MX2007007258A - Stereoselective process and crystalline forms of a camptothecin - Google Patents

Abstract

A stereoselective processfor preparing 7-[(E)-t-butyloxyiminomethyl]- camptothecin (also known as gimatecan) is herein disclosed. With the addition of further dissolution and precipitation steps carried out in appropriate different solvent mixtures, four new crystalline forms of gimatecan are also obtainable by using the same stereoselective process.

Description

STEREOSELECTIVE PROCESS AND CRYSTALLINE FORMS OF A CAMPOTOTECINE FIELD OF THE INVENTION This invention relates to a stereoselective process for preparing 7- [(E) -t-butyloxyiminomethyl] -camptothecin (also known as gimatecan). With the addition of additional dissolution and precipitation steps performed in different appropriate solvent mixtures, three new crystalline forms of gimatecan are obtainable using the same stereoselective process.

BACKGROUND OF THE INVENTION Camptothecin is an alkaloid, which was isolated by Wall et al (J. Am. Chem. Soc. 88, 3888-3890 (1966)) for the first time from the Camptoteca acuminata tree, a plant native to China, of the Nyssaceae family. The molecule consists of a pentacyclic structure that has a lactone in the E ring, which is essential for cytotoxicity. The drug demonstrated a broad spectrum of antitumor activity, in particular against colon tumors, other solid tumors and leukemias, and the first clinical trials were conducted in the early 70s. Since camptothecin (CPT) has low solubility in water and To prepare clinical trials, Ref. 182949 National Cancer Institute (NCI) prepared sodium salt (NSC100880), which is soluble in water. Phase I and phase II clinical trials were not completed due to the high toxicity shown by the compound (hemorrhagic cystitis, gastrointestinal toxicity, such as nausea, vomiting, diarrhea, and myelosuppression, especially leukopenia and thrombocytopenia.) Subsequently, many CPT analogues Two drugs are sold, irinotecan (CPT-11) (Camptosar® from Upjohn) and topotecan (Hycamtin ™ or Thycantin ™ from Smith Kline &Beecham). date contains the structure of origin with 5 rings, essential for cytotoxicity.It was shown that the modifications in the first ring, as in the case of the drugs mentioned above increases the solubility in water allows a greater tolerability of the drug. WO 97/31003 describes derivatives of camptothecines substituted at positions 7, 9 and 10. The position 7 pr provides the following substitutions: -CN, -CH (CN) -R4, -CH = C (CN) -R4, -CH2-CH = C (CN) -R4, -C (= NOH) -NH2, -CH = C (N02) -R4, -CH (CH2N02) -R4,5-tetrazolyl, 2- (4,5-dihydroxazolyl), 1, 2,4-oxadiazolidin-3-yl-5-one, where R is hydrogen , linear or branched alkyl from 1 to 6 carbon atoms, nitrile, carboxyalkoxy. Of these compounds, the best proved to be 7-nitrile (7-CN), then named CPT 83, with cytotoxic activity in non-small cell lung carcinoma (non-SCLC, H-460). This tumor line is intrinsically resistant to cytotoxic therapy and is only moderately sensitive to topoisomerase I inhibitors, despite overexpression of the target enzyme. CPT 83 is more active than topotecan, taken as reference compound and in general offers a better pharmacological profile, even in terms of tolerability, consequently a better therapeutic index. CPT 83 was prepared through a synthetic route comprising the oxidation of 7-hydroxymethylcamptothecin to 7-aldehyde of camptothecin, the transformation of the latter into oxime and final conversion to nitrile. The starting compound and intermediates are described in Sawada et al., Chem. Pharm. Bull., 39, 5272 (1991). This document refers to a family of patents with priority of 1981, for example European patent application EP 0056692, published in 1982. In these publications the 7-aldehyde of camptothecin and its oxime are described among others. The utility of these derivatives is to provide compounds with antitumor activity that have low toxicity starting from 7-hydroxymethylcamptothecin. In the document published in Chem. Pharm. Bull. 39, 5272 (1991), the authors show that, with respect to camptothecin, the 7-alkyl and 7-acyloxymethyl derivatives, which were not provided for in the aforementioned patent application, are the most active compounds in lines of murine leukemia L1210, while lower activity, always with respect to to camptothecin, was observed in compounds bearing 7-substitutions with high polar character, such as hydrazones and oxime-CH (= NOH). In the patent application EP1044977 and in Dallavalle S. et al., J. Med. Chem. 2001, 44, 3264-3274, the camptothecin derivatives are described which carry an O-substituted alkyloxime in the 7-position and which they are endowed with antitumor activity greater than the reference compound topotecan. In addition, these camptothecin derivatives which carry an imino group in the 7-position also show an improved therapeutic index. Among these compounds it was shown that one of the preferred molecules is 7-t-butoxyiminomethylcamptothecin (CPT 184). When this molecule was prepared as described in EP1044977 and in the above Dallavalle document, a mixture of the two E and Z isomers, in 8: 2 ratio, was obtained from a solvent mixture containing ethanol and pyridine.

All the processes described in the aforementioned literature to obtain camptothecin derivatives carrying O-substituted alkyloxime at position 7 lead to a mixture of the two isomers E and Z of the oxime or the alkyloxime.

BRIEF DESCRIPTION OF THE INVENTION Therefore, it is desirable to make available a stereoselective process leading to unique E, Z isomers, respectively, more particularly the E isomer. Many drugs, old and new, were discovered and rushed into the market as their forms 'adequate' crystalline crystals and have never been completely selected for their potential polymorphic forms. With the recent technological advancement of solid-state chemistry, it is possible that new polymorphic forms may be discovered, which have never been seen before. The new polymorphic forms are often able to provide therapeutic advantages and represent one of the new challenges of the pharmaceutical industry. Actually polymorphism, the ability of a molecule to crystallize in more than one crystal array, can have a profound effect on the shelf life, solubility, formulation properties, and processing properties of a drug. More seriously, the action of a drug can be affected by the polymorphism of the drug molecules. Different polymorphs can have different absorption ratios in the body, leading to biological activity lower than the desired one. In extreme cases, an unwanted polymorph can still be toxic. The occurrence of a polymorphic form not known during manufacturing can have a huge impact on a pharmaceutical company. Therefore, it is vital that researchers involved in the formulation of crystalline products be able to select the polymorph with the correct properties and anticipate problems such as the undesired crystallization of other polymorphs. Surprisingly, a very large number of pharmaceutical preparations exhibit the phenomenon of polymorphism. 70% of barbiturates, 60% of sulfonamides and 23% of steroids exist in different polymorphic forms. The problem of polymorphism in organic compounds is generically reviewed by Caira, M.R. "Crystalline Polymorphism of Organic Compounds," Topics in Current Chemistry, Springler, Berlin, DE, Vol. 198, 1998, pages 163-208. Conducting a crystallization study on gimatecan the applicant arrived at the claimed invention.

BRIEF DESCRIPTION OF THE FIGURES Figure 1 reports to the left the structural formula of 7- [(E) -t-butyloxyiminomethyl] -camptothecin (gimatecan) and to the right the formula of 7 - [(Z) -t-butyloxyiminomethyl] - camptothecin. Figure 2 reports the X-ray diffraction pattern of crystalline form I of 7 - [(E) -t-butyloxyiminomethyl] -camptothecin (gimatecan). Figure 3 reports the X-ray diffraction pattern of crystal form II of 7 - [(E) -t-butyloxyiminomethyl] -camptothecin (gimatecan). Figure 4 reports the X-ray diffraction pattern of crystalline form III of 7 - [(E) -t-butyloxyiminomethyl] -camptothecin (gimatecan).

DETAILED DESCRIPTION OF THE INVENTION A stereoselective process for preparing 7- [(E) -t-butyloxyiminomethyl] -camptothecin (also known as gimatecan) has surprisingly been found. It has also been found that it is possible to obtain the complete conversion of the Z isomer in the E-isomer. For clarity, the structural formulas of the two isomers are shown in Figure 1. Furthermore, it was found that this product can exist under different crystalline forms and that these forms can be obtained using the same stereoselective process with the addition of additional dissolution and precipitation steps performed in different appropriate solvent mixtures. Therefore, the main object of the present invention is a process for the stereoselective preparation of 7- [(E) -t-butyloxyiminomethyl] -camptothecin which comprises reacting a 7-formyl-camptothecin acetal with Ot-butylhydroxylamine hydrochloride. in an aprotic organic or polar protic solvent, preferably under acidic conditions (Ph <7). Indeed, it has been found that the amount of Z isomer is proportional to the amount of base (for example pyridine) added. Therefore, the process of the present invention should be carried out in the absence of an organic base, in particular, in the absence of pyridine. Different modalities and variations of the above process are included in the present invention. Preferably, the aprotic or polar protic organic solvent is an alcohol, such as methanol, ethanol, n-propanol, i-propanol, n-butanol, i-butanol. More preferably, it is ethanol or methanol. The pH is preferably acid, but it can be achieved at higher values (close but not equal to 7) with the addition of an inorganic base. Preferably, the inorganic base is sodium or potassium hydroxide. Preferably, the inorganic base is added in a molar ratio of 0.5-0.9: 1 with respect to hydroxylamine hydrochloride. The 7-formyl-camptothecin acetal is a dialkyl acetal, preferably methyl or ethyl acetal. The temperature of the reaction is usually between room temperature and the boiling point of the solvent. At the end of the reaction the precipitate is isolated from the reaction mixture, for example by filtration. According to the process of the present invention, the E-isomer is always obtained in a ratio of at least 95: 5 with respect to the Z-isomer. The examples show that the process of the invention allows to obtain the E-isomer up to a ratio of 99.8. : 0.2 with respect to the Z-isomer. According to a preferred embodiment of the invention, the process described above comprises additional steps, such as dissolving the previously obtained precipitate in dichloromethane, adding a co-solvent, concentrating the obtained solution and crystallizing the product. thus obtained. Depending on the co-solvent used, different crystalline forms are obtained as follows. These different crystalline forms are a further object of the present invention.

SOLVENTS Polymorph (by Polymorph (by IR and DSC) powder X-ray diffraction) Acetone I I MeOH III III EtOH III III Hexane II 75% II (with a substantial amount of amorphous) EtOAc II II Toluene II II n-Butyl II II Chloride Methyl t-butyl ether II 90% II Using acetone as co-solvent, crystalline form I of gimatecan was obtained, which is characterized by an X-ray diffraction pattern powder obtained by X-ray CuK-a 1 irradiation, as shown in Figure 2. The main diffraction peaks characteristic of this form are given in the following table: Degrees 2-Theta Relative intensity (%) 7. 2 100 9.2 4.8 10.2 7.3 12.7 16.3 14.0 8.1 14.7 9.5 15.2 13.0 16.0 2.4 16.7 4.06 19.7 3.2 20.5 3.2 20.7 4.06 22.2 6.5 26.5 3.2 32.5 2.4 Using ethanol or methanol as co-solvent, crystalline form III of gimatecan was obtained, which is characterized by a powder X-ray diffraction pattern obtained by X-ray CuK-a 1 irradiation, as shown in Figure 4 The main diffraction peaks characteristic of this form are given in the following table: Degrees 2-Theta Relative intensity (%) 6. 0 1.0 7.5 100.0 8.51 8.1 12.3 4.8 16.0 6.0 17.0 11.0 18.0 6.6 18.2 4.0 18.7 6.0 23.2 2.4 25.2 3.6 Using ethyl acetate, toluene, n-butyl chloride, methyl t-butyl ether or hexane as co-solvent, crystalline form II of gimatecan was obtained, which is characterized by a powder X-ray diffraction pattern obtained by X-ray irradiation CuK-1, as shown in Figure 3. The main diffraction peaks characteristic of this form are given in the following table: Degrees 2-Theta Relative intensity 6. 7 100.0 7.2 4.8 9.7 6.0 11.2 24.0 13.2 3.0 14.5 4.8 16.0 2.4 16.7 21.6 17.0 31.2 17.5 10.8 19.0 3.0 21.0 4.8 23.0 3.6 25.5 7.2 26.5 6.0 28.2 3.0 These new crystalline forms I, II and II of gimatecan are additional objects of the present invention. Crystal form I of gimatecan is preferred. The amorphous form I of gimatecan is a further object of the present invention. Another object of the present invention is the use of any crystalline form I, II, II of gimatecan, or a mixture thereof, as medicaments, in particular for the preparation of a medicament for treating pathological conditions which arise from or are exacerbated by cell proliferation. A further object of the present invention are compositions, in particular pharmaceutical compositions, comprising at least one of the crystalline forms mentioned above as an active ingredient, the pharmaceutical compositions are in admixture with at least one pharmaceutically acceptable carrier and / or diluent. In addition, the pharmaceutical compositions of the present invention may also contain one or more pharmaceutically acceptable excipients. Gimatecan shows an antiproliferative activity, therefore its crystalline forms are useful for its therapeutic activity, and it has physicochemical properties that make them suitable to be formulated in pharmaceutical compositions. The pharmaceutical compositions comprise at least one of the crystalline forms of gimatecan mentioned above, in an amount such as to produce a significant therapeutic effect, in particular antitumor effect. The compositions comprised within the present invention are conventional and are obtained by methods commonly used in the pharmaceutical industry. According to the desired administration route, the compositions will be in solid or liquid form, suitable for the oral, parenteral, intravenous route. The compositions according to the present invention comprise together with the active ingredients, at least one pharmaceutically acceptable carrier or excipient. Formulation co-adjuvants, for example solubilization, dispersion, suspension, emulsification agents may be particularly useful. The crystalline forms of gimatecan mentioned above can also be used in combination with other active ingredients, for example other antitumor drugs, both in separate forms, and in a single dose form. The crystalline forms of gimatecan mentioned above according to the present invention are useful as medicaments with antitumor activity, for example in lung tumors, such as non-small cell lung tumor, colorectal tumors, prostate, gliomas. Cytotoxic activity was assayed in human tumor cell cell systems, using the antiproliferative activity test as a method of assessing the cytotoxic potential. These and other objects of the present invention should be illustrated in detail also by means of the following examples. The following examples further illustrate the invention.

Introduction Examples 1 and 2 deal with the synthesis of 7- [(E) -t-butyloxyiminomethyl] -camptothecin using dimethylacetal 7-formyl-camptothecin as a starting material. Examples 3 and 4 report the synthesis of 7- [(E) -t-butyloxyiminomethyl] -camptothecin using 7-formyl-camptothecin as starting material under conditions that produce the E-isomer. All reactions in this group are faster than the reactions reported in Examples 1 and 2, indicating that the hydrolysis of the acetal is plausibly slower than the reaction of the aldehyde to produce the oxime. Example 5 reports the conversion of the Z isomer into the E isomer. Example 6 reports the synthesis and characterization of the different crystalline (polymorphic) forms that can be obtained for 7 - [(E) -t-butyloxyiminomethyl] -camptothecin ( gimatecan). HPLC: Analyzes were performed on an instrument equipped with a quaternary pump (Waters Alliance 2690) with automatic injector (5 μm injected volume) and with a UV detector operating at 260 nm (Waters 2487) controlled by Waters' software Empower Pro '. A C18 reverse phase column (Symmetry C18; 75x4.6 mm Waters) was used with a linear elution gradient (see table below), with flow rate of 1.0 ml / min.

Gradient program H2O / CH3CN 60/40 (v / v) H2O / CH3CN 30/70 (v / v) Time (min)% A% B 0 100 or 30 100 O 40 O 100 45 100 0 50 100 0 The retention time of 7 - [(E) -tert-butyloxyiminomethyl] -camptothecin is 12 minutes, and the retention time of the Z isomer is 8 minutes.

Example 1 Preparation of 7- [(E) -tert-butyloxyiminomethyl] -camptothecin from 7-formylcamptothecin-dimethylacetal 7-formyl-camptothecin-dimethylacetal (500 mg, 1.2 mmol) and O-tert-butylhydroxylamine hydrochloride ( 372 mg, 2.9 mmol) to 95% ethanol (12.5 ml) in a three-necked flask, protected from light and equipped with a magnetic stirrer and a condenser. The mixture was refluxed for 4 h. The CLAR analysis showed an E: Z ratio of 99.8: 0.2. The crude product was obtained as precipitated from the reaction mixture and isolated by filtration. After chromatographic purification on silica gel (20 g), eluting with dichloromethane-methanol 95: 5, gimatecan (460 mg) was obtained as a yellow powder (yield: 87%).

Example 2 Preparation of 7- [(E) -tert-butyloxyiminomethyl] -camptothecin from 7-ormilcamptothecin-dimethylacetal 7-formyl-camptothecin-dimethylacetal (500 mg, 1.2 mmol), O-tert-butylhydroxylamine hydrochloride ( 372 mg, 2.9 mmol) and sodium hydroxide (59 mg, 1.47 mmol) to 95% ethanol (12.5 ml) in a three-necked flask, protected from light and equipped with a magnetic stirrer and a condenser. The mixture was heated to reflux 24 h. The CLAR analysis showed an E: Z ratio of 98.8: 1.2. The crude product was obtained as precipitated from the reaction mixture and isolated by filtration. After chromatographic purification on silica gel (20 g), eluting with dichloromethane-methanol 95: 5, gimatecan was obtained as a yellow powder (yield: 80%).

Example 3 (Reference example) Preparation of 7- [(E) -tert-butyloxyiminomethyl] -camptothecin from 7-formylcamptothecin 7-formyl-camptothecin (500 mg, 1.33 mmol), O-tert-butylhydroxylamine hydrochloride were added (417 mg, 3.3 mmol) and sodium hydroxide (67 mg, 1.65 mmol) to 95% ethanol (12.5 ml) in a three-necked flask, protected from light and equipped with a magnetic stirrer and condenser. The mixture was heated to reflux for 2 hours. The CLAR analysis showed an E: Z ratio of 97.4: 2.6. The crude product was obtained as precipitated from the reaction mixture and isolated by filtration. After chromatographic purification on silica gel (20 g), eluting with dichloromethane-methanol 95: 5, gimatecan (480 mg) was obtained as a yellow powder (yield: 80%).

Example 4 (Reference example) Preparation of 7- [(E) -tert-butyloxyiminomethyl] -camptothecin from 7-formylcamptothecin 7-formyl-camptothecin (500 mg; 1.33 mmol), O-tert-butylhydroxylamine hydrochloride (417 mg, 3.3 mmol) and sodium hydroxide (120 mg, 3 mmol) to 95% ethanol (12.5 mL) in a three-necked flask, protected from light and Equipped with a magnetic stirrer and a condenser. The mixture was heated to reflux for 2 hours. The CLAR analysis showed an E: Z ratio of 95.5. The crude product was obtained as precipitated from the reaction mixture and isolated by filtration. After chromatographic purification on silica gel (20 g), eluting with dichloromethane-methanol 95: 5, gimatecan (550 mg) was obtained as a yellow powder (yield: 93%).

Example 5 Conversion of Isomer 7- [(Z) -tert-Butyloxyiminomethyl] -camptothecin (100 mg) was dissolved in dichloromethane (30 mL). Hydrochloric acid (0.2 ml) was added at room temperature and the mixture was subjected to irradiation with a U.V. lamp. high pressure Hg of 125 W for 1 hour. The HPLC analysis showed that the Z-isomer was completely converted to the E-isomer.

Example 6 Crystallization Studies 7- [(E) -tert-Butyloxyiminomethyl] -camptothecin (2.5 g) was dissolved in dichloromethane (500 mL). A co-solvent (500 ml) was added to the solution, then by means of a rotary evaporator, the mixture was concentrated at a temperature of 40 ° C to a volume of 250 ml. The suspension was kept under stirring at room temperature for 30 minutes, then the solid formed was filtered by washing twice with 20 ml of the co-solvent. After one night in an oven at 50 ° C under vacuum, 2.1 g of product were obtained. The co-solvents used were the following: acetone, ethanol, methanol, ethyl acetate, toluene, n-butyl chloride, methyl tert-butyl ether, and hexane. The obtained crystals were analyzed by X-ray powder diffractometer. The diffractograms were obtained in 20-50 mg of powder using a Siemens D-500 computer-controlled diffractometer equipped with a monochromatic CuK-cx radiation source with graphite crystals ( 002), with Soller slits and narrow divergence (0.3 °) and reception openings. The confidence limits of the scattering angles are ± 0.5 2-Theta. The samples obtained using acetone as co-solvent (form I) produced the following results. The diffractogram of X-ray powder is characteristic of a crystalline substance. The main diffraction peaks characteristic of this form are given in the following table: Degrees 2-Theta Relative intensity (%) 7. 2 100 9.2 4.8 10.2 7.3 12.7 16.3 14.0 8.1 14.7 19.5 15.2 13.0 16.0 2.4 Degrees 2-Theta Relative intensity (%) 16. 7 4.06 19.7 3.2 20.5 3.2 20.7 4.06 22.2 6.5 26.5 3.2 32.5 2.4 The samples obtained using ethanol or methanol as co-solvent (form III) produced the following results. The diffractogram of X-ray powder is characteristic of a crystalline substance. The main diffraction peaks characteristic of this form are given in the following table: Degrees 2-Theta Relative intensity (%) 6. 0 11.0 7.5 100.0 8.5 18.1 12.3 4.8 16.0 6.0 17.0 11.0 18.0 6.6 18.2 4.0 18.7 6.0 23.2 2.4 25.2 3.6 The samples obtained using ethyl acetate, toluene, n-butyl chloride, methyl t-butyl ether or hexane as co-solvent ( form II) produced the following results. The diffractogram of X-ray powder is characteristic of a crystalline substance. The main diffraction peaks characteristic of this form are given in the following table: Degrees 2-Theta Relative intensity (%) 6. 7 100.0 7.2 4.8 9.7 6.0 11.2 24.0 13.2 3.0 14.5 4.8 16.0 2.4 16.7 21.6 17.0 31.2 17.5 10.8 19.0 3.0 21.0 4.8 23.0 3.6 25.5 7.2 26.5 6.0 28.2 3.0 To further characterize these crystalline forms of gimatecan, the same samples were examined by IR spectroscopy. In the following table the characteristic peaks of the three forms are given Form I (acetone) Form II (AcOEt) * Form III (EtOH) * Frequency (cm-1) Frequency (cm-1) Frequency (cm-1) 1751. 7 1761.7 1739.3 1606.4 1605.0 1619.8 1162.2 1156.7 1154.4 766.2 764.3 759.5 * identical data were also observed for the obtained forms of toluene, n-butyl chloride, methyl t-butyl ether or hexane ** identical data were also observed for the methanol form obtained The IR spectra were collected at 4 was "1 pellet of KBr at 1% with a Perkin Elmer Spectrum 1000 FT-IR." It is noted that in relation to this date, the best method known by the applicant to carry out the cited invention, is that which is clear from the present description of the invention.

Claims (36)

1. CLAIMS Having described the invention as above, the contents of the following claims are claimed as property: 1. Process for the stereoselective preparation of 7- [(E) -t-butyloxyiminomethyl] -camptothecin, characterized in that it comprises reacting a 7-formyl-camptothecin acetal with 0-t-butylhydroxylamine hydrochloride in an aprotic or polar protic organic solvent.
2. 2. Process according to claim 1, characterized in that the reaction is carried out under acidic conditions. Process according to claim 1, characterized in that the aprotic organic or polar protic solvent is an alcohol. Process according to any preceding claim, characterized in that the aprotic organic or polar protic solvent is ethanol or methanol. Process according to any preceding claim, characterized in that an inorganic base is added to the reaction medium in a molar ratio of 0.5-0.9: 1 with respect to hydroxylamine hydrochloride. 6. Process according to claim 5, characterized in that the inorganic base is sodium or potassium hydroxide. Process according to claim 5, characterized in that the precipitate is isolated from the reaction mixture by filtration. Process according to any preceding claim, characterized in that the acetal of 7-formyl-camptothecin is a dialkyl acetal. Process according to any preceding claim, characterized in that the acetal of 7-formyl-camptothecin is dimethyl or diethyl acetal. 10. Process according to any preceding claim, characterized in that the reaction temperature is maintained between room temperature and boiling point of the solvent. 11. Process according to any of claims 1-10, characterized in that at the end of the reaction the precipitate is isolated from the reaction mixture. 12. Process according to claim 11, characterized in that the precipitate is isolated from the reaction mixture by filtration. 13. Process according to claim 11 or 12, characterized in that it additionally comprises dissolving the precipitate in dichloromethane, adding a co-solvent, concentrating the solution thus obtained and allowing the reaction product to precipitate and crystallize. 14. Process according to claim 13, characterized in that the co-solvent is selected from acetone, toluene, n-butyl chloride, methyl t-butyl ether or hexane, ethyl acetate, ethanol, methanol. 15. A compound obtainable by the process according to claim 13 or 14, characterized in that it is a crystalline form of 7 - [(E) -t-butyloxyiminomethyl] -camptothecin. 16. Compound in accordance with the claim 15, characterized in that it is crystalline form I of 7 - [(E) -t-butyloxyiminomethyl] -camptothecin. 17. Compound in accordance with the claim 16, characterized in that it shows a X-ray diffraction of a peak at a refractive angle 2 theta (T) of 7.2 ± 0.2 degrees. 18. Compound in accordance with the claim 17, characterized in that it has an X-ray diffraction pattern, expressed in terms of 2 T angles, which includes five or more peaks selected from the group consisting of approximately 10.2, 12.7, 14.0, 14.7 and 15.2 ± 0.02 degrees. 19. Compound according to any of claims 16-18, characterized in that it has substantially the same X-ray diffraction pattern as shown in Figure 2. 20. Compound according to claim 15, characterized in that it is crystalline form II of 7 - [(E) -t-butyloxyiminomethyl] -camptothecin. 21. Compound in accordance with the claim 20, characterized in that it shows a X-ray diffraction of a peak at a refractive angle 2 theta (T) of 6.7 ± 0.2 degrees. 22. Compound in accordance with the claim 21, characterized in that it has an X-ray diffraction pattern, expressed in terms of 2 T angles, which includes five or more peaks selected from the group consisting of approximately 11.2, 16.7, 17.0, 17.5 and 25.5 ± 0.02 degrees. 23. Compound according to any of claims 20-22, characterized in that it has substantially the same X-ray diffraction pattern as shown in figure 3. 24. Compound according to claim 15, characterized in that it is crystalline form III. of 7 - [(E) -t-butyloxyiminomethyl] -camptothecin. Compound according to claim 24, characterized in that it shows an X-ray diffraction of a peak at a refractive angle 2 theta (T) of 6.7 ± 0.2 degrees. 26. Compound according to claim 25, characterized in that it has an X-ray diffraction pattern, expressed in terms of 2 T angles, which includes five or more peaks selected from the group consisting of approximately 11.2, 16.7, 17.0, 17.5 and 25.5 ± 0.02 degrees. 27. Compound according to any of claims 24-26, characterized in that it has substantially the same X-ray diffraction pattern as shown in Figure 4. 28. Compound, characterized in that it is 7 - [(E) -t- butyloxyiminomethyl] -camptothecin. 29. Compound, characterized in that it is selected from the group consisting of a crystalline form I, crystalline form II, crystalline form III and amorphous 7 - [(E) -t-butyloxyiminomethyl] -camptothecin. 30. Composition, characterized in that it comprises a compound according to any of claims 15-29. 31. Pharmaceutical composition, characterized in that it comprises: (a) a compound according to any of claims 15-29; and (b) a pharmaceutically acceptable carrier or diluent. 32. Pharmaceutical composition according to claim 31, characterized in that it additionally comprises one or more pharmaceutically acceptable excipients. 33. Pharmaceutical composition according to claim 31 or 32, characterized in that it is a dosage form suitable for oral administration. 34. Pharmaceutical composition according to any of claims 31-33, characterized in that the dosage form is selected from a tablet, capsule or solution. 35. Use of a compound according to any of claims 15-29, for the preparation of a medicament for the treatment of a tumor disease. 36. Method for treating a mammal suffering from a tumor disease, characterized in that it comprises administering a therapeutically effective amount of a compound according to claims 15-29 or pharmaceutical composition according to claims 31-34.