WO2006082053A1

WO2006082053A1 - 7-ethyl-10-hydroxy-camptothecin lipid ester derivatives

Info

Publication number: WO2006082053A1
Application number: PCT/EP2006/000912
Authority: WO
Inventors: Christoph Müller; Brigitte HECKL-ÖSTREICHER; Joris Braspenning; Michael Kulke; Christian Lutz
Original assignee: Heidelberg Pharma GmbH
Current assignee: Heidelberg Pharma Research GmbH
Priority date: 2005-02-02
Filing date: 2006-02-02
Publication date: 2006-08-10
Anticipated expiration: 2007-08-02

Abstract

The subject of the present invention are specific lipidesters of 7-ethyl-10-hydroxycamptothecin, their preparation, pharmaceutical compositions containing such compounds and the use of such lipidesters in the treatment of tumors.

Description

7-EthvHO-hvdroxy-camptothecin Lipid Ester Derivatives

The subject of the present invention are specific lipidesters of 7-ethyl-10-hydroxy- camptothecin of the general formula I,

wherein

R¹ is a straight-chain or branched, saturated or unsaturated alkyl residue having 1-20 carbon atoms, optionally mono- or polysubstituted by halogen, CrC₆ alkoxy, CrC₆ alkylmercapto, Ci-C₆ alkoxycarbonyl, Ci-C₆ alkylsulfinyl or Ci-C₆ alkylsulfonyl groups,

R² is hydrogen, a straight-chain or branched, saturated or unsaturated alkyl chain having 1-20 carbon atoms, optionally mono- or polysubstituted by halogen, C₁- C₆ alkoxy, C₁-C₆ alkylmercapto, CrC₆ alkoxycarbonyl, C₁-C₆ alkylsulfinyl or C₁-C₆ alkylsulfonyl groups;

X represents oxygen, sulfur, a sulfinyl or sulfonyl group, and Y represents oxygen, sulfur, a sulfinyl or a sulfonyl group

their tautomers and their physiologically acceptable salts of inorganic and organic acids and bases, as well as processes for their preparation and medicaments containing these compounds as active ingredients.

Since the compounds of the general formula I contain asymmetric carbon atoms, all optically-active forms and racemic mixtures of these compounds are also the subject of the present invention.

Camptothecin is a potent antitumor antibiotic isolated by Monroe E Wall and Mansukh C. Wani in 1958 from extracts of Camptotheca acuminata, a tree native to China and Tibet which has been extensively used in traditional Chinese medicine. The structure was determined to be that of a pentacyclic alkaloid and was first reported in 1966. It was shown that camptothecin is capable of inhibiting DNA synthesis via strand scission, thus causing cell death during S-phase of the cell cycle. The finding that the treatment of cultured cells with camptothecin led to protein-associated DNA strand breaks provided the key clue that led to the identification of a DNA-Protein complex as the target for camptothecin. The S-phase cytotoxicity is attributed to cessation of DNA synthesis and double - strand breakage when the replication fork encounters the covalently bound DNA- topoisomerase I site. Different lines of evidence support toposisomerase I-DNA interaction as the locus of action of camptothecin. For example, a number of camptothecin resistant cell lines have been studied, all of these are characterized by specific mutations within topoisomerase I. Further, deletion of the gene for topoisomerase I from Saccharomyces cerevisae resulted in viable cells that were fully resistant to camptothecin. Reexpression of the yeast or human enzymes in S. cerevisae restored sensitivity to camptothecin. The discovery that the primary cellular target of camptothecin is type I DNA topoisomerase created great interest in the drug. The natural camptothecin and its derivative 7-ethyl-10-hydroxy-camptothecin (SN38) are hardly soluble in water. Therefore their water soluble sodium salt was used in clinical trials. This form proved to be less efficacious and was accompanied by unpredictable and severe levels of toxicity associated with treatment, including hemorrhagic cystitis and myelotoxicity, resulting in suspension of the trials. Advances in medicinal chemistry of camptothecin resulted in semisynthetic , more water-soluble analogues, such as topotecan (9-(dimethylamino)- methyl-10-hydroxy-camptothecin) disclosed in US Pat. 5004758 and irinotecan (7-ethyl-10-[4-(1-piperidino)-1-piperidino]carbonyloxycamptothecin) disclosed in US Pat. 4604463. They are used clinically for the treatment of ovarian cancers and colon, respectively. Irinotecan is a prodrug of SN38 and has to be activated by carboxylesterases. The enzymatic cleavage of irinotecan has been shown to occur predominantly in the liver releasing free SN38. As a consequence the biliary excretion of SN38 seems to be responsible for the severe diarrhoea which is the dose -limiting toxicity in cancer patients.

In addition the camptothecin derivatives presently used have two major limitations:

1. at physiological pH, the labile alpha hydroxylactone function, which is essential for camptothecin activity is in equilibrium with its inactive (carboxylate) form, which is bound to serum albumin and

2. the camptothecin-trapped cleavage complex reverses within minutes after drug removal, which imposes long and/or repeated infusions for cancer treatment.

Phosphates of 7-ethyl-10-hydroxy-camptothecin are disclosed in Chem. Pharm. Bull. 1992, 40(1), 131-135. However the disclosed compounds show limited antitumor activity.

Ether-lipid-phosphates are generally known as conjugates of nucleosides like AZT to penetrate into cells, whereafter they are cleaved into nucleoside- monophosphates (W OA-9615234). Surprisingly it was found that ether-lipid-phosphate esters of 7-ethyl-10-hydroxy- camptothecin (formula I) possess excellent qualities in comparison to SN38 and the known derivatives topotecan and irinotecan.

The compounds of formula I are able to inhibit the target enzyme topoisomerase I like 7-ethyl-10-hydroxy-camptothecin itself (example 3). Obviously the 7-ethyl-10- hydroxy-camptothecin derivative must not be cleaved enzymatically to become active, but behaves like a normal drug. This is different from nucleoside - conjugates. In order to be therapeutically active they have to be cleaved by specific enzymes to release the nucleoside monophosphate as active drug. They are typical prodrugs. Also the 7-ethyl-10-hydroxy-camptothecin- analogue irinotecan is a prodrug. It must be cleaved by carboxylesterases to be therapeutically active. Compounds of the present invention are active drugs per se.

In contrast to 7-ethyl-10-hydroxy-camptothecin which is not soluble in water the compounds of the present invention show improved solubility in aqueous phase. It allows an applicability as intravenous drug and is a good prerequisite for the preparation of other galenic formulations.

The compound of the present invention show potent cytotoxic activity in cell culture. In comparison to irinotecan it is at least 100 times more potent. This is in accordance with in vitro activity of nucleoside conjugates which also are regularly less potent than their parent drug. This finding is a further proof that the compound of the present invention acts directly and not as a prodrug. A comparison of the antitumoral activity of the compound of the present invention and irinotecan shows that the compound of the present invention is more potent at pharmacological relevant doses. Toxic side effects of the parent compound is/are ameliorated, and/or the covalently bound lipid moiety improves the bioavailability of the coupled drug substance and thus appears to contribute to enhanced selectivity and effectiveness of the compounds.

The inventive derivative with the lipid moiety prevents the compounds from glucuronidation and therefore rapid elimination from the blood stream. The compounds of the present invention have valuable pharmacological properties. In particular, they are suitable for therapy and prophylaxis of malignant tumors including carcinomas, sarcomas, or leukemias.

Compared to the unconjugated camptothecin derivatives hitherto employed in treatment of malignant tumors, the compounds according to the invention have enhanced potency/efficacy for specific indications or lower toxicity and consequently have a wider therapeutic window. In some embodiments of the present invention, the administration of pharmaceutical compositions comprising these compounds may be conducted continuously over a prolonged period of time. Incidences of withdrawal of the preparation or intermittent administration, which frequently are routine with chemotherapeutic agents due to their undesirable side- effects, may be reduced with the compounds according to this invention as compared to the parent compound. Further, higher dose levels may be employed due to the amelioration of toxic side effects due to enhanced selectivity for tumor cytotoxicity.

The lecithin-like structure of the lipid moiety is desirable for the claimed improvements of the compounds of general formula I. The penetration through membranes and resorption barriers is facilitated and the conjugates according to formula I show a depository effect in different tissues. The formation of lipid derivatives may also facilitate crossing the blood brain barrier due to better diffusion or active transport processes.

Similarly, the compounds of the present invention and their pharmaceutical formulations may be employed in free or fixed combination with other drugs for the treatment and prophylaxis of the diseases mentioned above. Examples of these further drugs involve agents such as, e.g., mitosis inhibitors such as colchicines, vinblastine, alkylating cytostatic agents such as cyclophosphamide, melphalan, myleran or cis-platin, antimetabolites such as folic acid antagonists (methotrexate) and antagonists of purine and pyrimidine bases (mercaptopurine, 5-fluorouridine, cytarabine), cytostatically active antibiotics such as anthracyclines (e.g., doxorubicin, daunorubicin), hormones such as fosfestrol, taxanes, e.g. taxol, tamoxifen and other cytostatically/cytotoxically active chemotherapeutic and biologic agents.

Embodiments of the invention also encompass salts of the compounds of the general formula I, including alkali, alkaline earth and ammonium salts of the phosphate group. Examples of the alkali salts include lithium, sodium and potassium salts. Alkaline earth salts include magnesium and calcium salts. Ammonium salts are understood to be those containing the ammonium ion, which may be substituted up to four times by alkyl residues having 1-4 carbon atoms, and/or aryl residues such as benzyl residues. In such cases, the substituents may be the same or different.

The compounds of general formula I may contain basic groups, particularly amino groups, which may be converted to acid addition salts by suitable inorganic or organic acids. To this end, preferred as the acids are, in particular: hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid, fumaric acid, succinic acid, tartaric acid, citric acid, lactic acid, maleic acid or methanesulfonic acid. In general formula I₁ R¹ preferably represents a straight-chain C₈-Ci₅ alkyl residue which may be further substituted by a CrC₆ alkoxy or a C-i-Cβ alkylmercapto group. More specifically, R¹ represents a substituted or unsubstituted nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl or pentadecyl residue. Preferably, methoxy, ethoxy, butoxy and hexyloxy groups are possible as substituents of R¹ residue. In case R¹ is substituted by a Ci-C₆ alkylmercapto residue the methylmercapto, ethylmercapto, propyl mercapto, butylmercapto and hexylmercapto residue are preferred.

Preferably, R² represents a straight-chain C₈-Ci₅ alkyl group which may be further substituted by a Ci-Cβ alkoxy or a Ci-C₆ alkylmercapto group. More specifically, R² represents an octyl, nonyl, decyl, undecyl, dodecyl, tridecyl or tetradecyl group. Methoxy, ethoxy, propoxy, butoxy and hexyloxy groups are preferred as the Ci-C₆ alkoxy substituents of R² and methylmercapto, ethylmercapto, propylmercapto, butylmercapto, pentylmercapto and hexylmercapto residues as CrC₆ alkylmercapto substituents.

In general formula I, R¹ and R² are preferably unsubstituted C₈ - C₁₅ alkyl residues.

A preferred lipid moiety is the group

wherein

R ¹ is C₈ - Ci₅ alkyl

R ² is C₈ - Ci5 alkyl

X is S, SO or SO₂ and

Y is O. The presently most preferred compounds are (7-ethylcamptothecin-10- yl)phosphoric acid-(3-dodecylmercapto-2-decyloxy)propyl ester, (7- ethylcamptothecin-10~yl)phosphoric acid-(3-dodecylsulfinyl-2-decyloxy)propyl ester, (7-ethylcamptothecin-10-yl)phosphoric acid-(3-dodecylsulfonyl-2- decyloxy)propyl ester.

The compounds of the general formula I may be prepared by several routes three of which are exemplified below.

1. Reacting a compound of general formula Il

wherein R¹, R², X and Y have the meaning as indicated, with a compound of formula III

The compound of formula Il may be activated in the presence of an appropriate acid chloride, such as 2,4,6-triisopropylbenzenesulfonic chloride, and a tertiary nitrogen base, e.g., pyridine or lutidine, in an inert solvent, such as toluene, or immediately in anhydrous pyridine.

2. Reacting a lipidalcohol of the general formula IV

with a 10-monophosphate ester of a compound corresponding to formula III in the same manner as mentioned above.

3. Reacting a compound of general formula III with phosphoryl chloride, followed by subsequent addition of an lipidalcohol of the general formula IV.

4. Reacting a compound of general formula V,

wherein R¹, R², X and Y have the above-mentioned meaning, with a compound of general formula III, in the presence of phospholipase D from Streptomyces in an inert solvent, such as chloroform, in the presence of a suitable buffer.

The preparation of the compounds of the general formula II, IV and V may be performed in analogy to Lipids 22, 947 (1987) and J. Med. Chem. 34, 1377 (1991 ). Compounds of formula Kl are prepared in analogy to US Pat. 4473692. Compounds of formula I, where X or Y are a sulfinyl or a sulfonyl group may be obtained by oxidation of compounds of formula I wherein X or Y are sulfur, e.g. by m-chlorobenzoic acid or a mixture of H₂O₂ and acetic acid.

Salts of compounds of general formula I may be prepared by reacting the free acid with alkali or alkaline earth hydroxides, alcoholates or acetates.

The "enantiomers" in the lipid parts of the compounds of formula I may be prepared by separation via diastereomeric salts or by enantioselective synthesis of the lipid residues starting with optically active C₃ -precursors of formula II, IV or V.

The drugs containing compounds of formula I for the treatment of cancer may be administered in liquid or solid forms on the oral or parenteral route. All common application forms are possible, such as tablets, capsules, coated tablets, syrups, solutions, or suspensions.

Preferably, water is used as the injection medium, containing additives such as stabilizers, solubilizers and buffers as are common with injection solutions. Such additives are, e.g. tartrate and citrate buffers, ethanol, complexing agents such as ethylenediaminetetraacetic acid and its non-toxic salts, high-molecular polymers such as liquid polyethylene oxide for viscosity control. Liquid vehicles for injection solution need to be sterile and are filled in ampoules, preferably.

Solid carriers are, for example, starch, lactose, mannitol, methylcellulose, talc, highly dispersed silicic acids, higher-molecular fatty acids such as stearic acid, gelatine, agar-agar, calcium phosphate, magnesium stearate, animal and plant fats, solid high-molecular polymers such as polyethylene glycol, etc. If desired, formulations suitable for oral application may include flavorings or sweeteners. The dosage may depend on various factors such as mode of application, species, age, or individual condition. The compounds according to the invention may suitably be administered orally or intravenously (i.v.) in amounts in the range of 0.1 - 100 mg, preferably in the range of 0.2 - 80 mg per kg of body weight and day. In some dosage regimens, the daily dose is divided into 2 - 5 applications, with tablets having an active ingredient content in the range of 0.5 - 500 mg being administered with each application. Similarly, the tablets may have sustained release properties, reducing the number of applications, e.g. to 1 - 3 per day. The active ingredient content of sustained-release tablets may be in the range of 2 - 1000 mg. The active ingredient may also be administered by i.v. bolus injection or continuous infusion, where amounts in the range of 5 - 1000 mg per day are normally sufficient.

In addition to the compounds mentioned in the examples, the following compounds of formula I and their pharmacologically acceptable salts further exemplify compounds of the present invention:

1. (Z-ethylcamptothecin-IO-yOphosphoric acid-(3-dodecylmercapto-2- decyloxy)propyl ester

2. (7-ethylcamptothecin-10-yl)phosphoric acid-(3-dodecylsulfinyl-2- decyloxy)propyl ester

3. (7-ethylcamptothecin-10-yl)phosphoric acid-(3-dodecylsulfonyl-2- decyloxy)propyl ester

4. (7-ethylcamptothecin-i 0-yl)phosphoric acid-(3-undecylmercapto-2- decyloxy)propyl ester

5. (7-ethylcamptothecin-10-yl)phosphoric acid-(3-undecylmercapto-2- undecyloxy)propyl ester

6. (7-ethylcamptothecin-i 0-yl)phosphoric acid-(3-decylmercapto-2- dodecyloxy)propyl ester 7. (7-ethylcamptothecin-i 0-yl)phosphoric acid-(3-dodecylmercapto-2- dodecyloxy)propyl ester

8. (7-ethylcamptothecin-i 0-yl)phosphoric acid-(3-decylmercapto-2- decyloxy)propyl ester

9. (7-ethylcamptothecin-i 0-yl)phosphoric acid-(3-undecylsulfinyl-2- decyloxy)propyl ester

10. (7-ethylcamptothecin-i 0-yl)phosphoric acid-(3-undecylsulfonyl-2- decyloxy)propyl ester

11. (7-ethylcamptothecin-10-yl)phosphoric acid-(3-undecylsulfinyl-2- undecyloxy)propyl ester

12. (7-ethylcamptothecin-10-yl)phosphoric acid-(3-undecylsulfonyl-2- undecyloxy)propyl ester

13. (7-ethylcamptothecin-i 0-yl)phosphoric acid-(3-tridecylmercapto-2- undecyloxy)propyl ester

14. (7-ethylcamptothecin-i 0-yl)phosphoric acid-(3-tridecylmercapto-2- decyloxy)propyl ester

15. (7-ethylcamptothecin-10-yl)phosphoric acid-(3-tridecylsulfinyl-2- decyloxy)propyl ester ell as their optical isomers

EXAMPLE 1

Preparation of (T-ethylcamptothecin-IO-ylJphosprtoric acid-(3-dodecyl- mercapto-2-decyloxy)propyl ester (SN38-lipidester)

1.96 g of 7-ethyl-IO-hyclroxycamptotecin was dissolved in dry pyridine and cooled to 0 to +4 ⁰C in an ice bath. 1.84 ml phosphoyl chloride were added within 5 min. Subsequently the ice bath was removed and the mixture was stirred at room temperature for 1.5 h. Then 25 g S-dodecylthio^-decyloxy-i-propanol was added and stirring was continued for additional 1.5 h. After that the reaction was quenched with 2 ml of water and the mixture was freed from solvent under vacuum, and stripped twice using 20 ml of toluene. The residue was stirred in acetone (200 ml) at 0 ⁰C for 12 h and the precipitate was filtered off. The crude product was purified by column chromatography on LiChrospher™ 60 RP-select B with methanol/aqueous 40 mM sodium acetate 85:15 as the eluent. The product containing fractions are evaporated to aprox. 20 % of their original volume and kept in an refrigerator. The precipitated sodium salt of the product was filtered off and dried in vacuo to give 1.22 g of a slight yellow powder. ¹H NMR (300 MHz, DMSO-Cl₆): 8.01 (d, 1 H₁ J = 9.0 Hz), 7.95 (s, 1 H), 8.74 (d, 1 H, J = 9.0 Hz), 7.30 (s, 1H), 6.40 (s, 1 H), 5.41 (d, 1 H, J = 16 Hz), 5.40 (d,1 H, J = 16Hz), 5.27 (s, 2H), 3.81 (m, 2H, POCH₂), 3.20-3.50 (m, 3H, >CHOCH₂-), 3,10 (q, 2H), 2.35-2.65 (m, 4H, CH₂SCH₂), 1.80-1.95 (m, 2H), 1.1-1.5 (m, 39H), 0.7-0.9 (m, 9H);

³¹P NMR (121.5 MHz₁ DMSO-d₆): -5.38 ppm

UV (methanol) λ_maxi 216 nm, λ_maχ2 255 nm, λ_maX3 356 nm, λ_max4 369 nm; mass spec. (FAB^""): m/z = 869 [M-Na⁺ = C₄₇H₇₀N₂O₉PS],

EXAMPLE 2 Tablet formulation

1.50 kg (7-ethylcamptothecin-10-yl)phosphoric acid-(3-dodecylmercapto-2- decyloxy)propyl ester sodium salt, 1.42 kg microcrystalline cellulose, 1.84 kg lactose, 0.04 kg Polyvinylprrolidine and 0.20 kg magnesium stearate

were mixed in dry form, moistened with water and granulated. After drying the material was pressed to tablets of 500 mg weight.

EXAMPLE 3 Inhibition of Topoisomerase I by a SN38-lipidester (Compound of Exp.1)

To study the inhibitory activity of the derivative, human type I topoisomerase (5 units; TopoGen) was incubated in 300 μl 10X Topoisomerase I assay/cleavage buffer (Ix TGS buffer is 10 mM TrisHCI pH 7.9, 1 mM EDTA, 0.15 M NaCI, 0.1 % BSA, 0.1 mMM Spermidine, 5 % glycerol) with its substrate supercoiled form I DNA (25 μg/ 100μl TE; 10 mM TrisHCI pH7.5, 1 mM EDTA) for 30 min at 37 ⁰C. The reaction was stopped with SDS termination buffer (10 % sodium dodecyl sulfate (SDS) termination buffer). After digestion with proteinase K (50 μg/ml, 60 min at 37 ⁰C), samples were loaded onto a 1 % agarose gel. Under these conditions, topoisomerase I is able to perform the conversion of supercoiled (form I) DNA into open circular (OC) DNA. The conversion of supercoiled (form I) DNA to open circular (OC DNA) was prevented by addition of the SN38-lipidester (compound of Exp. 1 ) showing that the molecule acts directly as a substrate of the enzyme. Therefore cleavage of the conjugate is not necessary to for activitiy. A direct comparison of two different concentrations (1 and 10 mM) of SN38 and compound of Exp.1 demonstrated their specific inhibitory activity towards topoisomerase I.

Surprisingly the compound of Exp. 1 dissolves in H₂O in contrast to SN38 which only can be dissolved in DMSO.

EXAMPLE 4

Comparison of the cytotoxic activity of SN38-lipidester (Compound of Exp.1), SN38 and irinotecan

In vitro antiproliferative activity of test compounds was determined using a colorimetric assay for the quantification of cell proliferation and cell viability based on the cleavage of the tetrazolium salt WST- 1 (Berridge MV, Tan AS, McCoy KD, Wang R. The Biochemical and Cellular Basis of Cell Proliferation Assays That Use Tetrazolium Salts. Biochemica 1996;4:14-19). Experiments were performed in triplicates in 96-welI cell culture plates (Falcon, BD Biosciences, Heidelberg, Germany). Dilution series of 1 :3 or 1 :10 were carried out directly on the plates in a volume of 50 μl culture medium. Cells (2,5 x 10⁴ cells/ml RPMI) were added in 50 μl culture medium, resulting in a total volume of 100 μl per well. Cell cultures without added drugs (medium only) served as controls. Plates were then incubated for 1, 2 and 3 days at 37 ⁰C, 5 % by Vol. CO₂ and 95 % humidity. Cultures were pulsed with 10 μl of cell proliferation reagent WST-1 , supplied as ready-to-use solution (Roche Molecular Biochemicals, Mannheim, Germany) for 4 h. Plates were gently shaken for 10 min and the optical density (O. D.) was measured in an ELISA reader (SpectraMAX 340_Pc, Molecular Devices, European Technical Centre, Germany) at wavelength settings of 440 nm- 650 nm. Results shown in table 1 indicate that compound of Exp. 1 is, compared to Irinotecan, at least 15 times more cytotoxic (HeI, d2) in all cell lines tested. This ratio expands with increasing incubation times (up to 16000 times in Molt4, d3).

Table 1:

IC₅₀-values [μM] of cells treated with SN38-lipidester (Exp. 1), Irinotecan and

SN38 in different cell lines

Molt 4: Acute lymphoplastic leukaemia, T lymphoblast

HeI: Human erythroleukemia

K562: Human chronic myeloide leukaemia in blast crisis EXAMPLE 5

Comparison of the anti-tumour activity of (7-ethylcamptothecin-IO- yl)phosphoric acid-(3-dodecylmercapto-2-decyloxy)propyl ester (SN38- lipidester) and lrinotecan

The antitumor activity of the SN38-lipidester and lrinotecan has been compared in the human colon carcinoma xenograft HT-29 model in nude mice.

Tumor bearing mice were randomized on day 5 after HT-29 tumor cell inoculation and were distributed to treatment groups of n = 9 animals per group. Treatment was started on day 6. The animals were treated intraperitoneally (ip) once daily on days 6 - 10 and 13 - 17 with SN38-lipidester or lrinotecan. Dosages included 100 %, 50 % and 25 % of the Maximum Tolerable Doses (MTD's). Control animals were injected with the corresponding solvent (Vehicle). Tumor volumes were determined twice weekly by calipers. The time courses of the median tumor volumes are shown in Figure 1. The antitumor efficacy of the SN38-lipidester was significantly higher (p < 0.01) than that of lrinotecan at the MTD. In the treatment free period (days 18-27) median tumor volumes remained below the tumor volume prior to dosing.

EXAMPLE 6 Formulation for injection

10.0 g (7-ethylcamptothecin-10-yl)phosphoric acid (3-dodecylmercapto-2- decyloxy)propyl ester sodium salt were dissolved in 500 ml physiologic sodium chloride solution, 5 ml each filled in ampoules and sterilized. The solution may be applied by intravenous injection.

Claims

1. A camptothecin derivative of formula I

wherein

R¹ is selected from the group consisting of a straight-chain or branched, saturated or unsaturated alkyl chain having 1-20 carbon atoms, which is unsubstituted or substituted with one or more halogen, C-i-C-₆ alkoxy, C₁-C₆ alkylmercapto, C₁- C₆ alkoxycarbonyl, Ci-C₆ alkylsulfinyl or C_rC₆ alkylsulfonyl groups;

R² is selected from the group consisting of hydrogen, a straight-chain or branched, saturated or unsaturated alkyl chain having 1-20 carbon atoms, which is unsubstituted or substituted with one or more halogen, C₁-C₆ alkoxy, Ci-C₆ alkylmercapto, CrC₆ alkoxycarbonyl, Ci-C₆ alkylsulfinyl or CrC₆ alkylsulfonyl groups;

X represents oxygen, sulfur, a sulfinyl group or a sulfonyl group,

Y represents oxygen, sulfur, a sulfinyl group or a sulfonyl group,

their tautomers, their optically active forms and racemic mixtures, and their physiologically acceptable salts of inorganic and organic acids or bases.

2. The camptothecin derivative according to claim 1 , wherein R¹ is a straight- chain Ca-Ci₅ alkyl group, which is unsubstituted or substituted by a CrC₆ alkoxy or a C₁-Ce alkylmercapto group.

3. The camptothecin derivative according to claim 1 , wherein R² represents a straight-chain C₈-Ci₅ alkyl group, which is unsubstituted or substituted by a C₁- C₆ alkoxy or a d-C-₆ alkylmercapto group.

4. The camptothecin derivative according to claims 1 to 3, wherein X represents sulfur, a sulfinyl or sulfonyl group.

5. The camptothecin derivative according to claim 1 to 4 wherein Y represents oxygen.

6. The camptothecin derivative according to claim 1 , wherein the compound is:

wherein X is sulfur, sulfinyl or sulfonyl.

7. A pharmaceutical composition comprising at least one compound according to claims 1 - 6 in combination with one or more pharmaceutically acceptable additive(s) and/or one or more carrier(s).

8. A method for treating malignant tumors comprising administering to a patient in need of such treatment an amount of the composition according to claim 7 or the compound according to claim 1 - 6 effective to treat said tumors.

9. The method according to claim 8, wherein said tumor is selected from the group consisting of carcinomas, sarcomas or leukemias.

10. The use of a compound according to claims 1 to 6 for the manufacture a medicament for the treatment of tumors.