WO2021045582A1 - 2,6-bis-(2-aminopyrimidin-4-yl)pyridin-3-ol dihydrochloride and pharmaceutical composition comprising same - Google Patents

2,6-bis-(2-aminopyrimidin-4-yl)pyridin-3-ol dihydrochloride and pharmaceutical composition comprising same Download PDF

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WO2021045582A1
WO2021045582A1 PCT/KR2020/011992 KR2020011992W WO2021045582A1 WO 2021045582 A1 WO2021045582 A1 WO 2021045582A1 KR 2020011992 W KR2020011992 W KR 2020011992W WO 2021045582 A1 WO2021045582 A1 WO 2021045582A1
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cancer
aminopyrimidin
bis
pyridin
dihydrochloride
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민창희
박민영
서진수
나기현
손훈영
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비욘드바이오주식회사
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    • C—CHEMISTRY; METALLURGY
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
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    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A—HUMAN NECESSITIES
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    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
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    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/513—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim having oxo groups directly attached to the heterocyclic ring, e.g. cytosine
    • A—HUMAN NECESSITIES
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    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/13—Crystalline forms, e.g. polymorphs

Definitions

  • the present invention relates to 2,6-bis-(2-aminopyrimidin-4-yl)pyridin-3-ol dihydrochloride and a pharmaceutical composition comprising the same. More specifically, the present invention provides 2,6-bis-(2-aminopyrimidin-4-yl)pyridin-3-ol dihydrochloride that can be effectively used in pharmaceutical compositions due to excellent stability and solubility, and pharmaceuticals containing the same. It relates to the composition.
  • 2,6-bis-(2-aminopyrimidin-4-yl)pyridin-3-ol represented by the following formula (I) is a cyclin-dependent kinase (CDK) inhibitor, including colon cancer, lung cancer, and glioma It is known to be effective in the treatment of cancer and degenerative brain diseases such as Alzheimer's disease [see Korean Patent Registration No. 10-1783642].
  • CDK cyclin-dependent kinase
  • the compound represented by Formula I has low solubility in water, and acid addition salts such as trihydrochloride, oxalate, malonate, and sulfate have been developed to improve this, but these acid addition salts have low stability and are difficult to obtain in a crystalline form. There was a problem.
  • the present inventors have conducted intensive research and review to overcome the problems of the conventional 2,6-bis-(2-aminopyrimidin-4-yl)pyridin-3-ol and acid addition salts thereof.
  • an object of the present invention is to provide 2,6-bis-(2-aminopyrimidin-4-yl)pyridin-3-ol dihydrochloride having excellent stability and solubility.
  • Another object of the present invention is to provide a pharmaceutical composition comprising the 2,6-bis-(2-aminopyrimidin-4-yl)pyridin-3-ol dihydrochloride.
  • One embodiment of the present invention relates to a 2,6-bis-(2-aminopyrimidin-4-yl)pyridin-3-ol dihydrochloride represented by the following formula (II).
  • 2,6-bis-(2-aminopyrimidin-4-yl)pyridin-3-ol dihydrochloride may be in a crystalline form, and I/I 0 ( I: The intensity of the peak at each diffraction angle, I 0 : The intensity of the largest peak) is 10.8 ⁇ 0.2, 11.3 ⁇ 0.2, 12.2 ⁇ 0.2, 14.6 ⁇ 0.2, 23.9 ⁇ Can be 0.2 and 27.2 ⁇ 0.2.
  • 2,6-bis-(2-aminopyrimidin-4-yl)pyridin-3-ol dihydrochloride crystalline form according to an embodiment of the present invention was obtained from a differential scanning calorimetry (DSC) analysis, starting at 147° C. and 150° C. Shows the endothermic peak with the lowest point in.
  • DSC differential scanning calorimetry
  • 2,6-bis-(2-aminopyrimidin-4-yl)pyridin-3-ol dihydrochloride is 2,6-bis-(2-aminopyrimidin-4-yl) It can be prepared by dissolving pyridin-3-ol in methanol, adding about 45 to 55 equivalents of hydrochloric acid, stirring, filtering, washing, and drying at room temperature. Then, by recrystallization from water and acetone, a crystalline form of 2,6-bis-(2-aminopyrimidin-4-yl)pyridin-3-ol dihydrochloride can be obtained.
  • One embodiment of the present invention is a cyclin-dependent kinase comprising the 2,6-bis-(2-aminopyrimidin-4-yl)pyridin-3-ol dihydrochloride salt together with a pharmaceutically acceptable carrier.
  • kinase, CDK kinase, CDK inhibitory pharmaceutical composition, specifically, to a pharmaceutical composition for the treatment or prevention of cancer or degenerative brain disease.
  • the 2,6-bis-(2-aminopyrimidin-4-yl)pyridin-3-ol dihydrochloride inhibits CDK, thereby inducing an anticancer effect through cell cycle regulation, Acute lymphoblastic leukemia (ALL), chronic lymphoblastic leukemia (CLL), acute myeloid leukemia (AML), chronic myeloid leukemia (CML), multiple myeloma , MM), Hodgkin's lymphoma, non-Hodgkin's lymphoma, and other hematologic cancers and non-small cell lung cancer, small cell lung cancer, gastric cancer, pancreatic cancer, glioma, colon cancer, breast cancer, head and neck squamous It can be usefully used to treat solid cancers such as epithelial cancer, liver cancer, melanoma, uterine cancer, prostate cancer, ovarian cancer, thyroid cancer, biliary tract cancer, gallbladder cancer, bladder cancer, kidney cancer, and
  • the 2,6-bis-(2-aminopyrimidin-4-yl)pyridin-3-ol dihydrochloride freely passes through the blood brain barrier (BBB) to form an astrocytoma and anaplasticity.
  • BBB blood brain barrier
  • Metastasis from glioma such as anaplastic astrocytoma or glioblastoma
  • brain tumor such as pituitary adenoma, medulloblastoma, meningioma, or lung cancer, breast cancer, melanoma, etc. It can be effectively used for the treatment of metastatic brain tumors.
  • the 2,6-bis-(2-aminopyrimidin-4-yl)pyridin-3-ol dihydrochloride is phosphorylation of tau protein and A ⁇ , which is the cause of Alzheimer's disease, through CDK5 inhibition.
  • Alzheimer's disease Lewy body dementia, frontotemporal dementia, Pick's disease, Parkinson's disease, multisystem atrophy, It can be usefully used in the treatment of ALS, Huntington's disease, cerebral ischemia or dementia caused by cerebral hemorrhage (Shah K et al., Mol Neurobiol. (2017) 54(3):2255-2268).
  • the pharmaceutical composition according to the present invention can be administered orally (e.g., ingestion or inhalation) or parenterally (e.g., injection, deposition, implantation, suppository), and the injection is, for example, intravenous , It may be a subcutaneous injection, an intramuscular injection, or an intraperitoneal injection.
  • the pharmaceutical composition according to the present invention is formulated as tablets, capsules, granules, fine subtilae, powders, sublingual tablets, suppositories, ointments, injections, emulsions, suspensions, syrups, sprays, etc. It can be formulated.
  • compositions according to the present invention may be prepared by known techniques using a pharmaceutically acceptable carrier commonly used in each formulation.
  • pharmaceutically acceptable carriers include excipients, binders, disintegrating agents, lubricants, preservatives, antioxidants, isotonic agents, buffering agents, coating agents, sweetening agents, solubilizing agents, bases, dispersing agents, wetting agents. , Suspending agents, stabilizers, colorants, and the like.
  • the pharmaceutical composition according to the present invention varies depending on the form of the drug, but contains about 0.01 to 95% by weight of the compound of the present invention or a pharmaceutically acceptable salt thereof.
  • the specific dosage of the pharmaceutical composition of the present invention may vary depending on the type, weight, sex, degree of disease, judgment of a doctor, and the like of the mammal including the person to be treated.
  • the total daily dosage may be administered at once or divided into several times depending on the degree of disease, judgment of a doctor, and the like.
  • the 2,6-bis-(2-aminopyrimidin-4-yl)pyridin-3-ol dihydrochloride is capecitabine, 5-fluorouracil, and Thioguanine, chlorambucil, oxaliplatin, cisplatin, carboplatin, paclitaxel, docetaxel, irinotecan, doxorubicin, vinorelbine, gemcitabine, pemetrexed, etoposide, vincristine, cytarabine, cyclophosphamide, ifosfamide , Tamoxifen, anastrozole, letrozole, exemestein, fulvestrant, temozolomide, carmustine, lomustine, epirubicin, eribuline, toremifene, goserelin, megestrol, vinblastine, Bendamustine, Thiotepa, Bleomycin, Topotecan, Leuco
  • 2,6-bis-(2-aminopyrimidin-4-yl)pyridin-3-ol dihydrochloride according to the present invention not only has excellent stability and solubility, but also can be prepared in a crystalline form, so that it can be effectively used in pharmaceutical compositions. have.
  • 1 is an X-ray powder diffraction diagram of a crystal form of 2,6-bis-(2-aminopyrimidin-4-yl)pyridin-3-ol dihydrochloride.
  • Figure 2 is a differential scanning calorie analysis diagram of a crystal form of 2,6-bis-(2-aminopyrimidin-4-yl)pyridin-3-ol dihydrochloride.
  • thermogravimetric analysis diagram of a crystal form of 2,6-bis-(2-aminopyrimidin-4-yl)pyridin-3-ol dihydrochloride.
  • 2,6-bis-(2-aminopyrimidin-4-yl)pyridin-3-ol (10 g, 35.552 mmol) was reacted with hydrochloric acid (150 mL, 1,690 mmol) in methanol solvent (200 mL) at room temperature. It was stirred for 24 hours. The resulting solid was filtered and washed with acetone. The dried compound was dissolved in water (120 ml) and recrystallized with acetone (1,200 ml) to obtain the light brown title compound (11.3 g, 89.8%).
  • X-ray powder diffraction (XRD) analysis was performed under the following conditions using an X-Pert PRO MPD (Philips, Netherlands) analyzer.
  • Anti-scatter slit 0.3°
  • Fig. 1 shows the XRD results of the obtained 2,6-bis-(2-aminopyrimidin-4-yl)pyridin-3-ol dihydrochloride crystalline form.
  • peaks having a relative intensity of 10% or more in the XRD pattern are shown in Table 1 below.
  • DSC Differential Scanning Calorimeter
  • Figure 2 shows the DSC analysis results of the 2,6-bis-(2-aminopyrimidin-4-yl)pyridin-3-ol dihydrochloride crystalline form obtained above.
  • the crystalline form exhibited an endothermic peak having a starting point at about 147° C. and a lowest point at about 150° C.
  • Thermogravimetric Analysis was performed at 30° C. to 350° C. using a TG209 F1 Libra (Netzsch, Germany). The sample was weighed in an amount of 2 mg to 5 mg, and the temperature was measured directly in a vacuum state in a vertical top-loading method in which the sample can be mounted. Thereafter, the sample was heated from 30° C. to 350° C. at a rate of 10° C./min, and the heat weight calculated for exothermic and endothermic reactions occurring in the sample was observed by TGA.
  • Fig. 3 shows the TGA results of the 2,6-bis-(2-aminopyrimidin-4-yl)pyridin-3-ol dihydrochloride crystalline form obtained above.
  • the crystalline form was observed to have a weight change in the temperature range of 30° C. to 175° C., which was identified as a weight reduction of about 3.7%.
  • Example 2 The 2,6-bis-(2-aminopyrimidin-4-yl)pyridin-3-ol dihydrochloride crystalline form obtained in Example 1 was stored in a sealed state at 25 ⁇ 2° C. and 60 ⁇ 5% RH, while initial ( 0 months), 1 month, 3 months, 6 months, 9 months, 12 months, 18 months, and 24 months later, the changes in the amount of related substances and compound content were analyzed by high performance liquid chromatography (HPLC). The results are shown in Table 2 below.
  • Example 2 As shown in Table 2, the 2,6-bis-(2-aminopyrimidin-4-yl)pyridin-3-ol dihydrochloride crystalline form obtained in Example 1 is the maximum individual flexible among the total related substances and the total related substances. It was confirmed that it exhibited excellent stability up to 24 months without an increase in material and without loss of compound content.
  • Example 2 The 2,6-bis-(2-aminopyrimidin-4-yl)pyridin-3-ol dihydrochloride crystalline form obtained in Example 1 was stored in a sealed state under accelerated conditions of 40 ⁇ 2° C. and 75 ⁇ 5% RH. During the initial period (0 months), 1 month, 3 months, and 6 months later, changes in the amount of related substances and compound content were analyzed by high performance liquid chromatography (HPLC). The results are shown in Table 3 below.
  • Example 3 the 2,6-bis-(2-aminopyrimidin-4-yl)pyridin-3-ol dihydrochloride crystalline form obtained in Example 1 is among the total related substances and the total related substances under accelerated conditions. It was confirmed that it exhibited excellent stability up to 6 months without increasing the maximum individual related substances and without losing the compound content.
  • Example 2 The 2,6-bis-(2-aminopyrimidin-4-yl)pyridin-3-ol dihydrochloride crystalline form obtained in Example 1 was dissolved in water, and then stored in a sealed state at 37°C for an initial period (0 hours). , 1 hour, 2 hours, 3 hours, 6 hours, 9 hours, 12 hours, after 24 hours, the purity was analyzed by UPLC. The results are shown in Table 4 below.
  • Example 4 As shown in Table 4, the 2,6-bis-(2-aminopyrimidin-4-yl)pyridin-3-ol dihydrochloride crystalline form obtained in Example 1 is stable in water for up to 24 hours without any change in purity. appear.
  • Example 5 As shown in Table 5, the 2,6-bis-(2-aminopyrimidin-4-yl)pyridin-3-ol dihydrochloride crystalline form obtained in Example 1 exhibited excellent solubility at pH 1 to 4.
  • Example 1 DVS-Advantage Dynamic Vapor Adsorption System (Dynamic Vapor Sorption, Surface Measurement Systems) for the 2,6-bis-(2-aminopyrimidin-4-yl)pyridin-3-ol dihydrochloride crystalline form obtained in Example 1
  • Moisture content change was measured by repeating moisture absorption and dehumidification once in a range of 0 to 95% relative humidity (RH) under isothermal conditions of 25°C. The adsorption and desorption behavior of moisture according to the relative humidity is shown in FIG. 4.
  • the 2,6-bis-(2-aminopyrimidin-4-yl)pyridin-3-ol dihydrochloride crystalline form obtained in Example 1 is of moisture adsorption or desorption in a section of 80% or less of relative humidity. It can be seen that the change is within 3.6%, and the change in moisture adsorption or desorption in the section exceeding 80% and below 95% relative humidity is within 6.4%. Accordingly, it can be seen that the 2,6-bis-(2-aminopyrimidin-4-yl)pyridin-3-ol dihydrochloride crystalline form obtained in Example 1 is a crystalline form having low hygroscopicity in a normal humidity range.

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Abstract

The present invention provides 2,6-bis-(2-aminopyrimidin-4-yl)pyridin-3-ol dihydrochloride and a pharmaceutical composition comprising same. The 2,6-bis-(2-aminopyrimidin-4-yl)pyridin-3-ol dihydrochloride according to the present invention not only has superior stability and solubility, but can also be prepared in the form of crystals and thus may be effectively used in a pharmaceutical composition.

Description

2,6-비스-(2-아미노피리미딘-4-일)피리딘-3-올 2염산염 및 이를 포함하는 약제학적 조성물2,6-bis-(2-aminopyrimidin-4-yl)pyridin-3-ol dihydrochloride and pharmaceutical composition comprising same
본 발명은 2,6-비스-(2-아미노피리미딘-4-일)피리딘-3-올 2염산염 및 이를 포함하는 약제학적 조성물에 관한 것이다. 보다 구체적으로 본 발명은 안정성 및 용해도가 우수하여 약제학적 조성물에 효과적으로 사용될 수 있는 2,6-비스-(2-아미노피리미딘-4-일)피리딘-3-올 2염산염 및 이를 포함하는 약제학적 조성물에 관한 것이다.The present invention relates to 2,6-bis-(2-aminopyrimidin-4-yl)pyridin-3-ol dihydrochloride and a pharmaceutical composition comprising the same. More specifically, the present invention provides 2,6-bis-(2-aminopyrimidin-4-yl)pyridin-3-ol dihydrochloride that can be effectively used in pharmaceutical compositions due to excellent stability and solubility, and pharmaceuticals containing the same. It relates to the composition.
하기 화학식 Ⅰ로 표시되는 2,6-비스-(2-아미노피리미딘-4-일)피리딘-3-올은 사이클린 의존 키나아제(cyclin-dependent kinase, CDK) 억제제로서, 대장암, 폐암, 뇌교종과 같은 암, 알츠하이머 질환과 같은 퇴행성 뇌질환 등의 치료에 효과적인 것으로 알려져 있다 [대한민국 등록특허 제10-1783642호 참조].2,6-bis-(2-aminopyrimidin-4-yl)pyridin-3-ol represented by the following formula (I) is a cyclin-dependent kinase (CDK) inhibitor, including colon cancer, lung cancer, and glioma It is known to be effective in the treatment of cancer and degenerative brain diseases such as Alzheimer's disease [see Korean Patent Registration No. 10-1783642].
[화학식 I][Formula I]
Figure PCTKR2020011992-appb-I000001
Figure PCTKR2020011992-appb-I000001
그러나, 상기 화학식 Ⅰ로 표시되는 화합물은 물에 대한 용해도가 낮아 이를 개선하기 위해 3염산염, 옥살산염, 말론산염, 황산염과 같은 산부가염이 개발되었으나, 이들 산부가염은 안정성이 낮고 결정형으로 수득하기 어려운 문제점이 있었다.However, the compound represented by Formula I has low solubility in water, and acid addition salts such as trihydrochloride, oxalate, malonate, and sulfate have been developed to improve this, but these acid addition salts have low stability and are difficult to obtain in a crystalline form. There was a problem.
본 발명자들은 종래의 2,6-비스-(2-아미노피리미딘-4-일)피리딘-3-올 및 그의 산부가염이 가지는 문제점을 극복하고자 예의 연구 검토한 결과, 2,6-비스-(2-아미노피리미딘-4-일)피리딘-3-올 2염산염이 안정성 및 용해도가 우수할 뿐만 아니라 결정형으로 제조될 수 있음을 알아내고, 본 발명을 완성하게 되었다.The present inventors have conducted intensive research and review to overcome the problems of the conventional 2,6-bis-(2-aminopyrimidin-4-yl)pyridin-3-ol and acid addition salts thereof. As a result, 2,6-bis-( It was found that 2-aminopyrimidin-4-yl)pyridin-3-ol dihydrochloride is excellent in stability and solubility as well as can be prepared in a crystalline form, thereby completing the present invention.
따라서 본 발명의 목적은 안정성 및 용해도가 우수한 2,6-비스-(2-아미노피리미딘-4-일)피리딘-3-올 2염산염을 제공하는 것이다.Accordingly, an object of the present invention is to provide 2,6-bis-(2-aminopyrimidin-4-yl)pyridin-3-ol dihydrochloride having excellent stability and solubility.
본 발명의 다른 목적은 상기 2,6-비스-(2-아미노피리미딘-4-일)피리딘-3-올 2염산염을 포함하는 약제학적 조성물을 제공하는 것이다.Another object of the present invention is to provide a pharmaceutical composition comprising the 2,6-bis-(2-aminopyrimidin-4-yl)pyridin-3-ol dihydrochloride.
본 발명의 일 실시형태는 하기 화학식 II로 표시되는 2,6-비스-(2-아미노피리미딘-4-일)피리딘-3-올 2염산염에 관한 것이다.One embodiment of the present invention relates to a 2,6-bis-(2-aminopyrimidin-4-yl)pyridin-3-ol dihydrochloride represented by the following formula (II).
[화학식 II][Formula II]
Figure PCTKR2020011992-appb-I000002
Figure PCTKR2020011992-appb-I000002
본 발명의 일 실시형태에 따른 2,6-비스-(2-아미노피리미딘-4-일)피리딘-3-올 2염산염은 결정형일 수 있으며, X-선 분말 회절분석에서 I/I0 (I: 각 회절각에서의 피크의 강도, I0: 가장 큰 피크의 강도)가 30% 이상인 회절각(2θ)의 값이 10.8±0.2, 11.3±0.2, 12.2±0.2, 14.6±0.2, 23.9±0.2 및 27.2±0.2일 수 있다.2,6-bis-(2-aminopyrimidin-4-yl)pyridin-3-ol dihydrochloride according to an embodiment of the present invention may be in a crystalline form, and I/I 0 ( I: The intensity of the peak at each diffraction angle, I 0 : The intensity of the largest peak) is 10.8±0.2, 11.3±0.2, 12.2±0.2, 14.6±0.2, 23.9± Can be 0.2 and 27.2±0.2.
본 발명의 일 실시형태에 따른 2,6-비스-(2-아미노피리미딘-4-일)피리딘-3-올 2염산염 결정형은 시차주사열량(DSC) 분석에서, 147 ℃에서 시작점 및 150 ℃에서 최저점을 갖는 흡열 피크를 나타낸다.2,6-bis-(2-aminopyrimidin-4-yl)pyridin-3-ol dihydrochloride crystalline form according to an embodiment of the present invention was obtained from a differential scanning calorimetry (DSC) analysis, starting at 147° C. and 150° C. Shows the endothermic peak with the lowest point in.
본 발명의 일 실시형태에 따른 2,6-비스-(2-아미노피리미딘-4-일)피리딘-3-올 2염산염은 2,6-비스-(2-아미노피리미딘-4-일)피리딘-3-올을 메탄올에 용해하고 약 45 내지 55 당량의 염산을 가하여 교반한 다음, 여과하여 세척하고 상온에서 건조함으로써 제조할 수 있다. 그런 다음, 물과 아세톤으로 재결정하여 2,6-비스-(2-아미노피리미딘-4-일)피리딘-3-올 2염산염의 결정형을 수득할 수 있다.2,6-bis-(2-aminopyrimidin-4-yl)pyridin-3-ol dihydrochloride according to an embodiment of the present invention is 2,6-bis-(2-aminopyrimidin-4-yl) It can be prepared by dissolving pyridin-3-ol in methanol, adding about 45 to 55 equivalents of hydrochloric acid, stirring, filtering, washing, and drying at room temperature. Then, by recrystallization from water and acetone, a crystalline form of 2,6-bis-(2-aminopyrimidin-4-yl)pyridin-3-ol dihydrochloride can be obtained.
본 발명의 일 실시형태는 상기 2,6-비스-(2-아미노피리미딘-4-일)피리딘-3-올 2염산염을 약제학적으로 허용되는 담체와 함께 포함하는 사이클린 의존 키나아제(cyclin-dependent kinase, CDK) 억제용 약제학적 조성물, 구체적으로 암 또는 퇴행성 뇌질환의 치료 또는 예방용 약제학적 조성물에 관한 것이다. One embodiment of the present invention is a cyclin-dependent kinase comprising the 2,6-bis-(2-aminopyrimidin-4-yl)pyridin-3-ol dihydrochloride salt together with a pharmaceutically acceptable carrier. kinase, CDK) inhibitory pharmaceutical composition, specifically, to a pharmaceutical composition for the treatment or prevention of cancer or degenerative brain disease.
본 발명의 일 실시형태에서, 상기 2,6-비스-(2-아미노피리미딘-4-일)피리딘-3-올 2염산염은 CDK를 억제함으로써 세포주기 조절을 통한 항암 효과를 유도하여, 급성 림프구성 백혈병(Acute lymphoblastic leukemia, ALL), 만성 림프구성 백혈병(Chronic lymphoblastic leukemia, CLL), 급성 골수성 백혈병 (Acute myeloid leukemia, AML), 만성 골수성 백혈병(Chronic myeloid leukemia, CML), 다발성 골수종(multiple myeloma, MM), 호즈킨스 림프종(Hodgkin's lymphoma), 비호즈킨스 림프종(non-Hodgkin's lymphoma) 등의 혈액암과 비소세포성 폐암, 소세포성 폐암, 위암, 췌장암, 뇌교종, 대장암, 유방암, 두경부 편평상피암, 간암, 흑색종, 자궁암, 전립선암, 난소암, 갑상선암, 담도암, 담낭암, 방광암, 신장암, 식도암 등의 고형암 치료에 유용하게 사용될 수 있다.In one embodiment of the present invention, the 2,6-bis-(2-aminopyrimidin-4-yl)pyridin-3-ol dihydrochloride inhibits CDK, thereby inducing an anticancer effect through cell cycle regulation, Acute lymphoblastic leukemia (ALL), chronic lymphoblastic leukemia (CLL), acute myeloid leukemia (AML), chronic myeloid leukemia (CML), multiple myeloma , MM), Hodgkin's lymphoma, non-Hodgkin's lymphoma, and other hematologic cancers and non-small cell lung cancer, small cell lung cancer, gastric cancer, pancreatic cancer, glioma, colon cancer, breast cancer, head and neck squamous It can be usefully used to treat solid cancers such as epithelial cancer, liver cancer, melanoma, uterine cancer, prostate cancer, ovarian cancer, thyroid cancer, biliary tract cancer, gallbladder cancer, bladder cancer, kidney cancer, and esophageal cancer.
또한, 상기 2,6-비스-(2-아미노피리미딘-4-일)피리딘-3-올 2염산염은 혈관뇌장벽(blood brain barrier, BBB)을 자유롭게 통과하여 성상세포종(astrocytoma), 역형성 성상세포종(anaplastic astrocytoma), 교모세포종(glioblastoma)과 같은 교종(glioma)이나, 뇌하수체 종양(pituitary adenoma), 수모세포종(medulloblastoma), 수막종(meningioma)과 같은 뇌종양, 또는 폐암, 유방암, 흑색종 등에서 전이되어 생긴 전이성 뇌종양(metastatic brain tumor) 치료에 효과적으로 사용될 수 있다.In addition, the 2,6-bis-(2-aminopyrimidin-4-yl)pyridin-3-ol dihydrochloride freely passes through the blood brain barrier (BBB) to form an astrocytoma and anaplasticity. Metastasis from glioma such as anaplastic astrocytoma or glioblastoma, brain tumor such as pituitary adenoma, medulloblastoma, meningioma, or lung cancer, breast cancer, melanoma, etc. It can be effectively used for the treatment of metastatic brain tumors.
본 발명의 일 실시형태에서, 상기 2,6-비스-(2-아미노피리미딘-4-일)피리딘-3-올 2염산염은 CDK5 억제를 통하여 알츠하이머 질환의 원인인 tau 단백질의 인산화 및 Aβ의 생성을 억제할 뿐만 아니라, 다른 신경변성(neurodegeneration)과 연관되어 있는 신경염증 및 신경세포사(neuronal death) 등을 억제함으로써 알츠하이머병, 루이소체 치매, 전두측두엽 치매, 픽병, 파킨슨병, 다계통위축증, 루게릭병, 헌팅턴병, 뇌허혈 또는 뇌출혈로 인한 치매 등의 치료에 유용하게 사용될 수 있다(Shah K et al., Mol Neurobiol. (2017) 54(3):2255-2268). In one embodiment of the present invention, the 2,6-bis-(2-aminopyrimidin-4-yl)pyridin-3-ol dihydrochloride is phosphorylation of tau protein and Aβ, which is the cause of Alzheimer's disease, through CDK5 inhibition. Alzheimer's disease, Lewy body dementia, frontotemporal dementia, Pick's disease, Parkinson's disease, multisystem atrophy, It can be usefully used in the treatment of ALS, Huntington's disease, cerebral ischemia or dementia caused by cerebral hemorrhage (Shah K et al., Mol Neurobiol. (2017) 54(3):2255-2268).
본 발명에 따른 약제학적 조성물은 경구적으로(예를 들면, 복용 또는 흡입) 또는 비경구적으로(예를 들면, 주사, 침착, 이식, 좌약) 투여될 수 있으며, 주사는 예를 들면, 정맥주사, 피하주사, 근육내주사 또는 복강내주사일 수 있다. 본 발명에 따른 약제학적 조성물은 투여 경로에 따라, 정제, 캡슐제, 과립제, 파인 서브틸래(fine subtilae), 분제, 설하 정제, 좌약, 연고, 주사제, 유탁액제, 현탁액제, 시럽제, 분무제 등으로 제형화될 수 있다. 상기 여러 가지 형태의 본 발명에 따른 약제학적 조성물은 각 제형에 통상적으로 사용되는 약제학적으로 허용되는 담체(carrier)를 사용하여 공지기술에 의해 제조될 수 있다. 약제학적으로 허용되는 담체의 예는 부형제, 결합제, 붕해제(disintegrating agent), 윤활제, 방부제, 항산화제, 등장제(isotonic agent), 완충제, 피막제, 감미제, 용해제, 기제(base), 분산제, 습윤제, 현탁화제, 안정제, 착색제 등을 포함한다. The pharmaceutical composition according to the present invention can be administered orally (e.g., ingestion or inhalation) or parenterally (e.g., injection, deposition, implantation, suppository), and the injection is, for example, intravenous , It may be a subcutaneous injection, an intramuscular injection, or an intraperitoneal injection. According to the route of administration, the pharmaceutical composition according to the present invention is formulated as tablets, capsules, granules, fine subtilae, powders, sublingual tablets, suppositories, ointments, injections, emulsions, suspensions, syrups, sprays, etc. It can be formulated. The various types of pharmaceutical compositions according to the present invention may be prepared by known techniques using a pharmaceutically acceptable carrier commonly used in each formulation. Examples of pharmaceutically acceptable carriers include excipients, binders, disintegrating agents, lubricants, preservatives, antioxidants, isotonic agents, buffering agents, coating agents, sweetening agents, solubilizing agents, bases, dispersing agents, wetting agents. , Suspending agents, stabilizers, colorants, and the like.
본 발명에 따른 약제학적 조성물은 약제의 형태에 따라 다르지만, 본 발명의 화합물 또는 그의 약제학적으로 허용되는 염을 약 0.01 내지 95 중량%로 포함한다. The pharmaceutical composition according to the present invention varies depending on the form of the drug, but contains about 0.01 to 95% by weight of the compound of the present invention or a pharmaceutically acceptable salt thereof.
본 발명의 약제학적 조성물의 구체적인 투여량은 치료되는 사람을 포함한 포유동물의 종류, 체중, 성별, 질환의 정도, 의사의 판단 등에 따라 다를 수 있다. 바람직하게는, 경구투여의 경우에는 하루에 체중 1 kg당 활성성분 0.01 내지 50 mg이 투여되고, 비경구투여의 경우에는 하루에 체중 1 kg당 활성성분 0.01 내지 10 mg이 투여된다. 상기 총 일일 투여량은 질환의 정도, 의사의 판단 등에 따라 한번에 또는 수회로 나누어 투여될 수 있다. The specific dosage of the pharmaceutical composition of the present invention may vary depending on the type, weight, sex, degree of disease, judgment of a doctor, and the like of the mammal including the person to be treated. Preferably, in the case of oral administration, 0.01 to 50 mg of the active ingredient per 1 kg of body weight per day is administered, and in the case of parenteral administration, 0.01 to 10 mg of the active ingredient per 1 kg of body weight per day is administered. The total daily dosage may be administered at once or divided into several times depending on the degree of disease, judgment of a doctor, and the like.
본 발명의 일 실시형태에서, 상기 2,6-비스-(2-아미노피리미딘-4-일)피리딘-3-올 2염산염은 치료의 향상을 위해 카페시타빈, 5-플루오로유라실, 티오구아닌, 클로람부실, 옥살리플라틴, 시스플라틴, 카보플라틴, 파클리탁셀, 도세탁셀, 이리노테칸, 독소루비신, 비노렐빈, 젬시타빈, 페메트렉세드, 에토포사이드, 빈크리스틴, 시타라빈, 시클로포스파미드, 이포스파미드, 타목시펜, 아나스트로졸, 레트로졸, 엑세메스테인, 풀베스트란트, 테모졸로마이드, 카무스틴, 로무스틴, 에피루비신, 에리부린, 토레미펜, 고세렐린, 메게스트롤, 빈블라스틴, 벤다무스틴, 티오테파, 블레오마이신, 토포테칸, 루코보린, 트리플루리딘, 티피라실, 미토마이신씨, 알데스루킨, 템시롤리무스, 에버로리무스, 미토산트론, 메클로레타민, 메소트렉세이트, 페메트렉시드, 트라스투주맙, 베바시주맙, 세툭시맙, 아플리버셉트, 퍼투주맙, 라무시루맙, 파니투무맙, 니보루맙, 넥시투무맙, 펨브롤리주맙, 세미플리맙, 아테졸리주맙, 아벨루맙, 더발루맙, 이필리무맙, 오비누투주맙, 오파투무맙, 에로티닙, 제피티닙, 소라페닙, 라파티닙, 팔보시클립, 레고라페닙, 이마티닙, 수니티닙, 악시티닙, 파조파닙, 아파티닙, 세리티닙, 크리조티닙, 오시머티닙, 보수티닙, 다사티닙, 닐로티닙, 포나티닙, 히드록시우레아, 및 프로카르바진으로 구성된 군으로부터 선택된 하나 이상의 항암제, 또는 도네페질, 리바스티그민, 갈라타민, 메만틴, 아두카누맙, 레보도파, 카비도파, 벤세라지드, 브로모크립틴, 로피니롤, 프라미펙솔, 로티고틴, 트리헥시페니딜, 벤즈트로핀, 프로싸이클리딘, 엔타카폰, 셀레길린, 라사길린, 아만타딘, 리루졸, 테트라베나진, 듀테트라베나진 및 액티라제로 구성된 군으로부터 선택된 하나 이상의 퇴행성 뇌질환 치료제와 함께 병용 투여될 수 있다. 이때 다른 약물의 투여시간 및 용량은 달라질 수 있다.In one embodiment of the present invention, the 2,6-bis-(2-aminopyrimidin-4-yl)pyridin-3-ol dihydrochloride is capecitabine, 5-fluorouracil, and Thioguanine, chlorambucil, oxaliplatin, cisplatin, carboplatin, paclitaxel, docetaxel, irinotecan, doxorubicin, vinorelbine, gemcitabine, pemetrexed, etoposide, vincristine, cytarabine, cyclophosphamide, ifosfamide , Tamoxifen, anastrozole, letrozole, exemestein, fulvestrant, temozolomide, carmustine, lomustine, epirubicin, eribuline, toremifene, goserelin, megestrol, vinblastine, Bendamustine, Thiotepa, Bleomycin, Topotecan, Leucovorin, Trifluridine, Tipiracil, Mitomycin Seed, Aldesleukin, Temsirolimus, Everolimus, Mitosantron, Mechloretamine, Mesotrec Sate, Pemetrexed, Trastuzumab, Bevacizumab, Cetuximab, Aflibercept, Pertuzumab, Ramucirumab, Panitumumab, Niborumab, Nexitumumab, Pembrolizumab, Semiplimab, Ate Jolizumab, Abelumab, Duvalumab, Ipilimumab, Obinutuzumab, Ofatumumab, Erotinib, Gefitinib, Sorafenib, Lapatinib, Palbociclib, Regorafenib, Imatinib, Sunitinib, Ak From the group consisting of citinib, pazopanib, afatinib, ceritinib, crizotinib, osimertinib, bosutinib, dasatinib, nilotinib, ponatinib, hydroxyurea, and procarbazine One or more selected anticancer agents, or donepezil, rivastigmine, galatamine, memantine, aducanumab, levodopa, carbidopa, bencerazide, bromocriptine, ropinirol, pramipexole, rotigotine, trihec Treatment of one or more degenerative brain diseases selected from the group consisting of cifenidyl, benztropine, procyclidine, entacapone, selegiline, rasagiline, amantadine, rirusol, tetrabenazine, deuterabenazine, and actirase It can be administered in combination with. At this time, the administration time and dose of other drugs may vary.
본 발명에 따른 2,6-비스-(2-아미노피리미딘-4-일)피리딘-3-올 2염산염은 안정성 및 용해도가 우수할 뿐만 아니라 결정형으로 제조될 수 있어 약제학적 조성물에 효과적으로 사용될 수 있다.2,6-bis-(2-aminopyrimidin-4-yl)pyridin-3-ol dihydrochloride according to the present invention not only has excellent stability and solubility, but also can be prepared in a crystalline form, so that it can be effectively used in pharmaceutical compositions. have.
도 1은 2,6-비스-(2-아미노피리미딘-4-일)피리딘-3-올 2염산염 결정형의 X선 분말 회절도이다.1 is an X-ray powder diffraction diagram of a crystal form of 2,6-bis-(2-aminopyrimidin-4-yl)pyridin-3-ol dihydrochloride.
도 2는 2,6-비스-(2-아미노피리미딘-4-일)피리딘-3-올 2염산염 결정형의 시차주사열량 분석도이다.Figure 2 is a differential scanning calorie analysis diagram of a crystal form of 2,6-bis-(2-aminopyrimidin-4-yl)pyridin-3-ol dihydrochloride.
도 3은 2,6-비스-(2-아미노피리미딘-4-일)피리딘-3-올 2염산염 결정형의 열중량 분석도이다.3 is a thermogravimetric analysis diagram of a crystal form of 2,6-bis-(2-aminopyrimidin-4-yl)pyridin-3-ol dihydrochloride.
도 4는 2,6-비스-(2-아미노피리미딘-4-일)피리딘-3-올 2염산염 결정형의 동적 증기 흡착/탈착 곡선이다.4 is a dynamic vapor adsorption/desorption curve of a crystal form of 2,6-bis-(2-aminopyrimidin-4-yl)pyridin-3-ol dihydrochloride.
이하, 실시예에 의해 본 발명을 보다 구체적으로 설명하고자 한다. 이들 실시예는 오직 본 발명을 설명하기 위한 것으로, 본 발명의 범위가 이들 실시예에 국한되지 않는다는 것은 당업자에게 있어서 자명하다. Hereinafter, the present invention will be described in more detail by examples. These examples are for illustrative purposes only, and it will be apparent to those skilled in the art that the scope of the present invention is not limited to these examples.
실시예 1: 2,6-비스-(2-아미노피리미딘-4-일)피리딘-3-올 2염산염 결정형의 제조Example 1: Preparation of 2,6-bis-(2-aminopyrimidin-4-yl)pyridin-3-ol dihydrochloride crystalline form
2,6-비스-(2-아미노피리미딘-4-일)피리딘-3-올(10 g, 35.552 mmol)을 상온에서 메탄올 용매(200㎖) 하에 염산(150㎖, 1,690mmol)과 반응시키고 24시간 교반하였다. 생성된 고체를 여과하고 아세톤으로 세척하였다. 건조된 화합물을 물(120㎖)에 용해 후 아세톤(1,200㎖)으로 재결정화하여 밝은 갈색의 표제화합물(11.3g, 89.8%)을 얻었다.2,6-bis-(2-aminopyrimidin-4-yl)pyridin-3-ol (10 g, 35.552 mmol) was reacted with hydrochloric acid (150 mL, 1,690 mmol) in methanol solvent (200 mL) at room temperature. It was stirred for 24 hours. The resulting solid was filtered and washed with acetone. The dried compound was dissolved in water (120 ml) and recrystallized with acetone (1,200 ml) to obtain the light brown title compound (11.3 g, 89.8%).
1H NMR (600 MHz, DMSO-d 6) δ 14.23 (s, 1H), 8.54 (d, J = 4.8 Hz, 1H), 8.42 (d, J = 5.4 Hz, 1H), 8.36 (d, J = 8.4 Hz, 1H), 7.27 (d, J = 4.8 Hz, 1H), 7.58 (d, J = 9.0 Hz, 1H), 7.40 (br, 4H) 1 H NMR (600 MHz, DMSO- d 6 ) δ 14.23 (s, 1H), 8.54 (d, J = 4.8 Hz, 1H), 8.42 (d, J = 5.4 Hz, 1H), 8.36 (d, J = 8.4 Hz, 1H), 7.27 (d, J = 4.8 Hz, 1H), 7.58 (d, J = 9.0 Hz, 1H), 7.40 (br, 4H)
(1) X선 분말 회절 분석(1) X-ray powder diffraction analysis
X선 분말 회절(XRD; X-ray powder diffraction) 분석은 X-Pert PRO MPD (Philips, 네덜란드) 분석기를 사용하여 하기 조건으로 수행하였다.X-ray powder diffraction (XRD) analysis was performed under the following conditions using an X-Pert PRO MPD (Philips, Netherlands) analyzer.
음극 물질 (Kα): Cu-Kα (1.54056 Å)Cathode material (Kα): Cu-Kα (1.54056 Å)
스캐닝 범위: 5° 내지 90°Scanning range: 5° to 90°
발전기 설정: 40 mA, 40 kVGenerator setting: 40 mA, 40 kV
스캐닝 속도: 1 초/스텝Scanning speed: 1 second/step
다이버 슬릿 (diver slit): 0.3°Diver slit: 0.3°
안티 스캐터 슬릿 (Anti-scatter slit): 0.3°Anti-scatter slit: 0.3°
온도: 20 ℃Temperature: 20 ℃
스텝 크기: 0.02° 2θStep size: 0.02° 2θ
회전: 사용Rotation: use
상기에서 수득한 2,6-비스-(2-아미노피리미딘-4-일)피리딘-3-올 2염산염 결정형의 XRD 결과를 도 1에 나타내었다. 아울러, XRD 패턴에서 10% 이상의 상대 강도를 갖는 피크를 하기 표 1에 나타내었다.Fig. 1 shows the XRD results of the obtained 2,6-bis-(2-aminopyrimidin-4-yl)pyridin-3-ol dihydrochloride crystalline form. In addition, peaks having a relative intensity of 10% or more in the XRD pattern are shown in Table 1 below.
2θ2θ dd I/Io(%)I/I o (%) 2θ2θ dd I/Io(%)I/I o (%)
6.46.4 13.913.9 14.314.3 23.923.9 3.73.7 34.334.3
6.86.8 12.912.9 13.513.5 24.524.5 3.63.6 13.913.9
9.29.2 9.69.6 10.110.1 25.925.9 3.43.4 20.220.2
10.810.8 8.28.2 39.639.6 26.426.4 3.43.4 28.728.7
11.311.3 7.97.9 50.450.4 27.227.2 3.33.3 81.081.0
12.212.2 7.37.3 100100 28.828.8 3.13.1 17.017.0
14.614.6 6.16.1 54.654.6 29.629.6 3.03.0 14.014.0
15.215.2 5.85.8 14.314.3 31.131.1 2.92.9 14.014.0
17.917.9 4.94.9 14.014.0 32.632.6 2.72.7 10.910.9
18.718.7 4.74.7 10.810.8 33.233.2 2.72.7 10.410.4
20.920.9 4.24.2 19.919.9 34.634.6 2.62.6 13.413.4
21.721.7 4.14.1 20.620.6 35.635.6 2.52.5 16.216.2
22.722.7 3.93.9 23.723.7 37.137.1 2.42.4 13.013.0
2θ: 회절각, d: 결정면 사이의 거리, I/Io(%): 상대강도2θ: diffraction angle, d: distance between crystal planes, I/I o (%): relative intensity
(2) 시차주사 열량 분석(2) Differential scanning calorie analysis
시차주사 열량측정법 (DSC; Differential Scanning Calorimeter) 분석은 DSC204 F1 Phoenix (Netzsch, 독일)을 사용하여 0 ℃ 내지 300 ℃에서 수행하였다. 5 mg 내지 10 mg의 양으로 샘플을 칭량하여 알루미늄 DSC 팬에 부가하고, 알루미늄 DSC 팬은 밀폐하지 않는 방식으로 천공 알루미늄 뚜껑으로 봉쇄하였다. 이후, 상기 샘플을 10 ℃/분의 스캐닝 속도로 0 ℃에서 300 ℃로 가열하였고, 발생한 열 유동 반응을 DSC로 관찰하였다.Differential Scanning Calorimeter (DSC) analysis was performed at 0° C. to 300° C. using DSC204 F1 Phoenix (Netzsch, Germany). Samples were weighed in an amount of 5 mg to 10 mg and added to an aluminum DSC pan, and the aluminum DSC pan was sealed with a perforated aluminum lid in a non-sealing manner. Thereafter, the sample was heated from 0° C. to 300° C. at a scanning rate of 10° C./min, and the generated heat flow reaction was observed by DSC.
상기에서 수득한 2,6-비스-(2-아미노피리미딘-4-일)피리딘-3-올 2염산염 결정형의 DSC 분석 결과를 도 2에 나타내었다.Figure 2 shows the DSC analysis results of the 2,6-bis-(2-aminopyrimidin-4-yl)pyridin-3-ol dihydrochloride crystalline form obtained above.
상기 결정형은 약 147 ℃에서 시작점 및 약 150 ℃에서 최저점을 갖는 흡열 피크를 나타내었다.The crystalline form exhibited an endothermic peak having a starting point at about 147° C. and a lowest point at about 150° C.
(3) 열중량 분석(3) Thermogravimetric analysis
열중량 분석 (TGA; Thermogravimetric Analysis)은 TG209 F1 Libra (Netzsch, 독일)을 사용하여 30℃ 내지 350℃에서 수행하였다. 2 mg 내지 5 mg의 양으로 샘플을 칭량하였고 샘플을 장착할 수 있는 수직구조의 top-loading 방식으로, 진공 상태에서 직접 온도를 측정하였다. 이후, 상기 샘플을 10 ℃/분의 속도로 30℃에서 350℃로 가열하였고, 시료에서 발생하는 발열 및 흡열 반응을 계산한 열중량을 TGA로 관측하였다.Thermogravimetric Analysis (TGA) was performed at 30° C. to 350° C. using a TG209 F1 Libra (Netzsch, Germany). The sample was weighed in an amount of 2 mg to 5 mg, and the temperature was measured directly in a vacuum state in a vertical top-loading method in which the sample can be mounted. Thereafter, the sample was heated from 30° C. to 350° C. at a rate of 10° C./min, and the heat weight calculated for exothermic and endothermic reactions occurring in the sample was observed by TGA.
상기에서 수득한 2,6-비스-(2-아미노피리미딘-4-일)피리딘-3-올 2염산염 결정형의 TGA 결과를 도 3에 나타내었다.Fig. 3 shows the TGA results of the 2,6-bis-(2-aminopyrimidin-4-yl)pyridin-3-ol dihydrochloride crystalline form obtained above.
상기 결정형은 30 ℃ 내지 175 ℃의 온도 범위에서 중량 변화가 관찰되었으며, 이는 약 3.7% 정도의 중량 감소로 파악되었다.The crystalline form was observed to have a weight change in the temperature range of 30° C. to 175° C., which was identified as a weight reduction of about 3.7%.
실험예 1: 장기보존 안정성 시험Experimental Example 1: Long-term storage stability test
실시예 1에서 수득한 2,6-비스-(2-아미노피리미딘-4-일)피리딘-3-올 2염산염 결정형을 25±2 ℃, 60±5% RH에서 밀봉상태로 보관하면서 초기(0개월), 1개월, 3개월, 6개월, 9개월, 12개월, 18개월, 24개월 경과 후에 유연물질 발생량과 화합물 함량의 변화를 고성능액체크로마토그래피 (HPLC)로 분석하였다. 그 결과를 하기 표 2에 나타내었다.The 2,6-bis-(2-aminopyrimidin-4-yl)pyridin-3-ol dihydrochloride crystalline form obtained in Example 1 was stored in a sealed state at 25±2° C. and 60±5% RH, while initial ( 0 months), 1 month, 3 months, 6 months, 9 months, 12 months, 18 months, and 24 months later, the changes in the amount of related substances and compound content were analyzed by high performance liquid chromatography (HPLC). The results are shown in Table 2 below.
0개월0 months 1개월1 month 3개월3 months 6개월6 months 9개월9 months 12개월12 months 18개월18 months 24개월24 months
개개유연물질Individually related substances 최대 0.23%0.23% max 최대 0.22%0.22% max 최대 0.22%0.22% max 최대 0.22%0.22% max 최대 0.21%0.21% max 최대 0.25%0.25% max 최대 0.22%0.22% max 최대0.21%0.21% max
총 유연물질Total Related Substances 0.50%0.50% 0.54%0.54% 0.61%0.61% 0.50%0.50% 0.66%0.66% 0.65%0.65% 0.63%0.63% 0.61%0.61%
함량content 98.9%98.9% 99.9%99.9% 98.7%98.7% 96.7%96.7% 96.4%96.4% 99.3%99.3% 99.5%99.5% 103.3%103.3%
상기 표 2에서 보듯이, 실시예 1에서 수득한 2,6-비스-(2-아미노피리미딘-4-일)피리딘-3-올 2염산염 결정형은 총 유연물질과 총 유연물질 중 최대 개개유연물질의 증가 없이 그리고 화합물 함량 손실 없이 24개월까지 우수한 안정성을 나타냄을 확인하였다. As shown in Table 2, the 2,6-bis-(2-aminopyrimidin-4-yl)pyridin-3-ol dihydrochloride crystalline form obtained in Example 1 is the maximum individual flexible among the total related substances and the total related substances. It was confirmed that it exhibited excellent stability up to 24 months without an increase in material and without loss of compound content.
실험예 2: 열 및 수분에 대한 안정성 시험Experimental Example 2: Stability test against heat and moisture
실시예 1에서 수득한 2,6-비스-(2-아미노피리미딘-4-일)피리딘-3-올 2염산염 결정형을 40±2 ℃, 75±5% RH의 가속 조건에서 밀봉상태로 보관하면서 초기(0개월), 1개월, 3개월, 6개월 경과 후에 유연물질 발생량과 화합물 함량의 변화를 고성능 액체크로마토그래피 (HPLC)로 분석하였다. 그 결과를 하기 표 3에 나타내었다.The 2,6-bis-(2-aminopyrimidin-4-yl)pyridin-3-ol dihydrochloride crystalline form obtained in Example 1 was stored in a sealed state under accelerated conditions of 40±2° C. and 75±5% RH. During the initial period (0 months), 1 month, 3 months, and 6 months later, changes in the amount of related substances and compound content were analyzed by high performance liquid chromatography (HPLC). The results are shown in Table 3 below.
0개월0 months 1개월1 month 3개월3 months 6개월6 months
개개유연물질Individually related substances 최대 0.23%0.23% max 최대 0.22%0.22% max 최대 0.24%0.24% max 최대 0.23%0.23% max
총 유연물질Total Related Substances 0.50%0.50% 0.54%0.54% 0.59%0.59% 0.52%0.52%
함량content 98.9%98.9% 99.0%99.0% 102.7%102.7% 100.4%100.4%
상기 표 3에서 보듯이, 실시예 1에서 수득한 2,6-비스-(2-아미노피리미딘-4-일)피리딘-3-올 2염산염 결정형은 가속 조건에서 총 유연물질과 총 유연물질 중 최대 개개유연물질의 증가 없이 그리고 화합물 함량 손실 없이 6개월까지 우수한 안정성을 나타냄을 확인하였다. As shown in Table 3, the 2,6-bis-(2-aminopyrimidin-4-yl)pyridin-3-ol dihydrochloride crystalline form obtained in Example 1 is among the total related substances and the total related substances under accelerated conditions. It was confirmed that it exhibited excellent stability up to 6 months without increasing the maximum individual related substances and without losing the compound content.
실험예 3: 용매 안정성 시험Experimental Example 3: Solvent Stability Test
실시예 1에서 수득한 2,6-비스-(2-아미노피리미딘-4-일)피리딘-3-올 2염산염 결정형을 물에 녹인 후, 37 ℃에서 밀봉상태로 보관하면서 초기(0시간), 1시간, 2시간, 3시간, 6시간, 9시간, 12시간, 24시간 경과 후에 순도를 UPLC로 분석하였다. 그 결과를 하기 표 4에 나타내었다.The 2,6-bis-(2-aminopyrimidin-4-yl)pyridin-3-ol dihydrochloride crystalline form obtained in Example 1 was dissolved in water, and then stored in a sealed state at 37°C for an initial period (0 hours). , 1 hour, 2 hours, 3 hours, 6 hours, 9 hours, 12 hours, after 24 hours, the purity was analyzed by UPLC. The results are shown in Table 4 below.
최초first 1시간1 hours 2시간2 hours 3시간3 hours 6시간6 hours 9시간9 hours 12시간12 hours 24시간24 hours
순도water 100%100% 100%100% 100%100% 100%100% 100%100% 100%100% 100%100% 100%100%
상기 표 4에서 보듯이, 실시예 1에서 수득한 2,6-비스-(2-아미노피리미딘-4-일)피리딘-3-올 2염산염 결정형은 물 속에서 순도 변화 없이 24시간까지 안정한 것으로 나타났다.As shown in Table 4, the 2,6-bis-(2-aminopyrimidin-4-yl)pyridin-3-ol dihydrochloride crystalline form obtained in Example 1 is stable in water for up to 24 hours without any change in purity. appear.
실험예 4: 용해도 시험Experimental Example 4: Solubility Test
실시예 1에서 수득한 2,6-비스-(2-아미노피리미딘-4-일)피리딘-3-올 2염산염 결정형에 대해 pH에 따른 용해도 시험을 수행하고, 그 결과를 표 5에 나타내었다.2,6-bis-(2-aminopyrimidin-4-yl)pyridin-3-ol dihydrochloride crystal form obtained in Example 1 was subjected to a solubility test according to pH, and the results are shown in Table 5. .
pH에 따른 수용액aqueous solution depending on pH 용해도Solubility
0.1N HCl 수용액 [pH 1]0.1N HCl aqueous solution [pH 1] 녹는다.Melts.
0.01N HCl 수용액 [pH 2]0.01N HCl aqueous solution [pH 2] 녹는다.Melts.
0.15M 아세트산 완충액 [pH 4]0.15M acetic acid buffer [pH 4] 녹는다.Melts.
0.15M 인산염 완충액 [pH 6]0.15M phosphate buffer [pH 6] 거의 녹지 않는다.It hardly melts.
0.15M 인산염 완충액 [pH 8]0.15M phosphate buffer [pH 8] 매우 녹기 어렵다.Very difficult to melt.
상기 표 5에서 보듯이, 실시예 1에서 수득한 2,6-비스-(2-아미노피리미딘-4-일)피리딘-3-올 2염산염 결정형은 pH 1 내지 4에서 우수한 용해도를 나타내었다.As shown in Table 5, the 2,6-bis-(2-aminopyrimidin-4-yl)pyridin-3-ol dihydrochloride crystalline form obtained in Example 1 exhibited excellent solubility at pH 1 to 4.
실험예 5: 흡습성 시험Experimental Example 5: Hygroscopicity test
실시예 1에서 수득한 2,6-비스-(2-아미노피리미딘-4-일)피리딘-3-올 2염산염 결정형에 대해 DVS-Advantage 동적증기흡착장치(Dynamic Vapour Sorption, Surface Measurement Systems사)를 이용하여 수분함량 변화를 25℃의 등온 조건 하에, 상대습도(RH) 0 내지 95% 구간 내에서 흡습과 탈습을 1회 반복하여 측정하였다. 상대습도에 따른 수분의 흡착 및 탈착 거동을 도 4에 나타내었다.DVS-Advantage Dynamic Vapor Adsorption System (Dynamic Vapor Sorption, Surface Measurement Systems) for the 2,6-bis-(2-aminopyrimidin-4-yl)pyridin-3-ol dihydrochloride crystalline form obtained in Example 1 Moisture content change was measured by repeating moisture absorption and dehumidification once in a range of 0 to 95% relative humidity (RH) under isothermal conditions of 25°C. The adsorption and desorption behavior of moisture according to the relative humidity is shown in FIG. 4.
도 4를 통해, 실시예 1에서 수득한 2,6-비스-(2-아미노피리미딘-4-일)피리딘-3-올 2염산염 결정형은 상대습도 80% 이하 구간에서의 수분 흡착 또는 탈착의 변화가 3.6% 이내이고, 상대 습도 80% 초과 95% 이하 구간에서의 수분 흡착 또는 탈착의 변화가 6.4% 이내인 것을 확인할 수 있다. 따라서, 실시예 1에서 수득한 2,6-비스-(2-아미노피리미딘-4-일)피리딘-3-올 2염산염 결정형이 통상의 습도범위에서 흡습성이 낮은 결정형임을 알 수 있다.4, the 2,6-bis-(2-aminopyrimidin-4-yl)pyridin-3-ol dihydrochloride crystalline form obtained in Example 1 is of moisture adsorption or desorption in a section of 80% or less of relative humidity. It can be seen that the change is within 3.6%, and the change in moisture adsorption or desorption in the section exceeding 80% and below 95% relative humidity is within 6.4%. Accordingly, it can be seen that the 2,6-bis-(2-aminopyrimidin-4-yl)pyridin-3-ol dihydrochloride crystalline form obtained in Example 1 is a crystalline form having low hygroscopicity in a normal humidity range.

Claims (10)

  1. 하기 화학식 II로 표시되는 2,6-비스-(2-아미노피리미딘-4-일)피리딘-3-올 2염산염:2,6-bis-(2-aminopyrimidin-4-yl)pyridin-3-ol dihydrochloride represented by the following formula (II):
    [화학식 II][Formula II]
    Figure PCTKR2020011992-appb-I000003
    Figure PCTKR2020011992-appb-I000003
  2. 제1항에 있어서, X-선 분말 회절분석에서 I/I0 (I: 각 회절각에서의 피크의 강도, I0: 가장 큰 피크의 강도)가 30% 이상인 회절각(2θ)의 값이 10.8±0.2, 11.3±0.2, 12.2±0.2, 14.6±0.2, 23.9±0.2 및 27.2±0.2인 결정형의 2,6-비스-(2-아미노피리미딘-4-일)피리딘-3-올 2염산염.The method of claim 1, wherein in the X-ray powder diffraction analysis, the value of the diffraction angle (2θ) at which I/I 0 (I: intensity of the peak at each diffraction angle, I 0 : intensity of the largest peak) is 30% or more is Crystalline 2,6-bis-(2-aminopyrimidin-4-yl)pyridin-3-ol dihydrochloride in 10.8±0.2, 11.3±0.2, 12.2±0.2, 14.6±0.2, 23.9±0.2 and 27.2±0.2 .
  3. 제2항에 있어서, 시차주사열량(DSC) 분석에서, 147 ℃에서 시작점 및 150 ℃에서 최저점을 갖는 흡열 피크를 나타내는 결정형의 2,6-비스-(2-아미노피리미딘-4-일)피리딘-3-올 2염산염.The crystalline form of 2,6-bis-(2-aminopyrimidin-4-yl)pyridine according to claim 2, which exhibits an endothermic peak having a starting point at 147°C and a lowest point at 150°C in differential scanning calorimetry (DSC) analysis. -3-ol dihydrochloride.
  4. 제1항 내지 제3항 중 어느 한 항에 따른 2,6-비스-(2-아미노피리미딘-4-일)피리딘-3-올 2염산염 및 약제학적으로 허용되는 담체를 포함하는 암의 치료 또는 예방용 약제학적 조성물.Treatment of cancer comprising 2,6-bis-(2-aminopyrimidin-4-yl)pyridin-3-ol dihydrochloride according to any one of claims 1 to 3 and a pharmaceutically acceptable carrier Or a pharmaceutical composition for prophylaxis.
  5. 제4항에 있어서, 급성 림프구성 백혈병(Acute lymphoblastic leukemia, ALL), 만성 림프구성 백혈병(Chronic lymphoblastic leukemia, CLL), 급성 골수성백혈병(Acute myeloid leukemia, AML), 만성 골수성 백혈병(Chronic myeloid leukemia, CML), 다발성 골수종(multiple myeloma, MM), 호즈킨스 림프종(Hodgkin's lymphoma), 비호즈킨스 림프종(non-Hodgkin's lymphoma), 비소세포성 폐암, 소세포성 폐암, 위암, 췌장암, 뇌교종, 대장암, 유방암, 두경부 편평상피암, 간암, 흑색종, 자궁암, 전립선암, 난소암, 갑상선암, 담도암, 담낭암, 방광암, 신장암, 또는 식도암의 치료 또는 예방용인 약제학적 조성물.The method of claim 4, wherein acute lymphoblastic leukemia (ALL), chronic lymphoblastic leukemia (CLL), acute myeloid leukemia (AML), chronic myeloid leukemia (CML) ), multiple myeloma (MM), Hodgkin's lymphoma, non-Hodgkin's lymphoma, non-small cell lung cancer, small cell lung cancer, gastric cancer, pancreatic cancer, glioma, colon cancer, breast cancer , Head and neck squamous cell cancer, liver cancer, melanoma, uterine cancer, prostate cancer, ovarian cancer, thyroid cancer, biliary tract cancer, gallbladder cancer, bladder cancer, kidney cancer, or a pharmaceutical composition for the treatment or prevention of esophageal cancer.
  6. 제1항 내지 제3항 중 어느 한 항에 따른 2,6-비스-(2-아미노피리미딘-4-일)피리딘-3-올 2염산염 및 약제학적으로 허용되는 담체를 포함하는 퇴행성 뇌질환의 치료 또는 예방용 약제학적 조성물.Degenerative brain disease comprising 2,6-bis-(2-aminopyrimidin-4-yl)pyridin-3-ol dihydrochloride according to any one of claims 1 to 3 and a pharmaceutically acceptable carrier Pharmaceutical composition for the treatment or prevention of.
  7. 제6항에 있어서, 알츠하이머병, 루이소체 치매, 전두측두엽 치매, 픽병, 파킨슨병, 다계통위축증, 루게릭병, 헌팅턴병, 뇌허혈 또는 뇌출혈로 인한 치매의 치료 또는 예방용인 약제학적 조성물.According to claim 6, Alzheimer's disease, Lewy body dementia, frontotemporal dementia, Pick's disease, Parkinson's disease, multiple system atrophy, Lou Gehrig's disease, Huntington's disease, a pharmaceutical composition for the treatment or prevention of dementia caused by cerebral ischemia or brain hemorrhage.
  8. 제4항에 있어서, 2,6-비스-(2-아미노피리미딘-4-일)피리딘-3-올 2염산염과 함께 카페시타빈, 5-플루오로유라실, 티오구아닌, 클로람부실, 옥살리플라틴, 시스플라틴, 카보플라틴, 파클리탁셀, 도세탁셀, 이리노테칸, 독소루비신, 비노렐빈, 젬시타빈, 페메트렉세드, 에토포사이드, 빈크리스틴, 시타라빈, 시클로포스파미드, 이포스파미드, 타목시펜, 아나스트로졸, 레트로졸, 엑세메스테인, 풀베스트란트, 테모졸로마이드, 카무스틴, 로무스틴, 에피루비신, 에리부린, 토레미펜, 고세렐린, 메게스트롤, 빈블라스틴, 벤다무스틴, 티오테파, 블레오마이신, 토포테칸, 루코보린, 트리플루리딘, 티피라실, 미토마이신씨, 알데스루킨, 템시롤리무스, 에버로리무스, 미토산트론, 메클로레타민, 메소트렉세이트, 페메트렉시드, 트라스투주맙, 베바시주맙, 세툭시맙, 아플리버셉트, 퍼투주맙, 라무시루맙, 파니투무맙, 니보루맙, 넥시투무맙, 펨브롤리주맙, 세미플리맙, 아테졸리주맙, 아벨루맙, 더발루맙, 이필리무맙, 오비누투주맙, 오파투무맙, 에로티닙, 제피티닙, 소라페닙, 라파티닙, 팔보시클립, 레고라페닙, 이마티닙, 수니티닙, 악시티닙, 파조파닙, 아파티닙, 세리티닙, 크리조티닙, 오시머티닙, 보수티닙, 다사티닙, 닐로티닙, 포나티닙, 히드록시우레아, 및 프로카르바진으로 구성된 군으로부터 선택된 하나 이상의 항암제가 병용 투여되는 암의 치료 또는 예방용 약제학적 조성물.The method of claim 4, wherein with 2,6-bis-(2-aminopyrimidin-4-yl)pyridin-3-ol dihydrochloride, capecitabine, 5-fluorouracil, thioguanine, chlorambucil, Oxaliplatin, cisplatin, carboplatin, paclitaxel, docetaxel, irinotecan, doxorubicin, vinorelbine, gemcitabine, pemetrexed, etoposide, vincristine, cytarabine, cyclophosphamide, ifosfamide, tamoxifen, anastrozole, Letrozole, exemestein, fulvestrant, temozolomide, carmustine, lomustine, epirubicin, eriburin, toremifene, goserelin, megestrol, vinblastine, bendamustine, thiotepa, Bleomycin, Topotecan, Leucovorin, Trifluridine, Tipiracil, Mitomycin Seed, Aldesleukin, Tempsirolimus, Everolimus, Mitosantron, Mechloretamine, Mesotrexate, Pemetrexide, Tra Stuzumab, Bevacizumab, Cetuximab, Aflibercept, Pertuzumab, Ramucirumab, Panitumumab, Niborumab, Nexitumumab, Pembrolizumab, Semipleumab, Atezolizumab, Avelumab, More Valumab, ipilimumab, obinutuzumab, ofatumumab, erotinib, gefitinib, sorafenib, lapatinib, palbociclib, regorafenib, imatinib, sunitinib, axitinib, pazopanib, Concomitant administration of one or more anticancer agents selected from the group consisting of afatinib, ceritinib, crizotinib, osimertinib, bosutinib, dasatinib, nilotinib, ponatinib, hydroxyurea, and procarbazine A pharmaceutical composition for the treatment or prevention of cancer.
  9. 제6항에 있어서, 2,6-비스-(2-아미노피리미딘-4-일)피리딘-3-올 2염산염과 함께 도네페질, 리바스티그민, 갈라타민, 메만틴, 아두카누맙, 레보도파, 카비도파, 벤세라지드, 브로모크립틴, 로피니롤, 프라미펙솔, 로티고틴, 트리헥시페니딜, 벤즈트로핀, 프로싸이클리딘, 엔타카폰, 셀레길린, 라사길린, 아만타딘, 리루졸, 테트라베나진, 듀테트라베나진 및 액티라제로 구성된 군으로부터 선택된 하나 이상의 퇴행성 뇌질환 치료제가 병용 투여되는 퇴행성 뇌질환의 치료 또는 예방용 약제학적 조성물.According to claim 6, 2,6-bis-(2-aminopyrimidin-4-yl)pyridin-3-ol dihydrochloride with donepezil, rivastigmine, galatamine, memantine, aducanumab, levodopa , Carbidopa, bencerazide, bromocriptine, lopinirol, pramipexole, rotigotine, trihexifenidil, benztropine, procyclidine, entacapone, selegiline, rasagiline, amantadine , Rirusol, tetrabenazine, dutetrabenazine, and at least one degenerative brain disease therapeutic agent selected from the group consisting of actirase is administered in combination, a pharmaceutical composition for the treatment or prevention of degenerative brain disease.
  10. 제4항에 있어서, 2,6-비스-(2-아미노피리미딘-4-일)피리딘-3-올 2염산염과 함께 테모졸로마이드가 병용 투여되는 암의 치료 또는 예방용 약제학적 조성물.The pharmaceutical composition for the treatment or prevention of cancer according to claim 4, wherein temozolomide is administered in combination with 2,6-bis-(2-aminopyrimidin-4-yl)pyridin-3-ol dihydrochloride.
PCT/KR2020/011992 2019-09-06 2020-09-04 2,6-bis-(2-aminopyrimidin-4-yl)pyridin-3-ol dihydrochloride and pharmaceutical composition comprising same WO2021045582A1 (en)

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