Title of Invention	NOVEL 20(S)-CAMPTOTHECIN COMPOUNDS
Abstract	Abstract The present invention relates to Novel 20(S)-camptothecin compounds of general formula (I), their pharmaceutically acceptable salts, containing them where all symbols are as defined in the description.

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The present invention related to novel water soluble C-5-O-substituted analogues of 20(S)-Camptothecin having the general formula 1, or its pharmaceutically acceptable salts, wherein R1 represents hydrogen or a group selected from hydroxy, (C1-C6) alkoxy, nitro, substituted amino, where the amino group is mono or disubstituted wherein the substituent is selected from (C1-C6) alkyl or substituted (C1-C6) alkyl, wherein the substituents are selected from hydroxy, (C1-C6) alkoxy, or {C1-Cg) alkyiamino; R represents hydrogen or (C1-C6) alkyl; and R represents substituted (C[-C6) alkyl, where substituent is selected from halogen, hydroxy, (C1-C6) alkoxy, or amino in which the amino group can be unsubstituted or mono, or disubstituted wherein the substituent is selected from hydroxy, or (C1-C8) alkyl when the amino group is disubstituted the substitutents are independent or combined together to form a cyclic ring having 6 ring atoms, the ring atoms are carbon atoms and nitrogen atoms. All the compounds of the formula I are prepared by reacting the compounds of the general formula 2, having 20 (S)-chiral carbon where R', R have the meaning given above, with the compounds of the formula R-OH where R' has the meanings given above. and was isolated from Camptotheca acnuminata by Wall and co-workers in 1966. However, its development as a potential drug for cancer treatment has been abandoned due to several unacceptable side effects on humans and as well as its low water solubility and high toxicity problems. Since the discovery of its mechanism of action as an inhibitor of topoisomerise I by Liu and co-workers in 1985 [L.FXiu, etal., J.BiolChem. 260, 14873 (1985)], the research interests on camptothecin has once again taken momentum. To overcome this problem of low water solubility and high toxicity of camptothecin, over the last 30 years, several research groups all over the world have prepared and investigated a number of camptothecin analogues involving the modification of rings A-E or the introduction of a variety of substituents on all the five rings of camptothecin of the formula 3[ M.E, wall eta!., y-A/ef/C/iem., 2£, 2689 (1993); R.P. Hertzberg etal., J. MedChem, 715 (1989); S.W.Sawada etal,, Chem.Pharm.BuU, 11(2), 310 (1993)]. Among the various camptothecin analogues prepared to date, only one of them namely, CPT-ll having the formula 4[ Chem.Pharm.Bnll,2 1446 (1991) ], was introduced as anti-cancer drug in Japan and Mexico and two more compounds namely, topotecan of the formula 5 [ JMedChem., H, 981(1991) ] and 9-aminocamptothecin of the formula 6 [ J.MedChem., 22, 2358 (1986) ], were currently undergoing extensive clinical trials. The extensively studied Structure activity relationship(SAR) on camptothecin of the formula 3[M.E.Wall etal., JMed.Chem.M, 2689 (1993)] has revealed that 20(S)-a-hydroxy-5-Iactone (E-ring) moiety in camptothecin is essential for its activity. However, according to recent reports by Ejima et.al., an amino group at C-20 position in 7-ethyI-10-melhoxycamptothecin of the formula 7[ A. Ejima etal., Chem. Pharm.Buli, 42(3), 683 (1992)]. exhibited potent camptothecin like inhibititon of topoisomerase I activity. Both these reports are contrary to the assumption that 20(S)-a-hydroxy functionality in camptothecin is an essential feature for its anticancer activity. Based on the activity results obtained for the camptothecin analogues prepared so far in the literature, it was also established that ethyl substitution at C-7 position of camptothecin of the formula 3 plays an important role in the enhancement of anticancer activity by imparting stability to the E-ring lactone [T.G.Burke eta!., JMed.Chem 3Z 40 (1994)]. Although the modification of substituents on rings A and B of camptothecin was taken up at a rapid pace to generate novel CPT analogues, ring 'C analogues of camptothecins were limited presumably because of the research work catried out by Sawada et al., which claimed that the substituents at C-5 position of camptothecin has resulted into the reduction of anti-tumor activity of camptothecins and produced inactive analogues [Sawada S.et.al., Chem. Pharm. Bull, 39(10), 2574(1991) ]. The C-5 substituted camptothecins claimed by Sawada et a!., ( JP 58,154,584 ; US 4, 513,138 ; US 4, 473,692 ; US 4,545,880 ; US 4, 339, 282 ) have the stmctural formula 10, where R represents hydroxy, lower alkyl, lower alkoxy, acyloxy groups , R represents methoxy at 9th position, hydroxy, lower alkoxy, acyloxy, SH, thioalkyl, thioacyl, nitro, amino, alkylamino, acylamino and halogen at 10th position and R represents lower alkyl, lower aralkyl, CH2OH, COOH, COOMe, CH2OR' where R' represents lower alkyl or acyl group. The recent findings by K.H.Lee et al,,[ Bio.Org. MedChem.Lett.,(1), 77 (1995)] which includes the preparation of 5-hydroxymethyl camptothecin by the reaction of formaidehyde in N,N-dimethylformamide and 4-piperidinopiperidine on 20(S)-camptothecin, has revealed the reduced anti¬tumor activity of these compounds. Also, Danishefsky et al., prepared some of the C-5 substituted 20(RS)-camptothecin derivatives by a totally synthetic approach [ US 5,391,745 and US 5,446, 047]. However, the synthetically prepared 5-substituted camptothecin derivative of the formula II [ Terasawa et.al., Heierocycles, 1S,81(1994)] claimed to have anti-tumor activity comparable to that of 20(S)-camptothecin. ■ Keeping all these factors in mind, we focussed.our research studies on 20(S)-camptothecin aimed at the design of novel camptothecin analogues which can exhibit improved water solubility and improved stability of lactone form in solutioh. We identified an oxidative reaction in alcoholic solvents for this purpose. The resultant findings have culminated into the discovery of a novel synthetic transformation which can introduce a variety of alkoxy groups at C-5 position of 20(S)-camptothecins which upon acid hydrolysis produced C-5 hydroxy camptothecins of the formula 2, in which X represents NH, CH2 and sulfur which is the subject mattetiifr co-pending applications for Indian patent bearing the Nos respectively. USIMPS:?- The process of preparaing thefcompounds of the formula I have been described and claimed in our co-pending application no. _ ■_. These applications have been divided out of the application no. 914/MAS/ 94 where the invention was originally described. Hence, the discovery led to a facile and versatile semi-synthetic methodology by which virtually every camptothecin derivative known in the literature can be transformed into a vatriety of C-5 substituted camptothecin aniogues. Therefore, the present invention provides a novel process for the preaparation of various C-5-O-substituted 20(S)-camptothecin derivatives of the formula 1 starting from the compounds of the formula 2. Furthermore, the vast variety of substituents represented by OR- at the C-5 carbon of 20(S)-camptothccins of the general formula I made these compounds to possess water solubility ranging from O.OImg to 2mg per ml. All the compounds prepared by the present mvention exhibited significant in viiro anti-tumor activity against a wde range of human tumor cell lines. DETAILED DESCRIPTION OF THE INVENTION The present invention provides C-5-O-substituted water soluble analogues of 20(S)-Camptothecin having the formula 1, The term ' lower alkyl 'denotes a univalent, branched or straight hydrocarbon chain containing 1 to 8 carbon atoms. Representative of the alky! groups may be methyl, ethyl, propyl, isopropyl, butyl, sec.butyl, tert.butyl, pentyl, iso pentyl, tert, pentyl, hexyl, isohexyl, octyl. The term ' lower alkenyl' represents a branched or straight hydrocarbon chain having sp or sp carbon centers containing I to 8 carbon atoms. Representative of the alkenyl groups may be vinyl, propenyl, butenyl, pentenyl, isopropenyl, isobutenyl, proparginyl, hexenyl, octeny!. The term 'halogen' represents chlorine, bromine or fluorine. The term ' haloalkyl 'denotes alkyl groups substituted with halogens, preferably fluorine, bromine or chlorine. Representative of the haloalkyl groups may be chloroethyl, bromopropyl, fluoroethyl, trifluoroethyl, trichloroethyl , trifluoro butyl. The term 'lower alkoxy' denotes lower alkyl groups as defined above attached via oxygen linkage to the rest of the molecule. Representative of those groups are methoxy, ethoxy, isopropoxy, tert.butoxy, hexoxy, heptoxy,octoxy. The term 'lower alkanoyl' denotes lower alkyl or alkenyl groups as defined above attached via a carbonyl group to the rest of the molecule. Representative of those groups may be acetyl, propionyl, propenoyi, crotanoyi, butanoyl, pentanoyi, isopentanoyl. The term 'aminoalkyl' represents the lower alkyl groups as defined above having substituted with amino groups. Representative of the aminoalkyl groups may be 2-aminopropyI, 4-aminobutyl, 5-aminopentyl. The amino groups may also be mono or disubstituted and the representative of these substituted amino groups may be dimethylamino, diethyiamino, dibenzylamino, ethylisopropylamino, pyrrolidine, piperidino, morphilino, piperizino. The term 'heteroatom' refers to oxygen, nitrogen or sulfur. The term 'aryl or heteroaryl' represents the groups of aromatic nature having 5 or 6 membered rings which may be selected from phenyl, biphenyl, naphthyl, pyridyl, quinoline, isoquinoline, indole, pyrrol, furan, benzofuran, thiophene, pyramidine, piperizine, thiozolidine, imidazole. The term 'substituted' phenyl group used in the present invention refers to those substituents which can be selected from the groups such as hydroxyl, alkyl, haloalkyi, phenyl, benzyl, halogen, alkoxy, thioalkoxy, benzyloxy, carboxyl, cyano, nitro, amido, amino, alkylamino. Examples of such groups are 4-hydroxyphenyl, 3-methoxyphenyI, 4-fluorophenyl, 4-trifluoromethylphenyl, N,N-dimethylaminophenyl, 4-carbomethoxyphenyl, The term 'substituted' alkyl group used in the present invention refers to those substituents which can be selected from the groups such as hydroxyl, alkyl, haloalkyi, phenyl, benzyl, haloge.% alkoxy, thioalkoxy, benzyloxy, carboxyl, carbonyloxy, cyano, nitro, amido, amino, alkylamino. Examples of such groups are fluoroethyl, chloropropyl, hydroxyefhyl, methoxypropyl, N,N-diethylaminoethyl, N-benzoylaminopropyl, trifluoroethoxyethyl, phenoxyethyl, carbomethoxyethyl, (p-fluorobenzoyloxy)ethyl, aminopropyl, 2-thioethyl. The term 'substituted' amino group used in the present invention refers to those substituents which can be selected from the groups such as hydroxyl, alkyl, haloalkyi, benzyl, benzoyl, alkoxy, carboxyl, amido, amino, alkylamino. Also, both the substituents on the amino group can be combined together to form 5 or 6-membered cyclic ring system . Examples of such groups are N,N-diethylamino, N-benzoylamino, N-methoxyamino, N-carboethoxyamino, N-ch!oroethyIamino, pyrrolidino, piperidino, piperizino, morphilino. wherein R represents hydrogen, hydroxy, lower alkoxy, lower alkanoyl, nitre, cyano, halo, carboxy amino, substituted amino, lower alkyl, substituted lower alkyl; R' represents hydrogen, lower alkyl, lower aralkyl, hydrojcymethy! group or carboxymethyl group; and R represents phenyl or benzyl where the phenyl group can be unsubstituted or substituted with mono, di or trisubstituents which may be selected from hydroxy, alkoxy, cyano, carboxy, nitro, amino or substituted amino ; (€3-0) cycloalkyi, (C'C-j) cycloalkyl lower alkyl where the cyclic ring may contain at least one heteroatom, lower alkyl, substituted lower alkyl where the substituents can be halogen, hydroxy, alkoxy, carboxy, cyano, amino in which amino group can be unsubstituted or mono, or disubstituted in which both substituents are independent or combined together to form a cyclic ring system containing either carbon or oxygen or nitrogen atoms; were prepared by the process which comprises, where R has the meaning described above, in the presence of an acid to obtain the compounds of the formula 1 as defined above. The process developed consitutes a facile and versatile semi-synthetic method for the preparation of C-5 substituted camptothecin derivatives of the formula 1, starting Irom the compounds of the formiiJa 2. The compounds of the formula 1 prepared by the process of the present invention thus represents diastereomers containing the newly created C~5 chiral center. Indeed the compounds of the general formula 1 are isolated as a mixture of 20(S),5(S) and 20(S),5(R) diastereomers. However, by the application of convenional aniytical techniques such as medium preswure liquid chromatography(MPLC) or high pressure hquid chromatography (HPLC) or crystallisation methods, the two diastereomers have also been separated into their single optically pure entities. In general, compounds of the formula 1 where R , R and R have the meanings described above, may be synthesised starting from the compounds of the formula 2 by the process described above and can be illustrated by the examples shown in the Examples section. According to the process of the present invention, the reaction may be effective in the presence of an acid medium at a temperature in the range of 20 to 140oC to fijmish the compounds of the formula 1. The acids used in the reaction may be selected from sulftjric acid, hydrochloric acid, acetic acid, p-toluenesulfonic acid, pyridiunium-p-toluenesulfonic acid, camphorsulfonic acid, methanesulfonic acid, perchloric acid, or Lewis acids such as titanium tetrachloride, BF-etherate, and zinc chloride. The solvents used in the reaction may be selected from hexane, benzene, toluene, xylene, chloroform, carbontetrachloride, 1,2-dichloroethane, dimethoxyethane, dichloromethane and 1,4-dioxane. The temperature at which the reaction can be affected may be in the range of 40-140°C, but preferably in the range of 60-]00°C. Thus, the present invention is of particular significance in developing 5-substituted 20(S)-camptothecin derivatives as a new class of C-ring modified camptothecin analogues which are useiul as anti-tumor and /or anti-viral agents. The present invention is also of particular significance as the process developed and described here is highly versatile and amenable for large scale preparation of these camptothecin derivatives having the general formula 1. The methodology developed and described in the present invention will provide access to a wide variety of C-5 substituted C-ring analogues having diverse substituents on rings A and B of 20(S)-camptoth6cin Representative of such compounds are : 1) 5-methoxy CPT 2) 5-ethoxy CPT 3)5-ch[oroethoxyCPT 4) 9-methoxy-5-ethoxy CPT 5) IO-hydroxy-5-ethoxyCPT 6) 5-butoxy CPT 7) 9-hydroxy-5-ethoxy CPT 8) lO-hydroxy-5-trifluoethoxyCPT 9) 9-Nitro-5-ethoxy CPT 10) 7-ethyl -5-chloroethoxy CPT U) 5-(2'-Hydroxyethoxy) CPT 12) 10-hydroxy -5-(2'-hydroxyethoxy) -CPT 13) 7-ethyi-10-hyudroxy-5-(2'-hydroxyethoxy) CPT 14) 9-Nitro-5-trifluoroethoxy CPT where CPT refers to 20(S)-camptothecin. In fact, most of the compounds prepared by the present invention are having water solubility ranging from O.Olmg to 2mg per ml. at 37°C. Further, several compounds prepared in the present invention exhibited good in vitro anti-cancer activity towards various cancer cell lines, according to the results obtained from 60 human tumor cell line assay performed at National Cancer Institute (NCI), Washington, U.S.A. . Table I presents IC50 values for various C-5-O-substituted 20(S)-camptothecin analogues prepared in the present inventionshowed more selectivity and sensitivity towards renal cancer eel! lines. Some of the analogues prepared in the present invention exhibited good anti-tumor activity nt GI50 and TGI level towards CAKI-1 (renal cancer), BT-549 (breast cancer), SNB-I9 (CNS cancer) and SF-295 ( CNS cancer) cell lines as shown in the table 2. The results shown in Table 1 and 2 were obtained from conducting experiments at U. S. National Cancer Institute (NCI) . The proptocol followed for these experiments is given below : Each test compound was screened against a battery of 60 human cell lines obtained from eight organs. In a typical procedure, the cell suspensions that were diluted according to the particular ceU type and the expected target cell density (5000-40,000 cells per well based on cell growth characteristics) were added into 96-wen microliter plates. Inoculates were allowed a preincubation period of 24h at 37°C for stabilization. Dilutions at twice the intended test concentrations were added at time zero in 100-).i] aliquots to microtiter plate wells. Usaually test compounds were evaluated at five 10-fold dilutions. The highest well concentration used in the test is 10 M. The cells are then incubated in the presence of drug (the test compound ) for further 48h in 5% CO2 atmosphere and 100% humidity. At the end of this time, the adherent cells are fixed to the plate by means of trichloroacetic acid, and after a number of washes, the cell layer is treated with the protein stain Sulforhodamine B. The optical density which is proportional to protein mass, is then read by automated spectrophotometric plate readers at a wavelength of 515 nm. Readings are transfered to a microcomputer and final reports are generated using especially developed software. TABLE 1: IC 50 = the average value of the minimum drug concentration ((.im) of the agent required in the NCI 60 human tumor cell line assay that produced 50% cell growth inhibition ( GI50 ). All these compounds of the general formula 1 of the present invention, and their pharmaceutically acceptable salts thereof, and the composition containing them, are useful as anti¬cancer and anti-viral agents. Administration of the active compounds of the formula 1, in pure form or in an appropriate pharmaceutical composition can be carried out via any of the accepted modes of administration for serving similar utilities. Thus, administration can be, for example, orally, nasally, parenterally or topically, in the form of solid, semi-soUd, lyophilised powder, or liquid dosage forms, such as for example, tablets, suppositories, pills, capsules, powders, solutions, suspentions, emulsions, creams, lotions, aerosols, ointments or the like, preferably, in unit dosage forms suitable, for simple administration of precise dosages. The compositions will incude a conventional pharmaceutical carrier or excipient and an active compound of general formula 1 and, in addition, may include either medicinal agents, pharmaceutical agents, carriers, adjuvants, etc. EXAMPLE 1 Preparation of 10-Hydroxy-5-trifluQroethoxycamptothecin A mixture of 10,5-dihydroxycamptothecin (200mg) and trifluoroethanol (ImL) were suspended in 50ml of dichloroethane and heated to reflux in the presence of sulfuric acid (0.5ml) for ]8h. Reaction mixture was concentrated to dryness and the residue was extracted with ethylacetate. Organic layer was washed with water and brine and dried over anh. sodium sulfate. Evaporation of the solvent furnished an oily residue which was purified over silica gel column using acetone-chloroform as an eluent to get 140mg of lO-Hydroxy-5-trifluoroethoxycamptothecin as a solid ; mp : 237OC ; IR : 3420, 1748, 1664, 1605, 1159 cm"' ; % NMR (DMS0-d6) : 5 10.48(s, IH, D2O exchangeble), 8.45(s, IH), 8.04(d, J=9Hz, IH), 7.47(d, J=9Hz, IH), 7.40(s, IH), 7.18(s, IH), 7.11(s, 0.5H), 7.06(s, 0,5H), 6,58(s, IH, D2O exchangeble), 5.41(s,2H), 5.05-4.55(m,2H), 2.05-1.75(m,2H), 1.00-0.8(m,3H);C NMR (DMS0-d6) :5 172.4, 161.0, 157.7, 157.1, 151.2, 147.5, 144.3, 143.7, 131.0, 130.8, 129.8, 129.1, 124.0, 121.4, 120.7, 109.6,96.6,89.7,72.3,65.1,30.4, 7.8 : Mass(m/2) : 462(M+1), 418, 364, 320, 291, 263. EXAMPLE 2 Preparation nf9-Nitro-5-trif1uornetho; A mixture of 9-nitro-5-dihydroxycamptothecin (lOOmg) and trifluoroethanol (O.SmL) were Suspended in 25ml of dichloroethane and heated to reflux in the presence of sulfuric acid (0,3ml) for 18h. Reaction mixture was concentrated to dryness and the residue was extracted with ethylacetate. Organic layer was washed with water and brine and dried over anh. sodium sulfate. Evaporation of the solvent furnished an oily residue which was purified over silica gel column using acetone-chloroform as an eluent to get 60mg of 9-nitro-5-trifiuoroethoxycamptothecin as a solid.; mp: 210°C ; ER.: 3457, 1745, 1665, 1623, 1527, 1154, 1000 cm"' ; 'H NMR (CDDJ) : 5 9.30(s,lH), 8.53(d, J=8.6H2, IH). 8.49(d, J=8.6Hz, IH), 7.94(t, J=8Hz, IH), 7.62(s, 0.5H), 7.60(s, 0,5H), 6.87(s, 0.5H), 6,81(s, 0.5H), 5.69(d, J=16H2, IH), 5,29{d, J=16Hz, IH), 4.97(m,lH), 4.52(m,lH), 3.90{br s,lH, D2O exchanheble), 1.90(m,2H), 1.05(t, J=7H2, 3H),; Mass (m./z) ; 491(M+1), 461, 446, 418, 393, 364,349,319,290,216. EXAMPLE 3 Preparation of 5-(2'-fluQrQethQKy)camptQthgcin A mixture of 5-hydroxycamptothecin (200mg) and 2-fluoroethanol (2mL) were suspended in 30ml of dichloroethane and heated to reflux in the presence of sulfuric acid (0,3ml) for 18h. Reaction mixture was concentrated to dryness and the residue was extracted with ethylacetate. Organic layer was washed with water and brine and dried over anh, sodium sulfate. Evaporation of the solvent furnished an oily residue which was purified over silica gel column using acetone-chloroform as an eluent to get 130mg of 5-(2'-f!uoroethoxy)camptothecin as a solid ; mp : 174 "-"C ; IR : 1745, 1664, 1615, 1160, 1040, 752 cm ;H NMR (CDC13 + DMS0-d6) : 5 8.46(s, IH), 8.20(d, J=8Hz, IH ), 7.95(d, J=8Hz, IH ), 7.83 (t, J= 6,8Hz, IH), 7.65-7,55(m, 2H), 6.86(s, 0.5H), 6.78(s, 0.5H), 5.68(d, J=16.5Hz, IH), 5.26(d, J=16.5Hz,lH), 4,90-4.20 (m,4H), 4.44(s, IH, D20 exchangeble), 2.05-l,85(m, 2H), 1.12- 0,95(m, 3H) ; Mass(m/z) : 4!0(M+1), 365, 348, 319, 304, EXAMPLE 4 Preparation of 1 Q-Hydroxy-5-(2'-fluoroftthoxy)c;amptnthecin A mixture of 10,5-dihydroxycamptothecin (lOOmg) and 2-fluoroethano! (2mL) were suspended in 25ml of dichloroethane and heated to reflux in the presence of sulfijric acid (0.2ml) for 16h. Reaction mixture was concentrated to dryness and the residue was extracted with ethylacetate. Organic layer was washed with water and brine and dried over anh. sodium sulfate. Evaporation of the solvent furnished an oily residue which was purified over silica gel column using acetone-chloroform as an eluent to get 60mg of lO-Hydroxy-5-fluoroethoxycamptothecin as a solid ; mp: 258-260°C;IR:3225, 1748, 1660, 1593, 1159 cm-HNMR ( CDC!3 + DMS0-d6) : 5 10.0(br s, IH, D2O exchangeble), 8.3 l(s, IH), S.OO(d, J-6Hz, IH), 7.80(s, IH), 7.45{d, J=5Hz, IH), 7.40(s, IH), 6.85(s, 0.5H), 6,80(s, 0,5H), 6.15{s, IH, D2O exchangable), 5.55(d, J=16Hz, IH), 5.23{d, J=16Hz. IH), 4.85-4.20(m,4H), 2.05-1.81(m,2H), 1.0(t, J=7Hz. 3H) ; Mass(nVz) 426(M+1), 382, 364, 320. EXAMPLES Preparation of 5-(2'-Fluoroethoxy)-7-ethylcamptothecin To a mixture of 80mg of 5-hydroxy-7-ethylcamptothecin and O.lmi of p-to!unesu!fonic acid suspended in 12ml of benzene, 20mg of 2-fluoroethanol was added and heated the mixture to reflux temperature for ]4h. Reaction was quenched with a drop of pyridine and extracted with ethyl acetate. Organic layer was washed with water, NaHC03, brine and concentrated to dryness. The residue was purified by silica gel column chormatography using ethyl acetate-chloroform as eluent to afford 60mg of 5-(2'-fluoroethoxy)-7-ethylcamptothecin ; mp : U2°C ; IR : 3070, 1748, 1665, 1605, 1456, 1155, 1038, 767 cm"'; 'H NMR (CDO) : 5 8.21 (d, J=9,2Hz, IH), S.I7(d, J9.2Hz, IB), 7.82(t, J=7.4Hz, IH), 7.67(t, J=7,4Hz, IH), 7.57(s, 0,5H), 7.54(s, 0.5H), 7.00(s, 0.5H), 6.89(s, 0.5H), 5.69(d, J=16Hz, IH), 5.27(d, J=!6Hz, JH), 4.81-4J2(m,4H), 3.51-3.15(m,2H), ].93(m,2H). 1.45(t, J=7Hz, 3H), 1.05(m,3H).;Mass(m/z) : 438{M+]), 420, 406, 376, 347, 332, 317, 245, 91. EXAMPl.R 6 Preparation of 5t;2'-HydrnxyethoxyV7-ethylcamptnthecin To a mixture of 250mg of 5-hydroxy-7-ethylcamptothecin and lOil of conc.sulfuric acid suspended in 25ml of dichloroethane, 0.5ml of ethylene glycol was added and heated the mixture to reflux temperature for 14h. Reaction was quenched with a drop of pyridine and extracted with ethyl acetate. Organic layer was washed with water and brine and concentrated to. dryness. The residue was purified by silica gel column chromatography using ethyl acetate-chloroform as eluent to furnish ISOmg of 5-{2'-hydroxyethoxy)-7-ethylcamptothecinand 25mg of starting material.; 'H NMR (CDCI3, 200MHz) : 5 8.20(d, J=8Hz,IH), 8.15(d, J=8Hz, IH), 7.85( t, J=6.8Hz, IH), 7.69(t, 7.3Hz, IH), 7.56( s, 0.5H), 7.54(s, 0.5H), 7,ll(s, 0.5H), 6.99(s, 0.5H), 5.72(d, J=16.5Hz, IH), 5.2S(d, J=I6,5Hz, Q.5U), 5.26(d, J=I6.5Hz, 0,5H), 3,95-3.65(m, 4H), 3.78 (br s, 2H, D2O exchangeble), 3.3-3,18 (m, 2H), ].95-1.81(m, 2H), I.45(t, J=7.5Hz, 3H), 1.06(m,3H). EXAMPLE 7 Preparation of 5-(2'-HyrirnxyethoxyVlQ-hydroxycamptothecin To a mixture of 60mg of 10,5-dihydroxycamptothecin and 5mg of p-toluenesulfonic acid suspended in 10ml of dichloroethane, 25mg of ethylene glycol was added and heated the mixture to reflux temperature for 16h. Reaction was quenched with a drop of pyridine and extracted with ethyl acetate. Organic layer was washed with water and brine and concentrated to dryness. The residue was purified by silica gel column chromatography using methanol- chloroform as eluent to iurnish 40mg of 5-(2'-hydroxyethoxy)-10-hydroxycamptothecin and lOmg of starting material. ; IR; 3070, 1760, 1660, 1600, 1558, 1509, 1384, 1160. 1047, 832 cm-'; 'HNMR ( CDClj+DMSO) : 5 10.05( br, IH, D2O exchangeble), 8.35(s,lH), 8.05{d, J=9Hz, IH), 7.75(s, IH), 7.45(d, J=9Hz, IH), 7,28(s, IH), 6.95(s, 0.5H), 6.85(s, 0.5H), 5,65(d, J=16Hz, IH), 5.25(d, J-16Hz, IH), 4.n(m,2H), 3.78(m.2H), 4.05(br s,lH, DjO exchangeble), I.98(m,2H), I,05(t. J=7Hz, 3H) ; Mass (m/z) : 425, 408, 380, 364, 336, 320, 305, 264, 235, 147, 105. EXAMELE_5. Prepartttion of 5-chloroethnxy camptothecin To a mixture of SOOmg of 5-hydroxycamptothecin and 1ml of sulfuric acid suspended in 80mi of benzene, SOOOmg of 2-chloroethanoI was added and heated the mixture to reflux temperature using Dean-Stork apparatus for 12h. Reaction was quenched with addition of pyridine and extracted with ethyl acetate. Organic layer was washed with water, NaHCO, brine and concentrated to dryness. The residue was purified by silica ge) column chromatography using methanol- chloroform as eluent to obtain 420mg of 5-chloroethoxy camptothecin.; mp: 202°C ; [ajj at 28°C = +5.37 (c 0.093, CHCI3); IR : 3354, 1744, 1662, 1622, 1223, 1160, 1090, 1044, 752, 663 cm"'; Partial 'H NMR data in CDCI3 : 5 6.92 (s, 0.5H), 6.82(s, 0.5H), 4.51(t, J=5Hz, 1.5H), 4.38(t, J=5Hz, 1.5H), 3.75(s, IH, D2O exchangeble ), 3.85-3.58(m, 2H), 2.00-I.78(m, 2H), l,06(t, J=7.5Hz, 3H) ; Mass(m/2) : 426(M+1), 391, 377, 363, 348, 319, 105, 84, 51. EXAlVfPLE 9 Preparation of 5-(2'-Hydro?cyethoxy)-]0-hydroxy-7-ethylcamptothecin To a mixture of lOOmg of 10,5-dihydroxy-7-ethylcamptothecin and 5mg of p-toluenesulfonic acid suspended in 10ml of dichloroethane, 50mg of ethylene glycol was added and heated the mixture to reflux temperature for 16h. Reaction was quenched with a drop of pyridine and extracted with ethyl acetate. Organic layer was washed with water and brine and concentrated to dryness. The residue was purified by silica gel column chromatography using methanol- chloroform as eluent to / furnish 60mg of 5-(2'-hydroxyethoxy)-10-hydroxy-7-ethylcamptothecin and 12mg of starting material.; mp :124C ;'H NMR ( CDCI3+DMSO) : 5 10.0 ( br s,IH, D2O exchangeble ), 8.02(d, J=9Hz, IH), 7.55-7,39(m,3H), 7.02(s, 0.5H), 6.93(s, 0,5H), 6,05{br s,lH,D20 exchangeble), 5.63(d, J=16Hz, IH), 5.23(d, J=16Hz, IH), 3.94-3.54(m,2H), 3.41-3.05(m 2H), !.93(m,2H), L40(t, J=7Hz,3H), 1.02{m,3H);Mass(m/z) : 408(M+1), 379, 364, 347, 335, 285, 169, 119, 101, 83. EXAMPLE 10 Preparation of 5-(2'-aminnefhoxy) campfofhectn To a mixture of 60mg of 5-hydroxycamptothecin and 5mg of p-toluenesulfonic acid suspended in 10ml of benzene, 15mg of 2-aminoethanol was added and heated the mixture to reflux temperature for 14h. Reaction was quenched with a drop of pyridine and extracted v/ith ethyl acetate. Organic layer was washed with water, NaHCOj, brine and concentrated to dryness. The residue was purified by silica gel column chromatography using methanol- chloroform as eJuent to furnish 36mg of 5-(2'-aminoethoxy)camptothecin and lOmg of starting material ; mp: 170°C;IR: 3451, 1740, 1664, 1604, 1383, 1189, 1042 cm' ; Partial % NMR data in (CDCI3 + DMS0-d6) : 5 7.5(d, D2O exchangable, IH), 7.15(d, D2O exchangeble, IH ), 7,02 (s, 0.5H), 6.92(s, 0,5H), 5.65(d, J=16Hz, IH), 5.28(d, J=]6Hz, IH), 4,24-3.85(m, 2H), 2.35(s, DO exchangeble, IH), 2.34(m, IH), 2.15-1.85(m, 3H), ].12-0.95(m, 3H); Mass ( miz) : 408(M+1) , 364, 347. 319, 305, 291, 249, 103, 62. EXAMPLE 11 Preparafinnof5-(2'-?)mmoethnxy}-7-elhylcamptofhecin To a mixture of 85mg of 7-ethyi-5-hydroxycamptothecin and 5mg of p-toluenesulfonic acid suspended in 20ml of benzene, 1 Img of 2-aminoethanol was added and heated the mixture to reflux temperature for lOh. Reaction was quenched with a drop of pyridine and extracted with ethyl acetate. Organic layer was washed with water, NaHC03, brine and concentrated to dryness. The residue was purified by siHca gel column chromatography using methanol-chloroform as eluent to afford 65mg of 5-(2'-aminoethoxy)-7-ethylcamptothecin .mp : 230*0 ; Partial % NMR in (CDCI3 + DMS0-d6): 5 7.5(d, D2O exchangable, IH), 7.15(d, D2O exchangable, IH), 7.02(s, 0.5H), 6.92(s, 0.5H), 5.65(d, J=]6Hz, IH), 5.28(d, J=!6Hz, IH), 4.24-3.85(m, 2H), 2.35(s, DjO exchangeble, IH), 2.34(m, IH), 2.15-1.85(m, 3H), 1.12-0.95(m, 3H) ; Mass (m/z) ; 408(M+1), 364,347.319,305, 103,74,62. F,XAMPLE \1 Preparation of 5-f3'-dimelhylaminopropoxyV7-ethvIcamptnthecin To a mixture of 50mg of 7-ethy 1-5-hydroxycamptothecin and 0.05ml of sulfuric acid suspended in 20ml of benzene, 30mg of 3-dimethylamino-l-propanol was added and heated the mxluie to reflu-x temperature for 12h. Reaction was quenched with a drop of pyridine and extracted with ethyl acetate. Organic layer was washed with water, NaHC03, brine and concentrated to dryness. The residue was purified by sihca gel column chromatography using methaiio]- ch\oTofovm as eluent to obtain 42mg of 5-(3'-dimethy!an]Jnopropoxy)-7-ethylcamptothecin. mp : USC; PartialHNMRdata in (CDCI3+DMS0-d6) : 5 6.95 (s, 0.5H), 6.85(s, 0.5H), 5.65{d, J=16Hz, IH), 5.35(d. J=16Hz, 0,5H), 5,25Cd, J=16Hz, 0,5H), 3.95-3,57(m, 2H), 3.30-3.05(m, 2H), 2.S5(s, 3H), 2,83(s, 3H), 2.15-1,72(m, 6H), l,45(t, J=7.5Hz, 3H), 1.12-0.95(m, 3H); Mass (m/z) : 478(M+1), 434, 375, 347, 331, 169, 102, 84 ;Mass(m/z) : 478(M+1), 434, 375, 347, 331, 169, 102, 84 . EXAMPLR 13 Preparation nf 5-f2'-N-pyrrQlidinoethoxy)-7-ethylcamptQthecin To a mixture of lOOmg of 7-ethyl-5-hydroxycamptothecin and lOmg of camphorsulfonic acid suspended in 25ml of benzene, 30mg of 1-(2-hydroxyethyl) pyrrolidine was added and heated the mixture to reflux temperature for 16h. Reaction was quenched with a drop of pyridine and extracted with ethyl acetate. Organic layer was washed with water, NaHCOj, brine and concentrated to dryness. The residue was purified by silica gel column chromatography using methanol-chloroform as eluent to fijmish 85mg of 5-(2'-N-pyrrolidinoethoxy)-7-elhylcamptothecin ; mp : 225°C ; IR ; 3424, 1749, 1666, 1616, 1384, 1156, 1078, 1049 cm ; PartialH NMR data in CDCI3 : d 7,02 (s, 0.5H), 6.95(s, 0.5H), 5,70(d, J=16Hz, IH), 5.33(d, J=16Hz, 0.5H), 5.26(d, J=16Hz, 0,5H), 4.18- 3,88(m, 2H), 3.45-3.15(m,2H), 3.06-2.58(m, 6H), 2,05-1.72(m, 6H), i.43(t, J=SHz, 3H), I,]5-0.95(m,3H); Mass (m/z): 446 (M+i), 375, 347, 331, 245, 169, 116,97,84; EXAMPLF, 14 Preparation of 5-(2'-chlnroethoxv1-7-ethylcamptnthftdn To a mixture of 500mg of 7-ethyl-5-hydroxycaraptothecin and 0.1ml of conc.sulfuric acid suspended in 30ml of benzene, 700mg of 2-chloroethanol was added and heated the mixture to reflux temperature using Dean-Stork apparatus for 8h, Reaction was quenched with a drop of pyridine and extracted with ethyl acetate. Organic layer was washed with water,aHCO, brine and concKitrated to dryness. The residue was purified by silica gel column chromatography using e|hyl acetate-chloroform as eluent to provide 400mg of 5-(2'-chloroethoxy)-7-ethylcamptothecin ; mp : 168°C ';H NMR (CDClg, 200MHz ) ;5 8.20(d, J=9,5Hz, IH), S.15(d, J=9.5Hz, IH), 7.82(t, J-8HZ, IH), 7.67(t, J= 8Hz, IH), 7.54(d, 6,2Hz, IH), 7.02(s, 0.5H), 6.90(s, 0.5H), 5.70(d, J-I6H2, 0.5H), 5.69(d, J=I6Hz, 0.5H), 5.26(ci, J=I6Hz, 0.5H), 5.25(d, J=I6Hz, 0.5H), 4.61-3.95(m, 2H), 3.78-3.58(m , 2H), 3,50-3.15(m, 2H), l,98-1.78(m, 2H), 1.45-(t, J=7.5Hz, 3H), 1.12-0.95(m,3H); Mass (m/z) : 455(M+1), 437, 409, 392, 376,347, 331, 245. U5, 81 ; KXAMPLE 15 Preparation of 5-f2'-dimethylaminnethnxy)-7-ethylcamptQthecin To a mixture of lOOmg of 7-ethyl-5-hydroxycamptothecin and 0.1ml of cone.sulfuric acid suspended in 10ml of benzene, 50mg of 2-N,N-dimethylaminoethanol was added and heated the mixture to reflux temperature using Dean-Stork apparatus for lOh. Reaction was quenched with a drop of pyridine and extracted with ethyl acetate. Organic layer was washed with water, NaHCOj, brine and concentrated to dryness. The residue was purified by silica gel column chromatography using methanol-chloroform as eluent to get 65mg of 5-C2'-dimethylaminoethoxy)-7-ethykamptothecin ; Partial % NMR data in CDO : 5 1.05 (s, 0.5K), 6.93(s, 0.5H), 5.74(d, J=16Hz, 0.5H). 5.73(d, J=16Hz, 0.5H), 5.29(d, J=16Hz, IH), 4.41-3.75(m, 2H), 3.53-3.18(m, 2H), 2.57(q, /=6Hz, 2H), 2.26(s, 3H), 2,23(s, 3H), 2.05-I.86(ra, 2H), I.47(t, J=8Hz, 3H), I.I8-1.01(m, 3H); F.XAMPI.E 16 Preparation of 5-(4'-aminohutoxy) campfolhecin To a mixture of 53mg of 5-hydroxycamptothecin and 8mg of p-toluenesulfonic acid suspended in 16ml of benzene, 14mg of 4-aminobutanol was added and heated the mixture to reflux temperature for lOh. Reaction was quenched with a drop of pyridine and extracted with ethyl acetate. Organic layer was washed with water, NaHCOj, brine and concentrated to dryness. The residue was purified by silica gel column chromatography using ethyl acetate- chloroform as eluent to furnish 45mg of 5-(4'-aminobutoxy) camptothecin.; mp: 150°C; IR: 3397, 1745, 1664, 1617, 1384, 1224, 1162, 1038, 684, 570cm"; PartialH NMR data in (CDC13+ DMS0-d6): 5 7.50(d, D2O exchangeble, IH), 6.95(s, 0.5H), 6.85(s, 0,5H), 6.25(d, D2O exchangeble, IH), 5.65(d, J=16Hz, IH), 5.35(d, J=16Hz, 0.5H), 5.25(d, J=16Hz, 0.5H), 4.15-3.80(m, 2H), 2.15-i.65(m, 8H),1.15-0.98(m, 3H);Mass (iWz) : 436(M+1),392, 347,333, 305, 153, 123, 105,90, 62 ; EXAMPLE 17 reparation of-(2'-methexy-yethnxy}camptothecin To a mixture of 120mg of 5-hydroxycamptothecin and 0.13ml of sulfuric acid suspended in ISinJ of chloroform, 20fng of ethyleneglycol monomethylether was added and heated the mixture to reflux temperature for 1 Oh. Reaction was quenched with a drop of pyridine and extracted with ethyl acetate. Organic layer was washed with water, NaHC03, brine and concentrated to dryness. The residuevas purified by silica gel column chormatography using ethyl acetate-chloroform as eluent to furnish 80mg of 5-(2'-raethoxyethoxy)camptothecin ; mp: 123°C; IR; 3294, 2933, 1748, 1665, 1617, 1384, 1155, 1077, 1045, 761 cm'; % NMR (CDCI3) : 6 8,51(s, IH), 8.24(d, J=8Hz, IH), 7.93(d, J=8Hz,lH), 7.79(t, J=6.8Hz, IH), 7.65Ct, J=6,8Hz. IH), 7.58(s, 0.5H), 7.56{s, 0.5H), 6.91(s, 0,5H), 6.82(s, 0,5H), 5.71(d, J=16Hz, IH), 5.28(d, J=16Hz, IH), 4.55-4.05(m,2H), 3.95(br s, IH, DjO exchangeble), 3,81-3.56(m,2H), 3.48(s, 1.5H), 3,44(s, 1,5H), 1.94 (m,2H), 1.05(t, J=7Hz, 3H); Mass(m/z) : 423(M+1), 364, 347, 319,304,275,218, 128, 101,82. EXAMPLE 18 PrRparatinn of 5-f2'-Hydrnxyethoxy; camptothecin To a mixture of SOOmg of 5-hydroxy camptothecin and 3ml of boron trifluoro-etherate suspended in 45ml of dichloroethane, 2ml of ethylene glycol was added and heated the mixture to reflux temperature for I4h. Reaction mixture was quenched with pyridine and extracted with ethyl acetate. Organic layer was washed with water and brine and concentrated to dryness. The residue was purified by silica gel column chromatography using ethyl acetate-chloroform as eluent to furnish 410mg of 5-(2'-hydroxyethDxy) campothecin and 25mg of starting material.; mp; 19D°C ; [a] at 26*0 = + 28,30 (c 0.106, CHCI3); IR :3300, 3285, 1745, 1665, 1620, 1605, 1227, 1160, 1112, 1047 cm'; Partial 'H NMR data in CDCI3 : 5 7.01 (s, 0.5H), 6.92 (s, 0.5H), 4.30-3.71(m, 4H), 3.75( br s,2H, D2O exchangeble), 2.0-],79(m 2H), 1.15-0.95 (m, 3H) ; Mass (m/z) : 408(M+1), 390,378,364,348,319, 101,76, We claim: 1) Compounds of the Formula 1, or its pharmaceutically acceptable salts, wherein R1 represents hydrogen or a group selected from hydroxy, (C1-C8) alkoxy, nitro, substituted amino, where the amino group is mono or disubstituted wherein the substituent is selected from (C1-C8) alkyl or substituted (C1-C8) alkyl, wherein the substituents are selected from hydroxy, (C1-C8) alkoxy, or (C1-C8) alkylamino; R2 represents hydrogen or (C1-C6) alkyl; and R3 represents substituted (C1-C8) alkyl, where substituent is selected irom halogen, hydroxy, (C|-Cg) alkoxy, or amino in which the amino group can be unsubstituted or mono, or disubstituted wherein the substituent is selected from hydroxy, or (C|-C8) alkyl when the amino group is disubstituted the substitutents are independent or combined together to form a cyclic ring having 6 ring atoms, the ring atoms are carbon atoms and nitrogen atoms. (2) Compounds of the formula 1 where R1 and R2 have the meaning described in claim 1, as a mixture of two diastereomers each having 20(S),5{R) and 20(S),5(S) configurations. (3) Compounds of the formula I, where R1, R2 have the meaning described in claim 1, in which each of the diastereomers having 20(S),5(R) or 20(S),5(S) configurations as individual diastereomer, substantially free from the other isomer.

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