Title of Invention

"A NOVEL BETULINIC ACID DERIVATIVE"

Abstract

1. A novel betulinic acid derivative of formula 2: wherein R, R1, R2, R3, R4, R5 and R6 independently or in combination represent: R is H; R1 is H, Br, Cl, F or I; R2 is H and R3 is OH, OCOCH3, OCO(CH2)nCH3 where (n=l to 5), OCOq(CH3)3, OCO(CH2)n Cl (where n=l to 10), OCOC6H5, OSO2CH3, NH2/ NHCH2 CH2OH, NHCH2CH2OCOCH3/ N=CH C6H3 (NO2)2, N=CHC6H4C1 N=CHC6 HiBr, N=CHC6 H4NO2, N=CHC6 H3 Br2, N=CHC6 H3C12, N=CHC6H3(CH3)CF3 N=CHC6 H4CF3 N=CHC6 H4F, OCOC6 H2Cl3, OCOCH(OCOCH3) CH3, OCOCH(OCOCH3)C6H5, OCOCH2 C6H5/ OCO(CHOH)CH3, OCOC6 H4Br, OCO C6H4C1, OCOC6H4F, OCOC6 H4I, OCOC6 H3C12/ OCOC6 H3F2, OCOC6 H4CF3, NHNHC6H5, NHNHC6H4OMe, or N=CHC6H3F2/ or R2 and R3 together are O, NNHC6H5 or derivatives thereof such as herein described, NNHC6H2Cl3, NNHC6H4OCH3, NNHC6H4OH, NNHC6H3(Br)(OCH3), NNHC6H4F, NNHCH(OH)C6H5,NNHCOC6H5, NCH2C6H5, NNHCH2C6H5F, NNHC6H4F, or N-OX (X being H, COCH3, SO2C6H6CH3 or CO(CH2)nCH3 (where n=l to 5)); R4 is OH, -OCH3, O(CH2)nCOOCH3,O(CH2)nCOOC2H5,

Full Text

The present invention relates to a novel Betulinic acid derivative and a composition comprising the same. Field of the Invention The invention relates to the use of betulinic acid and its derivatives for the inhibition/prevention of cancer growth, novel betulinic acid derivatives useful for the inhibition of tumor/cancer cells and a process for the preparation of the said derivatives. The invention also relates to the antileukaemic, and anti-lymphoma activity of said novel betulinic acid derivatives, useful for treatment of prostate, ovarian and lung cancer. Background and prior art references to the Invention Under the auspices of a National Cooperative Natural Product Drug Discovery Group supported by the National Cancer Institute, the potential antitumor activity of approximately 2500 extracts derived from globally collected plants was evaluated in a panel of enzyme based assays and in a battery of cultured human tumor cell lines. One such extract, prepared from the stem bark of Ziziphus mauritiana Lam. (Rhamnaceae), displayed selective cytotoxicity against cultured human melanoma cells (Nature Medicine, Vol. 1 (10), 1995, WO 96/29068). As a result of bioactivity guided fractionation, betulinic acid, a pentacyclic triterpene, was identified as a melanoma-specific cytotoxic agent. In follow-up studies conducted with athymic mice carrying human melanomas, tumor growth was completely inhibited without toxicity. As judged by a variety of cellular responses, antitumor activity was mediated by the induction of apoptosis. A number of triterpenoids, including betulinic acid, have several known medical applications, including use as an anticancer drug. Anderson et al., in WO 95/04526, have discussed the derivatives of triterpenoids which have been used in cancer therapy, including their activity against polyamines which are required by cells to grow at an optimal rate. Some of these triterpenoids have been found to interfere with enzymatic synthesis of polyamines required for optimal cell growth, and thus inhibit the growth of cancer cells, particularly by inhibiting ornithine decarboxylase (Yasukawa, K. et al. Oncology 48 : 72-76,1991). The anti-cancer activity of betulinic acid and some derivatives has been demonstrated using mouse sarcoma 180 cells implanted subcutaneously hi nude mice ( JP 87,301,580). Choi et al have shown that betulinic acid 3-monoacetate, and betulinic acid methyl ester exhibit EDso values of 10.5 and 6.8 ug/ml, respectively, against p388 lymphocytic leukemia cells (Choi, Y-H et al., Planta Medica vol XLVDL, pages 511 - 513, 1988). The ED*) values of these derivatives is greater than 4.0 ug/ml and hence may not be considered to be having any significant anticancer activity. Table 1 indicates anticancer activity (EDso values) of an derivatives and the applicants claim only derivatives which show ED^ Summary of the invention The present invention provides a pharmaceutical composition comprising betulinic acid derivatives useful for killing or inhibiting multiplication of cancer cells, novel betulinic acid derivatives, a process for the synthesis of the said novel derivatives of betulinic acid and testing the bio-activity using cultured human leukemia (MOLT-4, Jurkat E6.1, HL60, CEM.CM3), lymphoma cells (BR1STOL-8, U937), prostate cancer cells (DU 145), lung cancer cells (A 549) and ovarian cancer cells (PA-1) as the monitor. In a preferred embodiment, a pharmaceutically acceptable carrier, diluent, or solvent is used. The invention provides a method of treatment for humans, mammals, or other animals suffering from cancer or other tumors. The method may suitably comprise essentially of administering a therapeutically effective dose of the pharmaceutical composition so as to kill or inhibit the multiplication of cancer or tumor cells. The method of treatment of the present invention is particularly useful in the treatment of leukemias and lymphomas and in general in the treatment of prostate cancer, ovarian and lung cancer. Objects of the invention An object of the present invention is to provide a method and composition for inhibiting tumor growth and, particularly, for inhibiting the growth of leukemias and lymphomas and in general for inhibiting the growth of prostate, ovarian and lung cancer using a natural product-derived compound and its derivatives. Another object of the invention is to provide a treatment method using betulinic acid derivatives to prevent the growth of cancerous cells, wherein betulinic acid derivative is administered systemically. Still another object of the invention is to overcome the problem of high toxicity associated with standard chemotherapeutic agents by using a natural product-derived compound, e.g., betulinic acid derivatives. Yet another object of the invention is to overcome the problem of insufficient availability associated with synthetic anticancer agents by using synthetic derivatives of betulinic acid. It is also an object of the invention to overcome the problem of high cost of synthetic anticancer agents by utilizing the readily available natural product derived compound, e.g., betulinic acid derivatives that would be of substantially cheaper cost. One more object of the invention is to provide novel betulinic acid derivatives and a process for producing such derivatives. Yet another object of the invention is to provide a pharmaceutical formulation containing betulinic acid derivatives alone or in combination. Statement of the Invention Accordingly, the present invention relates to a novel betulinic acid derivative of formula 2: (Formula Removed) wherein R, R1, R2, R3, R4, R5 and R6 independently or in combination represent: R is H; R1 is H, Br, Cl, F or I; R2 is H and R3 is OH, OCOCH3, OCO(CH2)nCH3 where (n=l to 5), OCOC(CH3)3, OCO(CH2)n Cl (where n=l to 10), OCOC6H5, OSO2CH3, NH2, NHCH2 CH2OH, NHCH2CH2OCOCH3, N=CH C6H3 (NO2)2, N=CHC6H4Cl N-CHC6 H4Br, N=CHC6 H4N02, N=CHC6 H3 Br2, N=CHC6 H3C12, N=CHC6H3(CH3)CF3 N=CHC6 H4CF3, N=CHC6 H4F, OCOC6 H2C13, OCOCH(OCOCH3) CH3, OCOCH(OCOCH3)C6H5, OCOCH2 C6H5, OCO(CHOH)CH3, OCOC6 H4Br, OCO C6H4C1, OCOC6H4F, OCOC6 H4I, OCOC6 H3C12, OCOC6 H3F2, OCOC6 H4CF3, NHNHC6H5, NHNHC6H4OMe, or N=CHC6H3F2, or R2 and R3 together are O, NNHC6H5 or derivatives thereof such as herein described, NNHC6H2C13, NNHC6H4OCH3, NNHC6H4OH, NNHC6H3(Br)(OCH3), NNHC6H4F, NNHCH(OH)C6H5, NNHCOC6H5, NCH2C6H5, NNHCH2C6H5F, NNHC6H4F, or N-OX (X being H, COCH3, SO2C6H6CH3 or CO(CH2)nCH3 (where n=l to 5)); R4 is OH, -OCH3, 0(CH2)nCOOCH3, O(CH2)nCOOC2H5, 0(CH2)n, COOH, 0(CH2)nCOCl (where n=l to 5), OCH2CH2OC2H5, OCH2CH2OH, OCH2CH2OCOCH3, Cl, N3, NHNH2, C6H4OMe, HNNHC6H2C13, NH2, or NH(CH2)nCH3 (where n=0 to 9); R5 is H, or Br; R6 is CH3, CH2Br, CH2OH, CHO, CH2OCOCH3, COOH, COO(CH2)n COOCH3, COO(CH2)nCOOC2H5, COO(CH2)n COOH (where n=l to 5); or R5 and Re together are =CH2 or -CH3. Brief Description of the accompanying Drawings Fig. 1 represents the formula for betulinic ackL Fig. 2 represents a general formula of derivatives of betulinic acid. Fig. 3 represents a general formula of derivatives of betulinic acid. Fig. 4 represents a general formula of derivatives of betulinic acid. Fig. 5 represents a general formula of derivatives of betulinic acid. Fig. 6 represents a general formula of derivatives of betulinic acid. Detailed Description of the Invention The invention mainly relates to a method of treating a patient with leukemia or prostate, lung or ovarian cancer, said method comprising administering a pharmaceutically effective dosage of betulinic acid, or a betulinic acid derivative alone or in combination thereof to the patient. The patient includes a human, mammal or other animal and the ED50 value of active betulinic acid derivatives against leukemia or lymphoma is in the range of 0.4 to 3.5 µg/ml. The preferred ED50 values of active betulinic acid derivatives are in the ranges of 0.4 to 40 µg/ml, 0.7 to 4.0 µg/ml, 1.2 to 4.0 µg/ml against prostate cancer, lung cancer and ovarian cancer respectively. The invention also relates to novel derivatives of betulinic acid, which are used for treating patient with leukemia or prostate, lung or ovarian cancer, the general formula of betulinic acid is shown as structure 1 here below. Structure 1 (Formula Removed) The novel derivatives of betulmic acid have been shown in structures 2 to 6 herebelow Structure 2 (Formula Removed) wherein R, R1, R2, R3, R4, R5 and R6 independently or in combination represent: R is H; R1 is H,Br,Cl,ForI; R2 is H and R3 is OH, OCOCH3, OCO(CH2)nCH3 where (n-1 to 5), OCOC(CH3)3, OCOCCH2)n Cl (where n=l to 10), OCOC6H5, OSO2CH3, NH2, NHCH2 CH2OH, NHCH2CH2OCOCH3, N=CH C6H3 (NO2)2, N=CHC6H4Cl N=CHC6 H4Br, N=CHC6 H4NO2, N=CHC6 H3 Br2, N=CHC6 H3C12, N=CHC6H3(CH3)CF3 N=CHC6 H4CF3, N=CHC6 H4F, OCOC6 H2C13, OCOCH(OCOCH3) CH3, OCOCH(OCOCH3)C6H5, OCOCH2 C6H5, OCO(CHOH)CH3, OCOC6 H4Br, OCO C6H4Cl, OCOC6H4F, OCOC6 H4l, OCOC6 H3C12, OCOC6 H3F2, OCOC6 H4CF3, NHNHC6H5, NHNHC6H4OMe, or N=CHC6H3F2nor R2 and R3 together are O, NNHC6H5 or derivatives thereof such as herein described, NNHC6H2C13, NNHC6H4CH3, NNHC6H4OH, NNHC6H3(Br)OCH3), NNHC6H4F, NNHCH(OH)C6H5, NNHCOCgHs, NCH2C6H5, NNHCH2C6H5F, NNHC6H4F, or N-OX (X being H, COCH3, SO2C6H6CH3 or CO(CH2)nCH3 (where n=l to 5)); R4 is OH, -OCH3, O(CH2)nCOOCH3, O(CH2)nCOOC2H5, 0(CH2)n, COOH, 0(CH2)nCOCl (where n=l to 5), OCH2CH2OC2H5, OCH2CH2OH, OCH2CH2OCOCH3, Cl, N3, NHNH2, C6H4OMe, HNNHC6H2C13, NH2, or NH(CH2)nCH3 (where n=0 to 9); R5 is H, or Br; R6 is CH3, CH2Br, CH2OH, CHO, CH2OCOCH3, COOH, COO(CH2)n COOCH3, COO(CH2)nCOOC2H5, COO(CH2)n COOH (where n=l to 5); or R5 and R6 together are =CH2 or -CH3, Structure 3 (Formula Removed) wherein R= H; Rl = H; R2 = H; R3 = OSO2CH3 , NHCH2CH2OH, N=CHC6H4F, N=CHC6H4C1, N=CHC6H4NO2, OCOC6H4Br, OCOC6H3F2, OCOC6H4CF3 , OCOC6H4F and R4 =OH or OCH2C Structure 4 (Formula Removed) Wherein R= H; R1= H; R2 = H; R3 = NH2, OSO2CH3, NHCH2CH2OH, N=CHC6H4NO2, N=CHC6H4 F, N=CHC6H4Br, OCOC6H4Br, NHNHC6H5, NHNHC6H4OMe, OCOC6H3F2, OCOC6H4CF3, OCOC6H4F, N=CHC6H4C1, N=CHC6H3F2, NHCH2CH2OCOCH3 and R4 =OH Structure 5 (Formula Removed) Wherein R= H; R1= H; R2= NNHC6H4F, NNHCH(OH)C6H5, and R4 Structure 6 (Formula Removed) Wherein R= H; RI= H or Br; R2= NNHCOC6H5, NCH2C6H5, NNHCH2C6H5, NNHC6H4F, O and R4= OH or OCH2CH2COOCH3. In addition, the invention relates to methods of preparing the novel compounds and in the examples below the term "substrate" refers to either betulinic acid, dihydrobetulinic acid or their derivatives as starting material unless otherwise indicated. Dihydrobetulinic acid is obtained from betulinic acid by reduction of C20-29 double bond, whereas dihydrobetulinic acid derivatives refers to its derivatisation at either C3 and /or C17 positions. Conventional procedures known to those skilled in the art can be used in the preparation of the various betulinic acid derivatives wherein the starting material is betulinic acid or a derivative thereof unless otherwise specifically mentioned. The diluents used hi the present invention is selected from dicalcium phosphate, calcium sulphate, lactose, cellulose, kaolin, mannitol, sodium chloride, dry starch, powdered sugar and for prolonged release tablet - hydroxy propyl methyl cellulose (HPMC). The binders are selected from starch, gelatin and fillers such as sucrose, glucose, dextrose, and lactose. Natural and synthetic gums used in the present invention are selected from sodium alginate, ghatti gum, carboxymethylcellulose methylcellulose, polyvinyl pyrrolidone and veegum. The excipient used the present process is selected from microcrystalline cellulose, calcium sulfate, dicalcium phosphate, starch, magnesium stearate, lactose, sucrose. Stabilizers used are polysaccharides such as acacia, agar, alginic acid, guar gum and tragacanth, amphotsics such as gelatin and synthetic and semi-synthetic polymers such as carbomer resins, cellulose ethers, and carboxymethyl chitin. The solvents used in the present invention are selected from Ringers solution, water, distilled water, dimethyl sulfoxide to 50% in water, propylene glycol (neat or in water), phosphate buffered saline, balanced salt solution, glycol and other conventional fluids that are suitable for intravenous administration. The procedures mentioned below are either used alone or in combination to produce the novel derivatives. Preparation of Betulinic acid derivatives Example 1 Preparation of 3-o- benzoyl derivatives Substrate in organic base is treated with suitable benzoyl chloride for approximately 6-16 hours at an ambient temperature. Examples of benzoyl chloride that can be used are represented by general formula Rn(Ar)CoCl wherein n = 1 to 3, R = H, Cl, Br, F, CF3 and Ar = C6H5, C6H4, C6H3 or C6H2- The reaction was worked up by addition of water and extraction with organic solvent. The organic layer was dried over anhydrous sodium sulphate, evaporated and residue crystallized to yield pure 3-o-benzoyl derivatives respectively. Examples of organic bases that can be used are pyridine, piperidine. Example 2 Preparation of 3-o- mesylate derivatives Substrate is dissolved in halogenated solvent and added methane sulphonyl chloride slowly to it at 5-10°C. Stirred the mixture at an ambient temperature for 2-4 hours. Worked up the reaction mixture by washing the organic layer with water. Organic layer dried over anhydrous sulfate, filtered, evaporated to dryness to get a residue which was crystallized from acetonitrile to yield pure 3-o-mesylate derivative. Example 3 Preparation of 3-phenyI hydrazino or its phenyl substituted derivative 3-phenylbydrazone or its phenyl substituted derivative of betulinic acid or dihydrobetulinic acid is dissolved in glacial acetic acid and shaken under hydrogen atmosphere (50-70- psi) in presence of platinum sponge catalyst for 3-5 hours. Reaction mixture was filtered, mother liquor evaporated under vacuum to remove glacial acetic acid and the residue crystallized from alcoholic solvent to yield pure 3-phenyl hydrazino or its phenyl substituted derivative. Alcoholic solvents used are methanol, ethanol or iso propanol. Example 4 Preparation of 3-N-Hydroxyethyl derivative 3-oxo-derivative is dissolved in absolute alcoholic solvent such as methanol / ethanol and to it added 15-20% alcoholic hydrochloric acid and 2-aminoethanol and stirred at room temperature for 30 - 60 minutes. To this added sodium cyanoborohydride and further stirred at room temperature for approximately 72 hours. Worked up by adding water followed by filtration of solid to yield crude product, which was crystallized from alcohol to yield pure 3-N-hydroxyethyl derivative. Example 5 Preparation of 3-N-Benzylidene derivative 3-Amino derivative is dissolved in alcoholic solvent, such as methanol / ethanol and to it added benzaldehyde or substituted benzaldehyde derivative in presence or absence of alkali carbonate, such as sodium or potassium carbonate. The mixture was stirred for few hours at ambient temperature to 50°C approximately. The reaction mixture was worked up by removing alcohol under vacuum and addition of water. The aqueous layer either filtered or extracted with halogenated organic solvent, followed by evaporation yielded 3-N-benzylidene derivative. Example 6 Preparation of 3-amino derivatives: 3-amino derivatives is dissolved in glacial active acid and shaken under hydrogen atmosphere (60-70 psi) in presence of platinum oxide catalyst for several horro-reaction mixture is filtered, molten liquor evaporate under vacuum to remove glacial acetic acid and the residue worked up in the usual manner to yield the corresponding 3-amino derivative. Example 7 Preparation of 3-oxo derivatives: The substrate was dissolved in the organic solvent and the conventional oxidising agent was added under normal reaction conditions. The reaction was worked up to yield the corresponding 3-oxo derivatives in the pure form. Example 8 Preparation of 3-oximino derivative The 3-oxo derivative was taken in an alcoholic solvent. To this was added hydroxylamine hydrochloride and sodium acetate and refluxed for few hours. The reaction mixture was evaporated to dryness. The reaction, worked up as descried in Method 1 yield crude-3-oximino derivative which was crystallized to yield the corresponding pine 3-oximino derivative. Example 9 Preparation of phenyihydrazone of 3-oxo derivative Phenylhydrazine was added to 3-oxo derivative dissolved in alcoholic solvent and refluxed for four hours. The reaction was worked up as described in Method 1 to yield the corresponding pheynylhydrazone derivative in the pure form. Example 10 In vitro cytotoxic activity of novel betulinic acid derivatives was determined by performing the MTT cytotoxicity assay (Mosmann T., J Immunological Methods, 65 : 55 ; 1983). Briefly, the cultured tumor cells were separately seeded in a 96-well culture plate and co-incubated with betulinic acid or its derivatives dissolved in methanol, dimethyl formamide, dimethyl sulfoxide or isopropyl alcohol with relevant controls at 37°C in a CO2 incubator. After 72 hours, the assay was terminated and percent cyotoxicities calculated. As shown in Table I, metabolic activity of leukemia cells (MOLT-4, Jurkat E6.1, HL60, CEM.CM3) was inhibited by active betuhnic acid derivatives, i.e., an EDso value of about 04 - 3.5µg/ml. The ED50 value of active betulinic acid derivatives for lymphoma cells (BRISTOL-8, U937) was in the range of 1 8 to 3.1 µg/ml. Further active betulinic acid denvatives showed an ED50 value of 0.4 - 4.0 µg/ml, 1.2 - 4.0 µg/ml and 0.7 - 4.0µg/ml against DU145 (human prostate), PA-1 (human ovary) and A549 (human lung) respectively. Table I (Table Removed) Example 11 Making structural changes at and/or C2, C3 and C17 positions of betulinic acid as described in Example 2, prepared forty-four derivatives of betulinic acid. The derivatives were characterized on the basis of spectral data. Table II to Table V comprising of basic skeleton of betulinic acid as indicated in Figure 3 to 6 respectively lists the structures of eight derivatives mentioned in Table I. Table II (Table Removed) Table III (Table Removed) Table IV (Table Removed) Table V (Table Removed) Numerals in parantheses after the functional groups in the above tables indicate the position of substituents (e.g. NO2, Cl, F or Br) on the benzene ring. Example 12 A suitable formulation of betulinic acid derivatives was prepared as follows Betulinic acid derivatives were solubilized in a minimum volume of methanol Betulinic acid derivatives may also be solubilized in isopropyl alcohol, dimethylformamide, dimethylsulfoxide or any other suitable solvent. Substituted beta-cyclodextrin, such as 2-hydroxypropyl beta-cyclodextrin, sulfobutyl ether beta-cyclodextrin was separately dissolved in water to a concentration of approximately 50 to 1000 mg per ml, preferably 250 to 750 mg per ml. The solubilized betulinic acid or its derivative was added in small aliquots to the derivatized beta cyclodextrin solution and sonicated at low temperature until a clear solution developed. The organic solvent was then removed by rotary evaporation and the final solution filtered to give a sterile product. The resulting solution was lyophilized Systemic administration refers to oral, rectal, nasal, transdermal and parentral (i.e., intramuscular, mtiapentoneal. subcutaneous or intravenous). In accordance with good clinical practice, it is preferred to administer the composition at a dose that will produce antiangiogemc effects without causing undue harmful side effects The composition may be administered either alone or as a mixture with other therapeutic agents. The composition of the invention may contain betulinic acid derivatives alone or in combination. Pharmaceutical compositions which provide from about 10 mg to 1000 mg of the composition per unit dose are preferred as tablets, lozenges, capsules, powders, aqueous or oily suspensions, syrups, elixirs, implants or aqueous solutions by any conventional method. The nature of pharmaceutical composition employed will, of course, depend on the desired route of administration. The human dosage of the composition is in the range of 1.0 to 200 mg/kg/day and the preferred range is 1.0 to 50 mg/kg/day. WE CLAIM: 1. A novel betulinic acid derivative of formula 2: (Formula Removed) wherein R, R1, R2, R3, R4, R5 and R6 independently or in combination represent: R is H; R1 is H, Br, Cl, F or I; R2 is H and R3 is OH, OCOCH3, OCO(CH2)nCH3 where (n=l to 5), OCOC(CH3)3, OCO(CH2)n Cl (where n=l to 10), OCOC6H5, OSO2CH3, NH2, NHCH2 CH2OH, NHCH2CH2OCOCH3, N=CH C6H3 (NO2)2/ N=CHC6H4Cl N=CHC6 H4Br, N=CHC6 H4NO2, N=CHC6 H3 Br2/ N=CHC6 H3C12, N=CHC6H3(CH3)CF3 N=CHC6 H4CF3/ N=CHC6 H4F/ OCOC6 H2Cl3, OCOCH(OCOCH3) CH3, OCOCH(OCOCH3)C6H5, OCOCH2 C6H5/ OCO(CHOH)CH3, OCOC6 H4Br/ OCO C6H4C1, OCOC6H4F, OCOC6 H4I, OCOC6 H3C12, OCOC6 H3F2/ OCOC6 H4CF3/ NHNHC6H5/ NHNHC6H4OMe, or N=CHC6H3F2/ or R2 and R3 together are O, NNHC6H5 or derivatives thereof such as herein described, NNHC6H2Cl3, NNHC6H4OCH3/ NNHC6H4OH, NNHC6H3(Br)(OCH3), NNHC6H4F, NNHCH(OH)C6H5, NNHCOC6H5, NCH2C6H5, NNHCH2C6H5F, NNHC6H4F, or N-OX (X being H, COCH3, SO2aH6CH3 or CO(CH2)nCH3 (where n=l to 5)); R4 is OH, -OCH3, O(CH2)nCOOCH3 O(CH2)nCOOC2H5, O(CH2)n, COOH, O(CH2)nCOCl (where n=l to 5), OCH2CH2OC2H5, OCH2CH2OH, OCH2CH2OCOCH3/ Cl, N3, NHNH2/ C6H4OMe, HNNHC6H2C13, NH2 or NH(CH2)nCH3 (where n=0 to 9); R5 is H, or Br; R6 is CH3, CH2Br, CH2OH, CHO, CH2OCOCH3/ COOH, COO(CH2)n COOCH3, COO(CH2)nCOOC2H5, COO(CH2)n COOH (where n=l to 5); or Rs and Re together is =CH2- 2. The betulinic acid derivative as claimed in claim 1, having structure 3: (Formula Removed) wherein R=H: R1=H; R2=H; R3=OSOCH3 NHCH2CH2OH, N=CHC6H4CI, N=CHC6H4 NO2, OCOC6H4Br,OCOC6H3F2, OCOC6H4F and R4=OH or OCH2COOCH3. 3. The betulinic acid derivative as claimed in claim 1, having structure 4: (Formula Removed) wherein R=H: R1=H; R2=H; R3=NH2, OSO2CH3, NHCH2CH2OH, N=CHC6H4NO2, N=CHC6H4F, N=CHC6H4Br, OCOC6H4Br, NHNHC6H5, NHNHC6H4OMe, OCOC6H3F2, OCOC6H4CF3, OCOC6H4F, N=CHC6H4C1, N=CHC6H3F2, NHCH2CH2OCOCH3 and R4=OH. 4. The betulinic acid derivative as claimed in claim 1, having structure 5: (Formula Removed) wherein R=H; R1=H; R2=NNHC6H4F, NNHCH(OH)C6H5 and R4=OH. 5. The betulinic acid derivative as claimed in claim 1, having structure 6: (Formula Removed) wherein R=H; R1=H or Br; R2=NNHCOC6H5, NCH2C6H5, NNHC6H4F and R4=OH or OCH2CH2COOCH3. 6. A composition for treating cancer, leukemia, lymphoma, prostate, lung or ovarian cancer, said composition comprising betulinic acid derivative as claimed in claim 1 and a pharmaceutically acceptable additive, diluent, excipient, solvent, binder, stabilizer, carrier, filler or lubricant. 7. The composition as claimed in claim 6, comprising 10 mg to 1000 mg of betulinic acid derivatives as claimed in any of the preceding claims. 8. A novel Betulinic acid derivatives substantially as herein described with reference to the accompanying drawings.

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1211-del-2002-abstract.pdf

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1211-del-2002-form-19.pdf

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