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WO2023046182A1 - Utilisation d'un composé de pyrido[1,2-a]pyrimidone - Google Patents

Utilisation d'un composé de pyrido[1,2-a]pyrimidone Download PDF

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Publication number
WO2023046182A1
WO2023046182A1 PCT/CN2022/121443 CN2022121443W WO2023046182A1 WO 2023046182 A1 WO2023046182 A1 WO 2023046182A1 CN 2022121443 W CN2022121443 W CN 2022121443W WO 2023046182 A1 WO2023046182 A1 WO 2023046182A1
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twenty
tumor
independently
substance
optionally substituted
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English (en)
Chinese (zh)
Inventor
李永国
隗维
叶未
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Shanghai Jia Tan Pharmatech Co Ltd
Guangzhou Joyo Pharmatech Co Ltd
Original Assignee
Shanghai Jia Tan Pharmatech Co Ltd
Guangzhou Joyo Pharmatech Co Ltd
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00

Definitions

  • the invention relates to the application of a pyrido[1,2-a]pyrimidinone compound.
  • Insulinomas are very rare neuroendocrine tumors characterized clinically by hyperinsulinemia leading to hypoglycemic syndrome. Although insulinomas are less malignant, long-term hypoglycemia caused by insulinomas can cause irreversible damage to vital organs of the human body, seriously affecting the quality of life of patients and even threatening their lives. For example, the symptoms of hypoglycemia caused by insulinoma include: slow thinking, abnormal speech behavior, limb paralysis, and finally coma and death. Controlling hypoglycemic syndrome and inhibiting tumor growth are the goals of treating insulinoma.
  • Limited-stage neuroendocrine tumors can be surgically resected. However, about half of neuroendocrine tumors are diagnosed as locally advanced or have distant metastases. Radical surgical resection is difficult, and drug therapy is required to delay tumor progression and prolong patient survival.
  • the technical problem to be solved by the present invention is that the existing drug structure for treating pancreatic neuroendocrine tumors is relatively single, and cannot well improve the hypoglycemia symptoms of patients. Therefore, the present invention provides an application of pyrido[1,2-a]pyrimidinone compounds. The compound was able to inhibit the growth of pancreatic neuroendocrine tumors and increase blood sugar levels.
  • the present invention provides a kind of application of substance X in the preparation of medicine, and said substance X is the compound as shown in formula I, its pharmaceutically acceptable salt, its solvate or its pharmaceutically acceptable salt A solvate; the drug is a drug for treating pancreatic neuroendocrine tumors;
  • E is a C 1-6 alkyl group optionally substituted by R 3 , a C 3-10 cycloalkyl group optionally substituted by R 3 or a C 3-10 heterocycloalkyl group optionally substituted by R 3 ;
  • Q is a single bond or -C(R 3 )(R 3 )-;
  • A is N or C (R 3 );
  • n 1 0, 1, 2 or 3;
  • R 1 , R 2 and R 3 are independently H, F, Cl, Br, I, CN, -OR a , -N(R b )(R c ), C 1-3 alkane optionally substituted by R d base,
  • n is independently 1, 2, 3, 4, 5 or 6;
  • D 2 is independently -C(R a )(R a )-;
  • R a , R b and R c are independently H, C 1-6 alkyl optionally substituted by R d or C 3-6 cycloalkyl optionally substituted by R d ;
  • R e is H, C 1-6 alkyl optionally substituted by R d , C 1-6 alkoxy optionally substituted by R d , C 3-6 cycloalkyl optionally substituted by R d , or any A C 3-6 cycloalkoxy group substituted by R d ;
  • Rd is independently 1, 2 or 3;
  • Rd is independently F, Cl, Br, I, CN, -OH, -CHO, -COOH, CH3- , CF3- , CH3O- or CH3CH2O- ;
  • any two R 1 , between R a and R a in the same D 2 , between two D 2 , or between R a and a D 2 are jointly connected to the same carbon atom or oxygen
  • One or two 3, 4, 5 or 6-membered carbocyclic rings or oxygen heterocyclic rings are formed on the atoms, and the number of oxygen atoms is 1 or 2.
  • E is C 1-6 alkyl substituted by R 3 or C 3-6 cycloalkyl substituted by R 3 , and the number of R 3 is 1, 2 or 3 independently.
  • E is C 1-6 alkyl or C 3-6 cycloalkyl.
  • G 17 is N or C (R 3 );
  • said substance X can be a compound represented by formula (Ia), its pharmaceutically acceptable salt, its solvate or its pharmaceutically acceptable salt solvate;
  • the XRPD pattern of the compound represented by formula (Ia) can be as shown in Figure 1 , Figure 2 , Figure 3 , Figure 4 , Figure 5 or Figure 6 .
  • said pancreatic neuroendocrine tumor may be insulinoma, amine precursor uptake and decarboxylation cell tumor, vasoactive intestinal peptide tumor, glucagon tumor, pancreatic polypeptide tumor or gastrinoma.
  • said drug is a drug used for treating pancreatic neuroendocrine tumors and increasing blood sugar concentration.
  • the present invention provides a method of treating pancreatic neuroendocrine tumors comprising administering to a patient in need thereof a therapeutically effective amount of substance X as described herein.
  • the pancreatic neuroendocrine tumor may be an insulinoma, an amine precursor uptake and decarboxylation cell tumor, a vasoactive intestinal peptide tumor, a glucagon tumor, a pancreatic polypeptide tumor, or a gastrinoma.
  • the administration regimen of substance X (including administration route, administration dose, administration interval, etc.) can be adjusted by those skilled in the art as needed to provide the optimal therapeutic effect.
  • the substance X can be administered by any suitable route known in the art, including oral, injection (eg intravenous, intramuscular, subcutaneous) and the like.
  • the substance X is administered orally.
  • the substance X can be administered according to the weight of the patient, a non-limiting example range can be 0.01-1 mg/kg (referring to a single dose), such as 0.01 mg/kg, 0.05 mg/kg, 0.1 mg/kg, 0.15 mg/kg kg, 0.2mg/kg, 0.25mg/kg, 0.3mg/kg, 0.35mg/kg, 0.4mg/kg, 0.45mg/kg, 0.5mg/kg, 0.55mg/kg, 0.6mg/kg, 0.7mg/kg kg, 0.8mg/kg, 0.9mg/kg or 1mg/kg.
  • the dose of Compound I is 0.05-0.2 mg/kg, such as 0.05 mg/kg, 0.1 mg/kg or 0.2 mg/kg.
  • the above doses of the substance X may be administered according to the frequency of QD (once a day), QOD (one day apart) or QW (once a week).
  • the substance X is administered on a QD frequency.
  • the substance X is administered orally according to the dosage and frequency mentioned above.
  • the substance X is administered orally at 0.2 mg/kg, QD.
  • the substance X is administered orally at 0.2 mg/kg, QD, and the substance X is a compound represented by formula (Ia).
  • the substance X may also be administered to the patient in fixed doses, ie a fixed or predetermined amount of dose is given to the patient.
  • a non-limiting example of a fixed dose (referred to as a single dose) may range from 0.01 to 50 mg, such as 0.01 mg, 0.1 mg, 0.5 mg, 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg, 11mg, 12mg, 13mg, 14mg, 15mg, 16mg, 17mg, 18mg, 19mg, 20mg, 21mg, 22mg, 23mg, 24mg, 25mg, 26mg, 27mg, 28mg, 29mg, 30mg, 31mg, 32mg, 33mg, 34mg, 35mg, 36mg, 37mg, 38mg, 39mg, 40mg, 41mg, 42mg, 43mg, 44mg, 45mg, 46mg, 47m
  • the above-mentioned fixed doses of the substance X may be administered at a frequency of QD (once a day), QOD (once a day) or QW (once a week).
  • the substance X is administered on a QD frequency.
  • pharmaceutically acceptable salt refers to a salt obtained by reacting a compound with a pharmaceutically acceptable (relatively non-toxic, safe, and suitable for use by patients) acid or base.
  • base addition salts can be obtained by contacting the free form of the compound with a sufficient amount of a pharmaceutically acceptable base in a suitable inert solvent.
  • Pharmaceutically acceptable base addition salts include, but are not limited to, sodium salts, potassium salts, calcium salts, aluminum salts, magnesium salts, bismuth salts, ammonium salts, and the like.
  • acid addition salts can be obtained by contacting the free form of the compound with a sufficient amount of a pharmaceutically acceptable acid in a suitable inert solvent.
  • Pharmaceutically acceptable acid addition salts include, but are not limited to, hydrochlorides, sulfates, methanesulfonates, and the like. See Handbook of Pharmaceutical Salts: Properties, Selection, and Use (P. Heinrich Stahl, 2002) for details.
  • solvate refers to a substance formed when a compound is combined with a solvent (including but not limited to: water, methanol, ethanol, etc.). Solvates are divided into stoichiometric solvates and non-stoichiometric solvates.
  • solvate of a pharmaceutically acceptable salt refers to a compound with a pharmaceutically acceptable (relatively non-toxic, safe, and suitable for patient use) acid or base, solvent (including but not limited to: water, methanol, ethanol etc.), wherein the pharmaceutically acceptable salt has the same meaning as the term “pharmaceutically acceptable salt” above, and the solvent is stoichiometric or non-stoichiometric.
  • solvent including but not limited to: water, methanol, ethanol etc.
  • Solvates of pharmaceutically acceptable salts include, but are not limited to, hydrochloride monohydrate.
  • the reagents and raw materials used in the present invention are all commercially available.
  • crystal forms I, II, III, IV, V and VI used in the present invention are prepared according to the method described in CN201680072859.0.
  • the positive progress effect of the present invention lies in that the compound can inhibit the growth of pancreatic neuroendocrine tumors and improve the blood sugar level.
  • Figure 1 is the Cu-K ⁇ radiation XRPD spectrum of Form I.
  • Fig. 2 is the Cu-K ⁇ radiation XRPD spectrum of the II crystal form.
  • Fig. 3 is the Cu-K ⁇ radiation XRPD spectrum of the III crystal form.
  • Fig. 4 is the Cu-K ⁇ radiation XRPD spectrum of the IV crystal form.
  • Fig. 5 is the Cu-K ⁇ radiation XRPD spectrum of V crystal form.
  • Fig. 6 is the Cu-K ⁇ radiation XRPD spectrum of VI crystal form.
  • Compound (Ia) in the following examples refers to Provided by Shanghai Jiatan Pharmaceutical Technology Co., Ltd., prepared according to Example 176 of CN 105461712 A.
  • the XRPD pattern analysis data of compound (Ia) are shown in Table 1, Table 2, Table 3, Table 4, Table 5 or Table 6; the XRPD pattern of compound (Ia) is shown in Figure 1, Figure 2, Figure 3, Figure 4, Figure 5 or Figure 6.
  • DMSO purchased from Sigma
  • Matrigel purchased from Corning
  • fetal bovine serum purchased from GIBCO
  • PRMI1640 purchased from GIBCO
  • trypsin purchased from GIBCO
  • INS-1 cells purchased from Shanghai Fuxiang Biotechnology Co., Ltd.
  • Experimental model rat-derived insulinoma INS-1 cell line subcutaneously allografted female BALB/c nude mouse model
  • Cell culture In vitro monolayer culture of rat insulinoma INS-1 cells, the culture conditions are RPMI1640 medium plus 10% fetal bovine serum, 100 U/mL penicillin and 100 ⁇ g/mL streptomycin, 37 ° C, 5% CO 2. Cultivate under the condition of 95% relative humidity, passage with trypsin twice a week, when the cells are in the logarithmic growth phase, digest the cells for inoculation.
  • mice BALB/c nude mice, female, 7-8 weeks (the age of mice at the time of tumor cell inoculation), weighing 19-23 g, provided by Jiangsu Jicui Yaokang Biotechnology Co., Ltd.
  • Tumor inoculation Experimental mice were subcutaneously inoculated with 10 7 /mouse INS-1 cells, the cells were resuspended in 1:1 PBS and Matrigel, and the tumor growth was observed regularly. The day of tumor cell inoculation was defined as day 0. The initial blood glucose of 5 animals was randomly measured before inoculation. Afterwards, the blood glucose of 5 animals was randomly measured every week to monitor the blood glucose changes during the growth of insulinoma. After the blood glucose of some animals was observed to drop to ⁇ 4mM, the blood glucose at the tip of the tail of all animals was taken to measure the blood glucose. Grouped according to the blood sugar level, and started administration, the average blood sugar level of each group before administration was 5.36mM (the 23rd day).
  • test compound (Ia) (0.2mg/kg) group, test compound (Ia) (0.1mg/kg) group, test compound (Ia) (0.05mg/kg) group and Everolimus (1mg/kg) group, 5 rats in each group, the test compound (Ia) and Everolimus were administered orally by gavage, once a day, see Table 7 for details. Three days after administration, the blood glucose curve was analyzed.
  • Vehicle one 1% DMSO + 99% (1% methylcellulose aqueous solution), the percentages are volume percentages.
  • the average tumor volume of mice in the vehicle control group was 2465.09mm 3
  • the second group of compound (Ia), 0.2mg/kg treatment group, the third group of compound ( Ia), 0.1mg/kg treatment group, the fourth compound (Ia), 0.05mg/kg treatment group and the fifth Everolimus, 1mg/kg treatment group mean tumor volumes were 1902.62mm 3 , 2113.97mm 3 , 2233.47mm 3 and 2162.24mm 3 .
  • mice The tumor volumes of mice in each treatment group and control group are shown in Table 10-11 (tumor volume growth curves of mice in each treatment group and control group).
  • TGI tumor growth rate
  • compound (Ia) can significantly increase the blood glucose and inhibit tumor growth in mice.
  • compound (Ia) compared with Everolimus, compound (Ia) has a stronger effect on improving blood sugar level and inhibiting tumor growth in mice.

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  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
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  • Engineering & Computer Science (AREA)
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Abstract

L'invention concerne une utilisation d'un composé de pyrido[1,2-a]pyrimidone, et en particulier une utilisation d'une substance X dans la préparation d'un médicament. La substance X est un composé représenté par la formule I, un sel pharmaceutiquement acceptable, un solvate de celui-ci, ou un solvate d'un sel pharmaceutiquement acceptable de celui-ci ; et le médicament est utilisé pour traiter des tumeurs neuroendocrines pancréatiques. Le composé peut inhiber la croissance de tumeurs neuroendocrines pancréatiques et améliorer le taux de glycémie.
PCT/CN2022/121443 2021-09-27 2022-09-26 Utilisation d'un composé de pyrido[1,2-a]pyrimidone Ceased WO2023046182A1 (fr)

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CN202111138382 2021-09-27

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP4282866A4 (fr) * 2021-01-25 2024-07-03 Guangzhou Joyo Pharmatech Co., Ltd Utilisation d'un analogue de pyrido[1,2-a]pyrimidone

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008144463A1 (fr) * 2007-05-18 2008-11-27 Smithkline Beecham Corporation Dérivés de quinoline en tant qu'inhibiteurs de pi3 kinase
CN105461711A (zh) * 2014-06-17 2016-04-06 南京明德新药研发股份有限公司 作为PI3K抑制剂的吡啶并[1,2-a]嘧啶酮类似物
CN105461712A (zh) * 2014-06-17 2016-04-06 南京明德新药研发股份有限公司 作为mTOR/PI3K抑制剂的吡啶并[1,2-a]嘧啶酮类似物

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008144463A1 (fr) * 2007-05-18 2008-11-27 Smithkline Beecham Corporation Dérivés de quinoline en tant qu'inhibiteurs de pi3 kinase
CN105461711A (zh) * 2014-06-17 2016-04-06 南京明德新药研发股份有限公司 作为PI3K抑制剂的吡啶并[1,2-a]嘧啶酮类似物
CN105461712A (zh) * 2014-06-17 2016-04-06 南京明德新药研发股份有限公司 作为mTOR/PI3K抑制剂的吡啶并[1,2-a]嘧啶酮类似物

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
HAN XU, WEN-HUI LOU: "Advances in Ｒesearch on Genotyping and the Molecular Mechanism of Pancreatic Neuroendocrine Neoplasias", MEDICAL JOURNAL OF PEKING UNION MEDICAL COLLEGE HOSPITAL, vol. 11, no. 4, 31 July 2020 (2020-07-31), pages 377 - 382, XP093054273, ISSN: 1674-9081, DOI: 10.3969/j.issn.1674-9081.2020.04.004 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP4282866A4 (fr) * 2021-01-25 2024-07-03 Guangzhou Joyo Pharmatech Co., Ltd Utilisation d'un analogue de pyrido[1,2-a]pyrimidone

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