WO2014190533A1 - Ligand du platine et complexe associé - Google Patents

Ligand du platine et complexe associé Download PDF

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Publication number
WO2014190533A1
WO2014190533A1 PCT/CN2013/076528 CN2013076528W WO2014190533A1 WO 2014190533 A1 WO2014190533 A1 WO 2014190533A1 CN 2013076528 W CN2013076528 W CN 2013076528W WO 2014190533 A1 WO2014190533 A1 WO 2014190533A1
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WO
WIPO (PCT)
Prior art keywords
compound
targeting
reaction
group
independently
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Application number
PCT/CN2013/076528
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English (en)
Chinese (zh)
Inventor
臧林泉
郭言明
陈亮
Original Assignee
广东药学院
广州龙沙研究开发中心
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
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Application filed by 广东药学院, 广州龙沙研究开发中心 filed Critical 广东药学院
Priority to PCT/CN2013/076528 priority Critical patent/WO2014190533A1/fr
Publication of WO2014190533A1 publication Critical patent/WO2014190533A1/fr

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/24—Heavy metals; Compounds thereof
    • A61K33/243—Platinum; Compounds thereof
    • 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
    • C07F15/00—Compounds containing elements of Groups 8, 9, 10 or 18 of the Periodic Table
    • C07F15/0006—Compounds containing elements of Groups 8, 9, 10 or 18 of the Periodic Table compounds of the platinum group
    • C07F15/0086—Platinum compounds
    • C07F15/0093—Platinum compounds without a metal-carbon linkage
    • 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
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/02—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link
    • C07K5/0215—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link containing natural amino acids, forming a peptide bond via their side chain functional group, e.g. epsilon-Lys, gamma-Glu

Definitions

  • the present invention generally relates to a conjugate, and more particularly to a targeting conjugate.
  • Tumors especially malignant tumors, directly affect human health and life, and bring enormous economic burden to society and patients.
  • the incidence of malignant tumors in China is generally on the rise, and the incidence rate is increasing at an average annual rate of 3% to 5%.
  • China's cancer spectrum presents new characteristics. It has both the developed countries and the dual characteristics of developing countries, that is, the double burden of malignant tumors.
  • the top five incidences of malignant tumors in China were lung cancer, stomach cancer, and colorectal. Cancer, liver cancer, breast cancer [ 1–3] .
  • the incidence of lung cancer increased from 1.63% to 3% in 1988-2005.
  • the number of new cases of lung cancer increased by 120,000 between 2000 and 2005 [4] , and its morbidity and mortality increased year by year.
  • the prognosis of lung cancer is closely related to clinical stage.
  • the overall 5-year survival rate of patients with stage I-IV is only about 15%.
  • the main cause of lung cancer mortality is late detection, most patients are detected in the late stage of lung cancer or even after distant metastasis [5] .
  • cytotoxic drugs such as cisplatin, carboplatin, oxaliplatin and other synthetic cisplatin compounds, such as vinblastine and paclitaxel.
  • cytotoxic drugs also have serious side effects while killing cancer cells. This side effect includes, but is not limited to, severe adverse effects such as myelosuppression, gastrointestinal reactions, and neurotoxicity, which limits the clinical utility of such drugs.
  • Cisplatin was first discovered by American physiologist Rosenberg B. It is a heavy metal complex with divalent platinum combined with two chlorine atoms and two ammonia molecules. It is similar to a bifunctional alkylating agent and acts on hypoxic cells. The human body diffuses through the charged cell membrane, first dissociates the contained chlorine, and then forms a cross-link between the 6 and 7 positions of the guanine in the DNA molecule, or forms two points within the DNA single strand with adenine and cytosine. The cross-linking may also form a cross-link between the double strands, thereby disrupting the structure and function of the DNA. The inhibition of RNA and protein synthesis is weak. It is a non-specific drug of the cycle.
  • cisplatin Since its discovery, cisplatin has become one of the most effective drugs for the treatment of lung cancer. It has a wide anti-tumor spectrum, strong effect, synergy with a variety of anti-tumor drugs, and no cross-resistance. Although other platinum compounds such as carboplatin and oxaliplatin have a certain decrease in adverse reactions, the antitumor effect is still far from that of cisplatin. Therefore, cisplatin is still the most commonly used drug in the current combination chemotherapy. one.
  • tumor-targeting polypeptides In recent years, some key enzymes of cell signal transduction pathways involved in the differentiation and proliferation of tumor cells have been used as drug screening targets, and new, highly effective, low-toxicity and specific anticancer drugs that selectively act on specific targets have been discovered. Molecular targeting drugs and antibody-targeted drugs have become an important direction for the development of anti-tumor drugs.
  • the discovery of tumor-targeting polypeptides, tumor-targeting carrier polypeptides, polypeptides that inhibit tumor cell growth, and related polypeptide hormones or growth factors that inhibit lung cancer growth have laid the foundation for the treatment of targeted drugs.
  • these peptides or receptors can be used as targeting carriers and play a pivotal role in tumor-targeted therapy, which can increase the solubility of drugs and change the distribution of anti-tumor drugs in various tissues and organs in the body [11] . It is also possible to target the chemotherapeutic drug to the tumor tissue, thereby improving the therapeutic effect of the tumor and reducing the side effects of the chemotherapy drug, thereby realizing targeted therapy of the tumor. These drugs are expected to achieve high affinity and high specificity of tumor tissues, and are expected to significantly reduce the side effects of chemotherapy drugs.
  • Another object of the invention is to provide a targeted platinum ligand.
  • Z is a saturated carbon chain of C2 ⁇ 4
  • X and Y are independently NH 2 , NR' 2 , SR', C00H groups, respectively attached to different carbons of Z, R' is C1-4 alkyl.
  • X and Y are independently NH 2 , SR′, and in particular, X and Y are independently NH 2 .
  • Z is a saturated carbon chain of C2 ⁇ 4
  • X and Y are independently NH 2 , NR' 2 , SR ', C00H groups, respectively attached to different carbons of Z
  • R is a target To the recognition sequence
  • R' is a C1-4 alkyl group.
  • R is a targeted recognition polypeptide sequence.
  • X and Y are independently NH 2 , SR′, and in particular, X and Y are independently NH 2 .
  • a targeting agent is prepared by complexing a target polypeptide modified by the above terminal with a functional compound.
  • the functional compound is selected from an antitumor drug, a detection reagent.
  • the antitumor drug is selected from the group consisting of a platinum antitumor drug and an active antitumor polypeptide, wherein
  • the general formula of the targeted platinum-containing antitumor drug obtained by the combination is as shown in formula III:
  • Z is a saturated carbon chain of C2 ⁇ 4
  • X and Y are independently NH 2 , NR' 2 , SR', COOH groups, respectively attached to different carbons of Z
  • R' is C1-4 alkyl
  • R is a targeting recognition sequence
  • X and Y are independently NH 2 , SR′, in particular, X and Y are independently NH 2
  • R 2 is an independent group, respectively, or R 2 Covalently connected into a ring.
  • the antitumor drug is selected from the group consisting of cisplatin, carboplatin, and oxaliplatin; and Ri, R 2 is independently C1 or H 2 0.
  • the platinum ligand of the present invention can be well coupled to a plurality of reagents, and can be linked to a targeting sequence thereon, and can serve as a ligand for a plurality of reagents.
  • the ligand itself has a simple structure, a low synthesis cost, and is easy to mass-produce.
  • the targeting ligand of the invention has good targeting property, and is easily localized in the body after coordinating with the platinum reagent, thereby achieving better effects.
  • the targeting agent of the invention has good targeting and can be well applied to targeted therapy and diagnosis of tumors.
  • Figure 1 is a nuclear magnetic resonance diagram of a compound intermediate of the present invention
  • Figure 4 is a nuclear magnetic resonance diagram of another compound intermediate of the present invention.
  • Figures 5 to 10 are mass spectra of different compound intermediates of the present invention.
  • Orn ornithine
  • 5-AVA 5-aminovaleric acid
  • TFA trifluoroacetic acid
  • HOBt 1-hydroxybenzotriazole
  • DMF dimethylformamide
  • Ala 3-aminopropionic acid
  • Dab 2,4-diaminobutyric acid
  • RGD Arg-Gly-Asp
  • RGN Arg-Gly-Asn
  • HOSu N-hydroxysuccinimide
  • the NMR data for Compound 4 are: 1H NMR (400 Hz, CDCl 3 ) ⁇ : 4.75 (m, 1H), 3.19-3.20 (m, 1H), 2.86 (s, 4H), 1.85-2.00 (m, 2H), 1.68 (m, 2H), 1.47 (s, 18H), 1.22-1.23 (m, 2H), and its magnetic resonance spectrum is shown in Fig. 1.
  • the reaction mixture was concentrated by rotary evaporation to about 50 ml of the reaction mixture, and poured into 500 ml of ice-cold isopropyl ether. A white precipitate was precipitated, and after standing for a while, it was centrifuged and dried. Obtaining a white product;
  • the reaction mixture was rotary evaporated to about 50 ml of the reaction mixture, poured into 500 ml of ice-cold isopropyl ether, and a white precipitate was precipitated. After standing for a while, it was centrifuged and dried. Obtaining a white product;
  • Boc-Met-OH and HOSu were dissolved in EA, and the DCC/EA mixed solution was slowly added dropwise. After the completion of the dropwise addition, the ice bath was removed, and the reaction was continued for 2 hours; the reaction was completely filtered, and the filtrate was evaporated to a white solid; toluene was added and stirred in a water bath at 60 ° C until the solid was completely dissolved; It was filtered and washed with a small amount of toluene and diethyl ether and dried in a dry room for 2h to give a white solid.
  • TFA.H-Met-5-AVA-OH is dissolved in water, the pH is adjusted to 8 ⁇ 9 with Na 2 CO 3 , K 2 PtC solution is added, pH is continuously monitored during the reaction, pH 8 ⁇ 9 is maintained, and the reaction is overnight; It was suction filtered and dried to give a yellow solid.
  • the above actual examples are merely illustrative and are not to be considered as limiting the invention.
  • the above-mentioned targeted recognition sequence may be other tripeptides well known to those skilled in the art, such as RGE, RGQ, HGD, HGE, HGN, HGQ KGD, KGE, KGN, KGQ DGR, in addition to the above RGD, RGN. , DGK, NGR, etc., may also be other polypeptides that have been reported to have tumor targeting properties.
  • mice Healthy Balb-c nude mice, male and female, were inoculated for 3-4 weeks after inoculation of nude mice with a tumor diameter of about 0.3-0.5 cm.
  • Drugs Peptide-cisplatin-conjugated complex RGD-5-AVA-Om-PtCl 2 (batch number: zp-2-pl9), cisplatin for injection (Shandong Qilu, Lot No. 203008CF).
  • the peptide-cisplatin-conjugated complex was dissolved in physiological saline for injection, mixed, and sterilized by filtration through a 0.22 ⁇ filter in a clean bench.
  • the cisplatin for injection was dissolved in physiological saline solution for injection in a clean bench, and mixed for use.
  • Grouping Experimental setting negative control group, positive control group and RGD-cisplatin complex experimental group (high, medium and low dose groups, set at 6:3:1). Each group included 6 nude mice that had been successfully modeled.
  • the dose of RGD-cisplatin complex is: high dose group 90 ⁇ .13 ⁇ 4- medium dose group 30 ⁇ .13 ⁇ 4- low dose group 10 ⁇ .13 ⁇ 4-cisplatin group 10 ⁇ .13 ⁇ 4- ⁇ administered by tail vein injection, The amount of administration was determined according to the body weight, once a day, for 5 days.
  • mice Healthy Balb-c nude mice, male and female, about 3 weeks old, weighing 18-22g.
  • Human lung squamous cell carcinoma cell line NCI-H1299 was cultured in large amounts, digested with 0.25% trypsin containing 0.01% EDTA, centrifuged at 1000 rpm for 1.5 min, de-cleared, resuspended in serum-free DMEM medium, and cell count adjusted for cell density.
  • Nude mice were inoculated with 2 ⁇ 10 6 cells/nose in front of the right axilla, and the tumor formation rate was about 95%. After 3-4 weeks of inoculation, nude mice with a tumor diameter of about 0.3-0.5 cm were used for the nude mice. experiment.
  • the polypeptide-cisplatin-conjugated complex was dissolved in physiological saline for injection, mixed, and sterilized by filtration through a 0.22 ⁇ filter in a clean bench.
  • the cisplatin for injection was dissolved in physiological saline solution for injection in a clean bench, and mixed for use. Weigh before dosing, press
  • the mode dose dose low dose cisplatin group high type 15 body weight determines the dose.
  • the drug was administered by tail vein injection once a day for 5 days, and after the end of the administration, the observation was continued for 9 days, and on the 15th day, the animals were sacrificed, and organs and tumors were taken.
  • mice Healthy Kunming mice, male and female, about 4 weeks old, weighing 18-22g, purchased from Guangdong Medical Laboratory Animal Center.
  • zp-2-pl9 is dissolved in physiological saline for injection, mixed, and passed through a 0.22 ⁇ filter in a clean bench. Filter the bacteria.
  • the cisplatin for injection was dissolved in physiological saline solution for injection in a clean bench, and mixed for use.
  • Grouping A small number of animals were used to gradually explore the upper and lower limits, even the minimum dose (Dm) for all animals and the maximum dose (Dn) for an animal. The number of experimental groups and the dose were determined based on the results of the preliminary experiments, and the animals were divided into 7 dose groups.
  • Methods Grouped by random method, sorted by weight from low to high, grouped according to random number table method.
  • Quantity Meets statistical requirements, usually consisting of at least 10 animals per dose group.
  • Dosage A formal test is performed on a pre-test basis.
  • the Zp-2 dose was set to 152.82 mg.kg - 230 mg.kg 1 , 305.64 mg.kg” 1 382.05 mg.kg” 1 420.26 mg.kg” 1 458.46 mg.kg” 1 611.28 mg.kg - 1 7 groups .
  • the cisplatin dose was set to 5.00 mg.kg” 1 8.75 mg.kg” 1 13.10 mg.kg” 1 17.50 mg.kg” 1 26.25 mg.kg” 1 35.00 mg.kg" 1 52.50 mg.kg - 1 seven groups.
  • Method of administration Fasting for 6-12 hours before administration and fasting for 3-4 hours after administration.
  • Test indicators Observe the changes in animal weight, diet, appearance, behavior, secretions, excretion and poisoning symptoms, record the death of the animal, the symptoms of poisoning and the start time, severity, duration of the poisoning reaction, etc. Animal body weight (D0), day 3 (D3), and day 5 (D5) were weighed. The results are shown in Table 5 and Table 6.
  • Cisplatin y (Probit) :-2.102+6.0344Log(D) 50.08

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Medicinal Chemistry (AREA)
  • Veterinary Medicine (AREA)
  • Organic Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Inorganic Chemistry (AREA)
  • Epidemiology (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Peptides Or Proteins (AREA)

Abstract

La présente invention concerne un ligand ayant la structure représentée par la formule (I) et un complexe constitué de platine et dudit ligand. Ledit ligand est de structure simple, est capable de s'associer à divers réactifs, est caractérisé par un faible coût de synthèse et assure un bon ciblage, si bien qu'il peut être utilisé dans le cadre d'une thérapie ciblée et du diagnostic des tumeurs.
PCT/CN2013/076528 2013-05-31 2013-05-31 Ligand du platine et complexe associé WO2014190533A1 (fr)

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PCT/CN2013/076528 WO2014190533A1 (fr) 2013-05-31 2013-05-31 Ligand du platine et complexe associé

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Application Number Priority Date Filing Date Title
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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN115068501A (zh) * 2022-05-25 2022-09-20 中国科学院深圳先进技术研究院 一类抗肿瘤四价铂配合物前药及其制备方法和应用

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5110797A (en) * 1985-10-14 1992-05-05 Nippon Zoki Pharmaceutical Co., Ltd. Peptide compound and a pharmaceutically acceptable salt thereof
CN102311482A (zh) * 2010-05-20 2012-01-11 中国医学科学院药物研究所 阿罗肽、及制备方法和其药物组合物与用途
CN102389102A (zh) * 2011-11-01 2012-03-28 南京农业大学 一种低钠复合盐
CN103288673A (zh) * 2013-05-28 2013-09-11 广东药学院 一种铂配体及其配合物

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5110797A (en) * 1985-10-14 1992-05-05 Nippon Zoki Pharmaceutical Co., Ltd. Peptide compound and a pharmaceutically acceptable salt thereof
CN102311482A (zh) * 2010-05-20 2012-01-11 中国医学科学院药物研究所 阿罗肽、及制备方法和其药物组合物与用途
CN102389102A (zh) * 2011-11-01 2012-03-28 南京农业大学 一种低钠复合盐
CN103288673A (zh) * 2013-05-28 2013-09-11 广东药学院 一种铂配体及其配合物

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN115068501A (zh) * 2022-05-25 2022-09-20 中国科学院深圳先进技术研究院 一类抗肿瘤四价铂配合物前药及其制备方法和应用
CN115068501B (zh) * 2022-05-25 2023-08-11 中国科学院深圳先进技术研究院 一类抗肿瘤四价铂配合物前药及其制备方法和应用

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