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WO2015049883A1 - Agent anticancéreux sans effets indésirables - Google Patents

Agent anticancéreux sans effets indésirables Download PDF

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Publication number
WO2015049883A1
WO2015049883A1 PCT/JP2014/052877 JP2014052877W WO2015049883A1 WO 2015049883 A1 WO2015049883 A1 WO 2015049883A1 JP 2014052877 W JP2014052877 W JP 2014052877W WO 2015049883 A1 WO2015049883 A1 WO 2015049883A1
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Prior art keywords
cancer
irinotecan
formula
compound
body weight
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English (en)
Japanese (ja)
Inventor
ヒィ ジン チェン
正和 福島
清 江島
ギャリー アシュレー
ダニエル ブイ サンティ
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Delta Fly Pharma Inc
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Delta Fly Pharma Inc
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Priority to HK16102091.6A priority Critical patent/HK1214145B/xx
Priority to CN201480006400.1A priority patent/CN104981245B/zh
Priority to KR1020157021404A priority patent/KR101678881B1/ko
Priority to SG11201506026PA priority patent/SG11201506026PA/en
Publication of WO2015049883A1 publication Critical patent/WO2015049883A1/fr
Anticipated expiration legal-status Critical
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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
    • A61K31/435—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
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4738—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4745—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems condensed with ring systems having nitrogen as a ring hetero atom, e.g. phenantrolines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/54—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound
    • A61K47/55—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound the modifying agent being also a pharmacologically or therapeutically active agent, i.e. the entire conjugate being a codrug, i.e. a dimer, oligomer or polymer of pharmacologically or therapeutically active compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the present invention relates to the usage and dosage of an anticancer agent of the type in which SN-38 and 4-arm peg (PEG), which are anticancer active substances, are covalently chemically bonded via a linker for long-term sustained release of SN-38.
  • the present invention relates to a characteristic pharmaceutical composition for cancer treatment and a therapeutic method.
  • Non-patent Document 1 Research into increasing the stability and increasing the efficacy of PEG-modified low-molecular-weight drugs is progressing (Non-patent Document 1).
  • PEGylated drugs for anticancer drugs such as camptothecin, irinotecan, doxorubicin, SN-38, paclitaxel, docetaxil, cisplatin, gemcitabine have been developed.
  • SN-38 (official name: 7-ethyl-10-hydroxycamptothecin) is an active ingredient of Irinotecan (also called “CPT-11”). In that sense, irinotecan is a prodrug of SN-38.
  • Irinotecan is an antineoplastic agent synthesized using camptothecin found from the dogwood pheasant as a lead compound, and is activated in vivo. It is converted to the active metabolite SN-38 by carboxylesterase in tissues such as the liver. Antitumor activity by inhibiting type I DNA topoisomerase activity, widely used in cancer chemotherapy such as lung cancer, cervical cancer, ovarian cancer, gastric cancer, colorectal cancer (colon cancer), breast cancer, malignant lymphoma . It is said that fatal side effects occur in patients with symptoms such as suppression of bone marrow function, infection, diarrhea, and intestinal obstruction (Patent Document 1, Non-Patent Document 2).
  • Patent Document 2 describes a polymeric prodrug consisting of 4-arm PEGylated irinotecan, and SN-38 similar to this is described in Patent Documents 3 and 4.
  • an ester bond (-O-CO-) in which the OH group at the 20-position of irinotecan or SN-38 and 4-arm PEG are easily hydrolyzed by esterases in the blood.
  • Patent Document 5 describes a conjugate of a macromolecular carrier and a drug, including a linker that releases the drug or prodrug via ⁇ -elimination with controlled rate, specifically, 4-arm PEGylated SN-38 is exemplified, and the binding site between the linker and SN-38 is the phenolic hydroxyl group of SN-38, and a bond different from the ester bond is used.
  • Multi-arm and water-soluble polymer drug conjugates such as the prodrugs as exemplified above, especially polymer-based prodrugs are also described in US Pat.
  • the linking part between the active substances is preferably one that is easily hydrolyzed in vivo, and is usually a carboxylic acid ester, carbonate ester, phosphate ester, acid anhydride, acetal, ketal, acyloxyalkyl ether, imine, orthoester, oligo Although it is a nucleotide or the like, it is described that an ester of carboxylic acid or carbonic acid is preferable.
  • Irinotecan an anticancer drug, has anticancer activity against a wide range of cancers, but is known to have side effects such as gastrointestinal tract disorders with severe diarrhea and marked leukocyte and neutropenia (bone marrow suppression). Yes.
  • the object of the present invention is that it is not necessary to take a drug holiday to wait for the recovery of the physical strength of the cancer patient because of serious side effects, and thus it can be administered repeatedly, and as a result, the physical strength of the patient side is significantly consumed.
  • SN-38 is linked to 4-arm PEG via a linker (with the ability to control the sustained release of SN-38 over a long period of time). It is to provide a pharmaceutical composition for cancer treatment and a method of treatment characterized by the usage and dosage of an anticancer agent of the type.
  • the present invention has the following characteristics.
  • a pharmaceutical composition for cancer treatment comprising as an active ingredient a compound represented by the formula: once a week for a subject having cancer in a single dose of about 0.01 ⁇ mol / kg body weight to about 11 ⁇ mol / kg body weight It can be used every other week for parenteral administration and dosage for at least 2 weeks, and irinotecan-like side effects at doses lower than 1/10 (molar ratio) of irinotecan
  • the composition is characterized in that it has a cancer growth inhibitory activity comparable to or higher than that of irinotecan.
  • R 1 , R 2 , X 2 and n are as defined above, and X 1 is (CH 2 ) 1-5 -CONH- (CH 2 ) 1 -20 or (CH 2) 1-5 -NHCO- (CH 2) 1-20, composition according to (1).
  • X 1 and X 2 are as defined above, R 1 is substituted methyl, R 2 is 4-substituted phenyl, and n is from 200 to The composition according to (2) or (3), which is an integer of 800.
  • composition according to any one of (1) to (5) which is selected from the group consisting of:
  • a composition according to any one of (1) to (5) is administered to a subject having cancer in a week with a single dose of a compound of about 0.01 ⁇ mol / kg body weight to about 11 ⁇ mol / kg body weight.
  • a parenteral administration at a frequency of once every other week for at least 2 weeks, and severe diarrhea, leukopenia and / or eosinophils at doses of 1/10 (molar ratio) or less of irinotecan A method for treating cancer, which has no irinotecan-like side effects including reduction and imparts a cancer growth inhibitory activity equivalent to or higher than that of irinotecan.
  • parenteral administration is intravenous administration.
  • the pharmaceutical composition and treatment method of the present invention can be repeatedly administered because it is not necessary to take a drug holiday to restore the physical strength of the cancer patient due to serious side effects, and impairs the physical strength of the cancer patient.
  • SN-38 can be covalently bound to 4-arm PEG via a linker (with the ability to control the sustained release of SN-38 over time) It is characterized by the administration conditions of certain types of anticancer agents.
  • subjects, including humans can be administered parenterally at a frequency of once a week every other week for at least 2 weeks, as shown by irinotecan (ie, irinotecan). Since there are no side effects such as severe diarrhea and repeated administration every two weeks is possible, the efficacy is maintained continuously, and as a result, a strong anticancer effect can be expected.
  • This figure shows the weight change of rats in the efficacy test. Tested with DFP-13318 (dose 50 mg / kg, 100 mg / kg, 200 mg / kg) and Irinotecan (dose 70 mg / kg (first dose) / 50 mg / kg (second dose)) as test substances did. Vehicle was used as a control. This figure shows the change in the average body weight of the group of rats during the efficacy test. Tested with DFP-13318 (dose 50 mg / kg, 100 mg / kg, 200 mg / kg) and Irinotecan (dose 70 mg / kg (first dose) / 50 mg / kg (second dose)) as test substances did. Vehicle was used as a control.
  • the compounds that are active ingredients in the pharmaceutical compositions and therapeutic methods of the present invention are represented by the following formula I: C-[-CH 2 -O-(-CH 2 CH 2 -O-) n -X 1 -CHR 1 -O-CO-NR 2 -CH 2 -X 2 ] 4 (I) (Wherein X 1 —CHR 1 —O—CO—NR 2 is a linker, X 1 is a spacer, R 1 is an optionally substituted alkyl having 1 to 4 carbon atoms, R 2 is a phenyl group or a substituted phenyl group, and X 2 is represented by the following formula II:
  • n is an integer from 200 to 1,000.
  • This compound has a group consisting of CHR 1 —O—CO—NR 2 —CH 2 between the group X 1 and the group X 2 .
  • a group similar to CHR 1 —O—CO—NR 2 —CH 2 is described in JP 2013-528593 (or WO 2011/140393), and such a group is probably present in the tumor.
  • -CHR 1 group is separated into a polymer part and an active substance by ⁇ -elimination by cleavage of a hydrogen atom (H) on a carbon atom of the group adjacent to the group and cleavage in an acidic environment, and the active substance is selectively selected by tumor Presumed to work.
  • the R 1 group preferably contains an electron withdrawing group as a substituent.
  • the electron withdrawing group include a cyano group, a methanesulfonyl group, a trifluoromethyl group, a nitro group, an acetoxy group, a C1-C4 alkoxycarbonyl group (for example, a methoxycarbonyl group or an ethoxycarbonyl group) and the like.
  • X 2 is the SN-38 moiety of the above formula II, and an ether bond between the phenolic hydroxyl group of SN-38 and CH 2 of X 1 -CHR 1 -O-CO-NR 2 -CH 2 ( -O-). In this respect, it differs from an ester bond which is said to be easily cleaved in vivo.
  • R 2 is a substituted phenyl group
  • the substituent may be, for example, halogen (fluoro, chloro, bromo or iodo), C1-C4 alkoxycarbonyl group (eg methoxycarbonyl or ethoxycarbonyl), N, N-diC1-C4 Alkyl carboxamides (for example, N, N-diethyl carboxamide), morpholinocarbonyl, morpholinosulfonyl, etc., and the number of substituents and substitution positions are not limited, but the number of substituents is 1 to 3, preferably 1, and the substitution position is o-, p- or m-position, preferably p-position (also referred to as “4-position”).
  • X 1 is a spacer for linking the PEG moiety and other moieties as in Formula I, for example, a linker comprising one or more methylene groups and a linking group such as CONH or NHCO, for example (CH 2 ) 1-5 -CONH- (CH 2 ) 1-20 , (CH 2 ) 1-5 -NHCO- (CH 2 ) 1-20 , CO- (CH 2 ) 1-5 -CONH- (CH 2 ) 1 -20 etc.
  • a linker comprising one or more methylene groups and a linking group such as CONH or NHCO, for example (CH 2 ) 1-5 -CONH- (CH 2 ) 1-20 , (CH 2 ) 1-5 -NHCO- (CH 2 ) 1-20 , CO- (CH 2 ) 1-5 -CONH- (CH 2 ) 1 -20 etc.
  • the compound of formula I includes derivatives having various functional groups at the end of 4-arm PEG, and (CH 1 moiety having a terminal functional group) —CHR 1 —O—CO—NR 2 —CH 2 —X 2 It can be produced by reacting.
  • Derivatives having various functional groups attached to the ends of 4-arm PEG can be obtained, for example, by binding PEG derivatives having various weight average molecular weights to a pentaerythritol nucleus via a spacer as necessary.
  • the 4-arm PEG derivative is available from, for example, JenKem Technology.
  • the n of the PEG polymer portion of the compound of formula I is, but is not limited to, about 65 or greater, for example about 100 to about 2,300, preferably about 200 to about 1,000, and the weight average molecular weight of the polymer is about 3 kDa To about 100 kDa, such as about 4 kDa to about 80 kDa, about 5 kDa to about 60 kDa, about 8 kDa to about 40 kDa, about 10 kDa to about 20 kDa, and the like. Considering the influence of the viscosity and toxicity of the 4-arm PEG derivative, about 10 kDa to about 20 kDa is preferable.
  • the said derivatives CH 2 -O - (- CH 2 CH 2 -O-) is connected to n-, -CH 2 -COO-NHS, -CH 2 CH 2 CH 2 CH 2 CH 2 -COO-NHS, -CH 2 CH 2 -CHO, -CH 2 CH 2 CH 2 NH 2 , -CH 2 CH 2 CH (OC 2 H 5 ) 2 , -CH 2 CH 2 CH 2
  • NHS represents N-hydroxysuccinimide.
  • examples of the terminal functional group of the X 1 moiety reactive with the terminal functional group of the PEG moiety are reactive with the NHS group, for example, NH 2 , OH or SH group, NH 2 group reactive with the CHO group, NH 2 group COOH group reacting with SH, SH reacting with SH group, maleimide or COOH group, NH 2 group reacting with (OC 2 H 5 ) 2 group, SH group reacting with maleimide group, etc., but is not limited thereto.
  • X 1 , X 2 and n are as defined above, R 1 is methyl, ethyl, substituted methyl or substituted ethyl, and R 2 is substituted phenyl.
  • R 1 is methyl, ethyl, substituted methyl or substituted ethyl
  • R 2 is substituted phenyl.
  • the substituents are as illustrated above.
  • n is as defined above.
  • the blood stability is determined from the area under the blood concentration-time curve (AUC) described in the Examples below, and its metabolites SN-38 and SN- About 50,000 times higher than 38G (which is a glucuronide conjugate of SN-38), once a week with a single dose of a compound of about 0.01 ⁇ mol / kg body weight to about 11 ⁇ mol / kg body weight Even when administered parenterally, SN-38, an anti-cancer active ingredient, is sustainedly released over a period of as long as a week, so that it exhibits the efficacy of the drug without serious irinotecan-like side effects Yes.
  • AUC blood concentration-time curve
  • Irinotecan-like side effects in the specification refer to side effects including symptoms such as bone marrow suppression such as leucopenia and eosinophilia, and diarrhea.
  • the above-mentioned compound which is an active ingredient of the present invention, is also free from serious side effects such as bone marrow suppression such as leukopenia and eosinophilia and diarrhea under the above administration conditions.
  • it can be administered parenterally to the subject repeatedly without taking a drug holiday for at least 2 weeks, preferably at least 4 weeks, at least 6 weeks.
  • the severe diarrhea symptoms of SN-38 are considered to be that SN-38G excreted from bile becomes SN-38 in the intestine, and this active substance damages the intestinal mucosa and induces diarrhea (K. Takasuna et al., “Cancer” Chemother. “Pharmacol.” 42: “280-286,” 1998).
  • the compound of formula I under the administration conditions of the present invention has a small amount of SN-38G produced in vivo, for example, 1/100 or less of irinotecan (see Table 10 below). For this reason, it is grounds that there are no side effects of severe diarrhea.
  • the compound of the present invention also imparts cancer growth inhibitory activity comparable to or higher than that of irinotecan (also referred to as CPT-11) at a low dose (refer to Table 6 below) of 1/10 (molar ratio) or less of irinotecan. (See Figure 3).
  • the compound of formula I above has been confirmed to have anticancer activity by an intravenous administration test in cancer-bearing rats (FIG. 3), so that the residence time in the blood is extremely long, and as a result, it contacts the tumor site. Probability is high, and since it is a high molecular weight substance, it is introduced into tumor cells by endocytosis, and the active substance SN-38 is released in the tumor cells. It is thought that it demonstrates. Tumor cells are more likely to take up high molecular weight compounds such as Formula I of the present invention because they have the property of being easier to take up high molecular weight substances than normal cells.
  • the present invention also provides a pharmaceutical composition for treating cancer comprising the above compound as an active ingredient.
  • the composition may be administered to a subject with cancer at a frequency of about 0.01 ⁇ mol / kg body weight to about 11 ⁇ mol / kg body weight of a compound at a frequency of once a week for at least 2 weeks every other week. It can be used in the dosage and dosage administered orally, and there is no irinotecan-like side effects at doses of 1/10 (molar ratio) or less of irinotecan, and it is the same or higher than that of irinotecan. It is possible to impart activity.
  • the dose of the compound per dose varies depending on the subject's sex, age, weight, symptoms, severity, etc., and is suitably in the range of about 0.01 ⁇ mol / kg body weight to about 11 ⁇ mol / kg body weight, For example, about 1 ⁇ mol / kg body weight to about 11 ⁇ mol / kg body weight, about 3.5 ⁇ mol / kg body weight to about 7 ⁇ mol / kg body weight, about 4 ⁇ mol / kg body weight to about 6 ⁇ mol / kg body weight, about 0.1 ⁇ mol / kg body weight to about 1.8 ⁇ mol / kg body weight, about 0.4 ⁇ mol / kg body weight to about 1 ⁇ mol / kg body weight.
  • an effective dose was found in an experiment using rats, but when the effective dose (mg / kg) of a rat was converted into a dose (mg / kg) in a human, the effective dose of the rat (mg / kg) kg) is known to be about 1/100 to about 1/6 (or about 1/10).
  • a suitable dose is within the range of about 0.5 mg / kg body weight to about 450 mg / kg body weight, for example, About 50 mg / kg body weight to about 450 mg / kg body weight, about 100 mg / kg body weight to about 300 mg / kg body weight, about 150 mg / kg body weight to about 300 mg / kg body weight, about 170 mg / kg body weight to about 250 mg / kg body weight, about 0.5 mg / kg body weight to about 75 mg / kg body weight, about 17 mg / kg body weight to about 42 mg / kg body weight.
  • the compound of formula I of the present invention contains 4 molecules of active ingredient SN-38 (MW392) per molecule.
  • Example 2 in animal experiments with rats, after intravenous administration of DFP-13318 at a dose of 225 mg / kg, the mean Tmax and Cmax values were 2 hours and 2 respectively for DFP-13318, respectively. It was 3.05 mg / mL, 1 hour and 97.6 ng / mL for SN-38, respectively, and 1 hour and 12.7 ng / mL for SN-38G, respectively. DFP-13318 also had an average plasma T 1/2 value of 36.8 hours. The average values of clearance and MRT last of DFP-13318 were 2.02 mL / hr / kg and 28.8 hours, respectively.
  • the average volume (Vss) of the distribution was 92.2 mL / kg, and the AUC last value and AUC inf value of DFP-13318 were 92.6 hr ⁇ mg / mL and 117 hr ⁇ mg / mL, respectively. Furthermore, the average AUC_% Extrap value was 24.0%.
  • a pharmaceutical composition containing the compound of formula I, which is an active ingredient, is formulated into a parenteral preparation.
  • Parenteral routes include, for example, intravenous, intraarterial, intraperitoneal, subcutaneous, intradermal, intramuscular, intracranial, intranasal, transmucosal, and the preferred route is the intravenous route.
  • the preparation is preferably formulated into a preparation for injection or (infusion) injection or for bolus administration.
  • Formulation can be performed using the methods, excipients, diluents, additives, and the like described in, for example, REMINGTON; THE SCIENCE AND PRACTICE OF PHARMACY (20th Ed).
  • Preparations for injection or (drip) infusion or bolus administration are prepared by dissolving the compound of formula I or formula III in the above-mentioned effective amount in a diluent such as physiological saline, buffer, Ringer's solution, and passing through a sterile filter. Can be formulated. If necessary, additives such as a solubilizer and a preservative can be contained.
  • a diluent such as physiological saline, buffer, Ringer's solution
  • the cancer to be treated is colon cancer, breast cancer, ovarian cancer, cervical cancer, uterine cancer, lung cancer, gastric cancer, pancreatic cancer, esophageal cancer, head and neck cancer, hepatocellular carcinoma, gallbladder cancer, biliary tract cancer,
  • irinotecan such as sarcomas and malignant lymphomas
  • the composition of the present invention has no irinotecan-like side effects such as severe diarrhea, leukopenia, and eosinophilia. Therefore, it can be used effectively for cancers other than the above.
  • the subject to be treated for cancer is an animal including a human, preferably a mammal such as a human, a pet animal (dog, cat, etc.) and the like.
  • the preferred animal is a human.
  • the present invention further provides the compound of formula I or formula II to a subject having cancer at a frequency of about 0.01 ⁇ mol / kg body weight to about 11 ⁇ mol / kg body weight once a week at a single dose of 1 Including parenteral administration for at least 2 weeks, at least 4 weeks, or at least 6 weeks every week, and severe diarrhea, leukopenia, and / or at doses of 1/10 (molar ratio) or less of irinotecan
  • the present invention provides a method for treating cancer, characterized by having no irinotecan-like side effects including eosinophilia and imparting a cancer growth inhibitory activity comparable to or higher than that of irinotecan.
  • the compound used in the treatment method of the present invention accumulates in a tumor in a dose-dependent manner after administration, such as intravenous administration, and further, SN-38, which is an active substance in the tumor, in a dose-dependent manner, and And has a feature of sustained release (FIGS. 4 and 5).
  • SN-38 which is an active substance in the tumor, in a dose-dependent manner, and And has a feature of sustained release (FIGS. 4 and 5).
  • SN-38 which is an active substance in the tumor, in a dose-dependent manner, and And has a feature of sustained release (FIGS. 4 and 5).
  • SN-38 was not detected at all (see Example 3).
  • the target cancer and the target subject are also as described above.
  • Preferred cancers are, for example, colon cancer, breast cancer, ovarian cancer, cervical cancer, uterine cancer, lung cancer, gastric cancer, pancreatic cancer, esophageal cancer, head and neck cancer, hepatocellular carcinoma, gallbladder cancer, biliary tract cancer, sarcoma, malignant lymphoma, etc. There are, but are not limited to them.
  • a preferred subject is a human.
  • parenteral administration is used, and the preferable route is intravenous administration as described above, and this administration preferably includes (instillation) infusion administration or bolus administration.
  • SN-38 (1.00 g, 2.55 mmol; Haorui) was suspended in 10 mL of anhydrous pyridine, and then concentrated to dryness at 50 ° C. under vacuum. This operation was similarly repeated with 10 mL of anhydrous THF. The obtained pale yellow solid was dissolved in a mixed solvent of 50 mL anhydrous THF and 50 mL anhydrous DMF under a nitrogen atmosphere, and cooled on ice, a 1.0 M solution of potassium t-butoxide in THF (2.55 mL, 2.55 mmol) was added. However, the initial dark green color changed to a deep orange suspension.
  • the pale yellow mixture was diluted with 200 mL of ethyl acetate, washed with 2 ⁇ 100 mL of water, washed with 100 mL of saturated brine, dried over MgSO 4 and evaporated after filtration. Excess DMF was removed by triturating the oily residue with water, and the residue was further dissolved in 50 mL of acetonitrile, filtered and evaporated to give 2.96 g of a yellow glassy material. The residue was subjected to silica gel chromatography with a step gradient (SiO 2 80 g). At this time, the step gradient used 200 mL each of hexane, acetone 20%, 40%, 60%, 80% and 100% in hexane. Chromatography gave azide-linker-SN-38 (1.66 g, 81%).
  • the analysis values are as follows.
  • Trimethylphosphine 1M solution in THF (2.9 mL, 2.9 mmol) was added to a solution of azide-linker-SN-38 (1.13 g, 1.4 mmol) and acetic acid (0.19 mL, 3.3 mmol) in 10 mL of THF. After stirring for 2 hours, water (1.0 mL) was added and the mixture was mixed for an additional hour. The residue was partitioned between ether and water, the aqueous phase was washed once with ethyl acetate and the resulting clear yellow aqueous phase was evaporated to give 800 mg of a yellow foam.
  • Example 2 ⁇ Anti-tumor properties of compound DFP-13318> 1. Test conditions Toxicity, pharmacokinetics and efficacy tests were performed under the conditions shown in Tables 1 and 2 by intravenous injection (iv) of test substances into cancer-bearing rats.
  • Test animals The following rats were used as test animals.
  • Cell line Human colorectal cancer cell line HT-29 was prepared in McCoy 5a modified medium (containing 10% heat-inactivated fetal bovine serum, 100 U / mL penicillin and 100 ⁇ g / mL streptomycin, L-glutamine (2 mM)), 37 Maintained in monolayer culture at 5 ° C., 5% CO 2 / air atmosphere. Tumor cells were passaged in a normal manner twice a week by trypsin-EDTA treatment. Exponentially growing cells were collected and the number of cells was counted and used for tumor inoculation.
  • Each nude rat was subcutaneously injected with HT-29 tumor cells (5 ⁇ 10 6 ) in 0.1 mL of PBS to develop tumors. Treatment began on day 9 after tumor inoculation when the average tumor size was approximately 120 mm 3 .
  • Each group consisted of 5 tumor-bearing nude rats each for efficacy and pharmacokinetic (PK) studies. In the case of the efficacy test, the test substance was administered intravenously once twice a week from the 9th day after inoculation of the tumor to the rat, whereas in the case of PK evaluation, it was administered once to the rats in the satellite group.
  • Table 3 shows the preparation of test substance formulations.
  • Tumor measurement and endpoint The main endpoint was to see if tumor growth could be delayed or whether the tumor had disappeared.
  • Body weight was measured twice a week and tumor difference size was measured twice a week in two dimensions using a caliper.
  • Pharmacokinetic test Blood samples were collected from the satellite group for the PK test at 0 hours (before administration), 1 hour, 72 hours, and 120 hours after administration. At each time interval, 0.5 mL of whole blood sample is collected from the retroorbital venous plexus of each tumor-bearing nude rat and added directly to 50 ⁇ L of 1 M citrate buffer / 0.1% Pluronic F68 solution (pH 4.5), and the pH of the sample , Preventing blood clotting, and stabilizing the intact conjugate of test substance remaining. Blood samples collected within 60 minutes were centrifuged at approximately 1,500 ⁇ g for 10 minutes at 4 ° C. to recover 200-250 ⁇ L of plasma.
  • the plasma was then divided into two aliquots, placed in syringe vials, stored in a -80 ° C. freezer, and transferred to the bioanalysis group for PK analysis (total 12 samples).
  • the concentrations of DFP-13318, SN-38 and SN-38G in plasma samples were analyzed using HPLC / FLD and LC-MS / MS methods.
  • Figure 1 and Figure 2 show the changes in body weight of tumor-bearing nude rats treated with DFP-13318 (dose 50 mg / kg, 100 mg / kg, 200 mg / ml) and Irinotecan® (70/50 mg / kg) in the efficacy test. It was shown to.
  • Tumor Growth Inhibitory Activity of Compound DFP-13318 Changes in tumor volume and tumor growth inhibition of each of the tumor-bearing rats treated with DFP-13318 and Irinotecan were examined.
  • the molar ratio of test substance administered is shown in Table 6.
  • TGI tumor growth inhibition
  • the TGI value was 45%, indicating moderate antitumor activity. Since the antitumor activity of DFP-13318 is due to released SN-38, which is less than 4% of the total weight from its PEG conjugate, for a fair comparison, the dose of the substance is shown in Table 6. As shown, the dose of test substance (mg / kg) should be converted and compared to the molar ratio of DFP-13318 to Irinotecan. When so compared, it is clear that the anti-tumor activity of DFP-13318 is very potent compared to Irinotecan.
  • DFP-13318® showed good drug resistance to cancer-bearing rats at three dose levels. Weight loss was at most less than 2.0% and no diarrhea was observed in the group treated with DFP-13318. This is considered to be because the production level of SN-38G, which is a cause of severe diarrhea, is 1/100 or less compared with irinotecan and is very low. Specifically, from the results of Table 10 and Table 11 described later, the production ratio of SN-38G to SN-38 is 0.07 times and 0.06 times when DFP-13318 is administered at 225 mg / kg and 450 mg / kg, respectively.
  • DFP-13318 On the day of administration, a predetermined amount of DFP-13318 is dissolved in 10 mM sodium acetate buffer (pH 5.0) to prepare a fresh solution of 45 mg / mL DFP-13318, which is 0.22 ⁇ m before administration. Sterilized by passing through a PVDF filter.
  • the blood sample collection schedule for the PK profile was as shown in Table 8.
  • Table 9 shows the measurement result of the plasma concentration of DFP-13318
  • Table 10 shows the measurement result of the plasma concentration of SN-38
  • Table 11 shows the measurement result of the plasma concentration of SN-38G.
  • Table 12 shows the calculation results of the PK parameters of DFP-13318
  • Table 13 shows the results of calculation of the PK parameters of SN-38
  • Table 14 shows the results of calculation of the PK parameters of SN-38G. It was.
  • the mean Tmax and Cmax values were 2 hours and 3.05 mg / mL for DFP-13318, 1 hour and 97.6 ng for SN-38, respectively. 1 hour and 12.7 ng / mL for / mL and SN-38G, respectively.
  • DFP-13318 also had an average plasma T 1/2 value of 36.8 hours.
  • the average values of clearance and MRT last of DFP-13318 were 2.02 mL / hr / kg and 28.8 hours, respectively.
  • the average volume (Vss) of the distribution was 92.2 mL / kg, and the AUC last value and AUC inf value of DFP-13318 were 92.6 hr ⁇ mg / mL and 117 hr ⁇ mg / mL, respectively. Furthermore, the average AUC_% Extrap value was 24.0%.
  • the mean plasma T 1/2 value is 33.2 hours for SN-38 and cannot be calculated because the measurement coefficient (r 2 ) is low for SN-38G (NC / NBC).
  • the mean values of MRT last for SN-38 and SN-38G were 27.2 hours and 9.65 hours, respectively.
  • the average values of AUC last and AUC inf are 1,775 hr ⁇ ng / mL and 2,252 hr ⁇ ng / mL for SN-38, 120 hr ⁇ ng / mL and 1,948 hr ⁇ ng / mL for SN-38G, respectively. there were.
  • the average values of AUC_% Extrap for SN-38 and SN-38G were 20.8% and 91.6%, respectively.
  • the average volume (Vss) of the distribution was 97.3 mL / kg, and the AUC last value and AUC inf value of DFP-13318 were 180 hr ⁇ mg / mL and 195 hr ⁇ mg / mL, respectively. Furthermore, the average AUC_% Extrap value was 7.42%.
  • the mean plasma T 1/2 values were 34.0 hours for SN-38 and 18.9 hours for SN-38G.
  • the mean values of MRT last for SN-38 and SN-38G were 30.8 hours and 19.55 hours, respectively.
  • the average values of AUC last and AUC inf were 6,803 hr ⁇ ng / mL and 7,499 hr ⁇ ng / mL for SN-38, and 407 hr ⁇ ng / mL and 584 hr ⁇ ng / mL for SN-38G, respectively.
  • the average values of AUC_% Extrap for SN-38 and SN-38G were 8.64% and 30.3%, respectively.
  • Example 3 ⁇ Confirmation of DFP-13318 accumulation in tumor>
  • DFP-13318 and its metabolite SN-38 were administered after intravenous administration of DFP-13318 to the human colon cancer cell line HT-29 subcutaneously transplanted nude rat model after pharmacokinetics / pharmacodynamics. This was done to confirm that it accumulated in the tumor tissue collected from the rats in the study.
  • DFP-13318 and SN-38 in tumor samples were quantified using HPLC / FLD and LC-MS / MS bioanalytical methods.
  • the bioanalytical procedure is as follows.
  • HPLC conditions are as follows.
  • the accuracy of at least 75% of the calibration standard is within the acceptance criteria (excluding LLOQ, which should fall within 85% to 115% of the nominal value, but should be within 80% to 120% of the nominal value). Satisfied. Calibration standards and calibration curve parameter concentrations in the tumor samples tested were calculated.
  • the variation of the low, medium and high samples ranged from 1.52% to 3.86% for DFP-13318 and 1.42% to 6.00% for SN-38.
  • DFP-13318 and its metabolite SN-38 in each tumor tissue are summarized in Table 17 and Table 18, respectively. 4 and 5 show the dose dependence of DFP-13318 content and SN-38 content in tumor tissue.
  • DFP-13318 When DFP-13318 is administered intravenously at doses of 50 mg / kg, 100 mg / kg and 200 mg / kg, the content of DFP-13318 and its metabolite SN-38 in HT-29 tumor tissue is Increased in a dose-dependent manner.
  • irinotecan a prodrug of SN-38
  • no SN-38 was detected in Group 5.
  • SN-38 content in HT-29 tumors is constant at approximately 1% of the content of DFP-13318, and the parent compound (4-arm PEG with 4 molecules of SN-38) ) Accumulated in tumor tissue after intravenous administration of the compound at doses of 50, 100 and 200 mg / kg (Table 17 and FIG. 4 respectively). It is suggested that the conversion from the parent compound maintains SN-38 levels persistently over a long period of time.
  • repeated intravenous administration once a week at a low dose is excellent without causing side effects such as severe diarrhea. Since it provides a medicinal effect and enables cancer treatment without side effects, it is extremely beneficial in the pharmaceutical industry.

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Abstract

La présente invention concerne une composition pharmaceutique permettant le traitement du cancer, la composition comprenant en tant qu'agent actif un composé représenté par la formule générale I : C-[-CH2-O-(-CH2CH2-O-)­n-X1-CHR1-O-CO-NR2-CH2-X2]4 (I) (X1-CHR1-O-CO-NR2 étant un lieur, X1 étant un espaceur, R1 représentant un groupe alkyle C1-4 éventuellement substitué, R2 représentant un groupe phényle ou un groupe phényle substitué, X2 représentant SN-38, et n étant un nombre entier compris entre 200 et 1 000). La composition est caractérisée : en ce qu'elle peut être utilisée chez un sujet atteint d'un cancer à un régime posologique faisant appel à une administration par voie parentérale d'une dose unique d'environ 0,01 à 11 µmoles/kg de poids corporel, à une fréquence d'une fois par semaine toutes les deux semaines, pour au moins deux administrations ; en ce qu'elle ne présente pas d'effets indésirables de type irinotécan tout en conférant une activité d'inhibition de la prolifération cancéreuse identique ou supérieure à celle de l'irinotécan à une dose qui est inférieure ou égale à 1/10 (rapport molaire) de celle l'irinotécan. La présente invention concerne également une méthode de traitement du cancer.
PCT/JP2014/052877 2013-10-04 2014-02-07 Agent anticancéreux sans effets indésirables Ceased WO2015049883A1 (fr)

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KR102314558B1 (ko) * 2020-05-14 2021-10-18 데루타-후라이 화마 가부시키가이샤 베네토클락스의 수용성 고분자 유도체
KR20250149067A (ko) 2024-04-08 2025-10-15 허원구 전통구들의 폐열을 이용한 난방시스템

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