WO2023077452A1 - Akr1c3活化的dna烷化剂及其医药用途 - Google Patents

Akr1c3活化的dna烷化剂及其医药用途 Download PDF

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Publication number
WO2023077452A1
WO2023077452A1 PCT/CN2021/129077 CN2021129077W WO2023077452A1 WO 2023077452 A1 WO2023077452 A1 WO 2023077452A1 CN 2021129077 W CN2021129077 W CN 2021129077W WO 2023077452 A1 WO2023077452 A1 WO 2023077452A1
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Prior art keywords
compound
cancer
group
tumor
days
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Ceased
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PCT/CN2021/129077
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English (en)
French (fr)
Chinese (zh)
Inventor
李安蓉
段建新
孟繁英
齐天阳
孟滕
张梦云
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Ascentawits Pharmaceuticals Ltd
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Ascentawits Pharmaceuticals Ltd
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Priority to EP21962965.6A priority Critical patent/EP4428138A4/en
Priority to PCT/CN2021/129077 priority patent/WO2023077452A1/zh
Priority to JP2024526649A priority patent/JP2024539385A/ja
Priority to KR1020247018893A priority patent/KR20240110013A/ko
Priority to CN202180103860.6A priority patent/CN118201940A/zh
Priority to TW111142123A priority patent/TW202320804A/zh
Publication of WO2023077452A1 publication Critical patent/WO2023077452A1/zh
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    • 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
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/66—Phosphorus compounds
    • A61K31/675—Phosphorus compounds having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C201/00—Preparation of esters of nitric or nitrous acid or of compounds containing nitro or nitroso groups bound to a carbon skeleton
    • C07C201/06—Preparation of nitro compounds
    • C07C201/12—Preparation of nitro compounds by reactions not involving the formation of nitro groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C205/00—Compounds containing nitro groups bound to a carbon skeleton
    • C07C205/27—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by etherified hydroxy groups
    • C07C205/35—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by etherified hydroxy groups having nitro groups and etherified hydroxy groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C205/00—Compounds containing nitro groups bound to a carbon skeleton
    • C07C205/27—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by etherified hydroxy groups
    • C07C205/35—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by etherified hydroxy groups having nitro groups and etherified hydroxy groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton
    • C07C205/36—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by etherified hydroxy groups having nitro groups and etherified hydroxy groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton to carbon atoms of the same non-condensed six-membered aromatic ring or to carbon atoms of six-membered aromatic rings being part of the same condensed ring system
    • C07C205/38—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by etherified hydroxy groups having nitro groups and etherified hydroxy groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton to carbon atoms of the same non-condensed six-membered aromatic ring or to carbon atoms of six-membered aromatic rings being part of the same condensed ring system the oxygen atom of at least one of the etherified hydroxy groups being further bound to a carbon atom of a six-membered aromatic ring, e.g. nitrodiphenyl ethers
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/553—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having one nitrogen atom as the only ring hetero atom
    • C07F9/564—Three-membered 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
    • C07B2200/05—Isotopically modified compounds, e.g. labelled

Definitions

  • the present invention provides the method for treating cancer or tumor, it comprises the step of a or b:
  • the IHC method is an immunohistochemical method, which is suitable for the detection of solid tumor samples.
  • the present invention provides a method for synthesizing the compound of the following structure I-1, I-2 or I-3, which comprises using compound II-1, II-2 or II-3 as the starting reactant to react with phosphorus oxyhalide for the first
  • the intermediate is obtained by one reaction, and then the intermediate is reacted with haloethylamine or the hydrohalide of haloethylamine for the second time, and finally the corresponding compounds I-1, I-2 or I-3 are respectively obtained:
  • Prodrug refers to a compound (or drug) that, upon administration or administration, is metabolized or otherwise converted to a biologically active or more active compound (or drug) with respect to at least one property.
  • Prodrugs are chemically modified relative to drugs in such a way that they are less or inactive relative to the drug, but chemically modified so that the corresponding drug is produced by metabolism or other biological processes after administration of the prodrug.
  • Prodrugs may have altered metabolic stability or delivery characteristics, fewer side effects or toxicity, or improved flavor relative to the active drug.
  • Prodrugs can be synthesized using reactants other than the corresponding drug.
  • X is each independently fluorine, chlorine, bromine, iodine
  • the haloethylamine is bromoethylamine
  • the haloethylamine hydrohalide is bromoethylamine hydrobromide
  • X is each independently fluorine, chlorine, bromine, iodine, preferably bromine;
  • the cells are routinely cultured until the cell saturation is 80%-90%, and the cells are collected when the number reaches the requirement.
  • IC 50 curves obtained by testing compounds A, B, C and AST-3424 are shown in Fig. 5 .
  • test group 0 days 3 days 7 days 10 days 14 days 17 days 21 days 24 days 28 days 31 days Group 1 103.74 169.79 401.62 775.57 1319.18 2113.82 2641.70 3149.10 the the Group 2 103.93 168.82 269.83 439.29 731.99 1076.45 1241.19 1504.89 2218.52 2313.01 Group 3 103.98 150.33 318.74 683.99 1404.42 2201.20 2739.12 3311.77 3362.07 the
  • test drug Sorafenib (Sorafenib) 30mg/kg (administered once a day, continuously for 21 days) group
  • test drug compound A 1.25mg/kg (administered every day, continuously for 5 days, after stopping for 2 days, Stop for another 2 weeks, a total of 2 dosing cycles)
  • 2.5mg/kg dosing every day for 5 consecutive days, stop for 2 days, then stop for another 2 weeks, a total of 2 dosing cycles
  • 5mg/kg (dosing every day medicine, given continuously for 5 days, stopped for 2 days, then stopped for 2 weeks, a total of 2 administration cycles) single drug group and 7.5% absolute ethanol + 7.5% polyoxyethylene (35) castor oil + 80% glucose injection D5W (pH7.4) control group, 5 groups in
  • test drug Gemcitabine (Gemcitabine) 120mg/kg group, test drug compound A 10mg/kg and 7.5% absolute ethanol + 7.5% polyoxyethylene (35) castor oil + 85% glucose injection D5W (pH7.4) Vehicle control group, a total of 3 groups, 5 mice in each group.
  • 7.5% absolute ethanol+7.5% polyoxyethylene (35) castor oil+85% glucose injection D5W (pH7.4) vehicle control group, test drug compound A 10mg/kg group are tail vein injection administration, each Dosing once a week for three consecutive weeks.
  • Sorafenib (Sorafenib) 20-30mg/kg group was intragastrically administered, during day0-day11, 30mg/kg dosage was administered once a day for 12 consecutive days, during day12-day20, due to the The body weight decreased significantly, and the dosage was adjusted from 30mg/kg to 20mg/kg, administered once a day for 9 consecutive days and observed for 33 days.
  • the curative effect is evaluated according to the relative tumor inhibition rate TGI (%), and the safety evaluation is carried out according to the animal body weight change and death.
  • mice in different groups were measured on different days, and the average value was obtained and drawn as a graph, as shown in FIG. 29 .
  • HepG2 is a model of cachexia
  • the model is characterized by spontaneous weight loss of tumor-bearing mice.
  • Compound A had a significant effect on the human liver cancer HepG2 model at doses of 10mg/kg (QWx2; 1week off; QWx2, i.v., Group 4) and 2.5mg/kg (QDx5; 2days off, 2weeks off; QDx5, i.p., Group 6).
  • the effect of inhibiting tumor growth was statistically significantly different from that of the control group. Under the above two test doses and administration methods of compound A, the tumor-bearing mice did not suffer severe weight loss or death.
  • AST-3424 1.25mg/kg administered once a week, continuously administered for two weeks, stopped for one week, and then continuously administered for two weeks
  • treatment group had certain tumor inhibition on the 28th day (Day 28) after the first administration
  • TGI tumor inhibition rate
  • No NADPH 10 ⁇ L of 20 mg/mL liver microsomes and 40 ⁇ L of ultrapure H2O were added to the culture medium. The final concentration of microsomes was 0.5 mg/mL.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Public Health (AREA)
  • Biochemistry (AREA)
  • Molecular Biology (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Epidemiology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Measuring Or Testing Involving Enzymes Or Micro-Organisms (AREA)
PCT/CN2021/129077 2021-11-05 2021-11-05 Akr1c3活化的dna烷化剂及其医药用途 Ceased WO2023077452A1 (zh)

Priority Applications (6)

Application Number Priority Date Filing Date Title
EP21962965.6A EP4428138A4 (en) 2021-11-05 2021-11-05 AKR1C3-ACTIVATED DNA ALKYLATING AGENT AND ITS MEDICAL USE
PCT/CN2021/129077 WO2023077452A1 (zh) 2021-11-05 2021-11-05 Akr1c3活化的dna烷化剂及其医药用途
JP2024526649A JP2024539385A (ja) 2021-11-05 2021-11-05 Ａｋｒ１ｃ３活性化ｄｎａアルキル化剤、およびその医学的応用
KR1020247018893A KR20240110013A (ko) 2021-11-05 2021-11-05 Akr1c3-활성화 dna 알킬화제 및 이의 의학적 적용
CN202180103860.6A CN118201940A (zh) 2021-11-05 2021-11-05 Akr1c3活化的dna烷化剂及其医药用途
TW111142123A TW202320804A (zh) 2021-11-05 2022-11-04 Akr1c3活化的dna烷化劑及其醫藥用途

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PCT/CN2021/129077 WO2023077452A1 (zh) 2021-11-05 2021-11-05 Akr1c3活化的dna烷化剂及其医药用途

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EP (1) EP4428138A4 (https=)
JP (1) JP2024539385A (https=)
KR (1) KR20240110013A (https=)
CN (1) CN118201940A (https=)
TW (1) TW202320804A (https=)
WO (1) WO2023077452A1 (https=)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP4206209A4 (en) * 2021-11-12 2024-07-03 Ascentawits Pharmaceuticals, Ltd. Deuterated compound, and preparation method therefor and use thereof
WO2024230831A1 (zh) 2023-05-11 2024-11-14 深圳艾欣达伟医药科技有限公司 一种注射液制剂、配伍药液及其制备方法
WO2025140580A1 (zh) * 2023-12-28 2025-07-03 深圳艾欣达伟医药科技有限公司 化合物晶型

Citations (6)

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Publication number Priority date Publication date Assignee Title
WO2016145092A1 (en) 2015-03-10 2016-09-15 Threshold Pharmaceuticals, Inc. Dna alkylating agents
CN108136214A (zh) * 2015-04-02 2018-06-08 深圳艾衡昊医药科技有限公司 硝基苄基衍生物抗癌试剂
CN108290911A (zh) * 2015-11-16 2018-07-17 深圳艾衡昊医药科技有限公司 (r)-及(s)-1-(3-(3-n,n-二甲基胺基羰基)苯氧基-4-硝苯基)-1-乙基-n,n’-双(伸乙基)胺基磷酸酯、组合物及其使用及制备方法
WO2020228685A1 (zh) * 2019-05-13 2020-11-19 深圳艾欣达伟医药科技有限公司 含氟化合物及抗癌医药用途
WO2021083310A1 (zh) * 2019-11-01 2021-05-06 深圳艾欣达伟医药科技有限公司 作为非pgp底物的抗癌化合物
WO2021120717A1 (zh) * 2019-12-20 2021-06-24 深圳艾欣达伟医药科技有限公司 抗癌化合物及其医药用途

Patent Citations (7)

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WO2016145092A1 (en) 2015-03-10 2016-09-15 Threshold Pharmaceuticals, Inc. Dna alkylating agents
CN107530556A (zh) 2015-03-10 2018-01-02 深圳艾衡昊医药科技有限公司 Dna烷化剂
CN108136214A (zh) * 2015-04-02 2018-06-08 深圳艾衡昊医药科技有限公司 硝基苄基衍生物抗癌试剂
CN108290911A (zh) * 2015-11-16 2018-07-17 深圳艾衡昊医药科技有限公司 (r)-及(s)-1-(3-(3-n,n-二甲基胺基羰基)苯氧基-4-硝苯基)-1-乙基-n,n’-双(伸乙基)胺基磷酸酯、组合物及其使用及制备方法
WO2020228685A1 (zh) * 2019-05-13 2020-11-19 深圳艾欣达伟医药科技有限公司 含氟化合物及抗癌医药用途
WO2021083310A1 (zh) * 2019-11-01 2021-05-06 深圳艾欣达伟医药科技有限公司 作为非pgp底物的抗癌化合物
WO2021120717A1 (zh) * 2019-12-20 2021-06-24 深圳艾欣达伟医药科技有限公司 抗癌化合物及其医药用途

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Title
FLANAGAN ET AL., BIOORGANIC AND MEDICINAL CHEMISTRY, 2014, pages 962 - 977
JESSICA D. SUNQIAN LIUDHARMENDRA AHLUWALIADAMIEN J. FERRAROYAN WANGDON JUNGMARK D. MATTEUCCICHARLES P. HART: "Comparison of hypoxia-activated prodrug evofosfamide (TH-302) and ifosfamide in preclinical non-small cell lung cancer models [J].", CANCER BIOLOGY & THERAPY, vol. 17, no. 4, 2016, pages 371 - 380, XP055682718, DOI: 10.1080/15384047.2016.1139268
See also references of EP4428138A4

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP4206209A4 (en) * 2021-11-12 2024-07-03 Ascentawits Pharmaceuticals, Ltd. Deuterated compound, and preparation method therefor and use thereof
JP2025500718A (ja) * 2021-11-12 2025-01-15 アセンタウィッツ ファーマシューティカルズ リミテッド 重水素化化合物、ならびにその製造方法および使用
WO2024230831A1 (zh) 2023-05-11 2024-11-14 深圳艾欣达伟医药科技有限公司 一种注射液制剂、配伍药液及其制备方法
WO2025140580A1 (zh) * 2023-12-28 2025-07-03 深圳艾欣达伟医药科技有限公司 化合物晶型

Also Published As

Publication number Publication date
TW202320804A (zh) 2023-06-01
CN118201940A (zh) 2024-06-14
EP4428138A1 (en) 2024-09-11
EP4428138A4 (en) 2025-08-27
JP2024539385A (ja) 2024-10-28
KR20240110013A (ko) 2024-07-12

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