Title of Invention

PHARMACEUTICAL SALTS OF 20 (S) CAMPOTHESINS

Abstract

The present invention relates to pharmaceutically acceptable salts of the general formula (I), their derivatives, their analogs, their tautomeric forms, their stereoisomers, their polymorphs and pharmaceutically acceptable compositions containing them. The compounds of the general formula (I) are useful for the treatment of melanoma, prostate, leukemia, lymphoma, non-small lung cancers, cancer of the central nervous system, breast, colon, ovarian or renal cancer..nnnnn

Full Text

Field of the Invention The present invention relates to pharmaceutically acceptable general formula (I), their derivatives, their analogs, their stereoisomers, their polymorphs and pharmaceutically acceptable containing them. The present invention also relates to a process for the said pharmaceutically acceptable salts, their derivatives, their analogs. forms, their stereoisomers, their polymorphs, and pharmaceutical containing them. The pharmaceutically acceptable salts having the general for the treatment of melanoma, prostate, leukemia, lymphoma, cancer of the central nervous system, breast, colon, ovarian or renal cancer The present invention also relates to pharmaceutical compounds of general formula (I) or mixmres thereof. The phamiaceutically acceptable salts having the general significant formulation and bulk handling advantages in view of the solubility. In our recently granted US patent no, 6,177,439 Bl, described the novel compounds of the formula (II), wherein R1, R2, R3 and R4 independently represent hydrogen or selected from hydroxy, lower alkoxy, lower alkanoyl, nitro, cyano. amino, substituted amino wherein the the ammo group is mono or substituents are selected from lower alkyl, lower haloalkyl, benzyl, amido or lower aikylamino; lower alkyl, or substituted lower alkul substituents are selected from hydroxy, lower haloalkyl, benzyl benzyloxy, cyano, nitro, amino or lower aikylamino; or R2 and R3 together ~0-(CH2)n-0- where n=l or 2, each of R1, R2 R3 and R4 are not the same each of R1 R2, R3 and R4 are hydrogen; R5 represents hydrogen, lower alkyl, substituted lower alkyl wherem are selected from hydroxy, halogen, lower alkoxy, benzyloxy, carboxy. where the amino group is mono or disubstituted and the substituents lower alkyl lower haloalkyl, benzyl, or benzoyl, when the amino group the substituents are independent or together with the linking samrated 5 or 6 membered heterocyclic ring of formula (A); where Y represents O, S, NH or CH2 when formula (A) is a represents CH2 when formula (A) is a 6-membered ring; or where the aryi group is selected from phenyl biphenyl or naphthyl; and R6 represents phenyl or benzyl where the phenyl group may be substituted with mono, di or trisubstituents selected from halogen, nitro, lower alkyl, amino, or substituted amino wherein the amino disubstituted with lower alkyl groups; cycloalkyl or cycloalkyl lower cyclic ring has 3 to 7 ring atoms all of the said ring atoms being groups substituted with saturated 5 or 6 membered heterocyclic ring of when formula (B) is a 5-membered ring X represents CH or N and NH or CH1 when formula (B) is a 6-membered ring, X represents represents CH2; substituted benzoyl wherein the substituents are alkyl lower haloalkyl halogen, lower alkoxy, thioalkoxy, cyano, or lower alkylamino; lower alkenyl; substituted lower alkyl, or alkenyl, wherein the substituents are selected from halogen, hydroxy. aryloxy, thio, thioalkyl, thioaryl, aryl, wherein the aryl group is selected biphenyl, or naphthyl; heteroaryl wherein the heteroaryl is selected quinoline, isoquinoline, indole, pyrrole, furan, benzofuran, thiophene. imidazole; carboxy, cyano, nitro amido or amino in which the ammo unsubstituted or mono or disubstituted , wherein the substituents are hydroxy, lower alkyl, lower haloalkyl, benzyl, benzoyl, lower alkoxy, or lower alkylamino, when the amino group is disubstituted the independent or together with the linking nitrogen atom form a membered heterocyclic group of formula (A), when formula (A) is a 5-membered ring, Y represents 0, S, NH or (A) is a 6-membered ring, Y represents CH2; or R6 represents substituted lower alkanoyl wherein the substituents halogen, lower alkoxy, aryloxy, thio, thioalkyl, thioaryl, aryl, wherein selected from phenyl biphenyl, or naphthyl; heteroaryl wherein selected from pyridyl, quinoline, isoquinoline, indole, pyrrole, thiophene, thiazolidme or imidazole; carboxy, cyano, nitro, amido the amino group can be unsubstituted or mono, or disubstituted wherein are selected from hydroxy, lower alkyl, lower haloalkyl, benzyl, carboxy, amido, ammo or lower alkylamino, when the amino group substituents are independent or together with the linking nitrogen atom 5 or 6 membered heterocyclic group of formula (A), when formula (A) is a 5-membered ring, Y represents O, S, NH or (A) represents a 6-membered ring Y represents CH2; and when R' amino or mitro, R2, R3, R4 and R5 represent hydrogen and R6 represents alkyl, alkanoyl or benzoyl groups. Background of Invention A few closely related camptothecin derivatives, and their reported to be useful in the treatment of cancer. Some of such the prior art are outlined below: (i) EP publication no. 0074256A1, US patent nos. 4473692 & compounds of formula (III) wherein R1 stands for a hydrogen atom, an alkyl group, a hydroxyl group or an acyloxy group; R2 for a hydrogen atom, an alkyl group, an hydroxymethyi group, a carboxymethyl group or an acyloxymethyl the grouping -XR' (where R' is a hydrogen atom, an alkyl group or an X is an oxygen atom or a sulfur atom), a nitro group, an amino group, an acylammo group or a halogen atom, with the proviso and R2 are hydrogen atoms, R3 should not be hydroxyl group, acetoxy group. Objective of the Invention The main objective of the present invention is pharmaceutically acceptable salts of novel 20(S)-Camptothecin formula (I), their analogs, their tautomeric forms, their stereoisomers, and pharmaceutical compositions containing them or their mixtures stability and solubility, which can be used for the treatment of leukemia, lymphoma, non-small lung cancers, cancer of the central breast, colon, ovarian or renal cancers with better efficacy, potency and Yet another objective of the present invention is to provide a preparation of pharmaceutically salts of novel 20(S)-Camptothecm the formula (I) as defined above, their analogs, their stereoisomers and their polymorphs. Still another objective of the present invention is to provide compositions containing compounds of the general formula (I), their derivatives, their tautomers, their stereoisomers, their polymorphs or their combination with suitable carriers, solvents, diluents and other medu: employed in preparing such compositions. hydroxy; R3 R and R5 represent hydrogen; and R6 represents hydrogen, substituted (C1-C6)alkyl, wherein the selected from halogen, hydroxy or (C1-C6)alkoxy group. M represents a counter ion or a moiety, which forms a pharmaceuticaliy p is an integer ranging from 1 to 2. Suitable groups represented by R1 are selected from substituted such as substimted methyl, substituted ethyl, substituted n-propyl, and the like; wherein the substituents are selected from methylamino, ethylamino, n-propylamino, iso-propylamino and the C^jalkylamino such as dimethylamino, diethylamino, dipropyiamino and Suitable groups represented by R6 are selected from hydrogen or C6)alkyl such as substituted methyl, substituted ethyl, substituted iso-propyl and the like; wherein the substituents are selected from fluorine, chlorine, bromine, iodine; hydroxy group or (C1-C6)alkoxy such ethoxy, propoxy and the like. Suitable groups represented by M may be selected from and the like. Suitable n is an integer ranging from 1 to 4, preferably n represents or 2. . Particularly useful compounds according to the present invention lO-Hydroxy-9- N, N-dimethylaminomethyl-5-hydroxy-[20(S),5(R)]-hydrochloride; lO-Hydroxy-9- N, N-dimethylaminomethyl-5-hydroxy-[20(S),5(S)] hydrochloride; lO-Hydroxy-9- N, N-dimethylaminomethyi-5-hydroxy-[20(S),5(RS)] hydrochloride; 10-Hydroxy-9- N, N-dimethylaminomethyl-5-(2'-hydroxyethoxy)-[20(S). camptothecm hydrochloride; lO-Hydroxy-9- N, N-dimethylaminomethyl-5-(2'-hydroxyethoxy)-[20(S). camptothecin hydrochloride; lO-Hydroxy-9- N, N-dimethylaminomethy 1-5-(2'-hydroxyethoxy)-camptothecin hydrochloride; 10-Hydroxy-9- N, N-dimethylaminomethyl-5-{2-"methoxyethoxy)-[20(S).5 camptothecin hydrochloride; lO-Hydroxy-9- N, N-dimethylaminomethyl-5"(2-methoxyethoxy)-[20(S).5( s camptothecin hydrochloride; lO-Hydroxy-9- N, N-dimethylaminomethyl-5-(2-"methoxyethoxy)-[20(S),:M K ^ fi^ camptothecin hydrochloride; lO-Hydroxy-9- N, N-dimethylaminomethyl-5-(2'-fluoroethoxy)-[20(S),5(R r-camptothecin hydrochloride; lO-Hydroxy-9- N, N-dimethylaminomethyl-5-(2'-fluoroethoxy)-[20(S).5(S -camptothecin hydrochloride and 10-Hydroxy-9-N, N-dimethyIaminomethyl-5-t2'-fluoroethoxy)-[20(S),5(RS)]-camptothecin hydrochloride. The compound of the formula (II) used may be either in optically pure form or in racemic form and are prepared by a procedure reported in US patent no. 6 1 77,439 Bi. The acid employed in the reaction may be selected from hydrochloric acid, acetic acid and the like. The solvent employed may be selected from ketones such as acetone, diethyl ketone, methyl ethyl ketone or their mixtures, methanol, ethanol, n-hexane„ ethylacetate, benzene, diethylamine, formaldehyde, chloroform, dichloromethane or mixmre thereof Various polymorphs of a compound of general formula (I) forming part of this invention may be prepared by crystallization of compound of formula (I) under different conditions. For example, using different solvents commonly used or their mixtures for recrystallization; crystallizations at different temperatures; various modes of cooling, ranging from very fast to very slow cooling during crystallizations. Polymorphs may also be obtained by heating or melting the compound followed by gradual or fast coohng. The presence of polymorphs may be determined by solid probe NMR spectroscopy, IR spectroscopy, differential scanning calorimetry (DSC), powder X-ray diffraction or such other techniques. The stereoisomers of the compounds forming part of this invention may be prepared by using compound of formula (I) in its single diastereoisomeric form in the process by resolving the mixture of stereoisomers by conventional methods. Some of the preferred methods include use of microbial resolution, resolving the diastereomenc salts formed with optically pure bases such as brucme, cinchona alkaloids and their derivatives, optically pure 2-alkyl phenethyl amine, phenyl glycinol and the like. The diastereomenc salts may be obtained in pure form by fractional crystallization. Commonly used methods are compiled by Jaques et. al in "Enantiomers, Racemates and Resolution" (Wiley Interscience, 1981). The present invention provides a pharmaceutical composition, containing the compounds of the general formula (I) as defined above, their derivatives, their analogs, their tautomeric forms, their stereoisomers, their polymorphs, their pharmaceuticaily acceptable solvates in combination with the usual pharmaceuticaily employed carriers, diluents and the like, useful for the treatment of leukemia, lymphoma, non-small lung cancer, cancer of the central nervous system, breast, colon, ovarian or renal cancer. The pharmaceutical composition may be in the forms normally employed, such as tablets, capsules, powders, syrups, solutions, suspensions and the like, may contain flavorants. sweeteners etc. in suitable solid or liquid carriers or diluents, or m suitable sterile media to form injectable solutions or suspensions. Such compositions typicaily contain from 1 to 20 %, preferably 1 to 10 % by weight of active compound, the remainder of the composition being pharmaceuticaily acceptable carriers, diluents or solvents. Suitable pharmaceuticaily acceptable carriers include solid fillers or diluents and sterile aqueous or organic solutions. The active ingredient will be present in such pharmaceutical compositions in the amounts sufficient to provide the desired dosage in the range as described above. Thus, for oral administration, the active ingredient can be combined with a suitable solid or liquid carrier or diluent to form capsules, tablets, powders, syrups, solutions, suspensions and the like. The pharmaceutical compositions. may, if desired, contain additional components such as flavourants, sweeteners, excipients and the like. For parenteral admmistration, the active ingredient can be combined with sterile aqueous or organic media to form injectable solutions or suspensions. For example, solutions in sesame or peanut oil, aqueous propylene glycol and the like can be used, as well as aqueous solutions of water-soluble pharmaceutically-acceptable acid addition salts or salts with base of the compounds. Aqueous solutions with the active ingredient dissolved in polyhydroxylated castor oil may also be used for injectable solutions. The injectable solutions prepared in this manner can then be administered intravenously, intraperitoneally, subcutaneously, or intramuscularly, with intramuscular administration being preferred in humans. For nasal administration, the preparation may contain the active ingredient of the present invention dissolved or suspended in a liquid carrier, in particular an aqueous earner, for aerosol application. The earner may contain additives such as solubilizmg agents, such as propylene glycol, surfactants, absorption enhancers such as lecithin (phosphatidylcholine) or cyclodextrin or preservatives such as parabenes. Tablets, dragees or capsules having talc and / or a carbohydrate earned binder and the like are particularly suitable for any oral application. Preferably, earners for tablets, dragees or capsules include lactose, cornstarch and / or potato starch. A syrup or elixir can be used in cases where a sweetened vehicle can be employed. The compound of the formula (I) as defined above are clinically administered to mammals, including man, via either oral, nasal, pulmonary, transdermal or parenteral. rectal, depot, subcutaneous, intravenous, intraurethral, intraniuscular, intranasal. ophthalmic solution or an ointment. Administration by the oral route is preferred, being more convenient and avoiding the possible pain and irritation of injection. However, in circumstances where the patient cannot swallow^ the medication, or absorption following oral administration is impaired, as by disease or other abnormality, it is essential that the drug be administered parenterally. By either route, the dosage is in the range of about 0.01 to about 100 mg / kg body weight of the subject per day or preferably about 0.01 to about 30 mg / kg body weight per day administered singly or as a divided dose. However, the optimum dosage for the individual subject being treated will be determined by the person responsible for treatment, generally smaller doses V ■ being administered initially and thereafter increments made to determine the most suitable dosage. The compounds of the present invention are- successfiilly implemented in the treannent of melanoma, prostate, leukemia, lymphoma, non-small lung cancers, cancer of the central nervous system, breast, colon, ovarian or renal cancer. This was demonstrated by in vitro as well as in vivo animal experiments. The invention is explained in detail in the examples given below which are provided by way of illustration only and therefore should not be construed to limit the scope of the invention. 10-Hydroxy-9-N, N-dimethylaminomethyl-5-ethoxy-20(S)-camptothecin (160 mg) was dissolved in ethanol (10 ml) and treated with 50% HCl (10 ml). The solution was heated to reflux for 20h. At the end of the reaction, excess water and ethanol were removed as an azeotropic mixture and the residue was neutralized with potassium carbonate solution and extracted with ethyl acetate. The organic layer was washed with brine and dried over anhydrous sodium sulfate. Concentration of the solvent afforded 10-hydroxy-9-N, N-dimethylaminomethyl-5-hydroxy-20(S)-camptothecin (100 mg) after purification over silica gel column chromatography using ethyl acetate-chloroform afforded a solid material. Purification of the solid residue over silica gel column chromatography using methanol-chloroform as an eluent yielded. lO-hydroxy-9-N, N-dimethylamino methyl-5-(2'-hydroxyethoxy)-20(S)-camptothecin (25 mg) as yellowish powder, mp: 220°C. 'H-NMR (DMSO): δ 11.7 (s, D2O exchangeable, 1H), 9.90 (s, D.O exchangeable, IH). 8.85 (s, 1H), 8.20 (d, J-lO.OHz, 1H), 7.70 (d, J=lO.OH2, 1H), 7.20 (s, 1H). 6.95 (s. 0.5H), 6.85 (s, 0.5H), 5,40 (s, 2H), 4,75 (s, 2H), 3.90-3.70 (m, 4H), 2.80 (s, 6H), 1.95-1.75 (m, 2H), 0.95-0.75 (m, 3H). A Mixture of lO-hydroxy-9-N, N-dimethylaminomethyl-5-hydroxy-20{S)-camptothecin (50 mg) (obtained in preparation 1), 0.4 N aqueous HCl (5 mi) was heated.while stirring for 4h. Then ethylacetate (40 ml) was poured into the reaction mixture in 3 lots. Re fluxed for -10 min each time. Decanted the organic layers. Washed with 10% acetone : chloroform. Finally aqueous layer was evaporated as benzene azeotrope at --SO'^C on rotavapour. The solid obtained was washed with ethylacetate and dried. 1H-NMR (DMSO. 200MHz): 5 11.78 (s, 1H), 10.0 (bs, 1H), 8.9 (s. 1H), 8.1 (dd. 2H). 7.18 (d, !H). 6.9 (d, 1H), 5.4 (s, 2H), 4.7 (s, 2H), 2.8 (d, 6H), 1.8 (bs, 2H). 0,9 (bs. SH). with 10% acetone : chloroform. Finally water was evaporated as benzene azeotrope at -80°C on rotavapour. The solid obtained was washed with ethylacetate and dried. 1H-NMR (DMSO, 200MHz): 5 8.63 (s, 1H), 7.95 (d, 1H), 7.4 (m, 2H), 6.9 (d, 1H), 5.4 (dd, 2H), 4.3-3.3 (bs, 8H), 2.5 (s, 6H), 1.9 (q, 2H), 0,9 (t, 3H). Anti-cancer activity: The compounds prepared in the present invention exhibited very good in vitro anti-cancer activity towards various human tumor cell lines. Each test compound was screened against a battery of cell lines representing eight different types of cancers. In a tj^icai procedure, 1 x 10 cells were seeded into each well of 96 well plate in 100|aL volume of RPMI 1640 medium containing antibiotics and 10% FCS. The plates were incubated at 37°C in presence of CO2. After 24 h, test compounds were evaluated at five 10-fold dilutions ranging frorh 100 to 0.01µM. To each test well lOOµL of test compound solution was added and medium with vehicle was added to control wells and the plates were further incubated. After 48 h of incubation, plates were terminated by Sulforhodamine B method. The optical density, which is proportional to protein mass, is then read by automated spectrophotometric plate reader at a wavelength of 515 nm. Readings were transferred to a microcomputer and mean 50 % Growth Inhibition (GI50) and mean Total Growth Inhibition were calculated. The compounds of the present invention showed anticancer activity, which can be seen from the data given below: Solubility by HPLC method: Excess of compound was soaked in 0.5 ml of 0.1 M sodium acetate buffer at pH 5.0 for 24h at room temperature. The solution was filtered through 0.45 micron PVDF syringe filter (Gelman Sciences). The filtrate was injected into HPLC at different volumes (10 & 20 µ1). Chromatograms were recorded. Responses recorded were extrapolated from the calibration curve and the solubility of the compound was calculated. (J. Med. Chem., 1995, 38, 400). Male Swiss Albino Mice (20-30 g) were used in the experiments. The animals were maintained under standard laboratory conditions and had free access to feed and water ad libitum. Before experimentation animals were fasted overnight (-15 h) during which they had free access to water ad libitum. Dose preparation and administration: An amount equivalent to 10 mg of drug was weighed accurately and transferred into a clean mortar and triturated to obtain a fine powder. To this 500 µl of DMSO (10%) was added to obtain a clear solution. To this 4.5 ml of sodium carboxy methyl cellulose (sodium CMC) was added to make up the volume to 5 ml. Based on the animal weight appropriate volume (body weight in gramsxlO = no. of µl of dose to be given) of the prepared solution was administered through oral gavage. Animal experimentation: After dosing, at designated time points (0.5, 1, 2, 3, 5, 8 and 12h) 100 (il of blood was collected from retro orbital plexus into 0.5 ml eppendorff tubes containing EDTA (5 µI of 200 mg/ml solution in Milli Q water). Blood was centrifuged at 12,800 rpm for ■s 2 mm and plasma was separated and immediately taken for analysis, without delay, in order to estimate both lactone and carboxylate forms of the compound. Bio-analysis procedure: 50 µl plasma was transferred into a clean 2 ml micro centrifuge tube. To this ice cold methanol was added (450µl) and vertex mixed for 15 sec to extract the compound. These contents were centrifuged for 2 min at 12,800 rpm dry centrifuge tube. Clear supernatant was separated in to a 300 µl of auto sampler vial maintained at 4°C and 20 µl of this was injected into HPLC column. HPLC conditions: HPLC system (Shimadzu) consisted of system controller (SCL-IOAVP). Isocratic pump (LC-IOATVP), auto sampler (SIL-IOADVP), fluorescence detector (Rf-lOAXL) and column oven at 25°C (CTO-IOASVP) was controlled by Class-VP software. Sample was eluted through column (Supelcosil-LC318, 5µ, 4.6 x 250 mm. 300°A) with mobile phase [1% TEAA (pH = 5.5) : Acetonitrile : MeOH :: 80:15:5) pumped at 1.0 ml/min flow rate and eluent was detected using fluorescence detector set at Ex. 370 nm/Em. 537 nm.The approx, RTs were carboxylate (CAl-4.1 mm. CA2=4.8 mm) and lactone (LA1=7.9 mm, LA2=11.6 min). Calibration and determination of concentration: For the determination of drug concentration, peak area ratios of the drug to mtemal standard versus the concentration (range: 0.05 - 10 jig/ml) for both carboxyiate and lactone forms were plotted separately and linear regression was applied using software 'Sigma Plot" (Jandel Scientific version, 2.0, USA). Correlation coefficients (r2)of0.99 or better were obtained. Computation and Data Analysis: Pharmacokinetic parameters were calculated for both carboxylate and lactone forms separately by non-compartmental model analysis. The peak plasma concentration (Cma.x) and the corresponding time (Tmax) were directly obtained from the raw data. The area under the plasma concentration versus time curve up to the last quantifiable time point, AUC,o-t> was obtained by the linear and log-linear trapezoidal summation. The AUCfO-t) extrapolated to infinity (i.e., AUC (o-Qo) by adding the quotient of Clasr/Keu where Clast represents the last measurable time concentration and Kei represents the apparent terminal rate constant. Kei was calculated by the linear regression of the log-transformed concentrations of the drug in the terminal phase. The half-life of the termmal elimination phase was obtained using the relationship ty, = 0.693/ Ke). their derivatives, their analogs, their tautomeric forms, their stereoisomers, their polymorphs, wherein R represents substituted (C1-C6)alkyl wherein the substiments are selected from mono(CrC6)alkyiamino or di(C1-C6)alkylamino; R2 represents hydroxy; R3 R4 and R5 represent hydrogen; and R6 represents hydrogen, substituted (C1-C6)alkyl, wherein the substituents are selected from halogen, hydroxy or (C1C6)alkoxy. M represents a counter ion or a moiety, which forms a pharmaceutically acceptable salt: p is an integer ranging from 1 to 2, 2. The compound according to claim 1 where R represents substituted {C1- C6)alkyi, wherein the substituent is selected from dimethylamino group. 3. Particularly useful compounds of the present invention include: iO-Hydroxy-9-N, N-dimethylaminomethyl-5-hydroxy-[20(S),5(R)]-camptothecin hydrochloride; 10-Hydroxy-9- N, N-dimethyiaminomethyl-5-hydroxy-[20(S),5(S)]-camptothecin hydrochloride; lO-Hydroxy-9- N, N-dimethylaminomethyl-5-hydroxy-[20(S),5(RS)]-camptothecin hydrochloride; lO-Hydroxy-9-N, N-dimethylaminomethyl-5-(2'-hydroxyethoxy)-[20(S),5(R)]- camptothecin hydrochloride; 10-Hydroxy-9-N,N-dimethylaminomethyl-5-(2'-hydroxyethoxy)420(S),5(S)]- camptothecin hydrochloride; 10-Hydroxy-9-N,N-dimethylaminomethyl-5-{2'-hydroxyethoxy)-[20(S),5(RS)]- camptothecin hydrochloride; lO-Hydroxy-9-N, N-dimethylaminomethyl-5-(2-methoxyethoxy)-[20(S),5(R)]-camptothecin hydrochloride; lO-Hydroxy-9-N, N-dimethylaminomethyl-5-(2'-methoxyethoxy)-[20(S),5(S)]-camptothecm hydrochloride; lO-Hydroxy-9-N, N-dimethylaminomethyl-5-(2'-methoxyethoxy)-[20(S),5(RS)]-camptothecin hydrochloride; lO-Hydroxy-9-N, N-dimethylaminomethyl-5-(2'-fIuoroethoxy)-[20(S),5(R)]- camptothecin hydrochloride; lO-Hydroxy-9-N, N-dimethylaminomethyl-5-(2'-fluoroethoxy)-[20(S),5(S)]- camptothecin hydrochloride and 10-Hydroxy-9-N,N-dimethyiaminomethyl-5-(2'-fluoroethoxy)-[20(S),5(RS)]- camptothecin hydrochloride. as defined in claim 1, and a pharmaceutically acceptable carrier, diluent, excipient or solvate, 6. A pharmaceutical composition as claimed in claim 5, in the form of a tablet, capsule, powder, syrup, solution or suspension. 7. A method of treating melanoma, prostate, leukemia, lymphoma, non-small lung cancers, cancer of the central nervous system, breast, colon, ovarian or renal cancer, which comprises administering an effective amount of a compound of formula (I) as claimed in claim 1, to a patient in need thereof. 8. A pharmaceutical composition which comprises an effective amount of a compound of formula (I) as defined in claim 3, and a pharmaceutically acceptable carrier, diluent, excipient or solvate. 9. A pharmaceutical composition as claimed in claim 8, in the form of a tablet. capsule, powder, syrup, solution or suspension. 10. A method for treating melanoma, prostate, leukemia, lymphoma, non-small lung cancers, cancer of the central nervous system, breast, colon, ovarian or renal cancer, which comprises administering an effective amount of a compound of formula (I) as claimed m claim 3, to a patient in need thereof.

Documents:

798-mas-2001-abstract.pdf

798-mas-2001-assignement.pdf

798-mas-2001-claims filed.pdf

798-mas-2001-claims granted.pdf

798-mas-2001-correspondnece-others.pdf

798-mas-2001-correspondnece-po.pdf

798-mas-2001-description(complete) filed.pdf

798-mas-2001-description(complete) granted.pdf

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