CN111825689B - Crystal form of dihydropyrazolone compound and preparation method thereof - Google Patents
Crystal form of dihydropyrazolone compound and preparation method thereof Download PDFInfo
- Publication number
- CN111825689B CN111825689B CN201910308629.5A CN201910308629A CN111825689B CN 111825689 B CN111825689 B CN 111825689B CN 201910308629 A CN201910308629 A CN 201910308629A CN 111825689 B CN111825689 B CN 111825689B
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- China
- Prior art keywords
- pyrazol
- azaspiro
- oxa
- decan
- pyrimidin
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Abstract
The invention relates to a crystal form of a dihydropyrazolone compound and a preparation method thereof. In particular, the invention relates to forms A and B of sodium 1- (6- (2-oxa-8-azaspiro [4.5] decan-8-yl) pyrimidin-4-yl) -4- (1H-1, 2, 3-triazol-1-yl) -1H-pyrazol-5-ol. Which is obtained by preparing 2- (6- (2-oxa-8-azaspiro [4.5] decan-8-yl) pyrimidin-4-yl) -4- (1H-1, 2, 3-triazol-1-yl) -1, 2-dihydro-3H-pyrazol-3-one into a sodium salt in an organic solvent and crystallizing. It can be used for preventing and/or treating diseases related to PHD activity.
Description
Technical Field
The invention relates to a crystal form A and a crystal form B of 1- (6- (2-oxa-8-azaspiro [4.5] decan-8-yl) pyrimidine-4-yl) -4- (1H-1, 2, 3-triazole-1-yl) -1H-pyrazol-5-sodium alkoxide and a preparation method thereof, and application thereof in preparing medicines for preventing and/or treating diseases related to PHD activity.
Background
In a hypoxic environment, the body is able to spontaneously undergo a hypoxic reaction to maintain the body's oxygen availability. In 1992, semeza et al found that a protein capable of specifically binding to the Hypoxia Response Element (HRE) of the erythropoietin gene and affecting the expression of certain genes was called Hypoxia Inducible Factor (HIF) (semeza GL et al mol. Cell biol.,1992,12,5447-5454). HIF targets are very broad and can affect body hematopoiesis, angiogenesis, iron ion transport, glucose utilization, resistance to oxidative stress, cell differentiation, cell survival and apoptosis, extracellular matrix homeostasis, and tumorigenesis. HIF is a heterodimer composed of alpha and beta subunits, wherein the alpha subunit belongs to a functional subunit, is very sensitive to the change of the intracellular oxygen concentration and highly regulated, and has the function of regulating HIF activity; beta subunits are structural subunits, also known as aryl hydrocarbon receptor nuclear transport proteins (ARNT), which are stably expressed in cells, whose mRNA transcription and protein expression levels are not affected by changes in oxygen concentration. The alpha and beta subunits of HIF are members of the basic helix-loop-helix transcription factor superfamily. Human HIFα has three subtypes of HIF-1. Alpha., HIF-2. Alpha., and HIF-3. Alpha. HIF-1 a is ubiquitously distributed in the body and plays an important role in the angiogenesis process induced by ischemia or hypoxia of the tissues, but has less influence on the iron metabolic process; HIF-2 a is locally distributed, plays an important role in the process of gene expression and synthesis of kidney tissue EPO (erythropoietin), and in addition, improves iron absorption in intestinal tracts by up-regulating the expression of cytochrome and divalent metal transporter-1 of the duodenum, has the effect of reducing the expression of hepatobactericidal peptide, and plays a leading role in the iron metabolism process; the structure of HIF-3. Alpha. Is different from other subtypes, and has no DNA binding region, so that gene expression cannot be affected. Studies have shown that HIF-3. Alpha. May have a negative regulatory role in HIF-mediated gene expression. Therefore, HIF-1. Alpha. And HIF-2. Alpha. Play a role in the hypoxia process. In a mouse test of HIF-1 alpha and HIF-2 alpha gene deletion, the necessity of HIF-1 alpha and HIF-2 alpha in the hypoxia reaction process is proved. In the development of compounds for treating chronic renal anemia, changes in HIF-2. Alpha. Are more important than those in HIF-1. Alpha. In the development of compounds for treating chronic renal anemia.
In 2001, HIF-PHD was found to be capable of converting O 2 And 2-OG as a substrate, specifically hydroxylating HIFα proline residues, thereby modulating HIF bioactivity. Catalytic cycling of HIF-PHD in Fe 2+ And 2-OG to the PHD active site. PHD and HIFα proline residues are then bound to each other with O 2 The replacement of water molecules completes the hydroxylation. Ascorbic acid is an indispensable catalyst in the whole process, fe 2+ 、O 2 2-OG is an indispensable factor.
HIF-PHD has three distinct subtypes PHD1, PHD2, PHD3, exhibits distinct tissue distributions, and selectively hydroxylates hifα subtypes. PHD1 expression is stable, and can not be induced due to hypoxia, so that the PHD1 has a certain effect in maintaining oxygen balance in vivo; PHD2 plays an important role in oxygen-dependent regulation of hifα activity; PHD2 and PHD3 respectively act on HIF-1 alpha and HIF-2 alpha selectively under normal oxygen environment, and proline residues at 402 th and 564 th positions of HIF-1 alpha and 405 th and 531 th positions of HIF-2 alpha are respectively hydroxylated, and the hydroxylated HIF-1 alpha and HIF-2 alpha can be combined with a VHL E3 ubiquitin ligase complex to be ubiquitinated and then enter a protease body to be degraded. PHD2 and PHD3 Activity factor O when the cell is in hypoxia environment 2 Scarcely inhibited, undegraded HIF-1α, HIF-2α entering the nucleus and HIF-beta binding, acting on Hypoxia Response Element (HRE) under the cooperation of p300/CBP, promotes the expression of related genes (such as EPO), and improves protein level, thereby promoting erythropoiesis and correcting anemia symptoms.
In the research of gene defect related to human HIF-PHD system, the mutation of pVHL (Von Hippel-Lindau tumor suppressor gene product, involved in mediating degradation of ubiquitinated HIF), PHD deletion and change of organism under the condition of HIF deletion are involved. Mutation of pVHL can induce human body to generate pVHL related diseases, and cause vascular tumor generation; mutation from position 598 of the C-terminal to the T-terminal of pVHL can lead to congenital erythrocytosis. In a patient with renal cancer caused by pVHL deletion, the research shows that HIF-1 alpha also has mutation, which indicates that the occurrence and the development of renal cancer and the mutation of HIF-1 alpha can have a certain relation. The HIF-2 alpha missense mutation and PHD2 mutation are prone to secondary erythrocytosis, thereby increasing the incidence of thrombosis.
In view of the initiation of HIF-PHD on the degradation process of HIF, the HIF-PHD inhibitor can improve the level of HIF, further promote the expression of target genes such as EPO, VEGF, iNOS, GLUT-1 and the like, and achieve the effect of treating diseases related to PHD activity. Thus, therapeutic uses for PHD (proline hydroxylase) inhibitors include, but are not limited to: treating and/or preventing cardiovascular diseases, in particular cardiac insufficiency, coronary heart disease, angina pectoris, myocardial infarction, stroke, arteriosclerosis, primary, pulmonary and malignant hypertension and peripheral arterial occlusive diseases; treating and/or preventing hematopoietic disorders such as primary anemia, renal anemia and anemia associated with neoplastic disease (particularly chemotherapy-induced anemia), infections (particularly HIV infection), or other inflammatory diseases such as rheumatoid arthritis; for the supportive treatment of anaemia due to blood loss, iron-deficiency anaemia, vitamin-deficiency anaemia (e.g. due to vitamin B12 deficiency or due to folic acid deficiency), hypoplasia and aplastic anaemia or hemolytic anaemia, or for the supportive treatment of anaemia due to iron utilization disorders (iron-loss anaemia) or due to other endocrine disorders (e.g. hypothyroidism); treating and/or preventing post-surgical operation related ischemic conditions and their continuous symptoms, particularly heart interventions using heart-lung machines (e.g., shunt surgery, heart valve implantation), carotid interventions, aortic interventions, and interventions using instrument openings or penetrating the calvaria; general treatment and/or prevention in surgery with the aim of accelerating wound healing and shortening recovery time; treatment and/or prophylaxis of cancer and for treatment and/or prophylaxis of damage to the health state occurring during the course of cancer treatment, in particular after the use of cytostatics, antibiotics and radiation therapy; treating and/or preventing a range of diseases in rheumatic forms and other forms of diseases that are considered autoimmune diseases, in particular for treating and/or preventing damage to the health state that occurs during the course of drug treatment of such diseases; treating and preventing continuous symptoms of acute and prolonged cerebral ischemic conditions (e.g., stroke, childbirth choking).
The present inventors have described in patent application No. 201811237690.7 that the compound 2- (6- (2-oxa-8-azaspiro [4.5] decan-8-yl) pyrimidin-4-yl) -4- (1H-1, 2, 3-triazol-1-yl) -1, 2-dihydro-3H-pyrazol-3-one, which is useful as a PHD inhibitor for the prevention and/or treatment of diseases associated with PHD activity, has the structure represented by the following formula (I):
the inventor conducts repeated experiments on the compound in the formula (I) and the hydrochloride thereof, and discovers that the compound in the formula (I) and the hydrochloride thereof have strong hygroscopicity, and respectively absorb moisture and increase weight by 1.81 percent and 1.86 percent under the relative humidity of 42 percent to 65 percent RH, which is not beneficial to the production and application of solid preparations. In addition, the compound of formula (I) and the hydrochloride thereof have poor solubility in water and various lower alcohols, which is unfavorable for preparing oral solid preparations.
Disclosure of Invention
The inventors examined various crystallization conditions of the sodium salt of the compound of formula (I) and obtained a series of crystalline products, and as a result, they have found crystals having improved solubility, hygroscopicity and the like and excellent stability by X-ray powder diffraction and DSC detection of the obtained crystalline products.
It is therefore an object of the present invention to provide a crystalline form a of sodium 1- (6- (2-oxa-8-azaspiro [4.5] decan-8-yl) pyrimidin-4-yl) -4- (1H-1, 2, 3-triazol-1-yl) -1H-pyrazol-5-ol characterized by an X-ray powder diffraction pattern comprising characteristic peaks at diffraction angles of 4.398 ° ± 0.2 °, 8.740 ° ± 0.2 °, 12.949 ° ± 0.2 °, 13.352 ° ± 0.2 °, 16.353 ° ± 0.2 °, 18.761 ° ± 0.2 °, 22.542 ° ± 0.2 °, 23.564 ° ± 0.2 °, 26.564 ° ± 0.2 °.
In one embodiment, the crystalline form a of sodium 1- (6- (2-oxa-8-azaspiro [4.5] decan-8-yl) pyrimidin-4-yl) -4- (1H-1, 2, 3-triazol-1-yl) -1H-pyrazol-5-ol according to the invention is characterized by an X-ray powder diffraction pattern as shown in fig. 1.
It is another object of the present invention to provide a crystalline form B of sodium 1- (6- (2-oxa-8-azaspiro [4.5] decan-8-yl) pyrimidin-4-yl) -4- (1H-1, 2, 3-triazol-1-yl) -1H-pyrazol-5-carboxylate characterized by an X-ray powder diffraction pattern comprising characteristic peaks at 2θ diffraction angles of 7.460 ° ± 0.2 °, 16.188 ° ± 0.2 °, 16.423 ° ± 0.2 °, 17.072 ° ± 0.2 °, 21.158 ° ± 0.2 °, 22.554 ° ± 0.2 °, 23.677 ° ± 0.2 °.
In one embodiment, a crystalline form B of sodium 1- (6- (2-oxa-8-azaspiro [4.5] decan-8-yl) pyrimidin-4-yl) -4- (1H-1, 2, 3-triazol-1-yl) -1H-pyrazol-5-ol according to the invention is characterized by an X-ray powder diffraction pattern comprising characteristic peaks at diffraction angles 2θ of 7.460 ° ± 0.2 °, 9.368 ° ± 0.2 °, 9.636 ° ± 0.2 °, 16.188 ° ± 0.2 °, 16.423 ° ± 0.2 °, 17.072 ° ± 0.2 °, 17.473 ° ± 0.2 °, 21.158 ° ± 0.2 °, 22.554 ° ± 0.2 °, 23.677 ° ± 0.2 °, 29.368 ° ± 0.2 °.
In another embodiment, the crystalline form B of sodium 1- (6- (2-oxa-8-azaspiro [4.5] decan-8-yl) pyrimidin-4-yl) -4- (1H-1, 2, 3-triazol-1-yl) -1H-pyrazol-5-ol according to the invention is characterized by an X-ray powder diffraction pattern as shown in fig. 4.
The present invention further provides a process for preparing crystalline form a of sodium 1- (6- (2-oxa-8-azaspiro [4.5] decan-8-yl) pyrimidin-4-yl) -4- (1H-1, 2, 3-triazol-1-yl) -1H-pyrazol-5-ol according to the invention, comprising the steps of:
1) Dispersing 2- (6- (2-oxa-8-azaspiro [4.5] decan-8-yl) pyrimidin-4-yl) -4- (1H-1, 2, 3-triazol-1-yl) -1, 2-dihydro-3H-pyrazol-3-one in an organic solvent under basic conditions; dropwise adding a sodium salt solution into the mixture under heating, preferably at 55-60 ℃, to prepare a 1- (6- (2-oxa-8-azaspiro [4.5] decan-8-yl) pyrimidin-4-yl) -4- (1H-1, 2, 3-triazole-1-yl) -1H-pyrazol-5-ol sodium solution;
2) Stirring and crystallizing the 1- (6- (2-oxa-8-azaspiro [4.5] decan-8-yl) pyrimidin-4-yl) -4- (1H-1, 2, 3-triazole-1-yl) -1H-pyrazol-5-ol sodium solution obtained in the step 1) at room temperature for preferably 1 to 2 hours, then continuing stirring and crystallizing at 5-10 ℃ for preferably 2 hours, and filtering the crystals;
3) Drying the crystals obtained in step 2) to obtain form A crystals of sodium 1- (6- (2-oxa-8-azaspiro [4.5] decan-8-yl) pyrimidin-4-yl) -4- (1H-1, 2, 3-triazol-1-yl) -1H-pyrazol-5-ol.
In a preferred embodiment, the process for the preparation of crystals of form A according to the invention, wherein, in step 1), 2- (6- (2-oxa-8-azaspiro [4.5] decan-8-yl) pyrimidin-4-yl) -4- (1H-1, 2, 3-triazol-1-yl) -1, 2-dihydro-3H-pyrazol-3-one is further dissolved in an organic solvent by heating, preferably at 55℃to 60℃and filtered thermally, and the sodium salt solution is added dropwise to the filtrate.
In another preferred embodiment, the process for the preparation of crystals of form A according to the invention, wherein, in step 1), the 1- (6- (2-oxa-8-azaspiro [4.5] decan-8-yl) pyrimidin-4-yl) -4- (1H-1, 2, 3-triazol-1-yl) -1H-pyrazol-5-ol sodium solution prepared is further incubated, preferably for 15 to 30 minutes.
In another preferred embodiment, the process for the preparation of crystals of form a according to the invention comprises the following steps:
1) Dispersing 2- (6- (2-oxa-8-azaspiro [4.5] decan-8-yl) pyrimidin-4-yl) -4- (1H-1, 2, 3-triazol-1-yl) -1, 2-dihydro-3H-pyrazol-3-one in an organic solvent under alkaline conditions, heating preferably to 55 ℃ to 60 ℃ to clarify the solution, and thermally filtering; dropwise adding a sodium salt solution to the filtrate under heating, preferably at 55-60 ℃, to prepare a 1- (6- (2-oxa-8-azaspiro [4.5] decan-8-yl) pyrimidin-4-yl) -4- (1H-1, 2, 3-triazol-1-yl) -1H-pyrazol-5-ol sodium solution, and incubating the solution, preferably for 15 to 30 minutes;
2) Stirring and crystallizing the 1- (6- (2-oxa-8-azaspiro [4.5] decan-8-yl) pyrimidin-4-yl) -4- (1H-1, 2, 3-triazole-1-yl) -1H-pyrazol-5-ol sodium solution obtained in the step 1) at room temperature for preferably 1 to 2 hours, then continuing stirring and crystallizing at 5-10 ℃ for preferably 2 hours, and filtering the crystals;
3) Drying the crystals obtained in step 2) to obtain form A crystals of sodium 1- (6- (2-oxa-8-azaspiro [4.5] decan-8-yl) pyrimidin-4-yl) -4- (1H-1, 2, 3-triazol-1-yl) -1H-pyrazol-5-ol.
In a preferred embodiment, the process for the preparation of crystals of form a according to the present invention, wherein the organic solvent is selected from tetrahydrofuran, 1, 4-dioxane, acetone, acetonitrile or mixtures thereof, or mixtures of the above solvents with water. Preferably a mixture of tetrahydrofuran and water. Particular preference is given to mixtures of tetrahydrofuran and water in a volume ratio of from 10:1 to 50:1, more preferably mixtures of tetrahydrofuran and water in a volume ratio of from 20:1 to 40:1.
In another preferred embodiment, the process for the preparation of crystals of form a according to the present invention, wherein the basic conditions are preferably triethylamine, N-diisopropylethylamine, pyridine, dimethylamine, ammonia, preferably triethylamine; wherein the sodium salt is selected from sodium bicarbonate, sodium hydrogen, sodium carbonate, sodium methoxide, sodium ethoxide and sodium hydroxide, preferably sodium hydroxide, and the concentration of the sodium hydroxide is preferably 20-45%.
The present invention further provides a process for preparing crystalline form B of sodium 1- (6- (2-oxa-8-azaspiro [4.5] decan-8-yl) pyrimidin-4-yl) -4- (1H-1, 2, 3-triazol-1-yl) -1H-pyrazol-5-ol according to the invention, comprising the steps of:
1) Dispersing 2- (6- (2-oxa-8-azaspiro [4.5] decan-8-yl) pyrimidin-4-yl) -4- (1H-1, 2, 3-triazol-1-yl) -1, 2-dihydro-3H-pyrazol-3-one in an organic solvent under basic conditions; dropwise adding a sodium salt solution into the mixture under heating, preferably at 55-60 ℃, to prepare a 1- (6- (2-oxa-8-azaspiro [4.5] decan-8-yl) pyrimidin-4-yl) -4- (1H-1, 2, 3-triazole-1-yl) -1H-pyrazol-5-ol sodium solution;
2) Stirring and crystallizing the 1- (6- (2-oxa-8-azaspiro [4.5] decan-8-yl) pyrimidin-4-yl) -4- (1H-1, 2, 3-triazol-1-yl) -1H-pyrazol-5-ol sodium solution obtained in the step 1) at 0-10 ℃ for preferably 2-20 hours, more preferably 20 hours, and filtering the crystals;
3) Drying the crystals obtained in step 2) to obtain a B-type crystal of 1- (6- (2-oxa-8-azaspiro [4.5] decan-8-yl) pyrimidin-4-yl) -4- (1H-1, 2, 3-triazol-1-yl) -1H-pyrazol-5-ol sodium.
In a preferred embodiment, the process for the preparation of crystals of form B according to the invention, wherein, in step 1), 2- (6- (2-oxa-8-azaspiro [4.5] decan-8-yl) pyrimidin-4-yl) -4- (1H-1, 2, 3-triazol-1-yl) -1, 2-dihydro-3H-pyrazol-3-one is further dissolved in an organic solvent by heating, preferably at 55 ℃ to 60 ℃, filtered thermally and the filtrate is added dropwise with a sodium salt solution.
In a preferred embodiment, the process for the preparation of crystals of form B according to the invention, wherein, in step 1), the solution of the sodium 1- (6- (2-oxa-8-azaspiro [4.5] decan-8-yl) pyrimidin-4-yl) -4- (1H-1, 2, 3-triazol-1-yl) -1H-pyrazol-5-ol obtained is further incubated for preferably 15 to 30 minutes.
In a preferred embodiment, the process for the preparation of crystals of form B according to the present invention, wherein, in step 2), the solution of sodium 1- (6- (2-oxa-8-azaspiro [4.5] decan-8-yl) pyrimidin-4-yl) -4- (1H-1, 2, 3-triazol-1-yl) -1H-pyrazol-5-ol obtained in step 1) is first stirred at room temperature for crystallization, preferably for 1 to 2 hours, and then stirred at 0℃to 10℃for crystallization, preferably for 2 hours, and the crystals are filtered.
In another preferred embodiment, the process for the preparation of crystals of form B according to the invention comprises the following steps:
1) Dispersing 2- (6- (2-oxa-8-azaspiro [4.5] decan-8-yl) pyrimidin-4-yl) -4- (1H-1, 2, 3-triazol-1-yl) -1, 2-dihydro-3H-pyrazol-3-one in an organic solvent under alkaline conditions, heating preferably to 55 ℃ to 60 ℃ to clarify the solution, and thermally filtering; dropwise adding a sodium salt solution to the filtrate under heating, preferably at 55-60 ℃, to prepare a 1- (6- (2-oxa-8-azaspiro [4.5] decan-8-yl) pyrimidin-4-yl) -4- (1H-1, 2, 3-triazol-1-yl) -1H-pyrazol-5-ol sodium solution, and incubating the solution, preferably for 15 to 30 minutes;
2) Stirring and crystallizing the 1- (6- (2-oxa-8-azaspiro [4.5] decan-8-yl) pyrimidin-4-yl) -4- (1H-1, 2, 3-triazole-1-yl) -1H-pyrazol-5-ol sodium solution obtained in the step 1) at room temperature for preferably 1 to 2 hours, then stirring and crystallizing at 0-10 ℃ for preferably 2 hours, and filtering the crystals;
3) Drying the crystals obtained in step 2) to obtain a B-type crystal of 1- (6- (2-oxa-8-azaspiro [4.5] decan-8-yl) pyrimidin-4-yl) -4- (1H-1, 2, 3-triazol-1-yl) -1H-pyrazol-5-ol sodium.
In a preferred embodiment, the process for the preparation of form B crystals according to the present invention, wherein the organic solvent is selected from the group consisting of C1-C4 alcohols, 1, 4-dioxane, acetonitrile, acetone or mixtures thereof, or mixtures of the above solvents with water; preferably a C1-C4 alcohol or a mixture of a C1-C4 alcohol and water; the C1-C4 alcohol is preferably methanol or ethanol.
In another preferred embodiment, the process for the preparation of crystals of form B according to the present invention, wherein the organic solvent is a mixture of a C1-C4 alcohol and water and the volume ratio of C1-C4 alcohol to water is from 1:2 to 40:1, preferably from 1:2 to 15:1.
In another preferred embodiment, the preparation method of the type B crystal according to the present invention, wherein the organic solvent is a mixture of methanol and water, and the volume ratio of methanol to water is 1:2 to 15:1.
In another preferred embodiment, the process for the preparation of form B crystals according to the present invention, wherein the basic conditions are preferably triethylamine, N-diisopropylethylamine, pyridine, dimethylamine, ammonia, preferably triethylamine; wherein the sodium salt is selected from sodium bicarbonate, sodium hydrogen, sodium carbonate, sodium methoxide, sodium ethoxide and sodium hydroxide, preferably sodium hydroxide, and the concentration of the sodium hydroxide is preferably 10-45%.
The 2- (6- (2-oxa-8-azaspiro [4.5] decan-8-yl) pyrimidin-4-yl) -4- (1H-1, 2, 3-triazol-1-yl) -1, 2-dihydro-3H-pyrazol-3-one used in the process for preparing crystals of type A or type B according to the invention is a compound of formula (I) which can be synthesized by the inverse synthetic methods known to the person skilled in the art, by conventional preparation methods, and in particular which can be obtained by the method described in example 8 of patent application No. 201811237690.7, in particular as examples of the invention. In addition, 2- (6- (2-oxa-8-azaspiro [4.5] decan-8-yl) pyrimidin-4-yl) -4- (1H-1, 2, 3-triazol-1-yl) -1, 2-dihydro-3H-pyrazol-3-one used in the present invention may be in any crystalline or amorphous form.
The C1-C4 alcohols used in the present invention may be any straight or branched chain alkane type alcohol commonly used in the art, such as methanol, ethanol, propanol, isopropanol, n-butanol, sec-butanol, tert-butanol, propylene glycol, ethylene glycol, and the like, preferably methanol or ethanol.
The sodium salt used in the present invention to form 1- (6- (2-oxa-8-azaspiro [4.5] decan-8-yl) pyrimidin-4-yl) -4- (1H-1, 2, 3-triazol-1-yl) -1H-pyrazol-5-ol sodium salt can be any sodium salt commonly known in the art that can be reacted to form salts with compounds of formula (I), such as sodium bicarbonate, sodium carbonate, sodium methoxide, sodium ethoxide, sodium hydroxide, preferably sodium hydroxide. The concentration of sodium hydroxide is preferably 10% -45%.
The form A and B crystals of the present invention were subjected to form measurement and study by X-ray diffraction (XRD) and differential scanning thermal analysis (DSC) and thermogravimetric analysis (TGA).
The A-type crystal and the B-type crystal of the 1- (6- (2-oxa-8-azaspiro [4.5] decan-8-yl) pyrimidine-4-yl) -4- (1H-1, 2, 3-triazole-1-yl) -1H-pyrazol-5-sodium alkoxide prepared by the method have good stability and bioavailability, and can be used as a medicine active ingredient.
In another aspect the present invention provides a pharmaceutical composition comprising as active ingredient the form a or form B crystals of 1- (6- (2-oxa-8-azaspiro [4.5] decan-8-yl) pyrimidin-4-yl) -4- (1H-1, 2, 3-triazol-1-yl) -1H-pyrazol-5-ol sodium according to the invention together with a pharmaceutically acceptable carrier.
The invention further provides the use of a crystalline form a or a crystalline form B of 1- (6- (2-oxa-8-azaspiro [4.5] decan-8-yl) pyrimidin-4-yl) -4- (1H-1, 2, 3-triazol-1-yl) -1H-pyrazol-5-ol sodium according to the invention or a pharmaceutical composition containing the same for the preparation of a medicament for the prevention and/or treatment of a disease associated with PHD activity, preferably selected from cardiovascular diseases, in particular cardiac insufficiency, coronary heart disease, angina pectoris, myocardial infarction, stroke, arteriosclerosis, primary, pulmonary and malignant hypertension and peripheral arterial occlusive diseases; chronic kidney disease; hematopoietic disorders such as primary anemia, renal anemia, and anemia associated with neoplastic disease (particularly chemotherapy-induced anemia); infection (in particular HIV infection) or other inflammatory diseases, such as rheumatoid arthritis; anemia due to blood loss, iron deficiency anemia, vitamin deficiency anemia (e.g. due to vitamin B12 deficiency or due to folic acid deficiency), hypoplastic and aplastic anemia or hemolytic anemia, anemia due to iron utilization disorder (iron-deficiency anemia) or due to other endocrine disorders (e.g. hypothyroidism); the ischemic state and its continuum following surgery associated with surgery, particularly heart interventions using heart-lung machines (e.g. shunt surgery, heart valve implantation), carotid interventions, aortic interventions and interventions using instrumental openings or penetrating the calvaria; wound healing in surgery; cancer and damage to health conditions that occur during cancer treatment, particularly after treatment with cytostatics, antibiotics and radiation, a range of diseases of rheumatic forms and other forms of disease that are considered autoimmune diseases, particularly damage to health conditions that occur during drug treatment of such diseases; continuous symptoms of acute and prolonged cerebral ischemic conditions (e.g., stroke, childbirth choking).
The term "pharmaceutically acceptable" as used herein is useful in preparing a pharmaceutical composition that is generally safe, neither biologically nor otherwise undesirable, and is acceptable for veterinary and human pharmaceutical use.
As used herein, "carrier" refers to a diluent, adjuvant, or excipient with which the compound is administered. Pharmaceutically acceptable carriers can be liquids, such as water and oils, including those of petroleum, animal, vegetable or synthetic origin, such as peanut oil, soybean oil, mineral oil, rapeseed oil, and the like. Pharmaceutically acceptable carriers may also be physiological saline, gum arabic, gelatin, starch paste, talc, keratin, silica gel, urea, etc. In addition, adjuvants, stabilizers, thickeners, lubricants, colorants, and the like may also be used.
It will be appreciated by those skilled in the art that the pharmaceutical compositions of the present invention may be formulated into various preparation forms well known in the art, such as oral dosage forms (powders, tablets, capsules, soft capsules, liquid medicines, syrups, elixirs, powders, sachets, granules), or topical application preparations (creams, ointments, lotions, gels, balsams, plasters, pastes, sprays, aerosols, etc.), or injection preparations (solutions, suspensions, emulsions), depending on the particular mode of administration. Among the pharmaceutical compositions of the invention, mention may be made in particular of those suitable for oral, parenteral (intravenous or subcutaneous) or nasal administration, for example tablets or dragees, sublingual tablets, gelatine capsules, lozenges, suppositories, creams, ointments, skin gels, injectable preparations, drinkable suspensions and the like.
The pharmaceutical composition according to the present invention may comprise a pharmaceutically acceptable carrier, adjuvant or diluent, for example: fillers, disintegrants, lubricants, suspending agents, binders, sweeteners, flavoring agents, preservatives, matrices, and the like. Fillers such as: starch, pregelatinized starch, lactose, mannitol, chitin, microcrystalline cellulose, sucrose, and the like; disintegrants such as: starch, pregelatinized starch, microcrystalline cellulose, sodium carboxymethyl starch, crosslinked polyvinylpyrrolidone, low-substituted hydroxypropyl cellulose, crosslinked sodium carboxymethyl cellulose, and the like; lubricants such as: magnesium stearate, sodium lauryl sulfate, talc, silica, and the like; suspending agents such as: polyvinylpyrrolidone, microcrystalline cellulose, sucrose, agar, hydroxypropyl methylcellulose, and the like; binders such as starch slurry, polyvinylpyrrolidone, hydroxypropyl methylcellulose, and the like. The compositions of the present invention may be formulated so as to provide quick, sustained or slow release of the active ingredient after administration by the patient by employing any of the methods known in the art.
The pharmaceutical compositions of the invention are administered to an individual animal such as a mammal (rat, mouse, domesticated animal or human) by a variety of routes, all of which are contemplated, e.g., oral, topical, rectal or intravenous, intramuscular, transdermal, intrathecal, epidural or intraventricular injection.
The dosage of the active ingredient of the present invention may vary depending on the individual condition and weight, the nature and severity of the condition, the pharmaceutical form, the route of administration and the period of administration, and may also be selected by those skilled in the art. The dosage may vary between 1-100 mg/day, and may be administered in a single dose per day or divided doses per day.
The present invention will be further elucidated below in connection with the drawings and the specific embodiments, but it will be understood that they are merely illustrative and do not in any way limit the scope of the invention.
Drawings
Figure 1 shows an X-ray powder diffraction pattern of form a of the present invention.
Figure 2 shows a DSC profile of form a of the present invention.
Figure 3 shows the TGA profile of form a of the present invention.
Figure 4 shows an X-ray powder diffraction pattern of form B of the present invention.
Figure 5 shows a DSC profile of form B of the present invention.
Figure 6 shows the TGA profile of form B of the present invention.
Detailed Description
The present invention will be explained in more detail with reference to the following examples, which are only for illustrating the technical aspects of the present invention and do not limit the spirit and scope of the present invention.
Experimental instrument:
1. DSC spectrum
Instrument model: TA Instruments Q200 MDSC
Sweep gas: nitrogen gas
Rate of temperature rise: 10 ℃/min
Temperature range: 0 ℃ to 400 DEG C
2. TGA Spectrometry
Instrument model: TA Instruments Q500 TGA
Sweep gas: nitrogen gas
Rate of temperature rise: 10 ℃/min
Temperature range: 0 ℃ to 500 DEG C
3. X-ray diffraction spectrum
Instrument model: bruker D8 advance diffractometer
Rays: 1.54nm K.alpha.X-ray
Scanning mode: 0.2 seconds/step, scan range: 3-40 deg.
The structure of the compounds is determined by Nuclear Magnetic Resonance (NMR) or/and Mass Spectrometry (MS). NMR shift at 10 -6 Units of (ppm) are given. NMR was performed using Bruker dps300 nuclear magnetic resonance apparatus with deuterated dimethyl sulfoxide (DMSO-d) 6 ) Deuterated chloroform (CDCl) 3 ) Deuterated methanol (CD) 3 OD), internal standard is Tetramethylsilane (TMS).
MS was measured using a 1100Series LC/MSD Trap (ESI) mass spectrometer (manufacturer: agilent).
The known starting materials of the present invention may be synthesized using or according to methods known in the art or may be purchased from commercial establishments, beijing couplings, sigma, carbofuran, yi Shiming, shanghai book, inoki, nanjing, an Naiji chemistry, and the like.
Example 1: preparation of 2- (6- (2-oxa-8-azaspiro [4.5] decan-8-yl) pyrimidin-4-yl) -4- (1H-1, 2, 3-triazol-1-yl) -1, 2-dihydro-3H-pyrazol-3-one (I)
A compound of formula (I) was prepared according to example 8 of patent application 201811237690.7, as follows:
step 1: synthesis of ethyl 2- (1H-1, 2, 3-triazol-1-yl) acetate (intermediate 1A)
1H-1,2, 3-triazole (100 g,1.45 mol) was added to a 1L reaction flask, to which were added ethyl acetate (300 mL), DIPEA (252 mL,1.45 mol), and stirred for 3 minutes under ice. Ethyl bromoacetate (152 mL,1.38 mol) was added to 200mL ethyl acetate, which was then slowly added dropwise to the reaction flask, and after the dropwise addition was completed, stirred at room temperature overnight. After completion of the reaction, filtration, washing of the filtrate with water and saturated brine each time, drying over anhydrous sodium sulfate, filtration, and concentration of the filtrate under reduced pressure gave 100g of the title product as a yellow oil, yield: 44.3%.
Step 2: synthesis of ethyl 3- (dimethylamino) -2- (1H-1, 2, 3-triazol-1-yl) acrylate (intermediate 1B)
Ethyl 2- (1H-1, 2, 3-triazol-1-yl) acetate (100 g,0.64 mol), DMA (100 mL) was added to a single flask, and the reaction was stirred at 60℃for 1 hour. After the reaction was completed, the reaction solution was cooled to room temperature, concentrated to dryness under reduced pressure, extracted with 300mL of water and 300mL of methylene chloride, and the organic phase was concentrated until methylene chloride was substantially not remained, 400mL of methyl t-butyl ether was added with stirring, stirred at room temperature for 1 hour, and filtered to obtain 62.2g of the title product as a pale yellow solid, yield: 45.9%.
Step 3: synthesis of 4-chloro-6-hydrazinopyrimidine (intermediate 1C)
4, 6-dichloropyrimidine (10 g,68 mmol) and ethanol (350 mL) were added to a 1L reaction flask, hydrazine hydrate (6.05 g,122 mmol) was added dropwise at room temperature, turbidity occurred during the process, ethanol (200 mL) was added, and after the addition was completed, the mixture was stirred at room temperature for 12 hours. After completion of the reaction, filtration, washing the filter cake twice with water and petroleum ether, and drying gave 6.3g of the title product as a yellow solid in 65.6% yield.
Step 4: synthesis of 2- (4-chloropyrimidin-2-yl) -4- (1H-1, 2, 3-triazol-1-yl) -1, 2-dihydro-3H-pyrazol-3-one (intermediate 1D)
4-chloro-6-hydrazinopyrimidine (5.19 g,36.3 mmol), ethyl 3- (dimethylamino) -2- (1H-1, 2, 3-triazol-1-yl) acrylate (6.25 g,29.7 mmol), ethanol (63 mL), TFA (1.37 g,8.8 mmol) were added sequentially to a 250mL reaction flask and heated to reflux and stirred for 12 hours. The reaction mixture was cooled to room temperature, 40mL of 1M dioxane hydrochloric acid gas was added dropwise, and after the completion of the addition, the mixture was stirred for 1 hour and filtered. The filter cake was added to 90mL of ethanol, 32mL of 25% sodium methoxide in methanol was added, and the mixture was stirred at room temperature for 2 hours, then pH was adjusted to 4-5 with 1N hydrochloric acid, and the mixture was stirred at room temperature for 2 hours. After completion of the reaction, filtration, washing the filter cake with ethanol once, and drying gave 6.9g of the title product as a yellow solid, yield: 87.8%.
Step 5:2- (6- (2-oxa-8-azaspiro [4.5] decan-8-yl) pyrimidin-4-yl) -4- (1H-1, 2, 3-triazol-1-yl) -1, 2-dihydro-3H-pyrazol-3-one (compound I)
2- (4-Chloropyrimidin-2-yl) -4- (1H-1, 2, 3-triazol-1-yl) -1, 2-dihydro-3H-pyrazol-3-one (6.9 g,0.026 mol), 2-oxa-8-azaspiro [4.5] decane oxalate (5.4 g,0.014 mol), DMSO 50mL, potassium carbonate (6.9 g,0.50 mol) were successively added to a 250mL reaction flask, and stirred at 100℃to 110℃for 8 hours. After completion of the reaction, cooled to room temperature, concentrated to dryness, adjusted to pH 4-5 with hydrochloric acid, filtered, and dried to give 3.3g of the title product as a white solid in yield: 54%, purity: 98.5%.
MS:m/z=369.9[M+H] + 。
1 H NMR(300MHz,DMSO):δppm 1.60(m,4H),1.79(m,2H),3.77(m,8H),7.42(s,1H),7.85(s,1H),8.21(s,1H),8.37(s,1H),8.51(s,1H)。
Example 2: preparation of form A of sodium 1- (6- (2-oxa-8-azaspiro [4.5] decan-8-yl) pyrimidin-4-yl) -4- (1H-1, 2, 3-triazol-1-yl) -1H-pyrazol-5-ol (II)
2- (6- (2-oxa-8-azaspiro [4.5] decan-8-yl) pyrimidin-4-yl) -5- (1H-1, 2, 3-triazol-1-yl) -1, 2-dihydro-3H-pyrazol-3-one (I) (3 g) prepared in example 1 was added to a mixed solution of 30ml of tetrahydrofuran and 1ml of water, triethylamine (0.83 g) was added, and the temperature was raised to 60℃until the solution was clear, and the solution was filtered thermally. The filtrate was warmed to 60℃and 45% aqueous NaOH (0.86 g) was added dropwise. And after the dripping is finished, preserving the heat for 30 minutes, closing heating, naturally cooling to room temperature, stirring and crystallizing at the room temperature for 2 hours, cooling and crystallizing at the temperature of 10 ℃ for 2 hours, and filtering. The filter cake was dried under reduced pressure at 55℃for 5 hours to give the product as a yellowish solid (1.8 g) in a yield of 56.3%.
The X-ray diffraction pattern of the crystalline sample is shown in figure 1, and the X-ray diffraction data is shown in table 1 below. DSC patterns are shown in figure 2, and TGA patterns are shown in figure 3. This form is defined as form a.
TABLE 1 correspondence of 2theta values to intensities for form A
Strength% | 2- |
100 | 4.398 |
5.1 | 8.740 |
8.2 | 12.949 |
5.5 | 13.352 |
18.9 | 16.353 |
4.5 | 18.761 |
7.3 | 22.542 |
7.2 | 23.564 |
22.1 | 26.564 |
10.7 | 29.563 |
Example 3: preparation of form A of sodium 1- (6- (2-oxa-8-azaspiro [4.5] decan-8-yl) pyrimidin-4-yl) -4- (1H-1, 2, 3-triazol-1-yl) -1H-pyrazol-5-ol (II)
2- (6- (2-oxa-8-azaspiro [4.5] decan-8-yl) pyrimidin-4-yl) -5- (1H-1, 2, 3-triazol-1-yl) -1, 2-dihydro-3H-pyrazol-3-one (I) (30 g) prepared in example 1 was added to a mixed solution of 200ml of tetrahydrofuran and 10ml of water, triethylamine (8.3 g) was added thereto and the temperature was raised to 55℃and a 20% aqueous NaOH solution (19.5 g) was added dropwise. And after the dripping is finished, preserving the heat for 15 minutes, closing heating, naturally cooling to room temperature, stirring and crystallizing at the room temperature for 2 hours, cooling and crystallizing at the temperature of 10 ℃ for 2 hours, and filtering. The filter cake was dried under reduced pressure at 55℃for 5 hours to give the product as a yellowish solid (28 g) in a yield of 87.6%.
The XRD patterns of the products are compared by study, and the products are determined to be A crystal forms.
Example 4: preparation of form A of sodium 1- (6- (2-oxa-8-azaspiro [4.5] decan-8-yl) pyrimidin-4-yl) -4- (1H-1, 2, 3-triazol-1-yl) -1H-pyrazol-5-ol (II)
2- (6- (2-oxa-8-azaspiro [4.5] decan-8-yl) pyrimidin-4-yl) -5- (1H-1, 2, 3-triazol-1-yl) -1, 2-dihydro-3H-pyrazol-3-one (I) (6 g) prepared in example 1 was added to a mixed solution of 40ml of tetrahydrofuran and 1ml of water, triethylamine (1.66 g) was added thereto and the temperature was raised to 60℃and a 25% aqueous NaOH solution (3.1 g) was added dropwise. And after the dripping is finished, preserving the heat for 30 minutes, closing heating, naturally cooling to room temperature, stirring and crystallizing at room temperature for 1 hour, cooling and crystallizing at 5 ℃ for 2 hours, and filtering. The filter cake was dried under reduced pressure at 55℃for 5 hours to give the product as a yellowish solid (5.8 g) in a yield of 90.6%.
The XRD patterns of the products are compared by study, and the products are determined to be A crystal forms.
Example 5: preparation of form B of sodium 1- (6- (2-oxa-8-azaspiro [4.5] decan-8-yl) pyrimidin-4-yl) -4- (1H-1, 2, 3-triazol-1-yl) -1H-pyrazol-5-ol (II)
2- (6- (2-oxa-8-azaspiro [4.5] decan-8-yl) pyrimidin-4-yl) -5- (1H-1, 2, 3-triazol-1-yl) -1, 2-dihydro-3H-pyrazol-3-one (I) (6 g) prepared in example 1 was added to 60ml of methanol and 12ml of water, triethylamine (1.6 g) was added, and the temperature was raised to 60℃until the solution was clear, and the solution was filtered thermally. The filtrate was warmed to 60℃and 30% NaOH solution (2.6 g) was added dropwise. And after the dripping is finished, preserving the heat for 20 minutes, closing heating, naturally cooling to room temperature, stirring and crystallizing at the room temperature for 2 hours, cooling and crystallizing at the temperature of 0 ℃ for 2 hours, and filtering. The filter cake was dried under reduced pressure at 50℃for 5 hours to give the product as a yellowish solid (5.2 g) in 82.3% yield.
The X-ray diffraction pattern of the crystalline sample is shown in FIG. 4, and the X-ray diffraction data is shown in Table 2 below. DSC patterns are shown in FIG. 5, and TGA patterns are shown in FIG. 6. This form is defined as form B.
TABLE 2 correspondence of 2theta values to intensities for form B
Strength% | 2-Theta |
59.7 | 7.460 |
10.8 | 9.368 |
16.1 | 9.636 |
50.1 | 16.188 |
54.6 | 16.423 |
25.1 | 17.072 |
13.5 | 17.473 |
24.2 | 21.158 |
100 | 22.554 |
26.6 | 23.677 |
12.1 | 29.368 |
Example 6: preparation of form B of sodium 1- (6- (2-oxa-8-azaspiro [4.5] decan-8-yl) pyrimidin-4-yl) -4- (1H-1, 2, 3-triazol-1-yl) -1H-pyrazol-5-ol (II)
2- (6- (2-oxa-8-azaspiro [4.5] decan-8-yl) pyrimidin-4-yl) -5- (1H-1, 2, 3-triazol-1-yl) -1, 2-dihydro-3H-pyrazol-3-one (I) (3 g) prepared in example 1 was added to a mixed solution of 24ml of methanol and 0.8ml of water, and triethylamine (0.83 g) was added thereto and the temperature was raised to 60℃and a 33% aqueous NaOH solution (1.19 g) was added dropwise. And (5) preserving heat for 30 minutes after the dripping is finished, closing heating, and naturally cooling to room temperature. Stirring and crystallizing at room temperature for 2 hours, cooling and crystallizing at 10 ℃ for 2 hours, and filtering. The filter cake was dried under reduced pressure at 55℃for 5 hours to give the product as a yellowish solid (2.3 g) in 71.5% yield.
The XRD patterns of the products are compared by study, and the products are determined to be B crystal forms.
Example 7: preparation of form B of sodium 1- (6- (2-oxa-8-azaspiro [4.5] decan-8-yl) pyrimidin-4-yl) -4- (1H-1, 2, 3-triazol-1-yl) -1H-pyrazol-5-ol (II)
2- (6- (2-oxa-8-azaspiro [4.5] decan-8-yl) pyrimidin-4-yl) -5- (1H-1, 2, 3-triazol-1-yl) -1, 2-dihydro-3H-pyrazol-3-one (I) (12 g,8.2 mmol) prepared in example 1 was added to a mixed solution of 120ml of methanol and 8ml of water, triethylamine (3.2 g) was added thereto and the temperature was raised to 60℃and a 16% aqueous NaOH solution (9.2 g) was added dropwise. And after the dripping is finished, preserving the heat for 15 minutes, closing heating, naturally cooling to room temperature, stirring and crystallizing at the room temperature for 2 hours, cooling and crystallizing at the temperature of 0 ℃ for 2 hours, and filtering. The filter cake was dried under reduced pressure at 50℃for 5 hours to give the product as a yellowish solid (9.6 g) in 78.3% yield.
The XRD patterns of the products are compared by study, and the products are determined to be B crystal forms.
Example 8: preparation of form B of sodium 1- (6- (2-oxa-8-azaspiro [4.5] decan-8-yl) pyrimidin-4-yl) -4- (1H-1, 2, 3-triazol-1-yl) -1H-pyrazol-5-ol (II)
2- (6- (2-oxa-8-azaspiro [4.5] decan-8-yl) pyrimidin-4-yl) -5- (1H-1, 2, 3-triazol-1-yl) -1, 2-dihydro-3H-pyrazol-3-one (I) (4 g) prepared in example 1 was added to a mixed solution of 40ml of methanol and 1ml of water, triethylamine (1.1 g) was added thereto and the temperature was raised to 55℃and a 45% aqueous NaOH solution (0.86 g) was added dropwise. And after the dripping is finished, preserving the heat for 20 minutes, closing heating, naturally cooling to room temperature, stirring and crystallizing at the room temperature for 2 hours, cooling and crystallizing at the temperature of 10 ℃ for 2 hours, and filtering. The filter cake was dried under reduced pressure at 55℃for 5 hours to give the product as a yellowish solid (3.1 g) in 94.8% yield.
The XRD patterns of the products are compared by study, and the products are determined to be B crystal forms.
Example 9: preparation of form B of sodium 1- (6- (2-oxa-8-azaspiro [4.5] decan-8-yl) pyrimidin-4-yl) -4- (1H-1, 2, 3-triazol-1-yl) -1H-pyrazol-5-ol (II)
2- (6- (2-oxa-8-azaspiro [4.5] decan-8-yl) pyrimidin-4-yl) -5- (1H-1, 2, 3-triazol-1-yl) -1, 2-dihydro-3H-pyrazol-3-one (I) (24 g) prepared in example 1 was added to a mixed solution of 240ml of methanol and 8ml of water, triethylamine (6.6 g) was added thereto and the temperature was raised to 55℃and a 25% aqueous NaOH solution (12.5 g) was added dropwise. And after the dripping is finished, preserving the heat for 30 minutes, closing heating, naturally cooling to room temperature, stirring and crystallizing at room temperature for 1 hour, cooling and crystallizing at 10 ℃ for 2 hours, and filtering. The filter cake was dried under reduced pressure at 50℃for 5 hours to give the product as a yellowish solid (18.4 g) in 71.5% yield.
The XRD patterns of the products are compared by study, and the products are determined to be B crystal forms.
Example 10: preparation of form B of sodium 1- (6- (2-oxa-8-azaspiro [4.5] decan-8-yl) pyrimidin-4-yl) -4- (1H-1, 2, 3-triazol-1-yl) -1H-pyrazol-5-ol (II)
2- (6- (2-oxa-8-azaspiro [4.5] decan-8-yl) pyrimidin-4-yl) -5- (1H-1, 2, 3-triazol-1-yl) -1, 2-dihydro-3H-pyrazol-3-one (I) (30 g) prepared in example 1 was added to a mixed solution of 300ml of methanol and 20ml of water, and triethylamine (8.3 g) was added thereto and the temperature was raised to 60℃and a 10% aqueous NaOH solution (39 g) was added dropwise. And after the dripping is finished, preserving the heat for 30 minutes, closing heating, naturally cooling to room temperature, stirring and crystallizing at the room temperature for 2 hours, cooling and crystallizing at the temperature of 10 ℃ for 2 hours, and filtering. The filter cake was dried under reduced pressure at 50℃for 5 hours to give the product as a yellowish solid (24 g) in 78.3% yield.
The XRD patterns of the products are compared by study, and the products are determined to be B crystal forms.
Example 11: preparation of form B of sodium 1- (6- (2-oxa-8-azaspiro [4.5] decan-8-yl) pyrimidin-4-yl) -4- (1H-1, 2, 3-triazol-1-yl) -1H-pyrazol-5-ol (II)
2- (6- (2-oxa-8-azaspiro [4.5] decan-8-yl) pyrimidin-4-yl) -5- (1H-1, 2, 3-triazol-1-yl) -1, 2-dihydro-3H-pyrazol-3-one (I) (3 g) prepared in example 1 was added to 15ml of methanol and 30ml of water, the temperature was raised to 55℃with stirring, triethylamine (0.83 g) was added dropwise, the mixture was stirred until it became clear, and the mixture was filtered while it was hot. The filtrate was warmed to 60℃and 45% NaOH saturated solution (0.9 g) was slowly added dropwise thereto with stirring. After the dripping is finished, the temperature is reduced to 0 ℃ and stirred for 20 hours for crystallization. Filtering, washing filter cake with a small amount of methanol, and drying under reduced pressure at 60 ℃ to obtain 0.8g of yellowish solid with yield: 25.1%.
The XRD patterns of the products are compared by study, and the products are determined to be B crystal forms.
Example 12: preparation of form B of sodium 1- (6- (2-oxa-8-azaspiro [4.5] decan-8-yl) pyrimidin-4-yl) -4- (1H-1, 2, 3-triazol-1-yl) -1H-pyrazol-5-ol (II)
2- (6- (2-oxa-8-azaspiro [4.5] decan-8-yl) pyrimidin-4-yl) -5- (1H-1, 2, 3-triazol-1-yl) -1, 2-dihydro-3H-pyrazol-3-one (I) (6 g,16 mmol) prepared in example 1 was added to 60ml of methanol and 60ml of water, triethylamine (1.6 g) was added, and the temperature was raised to 60℃until the solution was clear, and hot filtration was performed. The filtrate was warmed to 60℃and 45% NaOH saturated solution (0.86 g) was added dropwise. And after the dripping is finished, preserving the heat for 30 minutes, closing heating, naturally cooling to room temperature, stirring and crystallizing at the room temperature for 2 hours, cooling and crystallizing at the temperature of 10 ℃ for 2 hours, and filtering. The filter cake was dried under reduced pressure at 55℃for 5 hours to give the product as a yellowish solid (4.72 g) in 74.2% yield.
The XRD patterns of the products are compared by study, and the products are determined to be B crystal forms.
Example 13: moisture permeability test
The hygroscopicity of the form a prepared in example 3, the form B prepared in example 9 and the compound of formula (I) was tested according to the chinese pharmacopoeia, edition 2010, appendix XIX J. The specific method comprises the following steps: the dried glass weighing bottle (with the outer diameter of 50mm and the height of 15 mm) is taken and placed in a proper constant temperature dryer at 25+/-1 ℃ on the previous day, and is precisely weighed (m 0 ) Proper amount of sample, precision weighing (m 1 ) Spreading in the weighing bottle, and measuring the thickness of the sample to about 1mm; the weighing bottle is opened and placed under the constant temperature and humidity condition for 24 hours together with the bottle cap, the lid of the weighing bottle is covered, and the weighing bottle is precisely weighed (m 2 ) The percentage weight gain was calculated. Weight percent of moisturization (%) = (m 2 -m 1 -m 0 /m 1 )×100%。
According to the guiding principle of the drug hygroscopicity test, the experimental conditions are as follows: the hygroscopicity was examined at various relative humidities at 25.+ -. 1 ℃. The results of the hygroscopicity of each sample are shown in table 3 below.
TABLE 3 Table 3
Conclusion: under the relative humidity of 80% +/-2%, the calculated moisture absorption weight gain of the A crystal form is 0.82%, the calculated moisture absorption weight gain of the B crystal form is 0.33%, and the moisture absorption weight gain of the A crystal form belongs to slight moisture absorption according to the definition standard of the moisture absorption weight gain specified by pharmacopoeia. The weight gain of the compound of formula (I) was 3.33%. Therefore, the hygroscopicity of the A crystal form and the B crystal form of the invention is obviously improved compared with the compound of the formula (I), thereby being beneficial to the stability of the compound.
Example 14: stability study
Samples of form A prepared in example 4 and form B prepared in example 5Placing into a culture dish, spreading into a thin layer smaller than 5mm, exposing to high temperature 105+ -2deg.C and high humidity 92.5% + -2%, or visible light 4500+ -500 lx, ultraviolet light intensity not lower than 0.7W.h/m 2 . Samples were obtained after exposure or irradiation and the impurity content was measured using a Waters Aquicty Arc liquid chromatograph HPLC. The detection conditions are shown in table 4 below.
TABLE 4HPLC detection conditions
The test results are shown in table 5 below.
TABLE 5 stability results of the crystalline forms of the invention
Conclusion: the impurity content of the A crystal form and the B crystal form of the invention is not obviously changed under the conditions of high temperature, high humidity and illumination for 10 days or 20 days. The total impurities of compound (I) increase significantly under this condition. The invention shows that the A crystal form and the B crystal form have excellent stability.
Example 15: in vivo pharmacokinetic evaluation of the inventive crystalline form in SD rats
The compound of formula (I) prepared in example 1, the form a prepared in example 3 or the form B prepared in example 10 were administered to male 7-week-old SD rats (s Bei Fu (beijing) biotechnology limited) by intravenous injection (i.v.) or oral administration (p.o.), at an intravenous dose of 1mg/kg and an oral dose of 5mg/kg. Intravenous administration (1 mg/kg;0.2 mg/ml) preparation method: 2.5mg of the compound was weighed, suspended in 12.5ml of physiological saline and mixed well. Preparation method of oral administration (5 mg/kg;0.5 mg/ml): 37.5mg of the compound was weighed, suspended in 25ml of 0.5% CMC-Na and mixed well.
Intravenous injection was performed at 0, 0.083, 0.25, 0.50, 1.00, 2.00, 4.00, 6.00, 8.00, and 24.00 post-administration orbital blood collection, respectively; oral administration orbital blood collection was performed at 0, 0.167, 0.333, 0.50, 1.00, 2.00, 4.00, 6.00, 8.00 and 24.00 post administration, respectively. Blood was anticoagulated with heparin sodium (Sigma), centrifuged at 3500rpm at 4℃for 10 minutes, and plasma was obtained and stored at-20℃until tested.
A50. Mu.L sample of plasma was taken in a 1.5mL EP tube and vortexed for 1 minute to mix thoroughly. After vortexing, 0.2mL of acetonitrile was added, vortexing vigorously for 1 minute, and centrifuging at 16000rpm for 10 minutes. Remove 0.2mL of supernatant, filter in 0.22. Mu.M organic membrane (Cleman) and add to the sample vial, analyze by LC/MS (Waters, waters UPLC I Class, TQ-S micro) for hemorrhagic drug concentration, and analyze by DAS software 3.0 for pharmacokinetic parameters.
Pharmacokinetic parameters are shown in table 6 below.
TABLE 6 pharmacokinetic parameters of the crystalline forms of the invention
Conclusion: the bioavailability of the A crystal form and the B crystal form of the invention is obviously higher than that of the compound of the formula (I).
Example 16: effect of the inventive Compounds on Balb/C mouse EPO levels
The change in plasma EPO (erythropoietin) levels was measured 4 hours after a single oral administration of mice to measure the pharmaceutical activity.
Animals: balb/C mice, male, 18-20g; purchased from viviprilhua laboratory animal technologies limited, SPF grade, beijing; animal production license number: SCXK (jing) 2016-0011; evidence issuing unit: the scientific and technical committee of beijing.
Grouping: normal control group (0.5% CMC-Na vehicle group); group A crystals (0.88 mg/kg) prepared in example 3 and group B crystals (0.88 mg/kg) prepared in example 10; each group had 5 animals.
Sample preparation: the crystalline form of the invention was suspended in vehicle 0.5% CMC-Na.
Animals were fed adaptively 5-7 days after purchase for testing, and after a single oral administration of animals for 4 hours, were anesthetized with isoflurane for 3 minutes, collected by orbital venous plexus blood sampling (0.5 ml/animal), and anticoagulated with heparin sodium (sigma). 3500 rpm/heart for 10 min, plasma was isolated and stored at-20 ℃.
The detection index and method are as follows: plasma EPO levels were determined using an EPO ELISA kit (P137645, R & D System) and a microplate reader (station 3, biotek).
Table 7 shows the effect of form A of example 3 and form B of example 10 of the present invention on the secretion of EPO in mice at a dose of 0.88 mg/kg. Wherein A represents >1000pg/mL, B represents 500-100pg/mL, and C represents <500pg/mL.
TABLE 7 elevation of mouse EPO levels by the crystalline forms of the present invention
Conclusion: the crystal form of the invention obviously improves the EPO level of the plasma of the Balb/C mice, which proves that the crystal form of the invention can obviously promote the expression of the EPO of the Balb/C mice.
Example 17: the crystal form of the invention has the effect of improving the level of rat hemoglobin
Animals: wistar rats, male, 180-220g; purchased from viviprilhua laboratory animal technologies limited, SPF grade, beijing; animal production license number: SCXK (jing) 2016-0011; evidence issuing unit: the scientific and technical committee of beijing.
Grouping: normal control group (0.5% CMC-Na vehicle); group A (1.0, 2.5, 5.0 mg/kg) prepared in example 3 and group B (1.0, 2.5, 5.0 mg/kg) prepared in example 10, each group of 10 animals.
Sample preparation: the crystalline form of the invention was suspended in vehicle 0.5% CMC-Na.
Administration: after one week of adaptive feeding, rats were dosed by gavage, once daily. The normal control group was given 0.5% CMC-Na daily; the crystalline form group of the present invention is given daily corresponding doses of suspension. The administration was continued for 14 days.
The main detection index is as follows: the blood routine index hemoglobin level was measured using a full automatic blood cell analyzer (Mythic 22, ohfei, switzerland).
Results: after 14 days of continuous administration, forms a and B of the present invention significantly elevated the hemoglobin levels of the rats (table 8), wherein a represents greater than 190g/L; b represents 175-190g/L; c represents 160-175g/L; d represents 150-160g/L; e represents <150g/L.
TABLE 8 elevation of rat hemoglobin levels by the crystalline forms of the invention
Hemoglobin (g/L) | |
Normal control group | E |
Crystal form A (1.0 mg/kg) | C |
Crystal form A (2.5 mg/kg) | B |
Crystal form A (5.0 mg/kg) | A |
Crystal form B (1.0 mg/kg) | C |
Crystal form B (2.5 mg/kg) | B |
Crystal form B (5.0 mg/kg) | A |
Conclusion: the crystal form of the invention has obvious promotion effect on the hemoglobin of normal rats.
Example 18: the invention establishes the drug effect research of the renal anemia rat model by the 5/6 nephrectomy method
Animals: wistar rats, male, 180-220g; purchased from viviprilhua laboratory animal technologies limited, SPF grade, beijing; animal production license number: SCXK (jing) 2016-0011; evidence issuing unit: the scientific and technical committee of beijing.
And (3) molding: after one week of adaptive feeding, rats were anesthetized with 10% chloral hydrate (0.3 ml/kg) by intraperitoneal injection, fixed in prone position, topically prepared, and conventionally skin sterilized. 5/6 kidney excision is carried out by a two-step method, the incision on the right side is inclined outwards and downwards (kidney area) for 3-4cm, the right kidney is fully exposed, kidney envelope is separated, kidney pedicles are ligated, when kidney ischemia turns dark, the right kidney is excised, and suturing and disinfection are carried out. The 2 nd operation is performed 7-10 days later. As with the method of right kidney resection, the left side was cut obliquely downward (kidney zone) for 3-4cm to fully expose the left side kidney and peel off kidney capsule. The upper and lower poles of kidney are clamped first, the area to be clamped is dark purple and black due to ischemia, the upper and lower poles and the outer side margin of left kidney are cut off rapidly, about 2/3 kidney tissue is cut off altogether (the upper and lower poles are respectively cut off 1/3 of kidney), the wound surface is pressed by gelatin sponge to stop bleeding, physiological saline is used for flushing, penicillin is injected into abdominal cavity, and then muscle layer and skin are sutured, the abdominal cavity is closed, and disinfection is carried out. About 5/6 of the kidney was resected in total in two surgeries. After the rats wake up, the rats are put into a single cage for feeding, and the respiratory tract is kept smooth. After 24 hours of postoperative fasting, the patients are not forbidden to water, and skin incision, mental state and feeding water are closely observed after the operation. The sham group did not resect kidney tissue, only given 2 subsequent anesthetics and isolation of double kidney fat sacs.
Blood samples were collected every 2 weeks after nephrectomy by orbital blood collection for detection of blood normative (EDTA-2K anticoagulation) and the renal function index creatinine and urea nitrogen (non-anticoagulation). Rats meeting the characteristics of renal anemia were considered successful in molding and were included in subsequent intragastric administration experiments. Rats with successful modeling were included in compound in vivo pharmacodynamic evaluation studies.
Grouping: sham surgery group (0.5% CMC-Na vehicle); model group (0.5% CMC-Na vehicle); group A crystals prepared in example 3 (0.5, 1.0 and 2.5 mg/kg) and group B crystals prepared in example 10 (0.5, 1.0 and 2.5 mg/kg), each group of 10 animals.
Sample preparation: the crystalline form of the invention was suspended in vehicle 0.5% CMC-Na.
Administration: the medicine is administrated by stomach irrigation once a day. The sham and model groups were given daily vehicle 0.5% CMC-Na; the crystalline form group of the present invention is given daily corresponding doses of suspension.
And (3) modeling detection indexes: (1) Detecting blood conventional index (EDTA anticoagulation), erythrocyte count and hemoglobin level using a fully automatic blood cell analyzer (Mythic 22, ohfei, switzerland); (2) renal function index: serum urea nitrogen (BUN) and creatinine (Scr) levels were detected using a detection kit (beijing, libida medical technologies limited) by colorimetry.
The drug effect evaluation mainly detects the index: blood routine index and hemoglobin level were measured using a Mythic22 fully automated blood cell analyzer.
Results: as shown in table 9, the crystalline forms of the invention significantly increased the hemoglobin levels of the nephrectomized rat model after 4 weeks of administration. Wherein A represents more than 190g/L; b represents 170-190g/L; c represents 150-170g/L; d represents 140-150g/L; e represents <130g/L.
TABLE 9 elevation of hemoglobin levels in rats with renal anemia by the crystalline forms of the invention
Conclusion: the crystal form of the invention can obviously improve the hemoglobin level of a nephrectomy rat model and has obvious effect of improving anemia of the nephrectomy rat model.
Claims (35)
1. A crystalline form a of 1- (6- (2-oxa-8-azaspiro [4.5] decan-8-yl) pyrimidin-4-yl) -4- (1H-1, 2, 3-triazol-1-yl) -1H-pyrazol-5-ol sodium, characterized by an X-ray powder diffraction pattern comprising characteristic peaks at diffraction angles of 4.398 ° ± 0.2 °, 8.740 ° ± 0.2 °, 12.949 ° ± 0.2 °, 13.352 ° ± 0.2 °, 16.353 ° ± 0.2 °, 18.761 ° ± 0.2 °, 22.542 ° ± 0.2 °, 23.564 ° ± 0.2 °, 26.564 ° ± 0.2 °, 29.563 ° ± 0.2 °.
2. Form a crystals of sodium 1- (6- (2-oxa-8-azaspiro [4.5] decan-8-yl) pyrimidin-4-yl) -4- (1H-1, 2, 3-triazol-1-yl) -1H-pyrazol-5-ol according to claim 1, characterized in that their X-ray powder diffraction pattern is shown in figure 1.
3. A crystalline form B of 1- (6- (2-oxa-8-azaspiro [4.5] decan-8-yl) pyrimidin-4-yl) -4- (1H-1, 2, 3-triazol-1-yl) -1H-pyrazol-5-ol sodium, characterized by an X-ray powder diffraction pattern comprising characteristic peaks at 2Θ diffraction angles of 7.460 ° ± 0.2 °, 16.188 ° ± 0.2 °, 16.423 ° ± 0.2 °, 17.072 ° ± 0.2 °, 21.158 ° ± 0.2 °, 22.554 ° ± 0.2 °, 23.677 ° ± 0.2 °.
4. A form B crystal of sodium 1- (6- (2-oxa-8-azaspiro [4.5] decan-8-yl) pyrimidin-4-yl) -4- (1H-1, 2, 3-triazol-1-yl) -1H-pyrazol-5-ol according to claim 3, characterized in that its X-ray powder diffraction pattern comprises characteristic peaks at 2Θ diffraction angles of 7.460 ° ± 0.2 °, 9.368 ° ± 0.2 °, 9.636 ° ± 0.2 °, 16.188 ° ± 0.2 °, 16.423 ° ± 0.2 °, 17.072 ° ± 0.2 °, 17.473 ° ± 0.2 °, 21.158 ° ± 0.2 °, 22.554 ° ± 0.2 °, 23.677 ° ± 0.2 °, 29.368 ° ± 0.2 °.
5. The crystalline form B of 1- (6- (2-oxa-8-azaspiro [4.5] decan-8-yl) pyrimidin-4-yl) -4- (1H-1, 2, 3-triazol-1-yl) -1H-pyrazol-5-ol sodium according to claim 3 or 4, characterized by an X-ray powder diffraction pattern as shown in fig. 4.
6. A process for preparing form a crystals of 1- (6- (2-oxa-8-azaspiro [4.5] decan-8-yl) pyrimidin-4-yl) -4- (1H-1, 2, 3-triazol-1-yl) -1H-pyrazol-5-ol sodium according to claim 1 or 2, the process comprising the steps of:
1) Dispersing 2- (6- (2-oxa-8-azaspiro [4.5] decan-8-yl) pyrimidin-4-yl) -4- (1H-1, 2, 3-triazol-1-yl) -1, 2-dihydro-3H-pyrazol-3-one in a mixed solution of tetrahydrofuran and water under alkaline conditions; dropwise adding NaOH aqueous solution into the mixture under heating to prepare 1- (6- (2-oxa-8-azaspiro [4.5] decan-8-yl) pyrimidin-4-yl) -4- (1H-1, 2, 3-triazole-1-yl) -1H-pyrazol-5-sodium alkoxide solution;
2) Stirring and crystallizing the 1- (6- (2-oxa-8-azaspiro [4.5] decan-8-yl) pyrimidine-4-yl) -4- (1H-1, 2, 3-triazole-1-yl) -1H-pyrazol-5-sodium alkoxide solution obtained in the step 1) at room temperature, then continuously stirring and crystallizing at 5-10 ℃, and filtering the crystals;
3) Drying the crystals obtained in step 2) to obtain form A crystals of sodium 1- (6- (2-oxa-8-azaspiro [4.5] decan-8-yl) pyrimidin-4-yl) -4- (1H-1, 2, 3-triazol-1-yl) -1H-pyrazol-5-ol.
7. The method of claim 6, wherein the heating in step 1) is at 55 ℃ to 60 ℃.
8. The method of claim 6, wherein the stirring crystallization in step 2) is performed at room temperature for 1 to 2 hours.
9. The method of claim 6, wherein the stirring crystallization is continued at 5-10 ℃ for 2 hours in step 2).
10. The process according to claim 6, wherein in step 1), 2- (6- (2-oxa-8-azaspiro [4.5] decan-8-yl) pyrimidin-4-yl) -4- (1H-1, 2, 3-triazol-1-yl) -1, 2-dihydro-3H-pyrazol-3-one is further dissolved in a mixed solution of tetrahydrofuran and water by heating, filtered under heat, and an aqueous NaOH solution is added dropwise to the filtrate.
11. The method of claim 10, wherein the heating is at 55 ℃ -60 ℃.
12. The process according to claim 6 or 10, wherein in step 1) the solution of the sodium 1- (6- (2-oxa-8-azaspiro [4.5] decan-8-yl) pyrimidin-4-yl) -4- (1H-1, 2, 3-triazol-1-yl) -1H-pyrazol-5-ol obtained is further incubated.
13. The method of claim 12, wherein incubating is for 15 to 30 minutes.
14. The process of claim 6, wherein the basic conditions are selected from the group consisting of triethylamine, N-diisopropylethylamine, pyridine, dimethylamine, ammonia.
15. The method of claim 14, wherein the basic condition is triethylamine.
16. The method of claim 6, wherein the aqueous NaOH solution has a concentration of 20% to 45%.
17. A process for preparing form B crystals of 1- (6- (2-oxa-8-azaspiro [4.5] decan-8-yl) pyrimidin-4-yl) -4- (1H-1, 2, 3-triazol-1-yl) -1H-pyrazol-5-ol sodium according to any one of claims 3 to 5, the process comprising the steps of:
1) Dispersing 2- (6- (2-oxa-8-azaspiro [4.5] decan-8-yl) pyrimidin-4-yl) -4- (1H-1, 2, 3-triazol-1-yl) -1, 2-dihydro-3H-pyrazol-3-one in a mixed solution of methanol and water under alkaline conditions; dropwise adding NaOH aqueous solution into the mixture under heating to prepare 1- (6- (2-oxa-8-azaspiro [4.5] decan-8-yl) pyrimidin-4-yl) -4- (1H-1, 2, 3-triazole-1-yl) -1H-pyrazol-5-sodium alkoxide solution;
2) Stirring and crystallizing the 1- (6- (2-oxa-8-azaspiro [4.5] decan-8-yl) pyrimidine-4-yl) -4- (1H-1, 2, 3-triazole-1-yl) -1H-pyrazol-5-sodium alkoxide solution obtained in the step 1) at the temperature of 0-10 ℃, and filtering the crystal;
3) Drying the crystals obtained in step 2) to obtain a B-type crystal of 1- (6- (2-oxa-8-azaspiro [4.5] decan-8-yl) pyrimidin-4-yl) -4- (1H-1, 2, 3-triazol-1-yl) -1H-pyrazol-5-ol sodium.
18. The method of claim 17, wherein the heating in step 1) is at 55-60 ℃.
19. The method of claim 17, wherein the crystallization is stirred at 0 ℃ to 10 ℃ for 2 to 20 hours in step 2).
20. The method according to claim 17, wherein in step 1), 2- (6- (2-oxa-8-azaspiro [4.5] decan-8-yl) pyrimidin-4-yl) -4- (1H-1, 2, 3-triazol-1-yl) -1, 2-dihydro-3H-pyrazol-3-one is further dissolved in a mixed solution of methanol and water by heating, filtered by heating, and an aqueous NaOH solution is added dropwise to the filtrate.
21. The method of claim 20, wherein the heating is at 55 ℃ -60 ℃.
22. The process according to claim 17 or 20, wherein in step 1) the solution of the sodium 1- (6- (2-oxa-8-azaspiro [4.5] decan-8-yl) pyrimidin-4-yl) -4- (1H-1, 2, 3-triazol-1-yl) -1H-pyrazol-5-ol obtained is further incubated.
23. The method of claim 22, wherein incubating is for 15 to 30 minutes.
24. The process according to claim 17, wherein in step 2), the 1- (6- (2-oxa-8-azaspiro [4.5] decan-8-yl) pyrimidin-4-yl) -4- (1H-1, 2, 3-triazol-1-yl) -1H-pyrazol-5-ol sodium solution obtained in step 1) is stirred at room temperature for crystallization, and then stirred at 0 ℃ to 10 ℃ for crystallization, and the crystals are filtered.
25. The method of claim 24, wherein the crystallization is stirred at room temperature for 1 to 2 hours.
26. The method of claim 24, wherein the crystallization is stirred for 2 hours at 0 ℃ to 10 ℃.
27. The process of claim 17, wherein the basic conditions are selected from the group consisting of triethylamine, N-diisopropylethylamine, pyridine, dimethylamine, ammonia.
28. The method of claim 27, wherein the basic condition is triethylamine.
29. The method of claim 17, wherein the aqueous NaOH solution has a concentration of 10% to 45%.
30. A pharmaceutical composition comprising as an active ingredient the crystalline form a of 1- (6- (2-oxa-8-azaspiro [4.5] decan-8-yl) pyrimidin-4-yl) -4- (1H-1, 2, 3-triazol-1-yl) -1H-pyrazol-5-ol sodium according to any one of claims 1 or 2, together with a pharmaceutically acceptable carrier.
31. A pharmaceutical composition comprising the crystalline form B of 1- (6- (2-oxa-8-azaspiro [4.5] decan-8-yl) pyrimidin-4-yl) -4- (1H-1, 2, 3-triazol-1-yl) -1H-pyrazol-5-ol sodium according to any one of claims 3 to 5 as an active ingredient and a pharmaceutically acceptable carrier.
32. Use of form a crystals of 1- (6- (2-oxa-8-azaspiro [4.5] decan-8-yl) pyrimidin-4-yl) -4- (1H-1, 2, 3-triazol-1-yl) -1H-pyrazol-5-ol sodium according to any one of claims 1 or 2 or of a pharmaceutical composition according to claim 30 for the preparation of a medicament for the prevention and/or treatment of a disease associated with PHD activity.
33. The use according to claim 32, wherein the disease associated with PHD activity is selected from cardiovascular disease, chronic kidney disease, hematopoietic disorders, anaemia due to blood loss, iron deficiency anaemia, vitamin deficiency anaemia, hypoplastic and aplastic anaemia or hemolytic anaemia, anaemia due to iron utilization disorders, post-surgical operation related ischemic conditions and their continuous symptoms, surgical wound healing, cancer and damage to health conditions occurring during cancer treatment, continuous symptoms of acute and prolonged cerebral ischemic conditions.
34. Use of form B crystals of 1- (6- (2-oxa-8-azaspiro [4.5] decan-8-yl) pyrimidin-4-yl) -4- (1H-1, 2, 3-triazol-1-yl) -1H-pyrazol-5-ol sodium according to any one of claims 3 to 5 or of a pharmaceutical composition according to claim 31 for the preparation of a medicament for the prevention and/or treatment of a disease associated with PHD activity.
35. The use according to claim 34, wherein the disease associated with PHD activity is selected from cardiovascular disease, chronic kidney disease, hematopoietic disorders, anaemia due to blood loss, iron deficiency anaemia, vitamin deficiency anaemia, hypoplastic and aplastic anaemia or hemolytic anaemia, anaemia due to iron utilization disorders, post-surgical operation related ischemic conditions and their continuous symptoms, surgical wound healing, cancer and damage to health conditions occurring during cancer treatment, continuous symptoms of acute and prolonged cerebral ischemic conditions.
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