WO2013094581A1 - Nouveau dérivé de camptothécine - Google Patents

Nouveau dérivé de camptothécine Download PDF

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Publication number
WO2013094581A1
WO2013094581A1 PCT/JP2012/082738 JP2012082738W WO2013094581A1 WO 2013094581 A1 WO2013094581 A1 WO 2013094581A1 JP 2012082738 W JP2012082738 W JP 2012082738W WO 2013094581 A1 WO2013094581 A1 WO 2013094581A1
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WO
WIPO (PCT)
Prior art keywords
mmol
added
group
sn38pt
tert
Prior art date
Application number
PCT/JP2012/082738
Other languages
English (en)
Japanese (ja)
Inventor
義雄 竹内
隆 八重樫
松崎　健
卓弥 杉本
正人 長岡
朋也 藤原
Original Assignee
株式会社ヤクルト本社
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.)
Filing date
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Priority to JP2013550278A priority Critical patent/JP6043729B2/ja
Publication of WO2013094581A1 publication Critical patent/WO2013094581A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/12—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains three hetero rings
    • C07D491/14—Ortho-condensed systems
    • C07D491/147—Ortho-condensed systems the condensed system containing one ring with oxygen as ring hetero atom and two rings with nitrogen as ring hetero atom
    • 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 a novel camptothecin derivative useful for the treatment of various cancers.
  • Camptothecin is a compound that was isolated and structurally determined from Camptotheca cumacuminate in 1966 by Wall et al. (See Non-Patent Document 1). CPT has received a lot of attention because of its remarkable antitumor activity against mouse leukemia L1210. In the early 1970s, the National Cancer Institute conducted clinical trials using water-soluble sodium salts in which the E-ring lactone part of CPT was opened with an alkali. However, anti-tumor activity as expected was not obtained, and serious side effects such as myelosuppression and hemorrhagic cystitis occurred, and development as a therapeutic drug was abandoned (see Non-Patent Document 2, Non-Patent Document). Reference 3).
  • irinotecan hydrochloride (7-ethyl-10- [4- (1-piperidino) -1-piperidino] carbonyloxy CPT) (see Patent Document 1 and Non-Patent Document 4) and topotecan (9-dimethylaminomethyl-10) -Hydroxy CPT) has clinically useful activity.
  • Irinotecan hydrochloride is a prodrug in which the piperidinopiperidine side chain is cleaved by an enzyme in vivo to release the active main body 7-ethyl-10-hydroxy CPT (SN-38).
  • the mechanism of action of CPT derivatives such as CPT and SN-38 inhibits type I topoisomerase necessary for cell replication, stops DNA biosynthesis, and causes cell death (see Non-Patent Document 5).
  • Oxaliplatin is an organic platinum compound having a DACH (1,2-diaminocyclohexane) group (see Patent Document 2), and exhibits particularly strong activity against colorectal cancer cell lines. Oxaliplatin does not have cross-resistance to cisplatin-resistant cancer, and is therefore classified as an anticancer platinum derivative that is completely different from cisplatin and carboplatin.
  • the mechanism of action of oxaliplatin is not well understood, but is presumed to be similar to that of cisplatin. That is, after the bond between the leaving group and platinum is cleaved by biotransformation that does not involve the enzyme, it is converted to active species by adding water and chlorine atoms to platinum (see Non-Patent Document 6). This active species reacts with DNA to form a platinum-DNA adduct, thereby inhibiting DNA replication and causing cell death (see Non-Patent Document 7).
  • Patent No. 1660064 Japanese Patent Application No. 07-209149
  • An object of the present invention is to provide a compound containing a plurality of partial structures that can be expected to have different anticancer action mechanisms in the same molecule and exhibiting high antitumor activity in addition to low toxicity. There is.
  • the inventors have studied the creation of a novel clinically useful CPT derivative having an anticancer active structure in the same molecule with different mechanisms of action in anticipation of enhancing the anticancer effect and reducing the number of administrations.
  • the toxicity of a novel CPT derivative having a DACH platinum complex structure obtained by reacting a CPT derivative having a dicarboxyl group with a diaquo DACH platinum complex via a spacer is remarkably remarkable.
  • the present invention was completed by finding that it can be administered in an amount lower than the amount of active substances (DACH platinum and SN-38) in the maximum tolerated dose of oxaliplatin and irinotecan hydrochloride and exhibits excellent antitumor activity. did.
  • the present invention has the following general formula (1) or (2):
  • a and B each independently represent a substituted or unsubstituted alkylene group, an alkylenecarbonyl group, an acyclic or cyclic aminoalkyleneaminocarbonyl group
  • the camptothecin derivative which has a platinum complex structure represented by these is provided.
  • the present invention also provides a medicament or anticancer agent comprising the camptothecin derivative as an active ingredient.
  • the present invention also provides a pharmaceutical composition and an anticancer composition characterized by containing the camptothecin derivative in a form encapsulated in micelles.
  • the present invention also provides a method for treating cancer, which comprises administering an effective amount of the camptothecin derivative.
  • the present invention also provides use of the camptothecin derivative for producing a medicament.
  • the present invention also provides use of the camptothecin derivative for producing an anticancer agent.
  • the CPT derivative of the present invention has an anticancer active structure showing different mechanisms of action in the same molecule, has a significantly low toxicity, and is active in the maximum tolerated dose of oxaliplatin and irinotecan hydrochloride (DACH platinum and SN -38) It can be administered in an amount exceeding the amount and exhibits excellent antitumor activity, and is extremely promising as an anticancer agent.
  • the CPT derivative of the present invention is a single compound, it can be administered with a smaller number of administrations compared to multi-drug combination therapy.
  • the CPT derivative of the present invention has a platinum complex structure and is represented by the general formula (1) or (2).
  • a and B each independently represent a substituted or unsubstituted alkylene group, an alkylenecarbonyl group, an acyclic or cyclic aminoalkyleneaminocarbonyl group.
  • a and B each independently represent a substituted or unsubstituted alkylene group, an alkylenecarbonyl group, an acyclic or a cyclic aminoalkyleneaminocarbonyl group containing a nitrogen atom. More preferred.
  • a substituted or unsubstituted linear alkylene group having 1 to 6 carbon atoms a substituted or unsubstituted linear alkylene carbonyl group having 1 to 18 carbon atoms, and 1 to 3 unsaturated bonds.
  • R 1 represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms
  • R 1 represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms
  • An interrupted alkylene carbonyl group having 2 to 18 carbon atoms, a linear aminoalkylene (2 to 4 carbon atoms) aminocarbonyl group, a cyclic diaminocarbonyl group having 2 to 6 carbon atoms and the like are preferable.
  • A is independently absent, a substituted or unsubstituted linear alkylene group having 1 to 6 carbon atoms, a substituted or unsubstituted carbon number of 1 to 18 linear alkylenecarbonyl groups, substituted or unsubstituted C3-C18 linear alkylenecarbonyl groups having 1 to 3 unsaturated bonds, or one or more —CONR 1 —
  • R 1 represents a hydrogen atom or an alkylenecarbonyl group having 2 to 18 carbon atoms optionally interrupted by a hydrogen atom or an alkyl group having 1 to 6 carbon atoms
  • B independently represents a non-existing or linear aminoalkylene group Those having a (C2-4) aminocarbonyl group or a cyclic diaminocarbonyl group having 2-6 carbon atoms are particularly preferred.
  • CPT derivatives represented by the general formula (1) or (2) can be produced by a condensation reaction between the spacer portion and SN-38, followed by a complexation reaction with a diaquo DACH platinum complex.
  • Diaqua DACH platinum complex can be prepared, for example, according to the method described in JP-A-9-40685.
  • Each of these CPT derivatives can be produced by the following method.
  • SN38Pt-SM1 SN-38 dicarboxylic acid derivative
  • SN38Pt-SM1 and diaquo DACH platin are reacted in ethanol and water at 40-70 ° C using NaOH as the base.
  • the resulting crude product is purified by reverse phase HPLC to yield SN38Pt-1.
  • Synthesis of SN38Pt-5 Di-tert-butyl piperidine-4,4-dicarboxylate and monomethyl succinate are reacted using TCTU as a condensing agent, and then the ester is deprotected. The obtained carboxylic acid and PPC-SN38 ⁇ TFA are condensed using TCTU, and then the t-Bu group is deprotected with TFA to obtain an SN-38 dicarboxylic acid derivative (SN38Pt-SM5). SN38Pt-SM5 and diaquo DACH platin are reacted in ethanol and water at 40-70 ° C using NaOH as the base. The resulting crude product is purified by reverse phase HPLC to yield SN38Pt-5.
  • the resulting carboxylic acid and AEC-SN38 ⁇ TFA are condensed using TCTU, and then the t-Bu group is deprotected with TFA to obtain an SN-38 dicarboxylic acid derivative (SN38Pt-SM7).
  • SN38Pt-SM7 and diaquo DACH platin are reacted at 40-70 ° C using ethanol as the base and NaOH as the base.
  • the resulting crude product is purified by reverse phase HPLC to yield SN38Pt-7.
  • APC-SN38 ⁇ TFA and the previously synthesized carboxylic acid are condensed using TCTU, and then the t-Bu group is deprotected with TFA to obtain an SN-38 dicarboxylic acid derivative (SN38Pt-SM9).
  • SN38Pt-SM9 and diaquo DACH platin are reacted at 40-70 ° C using ethanol as the base and NaOH as the base.
  • the resulting crude product is purified by reverse phase HPLC to yield SN38Pt-9.
  • the obtained carboxylic acid and PPC-SN38 ⁇ TFA are condensed using TCTU, and then the t-Bu group is deprotected with TFA to obtain an SN-38 dicarboxylic acid derivative (SN38Pt-SM10).
  • SN38Pt-SM10 and diaquo DACH platin are reacted at 40-70 ° C using ethanol as the base and NaOH as the base.
  • the resulting crude product is purified by reverse phase HPLC to yield SN38Pt-10.
  • the CPT derivative of the present invention is remarkably low in toxicity, can be administered in an amount exceeding the amount of active substances (DACH platinum and SN-38) in the maximum tolerated dose of oxaliplatin and irinotecan hydrochloride, and has antitumor activity. Since it is excellent, it is extremely useful as a pharmaceutical or anticancer agent comprising this as an active ingredient.
  • the dose of the CPT derivative of the present invention may be appropriately adjusted according to the administration method, patient's symptoms, etc.
  • camptothecin derivative having a platinum complex structure represented by the general formula (1) or (2) It is preferable to administer 0.05 mg / kg to 0.2 g / kg, further 1.67 mg / kg to 0.2 g / kg, especially 8.33 mg / kg to 0.2 g / kg per day for an adult.
  • L-OHP and CPT-11 contained as active ingredients are each converted into an active substance (DACH platinum and SN-) converted from the maximum tolerated dose when administered alone. 38) Since administration exceeding the amount is possible and a dose-dependent antitumor effect is obtained, it is extremely useful as a pharmaceutical or anticancer agent comprising this as an active ingredient.
  • the maximum tolerated dose of L-OHP (20 mg / kg) (Anticancer Drugs 1997 Oct; 8 (9): 876-85) and the maximum tolerated dose of CPT-11 (270 mg / kg) (Oncology Reports 27: 189-197, 2012) )
  • the amount of active substance is 16 mg / kg of DACH platinum and 156 mg / kg of SN-38.
  • the CPT derivative (SN38Pt-4) of the present invention has almost no toxicity at 600 mg / kg, but the converted amount of the active substance at this dose is 157 mg / kg of DACH platinum.
  • SN-38 200 mg / kg it is possible to administer an amount of the active substance far exceeding the maximum tolerated dose of L-OHP and CPT-11, and a dose-dependent antitumor effect is obtained.
  • the CPT derivative of the present invention is used as a medicine or an anticancer agent
  • its dosage form is not particularly limited and can be prepared using commonly used additives.
  • the CPT derivative of the present invention can be produced by a condensation reaction between the spacer portion and SN-38 (anticancer agent A), followed by a complexation reaction with diaquo DACH platinum (anticancer agent B).
  • Derivatives obtained by substituting the SN-38 and / or diaquo DACH platinum with other anticancer agents can also be suitably used.
  • the anticancer agent A is not particularly limited, and for example, cyclophosphamide, melphalan, nimustine, ranimustine, methotrexate, pemetrexed, fluorouracil, doxyfluridine, capecitabine, cytarabine, enocytabine, gemcitabine, 6-mercaptopurine, fludarabine , Pentostatin, cladribine, hydroxyurea, doxorubicin, epirubicin, daunorubicin, idarubicin, pirarubicin, amrubicin, actinomycin D, bleomycin, pepleomycin, mitomycin C, aclarubicin, dinostatin, vincristine, vindesine, vinblastine, vinrelcerx, paclitaxel, paclitaxel, paclitaxel Irinotecan, Irinotecan active metabolite (SN-38), Nogitecan, D Examples include po
  • Examples thereof include platin, cisplatin, carboplatin, nedaplatin, or active metabolites thereof.
  • the anticancer agent A a plant alkaloid-based anticancer agent is preferable, and irinotecan, SN-38 or a salt thereof is particularly preferable.
  • the anticancer agent B a platinum complex anticancer agent is preferable, and oxaliplatin, cisplatin, or an active metabolite thereof is particularly preferable.
  • the CPT derivative of the present invention can be administered as it is, but it is mixed with a carrier such as a dispersion aid, excipient, etc., which is usually used for formulation, within a range that does not reduce the effect.
  • a carrier such as a dispersion aid, excipient, etc.
  • examples of such carriers include water-soluble monosaccharides or oligosaccharides or polysaccharides such as mannitol, lactose, and dextran; for example, gel-forming or water-soluble celluloses such as hydroxypropylcellulose, hydroxypropylmethylcellulose, and methylcellulose.
  • water-absorbing and poorly water-soluble celluloses such as crystalline cellulose, ⁇ -cellulose, crosslinked sodium carboxymethylcellulose, and derivatives thereof; for example, hydroxypropyl starch, carboxymethyl starch, crosslinked starch, amylose, amylopectin, Water-absorbing and poorly water-soluble polysaccharides such as pectin and derivatives thereof; for example, water-absorbing and poorly water-soluble gums such as gum arabic, tragacanth gum, glycomannan and derivatives thereof; Cross-linked vinyl polymers such as redone, cross-linked polyacrylic acid and salts thereof, cross-linked polyvinyl alcohol, polyhydroxyethyl methacrylate and derivatives thereof; lipids that form molecular aggregates such as liposomes such as phospholipids and cholesterol Can do.
  • a solubilization treatment can be performed.
  • a solubilization treatment a method that can be generally applied to a medicine, for example, a method of adding a surfactant such as polyoxyethylene alcohol ethers, polyoxyethylene acyl esters, sorbitan acyl esters, polyoxyethylene sorbitan acyl esters, Examples thereof include a method using a water-soluble polymer such as polyethylene glycol, a method of encapsulating in micelles, and the like. Further, if necessary, a method of forming a soluble salt, a method of forming an inclusion compound using cyclodextrin, and the like can be used.
  • the CPT derivative as a pharmaceutical composition or anticancer composition containing the micelle in an encapsulated form.
  • the method for preparing the micelle is not particularly limited, and examples thereof include an emulsion using a high-pressure homogenizer, a block polymer using a synthetic polymer, a gelling agent, and the like.
  • reagents used in preparing micelles include fats and oils such as SL-11 (manufactured by NOF Corporation), lecithin, polyethylene glycol, polylactic acid, polyglutamic acid, hydrophobic polysaccharides, emulsifiers and synthetic polymers.
  • the particle diameter when micelles are formed is preferably 5 to 200 nm, and more preferably 5 to 100 nm.
  • benzyl bis (2-hydroxyethyl) carbamate (5.0 g, 20.9 mmol) was dissolved in dichloromethane (100 mL) and cooled to 0 ° C. Carbon tetrabromide (16.6 g, 50.2 mmol) was added to it, and then triphenylphosphine A dichloromethane solution (20 mL) of (16.4 g, 62.7 mmol) was added dropwise, stirred at 0 ° C. for 10 minutes, and then stirred at room temperature for 2 hours. The reaction mixture was concentrated, ethyl acetate was added, and the resulting precipitate was removed by filtration.
  • Method A Dissolve (((Benzyloxy) carbonyl) azanediyl) bis (ethane-2,1-diyl) dimethanesulfonate (46.83 g, 0.118 mol) in a mixture of dehydrated tetrahydrofuran (2180 mL)-dehydrated N, N-dimethylformamide (180 mL) Then, di-tert-butyl malonate (26.50 g, 0.123 mol) was added, and sodium hydride and oily (11.86 g, 0.296 mol) were added little by little over about 1 hour with stirring at room temperature. After adding sodium hydride, the mixture was stirred with heating at 70 ° C. for 14 hours.
  • the reaction mixture was concentrated to dryness under reduced pressure, saturated aqueous ammonium chloride solution and water were added, and the mixture was extracted twice with ethyl acetate. The ethyl acetate layers were combined and washed with saturated brine, dried over anhydrous sodium sulfate, filtered off sodium sulfate, and concentrated to dryness under reduced pressure to give the crude title compound.
  • the crude title compound obtained by reaction and post-treatment in the same manner using 57.89 g of the starting mesyl compound was combined and purified by silica gel column chromatography (n-hexane: ethyl acetate 7: 1) to give a yellow viscous oil I got a thing.
  • Method B Under an argon gas atmosphere, sodium hydride, oily (1.18 g, 29.5 mmol) was suspended in N, N-dimethylformamide (25 mL) and cooled to 0 ° C. A di-tert-butyl malonate (3.29 mL, 14.8 mmol) in N, N-dimethylformamide solution (25 mL) was added dropwise thereto, and the mixture was stirred at 0 ° C. for 30 minutes.
  • Di-tert-butyl piperidine-4,4-dicarboxylate (6.0 g, 0.021 mol) is dissolved in dry toluene (120 mL), dry pyridine (4.3 ml) is added, and triphosgene (3.32 g, 0.011 mol) was added and stirred for 30 minutes. It was then stirred overnight at room temperature. Dichloromethane was added to the reaction mixture, and the mixture was washed with a saturated aqueous sodium hydrogen carbonate solution, water, and saturated brine in this order.
  • the dichloromethane layer was separated, dried over anhydrous sodium sulfate, and concentrated to dryness under reduced pressure to obtain crude di-tert-butyl 1- (chlorocarbonyl) piperidine-4,4-dicarboxylate as a yellow solution.
  • reaction mixture was concentrated to dryness under reduced pressure, the residue was purified by silica gel column chromatography (chloroform containing 3% methanol), fractions containing the desired product were collected and concentrated to dryness, and the residue was chloroform-n- Crystallization from hexanes afforded 13.32 g (90.1%) of the title compound as a pale yellowish white powder.
  • Trifluoroacetic acid 50 mL is added to 10- (4,4- (Di-tert-butoxycarbonyl) piperidin-1-yl) carbonyloxy-7-ethylcamptothecin (5.0 g, 7.10 mmol), and the mixture is stirred at room temperature for 4 hours.
  • the reaction mixture was concentrated to dryness under reduced pressure to give a yellow viscous oily residue.
  • Ethanol (20 mL) was added to the residue and dissolved by irradiation with ultrasonic waves (a yellow solid precipitated immediately after dissolution). Petroleum ether (40 mL) was added to the solution and stirred under ice cooling.
  • SN38Pt-SM1 (592 mg, 1.00 mmol) was dissolved in ethanol (250 mL) with heating, then diaquo DACH platinum complex (469 mg, 1.00 mmol) (prepared by the method described in JP-A-9-40685), distilled Water (40 mL) was added followed by 0.2 N aqueous sodium hydroxide (10 mL, 2.00 mmol). After stirring at 60-70 ° C. for 21 hours, insoluble matters were removed by filtration under reduced pressure (glass filter). Distilled water (300 mL) was added to the residue obtained by distilling off the solvent to form a suspension (sonication). The suspension was heated with hot water and filtered under reduced pressure (filter paper).
  • the obtained powder was dissolved by heating (60-70 ° C.) in a methanol / water (85/15) mixed solvent (about 200 mL), and insoluble matters were removed by filtration under reduced pressure (glass filter).
  • Method A Dissolve tert-Butyl piperazine-1-carboxylate (5.0 g, 26.85 mmol) in dry toluene (150 mL), add dry pyridine (5.5 mL), and add triphosgene (4.24 g, 14.29 mmol) with stirring under ice cooling. The mixture was further stirred for 1 hour. It was then stirred overnight at room temperature. Dichloromethane was added to the reaction mixture, and the mixture was washed with a saturated aqueous sodium hydrogen carbonate solution, water, and saturated brine in this order.
  • the reaction mixture was concentrated to dryness under reduced pressure, the residue was purified by silica gel column chromatography (chloroform containing 2% methanol), fractions containing the desired product were collected and concentrated to dryness, and the residue was chloroform-n- Crystallized from hexane. The crystals were collected by filtration, washed with n-hexane and dried (60 ° C., reduced pressure) to give 15.17 g (93.5%) of the title compound as a pale yellowish white powder.
  • the chloroform layer was washed with saturated brine, dried over anhydrous magnesium sulfate, the solvent was distilled off, and the residue was dried under vacuum.
  • the obtained residue was dissolved in pyridine (40 mL), SN-38 (2.04 g, 5.20 mmol) was added, and the mixture was stirred at room temperature overnight. Chloroform was added to the reaction solution, and the mixture was washed with a saturated aqueous sodium hydrogen carbonate solution and saturated brine. The chloroform layer was dried over anhydrous magnesium sulfate and the solvent was distilled off.
  • the obtained residue was purified by silica gel column chromatography (methanol / chloroform stepwise) to obtain 3.01 g (99%) of the title compound as a pale yellow solid.
  • Trifluoroacetic acid 25 mL was added to 10- (4- (tert-Butoxycarbony) lpiperazine-1-yl) carbonyloxy-7-ethylcamptothecin (10.0 g, 16.54 mmol) and dissolved by irradiation with ultrasonic waves. The solution was stirred at room temperature for 2.5 hours and the reaction mixture was concentrated to dryness under reduced pressure to give a greenish yellow viscous oily residue. Ethanol (100 mL) was added to the residue and dissolved.
  • Example 1 From Di-tert-butyl piperidine-4,4-dicarboxylate (0.75 g, 2.63 mmol), dry toluene (15 mL), dry pyridine (0.54 ml) and triphosgene (415 mg, 1.40 mmol), Example 1 (6) According to the method, crude Di-tert-butyl 1- (chlorocarbonyl) piperidine-4,4-dicarboxylate was obtained.
  • SN38Pt-SM2 (155 mg, 0.22 mmol) was dissolved in ethanol (175 mL) with heating, then diaquo DACH platinum complex (103 mg, 0.22 mmol), distilled water (25 mL), followed by 0.2 N aqueous sodium hydroxide ( 2.2 mL, 0.441 mmol) was added. After stirring at 60-70 ° C. for 24 hours, the solvent was distilled off. To the resulting residue, a methanol / water (85/15) mixed solvent (90 mL) was added to make a suspension (sonication). The suspension was heated with hot water, and then insoluble matters were removed by filtration (glass filter). The filtrate was concentrated and dried in vacuo to give the crude title compound.
  • 2-Bromoacetyl chloride (1.21 g, 7.71 mmol) was dissolved in dry dichloromethane (20 mL) and stirred under ice cooling with di-tert-butyl piperidine-4,4-dicarboxylate (2.00 g, 7.01 mmol) and triethylamine (A dry dichloromethane solution (20 mL) in which 780 mg, 7.71 mmol) was dissolved was added dropwise over 30 minutes. The reaction mixture was then stirred overnight at room temperature. The reaction mixture was was washed with 0.1 N hydrochloric acid and saturated brine, and the dichloromethane layer was separated, dried over anhydrous sodium sulfate, and concentrated to dryness under reduced pressure.
  • the chloroform layer was separated, dried over anhydrous sodium sulfate, and concentrated under reduced pressure (about 20 mL). N-Hexane was added to the concentrate with stirring under ice-cooling, and the mixture was stirred overnight. The precipitated crystals were collected by filtration, washed with n-hexane, and dried (50 ° C., reduced pressure) to give 1.06 g (78.9%) of the title compound as a white powder.
  • SN38Pt-SM3 (457 mg, 0.55 mmol) was dissolved in ethanol (165 mL) and distilled water (11 mL) with heating, and then 0.2 N aqueous sodium hydroxide solution (2.75 mL, 0.55 mmol) was added at 60-70 ° C. Stir for about 5 minutes. Then, diaquo DACH platinum complex (258 mg, 0.55 mmol), distilled water (22 mL), and then 0.2 N aqueous sodium hydroxide solution (5.5 mL, 1.1 mmol) were added. After stirring at 60-70 ° C. for 24 hours, the solvent was distilled off and vacuum-dried.
  • the dichloromethane layer was separated, dried over anhydrous magnesium sulfate, and concentrated to dryness under reduced pressure to obtain a colorless viscous oily residue.
  • the residue was purified by silica gel column chromatography (n-hexane: ethyl acetate 3: 1), and fractions containing the desired product were collected, concentrated to dryness under reduced pressure, dried (room temperature, reduced pressure), and colorless.
  • the title compound 5.19 g (98.9%) was obtained as a viscous oil.
  • Di-tert-butyl 1- (12-ethoxy-12-oxododecanoyl) piperidine-4,4-dicarboxylate (5.19 g, 9.87 mmol) is dissolved in methanol (50 mL) and stirred with ice cooling to 1 N hydroxide A sodium aqueous solution (12 mL, 12 mmol) was added, and the mixture was stirred at room temperature for 1 day (white crystals were precipitated). The reaction solution was concentrated under reduced pressure (methanol was distilled off), and acidified by adding 1 N hydrochloric acid to the alkaline aqueous solution containing the crystals while stirring under ice-cooling.
  • SN38Pt-SM4 (654 mg, 0.75 mmol) was dissolved in ethanol (185 mL) with heating, then diaquo DACH platinum complex (352 mg, 0.75 mmol), distilled water (30 mL), followed by 0.2 N aqueous sodium hydroxide ( 7.5 mL, 1.5 mmol) was added. After stirring at 50-60 ° C. for 22 hours, the solution was concentrated under reduced pressure.
  • SN38Pt-SM5 150 mg, 0.197 mmol was dissolved in ethanol (50 mL). Diaqua DACH platinum complex (93 mg, 0.197 mmol) and water (5.91 mL) were added there. Subsequently, 0.1 N sodium hydroxide aqueous solution (3.94 mL, 0.394 mmol) was added, and it stirred at 50 degreeC for 22 hours. The reaction mixture was concentrated to dryness, N, N-dimethylacetamide was added to the residue, and the mixture was centrifuged (8,000 rpm, 5 min).
  • the resulting supernatant was purified using reverse-phase HPLC (SunFire OBD, C18, 5 ⁇ m (30 mmID X 150 mm), solvent: methanol / water gradient, Flow rate: 20 mL / min, UV 254 nm), A peak containing SN38Pt-5 was collected. The fractions collected were collected and methanol was distilled off. The resulting aqueous solution was lyophilized to give 63 mg (29%) of the title compound as a white powder.
  • SN38Pt-SM6 200 mg, 0.245 mmol was dissolved in ethanol (60 mL). Diaqua DACH platinum complex (115 mg, 0.245 mmol) and water (7.35 mL) were added there. Subsequently, 0.1 N sodium hydroxide aqueous solution (4.90 mL, 0.490 mmol) was added, and it stirred at 50 degreeC for 23 hours. The reaction mixture was concentrated to dryness, N, N-dimethylacetamide was added to the residue, and the mixture was centrifuged (8,000 rpm, 5 min).
  • the resulting supernatant was purified using reverse-phase HPLC (SunFire OBD, C18, 5 ⁇ m (30 mmID X 150 mm), solvent: methanol / water gradient, Flow rate: 20 mL / min, UV 254 nm), A peak containing SN38Pt-6 was collected. The fractions collected were collected and methanol was distilled off. The resulting aqueous solution was lyophilized to give 82 mg (30%) of the title compound as a white powder.
  • dodecanedioic acid monoethyl ester (380 mg, 1.47 mmol) was dissolved in N, N-dimethylformamide (5 mL) and cooled to 0 ° C.
  • TCTU 523 mg, 1.47 mmol
  • N, N-diisopropylethylamine 750 ⁇ L, 4.41 mmol
  • di-tert-butyl piperidine-4,4-dicarboxylate 300 mg, 1.05 mmol was added, stirred at 0 ° C. for 10 minutes, and then stirred at room temperature for 1 hour.
  • Boc- ⁇ -Ala (946 mg, 5.00 mmol) was dissolved in tetrahydrofuran (15 mL) and cooled to ⁇ 20 ° C.
  • N-methylmorpholine (605 ⁇ L, 5.50 mmol) and chloroformic acid ethyl ester (524 ⁇ L, 5.50 mmol) were added thereto, and the mixture was stirred at ⁇ 20 ° C. for 20 minutes.
  • the reaction mixture was heated to 0 ° C., an aqueous solution (2.5 mL) of sodium azide (813 mg, 12.5 mmol) was added, and the mixture was stirred at 0 ° C. for 5 minutes.
  • tert-butyl (3-azido-3-oxopropyl) carbamate (1.07 g, 5.00 mmol) was dissolved in toluene (10 mL), and stirred at 65 ° C. for 30 minutes until no bubbles were generated.
  • the reaction mixture was cooled, and added to SN-38 (981 mg, 2.50 mmol) and triethylamine (681 ⁇ L, 5.00 mmol) in N, N-dimethylformamide (125 mL) under ice-cooling, and stirred at 0 ° C for 10 min. Thereafter, the mixture was stirred at room temperature overnight.
  • SN38Pt-SM7 80 mg, 0.0946 mmol was dissolved in ethanol (23 mL). Diaqua DACH platinum complex (44 mg, 0.0946 mmol) and water (2.84 mL) were added thereto. Subsequently, 0.1 N sodium hydroxide aqueous solution (1.89 mL, 0.189 mmol) was added, and it stirred at 50 degreeC for 23 hours. The reaction mixture was concentrated to dryness, N, N-dimethylacetamide was added to the residue, and the mixture was centrifuged (8,000 rpm, 5 min).
  • the resulting supernatant was purified using reverse-phase HPLC (SunFire OBD, C18, 5 ⁇ m (30 mmID X 150 mm), solvent: methanol / water gradient, Flow rate: 20 mL / min, UV 254 nm), A peak containing SN38Pt-7 was collected. The fractions collected were collected and methanol was distilled off. The resulting aqueous solution was lyophilized to give 18 mg (17%) of the title compound as a white powder.
  • eicosanedioic acid monomethyl ester 138 mg, 0.387 mmol
  • N, N-dimethylformamide 6 mL
  • TCTU 138 mg, 0.387 mmol
  • N, N-diisopropylethylamine 197 ⁇ L, 1.16 mmol
  • di-tert-butyl piperidine-4,4-dicarboxylate 92 mg, 0.323 mmol
  • Di-tert-butyl 1- (20-methoxy-20-oxoicosanoyl) piperidine-4,4-dicarboxylate (171 mg, 0.274 mmol) is dissolved in tetrahydrofuran (10 mL) and water (1 mL) and cooled to 0 ° C. did.
  • Lithium hydroxide monohydrate (16 mg, 0.384 mmol) was added thereto, the mixture was returned to room temperature and stirred for 12 hours, lithium hydroxide monohydrate (16 mg, 0.384 mmol) was added, and the mixture was stirred at room temperature for 24 hours. Furthermore, lithium hydroxide monohydrate (8 mg, 0.192 mmol) was added and stirred for 24 hours.
  • the reaction mixture was cooled to 0 ° C., 1N hydrochloric acid was added to adjust the pH to around 3, and the mixture was extracted with chloroform.
  • the chloroform layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off. The obtained residue was vacuum-dried to obtain 148 mg (89%) of the title compound as a white solid.
  • SN38Pt-SM8 80 mg, 0.0813 mmol was dissolved in ethanol (20 mL). Diaqua DACH platinum complex (38 mg, 0.0813 mmol) and water (2.44 mL) were added there. Subsequently, 0.1 N sodium hydroxide aqueous solution (1.63 mL, 0.163 mmol) was added, and it stirred at 50 degreeC for 23 hours. The reaction mixture was concentrated to dryness, N, N-dimethylacetamide was added to the residue, and the mixture was centrifuged (8,000 rpm, 5 min).
  • 6- [4,4-bis (tert-butoxycarbonyl) piperidin-1-yl] -6-oxohexanoic acid (631 mg, 1.40 mmol) was dissolved in N, N-dimethylformamide (4 mL) under an argon gas atmosphere. And cooled to 0 ° C.
  • TCTU (498 mg, 1.40 mmol) and N, N-diisopropylethylamine (714 ⁇ L, 1.40 mmol) were added thereto.
  • the chloroform layer was dried over anhydrous magnesium sulfate and the solvent was distilled off.
  • the obtained residue was purified by silica gel column chromatography (methanol / chloroform stepwise) to obtain 927 mg (93%) of the title compound as a pale yellow solid.
  • SN38Pt-SM9 200 mg, 0.225 mmol was dissolved in ethanol (56 mL). Diaqua DACH platinum complex (106 mg, 0.225 mmol) and water (6.75 mL) were added there. Subsequently, 0.1 N sodium hydroxide aqueous solution (4.51 mL, 0.451 mmol) was added, and it stirred at 50 degreeC for 23 hours. The reaction mixture was concentrated to dryness, N, N-dimethylacetamide was added to the residue, and the mixture was centrifuged (8,000 rpm, 5 min).
  • the resulting supernatant was purified using reverse-phase HPLC (SunFire OBD, C18, 5 ⁇ m (30 mmID X 150 mm), solvent: methanol / water gradient, Flow rate: 20 mL / min, UV 254 nm), A peak containing SN38Pt-9 was collected. The fractions collected were collected and methanol was distilled off. The resulting aqueous solution was lyophilized to give 157 mg (58%) of the title compound as a yellow powder.
  • oxalyl chloride (456 ⁇ L, 5.32 mmol) was dissolved in dichloromethane (6 mL) and cooled to ⁇ 78 ° C.
  • a dichloromethane solution (7 mL) of dimethyl sulfoxide (346 ⁇ L, 4.87 mmol) was added dropwise thereto, and the mixture was stirred at ⁇ 78 ° C. for 5 minutes.
  • a dichloromethane solution (5 mL) of methyl 10-hydroxydecanoate (896 mg, 4.43 mmol) was added dropwise, and the mixture was stirred at ⁇ 78 ° C. for 15 minutes.
  • Triethylamine (3.02 mL) was added to the reaction mixture all at once, and the mixture was stirred at ⁇ 78 ° C. for 10 minutes, and then stirred for 4 hours while gradually warming to room temperature.
  • the reaction solution was diluted with chloroform and washed with a saturated aqueous ammonium chloride solution and saturated brine.
  • the chloroform layer was dried over anhydrous magnesium sulfate and the solvent was distilled off.
  • the obtained residue was purified by silica gel column chromatography (ethyl acetate / n-hexane stepwise) to give the title compound (569 mg, 64%) as a colorless oil.
  • SN38Pt-SM10 80 mg, 0.0920 mmol was dissolved in ethanol (23 mL).
  • the diaquo DACH platinum complex 43 mg, 0.0920 mmol
  • water 2.76 mL
  • 0.1 N sodium hydroxide aqueous solution (1.84 mL, 0.184 mmol) was added, and it stirred at 50 degreeC for 23 hours.
  • the reaction mixture was concentrated to dryness, N, N-dimethylacetamide was added to the residue, and the mixture was centrifuged (8,000 rpm, 5 min).
  • the resulting supernatant was purified using reverse-phase HPLC (SunFire OBD, C18, 5 ⁇ m (30 mmID X 150 mm), solvent: methanol / water gradient, Flow rate: 20 mL / min, UV 254 nm), A peak containing SN38Pt-10 was collected. The fractions collected were collected and methanol was distilled off. The resulting aqueous solution was lyophilized to give 32 mg (30%) of the title compound as a yellow powder.
  • dodecanedioic acid monoethyl ester (1.50 g, 5.81 mmol) was dissolved in dichloromethane (20 mL) and cooled to 0 ° C.
  • a solution of t-butanol (1.29 g, 17.4 mmol) in dichloromethane (5 mL) and dimethylaminopyridine (568 mg, 4.65 mmol) were added thereto.
  • 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (EDCI) (1.23 g, 6.39 mmol) was added little by little, and the mixture was stirred at 0 ° C.
  • 12- (tert-butoxy) -12-oxododecanoic acid (777 mg, 2.71 mmol) was dissolved in N, N-dimethylformamide (8 mL) and cooled to 0 ° C.
  • TCTU (963 mg, 2.71 mmol) and N, N-diisopropylethylamine (1.38 mL, 8.13 mmol) were added thereto.
  • diaquo DACH platinum complex 27 mg, 0.058 mmol was suspended in chloroform (2.5 mL) and water (2.5 mL), and heated to 50 ° C.
  • SN38Pt-SM11 76 mg, 0.106 mmol was added there, then 0.1 N sodium hydroxide aqueous solution (1.06 mL, 0.106 mmol) was added, and it stirred at 50 degreeC for 23 hours.
  • the chloroform layer was separated and the aqueous layer was extracted with chloroform.
  • the chloroform layers were combined, washed with water, dried over anhydrous sodium sulfate, and the solvent was distilled off.
  • N, N-dimethylacetamide was added to the resulting residue and centrifuged (8,000 rpm, 5 min).
  • the resulting supernatant was purified using reverse-phase HPLC (SunFire OBD, C18, 5 ⁇ m (30 mmID X 150 mm), solvent: methanol / water gradient, Flow rate: 20 mL / min, UV 254 nm), A peak containing SN38Pt-11 was collected. The fractions collected were collected and methanol was distilled off. The resulting aqueous solution was lyophilized to give 21 mg (21%) of the title compound as a yellow powder.
  • Example 12 Anti-tumor effect of SN38Pt-4 (Example 4) was examined using a tumor growth inhibition rate (IR%) as an index in a human colon cancer cell (HT-29) xenograft tumor model transplanted into nude mice.
  • Table 1 shows the results of the antitumor effect test.
  • the amount of active ingredient contained in the total dose (mg / kg) of the administered test substance is the SN-38 amount (mg / kg) or DACH-Pt amount (mg / kg). ) In the same table.
  • mice As animals, 5-week-old male nude mice (BALB / c Slc-nu) were purchased from Japan SLC Co., Ltd. and used as 5 animals per group.
  • Tumor cells Human colorectal cancer cells (HT-29) were purchased from the American Type Culture Collection (ATCC) and Dulbecco's Modified Eagle's Medium containing 10% fetal bovine serum (FBS), 100 U / mL penicillin and 100 ⁇ g / mL streptomycin. (DMEM medium) (10% FBS / DMEM) was used for subculture under conditions of 5% CO 2 and 37 ° C.
  • oxaliplatin (6.7 mg / kg) or irinotecan hydrochloride (CPT-11) (71 mg / kg) was totaled 3 times (total 20, 213 mg / kg) Dissolved in physiological saline and administered intraperitoneally.
  • the control group received the solvent on a similar schedule.
  • the tumor growth inhibition rate IR (%) was determined by the following formula.
  • Tumor growth inhibition rate IR (%) (1-average tumor weight in treated group / average tumor weight in control group) x 100
  • the dose of CPT-11 is within the range that does not exceed the maximum tolerated dose (270 mg / kg) and is expected to have a sufficient antitumor effect.
  • the total dose is 213 mg / kg (71 mg / kg / 1 Times).
  • L-OHP was the maximum tolerated dose of 20 mg / kg (6.7 mg / kg / dose).
  • SN38Pt-4 showed a significant (p ⁇ 0.001) lower tumor weight in the HT-29 tumor model than the control group, confirming an excellent antitumor effect.
  • SN38Pt-4 showed an antitumor effect in a dose-dependent manner, with a significantly higher antitumor effect (IR 81.8%) in the 600 mg / kg group than in the L-OHP + CPT-11 combination group (IR 50.5%) Indicated.
  • IR 81.88% in the 600 mg / kg group than in the L-OHP + CPT-11 combination group
  • SN38Pt-4 had a higher dose (DACH-Pt In the equivalent amount), no death cases are observed, and an excellent antitumor effect can be obtained in a dose-dependent manner. More specifically, when considering the maximum tolerated dose of L-OHP (including 16 mg / kg as DACH-Pt amount), in this study, SN38Pt-4 is 600 mg / kg (DACH-Pt amount is about 10 times the amount) (157 mg / kg), almost no toxicity was observed (Mortality: 1/5), and a dose-dependent antitumor effect was obtained.
  • SN38Pt-4 can be used at higher doses (200 mg / kg as the SN-38 amount). Almost no toxicity was observed (Mortality: 1/5), and a dose-dependent antitumor effect was obtained.
  • Example 13 (Preparation of SN38Pt-4 micelles) SN38Pt-4 (14.29 mg) was suspended in ethanol (0.3 mL), and SL-11 (392 ⁇ L) (manufactured by NOF) that had been heated to 90 ° C. was added and dissolved by heating. Ethanol was distilled off using a centrifugal evaporator, and dissolved again by warming.Add 5% glucose solution (1608 ⁇ L) that had been heated to 90 ° C, and stirred to prepare micelles (SN38Pt per unit of micelles) -4 amount: 7 mg / mL).

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Abstract

La présente invention concerne un composé dans lequel une pluralité de sous-structures qui peuvent être attendues comme ayant différents mécanismes d'activité anticancéreuse sont incluses dans la même molécule, le composé présentant en outre une toxicité faible ainsi qu'une activité anticancéreuse élevée. Un dérivé de camptothécine a une structure de complexe de platine représentée par la formule générale (1) ou (2) (où A et B représentent indépendamment un groupe alkylène inexistant, substitué, ou non substitué, un groupe alkylènecarbonyle, ou un groupe aminoalkylène-aminocarbonyle non-cyclique ou cyclique).
PCT/JP2012/082738 2011-12-21 2012-12-18 Nouveau dérivé de camptothécine WO2013094581A1 (fr)

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2014203691A1 (fr) * 2013-06-18 2014-12-24 株式会社ヤクルト本社 Nouveau médicament contenant un complexe du platine
CN109776323A (zh) * 2019-01-28 2019-05-21 富乐马鸿凯（大连）医药有限公司 一种高效选择性制备脂肪二酸单叔丁酯的方法
CN111333505A (zh) * 2020-03-31 2020-06-26 东莞市东阳光生物药研发有限公司 制备长链脂肪二酸单苄酯的方法及其应用

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JPH02157291A (ja) * 1988-12-07 1990-06-18 Morishita Pharmaceut Co Ltd アントラサイクリン系抗生物質のｎ−ホルミルアミノ酸複合体およびその白金錯体組成物
WO1993009782A1 (fr) * 1991-11-15 1993-05-27 Smithkline Beecham Corporation Chimiotherapie combinee

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Publication number Priority date Publication date Assignee Title
JPH02157291A (ja) * 1988-12-07 1990-06-18 Morishita Pharmaceut Co Ltd アントラサイクリン系抗生物質のｎ−ホルミルアミノ酸複合体およびその白金錯体組成物
WO1993009782A1 (fr) * 1991-11-15 1993-05-27 Smithkline Beecham Corporation Chimiotherapie combinee

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KONTEK,R. ET AL.: "Genotoxic effects of irinotecan combined with the novel platinum(II) complexes in human cancer cells", CHEMICO- BIOLOGICAL INTERACTIONS, vol. 188, no. 1, 2010, pages 66 - 74 *

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2014203691A1 (fr) * 2013-06-18 2014-12-24 株式会社ヤクルト本社 Nouveau médicament contenant un complexe du platine
CN109776323A (zh) * 2019-01-28 2019-05-21 富乐马鸿凯（大连）医药有限公司 一种高效选择性制备脂肪二酸单叔丁酯的方法
CN111333505A (zh) * 2020-03-31 2020-06-26 东莞市东阳光生物药研发有限公司 制备长链脂肪二酸单苄酯的方法及其应用
WO2021197303A1 (fr) * 2020-03-31 2021-10-07 东莞市东阳光生物药研发有限公司 Procédé de préparation d'ester monobenzyl de diacide gras à longue chaîne et utilisation associée
CN111333505B (zh) * 2020-03-31 2022-07-26 东莞市东阳光生物药研发有限公司 制备长链脂肪二酸单苄酯的方法及其应用

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