WO2017063155A1 - Composé pour le traitement d'une lésion de la moelle osseuse provoquée par la radiothérapie ou la chimiothérapie - Google Patents

Composé pour le traitement d'une lésion de la moelle osseuse provoquée par la radiothérapie ou la chimiothérapie Download PDF

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Publication number
WO2017063155A1
WO2017063155A1 PCT/CN2015/091923 CN2015091923W WO2017063155A1 WO 2017063155 A1 WO2017063155 A1 WO 2017063155A1 CN 2015091923 W CN2015091923 W CN 2015091923W WO 2017063155 A1 WO2017063155 A1 WO 2017063155A1
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WIPO (PCT)
Prior art keywords
metformin
preparation
compound
bone marrow
hours
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PCT/CN2015/091923
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English (en)
Chinese (zh)
Inventor
卢学春
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吉林海格力斯医药生物科技发展有限公司
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Priority to PCT/CN2015/091923 priority Critical patent/WO2017063155A1/fr
Publication of WO2017063155A1 publication Critical patent/WO2017063155A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A61K31/155—Amidines (), e.g. guanidine (H2N—C(=NH)—NH2), isourea (N=C(OH)—NH2), isothiourea (—N=C(SH)—NH2)
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C277/00—Preparation of guanidine or its derivatives, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups
    • C07C277/08—Preparation of guanidine or its derivatives, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups of substituted guanidines
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C279/00—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups
    • C07C279/20—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups containing any of the groups, X being a hetero atom, Y being any atom, e.g. acylguanidines
    • C07C279/24—Y being a hetero atom
    • C07C279/26—X and Y being nitrogen atoms, i.e. biguanides
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C303/00—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides
    • C07C303/32—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of salts of sulfonic acids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C309/00—Sulfonic acids; Halides, esters, or anhydrides thereof
    • C07C309/01—Sulfonic acids
    • C07C309/02—Sulfonic acids having sulfo groups bound to acyclic carbon atoms
    • C07C309/03—Sulfonic acids having sulfo groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton
    • C07C309/04—Sulfonic acids having sulfo groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton containing only one sulfo group

Definitions

  • the invention belongs to the field of medicine.
  • the present invention relates to a novel compound for preventing and treating a bone marrow damage caused by radiation therapy and chemotherapy, a method for producing the compound, a pharmaceutical composition comprising the same, and the compound And use of the pharmaceutical composition for the preparation of a medicament for preventing and treating radiation-induced, chemotherapy-induced bone marrow damage.
  • Hematological tumors generally include acute and chronic leukemias and lymphomas, and hematopoietic stem cell transplantation is currently the only effective means of curing blood tumors.
  • the failure of bone marrow hematopoietic reconstitution after transplantation and infection and bleeding due to delayed hematopoietic reconstitution are the most important causes of hematopoietic stem cell transplantation failure. Therefore, research and development of drugs that promote hematopoietic reconstitution after transplantation is an urgent task in the field of hematopoietic stem cell transplantation.
  • Bone marrow-threatening diseases are diseases in which bone marrow hematopoietic function is caused by various causes, resulting in anemia, thrombocytopenia, and leukopenia. Clinically manifested as fatigue, bleeding and infection. Patients are life-threatening due to severe cytopenia and can also affect quality of life due to mild thrombocytopenia. Hematopoietic stem cell transplantation is currently considered to be the only effective means of radical cure. However, due to the limitations of donor sources and the inability of the elderly to perform hematopoietic stem cell transplantation, only a very small number of patients with bone marrow-defective diseases that can truly receive hematopoietic stem cell transplantation account for only a small number of patients. Therefore, the development of an effective drug for promoting bone marrow hematopoietic reconstitution is urgently needed in the field of treatment of bone marrow failure diseases.
  • the bone marrow hematopoietic microenvironment plays an important role in maintaining the proliferation and differentiation of bone marrow hematopoietic stem cells.
  • drugs for the prevention and treatment of bone marrow damage are biological agents, such as TPO receptor agonists.
  • TPO receptor agonists such as TPO receptor agonists.
  • thiophosphoric acid has a certain protective effect on bone marrow radiation damage, the mechanism is unknown and it is an injection type. Its anti-radiation damage effect needs to be administered 30 minutes before the radiation occurs, and it does not have the practical utility of radiation damage prevention. From the current treatment of bone marrow injury drugs, the protection of the bone marrow microenvironment and the protection of stem cells is an effective way to prevent and treat various types of bone marrow hematopoietic failure.
  • erythropoietin erythropoietin
  • rhTPO thrombopoietin
  • G-CSF granulocyte colony-stimulating factor that promotes granulocyte production.
  • proteins or polypeptides are easy to produce antibodies, are inconvenient to store, need to be stored under low temperature conditions, and have a short shelf life. Moreover, after a period of use, secondary blood cell reduction occurs due to the production of antibodies in the human body, such as secondary pure red blood cell aplastic anemia that occurs after the use of erythropoietin, and secondary thrombocytopenia after thrombopoietin production.
  • the advantage of the small molecule compound is that it is convenient to be administered, can be stored for a long time under normal temperature conditions, and does not produce antibodies after administration.
  • the present invention provides a novel compound for treating bone marrow damage caused by radiotherapy and chemotherapy, a preparation method of the compound, a pharmaceutical composition comprising the same, and a compound in the preparation of The use of a medicament for treating bone marrow damage caused by radiotherapy or chemotherapy.
  • the present invention provides a compound of the formula (I):
  • the preparation method of the compound represented by the formula (I) provided by the present invention comprises the following steps:
  • the metformin mineral acid salt in the step (1) is metformin hydrochloride
  • the inorganic strong base is selected from one or more of sodium hydroxide, potassium hydroxide, calcium hydroxide, barium hydroxide, lithium hydroxide, preferably sodium hydroxide;
  • the reaction temperature of the step (1) is room temperature, preferably 25 ° C;
  • the reaction time of the step (1) is 1-6 hours, preferably 2-4 hours;
  • the molar ratio of the metformin mineral acid salt to the inorganic strong base in the step (1) is 1:3-1:5.
  • the reaction temperature of the step (2) is 50-100 ° C, preferably 75-85 ° C;
  • the reaction time of the step (2) is 1-6 hours, preferably 2-4 hours;
  • the step (2) is carried out in a reaction solvent of ethanol and/or methanol;
  • the molar ratio of metformin free base to methanesulfonic acid in the step (2) is 1:1.2.
  • the preparation method of the compound represented by the formula (I) provided by the present invention comprises the following steps:
  • the invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising the invention according to the invention A compound or a compound prepared by the preparation method of the present invention or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable adjuvant.
  • the pharmaceutical composition of the present invention is a tablet, a suppository, a dispersible tablet, an enteric coated tablet, a chewable tablet, an orally disintegrating tablet, a capsule, a sugar coating agent, a granule, a dry powder, an oral solution, a small needle for injection, and a frozen for injection. Dry powder needle or large infusion.
  • the compound of the present invention has at least the following technical effects:
  • the compound of the present invention has the effects of treating bone marrow damage caused by radiotherapy and chemotherapy, and adjuvant treatment of aplastic anemia, and thus can be made into a related drug.
  • erythropoietin erythropoietin
  • rhTPO thrombopoietin
  • G-CSF granulocyte colony-stimulating factor that promotes granulocyte production.
  • proteins or polypeptides are easy to produce antibodies, are inconvenient to store, need to be stored under low temperature conditions, and have a short shelf life. Moreover, after a period of use, secondary blood cell reduction occurs due to the production of antibodies in the human body, such as secondary pure red blood cell aplastic anemia that occurs after the use of erythropoietin, and secondary thrombocytopenia after thrombopoietin production.
  • the compound of the invention is a small molecule compound. In the course of use, it has a promoting effect on multilineage hematopoiesis, including granulosa, erythroid and megakaryocytes to produce platelets. No antibodies are produced, and they can be stored at room temperature. The drug has a long shelf life. Moreover, in addition to promoting the recovery of hematopoietic function, there are still treatments for diabetes and anti-tumor effects.
  • the compound provided by the invention and the pharmaceutical composition comprising the same have the advantages of convenient administration and long-term preservation under normal temperature conditions. Since the drug is a small molecule compound, its homologue metformin hydrochloride has been clinically used for many years without autoantibody production. The phenomenon exists, and no antibodies are produced after the drug.
  • Example 1 is a plastic slice of a normal control group in Example 3 of the present invention.
  • Embodiment 2 is a plastic slice of a radiation chemotherapy model group in Embodiment 3 of the present invention.
  • Figure 3 is a plastic slice after administration of metformin mesylate for three weeks in Example 3 of the present invention.
  • Figure 4 is a plastic section of the metformin mesylate group after administration for three weeks in Example 3 of the present invention.
  • the molecular weight of metformin mesylate of the present invention is 225, but it is a mesylate salt, which is free in liquid-mass spectrometry, and only a molecule of metformin (molecular weight: 129) can be obtained.
  • 1H NMR (300MHz, D2O) ⁇ 2.83 (s, 3H), 2.75 (s, 6H). Melting point M.P. 193-195 °C.
  • the product obtained in the present application is metformin mesylate because of:
  • the metformin which was freed from the experiment was a liquid and was very soluble in methanol/ethanol, and the methanesulfonic acid used in the experiment was also a liquid which was extremely soluble in methanol/ethanol.
  • the methanol/ethanol solution of metformin was colorless and clarified. When methanesulfonic acid was added, a white precipitate was observed to be rapidly formed. It conforms to the solubility change of the compound: it has good solubility in aqueous solution after salt formation, and poor solubility in anhydrous methanol/ethanol.
  • the methyl hydrogen of methanesulfonic acid in H1-NMR and the two methyl hydrogen on metformin form a fixed ratio, and if it is two monomers, it does not exhibit a proportional relationship.
  • the molecular weight of metformin mesylate of the present invention is 225, but it is a mesylate salt, which is free in liquid-mass spectrometry, and only a molecule of metformin (molecular weight: 129) can be obtained.
  • 1H NMR (300MHz, D2O) ⁇ 2.83 (s, 3H), 2.75 (s, 6H). Melting point M.P. 193-195 °C.
  • the product obtained in the present application is metformin mesylate because of:
  • the metformin which was freed from the experiment was a liquid and was very soluble in methanol/ethanol, and the methanesulfonic acid used in the experiment was also a liquid which was extremely soluble in methanol/ethanol.
  • the methanol/ethanol solution of metformin was colorless and clarified.
  • methanesulfonic acid was added, it was observed that a white precipitate rapidly formed, which was consistent with the solubility change of the compound: after salt formation, the solubility was good only in the aqueous solution, but in the absence of Poor solubility in water methanol/ethanol.
  • the final product was tested by melting point and confirmed by comparison, the monomeric metformin And methanesulfonic acid is a liquid, no melting point.
  • the methyl hydrogen of methanesulfonic acid in H1-NMR and the two methyl hydrogen on metformin form a fixed ratio, and if it is two monomers, it does not exhibit a proportional relationship.
  • the molecular weight of metformin mesylate of the present invention is 225, but it is a mesylate salt, which is free in liquid-mass spectrometry, and only a molecule of metformin (molecular weight: 129) can be obtained.
  • 1H NMR (300MHz, D2O) ⁇ 2.83 (s, 3H), 2.75 (s, 6H). Melting point M.P. 193-195 °C.
  • the product obtained in the present application is metformin mesylate because of:
  • the metformin which was freed from the experiment was a liquid and was very soluble in methanol/ethanol, and the methanesulfonic acid used in the experiment was also a liquid which was extremely soluble in methanol/ethanol.
  • the methanol/ethanol solution of metformin was colorless and clarified.
  • methanesulfonic acid was added, it was observed that a white precipitate rapidly formed, which was consistent with the solubility change of the compound: after salt formation, the solubility was good only in the aqueous solution, but in the absence of Poor solubility in water methanol/ethanol.
  • the methyl hydrogen of methanesulfonic acid in H1-NMR and the two methyl hydrogen on metformin form a fixed ratio, and if it is two monomers, it does not exhibit a proportional relationship.
  • An animal model of bone marrow injury with radiotherapy and chemotherapy was prepared by combining gamma irradiation with chemotherapy drugs.
  • Kunming mice body weight 20.0 ⁇ 2.0g
  • intraperitoneal injection of cyclophosphamide 50mg/kg and chloramphenicol 62.5mg/kg were given once a day.
  • blood was taken for anticoagulation and blood routine analysis was performed to establish a mouse model.
  • Metformin mesylate was made into a 7 mg/ml solution, and the metformin mesylate group was intragastrically administered (0.5 ml/mouse); and the model group and the blank group were given an equal volume of physiological saline.
  • Kunming mice There were 10 Kunming mice in the blank control group, the chemoradiotherapy bone marrow injury model group and the treatment group.
  • mice Through the peripheral blood and bone marrow biopsy of mice, the therapeutic effect of metformin mesylate on bone marrow injury induced by radiotherapy and chemotherapy in mice was established, which could increase the peripheral blood picture (p ⁇ 0.01), the degree of myeloproliferation was restored, and the hematopoietic cells increased significantly. Hematopoietic cell capacity > 40%, Figure 3, 4).

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

La présente invention concerne des composés de formule I. La présente invention concerne également un procédé de préparation des composés et une composition de médicament comprenant les composés. La composition de médicament peut être utilisée pour le traitement d'une lésion de la moelle osseuse provoquée par une radiothérapie ou une chimiothérapie et pour le traitement d'appoint d'une anémie aplasique. <img file="dest_path_image002.jpg" he="46.57" img-content="drawing" img-format="jpg" inline="yes" orientation="portrait" wi="116.42"/>
PCT/CN2015/091923 2015-10-14 2015-10-14 Composé pour le traitement d'une lésion de la moelle osseuse provoquée par la radiothérapie ou la chimiothérapie WO2017063155A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
PCT/CN2015/091923 WO2017063155A1 (fr) 2015-10-14 2015-10-14 Composé pour le traitement d'une lésion de la moelle osseuse provoquée par la radiothérapie ou la chimiothérapie

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
PCT/CN2015/091923 WO2017063155A1 (fr) 2015-10-14 2015-10-14 Composé pour le traitement d'une lésion de la moelle osseuse provoquée par la radiothérapie ou la chimiothérapie

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WO2017063155A1 true WO2017063155A1 (fr) 2017-04-20

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PCT/CN2015/091923 WO2017063155A1 (fr) 2015-10-14 2015-10-14 Composé pour le traitement d'une lésion de la moelle osseuse provoquée par la radiothérapie ou la chimiothérapie

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR20110021691A (ko) * 2009-08-25 2011-03-04 한올바이오파마주식회사 메트포르민 메탄설폰산염, 그의 제조방법, 그를 포함하는 약학 조성물 및 그를 포함하는 복합제제
CN102871991A (zh) * 2012-10-24 2013-01-16 中国医学科学院放射医学研究所 二甲双胍在对放化疗损伤起保护作用的药物中的应用

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR20110021691A (ko) * 2009-08-25 2011-03-04 한올바이오파마주식회사 메트포르민 메탄설폰산염, 그의 제조방법, 그를 포함하는 약학 조성물 및 그를 포함하는 복합제제
CN102871991A (zh) * 2012-10-24 2013-01-16 中国医学科学院放射医学研究所 二甲双胍在对放化疗损伤起保护作用的药物中的应用

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