CN115010663A - Crystal form of quinolinone compound and application thereof - Google Patents

Abstract

The invention relates to a crystal form of quinolinone compounds and application thereof. The invention also relates to a pharmaceutical composition comprising the crystalline form and the use of the crystalline form or the pharmaceutical composition for the manufacture of a medicament for the treatment and/or prevention of HIF-related and/or EPO-related diseases (e.g. anemia).

Description

Crystal form of quinolinone compound and application thereof

Technical Field

The invention belongs to the technical field of medicines, relates to a crystal form of a quinolinone compound and application thereof, and particularly relates to a crystal form of 2- (7- (4-fluorophenoxy) -4-hydroxy-1-methyl-2-oxo-1, 2-dihydroquinoline-3-formamido) acetic acid and application thereof, and further relates to a pharmaceutical composition containing the crystal form and application thereof.

Background

In the case of anemia, trauma, tissue necrosis and defects, the tissue or cells are often in a hypoxic state. Hypoxia results in the expression of a series of transcription inducible factors that are involved in angiogenesis, iron, sugar metabolism, and cell growth and proliferation. Among them, Hypoxia Inducible Factor (HIF) is a transcription factor that is activated by body cells under reduced oxygen conditions, and is widely distributed in various parts of the body, particularly intima vascularis, heart, brain, kidney, liver, etc. HIF is a heterodimer comprising an oxygen-regulated α -subunit (HIF α) and a constitutively expressed β -subunit (HIF β/ARNT). In oxygenated (normoxic) cells, the HIF α subunit is rapidly degraded by the ubiquitination (ubiquitination) mechanism of the von Hippel-Lindau tumor suppressor (pVHL) E3 ligase complex. Under hypoxic conditions, HIF α is not degraded, and active HIF α/β complexes accumulate in the nucleus and activate the expression of various genes, including glycolytic enzymes, glucose transporters, Erythropoietin (EPO), and Vascular Endothelial Growth Factor (VEGF).

Erythropoietin (EPO) is a naturally occurring hormone produced by HIF α that stimulates the production of red blood cells (erythrocytes) that carry oxygen throughout the body. EPO is normally secreted by the kidney, and endogenous EPO is increased under conditions of reduced oxygen (hypoxia). All types of anemia are characterized by a reduced capacity of the blood to carry oxygen and are therefore accompanied by similar signs and symptoms, including the skinPale skin and mucous membranes, weakness, dizziness, easy fatigue and lethargy, leading to a decrease in quality of life. Anemia is often associated with conditions lacking red blood cells or hemoglobin in the blood. The common causes of anemia include iron and vitamin B ₁₂ And folate deficiency, and also in association with chronic diseases, such as inflammatory diseases, including diseases with secondary myeloinflammatory suppression, and the like. Anemia is also associated with kidney dysfunction, and most renal failure patients who are constantly dialyzing suffer from chronic anemia.

Prolyl Hydroxylase (PHD) is a key factor in the regulation of HIF. Under normoxic conditions, PHD can hydroxylate two key proline residues Pro402 and Pro564 of HIF α, increasing its affinity for pVHL, accelerating the degradation process. Under hypoxia and other pathological conditions, the PHD-catalyzed HIF response is hindered and the rate of protease degradation is slowed, causing HIF α to accumulate within the cell, which in turn causes a series of adaptive responses of the cell to hypoxia. By inhibiting PHD through a PHD inhibitor, the action of HIF is prolonged, and the expression of genes such as EPO is further increased, thus HIF-related and/or EPO-related diseases, such as anemia, ischemia and anoxia, can be effectively treated and prevented.

International application WO 2016034108 a1 discloses the compound 2- (7- (4-fluorophenoxy) -4-hydroxy-1-methyl-2-oxo-1, 2-dihydroquinoline-3-carboxamido) acetic acid (compound of formula (I)) which can treat or alleviate HIF-related and/or EPO-related disorders, such as anemia and the like. However, no research report related to the crystal form of the compound exists in the prior art.

Drug polymorphism is a common phenomenon in drug development and is an important factor affecting drug quality. Different crystal forms of the same drug may have significant differences in appearance, solubility, melting point, dissolution rate, bioavailability and the like, and also have different influences on the stability, bioavailability, curative effect and the like of the drug. Therefore, in drug development, the problem of polymorphism of drugs should be considered comprehensively.

Disclosure of Invention

The invention provides a crystal form of a compound shown in a formula (I), wherein the crystal form, particularly the crystal form IV can obviously improve the properties of the compound, such as stability, pharmacokinetics and the like, so that the compound has more excellent druggability.

In particular, the invention relates to a crystal form of the compound shown in formula (I), and application of the crystal form of the compound or a pharmaceutical composition containing the crystal form in preparing a medicament for treating or preventing HIF related and/or EPO related diseases. The crystalline forms of the invention may also be in the form of solvates, for example hydrates.

In one aspect, the invention provides a crystalline form of a compound of formula (I),

in some embodiments, the crystalline form of the compound of formula (I) of the present invention is crystalline form I, IV, V, VII, or VIII.

In some embodiments, form I of the present invention, wherein the form I has an X-ray powder diffraction pattern having diffraction peaks at the following 2 Θ angles: 5.19 ° ± 0.2 °,19.63 ° ± 0.2 °,21.20 ° ± 0.2 °,24.58 ° ± 0.2 °,28.62 ° ± 0.2 °.

In other embodiments, form I of the present invention, wherein the form I has an X-ray powder diffraction pattern having diffraction peaks at the following 2 Θ angles: 5.19 ° ± 0.2 °,12.39 ° ± 0.2 °,15.79 ° ± 0.2 °,17.53 ° ± 0.2 °,19.63 ° ± 0.2 °,20.15 ° ± 0.2 °,20.49 ° ± 0.2 °,21.20 ° ± 0.2 °,24.58 ° ± 0.2 °,28.62 ° ± 0.2 °.

In other embodiments, form I of the present invention, wherein the form I has an X-ray powder diffraction pattern having diffraction peaks at the following 2 Θ angles: 5.19 ° ± 0.2 °,10.15 ° ± 0.2 °,10.44 ° ± 0.2 °,12.39 ° ± 0.2 °,13.21 ° ± 0.2 °,13.58 ° ± 0.2 °,15.79 ° ± 0.2 °,17.53 ° ± 0.2 °,18.06 ° ± 0.2 °,19.63 ° ± 0.2 °,20.15 ° ± 0.2 °,20.49 ° ± 0.2 °,21.20 ° ± 0.2 °,21.71 ° ± 0.2 °,22.80 ° ± 0.2 °,24.58 ° ± 0.2 °,25.07 ° ± 0.2 °,25.80 ° ± 0.2 °,26.16 ° ± 0.2 °,28.62 ° ± 0.2 °,32.01 ° ± 0.2 °,33.29 ° ± 0.2 °,35.53 ° ± 0.2 °,36.46 ° ± 0.2 ° ± 0.86 ° ± 0.2 °.

In some embodiments, form I of the present invention, wherein the form I has an X-ray powder diffraction pattern substantially as shown in figure 1.

In some embodiments, form I of the present invention is characterized by a differential scanning calorimetry trace for form I comprising an endothermic peak at 226.68 ℃ ± 3 ℃.

In some embodiments, form I of the present invention is characterized by a differential scanning calorimetry trace substantially as shown in figure 2.

In some embodiments, form I of the present invention is characterized by a weight loss of 0.12% at about 200.14 ℃, and the weight loss ratio has a margin of error of ± 0.1%.

In some embodiments, form I of the present invention, wherein the form I has a thermogravimetric analysis profile substantially as shown in figure 3.

In some embodiments, form IV of the present invention is characterized by an X-ray powder diffraction pattern having diffraction peaks at the following 2 Θ angles: 15.57 ° ± 0.2 °,17.83 ° ± 0.2 °,24.87 ° ± 0.2 °,25.69 ° ± 0.2 °,26.89 ° ± 0.2 °.

In other embodiments, form IV of the present invention is characterized by an X-ray powder diffraction pattern having diffraction peaks at the following 2 Θ angles: 6.59 degrees +/-0.2 degrees, 11.64 degrees +/-0.2 degrees, 15.57 degrees +/-0.2 degrees, 17.83 degrees +/-0.2 degrees, 19.69 degrees +/-0.2 degrees, 23.28 degrees +/-0.2 degrees, 24.87 degrees +/-0.2 degrees, 25.69 degrees +/-0.2 degrees, 26.45 degrees +/-0.2 degrees and 26.89 degrees +/-0.2 degrees.

In other embodiments, form IV of the present invention is characterized by an X-ray powder diffraction pattern having diffraction peaks at the following 2 Θ angles: 6.59 ° ± 0.2 °,11.64 ° ± 0.2 °,13.17 ° ± 0.2 °,13.77 ° ± 0.2 °,15.57 ° ± 0.2 °,16.13 ° ± 0.2 °,16.32 ° ± 0.2 °,17.36 ° ± 0.2 °,17.83 ° ± 0.2 °,19.05 ° ± 0.2 °,19.69 ° ± 0.2 °,20.33 ° ± 0.2 °,22.92 ° ± 0.2 °,23.28 ° ± 0.2 °,24.10 ° ± 0.2 °,24.87 ° ± 0.2 °,25.69 ° ± 0.2 °,26.45 ° ± 0.2 °,26.89 ° ± 0.2 °,28.39 ° ± 0.2 °,29.85 ° ± 0.2 °,31.39 ° ± 0.2 °,31.89 ° ± 0.2 °,33.25 ° ± 0.2.33 ° ± 0.2 °.

In other embodiments, form IV of the present invention is characterized by an X-ray powder diffraction pattern having diffraction peaks at the following 2 Θ angles: 6.59 ° ± 0.2 °,11.64 ° ± 0.2 °,13.17 ° ± 0.2 °,13.77 ° ± 0.2 °,15.57 ° ± 0.2 °,16.13 ° ± 0.2 °,16.32 ° ± 0.2 °,17.36 ° ± 0.2 °,17.83 ° ± 0.2 °,19.05 ° ± 0.2 °,19.69 ° ± 0.2 °,20.33 ° ± 0.2 °,21.63 ° ± 0.2 °,22.92 ° ± 0.2 °,23.28 ° ± 0.2 °,24.10 ° ± 0.2 °,24.87 ° ± 0.2 °,25.69 ° ± 0.2 °,26.45 ° ± 0.2 ° ± 26.89 ° ± 0.2 °,27.58 ° ± 0.2 °,28.39 ° ± 0.2 °,29.85 ° ± 0.2 °,25.2 ° ± 0.2 ° ± 0.26 ° ± 0.2 °,27.7 ° ± 0.2 °,28.7 ° ± 0.7 ° ± 0.2 °,28.39 ° ± 0.39 ° ± 0.2 °, 28.2 ° ± 0.2 °,29.2 °,29.85 ° ± 0.26 ° ± 0.2 °,29.2 ° ± 0.2 °, and 33 ° ± 0.2 °.

In some embodiments, form IV of the present invention, wherein the form IV has an X-ray powder diffraction pattern substantially as shown in figure 4.

In some embodiments, form IV of the present invention is characterized by a differential scanning calorimetry trace comprising endothermic peaks at 165.50 ℃ ± 3 ℃ and 277.26 ℃ ± 3 ℃.

In some embodiments, form IV of the present invention is characterized by a differential scanning calorimetry trace substantially as shown in figure 5.

In some embodiments, form IV of the present invention is characterized by a 5.148% weight loss at about 149.90 ℃ and a margin of error of ± 0.1% for the weight loss ratio.

In some embodiments, form IV of the present invention, wherein the form IV has a thermogravimetric analysis profile substantially as shown in figure 6.

In some embodiments, form V of the present invention is characterized by an X-ray powder diffraction pattern having diffraction peaks at the following 2 Θ angles: 4.45 ° ± 0.2 °,14.76 ° ± 0.2 °,22.23 ° ± 0.2 °,25.27 ° ± 0.2 °,28.54 ° ± 0.2 °.

In some embodiments, form V of the present invention is characterized by an X-ray powder diffraction pattern having diffraction peaks at the following 2 Θ angles: 4.45 ° ± 0.2 °,13.10 ° ± 0.2 °,14.76 ° ± 0.2 °,19.24 ° ± 0.2 °,21.11 ° ± 0.2 °,22.23 ° ± 0.2 °,22.83 ° ± 0.2 °,25.27 ° ± 0.2 °,27.09 ° ± 0.2 °,28.54 ° ± 0.2 °.

In some embodiments, form V of the present invention is characterized by an X-ray powder diffraction pattern having diffraction peaks at the following 2 Θ angles: 4.45 ° ± 0.2 °,8.65 ° ± 0.2 °,8.98 ° ± 0.2 °,9.82 ° ± 0.2 °,11.47 ° ± 0.2 °,13.10 ° ± 0.2 °,14.76 ° ± 0.2 °,17.21 ° ± 0.2 °,18.01 ° ± 0.2 °,19.24 ° ± 0.2 °,19.65 ° ± 0.2 °,20.04 ° ± 0.2 °,20.54 ° ± 0.2 °,21.11 ° ± 0.2 °,21.45 ° ± 0.2 °,22.23 ° ± 0.2 °,22.83 ° ± 0.2 °,25.27 ° ± 0.2 °,26.41 ° ± 0.2 °,27.09 ° ± 0.2 °,28.54 ° ± 0.2 °,30.99 ° ± 0.2 °,33.04 ° ± 0.2.62 °, 3583 ° ± 0.2 °, 37.2 ° ± 0.2 °.

In some embodiments, form V of the present invention, wherein the form V has an X-ray powder diffraction pattern substantially as shown in figure 7.

In some embodiments, form V of the present invention is characterized by a differential scanning calorimetry trace comprising endothermic peaks at 186.65 ℃ ± 3 ℃ and 248.10 ℃ ± 3 ℃.

In some embodiments, form V of the present invention is characterized by having a differential scanning calorimetry pattern substantially as shown in figure 8.

In some embodiments, form V of the present invention is characterized by a weight loss of 3.582% at about 150.10 ℃, with a margin of error of ± 0.1%.

In some embodiments, form V of the present invention, wherein the form V has a thermogravimetric analysis profile substantially as shown in figure 9.

In some embodiments, the crystalline form VII of the present invention is characterized by an X-ray powder diffraction pattern having diffraction peaks at the following 2 Θ angles: 8.49 ° ± 0.2 °,15.71 ° ± 0.2 °,17.01 ° ± 0.2 °,22.68 ° ± 0.2 °,29.21 ° ± 0.2 °.

In some embodiments, the crystalline form VII of the present invention is characterized by an X-ray powder diffraction pattern having diffraction peaks at the following 2 Θ angles: 8.49 ° ± 0.2 °,15.71 ° ± 0.2 °,17.01 ° ± 0.2 °,18.50 ° ± 0.2 °,19.39 ° ± 0.2 °,20.36 ° ± 0.2 °,22.68 ° ± 0.2 °,23.26 ° ± 0.2 °,29.21 ° ± 0.2 °,31.41 ° ± 0.2 °.

In some embodiments, the crystalline form VII of the present invention is characterized by an X-ray powder diffraction pattern having diffraction peaks at the following 2 Θ angles: 4.24 ° ± 0.2 °,6.58 ° ± 0.2 °,8.49 ° ± 0.2 °,12.52 ° ± 0.2 °,13.16 ° ± 0.2 °,13.49 ° ± 0.2 °,15.71 ° ± 0.2 °,17.01 ° ± 0.2 °,17.79 ° ± 0.2 °,18.50 ° ± 0.2 °,18.99 ° ± 0.2 °,19.39 ° ± 0.2 °,20.36 ° ± 0.2 °,20.98 ° ± 0.2 °,21.76 ° ± 0.2 °,22.08 ° ± 0.2 °,22.68 ° ± 0.2 °,23.26 ° ± 0.2 °,24.11 ° ± 0.2 °,24.53 ° ± 0.2 °,24.84 ° ± 0.2 °,25.59 ° ± 0.2 °,26.93 ° ± 0.2.24 ° ± 0.2 °,27.2 ° ± 0.0.2 °,24 ° ± 0.2 °,24 ° ± 0.2.72 ° ± 0.36 ° ± 0.2 °,24 ° ± 0.2.2.2 °,24 ° ± 0.2 °,24 ° ± 0.2.2 °,24 ° ± 0.2 °,24 ° ± 0.2.2.2.2.2.2 °,24 ° ± 0.2.2.2 °,24 ° ± 0.2 °,24 ° ± 0.2.2 °,24 ° ± 0.2 °, 24.2.2.2.2.2 °,24 ° ± 0.2 °,24 ° ± 0.2.2 °,24 ° ± 0.2 °, 25.2.2 °,21 ° ± 0.2 °, 2.2.2 °, 2.2.33 ° ± 0.2.2 °,2 °, 2.2.2.2.2.33 ° ± 0.2 °,2 °, 2.2 °, 2.2.2 °,2 °,21 ° ± 0.2 °,2 ° ± 0.2 ° ± 0.33 ° ± 0.2 °,2 °, 2.2 °,2 °, 2.33 ° ± 0.2 °, 2.33 ° ± 0.2.2 ° ± 0.2.2.33 ° ± 0.2 °,2 ° ± 0.2 °,2 ° ± 0.33 ° ± 0.2 °, 2.2 ° 0.33 ° ± 0.2.33 ° ± 0.2.2.2 ° ± 0.2 °,2 ° ± 0.2 °, 2.2.2 °,2 ° ± 0.2 ° ± 0.2.2.2 ° ± 0.2 °,2 ° ± 0.2 ° ± 0.33 ° ± 0.2 °,2 ° ± 0.

In some embodiments, the crystalline form VII of the present invention is characterized by having an X-ray powder diffraction pattern substantially as shown in figure 10.

In some embodiments, crystalline form VII of the present invention is characterized by a differential scanning calorimetry trace comprising endothermic peaks at 132.47 ℃ ± 3 ℃, 162.45 ℃ ± 3 ℃ and 243.61 ℃ ± 3 ℃.

In some embodiments, the crystalline form VII of the present invention is characterized by a differential scanning calorimetry trace substantially as shown in figure 11.

In some embodiments, the crystalline form VII of the present invention is characterized by a weight loss of 11.56% at about 156.61 ℃ and a margin of error of ± 0.1% for the weight loss ratio.

In some embodiments, the crystalline form VIII of the present invention, wherein the crystalline form VIII has a thermogravimetric analysis profile substantially as shown in figure 12.

In some embodiments, the crystalline form VIII of the present invention is characterized by an X-ray powder diffraction pattern having diffraction peaks at the following 2 Θ angles: 7.30 ° ± 0.2 °,17.52 ° ± 0.2 °,21.92 ° ± 0.2 °,23.89 ° ± 0.2 °,24.47 ° ± 0.2 °.

In some embodiments, the crystalline form VIII of the present invention is characterized by an X-ray powder diffraction pattern having diffraction peaks at the following 2 Θ angles: 7.30 ° ± 0.2 °,12.36 ° ± 0.2 °,12.63 ° ± 0.2 °,17.52 ° ± 0.2 °,21.02 ° ± 0.2 °,21.92 ° ± 0.2 °,23.89 ° ± 0.2 °,24.47 ° ± 0.2 °,24.77 ° ± 0.2 °,28.78 ° ± 0.2 °.

In some embodiments, the crystalline form VIII of the present invention is characterized by an X-ray powder diffraction pattern having diffraction peaks at the following 2 Θ angles: 7.30 ° ± 0.2 °,7.84 ° ± 0.2 °,9.19 ° ± 0.2 °,10.62 ° ± 0.2 °,12.36 ° ± 0.2 °,12.63 ° ± 0.2 °,13.22 ° ± 0.2 °,15.05 ° ± 0.2 °,16.06 ° ± 0.2 °,17.52 ° ± 0.2 °,17.93 ° ± 0.2 °,18.57 ° ± 0.2 °,19.14 ° ± 0.2 °,19.92 ° ± 0.2 °,20.54 ° ± 0.2 °,21.02 ° ± 0.2 °,21.92 ° ± 0.2 °,22.55 ° ± 0.23 ° ± 0.2 °,23.89 ° ± 0.2 °,24.47 ° ± 0.9 ° ± 0.27 ° ± 0.9 ° ± 0.2 °,20.9 ° ± 2 °, 360.9 ° ± 0.9 ° ± 2.2 °, 360.9 ° ± 0.2 °,30 ° ± 0.9 ° ± 0.2 °,30.9 ° ± 0.2 °,30 ° ± 0.9 ° ± 0.2.2.2.2 °,30 ° ± 0.9 ° ± 0.2.2 °,30 ° ± 0.9 ° ± 0.2.9 ° ± 0.2.2.2 °,30 ° ± 0.9 ° ± 0.2.9 ° ± 0.2 °,30 ° ± 0.2.2.9 ° ± 0.9 ° ± 0.2.9 ° ± 0.2.2.2.2.9 ° ± 0.2 °,30 ° ± 0.9 ° ± 0.2 °,30 ° ± 0.2.2.9 ° ± 0.2 °,30 ° ± 0.9 ° ± 0.2.2 °,30 ° ± 0.9 ° ± 0.2 °,30 ° ± 0.9 ° ± 0.2 °,30 ° ± 0.9 ° ± 0.2.9 ° ± 0.9 ° ± 0.2.2.9 ° ± 0.2.2 °,30 ° ± 0.2.2.2.2 °,30 ° ± 0.9 ° ± 0.2 °,30 ° ± 0.2.2.2.9 ° ± 0.9 ° ± 0.2 °,30 ° ± 0.9 ° ± 0.2.9 ° ± 0.9 ° ± 0.2 °,30 ° ± 0.2.2.2 °,30 ° ± 0.2 °,30 ° ± 0.9 ° ±.

In some embodiments, the crystalline form VIII of the present invention, wherein the crystalline form VIII has an X-ray powder diffraction pattern substantially as shown in figure 13.

In some embodiments, crystalline form VIII according to the present invention, characterized in that the differential scanning calorimetry trace of crystalline form VIII comprises endothermic peaks at 132.43 ℃ ± 3 ℃ and 228.64 ℃ ± 3 ℃.

In some embodiments, the crystalline form VIII of the present invention, wherein the crystalline form VIII has a differential scanning calorimetry pattern substantially as shown in figure 14.

In some embodiments, the crystalline form VIII according to the present invention, wherein the crystalline form VIII loses 15.35% weight at about 136.47 ℃, and the weight loss ratio has a margin of error of ± 0.1%.

In some embodiments, the crystalline form VIII of the present invention, wherein the crystalline form VIII has a thermogravimetric analysis profile substantially as shown in figure 15.

In another aspect, the invention relates to a pharmaceutical composition comprising any of the crystalline forms described herein, and a pharmaceutically acceptable carrier, excipient, diluent, adjuvant, or combination thereof.

In one aspect, the invention relates to the use of any of the crystalline forms or the pharmaceutical composition for the preparation of a medicament for preventing, treating or alleviating hypoxia-inducible factor-related and/or erythropoietin-related diseases in a patient.

In some embodiments, the hypoxia-inducible factor-related and/or erythropoietin-related disorder of the invention is anemia, ischemia, a vascular disease, angina, myocardial ischemia, myocardial infarction, a metabolic disorder, or wound healing.

In another aspect, the invention relates to the use of any of the crystalline forms or the pharmaceutical composition for the manufacture of a medicament for preventing, treating or alleviating a disease in a patient mediated at least in part by the hypoxia inducible factor prolyl hydroxylase.

In some embodiments, the hypoxia-inducible factor-related and/or erythropoietin-related disorder of the invention is anemia, ischemia, a vascular disease, angina, myocardial ischemia, myocardial infarction, a metabolic disorder, or wound healing.

One aspect of the present invention relates to a method for preventing, treating or alleviating hypoxia-inducible factor-related and/or erythropoietin-related diseases in a patient, comprising administering to the patient an effective amount of the crystalline form of the present invention or the pharmaceutical composition.

In another aspect, the invention also relates to a preparation method of the crystal form of the compound shown in the formula (I).

The solvent used in the method for producing the crystalline form of the present invention is not particularly limited, and any solvent that can dissolve the starting materials to an extent that does not affect the properties thereof is included in the present invention. Further, many equivalents, substitutions, or equivalents in the art to which this invention pertains, as well as different proportions of solvents, solvent combinations, and solvent combinations described herein, are deemed to be encompassed by the present invention. The invention provides a preferable solvent used in each reaction step.

The experiments for the preparation of the crystalline forms of the invention are described in detail in the examples section. Meanwhile, the invention provides an activity test experiment (such as a pharmacokinetic experiment), a solubility experiment, a stability experiment, a hygroscopicity experiment and the like of the crystal form. Experiments prove that the crystal form IV has better biological activity, solubility and stability. Therefore, the crystal form IV has better biological activity, better solubility and higher stability, and is more suitable for pharmaceutical use.

In addition, according to the moisture absorption experimental result, the crystal form is not easy to deliquesce under the influence of high humidity, and is convenient for long-term storage and placement of the medicine.

Definitions and general terms

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 invention belongs. All patents and publications referred to herein are incorporated by reference in their entirety. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, the preferred methods, devices, and materials are described herein.

"crystalline form" or "crystalline form" refers to a solid having a highly regular chemical structure, including, but not limited to, single or multicomponent crystals, and/or polymorphs, solvates, hydrates, clathrates, co-crystals, salts, solvates of salts, hydrates of salts of compounds. Crystalline forms of the substance can be obtained by a number of methods known in the art. Such methods include, but are not limited to, melt crystallization, melt cooling, solvent crystallization, crystallization in a defined space, e.g., in a nanopore or capillary, on a surface or template, e.g., on a polymer, in the presence of an additive such as a co-crystallizing counter molecule, desolventization, dehydration, rapid evaporation, rapid cooling, slow cooling, vapor diffusion, sublimation, reactive crystallization, anti-solvent addition, milling, and solvent drop milling, among others.

"solvent" refers to a substance (typically a liquid) that is capable of completely or partially dissolving another substance (typically a solid). Solvents useful in the practice of the present invention include, but are not limited to, water, acetic acid, acetone, acetonitrile, benzene, chloroform, carbon tetrachloride, methylene chloride, dimethyl sulfoxide, 1, 4-dioxane, ethanol, ethyl acetate, butanol, t-butanol, N-dimethylacetamide, N-dimethylformamide, formamide, formic acid, heptane, hexane, isopropanol, methanol, methyl ethyl ketone, mesitylene, nitromethane, polyethylene glycol, propanol, pyridine, tetrahydrofuran, toluene, xylene, mixtures thereof, and the like.

By "anti-solvent" is meant a fluid that facilitates precipitation of the product (or product precursor) from the solvent. The anti-solvent may comprise a cold gas, or a fluid that promotes precipitation by a chemical reaction, or a fluid that reduces the solubility of the product in the solvent; it may be the same liquid as the solvent but at a different temperature, or it may be a different liquid than the solvent.

"solvate" refers to a compound having a solvent on a surface, in a crystal lattice, or on and in a crystal lattice, which may be water, acetic acid, acetone, acetonitrile, benzene, chloroform, carbon tetrachloride, methylene chloride, dimethyl sulfoxide, 1, 4-dioxane, ethanol, ethyl acetate, butanol, t-butanol, N-dimethylacetamide, N-dimethylformamide, formamide, formic acid, heptane, hexane, isopropanol, methanol, methyl ethyl ketone, methyl pyrrolidone, mesitylene, nitromethane, polyethylene glycol, propanol, pyridine, tetrahydrofuran, toluene, xylene, mixtures thereof, and the like. A specific example of a solvate is a hydrate, wherein the solvent on the surface, in the crystal lattice or on the surface and in the crystal lattice is water. The hydrates may or may not have other solvents than water on the surface of the substance, in the crystal lattice or both.

Crystalline forms can be identified by a variety of techniques, such as X-ray powder diffraction (XRPD), infrared absorption spectroscopy (IR), melting point methods, Differential Scanning Calorimetry (DSC), thermogravimetric analysis (TGA), nuclear magnetic resonance methods, raman spectroscopy, X-ray single crystal diffraction, dissolution calorimetry, Scanning Electron Microscopy (SEM), quantitative analysis, solubility, and dissolution rate, and the like.

X-ray powder diffraction (XRPD) can detect information such as change, crystallinity, crystal structure state and the like of a crystal form, and is a common means for identifying the crystal form. The peak positions of XRPD patterns depend primarily on the structure of the crystalline form, being relatively insensitive to experimental details, while their relative peak heights depend on a number of factors related to sample preparation and instrument geometry. Accordingly, in some embodiments, the crystalline form of the present invention is characterized by an XRPD pattern having certain peak positions, substantially as shown in the XRPD patterns provided in the figures herein. Also, the 2 θ measurement of the XRPD pattern may have experimental error, and the 2 θ measurement of the XRPD pattern may be slightly different from instrument to instrument and from sample to sample, so the 2 θ value cannot be considered absolute. The diffraction peaks have a tolerance of ± 0.2 ° according to the conditions of the instrument used in the test.

Differential Scanning Calorimetry (DSC) is to measure the temperature of a sample and an inert reference substance (usually alpha-Al) by continuously heating or cooling under the control of a program ₂ O ₃ ) The energy difference therebetween varies with temperature. The endothermic peak height of the DSC curve depends on many factors related to sample preparation and instrument geometry, while the peak position is relatively insensitive to experimental details. Thus, in some embodiments, the crystalline form of the present invention is characterized by a DSC profile with characteristic peak positions substantially as shown in the DSC profiles provided in the figures of the present invention. Meanwhile, the DSC spectrum can have experimental errors, different instruments andthe peak position and peak value of the DSC profile may differ slightly between different samples, and therefore the peak position or peak value of the DSC endothermic peak cannot be considered absolute. The endothermic peak has a tolerance of + -3 deg.C depending on the instrument used in the experiment.

Thermogravimetric analysis (TGA) is a technique for measuring the change in mass of a substance with temperature under program control, and is suitable for examining the loss of a solvent in a crystal or the sublimation and decomposition of a sample, and it can be presumed that the crystal contains crystal water or a crystal solvent. The change in mass shown by the TGA profile depends on many factors such as sample preparation and instrumentation; the mass change of the TGA detection varies slightly from instrument to instrument and from sample to sample. There is a tolerance of + -0.1% for mass change depending on the condition of the instrument used in the test.

In the context of the present invention, the 2 θ values in the X-ray powder diffraction pattern are all in degrees (°).

The term "substantially as shown" means that at least 50%, or at least 60%, or at least 70%, or at least 80%, or at least 90%, or at least 95%, or at least 99% of the peaks in the X-ray powder diffraction pattern or DSC pattern or raman spectrum or infrared spectrum are shown in the figure.

When referring to a spectrogram or/and data appearing in a graph, "peak" refers to a feature that one skilled in the art would recognize as not being attributable to background noise.

The present invention relates to novel crystalline forms of said 2- (7- (4-fluorophenoxy) -4-hydroxy-1-methyl-2-oxo-1, 2-dihydroquinoline-3-carboxamido) acetic acid, e.g., form I, IV, V, VII or VIII, which are present in substantially pure crystalline form.

By "substantially pure" is meant that a crystalline form is substantially free of one or more additional crystalline forms, i.e., the crystalline form is at least 80%, or at least 85%, or at least 90%, or at least 93%, or at least 95%, or at least 98%, or at least 99%, or at least 99.5%, or at least 99.6%, or at least 99.7%, or at least 99.8%, or at least 99.9% pure, or the crystalline form contains additional crystalline forms, the percentage of which in the total volume or weight of the crystalline form is less than 20%, or less than 10%, or less than 5%, or less than 3%, or less than 1%, or less than 0.5%, or less than 0.1%, or less than 0.01%.

By "substantially free" is meant that the percentage of one or more other crystalline forms in the total volume or weight of the crystalline form is less than 20%, or less than 10%, or less than 5%, or less than 4%, or less than 3%, or less than 2%, or less than 1%, or less than 0.5%, or less than 0.1%, or less than 0.01%.

"relative intensity" (or "relative peak height") in an XRPD pattern refers to the ratio of the intensity of the first strong peak to the intensity of the other peaks when the intensity of the first strong peak is 100% of all the diffraction peaks in the X-ray powder diffraction pattern.

In the context of the present invention, the word "about" or "approximately" when used or whether used, means within 10%, suitably within 5%, and especially within 1% of a given value or range. Alternatively, the term "about" or "approximately" means within an acceptable standard error of the mean, for one of ordinary skill in the art. Whenever a number is disclosed with a value of N, any number within the values of N +/-1%, N +/-2%, N +/-3%, N +/-5%, N +/-7%, N +/-8% or N +/-10% is explicitly disclosed, wherein "+/-" means plus or minus.

"room temperature" in the present invention means a temperature of from about 10 ℃ to about 40 ℃. In some embodiments, "room temperature" refers to a temperature of from about 20 ℃ to about 30 ℃; in other embodiments, "room temperature" refers to 20 ℃,22.5 ℃,25 ℃,27.5 ℃, and the like.

Pharmaceutical compositions, formulations, administration and uses of the crystalline forms of the invention

The pharmaceutical composition of the invention is characterized by comprising a crystal form of the compound shown in the formula (I) and a pharmaceutically acceptable carrier, adjuvant or excipient. The amount of the crystalline form of the compound in the pharmaceutical compositions of the invention is effective to detectably treat or ameliorate HIF-related and/or EPO-related conditions in a subject.

As described herein, the pharmaceutically acceptable compositions of the present invention further comprise a pharmaceutically acceptable carrier, adjuvant, or excipient, as used herein, including any solvent, diluent, or other liquid excipient, dispersant or suspending agent, surfactant, isotonic agent, thickening agent, emulsifier, preservative, solid binder or lubricant, and the like, as appropriate for the particular target dosage form. As described in the following documents: in Remington, The Science and Practice of Pharmacy,21st edition,2005, ed.D.B.Troy, Lippincott Williams & Wilkins, Philadelphia, and Encyclopedia of Pharmaceutical Technology, eds.J.Swarbrick and J.C. Boylan, 1988. Annu 1999, Marcel Dekker, New York, taken together with The disclosure of this document, suggests that different carriers may be employed In The preparation of pharmaceutically acceptable compositions and their well known methods of preparation. Except insofar as any conventional carrier vehicle is incompatible with the crystalline form of the compound of the invention, e.g., any adverse biological effect produced or interaction in a deleterious manner with any other component of a pharmaceutically acceptable composition, its use is contemplated by the present invention.

Materials that can serve as pharmaceutically acceptable carriers include, but are not limited to, ion exchangers; aluminum; aluminum stearate; lecithin; serum proteins, such as human serum albumin; buffer substances such as phosphates; glycine; sorbic acid; potassium sorbate; partial glyceride mixtures of saturated vegetable fatty acids; water; salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts; colloidal silica; magnesium trisilicate; polyvinylpyrrolidone; polyacrylate esters; a wax; polyethylene-polyoxypropylene-blocking polymers; lanolin; sugars, such as lactose, glucose and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; gum powder; malt; gelatin; talc powder; adjuvants such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; glycols, such as propylene glycol and polyethylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffering agents such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic salt; ringer's solution; ethanol; phosphoric acid buffer solution; and other non-toxic suitable lubricants such as sodium lauryl sulfate and magnesium stearate; a colorant; a release agent; coating the coating material; a sweetener; a flavoring agent; a fragrance; preservatives and antioxidants.

The pharmaceutical composition of the invention can be capsules, tablets, pills, powders, granules and aqueous suspensions or solutions; administration can be by the following route: oral administration, injection administration, spray inhalation, topical administration, rectal administration, nasal administration, buccal administration, vaginal administration or administration via an implantable kit.

Oral administration may be in the form of: tablets, pills, capsules, dispersible powders, granules or suspensions, syrups, elixirs and the like; administration by external application may be in the form of: ointment, gel, medicated plaster, etc.

The crystalline forms of the invention are preferably formulated as unit dosage forms to reduce the dosage and uniformity of dosage. The term "dosage unit form" as used herein refers to physically discrete units of a drug required for proper treatment of a patient. However, it will be appreciated that the total daily usage of a compound of formula (I) or a crystalline form thereof, or a pharmaceutical composition of the invention, will be determined by the attending physician, within the scope of sound medical judgment. The specific effective dosage level for any particular patient or organism will depend upon a variety of factors including the severity of the condition and disorder being treated, the activity of the specific compound or crystalline form thereof, the specific composition employed, the age, body weight, health, sex, and dietary habits of the patient, the time of administration, the route of administration and rate of excretion of the specific compound or crystalline form employed, the duration of the treatment, the drug regimen or combination with the specific compound or crystalline form thereof, and other factors well known in the pharmaceutical arts.

The effective dosage of the active ingredient employed may vary with the compound or crystalline form thereof employed, the mode of administration and the severity of the condition being treated. However, in general, satisfactory results are obtained when the compounds of the invention or crystalline forms thereof are administered daily at a dose of about 0.25 to 1000mg/kg animal body weight, preferably 2 to 4 divided doses per day, or in sustained release form. This dosage regimen may be adjusted to provide the best therapeutic response. In addition, due to the differences in the treatment conditions, several divided doses may be given daily, or the doses may be proportionally reduced.

The compounds or crystalline forms thereof, and pharmaceutical compositions of the invention are useful for inhibiting HIF hydroxylase activity, thereby modulating the stability and/or activity of HIF and activating expression of HIF regulatory genes. The compounds, or crystalline forms thereof, or the pharmaceutical compositions described can be used in methods of treating, pretreating, or delaying the onset or progression of a HIF-associated condition, including, but not limited to, anemia and ischemia, as well as conditions associated with hypoxia.

In particular, the present invention relates to compounds or crystalline forms thereof that are useful for increasing endogenous Erythropoietin (EPO). The compound or crystalline form thereof can be administered for the prevention, pre-treatment, or treatment of EPO-related disorders, including, for example, anemia and neurological disorders. Conditions associated with anemia include, but are not limited to: acute or chronic kidney disease, diabetes, cancer, ulcers, viral (e.g. HIV), bacterial or parasitic infections; inflammation, and the like. Additionally, anemia is associated with hemoglobin and/or red blood cell abnormalities, such as seen in disorders such as microcytic anemia, hypopigmentary anemia, aplastic anemia, and the like.

Drawings

Figure 1 is an X-ray powder diffraction (XRPD) pattern of crystalline form I of the compound of formula (I).

FIG. 2 is a Differential Scanning Calorimetry (DSC) profile of form I of the compound of formula (I).

FIG. 3 is a thermogravimetric analysis of the crystalline form I of the compound of formula (I).

Figure 4 is an X-ray powder diffraction (XRPD) pattern of form IV of the compound of formula (I).

FIG. 5 is a Differential Scanning Calorimetry (DSC) profile of form IV of a compound of formula (I).

FIG. 6 is a thermogravimetric analysis of the compound of formula (I) in crystalline form IV.

Figure 7 is an X-ray powder diffraction (XRPD) pattern of form V of the compound of formula (I).

FIG. 8 is a Differential Scanning Calorimetry (DSC) profile of form V of the compound of formula (I).

FIG. 9 is a thermogravimetric analysis of the crystalline form V of the compound of formula (I).

Figure 10 is an X-ray powder diffraction (XRPD) pattern of crystalline form VII of the compound of formula (I).

FIG. 11 is a Differential Scanning Calorimetry (DSC) profile of form VII of the compound of formula (I).

Fig. 12 is a thermogravimetric analysis of the crystalline form VII of the compound represented by formula (I).

Figure 13 is an X-ray powder diffraction (XRPD) pattern of crystalline form VIII of the compound of formula (I).

FIG. 14 is a Differential Scanning Calorimetry (DSC) profile of crystalline form VIII of the compound of formula (I).

FIG. 15 is a thermogravimetric analysis of the compound of formula (I) in crystalline form VIII.

Detailed Description

The invention is further illustrated by the following examples, which are not intended to limit the invention thereto.

The X-ray powder diffraction analysis method used by the invention comprises the following steps: an Empyrean diffractometer, using Cu-Ka radiation (45KV,40mA) to obtain an X-ray powder diffraction pattern. The powdered sample was prepared as a thin layer on a single crystal silicon sample holder, placed on a rotating sample stage and analyzed in 0.0167 ° steps over a range of 3 ° -40 °. Data Collector software was used to collect Data, HighScore Plus software processed the Data, and Data Viewer software read the Data.

The Differential Scanning Calorimetry (DSC) analysis method used in the invention comprises the following steps: differential scanning calorimetry was performed using a TA Q2000 module with a thermoanalytical controller. Data were collected and analyzed using TA Instruments Thermal Solutions software. About 1-5mg of the sample was accurately weighed into a specially made aluminum crucible with a lid and the sample analysis was performed from room temperature to about 300 c using a 10 c/min linear heating device. During use, the DSC cell was purged with dry nitrogen.

The Thermal Gravimetric Analysis (TGA) method used in the invention is as follows: the thermogravimetric loss was performed using a TA Q500 module with a thermoanalytical controller. Data were collected and analyzed using TA Instruments Thermal Solutions software. About 10mg of the sample was accurately weighed into a platinum sample pan and the sample analysis was performed from room temperature to about 300 c using a 10 c/min linear heating device. During use, the TGA furnace chamber was purged with dry nitrogen.

The solubility of the invention is measured by an Agilent 1200 high performance liquid chromatograph DAD/VWD detector, and the model of a chromatographic column is Agilent XDB-C18 (4.6X 50mm, 5 mu m). The detection wavelength is 266nm, the flow rate is 1.0mL/min, the column temperature is 35 ℃, and the ratio of mobile phase A: acetonitrile-0.01M ammonium acetate ═ 10: 90 (V: V) analysis method: acetonitrile-mobile phase a ═ 70: 30 (V: V), runtime: for 10 minutes.

The moisture absorption of the invention is measured by adopting a DVS INT-Std type dynamic moisture and gas adsorption analyzer of Surface Measurement Systems company in England, and the humidity test range is as follows: 0% -95%, airflow: 200mL/min, temperature: 25 ℃, test point: one test point was taken per liter of 5% humidity.

Detailed description of the invention

A specific synthesis of the compound 2- (7- (4-fluorophenoxy) -4-hydroxy-1-methyl-2-oxo-1, 2-dihydroquinoline-3-carboxamido) acetic acid of formula (I) is described in example 47 of International application WO 2016034108A 1.

Examples

Example 1 crystalline form I of the invention

1. Preparation of form I

Adding 2- (7- (4-fluorophenoxy) -4-hydroxy-1-methyl-2-oxo-1, 2-dihydroquinoline-3-formamido) acetic acid (102mg) into a 10mL glass bottle, adding acetic acid (4.0mL), heating to 70 ℃ under magnetic stirring, clarifying the system, transferring the reaction to room temperature, naturally cooling, and standing for 1 day; suction filtration and drying of the filter cake under vacuum at room temperature for 0.5 h gave an off-white solid powder (45mg, 44.12%).

2. Identification of form I

(1) Identified by Empyrean X-ray powder diffraction (XRPD) analysis: using Cu-ka radiation, having the following characteristic peaks, expressed in degrees 2 θ: 5.19 °,10.15 °,10.44 °,12.39 °,13.21 °,13.58 °,15.79 °,17.53 °,18.06 °,19.63 °,20.15 °,20.49 °,21.20 °,21.71 °,22.80 °,24.58 °,25.07 °,25.80 °,26.16 °,28.62 °,32.01 °,33.29 °,35.53 °,36.46 °,37.86 °, and 38.50 °, with a tolerance of ± 0.2 °.

(2) Identification by TA Q2000 Differential Scanning Calorimetry (DSC) analysis: scan speed 10 ℃/min, endotherm peak at 226.68 ℃, error tolerance of + -3 ℃

(3) Thermogravimetric analysis (TGA) identification by TA Q500: the heating rate is 10 ℃/min, the weight loss range is 0.12%, and the error tolerance of +/-0.1% exists.

Example 2 form IV of the invention

1. Preparation of form IV

Method 1

2- (7- (4-fluorophenoxy) -4-hydroxy-1-methyl-2-oxo-1, 2-dihydroquinoline-3-carboxamido) acetic acid (41mg) was charged into a 5mL glass bottle, a mixed solvent of N, N-dimethylformamide and dichloromethane (1.0mL, v/v ═ 4/1) was added, the mixture was stirred at room temperature for 1 day and then filtered under suction, and the filter cake was vacuum-dried at room temperature overnight to give an off-white solid powder (10mg, 24.39%).

Method two

2- (7- (4-fluorophenoxy) -4-hydroxy-1-methyl-2-oxo-1, 2-dihydroquinoline-3-carboxamido) acetic acid (41mg) was added to a 10mL glass bottle, N-methylpyrrolidone (1.5mL) was added, the mixture was sonicated until the system was clear, acetone (3.0mL) was added dropwise to the solution with stirring at room temperature, suction filtration was carried out after 1 hour, and the filter cake was vacuum-dried at room temperature for 4 hours to give an off-white solid powder (10mg, 24.39%).

2. Identification of form IV

(1) Identified by Empyrean X-ray powder diffraction (XRPD) analysis: using Cu-ka radiation, having the following characteristic peaks expressed in degrees 2 θ: 6.59 °,11.64 °,13.17 °,13.77 °,15.57 °,16.13 °,16.32 °,17.36 °,17.83 °,19.05 °,19.69 °,20.33 °,21.63 °,22.92 °,23.28 °,24.10 °,24.87 °,25.69 °,26.45 °,26.89 °,27.58 °,28.39 °,29.85 °,31.39 °,31.89 °,32.79 °,33.25 °,34.33 °,35.37 °,36.16 °,36.69 °,37.44 °, and 38.65 °, with a tolerance of ± 0.2 °.

(2) Identification by TA Q2000 Differential Scanning Calorimetry (DSC) analysis: scan speed of 10 ℃/min, endothermic peaks at 165.50 ℃ and 277.26 ℃, with a margin of error of + -3 ℃

(3) Thermogravimetric analysis (TGA) identification by TA Q500: the heating rate is 10 ℃/min, the weight loss range is 5.15 percent, and the error tolerance of +/-0.1 percent exists.

Example 3 form V of the invention

1. Preparation of form V

2- (7- (4-fluorophenoxy) -4-hydroxy-1-methyl-2-oxo-1, 2-dihydroquinoline-3-carboxamido) acetic acid (34mg) was added to a 4mL centrifuge tube, acetone (15.0mL) was added to a 30mL glass bottle, the tube was placed in the bottle, sealed, and left to stand at room temperature for 7 days, and the resulting solid was dried under vacuum at room temperature for 6 hours to give an off-white solid powder (33mg, 97.06%).

2. Identification of form V

(1) Identified by Empyrean X-ray powder diffraction (XRPD) analysis: using Cu-ka radiation, having the following characteristic peaks expressed in degrees 2 θ: 4.45 °,8.65 °,8.98 °,9.82 °,11.47 °,13.10 °,14.76 °,17.21 °,18.01 °,19.24 °,19.65 °,20.04 °,20.54 °,21.11 °,21.45 °,22.23 °,22.83 °,25.27 °,26.41 °,27.09 °,28.54 °,30.99 °,33.04 °,34.62 °,37.08 °, and 38.79 °, with a tolerance of ± 0.2 °.

(2) Identification by TA Q2000 Differential Scanning Calorimetry (DSC) analysis: the scan rate was 10 ℃/min, contained endothermic peaks at 186.65 ℃ and 248.10 ℃, with a margin of error of ± 3 ℃.

(3) Thermogravimetric analysis (TGA) identification by TA Q500: the heating rate is 10 ℃/min, the weight loss range is 3.58 percent, and the error tolerance of +/-0.1 percent exists.

Example 4 form VII

1. Preparation of form VII

2- (7- (4-fluorophenoxy) -4-hydroxy-1-methyl-2-oxo-1, 2-dihydroquinoline-3-carboxamido) acetic acid (42mg) was charged into a 5mL glass bottle, and a mixed solvent of dimethyl sulfoxide and 1, 4-dioxane (2.0mL, v/v. 1/4) was added, followed by stirring at room temperature overnight; suction filtration was performed, and the filter cake was vacuum dried at room temperature for 3 hours to give an off-white powder (20mg, 47.62%).

2. Identification of form VII

(1) Identified by Empyrean X-ray powder diffraction (XRPD) analysis: using Cu-ka radiation, having the following characteristic peaks expressed in degrees 2 θ: 4.24 °,6.58 °,8.49 °,12.52 °,13.16 °,13.49 °,15.71 °,17.01 °,17.79 °,18.50 °,18.99 °,19.39 °,20.36 °,20.98 °,21.76 °,22.08 °,22.68 °,23.26 °,24.11 °,24.53 °,24.84 °,25.59 °,26.93 °,27.24 °,27.72 °,28.36 °,29.21 °,29.60 °,30.21 °,30.73 °,31.41 °,32.82 °,33.33 °,34.36 °,35.74 °,36.72 ° and 37.43 °, with a tolerance of ± 0.2 °.

(2) Identified by TA Q2000 Differential Scanning Calorimetry (DSC) analysis: the scan rate was 10 ℃/min, contained endothermic peaks at 132.47 ℃, 162.45 ℃ and 243.61 ℃, with a margin of error of ± 3 ℃.

(3) Thermogravimetric analysis (TGA) identification by TA Q500: the heating rate is 10 ℃/min, the weight loss range is 11.56 percent, and the error tolerance of +/-0.1 percent exists.

Example 5 form VIII

1. Preparation of form VIII

2- (7- (4-fluorophenoxy) -4-hydroxy-1-methyl-2-oxo-1, 2-dihydroquinoline-3-carboxamido) acetic acid (51mg) was added to a 10mL glass bottle, N-dimethylformamide (1.0mL) was added, the mixture was stirred at room temperature until the system was clear, water (0.1mL) was added dropwise to cause solid precipitation, the mixture was filtered by suction, and the filter cake was vacuum-dried at room temperature for 2 hours to give an off-white solid powder (50mg, 98.04%).

2. Identification of form VIII

(1) Identified by Empyrean X-ray powder diffraction (XRPD) analysis: using Cu-ka radiation, having the following characteristic peaks expressed in degrees 2 θ: 7.30 °,7.84 °,9.19 °,10.62 °,12.36 °,12.63 °,13.22 °,15.05 °,16.06 °,17.52 °,17.93 °,18.57 °,19.14 °,19.92 °,20.54 °,21.02 °,21.92 °,22.55 °,23.29 °,23.89 °,24.47 °,24.77 °,25.46 °,25.89 °,26.46 °,26.72 °,27.50 °,28.78 °,29.59 °,30.25 °,30.95 °,31.69 °,32.47 °,33.46 °,34.36 °,34.93 °,35.98 °,36.58 °,37.89 °,38.38 °,39.04 °, and 39.43 °, there is an error tolerance of ± 0.2 °.

(2) Identification by TA Q2000 Differential Scanning Calorimetry (DSC) analysis: the scan rate was 10 ℃/min, contained endothermic peaks at 132.43 ℃ and 228.64 ℃, with a margin of error of ± 3 ℃.

(3) Thermogravimetric analysis (TGA) identification by TA Q500: the heating rate is 10 ℃/minute, the weight loss range is 15.35 percent, and the error tolerance of +/-0.1 percent exists.

Example 6 pharmacokinetic experiments of the crystalline forms of the invention

The crystal form filling capsule of the compound shown in the formula (I) is used for oral administration.

8-12kg of male Beagle dogs, 3 dogs in one group, were orally administered with capsules containing test samples at a dose of 5mg/kg, and blood was collected at time points of 0.25,0.5,1.0,2.0,4.0,6.0,8.0 and 24 hours. A standard curve of the appropriate range is established based on the sample concentration, and the concentration of the test sample in the plasma sample is determined in MRM mode using LC-MS/MS model AB SCIEX API4000 and subjected to quantitative analysis. Pharmacokinetic parameters were calculated according to the drug concentration-time curve using a WinNonLin 6.3 software non-compartmental model method. The results of the experiment are shown in table 1.

TABLE 1 pharmacokinetic experimental data for the crystalline forms of the invention

Test sample	T max (h)	C max (ng/ml)	AUC last (h*ng/ml)
				Example 1 (Crystal form I)	0.667	71.7	193
Example 2 (form IV)	0.667	102.0	360

The experimental conclusion is that:

as can be seen from table 1, the crystalline form IV of the present invention has good pharmacokinetic properties; and form IV of the invention has a higher exposure (AUC) in beagle dogs than form I _last ) And maximum blood concentration (C) _max ) And thus has better pharmacokinetic properties.

Example 7 stability experiments of the crystalline forms of the invention

(1)High temperature experiment: taking a proper amount of a sample to be tested, putting the sample into a flat weighing bottle, spreading the sample into a thin layer with the thickness of less than or equal to 5mm, placing the sample at the temperature of 40 +/-2 ℃ and/or 60 +/-2 ℃ for 30 days, sampling the sample in the 6 th, 10 th and 30 th days, and detecting according to a stability key examination item: the color change of the sample is observed, and the purity of the sample is detected by HPLC.

(2)High humidity experiment: taking a proper amount of a batch of samples to be tested, putting the samples into a flat weighing bottle, spreading the samples into a thin layer with the thickness of less than or equal to 5mm, placing the samples for 30 days under the conditions of 25 ℃, RH 90% +/-5% or 25 ℃ and RH 75% +/-5%, sampling the samples for 6 th, 10 th and 30 th days, and detecting according to key stability investigation items: the color change of the sample is observed, and the purity of the sample is detected by HPLC.

(3)Illumination experiment: taking a proper amount of a batch of samples, placing into a flat weighing bottle, spreading into a thin layer with thickness of less than or equal to 5mm, placing in a light box (with an ultraviolet lamp) with an opening, and irradiating at an illuminance of 4500 + -500 lx and an ultraviolet light of more than or equal to 0.7w/m ² Is allowed to stand for 30 days, and is taken on days 6, 10 and 30Detecting according to stability key survey items: the color change of the sample is observed, and the purity of the sample is detected by HPLC.

Experiments show that the crystal form has good stability under various lofting conditions and is suitable for pharmaceutical application.

Example 8 hygroscopicity test of the crystalline form of the invention

Taking a proper amount of a sample, and testing the hygroscopicity of the sample by using a dynamic moisture adsorption instrument.

Characterization of hygroscopicity and definition of hygroscopicity increase (Chinese pharmacopoeia 2020 edition Tong 9103 guidelines for hygroscopicity test of drugs, see Table 2 for details)

TABLE 2 hygroscopicity characterization and definition of hygroscopicity increase (25 ℃ C. + -1 ℃ C., 80% + -2% relative humidity)

Experiments show that the crystal form is not easy to deliquesce under the influence of high humidity.

The above description is only a basic description of the present invention, and any equivalent changes made according to the technical solution of the present invention should fall within the protection scope of the present invention.

In the description herein, references to the description of the term "one embodiment," "some embodiments," "an example," "a specific example," or "some examples," etc., mean that a particular feature, structure, material, or characteristic described in connection with the embodiment or example is included in at least one embodiment or example of the invention. In this specification, the schematic representations of the terms used above are not necessarily intended to refer to the same embodiment or example. Furthermore, the particular features, structures, materials, or characteristics described may be combined in any suitable manner in any one or more embodiments or examples. Moreover, various embodiments or examples and features of various embodiments or examples described in this specification can be combined and combined by one skilled in the art without being mutually inconsistent.

Although embodiments of the present invention have been shown and described above, it is understood that the above embodiments are exemplary and should not be construed as limiting the present invention, and that variations, modifications, substitutions and alterations can be made to the above embodiments by those of ordinary skill in the art within the scope of the present invention.

Claims (10)

1. Form IV of a compound of formula (I), characterized in that it has an X-ray powder diffraction pattern with diffraction peaks at the following 2 Θ angles: 15.57 ° ± 0.2 °,17.83 ° ± 0.2 °,24.87 ° ± 0.2 °,25.69 ° ± 0.2 °,26.89 ° ± 0.2 °;

2. form IV according to claim 1, characterized in that the form IV has an X-ray powder diffraction pattern with diffraction peaks at the following 2 Θ angles: 6.59 ° ± 0.2 °,11.64 ° ± 0.2 °,15.57 ° ± 0.2 °,17.83 ° ± 0.2 °,19.69 ° ± 0.2 °,23.28 ° ± 0.2 °,24.87 ° ± 0.2 °,25.69 ° ± 0.2 °,26.45 ° ± 0.2 °,26.89 ° ± 0.2 °.

3. Form IV according to claim 1 or 2, characterized in that the form IV has an X-ray powder diffraction pattern with diffraction peaks at the following 2 Θ angles: 6.59 ° ± 0.2 °,11.64 ° ± 0.2 °,13.17 ° ± 0.2 °,13.77 ° ± 0.2 °,15.57 ° ± 0.2 °,16.13 ° ± 0.2 °,16.32 ° ± 0.2 °,17.36 ° ± 0.2 °,17.83 ° ± 0.2 °,19.05 ° ± 0.2 °,19.69 ° ± 0.2 °,20.33 ° ± 0.2 °,21.63 ° ± 0.2 °,22.92 ° ± 0.2 °,23.28 ° ± 0.2 °,24.10 ° ± 0.2 °,24.87 ° ± 0.2 °,25.69 ° ± 0.2 °,26.45 ° ± 0.2 °,26.89 ° ± 0.2 °,27.58 ° ± 0.2 °,28.39 ° ± 0.2 °, 360.85 ° ± 0.2 °,25.2 ° ± 0.26 ° ± 0.2 °, 27.9 ° ± 0.26 ° ± 0.2.26 °, 360.9 ° ± 0.2 °,28 ° ± 0.7 ° ± 0.2.26 °, 28.9 ° ± 0.2.26 °,28 ° ± 0.7 ° ± 0.2 °,28.7 ° ± 0.2 °, 360.2 °, 28.26 ° ± 0.26.26 ° ± 0.2.2.9 ° ± 0.9 ° ± 0.2 °.

4. Form IV according to any one of claims 1 to 3, characterized in that it has an X-ray powder diffraction pattern substantially as shown in figure 4.

5. Form IV according to any one of claims 1 to 4, characterized in that the differential scanning calorimetry pattern of form IV comprises endothermic peaks at 165.50 ℃ ± 3 ℃ and 277.26 ℃ ± 3 ℃.

6. A crystalline form IV according to any one of claims 1 to 5, characterized by a differential scanning calorimetry pattern substantially as shown in figure 5.

7. A pharmaceutical composition comprising the crystalline form IV of any one of claims 1-6, and a pharmaceutically acceptable carrier, excipient, diluent, adjuvant, or combination thereof.

8. Use of the crystalline form IV according to any one of claims 1 to 6 or the pharmaceutical composition according to claim 7 for the preparation of a medicament for preventing, treating or alleviating hypoxia-inducible factor-related and/or erythropoietin-related diseases in a patient.

9. The use according to claim 8, wherein the hypoxia-inducible factor-related and/or erythropoietin-related disorder is anemia, ischemia, vascular disease, angina, myocardial ischemia, myocardial infarction, metabolic disorder or wound healing.

10. Use of the crystalline form IV of any one of claims 1-6 or the pharmaceutical composition of claim 7 for the manufacture of a medicament for preventing, treating, or ameliorating a disease in a patient mediated at least in part by the hypoxia inducible factor prolyl hydroxylase.

Images