WO2009100691A1 - Polymorphic form ( iii ) of the adamantylamino- platinum (iv) complex la- 12 - Google Patents

Polymorphic form ( iii ) of the adamantylamino- platinum (iv) complex la- 12 Download PDF

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Publication number
WO2009100691A1
WO2009100691A1 PCT/CZ2009/000014 CZ2009000014W WO2009100691A1 WO 2009100691 A1 WO2009100691 A1 WO 2009100691A1 CZ 2009000014 W CZ2009000014 W CZ 2009000014W WO 2009100691 A1 WO2009100691 A1 WO 2009100691A1
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iii
tricyclo
acetato
decylamine
bis
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PCT/CZ2009/000014
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French (fr)
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Petr Sova
Ales Kroutil
Ales Franc
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Pliva-Lachema A.S.
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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
    • A61K31/28—Compounds containing heavy metals
    • A61K31/282—Platinum compounds
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C211/00—Compounds containing amino groups bound to a carbon skeleton
    • C07C211/33—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to carbon atoms of rings other than six-membered aromatic rings
    • C07C211/34—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to carbon atoms of rings other than six-membered aromatic rings of a saturated carbon skeleton
    • C07C211/38—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to carbon atoms of rings other than six-membered aromatic rings of a saturated carbon skeleton containing condensed ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F15/00—Compounds containing elements of Groups 8, 9, 10 or 18 of the Periodic Table
    • C07F15/0006—Compounds containing elements of Groups 8, 9, 10 or 18 of the Periodic Table compounds of the platinum group
    • C07F15/0086—Platinum compounds
    • C07F15/0093—Platinum compounds without a metal-carbon linkage
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2603/00—Systems containing at least three condensed rings
    • C07C2603/56—Ring systems containing bridged rings
    • C07C2603/58—Ring systems containing bridged rings containing three rings
    • C07C2603/70—Ring systems containing bridged rings containing three rings containing only six-membered rings
    • C07C2603/74—Adamantanes

Definitions

  • the present invention relates to a novel polymorphic form of the compound (OC-6-43)- bis(acetato)(1-tricyclo[3,3,1 ,1 3i7 ]decylamine)amminedichloroplatinum(IV), (also called LA- 12), methods of preparation, isolation and identification thereof, pharmaceutical compositions containing the same, use of such polymorph and compositions in the treatment of oncological deseases.
  • platinum cytostatics cannot be administered orally due to their insufficient stability in gastro intestinal track. This problem has been bridged over by using platinum(IV) complexes, whose bioavailability after oral administration is generally higher in comparison with routinely used platinum cytostatics such as e.g. cisplatin, carboplatin or oxaliplatin. Said platinum(IV) complexes intended for oral administration have been described in EP 0 328 274, EP 0423 707 and WO 99/61451.
  • platinum(IV) complex is represented by the structural formula:
  • the complex is prepared from (OC-6-43)(1- -tricyclo[3,3,1,1 3 ' 7 ]decylamine)amminedichlorodihydroxoplatinum(IV) by reaction with excess of acetic anhydride to yield a solid which begins to decompose at 180 0 C.
  • Polymorphism is defined as the ability of an element or compound to crystallise in more than one distinct crystalline species.
  • polymorphs are distinct solids sharing the same molecular formula, however since the properties of any solid depends on its structure, different polymorphs may exhibit distinct physical properties such as different solubility profiles, different melting points, different dissolution profiles, different thermal and/or photostability, different shelf life, different suspension properties and different physiological absorption rate.
  • Inclusion of a solvent in the crystalline solid leads to solvates, and in the case of water as a solvent, hydrates.
  • Polymorphic forms of a compound may be distinguished by x-ray diffraction spectroscopy and other methods including infra-red spectrometry.
  • the present invention provides a polymorphic crystalline form (III) of (OC- -6-43)-bis(acetato)(1-tricyclo[3,3 l 1 ,1 37 ]decylamine)amminedichloroplatinum(IV) l characterized by substantially the same differential scanning calorimetry (DSC) thermograms as Figure 1 wherein the DSC was performed at Netzsch DSC 204 F1 at scan rate of 10 K/min.
  • DSC differential scanning calorimetry
  • the present invention provides a polymorphic crystalline form (III) of (OC-6-43)-bis(acetato)(1-tricyclo[3,3,1 ,1 3 ' 7 ]decylamine)amminedichloroplatinum(IV), characterized by substantially the same X-ray powder diffraction (XRPD) pattern as Figure 2, wherein the XRPD pattern is expressed in terms of 2 theta angles and obtained with a diffractometer using copper K ⁇ -radiation according to the procedures described herein.
  • XRPD X-ray powder diffraction
  • the present invention provides a polymorphic crystalline form (III) of (OC-6-43)-bis(acetato)(1 -tricyclo[3,3, 1 , 1 3(7 ]decylamine)amminedichloroplatinum(IV), characterized by an XRPD pattern expressed in terms of 2 theta angles obtained with a diffractometer copper using K ⁇ -radiation according to the procedures described herein and comprising 2 theta angles at 5.0 ⁇ 0.1 , 8.6 ⁇ 0.1 , 9.9 ⁇ 0.1 , 14.5 ⁇ 0.1 , 17.8 ⁇ 0.1 degrees or 17.8 ⁇ 0.1 , 10.3 ⁇ 0.1 , 8.9 ⁇ 0.1 , 6.1 ⁇ 0.1 , 5.0 ⁇ 0.1 A d-spacing.
  • the present invention provides a polymorphic crystalline form (III) of (OC-6-43)-bis(acetato)(1-tricyclo[3,3,1 ,1 3 ' 7 ]decylamine)amminedichloroplatinum(IV), characterized by substantially the same infrared (IR) spectrum as Figure 3 and 4, wherein the IR spectrum is obtained using a Nicolet-Magna 760 with DTGS KBr detector with a resolution of 0.5 cm "1 according to the procedures described herein.
  • IR infrared
  • the present invention provides a polymorphic crystalline form (III) of (OC-6-43)-bis(acetato)(1-tricyclo[3,3,1 ,1 3
  • the present invention provides a polymorphic crystalline form (III) of (OC-6-43)-bis(acetato)(1 -tricyclo[3,3, 1 , 1 37 ]decylamine)amminedichloroplatinum(IV), characterized by an IR spectrum obtained using a Nicolet-Magna 760 with DTGS KBr detector with a resolution of 0.5 cm “1 according to the procedures described herein and comprising peaks at 1544 ⁇ 2 cm "1
  • the present invention provides a procedure for the preparation of the polymorphic crystalline form (III) of (OC-6-43)-bis(acetato)(1-tricyclo[3, 3,1 ,1 3
  • the present invention provides a procedure for the preparation of the polymorphic crystalline form (III) of (OC-6-43)-bis(acetato)(1-tricyclo[3, 3,1 ,1 3 ' 7 ]- decylamine)amminedichloroplatinum(IV), as defined above, comprising precipitation carried out at a temperature of from 25 0 C to -30 0 C from a solution of (OC-6-43)- -bis(acetato)(1-tricyclo[3,3,1 ,1 37 ]decylamine)-amminedichloroplatinum(IV) in a dry solvent selected from acetone, diethylketone, methylethylketone, a primary alcohol with 1 to 8 carbon atoms, a secondary alcohol with 3 to 8 carbom atoms, dimethylformamide or acetamide by adding a dry aliphatic ether with 2 to 8 carbon atoms as antisolvent to reach a ratio solvent: anti
  • the present invention provides a dosage form for oral use comprising the polymorphic crystalline form (III) of (OC-6-43)-bis(acetato)(1- -tricyclo[3,3,1 ,1 3
  • the present invention provides a dosage form for parenteral use comprising the polymorphic crystalline form (III) of (OC-6-43)-bis(acetato)(1- -tricyclo[3,3,1 ,1 37 ]decylamine)amminedichloroplatinum(IV), as defined above, in admixture with at least one pharmaceutically acceptable excipient.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising the polymorphic crystalline form (III) of (OC-6-43)-bis(acetato)(1- -tricyclo[3,3,1 ,1 3
  • the present invention provides the polymorphic crystalline form (III) of (OC-6-43)-bis(acetato)(1 -tricyclo[3,3, 1 , 1 3i7 ]decylamine)amminedichloroplatinum(IV), as defined above, for use in therapy.
  • the present invention provides the polymorphic crystalline form (III) of (OC-6-43)-bis(acetato)(1-tricyclo[3,3,1 ,1 3(7 ]decylamine)amminedichloroplatinum(IV), as defined above, wherein the therapy is the treatment of an oncological disease.
  • the present invention provides a method of treatment of an oncological disease comprising administration of an effective amount of the polymorphic crystalline form (III) of (OC-6-43)-bis(acetato)(1-tricyclo[3,3,1 ,1 37 ]decylamine)- amminedichloroplatinum(IV), as defined above, to a patient in need thereof.
  • the present invention provides a use of the polymorphic crystalline form (III) of (OC-6-43)-bis(acetato)(1-tricyclo[3,3,1 ,1 37 ]decylamine)ammine- dichloroplatinum(IV), as defined, in the preparation of a medicament for the treatment of an oncological disease.
  • the present invention provides a polymorph of the compound (OC-6-43)-bis(acetato)(1-tricyclo[3,3,1 ,1 3i7 ]decylamine)amminedichloro- platinum(IV) designated "form (III)" and having the following structural formula:
  • This form (III) has a melting point of 197 ⁇ 2 0 C.
  • FIG. 1 The differential scanning calorimetry (DSC) thermogram for form (III) of compound of formula (I) according to the present invention. DSC was performed on Netzsch DSC 204 F1 at scan rate of 10 K/min according to the procedures described herein.
  • FIG. 1 The XRPD pattern of form (III) of compound of formula (I) according to the present invention.
  • the XRPD pattern is expressed in terms of 2 theta angles and obtained with a diffractometer using copper K ⁇ -radiation, according to the procedures described herein.
  • the present invention provides a novel crystalline form of compound of formula (I) exhibiting one or more advantageous pharmaceutical properties or other advantages over the known crude LA-12.
  • the crystalline form of the present invention is stable at ambient temperatures.
  • Decomposition of Polymorph III under thermal stress (120 0 C / 70 hours) is significantly smaller than decomposition of crude LA-12 under the same condition (0.4 % vs. 2.2 %).
  • XRPD X-ray powder diffraction
  • IR infrared
  • Raman spectra Raman spectra
  • DSC differential scanning calorimetry
  • TGA thermogravimetric analysis
  • DSC Differential Scanning Calorimetry
  • the DSC thermogram plots the differential rate of heating in miliwatts per miligram against temperature.
  • the DSC thermogram of form (III) of compound of formula (I) displays endotherm peak at 197°C ⁇ 2.
  • the enthalpy of fusion determined by integrating this peak is -72J/g ⁇ 10.
  • DSC thermogram of an unknown sample is substantially the same as the DSC thermogram of form (III) of the compound of formula (I). If the DSC thermogram is substantially the same as Figure 1 and the peak position is substantially the same as those for form (III), the previously unknown form can be readily and accurately identified as form (III).
  • the X-ray powder diffraction pattern of form (III) of the compound of formula (I) can be determined using conventional techniques and equipment known to those skilled in the art of analytical chemistry and physical characterization.
  • the diffraction pattern of Figure 2 was obtained using PHILIPS 1730/10 (Philips, Holland) attached to PC for data collection. Radiations generated from CuK ⁇ source, radiation (0,15419 nm). Exciting voltage: 4OkV, anode current: 35mA. The instrument was operated over the 2-theta range of 3°- 60°, step size: 0,01°. Sample: surface plain, in nickel sample holder, measured and stored at room temperature. Samples were presented as lightly pressed powder disk.
  • a lightly pressed powder disk sample of form (III) of the compound of formula (I) was used to produce the XRPD pattern of Figure 2.
  • 2 Theta angles in degrees (x-axis) is plotted against peak intensity in terms of the count rate per seconds (y-axis).
  • the XRPD pattern for each crystalline form is unique, exhibiting a unique set of diffraction peaks which can be expressed in 2 theta angles (°), d-spacings (A) and/or relative peak intensities.
  • Theta diffraction angles and corresponding d-spacing values account for positions of various peaks in the XRPD pattern. D-spacing values are calculated with observed 2 theta angles and copper Ka 1 wavelength using the Bragg equation. Slight variations in observed 2 theta angles and d-spacings are expected based on the specific diffractometer employed and the analyst's sample preparation technique. More variation is expected for the relative peak intensities. Large variations of relative peak intensities may be observed due to preferred orientation resulting from differences in crystal morphology. Identification of the exact crystal form of a compound should be based primarily on observed 2 theta angles or d-spacings with lesser importance place on relative peak intensities.
  • Form III is identified from these characteristic 2 theta angle peaks, in some circumstances it may be desirable to rely upon additional 2 theta angles or d-spacings for the identification of Form III compound of formula (I) according to Table 1.
  • At least 5, particularly 7 and more particularly all of the above are employed to identify form (III) of the compound of formula (I). Based upon the foregoing characteristic features of the XRPD pattern of Form III of compound of formula (I), one skilled in the art can readily identify form (III). It will be appreciated by those skilled in the art that the XRPD pattern of a sample of form (III) of the compound of formula (I), obtained using the methods described herein, may exhibit additional peaks.
  • the preferred method of comparing XRPD patterns in order to identify the particular form of a sample of compound of formula (I) is to overlay the XRPD pattern of the unknown sample over the XRPD pattern of a known form.
  • the preferred method of comparing XRPD patterns in order to identify the particular form of a sample of compound of formula (I) is to overlay the XRPD pattern of the unknown sample over the XRPD pattern of a known form.
  • overlay an XRPD pattern of an unknown sample of compound of formula (I) obtained using the method described herein, over Figure 2 and, using expertise and knowledge in the art, readily determine whether the XRPD pattern of the unknown sample is substantially the same as the XRPD pattern of form (III) of the compound of formula (I). If the XRPD pattern is substantially the same as Figure 2, the previously unknown form can be readily and accurately identified as form (III).
  • the IR spectrum of the crystalline form of compound of formula (I) according to the present invention can be determined using conventional equipment and techniques known to those skilled in the art of analytical chemistry and physical characterization.
  • the IR spectra of Figure 3 and 4 was obtained on a Nicolet-Magna 760 with DTGS KBr detector with a resolution of 0.5 cm "1 .
  • the wave number in cm "1 (x axis) is plotted against percentage transmittance (y axis).
  • Form (III) of compound of formula (I) can be identified by the presence of peaks at 1544 ⁇ 2 cm '1 .
  • one skilled in the art can overlay an IR spectrum of an unknown form of compound of formula (I), obtained using the methods described herein, over Figure 3 and 4 and, using expertise and knowledge in the art, readily determine whether the IR spectrum of the unknown sample is substantially the same as the IR spectrum of form (III) of compound of formula (I). If the IR spectrum is substantially the same as Figure 3 and 4, the previously unknown form can be readily and accurately identified as form (III) of the compound or formula (I).
  • any of the foregoing analytical techniques can be used alone or in combination to identify a particular form of compound of formula (I).
  • other methods of physical characterization can also be employed to identify the characterize form (III) of the compound of formula (I).
  • suitable techniques which are known to those skilled in the art to be useful for the physical characterization of identification of a crystalline form or solvate include but are not limited to melting point, and thermogravimetric analysis. These techniques may be employed alone or in combination with other techniques to characterize a sample of an unknown form and to distinguish form (III) from other forms of compound of formula (I).
  • Form (III) of the compound of formula (I) can be both in substantially pure form and in admixture with other forms of compound of formula (I).
  • substantially pure is meant that the composition comprises at least 90 percent form (III) of the compound of formula (I) as compared to the other forms of compound of formula (I) in the composition, more particularly at least 95 percent form (III) and in one embodiment, at least 97 percent form (III) of the compound of formula (I).
  • form (III) of the compound of formula (I) may be administered as the raw chemical, it is more suitable to present the active ingredient as a pharmaceutical composition.
  • the invention further provide a pharmaceutical composition comprising form (III) of the compound of the formula (I) and one or more pharmaceutically acceptable carriers, diluents, or excipients.
  • the carrier(s), diluent(s) or excipient(s) must be acceptable in the sense of being compatible with the other ingredients of the composition and not deleterious to the recipient thereof.
  • the crystalline form as mentioned above may be prepared by precipitation from suitable organic solvent. See Example 1.
  • the high melting point of form (III) enables aggressive milling of the substance itself and its eventual in-product during the preparation of the final dosage form.
  • Suitable pharmaceutical compositions of form (III) include those described in WO04/087126, WO06/026935, or WO06/029579; or a solid dispersion of the polymorph with polymetacrylate, suitably with the cationic copolymer of poly butyl methacrylate with 2- dimethylaminoethyl methacrylate and methyl methacrylate in the ratio of 1 :2:1.
  • Said cationic copolymer is commercially available under the name EUDRAGIT E.
  • treatment of an oncological diseases means inhibition of characteristic signs and symptoms of a disease on biological objects carrying a tumor, namely an inhibition of a tumor growth and increase of survival time of the biological object.
  • DSC was performed on a Netzsch DSC 204 F1 at scan rate of 10 K/min equipped with a refrigerated cooling system.
  • the DSC thermogram of Form III of compound of formula (I) displays a sharp peak at 197 0 C.
  • the enthalpy of fusion determined by integrating this peak was -72 J/g.
  • the margin of error is approximately ⁇ 3°C for the peak maximum and ⁇ 15 J/g for the heat of fusion.
  • the diffraction pattern of Figure 2 was obtained using copper Ka radiation on a Philips 1730/10 diffractometer.
  • the sample was packed in nickel holder, measured and stored at room temperature, scanned from 3 to 60° 2-theta, step size 0,01°, using the following acquisition parameters: 35 mA, 4OkV, 0.01° 2-theta step.
  • Form (III) of compound of formula (I) can be identified by certain characteristic 2 theta angle peaks at 5.0 ⁇ 0.1 , 8.6 ⁇ 0.1 , 9.9 ⁇ 0.1 , 14.5 ⁇ 0.1 , 17.8 ⁇ 0.1 degrees or 17.8 ⁇ 0.1 , 10.3 ⁇ 0.1 , 8.9 ⁇ 0.1 , 6.1 ⁇ 0.1 , 5.0 ⁇ 0.1 A d-spacing.
  • the margin of error in the foregoing peak assignments is approximately ⁇ 2 cm "1 .

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Abstract

The present invention relates to a novel polymorphic form of the compound (OC-6-43)- bis(acetato)(1-tricyclo[3,3,1,13,7]decylamine)amminedichloroplatinum(IV) (also called LA-12), methods of preparation, isolation and identification thereof, pharmaceutical compositions containing the same, use of such polymorph and compositions in the treatment of oncological deseases.

Description

POLYMORPHIC FORM (III) OF PLATINUM (IV) COMPLEX
FIELD OF THE INVENTION The present invention relates to a novel polymorphic form of the compound (OC-6-43)- bis(acetato)(1-tricyclo[3,3,1 ,13i7]decylamine)amminedichloroplatinum(IV), (also called LA- 12), methods of preparation, isolation and identification thereof, pharmaceutical compositions containing the same, use of such polymorph and compositions in the treatment of oncological deseases.
BACKGROUND OF THE INVENTION
Generally, platinum cytostatics cannot be administered orally due to their insufficient stability in gastro intestinal track. This problem has been bridged over by using platinum(IV) complexes, whose bioavailability after oral administration is generally higher in comparison with routinely used platinum cytostatics such as e.g. cisplatin, carboplatin or oxaliplatin. Said platinum(IV) complexes intended for oral administration have been described in EP 0 328 274, EP 0423 707 and WO 99/61451.
One such platinum(IV) complex is represented by the structural formula:
Figure imgf000002_0001
and is described in WO 99/61451. The complex is prepared from (OC-6-43)(1- -tricyclo[3,3,1,13'7]decylamine)amminedichlorodihydroxoplatinum(IV) by reaction with excess of acetic anhydride to yield a solid which begins to decompose at 180 0C.
Polymorphism is defined as the ability of an element or compound to crystallise in more than one distinct crystalline species. Thus polymorphs are distinct solids sharing the same molecular formula, however since the properties of any solid depends on its structure, different polymorphs may exhibit distinct physical properties such as different solubility profiles, different melting points, different dissolution profiles, different thermal and/or photostability, different shelf life, different suspension properties and different physiological absorption rate. Inclusion of a solvent in the crystalline solid leads to solvates, and in the case of water as a solvent, hydrates.
Polymorphic forms of a compound may be distinguished by x-ray diffraction spectroscopy and other methods including infra-red spectrometry.
SUMMARY OF THE INVENTION
As a first aspect, the present invention provides a polymorphic crystalline form (III) of (OC- -6-43)-bis(acetato)(1-tricyclo[3,3l1 ,137]decylamine)amminedichloroplatinum(IV)l characterized by substantially the same differential scanning calorimetry (DSC) thermograms as Figure 1 wherein the DSC was performed at Netzsch DSC 204 F1 at scan rate of 10 K/min.
As a further aspect, the present invention provides a polymorphic crystalline form (III) of (OC-6-43)-bis(acetato)(1-tricyclo[3,3,1 ,13'7]decylamine)amminedichloroplatinum(IV), characterized by substantially the same X-ray powder diffraction (XRPD) pattern as Figure 2, wherein the XRPD pattern is expressed in terms of 2 theta angles and obtained with a diffractometer using copper Kα-radiation according to the procedures described herein.
As a further aspect, the present invention provides a polymorphic crystalline form (III) of (OC-6-43)-bis(acetato)(1 -tricyclo[3,3, 1 , 13(7]decylamine)amminedichloroplatinum(IV), characterized by an XRPD pattern expressed in terms of 2 theta angles obtained with a diffractometer copper using Kα-radiation according to the procedures described herein and comprising 2 theta angles at 5.0±0.1 , 8.6±0.1 , 9.9±0.1 , 14.5±0.1 , 17.8±0.1 degrees or 17.8±0.1 , 10.3±0.1 , 8.9±0.1 , 6.1±0.1 , 5.0±0.1 A d-spacing.
As a further aspect, the present invention provides a polymorphic crystalline form (III) of (OC-6-43)-bis(acetato)(1-tricyclo[3,3,1 ,13'7]decylamine)amminedichloroplatinum(IV), characterized by substantially the same infrared (IR) spectrum as Figure 3 and 4, wherein the IR spectrum is obtained using a Nicolet-Magna 760 with DTGS KBr detector with a resolution of 0.5 cm"1 according to the procedures described herein. As a further aspect, the present invention provides a polymorphic crystalline form (III) of (OC-6-43)-bis(acetato)(1-tricyclo[3,3,1 ,13|7]decylamine)amminedichloroplatinum(IV), characterized by an IR spectrum obtained using a Nicolet-Magna 760 with DTGS KBr detector with a resolution of 0,5 cm"1 according to the procedures described herein comprising peaks at five or more positions selected from the group consisting of 2907 ±2 cm'1; 1661 +2 cm"1; 1602 ±2 cm"1; 1544 ±2 crτV1; 1365 ±2 cm"1; 1306 ±2 cm"1; 1283 ±2 cm" 1; 1085+2 cm"1; 707 ±2 cm"1.
As a further aspect, the present invention provides a polymorphic crystalline form (III) of (OC-6-43)-bis(acetato)(1 -tricyclo[3,3, 1 , 137]decylamine)amminedichloroplatinum(IV), characterized by an IR spectrum obtained using a Nicolet-Magna 760 with DTGS KBr detector with a resolution of 0.5 cm"1 according to the procedures described herein and comprising peaks at 1544 ±2 cm"1
As a further aspect, the present invention provides a procedure for the preparation of the polymorphic crystalline form (III) of (OC-6-43)-bis(acetato)(1-tricyclo[3, 3,1 ,13|7]decyl- amine)amrninedichloroplatinum(IV), as defined above, comprising heating (OC-6-43)- -bis(acetato)(1 -tricyclo[3,3, 1 , 13'7]decylamine)amminedichloroplatinum(IV) in a concentrated aliphatic carboxylic acid with 2 to 4 carbon atoms or an anhydride thereof or n-butanol at a temperature in range of from 50 ° to110 0C to form a saturated solution, followed by cooling the solution to a temperature in the range of from 30°C to -500C and collecting the precipitate formed.
As a further aspect, the present invention provides a procedure for the preparation of the polymorphic crystalline form (III) of (OC-6-43)-bis(acetato)(1-tricyclo[3, 3,1 ,13'7]- decylamine)amminedichloroplatinum(IV), as defined above, comprising precipitation carried out at a temperature of from 25 0C to -30 0C from a solution of (OC-6-43)- -bis(acetato)(1-tricyclo[3,3,1 ,137]decylamine)-amminedichloroplatinum(IV) in a dry solvent selected from acetone, diethylketone, methylethylketone, a primary alcohol with 1 to 8 carbon atoms, a secondary alcohol with 3 to 8 carbom atoms, dimethylformamide or acetamide by adding a dry aliphatic ether with 2 to 8 carbon atoms as antisolvent to reach a ratio solvent: antisolvent of from 1 :1 to 1:15 with protecting the precipitatiom mixture from humidity. As a further aspect, the present invention provides a dosage form for oral use comprising the polymorphic crystalline form (III) of (OC-6-43)-bis(acetato)(1- -tricyclo[3,3,1 ,13|7]decylamine)amminedichloroplatinum(IV), as defined above, in admixture with at least one pharmaceutically acceptable excipient.
As a further aspect, the present invention provides a dosage form for parenteral use comprising the polymorphic crystalline form (III) of (OC-6-43)-bis(acetato)(1- -tricyclo[3,3,1 ,137]decylamine)amminedichloroplatinum(IV), as defined above, in admixture with at least one pharmaceutically acceptable excipient.
As a further aspect, the present invention provides a pharmaceutical composition comprising the polymorphic crystalline form (III) of (OC-6-43)-bis(acetato)(1- -tricyclo[3,3,1 ,13|7]decylamine)amminedichloroplatinum(IV), as defined above, in conjunction with at least one pharmaceutically acceptable diluent or carrier therefor.
As a further aspect, the present invention provides the polymorphic crystalline form (III) of (OC-6-43)-bis(acetato)(1 -tricyclo[3,3, 1 , 13i7]decylamine)amminedichloroplatinum(IV), as defined above, for use in therapy.
As a further aspect, the present invention provides the polymorphic crystalline form (III) of (OC-6-43)-bis(acetato)(1-tricyclo[3,3,1 ,13(7]decylamine)amminedichloroplatinum(IV), as defined above, wherein the therapy is the treatment of an oncological disease.
As a further aspect, the present invention provides a method of treatment of an oncological disease comprising administration of an effective amount of the polymorphic crystalline form (III) of (OC-6-43)-bis(acetato)(1-tricyclo[3,3,1 ,137]decylamine)- amminedichloroplatinum(IV), as defined above, to a patient in need thereof.
As a further aspect, the present invention provides a use of the polymorphic crystalline form (III) of (OC-6-43)-bis(acetato)(1-tricyclo[3,3,1 ,137]decylamine)ammine- dichloroplatinum(IV), as defined, in the preparation of a medicament for the treatment of an oncological disease. As evident from the foregoing, the present invention provides a polymorph of the compound (OC-6-43)-bis(acetato)(1-tricyclo[3,3,1 ,13i7]decylamine)amminedichloro- platinum(IV) designated "form (III)" and having the following structural formula:
Figure imgf000006_0001
This form (III) has a melting point of 197 ±2 0C.
BRIEF DESCRIPTION OF THE DRAWINGS
Figure 1. The differential scanning calorimetry (DSC) thermogram for form (III) of compound of formula (I) according to the present invention. DSC was performed on Netzsch DSC 204 F1 at scan rate of 10 K/min according to the procedures described herein.
Figure 2. The XRPD pattern of form (III) of compound of formula (I) according to the present invention. The XRPD pattern is expressed in terms of 2 theta angles and obtained with a diffractometer using copper Kα-radiation, according to the procedures described herein.
Figure 3 and 4. The IR spectrum of form (III) of compound of formula (I) according to the present invention. The x-axis is wavenumber in cm"1 and the y-axis is percent transmitance. The IR spectrum is obtained using Nicolet-Magna 760 with DTGS KBr detector with a resolution of 0.5 cm'1, according to the procedures described herein. DETAILED DESCRIPTION OF THE INVENTION
The present invention provides a novel crystalline form of compound of formula (I) exhibiting one or more advantageous pharmaceutical properties or other advantages over the known crude LA-12. The crystalline form of the present invention is stable at ambient temperatures.
Decomposition of Polymorph III under thermal stress (120 0C / 70 hours) is significantly smaller than decomposition of crude LA-12 under the same condition (0.4 % vs. 2.2 %).
The various forms of compound of formula (I) may be characterized and differentiated using a number of conventional analytical techniques, including but not limited to X-ray powder diffraction (XRPD) patterns, infrared (IR) spectra, Raman spectra, differential scanning calorimetry (DSC), thermogravimetric analysis (TGA) and solid state NMR.
The term "form (III) of compound of formula (I)" as used herein refers to any of:
1) a crystalline compound of formula (I) characterized by substantially the same differential scanning calorimetry (DSC) thermograms as Figure 1 wherein the DSC was performed on Netzsch DSC 204 F1 at scan rate of 10 K/min according to the procedures described herein.
2) a crystalline compound of formula (I) characterized by substantially the same X-ray powder diffraction (XRPD) pattern as Figure 2, wherein the XRPD pattern is expressed in terms of 2 theta angles and obtained with a diffractometer using copper Kα-radiation, according to the procedures described herein.
3) a crystalline compound of formula (I) characterized by substantially the same infrared (IR) spectrum as Figure 3 and 4, wherein the IR spectrum is obtained using Nicolet- Magna 760 with DTGS KBr detector with a resolution of 0.5 cm'1, according to the procedures described herein.
Differential Scanning Calorimetry (DSC) was performed on Netzsch DSC 204 F1 at scan rate of 10 K/min.
The DSC thermogram plots the differential rate of heating in miliwatts per miligram against temperature. The DSC thermogram of form (III) of compound of formula (I) displays endotherm peak at 197°C±2. The enthalpy of fusion determined by integrating this peak is -72J/g ±10.
Slight variations in the observed peak is expected based on the specific instrument and pan configuration employed, the analyst's sample preparation technique, and the sample size. Some margin of error is present in the peak assignment reported above. The margin of error is approximately ±3 0C for the peak maximum and ±15 J/g for the heat of fusion.
One skilled in the art can determine whether the DSC thermogram of an unknown sample is substantially the same as the DSC thermogram of form (III) of the compound of formula (I). If the DSC thermogram is substantially the same as Figure 1 and the peak position is substantially the same as those for form (III), the previously unknown form can be readily and accurately identified as form (III).
The X-ray powder diffraction pattern of form (III) of the compound of formula (I) can be determined using conventional techniques and equipment known to those skilled in the art of analytical chemistry and physical characterization. The diffraction pattern of Figure 2 was obtained using PHILIPS 1730/10 (Philips, Holland) attached to PC for data collection. Radiations generated from CuK α source, radiation (0,15419 nm). Exciting voltage: 4OkV, anode current: 35mA. The instrument was operated over the 2-theta range of 3°- 60°, step size: 0,01°. Sample: surface plain, in nickel sample holder, measured and stored at room temperature. Samples were presented as lightly pressed powder disk.
A lightly pressed powder disk sample of form (III) of the compound of formula (I) was used to produce the XRPD pattern of Figure 2. 2 Theta angles in degrees (x-axis) is plotted against peak intensity in terms of the count rate per seconds (y-axis). The XRPD pattern for each crystalline form is unique, exhibiting a unique set of diffraction peaks which can be expressed in 2 theta angles (°), d-spacings (A) and/or relative peak intensities.
2 Theta diffraction angles and corresponding d-spacing values account for positions of various peaks in the XRPD pattern. D-spacing values are calculated with observed 2 theta angles and copper Ka 1 wavelength using the Bragg equation. Slight variations in observed 2 theta angles and d-spacings are expected based on the specific diffractometer employed and the analyst's sample preparation technique. More variation is expected for the relative peak intensities. Large variations of relative peak intensities may be observed due to preferred orientation resulting from differences in crystal morphology. Identification of the exact crystal form of a compound should be based primarily on observed 2 theta angles or d-spacings with lesser importance place on relative peak intensities. To identify form (III) of the compound of formula (I) certain characteristic 2 theta angle peaks occur at 5.0±0.1 , 8.6±0.1 , 9.9±0.1 , 14.5±0.1, 17.8±0.1 degrees or 17.8±0.1, 10.3±0.1 , 8.9±0.1 , 6.1 ±0.1 , 5.0±0.1 A d-spacing.
Although one skilled in the art can identify form (III) from these characteristic 2 theta angle peaks, in some circumstances it may be desirable to rely upon additional 2 theta angles or d-spacings for the identification of Form III compound of formula (I) according to Table 1.
Table 1 - XRPD characteristics of crystalline form (III)
Figure imgf000010_0001
In one aspect at least 5, particularly 7 and more particularly all of the above are employed to identify form (III) of the compound of formula (I). Based upon the foregoing characteristic features of the XRPD pattern of Form III of compound of formula (I), one skilled in the art can readily identify form (III). It will be appreciated by those skilled in the art that the XRPD pattern of a sample of form (III) of the compound of formula (I), obtained using the methods described herein, may exhibit additional peaks.
Some margin of error is present in each of the 2 theta angle assignments and d-spacings reported above. The error in determining d-spacings decreases with increasing diffraction scan angle or decreasing d-spacing. The margin of error in the foregoing 2 theta angles is approximately ±0.1 degrees for each of the foregoing peak assignments.
Since some margin of error is possible in the assignment of 2 theta angles and d- spacings, the preferred method of comparing XRPD patterns in order to identify the particular form of a sample of compound of formula (I) is to overlay the XRPD pattern of the unknown sample over the XRPD pattern of a known form. For example, one skilled in the art can overlay an XRPD pattern of an unknown sample of compound of formula (I), obtained using the method described herein, over Figure 2 and, using expertise and knowledge in the art, readily determine whether the XRPD pattern of the unknown sample is substantially the same as the XRPD pattern of form (III) of the compound of formula (I). If the XRPD pattern is substantially the same as Figure 2, the previously unknown form can be readily and accurately identified as form (III).
The IR spectrum of the crystalline form of compound of formula (I) according to the present invention (i.e., form (III)) can be determined using conventional equipment and techniques known to those skilled in the art of analytical chemistry and physical characterization. The IR spectra of Figure 3 and 4 was obtained on a Nicolet-Magna 760 with DTGS KBr detector with a resolution of 0.5 cm"1. The wave number in cm"1 (x axis) is plotted against percentage transmittance (y axis). Form (III) of compound of formula (I) can be identified by the presence of peaks at 1544 ±2 cm'1.
Slight variations in observed peaks are expected based on the specific spectrometer employed and the analyst's sample preparation technique. Some margin of error is present in each of the peak assignments reported above. The margin of error in the foregoing peak assignments is approximately ±2cm"1. Since some margin of error is possible in the peak assignments, a useful method of comparing IR spectra in order to identify the particular form of a sample of compound of formula (I) is to overlay the IR spectrum of the sample over the IR spectrum of each of the known forms. For example, one skilled in the art can overlay an IR spectrum of an unknown form of compound of formula (I), obtained using the methods described herein, over Figure 3 and 4 and, using expertise and knowledge in the art, readily determine whether the IR spectrum of the unknown sample is substantially the same as the IR spectrum of form (III) of compound of formula (I). If the IR spectrum is substantially the same as Figure 3 and 4, the previously unknown form can be readily and accurately identified as form (III) of the compound or formula (I).
Any of the foregoing analytical techniques can be used alone or in combination to identify a particular form of compound of formula (I). In addition, other methods of physical characterization can also be employed to identify the characterize form (III) of the compound of formula (I). Examples of suitable techniques which are known to those skilled in the art to be useful for the physical characterization of identification of a crystalline form or solvate include but are not limited to melting point, and thermogravimetric analysis. These techniques may be employed alone or in combination with other techniques to characterize a sample of an unknown form and to distinguish form (III) from other forms of compound of formula (I).
Form (III) of the compound of formula (I) can be both in substantially pure form and in admixture with other forms of compound of formula (I). By "substantially pure" is meant that the composition comprises at least 90 percent form (III) of the compound of formula (I) as compared to the other forms of compound of formula (I) in the composition, more particularly at least 95 percent form (III) and in one embodiment, at least 97 percent form (III) of the compound of formula (I).
While it is possible that, for use in therapy, form (III) of the compound of formula (I), according to the present invention, (either alone or in admixture with other forms of the compound of formula (I)), may be administered as the raw chemical, it is more suitable to present the active ingredient as a pharmaceutical composition. Accordingly, the invention further provide a pharmaceutical composition comprising form (III) of the compound of the formula (I) and one or more pharmaceutically acceptable carriers, diluents, or excipients. The carrier(s), diluent(s) or excipient(s) must be acceptable in the sense of being compatible with the other ingredients of the composition and not deleterious to the recipient thereof.
The crystalline form as mentioned above may be prepared by precipitation from suitable organic solvent. See Example 1.
The high melting point of form (III) enables aggressive milling of the substance itself and its eventual in-product during the preparation of the final dosage form.
Suitable pharmaceutical compositions of form (III) (either alone or in admixture with other forms of the compound of formula (I) include those described in WO04/087126, WO06/026935, or WO06/029579; or a solid dispersion of the polymorph with polymetacrylate, suitably with the cationic copolymer of poly butyl methacrylate with 2- dimethylaminoethyl methacrylate and methyl methacrylate in the ratio of 1 :2:1. Said cationic copolymer is commercially available under the name EUDRAGIT E.
The term "treatment of an oncological diseases" means inhibition of characteristic signs and symptoms of a disease on biological objects carrying a tumor, namely an inhibition of a tumor growth and increase of survival time of the biological object.
The method of how to prepare the crystalline form (III) of the compound of formula (I) according to the present invention is illustrated using the following example of the preferred embodiment, without any limitation of the scope of the invention.
Example 1
1 g of LA-12 synthesised according to the procedure described in WO 99/61451 was dissolved in 11 ml. of the concentrated acetic acid at the temperature of 65 0C. The resulting solution was cooled quickly in a deep-freezer to the temperature of -30 0C. Several hours later (12h) the precipitate formed was filtered. The yield was 0.8 g. XRPD, DSC and IR spectra were obtained by the procedures described herein, and the substance was designated crystalline form (III). Example 2
1 g of LA-12, synthesised according to the procedure described in WO 99/61451 was dissolved in 17 ml. of acetone at room temperature (22 0C). The resulting solution was mixed with 85 ml. of diethylether. Several hours later (20 h) the precipitate formed was filtered. The yield was 0.85 g. XRPD, DSC and IR spectra were obtained by the procedures described herein, and the substance was designated crystalline form (III).
Differential Scanning Calorimetry (DSC)
DSC was performed on a Netzsch DSC 204 F1 at scan rate of 10 K/min equipped with a refrigerated cooling system.
The DSC thermogram of Form III of compound of formula (I) displays a sharp peak at 197 0C. The enthalpy of fusion determined by integrating this peak was -72 J/g.
The margin of error is approximately ±3°C for the peak maximum and ±15 J/g for the heat of fusion.
X-rav powder diffraction (XRPD)
The diffraction pattern of Figure 2 was obtained using copper Ka radiation on a Philips 1730/10 diffractometer. The sample was packed in nickel holder, mesured and stored at room temperature, scanned from 3 to 60° 2-theta, step size 0,01°, using the following acquisition parameters: 35 mA, 4OkV, 0.01° 2-theta step.
A powder sample of form (III) of the compound of formula (I) was used to produce the XRPD pattern of Figure 2.
Form (III) of compound of formula (I) can be identified by certain characteristic 2 theta angle peaks at 5.0±0.1 , 8.6±0.1 , 9.9±0.1 , 14.5±0.1 , 17.8±0.1 degrees or 17.8±0.1 , 10.3±0.1 , 8.9±0.1 , 6.1 ±0.1 , 5.0±0.1 A d-spacing.
The margin of error in the foregoing 2 theta angles is approximately ±0.1 degrees for each of the foregoing peak assignments. Infrared (IR) Spectroscopy
IR analysis was performed on Nicolet-Magna 760 with DTGS KBr detector with a resolution of 0.5 cm"1.
Representative peaks observed in the IR spectrum of form (III) of compound of formula (I) were as follows: 1661 ±2 cm"1; 1602 ±2 cm"1; 1544 ±2 cm"1; 1365 ±2 cm"1; 1306 ±2 cm"1; 1283 ±2 cm"1; 1085 ±2 cm"1; 707 ±2 cm"1.
The margin of error in the foregoing peak assignments is approximately ±2 cm"1.

Claims

1. A polymorphic crystalline form (III) of (OC-6-43)-bis(acetato)(1- -tricyclo[3,3,1 ,13'7]decylamine)amminedichloroplatinum(IV), characterized by substantially the same differential scanning calorimetry (DSC) thermograms as Figure 1 wherein the DSC was performed at Netzsch DSC 204 F1 at scan rate of 10 K/min.
2. A polymorphic crystalline form (III) of (OC-6-43)-bis(acetato)(1- -tricyclo[3,3,1 ,13|7]decylamine)amminedichloroplatinum(IV), characterized by substantially the same X-ray powder diffraction (XRPD) pattern as Figure 2, wherein the XRPD pattern is expressed in terms of 2 theta angles and obtained with a diffractometer using copper Kα-radiation according to the procedures described herein.
3. A polymorphic crystalline form (III) of (OC-6-43)-bis(acetato)(1- -tricyclo[3,3,1 ,13i7]decylamine)amminedichloroplatinum(IV), characterized by an XRPD pattern expressed in terms of 2 theta angles obtained with a diffractometer copper using Kα-radiation according to the procedures described herein and comprising 2 theta angles at 5.0±0.1 , 8.6±0.1 , 9.9±0.1 , 14.5±0.1 , 17.8±0.1 degrees or 17.8±0.1 , 10.3±0.1 , 8.9±0.1 , 6.1 ±0.1 , 5.0±0.1 A d-spacing.
4. A polymorphic crystalline form (III) of (OC-6-43)-bis(acetato)(1- -tricyclo[3,3,1 ,13|7]decylamine)amminedichloroplatinum(IV), characterized by substantially the same infrared (IR) spectrum as Figure 3 and 4, wherein the IR spectrum is obtained using a Nicolet-Magna 760 with DTGS KBr detector with a resolution of 0.5 cm"1 according to the procedures described herein.
5. A polymorphic crystalline form (III) of (OC-6-43)-bis(acetato)(1- -tricyclo[3,3,1 ,137]decylamine)amminedichloroplatinum(IV), characterized by an IR spectrum obtained using a Nicolet-Magna 760 with DTGS KBr detector with a resolution of 0,5 cm"1 according to the procedures described herein comprising peaks at five or more positions selected from the group consisting of 2907 ±2 cm"1; 1661 ±2 cm'1; 1602 ±2 cm"1; 1544 ±2 cm'1; 1365 ±2 crτT1; 1306 ±2 cm"1; 1283 ±2 cm"1; 1085+2 cm"1; 707 +2 cm"1.
6. A polymorphic crystalline form (III) of (OC-6-43)-bis(acetato)(1- -tricyclo[3,3,1 ,137]decylamine)amminedichloroplatinum(IV), characterized by an IR spectrum obtained using a Nicolet-Magna 760 with DTGS KBr detector with a resolution of 0.5 cm"1 according to the procedures described herein and comprising peaks at 1544 ±2 cm'1
7. A procedure for the preparation of the polymorphic crystalline form (III) of (OC-6- 43)-bis(acetato)(1-tricyclo[3,3,1 ,13'7]decylamine)amminedichloroplatinum(IV), as claimed in anyone of claims 1 to 6, comprising heating (OC-6-43)-bis(acetato)(1- -tricyclo[3,3,1 ,13'7]decylamine)amminedichloroplatinum(IV) in a concentrated aliphatic carboxylic acid with 2 to 4 carbon atoms or an anhydride thereof or n-butanol at a temperature in range of from 50 ° to110 0C to form a saturated solution, followed by cooling the solution to a temperature in the range of from 300C to -500C and collecting the precipitate formed.
8. A procedure for the preparation of the polymorphic crystalline form (III) of (OC-6- 43)-bis(acetato)(1-tricyclo[3,3,1 ,13|7]decylamine)amminedichloroplatinum(IV), as claimed in anyone of claims 1 to 6, comprising precipitation carried out at a temperature of from 25
0C to -30 0C from a solution of (OC-6-43)-bis(acetato)(1-tricyclo[3,3,1 ,137]decylamine)- amminedichloroplatinum(IV) in a dry solvent selected from acetone, diethylketone, methylethylketone, a primary alcohol with 1 to 8 carbon atoms, a secondary alcohol with 3 to 8 carbom atoms, dimethylformamide or acetamide by adding a dry aliphatic ether with 2 to 8 carbon atoms as antisolvent to reach a ratio solventantisolvent of from 1 :1 to 1 :15 with protecting the precipitatiom mixture from humidity.
9. A dosage form for oral use comprising the polymorphic crystalline form (III) of (OC- -6-43)-bis(acetato)(1 -tricyclo[3,3, 1 , 13i7]decylamine)amminedichloroplatinum(IV), as claimed in anyone of claims 1 to 6, in admixture with at least one pharmaceutically acceptable excipient.
10. A dosage form for parenteral use comprising the polymorphic crystalline form (III) of (OC-6-43)-bis(acetato)(1-tricyclo[3,3,1 ,13|7]decylamine)amminedichloroplatinum(IV), as claimed in anyone of claims 1 to 6, in admixture with at least one pharmaceutically acceptable excipient.
11. A pharmaceutical composition comprising the polymorphic crystalline form (III) of (OC-6-43)-bis(acetato)(1-tricyclo[3,3,1 ,13|7]decylamine)amminedichloroplatinum(IV), as claimed in anyone of claims 1 to 6, in conjunction with at least one pharmaceutically acceptable diluent or carrier therefor.
12. The polymorphic crystalline form (III) of (OC-6-43)-bis(acetato)(1- -tricyclo[3,3,1 ,137]decylamine)amminedichloroplatinum(IV), as claimed in any of claims 1 to 6, for use in therapy.
13. The polymorphic crystalline form (III) of (OC-6-43)-bis(acetato)(1- -tricyclo[3,3,1 ,13|7]decylamine)amminedichloroplatinum(IV), as claimed in claim 12, wherein the therapy is the treatment of an oncological disease.
14. A method of treatment of an oncological disease comprising administration of an effective amount of the polymorphic crystalline form (III) of (OC-6-43)-bis(acetato)(1-
-tricyclo[3,3,1 ,13i7]decylamine)amminedichloroplatinum(IV), as claimed in any of claims 1 to 6, to a patient in need thereof.
15. Use of the polymorphic crystalline form (III) of (OC-6-43)-bis(acetato)(1- -tricyclo[3,3,1 ,13i7]decylamine)amminedichloroplatinum(IV), as claimed in any of claims 1 to 6, in the preparation of a medicament for the treatment of an oncological disease.
PCT/CZ2009/000014 2008-02-12 2009-02-12 Polymorphic form ( iii ) of the adamantylamino- platinum (iv) complex la- 12 WO2009100691A1 (en)

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Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999061451A1 (en) * 1998-05-27 1999-12-02 Pliva-Lachema A.S. Platinum complex, its preparation and therapeutic application

Patent Citations (1)

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Publication number Priority date Publication date Assignee Title
WO1999061451A1 (en) * 1998-05-27 1999-12-02 Pliva-Lachema A.S. Platinum complex, its preparation and therapeutic application

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ZAK, FRANTISEK ET AL: "Platinum(IV) Complex with Adamantylamine as Nonleaving Amine Group: Synthesis, Characterization, and in Vitro Antitumor Activity against a Panel of Cisplatin-Resistant Cancer Cell Lines", JOURNAL OF MEDICINAL CHEMISTRY , 47(3), 761-763 CODEN: JMCMAR; ISSN: 0022-2623, 2004, XP002526512 *
ZAK, FRANTISEK ET AL: "Platinum(IV) Complex with Adamantylamine as Nonleaving Amine Group: Synthesis, Characterization, and in Vitro Antitumor Activity against a Panel of Cisplatin-Resistant Cancer Cell Lines", JOURNAL OF MEDICINAL CHEMISTRY , SUPPORTING INFORMATION, pages 1 - 11, XP002526513, Retrieved from the Internet <URL:http://pubs.acs.org> [retrieved on 20090504] *

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