of the target concentration. Experimental operation: cells were resuspended in phosphate buffer at a density of 5X 10 6 cells/mL. 0.1mL of PBS solution containing 5X 10 5 B16F10-OVA-hPD-L1 cells was subcutaneously inoculated on the right back of each mouse, and 10 mice in each group were randomly grouped according to the body weight of the mice on the day of inoculation, and administration was started, 2 times daily for 19 days. Throughout the experiment, animals were weighed daily and monitored for health. Tumor diameters were measured twice weekly with vernier calipers.
The calculation formula of the tumor volume V is: v=0.5×a×b 2, and a and b represent the long and short diameters of the tumor, respectively.
The tumor-inhibiting effect of the compound was evaluated by the relative tumor proliferation rate T/C (%). Relative tumor proliferation rate T/C (%) =vt/vc×100% (Vt: mean tumor volume in treatment group; vc: mean tumor volume in negative control group). Vt and Vc take the same day data. The results at the end of administration are shown in Table 17.
TABLE 17 relative tumor proliferation Rate obtained in test example 3
EXAMPLE 2 preparation of free base form I
Method one
About 20mg of the compound of formula X (amorphous) prepared according to example 1 was weighed into a glass vial, 1mL of ethanol was added and heated to a clear solution at about 50℃and the glass vial was taken out and cooled to room temperature, cooled to 0-4℃in a refrigerator after cooling to room temperature, and after solid precipitation, the supernatant was discarded after centrifugation and the solid was dried in an oven for XPRD detection. The XPRD diagram of the resulting solid product is shown in FIG. 1 and is defined in the present application as the free base form I. The DSC spectrum of the free base form I is shown in figure 2, wherein the endothermic peak is 179.10 ℃, the endothermic peak is at 104.32 ℃, the TGA spectrum is shown in figure 3, and the weight loss is about 8.8% before 150 ℃; the free base form I is described as containing the solvent ethanol.
Method II
About 20mg of the compound of formula X (amorphous) prepared according to example 1 was weighed into a glass vial, 1mL of methanol was added and heated to a clear solution at about 50 ℃, the glass vial was taken out and slowly cooled at room temperature, cooled to 0-4 ℃ in a refrigerator after cooling to room temperature, the supernatant was discarded after solid precipitation, the solid was dried in an oven and XPRD detection was performed, confirming that the free base form I was obtained.
Method III
About 19g of the compound of formula X (amorphous) prepared as described in example 1 was weighed into a glass vial, 100mL of ethanol was added, and heated to reflux (about 75 ℃). Cooling to room temperature, separating out solid, and filtering to obtain solid product. XPRD detection is performed on the obtained solid, and the free base crystal form I is obtained.
EXAMPLE 3 preparation of free base form IV
Method one
About 20mg of the compound of formula X (free base form I) was weighed into a glass vial, 1mL of isopropyl alcohol was added, the glass vial was suspended and shaken at room temperature for 24 hours, the supernatant was discarded after centrifugation, and the solid was placed in an oven to be dried for XPRD detection. The XPRD diagram of the solid product obtained is shown in FIG. 4 and is defined in the present application as the free base form IV. The DSC pattern of the free base form IV is shown in FIG. 5, which has an endothermic peak at 170.43 ℃.
Method II
About 20mg of the compound of formula X (free base form I) was weighed into a glass vial, 1mL of isopropanol or water was added, the glass vial was suspended and shaken at room temperature for 7 days, the supernatant was discarded after centrifugation, and the solid was placed in an oven for drying, XPRD detection was performed, confirming that free base form IV was obtained.
EXAMPLE 4 preparation of free base form V
Method one
About 20mg of the compound of formula X (amorphous) is weighed into a glass vial, 1mL of acetone is added to dissolve the compound, the solution is left at room temperature for slow volatilization, the volatilized solid powder is taken for XPRD detection, and the XPRD diagram of the obtained solid product is shown in FIG. 6 and defined as free base form V in the present application. The DSC profile of form V of the free base is shown in FIG. 7, with an endothermic peak at 179.02 ℃.
Method II
About 20mg of the compound of formula X (free base form I) was weighed into a glass vial, 1mL of methyl tert-butyl ether was added, the glass vial was suspended and shaken at room temperature for 7 days, the supernatant was discarded after centrifugation, and the solid was placed in an oven for drying, XPRD detection was performed, confirming that free base form V was obtained.
EXAMPLE 5 preparation of free base form VIII
10Mg of the free base form I, the free base form IV and the free base form V are respectively weighed and fully mixed, 20mg of the mixture is taken in a glass vial, 1mL of acetone or 50% ethanol is added, the mixture is suspended and shaken for 3 days at room temperature, the precipitate is centrifugally taken, and XPRD is measured after drying. The XPRD diagram of the resulting solid product is shown in FIG. 8 and is defined in the present application as the free base form VIII. The DSC chart of the free base form VIII is shown in figure 9, and the free base form VIII has an endothermic peak at 162.93 ℃.
EXAMPLE 6 preparation of hydrochloride form I
Weighing 20mg of compound (amorphous) of formula X, adding 1M hydrochloric acid solution according to the molar ratio of acid (hydrogen ions) to free base of 1.2:1, adding 2mL of ethyl acetate or acetone, heating and ultrasonically clarifying, reacting at 50 ℃ for 4 hours, slowly cooling to precipitate solid, and centrifuging to collect the solid. The resulting solid was used for XRPD testing after evaporation of the solvent, and its X-ray powder diffraction pattern is shown in fig. 10, defined herein as hydrochloride form I.
EXAMPLE 7 preparation of sulfate form I
20Mg of the compound of formula X (amorphous) is weighed, 0.5M sulfuric acid solution is added according to the mol ratio of acid (hydrogen ions) to free base of 1.2:1, then 2mL of ethyl acetate or acetone is added, heating and ultrasonic treatment are carried out to clarify, the temperature is kept at 50 ℃ for 4 hours, then slow cooling is carried out to precipitate solid, and the solid is collected by centrifugation. The resulting solid was used for XRPD testing after evaporation of the solvent, and its X-ray powder diffraction pattern is shown in fig. 11, defined herein as sulfate form I.
EXAMPLE 8 preparation of citrate Crystal form I
Weighing 20mg of a compound (amorphous) of the formula X, adding 0.5mol/L citric acid solution according to the mol ratio of acid (hydrogen ions) to free base of 1.2:1, adding 2mL of acetone, heating and ultrasonic treatment to clarify, carrying out heat preservation reaction for 4 hours at 50 ℃, slowly cooling to room temperature, adding anti-solvent n-heptane to precipitate solid, and centrifuging to collect the solid. The resulting solid was used for XRPD testing after evaporation of the solvent, and its X-ray powder diffraction pattern is shown in fig. 12, defined herein as citrate form I.
EXAMPLE 9 preparation of fumarate salt form I
20Mg of the compound of formula X (amorphous) is weighed, 0.25mol/L fumaric acid solution is added according to the mol ratio of acid (hydrogen ions) to free base of 1.2:1, 2mL ethyl acetate is added, heating and ultrasonic treatment are carried out to clarify, the reaction is carried out for 4 hours at 50 ℃, then the reaction time is slowly reduced to room temperature, anti-solvent n-heptane is added to precipitate solid, and the solid is collected by centrifugation. The resulting solid was used for XRPD testing after evaporation of the solvent, and its X-ray powder diffraction pattern is shown in fig. 13, defined herein as fumarate salt form I.
EXAMPLE 10 preparation of succinate crystalline form I
20Mg of the compound of formula X (amorphous) is weighed, 0.5mol/L succinic acid solution is added according to the mol ratio of acid (hydrogen ions) to free base of 1.2:1, then 2mL ethyl acetate is added, heating and ultrasonic treatment are carried out to clarify, the reaction is carried out for 4 hours at 50 ℃, then the reaction time is slowly reduced to room temperature, anti-solvent n-heptane is added to precipitate solid, and the solid is collected by centrifugation. The resulting solid was used for XRPD testing after evaporation of the solvent, and its X-ray powder diffraction pattern is shown in fig. 14, defined herein as succinate form I.
EXAMPLE 11 preparation of succinate form II
Weighing 20mg of a compound (amorphous) of the formula X, adding 0.5mol/L succinic acid solution according to the mol ratio of acid (hydrogen ions) to free base of 1.2:1, adding 2mL of acetone, heating and ultrasonic treatment to clarify, carrying out heat preservation reaction for 4 hours at 50 ℃, slowly cooling to room temperature, adding anti-solvent n-heptane to precipitate solid, and centrifuging to collect the solid. The resulting solid was used for XRPD testing after evaporation of the solvent, and its X-ray powder diffraction pattern is shown in fig. 15, defined herein as succinate form ii.
The technical features of the above-described embodiments may be arbitrarily combined, and all possible combinations of the technical features in the above-described embodiments are not described for brevity of description, however, as long as there is no contradiction between the combinations of the technical features, they should be considered as the scope of the description.
The above examples merely represent a few embodiments of the present application, which facilitate a specific and detailed understanding of the technical solutions of the present application, but are not to be construed as limiting the scope of the application. It should be noted that it will be apparent to those skilled in the art that several variations and modifications can be made without departing from the spirit of the application, which are all within the scope of the application. It should be understood that, based on the technical solutions provided by the present application, those skilled in the art may obtain technical solutions through logical analysis, reasoning or limited experiments, which are all within the scope of protection of the appended claims. The scope of the patent is therefore intended to be covered by the appended claims, and the description and drawings may be interpreted as illustrative of the contents of the claims.

Claims (11)

  1. A polymorph of a compound of formula X or a pharmaceutically acceptable salt thereof,
    The pharmaceutically acceptable salt is selected from: hydrochloride, sulfate, citrate, fumarate or succinate salts.
  2. The polymorph of claim 1, wherein the polymorph of a compound of formula X is selected from any one of the group consisting of:
    A free base crystalline form I of a compound of formula X, having an X-ray powder diffraction pattern with characteristic diffraction peaks at the following 2Θ (°) angles:
    7.57.+ -. 0.2, 13.41.+ -. 0.2, 14.64.+ -. 0.2, 19.81.+ -. 0.2 and 24.43.+ -. 0.2;
    a free base form IV of a compound of formula X having an X-ray powder diffraction pattern with characteristic diffraction peaks at the following 2Θ (°) angles:
    11.88+ -0.2, 14.17+ -0.2, 16.96+ -0.2, 22.63+ -0.2, 23.56+ -0.2 and 25.66+ -0.2;
    A free base form v of a compound of formula X having an X-ray powder diffraction pattern with characteristic diffraction peaks at the following 2Θ (°) angles:
    11.88.+ -. 0.2, 16.36.+ -. 0.2, 16.99.+ -. 0.2, 22.99.+ -. 0.2, 23.47.+ -. 0.2 and 26.41.+ -. 0.2; and
    A free base crystalline form VIII of a compound of formula X having an X-ray powder diffraction pattern with characteristic diffraction peaks at the following 2Θ (°) angles:
    6.40.+ -. 0.2, 13.12.+ -. 0.2, 15.91.+ -. 0.2, 22.69.+ -. 0.2 and 26.95.+ -. 0.2.
  3. The polymorph of claim 2, wherein the polymorph of a compound of formula X is selected from any one of the group consisting of:
    A free base crystalline form I of a compound of formula X, having an X-ray powder diffraction pattern further comprising 1 or 2 characteristic diffraction peaks at 2Θ (°) angles selected from: 24.87+ -0.2 and 27.46 + -0.2;
    A free base form IV of a compound of formula X, having an X-ray powder diffraction pattern further comprising at least one characteristic diffraction peak at 2Θ (°) angle selected from: 15.76.+ -. 0.2 and 26.08.+ -. 0.2;
    A free base form v of a compound of formula X, having an X-ray powder diffraction pattern further comprising at least one characteristic diffraction peak at 2Θ (°) angle selected from: 7.90.+ -. 0.2, 13.71.+ -. 0.2, 14.14.+ -. 0.2, 15.31.+ -. 0.2, 17.80.+ -. 0.2, 18.76.+ -. 0.2, 21.34.+ -. 0.2, 24.82.+ -. 0.2, 25.51.+ -. 0.2, 27.88.+ -. 0.2 and 30.46.+ -. 0.2; and
    A free base crystalline form VIII of a compound of formula X, having an X-ray powder diffraction pattern further comprising at least one characteristic diffraction peak at 2Θ (°) angles selected from: 11.62.+ -. 0.2, 12.36.+ -. 0.2, 16.62.+ -. 0.2, 18.34.+ -. 0.2, 18.88.+ -. 0.2, 24.94.+ -. 0.2 and 29.65.+ -. 0.2.
  4. The polymorph of claim 2, wherein
    The X-ray powder diffraction pattern of the free base form I is substantially as shown in figure 1;
    The X-ray powder diffraction pattern of the free base form IV is substantially as shown in figure 4;
    the X-ray powder diffraction pattern of the free base form v is substantially as shown in figure 6; or (b)
    The X-ray powder diffraction pattern of the free base form VIII is substantially as shown in figure 8.
  5. The polymorph of claim 2, wherein
    The differential scanning calorimetric curve of the free base crystal form I has an endothermic peak at 179.10 +/-3 ℃;
    The differential scanning calorimetric curve of the free base crystal form IV has an endothermic peak at 170.43 +/-3 ℃;
    the differential scanning calorimetric curve of the free base form v has an endothermic peak at 179.02±3 ℃; or (b)
    The differential scanning calorimetry curve of the free base form VIII has an endothermic peak at 162.93 ±3 ℃.
  6. The polymorph of claim 1, wherein the polymorph of a pharmaceutically acceptable salt of a compound of formula X is selected from any one of the following groups:
    a hydrochloride salt form I of a compound of formula X having an X-ray powder diffraction pattern with characteristic diffraction peaks at the following 2Θ (°) angles:
    11.95.+ -. 0.2, 24.37.+ -. 0.2, 25.21.+ -. 0.2 and 26.35.+ -. 0.2;
    a crystalline sulfate salt form I of a compound of formula X, having an X-ray powder diffraction pattern with characteristic diffraction peaks at the following 2Θ (°) angles:
    8.22.+ -. 0.2, 11.29.+ -. 0.2, 14.14.+ -. 0.2, 16.96.+ -. 0.2, 18.13.+ -. 0.2, 22.27.+ -. 0.2, 23.86.+ -. 0.2 and 27.79.+ -. 0.2;
    a citrate crystalline form I of a compound of formula X, having an X-ray powder diffraction pattern with characteristic diffraction peaks at the following 2Θ (°) angles:
    12.55.+ -. 0.2, 14.50.+ -. 0.2, 21.55.+ -. 0.2 and 22.75.+ -. 0.2;
    a fumarate salt form I of a compound of formula X, having an X-ray powder diffraction pattern with characteristic diffraction peaks at the following 2Θ (°) angles:
    7.12.+ -. 0.2, 11.71.+ -. 0.2, 16.90.+ -. 0.2, 23.26.+ -. 0.2, 23.65.+ -. 0.2, 24.64.+ -. 0.2 and 25.54.+ -. 0.2;
    a succinate salt of a compound of formula X, form I, having an X-ray powder diffraction pattern with characteristic diffraction peaks at the following 2Θ (°) angles:
    4.87.+ -. 0.2, 9.31.+ -. 0.2, 13.78.+ -. 0.2, 14.14.+ -. 0.2, 18.16.+ -. 0.2, 20.71.+ -. 0.2, 22.12.+ -. 0.2 and 26.83.+ -. 0.2; and
    A succinate salt form ii of a compound of formula X, having an X-ray powder diffraction pattern with characteristic diffraction peaks at the following 2Θ (°) angles:
    11.86.+ -. 0.2, 12.49.+ -. 0.2, 14.50.+ -. 0.2, 15.22.+ -. 0.2, 16.90.+ -. 0.2, 21.64.+ -. 0.2, 22.87.+ -. 0.2 and 25.75.+ -. 0.2.
  7. The polymorph of claim 6, wherein
    The ray powder diffraction pattern of the hydrochloride crystal form I is substantially as shown in fig. 10:
    the X-ray powder diffraction pattern of sulfate form I is substantially as shown in fig. 11;
    the X-ray powder diffraction pattern of citrate form I is substantially as shown in figure 12;
    The X-ray powder diffraction pattern of fumarate salt form I is substantially as shown in figure 13;
    The X-ray powder diffraction pattern of succinate crystalline form I is substantially as shown in figure 14; or (b)
    The X-ray powder diffraction pattern of succinate form ii is substantially as shown in figure 15.
  8. A pharmaceutical composition comprising:
    (a) The polymorph of any one of claims 1 to 7; and
    (B) A pharmaceutically acceptable carrier.
  9. Use of the polymorph of any one of claims 1 to 7, or a pharmaceutical composition of claim 8, for the preparation of an a 2A receptor inhibitor or an a 2B receptor inhibitor.
  10. Use of the polymorph of any one of claims 1-7, or a pharmaceutical composition of claim 8, in the manufacture of a medicament for the prevention or treatment of cancer or immune related diseases mediated by adenosine a 2A receptor or adenosine a 2B receptor.
  11. A method for preventing or treating cancer or immune related diseases mediated by the adenosine a 2A receptor or the adenosine a 2B receptor, comprising administering to a patient in need thereof a therapeutically effective amount of the polymorph of any one of claims 1 to 7, or a pharmaceutical composition of claim 8.
CN202280060100.6A 2021-09-15 2022-09-14 Polymorphs, pharmaceutical compositions and uses of azaaromatic ring compounds and pharmaceutically acceptable salts thereof Pending CN117915919A (en)

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EP3327014A4 (en) * 2015-07-24 2019-01-02 Shanghai Haiyan Pharmaceutical Technology Co., Ltd. Egfr inhibitor and pharmaceutically acceptable salt and polymorph thereof, and use thereof
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AU2018210272B2 (en) * 2017-01-20 2022-02-24 Arcus Biosciences, Inc. Azolopyrimidine for the treatment of cancer-related disorders
US20210188813A1 (en) * 2018-04-24 2021-06-24 Shanghai Haiyan Pharmaceutical Technology Co., Ltd. Ezh2 inhibitor and pharmaceutically acceptable salts and polymorphic substances thereof, and application of ezh2 inhibitor
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