WO2004099224A1 - Complexes de platine (ii) de type carboplatine - Google Patents

Complexes de platine (ii) de type carboplatine Download PDF

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Publication number
WO2004099224A1
WO2004099224A1 PCT/EP2004/004680 EP2004004680W WO2004099224A1 WO 2004099224 A1 WO2004099224 A1 WO 2004099224A1 EP 2004004680 W EP2004004680 W EP 2004004680W WO 2004099224 A1 WO2004099224 A1 WO 2004099224A1
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WO
WIPO (PCT)
Prior art keywords
carboplatin
platinum
complexes
derivatives according
diaminocyclohexane
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PCT/EP2004/004680
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German (de)
English (en)
Inventor
Henri Brunner
Nick Gruber
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Universität Regensburg
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Publication date
Priority claimed from DE10351021A external-priority patent/DE10351021A1/de
Application filed by Universität Regensburg filed Critical Universität Regensburg
Publication of WO2004099224A1 publication Critical patent/WO2004099224A1/fr

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    • 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 System
    • C07F15/0006—Compounds containing elements of Groups 8, 9, 10 or 18 of the Periodic System compounds of the platinum group
    • C07F15/0086—Platinum compounds
    • C07F15/0093—Platinum compounds without a metal-carbon linkage

Definitions

  • the cisplatin which has been approved since 1978, is used as a single preparation or in combination with other synergistic cytostatics such as bleomycin, vinblatin, methotrexate, adriamycin, cyclophosphamide, doxo-rubicin or ethidium bromide against testicular, ovarian, bladder and lung carcinomas and against Tumors used in the neck and head area.
  • cytostatics such as bleomycin, vinblatin, methotrexate, adriamycin, cyclophosphamide, doxo-rubicin or ethidium bromide against testicular, ovarian, bladder and lung carcinomas and against Tumors used in the neck and head area.
  • cytostatics such as bleomycin, vinblatin, methotrexate, adriamycin, cyclophosphamide, doxo-rubicin or ethidium bromide against testicular, ovarian
  • cisplatin therapy is associated with a number of serious side effects.
  • the intravenously administered cisplatin leads to immediate side effects such as impairments of the gastrointestinal area (loss of appetite, nausea, vomiting), nephrotoxicity (kidney-damaging effect), ototoxicity (hearing damage), myeloid toxicity (bone marrow-damaging effect) and peripheral neuropathies (peripheral nerve damage) mental stress.
  • the toxicological effects of cisplatin are mainly based on the coordination of platinum to thiol groups of proteins.
  • the dose-limiting factor today is primarily myelotoxicity, since the strong nephroticity can be reduced by additional administration of sulfur compounds such as thiourea or sodium diethyldithiocarbamate, as well as by hydration and mannitol-induced diuresis, because the renal excretion of platinum compounds is accelerated.
  • sulfur compounds such as thiourea or sodium diethyldithiocarbamate
  • hydration and mannitol-induced diuresis because the renal excretion of platinum compounds is accelerated.
  • sulfur compounds such as glutathione
  • carboplatin The best analogue to cisplatin has been carboplatin (US 4,657,927), which has been on the market since 1990.
  • Carboplatin shows an efficacy comparable to cisplatin in ovarian, bronchial and cervical carcinomas as well as head and neck tumors.
  • a major advantage of carboplatin is the significantly reduced nephrotoxicity, which no longer plays a role in the dose range used, a lower emetic potential, ie reduction in nausea and vomiting, and the reduced neurotoxicity and ototoxicity. However, this is bought with a higher bone marrow toxicity and associated thrombocytopenia and leukocytopenia. This myelotoxicity is dose-limiting for carboplatin.
  • carboplatin In contrast to cisplatin, carboplatin carries 1, 1-cyclobutanedicarboxylic acid as a leaving group and is therefore more stable to hydrolysis.
  • the non-coplanar structure of carboplatin due to the tetrahedrally configured spiro-carbon atom may lead to a reduced degradation to damaging derivatives.
  • the half-life in blood plasma at 37 ° C. is 30 hours for carboplatin, but only 1.5 to 3.6 hours for cisplatin (S. Hanessian, J. Wang, Can. J. Chem. 1993, 71, 896).
  • R 7 alkyl, aryl, acetyl or acyl, C n F 2n + ⁇ , at least one of the radicals R 1 to R 6 not being H,
  • R 8 and R 9 independently of one another NH 3 ;
  • the inventors could now surprisingly show that by introducing electron-attracting substituents such as. B. halogens or hydroxyl groups in carboplatin the activity profile of such carboplatin derivatives is significantly improved compared to cisplatin and carboplatin.
  • the carboplatin derivative in which R 1 is chlorine is particularly preferred.
  • the invention further relates to medicaments which contain the carboplatin derivatives described above.
  • the medicinal products contain carriers and auxiliary substances known per se, so that a correspondingly compatible formulation can be produced.
  • the invention further relates to the use of the carboplatin derivatives according to general formula I for the manufacture of a medicament for tumor therapy. As will be shown below, it has been found that the novel carboplatin derivatives are particularly suitable for this.
  • Activation is carried out by first rinsing the ion exchanger with 100 ml of 2N NaOH and then eluting with H 2 0 until the eluate running off has a pH of 9. After the solvent has been stripped off in public transport, a glassy, light-sensitive residue is obtained which can be stored in the dark at -20 ° C for a long period. Only immediately before use is the residue taken up in 50 ml of H 2 O / EtOH (1: 1).
  • the ligands To complex the 1,1-cyclobutanedicarboxy-lato ligands derived from 3-chloro-1,1-cyclobutanedicarboxylic acid 9 and 3-hydroxy-1,1-cyclobutanedicarboxylic acid 14 with the water-soluble ice
  • the ligands To achieve diammine (diaqua) platinum (II) dihydroxide 2, the ligands must be dissolved in water or at least in a water-miscible solvent such as methanol, ethanol, tetrahydrofuran, acetone or dimethylforamide.
  • ligands 9 and 14 are dissolved in water.
  • diammine (diaqua) platinum (II) dihydroxide solution After adding an equimolar amount of diammine (diaqua) platinum (II) dihydroxide solution, the reaction solution is stirred for five days at room temperature with the exclusion of light. The metallic platinum formed is filtered off and the solvent of the filtrate is distilled off to dryness in an oil pump vacuum. The yellowish crude product is recrystallized from water to 1 cleaning. Care should be taken not to heat, otherwise the complex will decompose.
  • the two new carboplatin-like complexes cis-diammine (3-chloro-l, 1-cyclobutanedicarboxylato) plati (II) 89 and cis-diammin (3-hydroxy-1, 1-cyclobutanedicarboxylato) platinum (II) 90 can be synthesized (Fig. 2).
  • the two complexes 89 and 90 can be isolated in the form of colorless crystals.
  • the water solubility of both compounds is around 18 g-1 "1 in the carboplatin range.
  • the hydroxy complex 90 is, as expected, more water-soluble than the corresponding chlorine complex 89.
  • the starting compound for the synthesis of 1,1-cyclobutanedicarboxylic acid dichloride is the commercially available 1,1-cyclobutanedicarboxylic acid.
  • An excess of freshly distilled thionyl chloride is slowly added dropwise to this.
  • the reaction mixture is then heated under reflux with exclusion of moisture until the evolution of gas has ended.
  • the reaction produces the gaseous products 0 2 and HCl.
  • the excess of thionyl chloride is distilled off on a water bath.
  • the yellowish, liquid crude product is purified by fractional distillation in a water jet vacuum.
  • 1,1-cyclobutanedicarboxylic acid dichloride is slightly warmed with catalytic amounts of AIBN and an equimolar amount of freshly distilled sulphuryl chloride, an exothermic reaction being observed.
  • the orange-colored crude product still contains educt as an impurity and is purified by repeated fractional distillation. It is known that the radical chlorination of 1,1-cyclobutanedicarboxylic acid with sulfuryl chloride has a high selectivity, so that the chlorination takes place practically exclusively in the 3 position.
  • 3-chloro-1,1-cyclobutanedicarboxylic acid In order to obtain 3-chloro-1,1-cyclobutanedicarboxylic acid, the 3-chloro-1,1-cyclobutanedicarboxylic acid dichloride must be hydrolyzed. For this purpose, a slight excess of water is added to 3-chloro-l, 1-cyclobutanedicarboxylic acid dichloride and gently warmed on the water bath. After a short induction period, an exothermic reaction begins. Extraction of the aqueous phase with diethyl ether enables 3-chloro-l, 1-cyclobutanedicarboxylic acid to be isolated as a colorless solid in good yields.
  • the complexation with the platinum fragment is carried out according to the proven scheme.
  • Cisplatin is stirred for one week with the exclusion of light with two molar equivalents of silver nitrate in aqueous solution.
  • the two chloride ligands are replaced by aqua ligands.
  • Silver chloride precipitates and nitrate ions ensure charge balance.
  • the nitrate ions are then exchanged for hydroxide ions by chromatography over a strongly basic ion exchanger. This forms cis-diammine (diaqua) platinum (II) dihydroxide, which is taken up for complexation in the water / ethanol (1: 1) solvent mixture.
  • First 3-chloro-1, 1-cyclobutanedicarboxylic acid is dissolved in water.
  • PI-LISIMS m / z (%) (glycerol / H 2 0): 407 (100), MH + .
  • 1, 3-Dibromo-2-benzyloxypropane is synthesized by reacting epibromohydrin ((+) -l-bromo-2, 3-epoxypropane) with benzyl bromide and catalytic amounts of HgCl 2 .
  • the reaction mixture is heated to an internal temperature of 155-160 ° C. for eight hours, during which a dark brown coloration occurs.
  • the product is purified by distillation in an oil pump vacuum. To increase the yield, the forerun, which contains the starting materials, is again heated with HgCl 2 and worked up accordingly.
  • the first variant uses the reaction of 1,3-dibromo-2-benzyloxypropane with diethyl malonate in the presence of sodium ethanolate in benzene as solvent.
  • an autoclave is required as the reaction vessel.
  • half of the required amount of sodium ethanolate solution is added to the reaction mixture.
  • the reaction solution is allowed to cool, the rest of the sodium ethanolate solution and a little benzene and heat for a further six hours to 170 ° C. This builds up a pressure of about 10 atm.
  • the neutral solution obtained is separated from the precipitated NaBr by suction and evaporated on a water bath.
  • the NaBr is dissolved in water, the solution extracted with ether and the ethereal extract concentrated.
  • the crude product contained therein is then combined with the main fraction and purified by repeated fractional distillation.
  • PI-LISIMS m / z (%) (glycerol / H 2 0): 388 (100), MH + .
  • Crystals suitable for X-ray structure analysis were obtained from cis-diammine (3-hydroxy-l, 1-cyclobutanedicarboxy-lato) platinum (II) (90) by slow crystallization. For this, 90 is dissolved in water and covered with a little acetone. The clear solution is left in the dark at room temperature with the flask open so that the solvent can slowly evaporate. 90 crystallizes in the form of colorless, platelet-shaped crystals. The result of the crystal structure analysis is shown in Fig. 3. The square-planar coordination of Ptl within the scope of the measuring accuracy is clearly recognizable.
  • the hydrogen atoms of the NH 3 groups connect the molecules via the carboxylate oxygen atoms through hydrogen bonds.
  • the specified bond lengths and angles correspond to the values of carboplatin.
  • a carbon atom of the cyclobutane ring, the C5 atom shows a pronounced thermal movement. This can be interpreted as the dynamic folding of the cyclobutane ring.
  • the cyclobutane ring undergoes dynamic inversion between two conformations at room temperature.
  • the bond lengths show that the CO bonds of the chelate ring are about 50 pm longer than those of 02 and 03 and are therefore more of a single bond type. Both are within the characteristic range for CO double bonds.
  • the C5-05 bond length of 1,411 ⁇ is on the order of a single CO bond.
  • This activated species 91 is reacted with the cyclobutanedicarboxylato ligands 9 and 14 dissolved in water.
  • the mixture is then stirred for five days at room temperature with the exclusion of light.
  • the metallic platinum that is formed is filtered off through a membrane filter and the solvent of the filtrate is distilled off to dryness in an oil pump vacuum, the heating should not be excessive, since otherwise the complex will decompose.
  • the yellowish crude product is purified by recrystallization from water at room temperature, colorless crystal needles being obtained from complexes 93 and 94 (FIG. 5).
  • complex 94 was able to obtain crystals suitable for X-ray structure analysis. To do this, the compound 94 is dissolved in water and the clear solution is left to stand in the dark at room temperature with the flask open to ensure slow evaporation of the solvent.
  • the X-ray structure analysis of the colorless crystal needles obtained shows, as would be expected, that the measured crystals are composed of a 1: 1 mixture of the two diastereomers.
  • This finding results from the use of the racemate (+) -trans-1,2-diaminocyclohexane for the complexation in the synthesis of the precursor complex 88, taking into account the spatial arrangement of the OH group on the cyclobutane ring.
  • the result of the X-ray diffractometric examinations is shown in FIG. 6.
  • the square-planar coordination of Ptl or Pt2 can be clearly seen here.
  • the six-membered chelate ring is also present in the tub conformation, since the C3 atom and also the Ptl atom are folded out of the plane 01-C1-C2-03 in the same direction.
  • the torsion angle C6-C3-C4-C5 of 12.6 (5) ° (Table 2) illustrates the twisting of the cyclobutane ring with the hydroxyl group arranged in the equatorial position.
  • Table 2 illustrates the twisting of the cyclobutane ring with the hydroxyl group arranged in the equatorial position.
  • Table 2 A summary of the most important binding parameters can be found in Table 2.
  • the structural data of the second diastereomer correspond to the given values within the measurement accuracy.
  • Table 2 Selected structural data of the diamine platinum (II) complex 94.
  • N2-PH-O3-C2 -136.8 N2-H2B ... O6; 2.4749; 122.72
  • the urothelial carcinoma cell line J82 [G3] was selected as an in vitro model.
  • the T / C value was determined as a measure of the effectiveness.
  • T cell density after exposure to the test substance
  • the T / C values indicate the percentage inhibition of cell growth in comparison to a reference (only solvents without substance incubation). 0% means that cell growth has stopped, while 100% indicates growth corresponding to the untreated reference. According to the definition of the T / C value, values over 100% are also possible. These signal stimulated cell growth by the active ingredient. Negative values result from a lower cell density than the reference, i.e. H. the substances do not exert a cytostatic, but a cytotoxic effect. Thus, T / C values around 0% indicate optimal effectiveness.
  • FIG. 7 shows the test results for carboplatin and the carboplatin-like diamminplatin (II).
  • Fig. Shows that in aqueous physiological saline solution of Cl-carboplatin occurred already after one hour of hydrolysis products and in the course of 168 hours, an approximately 40% reduction for 'cisplatin was. 11 Cl-carboplatin is therefore • much more sensitive to hydrolysis than carboplatin.
  • the chlorine substituent reduces the electron density at the oxygen atoms of the carboxylic acid groups and thus influences the rate of substitution.
  • the faster hydrolysis enables a faster release of the cis-diamminplatin (II) fragment, which in turn, through interaction with the DNA bases, influences the processes during cell division and is responsible for the cytostatic properties.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

L'invention concerne des dérivés carboplatine, des agents pharmaceutiques contenant ces dérivés, ainsi que l'utilisation des dérivés carboplatine dans la fabrication d'agents pharmaceutiques destinés à la thérapie de tumeurs.
PCT/EP2004/004680 2003-05-05 2004-05-03 Complexes de platine (ii) de type carboplatine WO2004099224A1 (fr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
DE10320222.6 2003-05-05
DE10320222 2003-05-05
DE10351021.4 2003-10-31
DE10351021A DE10351021A1 (de) 2003-05-05 2003-10-31 Carboplatin-artige Platin (II)-Komplexe

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Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007029031A1 (fr) * 2005-09-05 2007-03-15 Johnson Matthey Plc Compose metallique et son procede de preparation
CN1307256C (zh) * 2002-05-16 2007-03-28 拜尔公司 用于减振装置的胶料
CN101914117A (zh) * 2010-02-11 2010-12-15 中国科学院上海药物研究所 含有二氯乙酰氧基的铂(ii)类抗癌配合物
CN103224533A (zh) * 2012-01-30 2013-07-31 东南大学 含硝酸酯基团的烷基羧酸根为配体的抗肿瘤铂(ii)配合物
WO2014067336A1 (fr) * 2012-10-29 2014-05-08 东南大学 Complexe du platine bivalent antitumoral et procédé de préparation d'un complexe et d'un ligand de complexe
WO2016187191A1 (fr) 2015-05-18 2016-11-24 Medoc Pharmaceutical Co., Ltd. Co-cristal pharmaceutique et son utilisation
US10421770B2 (en) 2015-06-19 2019-09-24 Syn-Nat Products Enterprise LLC Pharmaceutical composition of carboplatin based co-crystals and use thereof
US10428099B2 (en) 2015-06-25 2019-10-01 Syn-Nat Products Enterprise LLC Pharmaceutical co-crystal composition and use thereof

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
CANADIAN JOURNAL OF CHEMISTRY , 71(6), 896-906 CODEN: CJCHAG; ISSN: 0008-4042, 1993 *
DATABASE CHEMABS [online] CHEMICAL ABSTRACTS SERVICE, COLUMBUS, OHIO, US; HANESSIAN, STEPHEN ET AL: "Design and synthesis of a cephalosporin-carboplatinum prodrug activatable by a .beta.-lactamase", XP002295341, retrieved from STN Database accession no. 1994:22366 *
DATABASE CHEMABS [online] CHEMICAL ABSTRACTS SERVICE, COLUMBUS, OHIO, US; PASHKOVSKII, F. S. ET AL: "General approach to synthesis of carboplatin analog containing fragments of carboxylic fatty acids in acid ligand", XP002295340, retrieved from STN Database accession no. 2002:940369 *
DOKLADY NATSIONAL'NOI AKADEMII NAUK BELARUSI , 46(4), 63-65 CODEN: DNABFW; ISSN: 1561-8323, 2002 *

Cited By (16)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1307256C (zh) * 2002-05-16 2007-03-28 拜尔公司 用于减振装置的胶料
WO2007029031A1 (fr) * 2005-09-05 2007-03-15 Johnson Matthey Plc Compose metallique et son procede de preparation
CN101914117A (zh) * 2010-02-11 2010-12-15 中国科学院上海药物研究所 含有二氯乙酰氧基的铂(ii)类抗癌配合物
CN101914117B (zh) * 2010-02-11 2013-01-23 中国科学院上海药物研究所 含有二氯乙酰氧基的铂(ii)类抗癌配合物
CN103224533B (zh) * 2012-01-30 2015-10-07 东南大学 含硝酸酯基团的烷基羧酸根为配体的抗肿瘤铂(ii)配合物
CN103224533A (zh) * 2012-01-30 2013-07-31 东南大学 含硝酸酯基团的烷基羧酸根为配体的抗肿瘤铂(ii)配合物
US9227991B2 (en) 2012-10-29 2016-01-05 Southeast University Anti-tumor bivalent platinum complex and preparation method for complex and ligand of complex
EP2913335A1 (fr) * 2012-10-29 2015-09-02 Southeast University Complexe du platine bivalent antitumoral et procédé de préparation d'un complexe et d'un ligand de complexe
WO2014067336A1 (fr) * 2012-10-29 2014-05-08 东南大学 Complexe du platine bivalent antitumoral et procédé de préparation d'un complexe et d'un ligand de complexe
JP2016500126A (ja) * 2012-10-29 2016-01-07 ▲東▼南大学Ｓｏｕｔｈｅａｓｔ Ｕｎｉｖｅｒｓｉｔｙ 抗腫瘍二価白金錯体並びに錯体および錯体のリガンドの製造方法
EP2913335A4 (fr) * 2012-10-29 2016-04-20 Univ Southeast Complexe du platine bivalent antitumoral et procédé de préparation d'un complexe et d'un ligand de complexe
WO2016187191A1 (fr) 2015-05-18 2016-11-24 Medoc Pharmaceutical Co., Ltd. Co-cristal pharmaceutique et son utilisation
JP2018521969A (ja) * 2015-05-18 2018-08-09 シン−ナット プロダクツ エンタープライズ エルエルシー 医薬用共結晶及びその用途
EP3297624A4 (fr) * 2015-05-18 2018-12-05 Syn-Nat Products Enterprise LLC Co-cristal pharmaceutique et son utilisation
US10421770B2 (en) 2015-06-19 2019-09-24 Syn-Nat Products Enterprise LLC Pharmaceutical composition of carboplatin based co-crystals and use thereof
US10428099B2 (en) 2015-06-25 2019-10-01 Syn-Nat Products Enterprise LLC Pharmaceutical co-crystal composition and use thereof

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