WO2007085370A1

WO2007085370A1 - 9-(dimethylamino)-methyl-10-hydroxy-camptothecin lipidester derivatives

Info

Publication number: WO2007085370A1
Application number: PCT/EP2007/000396
Authority: WO
Inventors: Christoph Müller
Original assignee: Heidelberg Pharma Ag
Priority date: 2006-01-25
Filing date: 2007-01-18
Publication date: 2007-08-02

Abstract

The subject of the present invention are specific lipidesters of 9-(dimethylamino)-methyl-10-hydroxycamptotecin, their preparation, pharmaceutical composition containing such compounds in the treatment of tumors and the use of such lipidesters in the treatment of tumors.

Description

9-(Dimethylamino)-methyl-10-hydroxy-camptothecin Lipidester Derivatives

The subject of the present invention are specific lipidesters of 9-(dimethylamino)- methyl-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, C₁-C₆ alkoxy, CrC₆ alkylmercapto, CrC₆ alkoxycarbonyl, CrC₆ alkylsulfinyl or CrC₆ alkylsulfonyl groups,

R² is hydrogen, a straight-chain or branched, saturated or unsaturated alkyl chain having 1 -20 carbon atoms, optionally mono- or nolysnhstjtπted by halogen, C;- C₆ alkoxy, Ci-C₆ alkylmercapto, CrC₆ alkoxycarbonyl, CrC₆ alkylsulfinyl or CrC₆ 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 L>y specific mutaiions 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 is hardly soluble in water. The corresponding water soluble sodium salt was used in clinical trials. But this form proved to be less efficacious and was accompanied by unpredictable and severe levels of toxicity associated with treatment resulting in suspension of the trials. Advances in medicinal chemistry of camptothecin resulted in semi-synthetic, 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.

The camptothecin derivatives presently in the clinic have several 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, 2/ the camptothecin-trapped cleavage complex reverse within minutes after drug removal, which imposes long and/or repeated infusions for cancer treatment and 3/ Camptothecine resistance is said to be correlated with expression of breast-cancer resistance protein (BCRP) (Mathijssen et al. Current cancer drug targets 2002; ). This correlation could be overcome by 9-(dimethylamino)-methyl-10-hydroxy-camptothecin lipidester derivatives.

Ether-lipid-phosphates are generally known as conjugates of nucleosides like AZT to penetrate into cells, whereafter they are cleaved into nucleoside- monopnospi iaie (vVO-A-9b1 b234).

Surprisingly it was found that ether-lipid-phosphate esters of 9-(dimethylamino)- methyl-10-hydroxy-camptothecin (formula I) posses excellent qualities in comparison to topotecan. The compounds of formula I are able to inhibit its target enzyme topoisomerase I like 9-(dimethylamino)-methyl-10-hydroxy-camptothecin itself (example 3). Obviously the 9-(dimethylamino)-methyl-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. So nucleoside-conjugates are typical prodrugs. Compounds of the present invention are active drugs per se.

The compounds of the present invention show potent cytotoxic activity in cell culture. In comparison to the camptothecin prodrug irinotecan, the current invention is at least 100x more potent. This is in accordance with in vitro activity of nucleoside conjugates, also prodrugs. These are generally less potent than their parent drug. This finding is a further prove 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 topotecan 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 ot the present invention have valuable pharmacological properties. In particular, they are suitable for therapy and prophylaxis of malignant tumors including carcinomas, sarcomas, leukemias and malignancies caused by human deficiency virus. 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 compounds. 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 I₁ 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 and 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 compound of general formula I contain a basic amino group, which may be converted to acid addition salts by suitable inorganic or organic acids. To this end, possible 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 I, R¹ preferably represents a straight-chain C₈-C₁₆ alkyl residue which may be further substituted by a CrC₆ alkoxy or a Ci-C₆ alkylmercapto group. More specifically, R¹ represents a 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, this is understood to be the methylmercapto, ethylmercapto, propylmercapto, butylmercapto and hexylmercapto residue, in particular.

Preferably, R² represents a straight-chain C₈-Ci₅ alkyl group which may be further substituted by a Ci-C₆ alkoxy or a CrC₆ alkylmercapto group. More specifically, R² represents an octyl, nonyl, decyl, undecyl, dodecyl, tridecyl or tetradecyl group. Preferably, methoxy, ethoxy, propoxy, butoxy and hexyloxy groups are preferable as the CrCβ alkoxy substituents of R². In case R² is substituted by a CrC₆ alkylmercapto residue, this is understood to be the methylmercapto, ethylmercapto, propylmercapto, butylmercapto, pentylmercapto and hexylmercapto residue, in particular.

A preferred lipid moiety is the group

wherein

R¹ is C₈ - C₁₅ alkyl R² is C₈ - Ci₅ alkyl X is S, SO or SO₂ and Y is O.

The most preferred compounds are (9-(dimethylamino)-methyl-camptothecin-10- yl)phosphoric acid-(3-dodecylmercapto-2-decyloxy)propyl ester, (9- (dimethylamino)-methyl-camptothecin-10-yl)-phosphoric acid-(3-dodecylsulfinyl-2- decyloxy)propyl ester, (9-(dimethylamino)-methyl-camptothecin-10-yl)phosphoric acid-(3-dodecylsulfonyl-2-decyloxy)propyl ester and its pharmacological acceptable salts and esters.

The compounds ot the general formula I may be prepared by

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,

or

reacting a lipidalcohol of the gen^pral formula !V

(IV) with a 10-monophosphate ester of a compound corresponding to formula III in the same manner as mentioned above, or

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

or

3. 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 is performed in anaiogy to Lipids Zl, 947 (1987) and J. Med. Chem. 34, 1377 (1991 ). Compounds of formula III can be prepared in analogy to US PAT. 5 004 758 .

Compounds of formula I, where X or Y are a sulfinyl or a sulfonyl group are obtained by oxidation of compounds of formula I wherin X or Y are sulfur, e.g. by m-chlorobenzoic acid or H₂O₂/acetic acid. Salts of compounds of general formula I are 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. 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 auiiabie 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- 100mg, preferably in the range of 0.2 - 80mg per kg of body weight and per 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- 500mg being administered with each application. Similarly, the tablets may have sustained release, 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- 1000mg. The active ingredient may also be administered by i.v. bolus injection or continuous infusion, where amounts in the range of 5- IOOOmg 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. (9-(dimethylamino)-methyl-camptothecin-10-yl)phosphoric acid-(3- dodecylmercapto-2~decyloxy)propyl ester

2. (θ-CdimethylaminoJ-methyl-camptothecin-i 0-yl)phosphoric acid-(3- dodecylsulfinyl-2-decyloxy)propyl ester

3. (9-(dimethylamino)-methyl-camptothecin-10-yl)phosphoric acid-(3- dodecylsulfonyl-2-decyloxy)propyl ester

4. (9-(dimethylamino)-methyl-camptothecin-10-yl)phosphoric acid-(3- undecylmercapto-2-decyloxy)propyl ester

5. (9-(dimethylamino)-methyl-camptothecin-10-yl)phosphoric acid-(3- undecylmercapto-2-undecyloxy)propyl ester

6. (9-(dimethylamino)-methyl-camptothecin-10-yl)phosphoric acid-(3- decy !ι i iei uaμio-2-doαecyloxy)propyl ester

7. (9-(dimethylamino)-methyl-camptothecin-10-yl)phosphoric acid-(3- dodecylmercapto-2-dodecyloxy)propyl ester

8. (9-(dimethylamino)-methyl-camptothecin-10-yl)phosphoric acid-(3- decylmercapto-2-decyloxy)propyl ester 9. (9-(dimethylamino)-methyl-camptothecin-10-yl)phosphoric acid-(3- undecylsulfinyl-2-decyloxy)propyl ester

10. (θ-CdimethylaminoJ-methyl-camptothecin-i 0-yl)phosphoric acid-(3- undecylsulfonyl-2-decyloxy)propyl ester

11. (9-(dimethylamino)-methyl-camptothecin-10-yl)phosphoric acid-(3- undecylsulfinyl-2-undecyloxy)propyl ester

12. (9-(dimethylamino)-methyl-camptothecin-10-yl)phosphoric acid-(3- undecylsulfonyl-2-undecyloxy)propyl ester

13. (9-(dimethylamino)-methyl-camptothecin-10-yl)phosphoric acid-(3- tridecylmercapto-2-undecyloxy)propyl ester

14. (9-(dimethylamino)-methyl-camptothecin-10-yl)phosphoric acid-(3- tridecylmercapto-2-decyloxy)propyl ester

15. (9-(dimethylamino)-methyl-camptothecin-10-yl)phosphoric acid-(3- tridecylsulfinyl-2-decyloxy)propyl ester as well as their optical isomers

EXAMPLE 1

Preparation of (9-(dimethylamino)-methyl-camptothecin-10-yl)phosphoric acid-(3-dodecylmercapto-2-decyloxy)propyl ester (TPT-lipidester)

1.73 g of phosphoric acid-(3-dodecylmercapto-2-decyloxy)propyl ester was treated twice with 25 ml of anhydrous pyridine and concentrated by evaporation. The residue was dissolved in 100 ml of anhydrous pyridine at room temperature, treated with 3.64 g of 2,4,6-triisopropylbenzenesulfonyl chloride (trisyl choride) under nitrogen and stirred at 20 ⁰C for 2 hours. Then 1.19 g of 9-dimethyl- aminnethy!-10-hydrcxycGrr;ptotscir. was aclϋ'eu ai uπue, and ihe reaction mixture was stirred under nitrogen for 16 hours. Hydrolysis was performed by adding 10 ml of water, the mixture was stirred for another 0.5 hour at room temperature, evaporated to dryness and coevaporated using 100 ml of toluene. The residue was stirred in chloroform (100 ml) and 2N hydrochloric acid (20 ml) for 10 min. The organic phase was seperated, again washed with 2N hydrochloric acid (20 ml) and evaporated to dryness. The residue was purified by column chromatography on LiChrospher™ 60 RP-select B with methanol/aqueous 4OmM sodium acetate 90:10 as the eluent. The product containing fractions are evaporated to dryness and stirred in chloroform. After filtration of the sodium acetate the solvent was evaporated and the residue lyophilized from f-butanol to give 0.46 g of a slight yellow powder.

¹H NMR (300 MHz₁ CDCI₃): 8.7 (s, 1 H), 8.3 (s, 1 H), 7.9 (d, 1 H), 7.6 (s,1 H), 5.65 (d, 1 H), 5.2-5.3 (m, 2H), 4.7 (m, 1 H), 4.3 (m, 1 H), 3.5-3.8 (m, 2H), 2.9 (s, 6H)₁ 2.6-2.8 (m, 2H); 2.5-2.6 (m, 2H), 1.8-2.0 (m, 6H), 1.5-1.6 (m, 4H), 1.1-1.4 (m, 32H), 1.0 (m, 3H), 0.85 (m, 6H);

³¹P NMR (121.5 MHz, CDCI₃): -3.33 ppm;

UV (methanol) λ_maxi 216 nm, λ_maX2253 nm, λ_max3354 nm, λ_maχ₄ 369 nm; mass spec. (FAB⁺): m/z = 900 [MH⁺ -Na = C₄₈H₇₄N₃O₉PS].

EXAMPLE 2

Inhibition of Topoisomerase I by a Topotecan-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 pH7.9, 1 mM EDTA, 0.15 M NaCI, 0.1 % BSA, 0.1 mM 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 10% sodium dodecyl sulfate (SDS) termination buffer. After digestion with proteinase K (50 μg/ml, 60 min at 37°C), 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 Topotecan-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 be active. A direct comparison of two different concentrations (1 and 10 mM) of Topotecan and compound of Exp.1 demonstrated their specific inhibitory activity towards topoisomerase I.

EXAMPLE 3

Determination of the cytotoxic activity of Topotecan-lipidester in-vitro

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 [1].

Experiments were performed in triplicates in 96-well 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 or 100 μl culture medium. Cells (2,5 x 10⁴ cells/ml culture medium) were added in 50 or 100 μl culture medium, resulting in a total volume of 100 μl per well, or 200 μl per well respectively.

Cell cultures without added drugs (medium only) served as controls. Plates were then incubated for three days at 37°C, 5% CO₂ and 95% humidity. Cultures were pulsed with 10 μl or 20 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 340pc, Molecular Devices, European Technical Centre, Germany) at wavelength settings of 440 nm- 650 nm. Results shown in table 1 indicate that compound Topotecan-lipidester is cytotoxic in all cell lines tested in a range from 0.086 μM - 0.98 μM. Table 1:

IC₅₀-values [μM] of cells treated with Topotecan-lipidester

[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.

Example 4

Comparison of the anti-tumour activity of (9-(dimethylamino)-methyl- camptothecin-10-yl)phosphoric acid-(3-dodecylmercapto-2-decyloxy)propyl ester (Topotecan-lipidester) and Topotecan

The antitumor activity of Topotecan (TPT)-lipidester and Topotecan (TPT) was compared in the B cell leukemia model L1210 in DBA/2 mice.

Female DBA/2 mice (10 mice per group) were treated intraperitoneally (ip) once daily on days 1-5 and 7-11 with Topotecan (TPT)-lipidester or the parent compound TPT starting one day after intraperitoneal inoculation of 10⁵ L1210 tumor cells per animal. Dosages included 100, 66 and 33 % of the Maximum Tolerable Doses (MTD's). Survival was monitored for a period of 60 days after tumor inoculation. The increase in median survival time in the different treatment groups in comparison with that of saline treated control mice was determined as a measure of antitumor activity. In Figure 1 the Median Survival Time was expressed as percentage of that of the control group (T/C %).

After treatment with Topotecan-lipidester survival time and rate was significantly prolonged compared to Topotecan

Figure 1

EXAMPLE 5

Comparison of the bone marrow tolerability of (9-(dimethylamino)-methyl- camptothecin-10-yl)phosphoric acid-(3-dodecylmercapto-2-decyioxy)propyi ester (Topotecan-lipidester) and Topotecan

The bone marrow tolerability of Topotecan (TPT)-lipidester and Topotecan (TPT) was compared in mice. Female NMRI mice (8 mice per group) were treated intraperitoneally (ip) once daily for 4 days with equimolar doses of Topotecan (TPT)-lipidester or the parent compound TPT. Bone marrow cell count was determined 24 hours after the last treatment.

Bone marrow cell count was significantly less decreased after treatment with Topotecan-lipidester compared to Topotecan (Figure 2).

Figure 2

D Topotecan π Topotecan-lipidester

Controls 0.75 / 1.5 1.5 / 3.0 3.0 / 6.0 Dosages (mg/kg/d)

EXAMPLE 6

Tablet formulation

1.50 kg (9-(dimethylamino)-methyl-camptothecin-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 7

Formulation for injection

10.0 g of (^(dimethylaminoJ-methyl-camptothecin-IO-yOphosphoric acid-(3- dodecylmercapto-2-decyloxy)propyl ester (Topotecan-lipidester) were dissolved in 1000 ml 10% Tween 80 (Polysorbat 80), filtered, filled at 5 ml 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 at least once by halogen, C₁-C₆ alkoxy, C₁-C₆ alkylmercapto, C₁-C₆ alkoxycarbonyl, Ci-C₆ alkylsulfinyl or CrC₆ 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 unsuhfititutfiri nr suhRtitnterl at lpast nnr.fi hy halnnp»n HH-H₅ alknvy C₁-C₆ alkylmercapto, CrCβ alkoxycarbonyl, CrCβ alkylsulfinyl or Ci-C₆ 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 C₈-C_1S alkyl group, which is unsubstituted or substituted by a C₁-Ce alkoxy or a C₁-C₆ alkylmercapto group.

3. The camptothecin derivative according to claim 1 , wherein R² represents a straight-chain C₈-C₁₅ alkyl group, which is unsubstituted or substituted by a C₁- C₆ alkoxy or a C₁-C₆ 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 3 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 a pharmaceutically acceptable adjuvant or vehicle.

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 1-7 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 claim 1-6 for the preparation of a medicament for treating malignant tumours.