Title of Invention	NOVEL CARVIDELOL DERIVATIVES, USEFUL IN THE TREATMENT OF CANCER
Abstract	The invention relates to novel carvidelol derivatives having anti-cancer activity, processes for producing such derivatives and their usefortreating or cancer of the lung, prostrate, etc.

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FIELD OF THE INVENTION The present invention provides novel pharmaceutical compositions comprising carvedilol for treatment of cancer. More particularly the invention relates to novel carvedilol derivatives and their use in pharmaceutical compositions for treatment of lung, prostrate, ovarian, colon, pancreatic, breast, laryngeal and other forms of cancer. The invention also provides method for the preparation of these novel carvedilol derivatives and treatment of cancer using these derivatives. BACKGROUND OF THE INVENTION Carvedilol is a nonselective -adrenergic blocking agent with 1 -blocking activity. (±)-l-(carbazol-4-yloxy)-3-[(2-(o-methoxyphenoxy)ethyl]amino]-2-propanol, better known as 'carvedilol1 has the structural formula shown in figure 1. It is a racemic mixture. Carvedilol is a white to off-white powder with a molecular weight of 406.5, represented by the molecular formula C24Hj6N2O4 Carvedilol is a racemic mixture in which the S(-) enantiomer exhibits nonselective B-adrenoreceptor blocking activity and both R(+) and S (-) enantiomers at equal potency exhibit adrenergic blocking activity. Carvedilol has no intrinsic sympathomimetic activity. (Figure Removed) Fig. 1 Carvedilol is rapidly and extensively absorbed following oral administration due to a significant degree of first-pass metabolism. Following oral administration, the apparent mean terminal elimination half-life of carvedilol generally ranges from 7 to 10 hours. Carvedilol is extensively metabolized. Carvedilol is metabolized primarily by aromatic ring oxidation and glucuronidation. The oxidative metabolites are further metabolized by conjugation via glucuronidation and sulfation. The metabolites of carvedilol are excreted primarily via the bile into the feces. Demethylation and hydroxylation at the phenol ring produce three active metabolites with B-receptor blocking activity. Based on preclinical studies, the 4'-hydroxyphenyl metabolite is approximately 13 times more potent than carvedilol for 6-blockade. Compared to carvedilol, the three active metabolites exhibit weak vasodilating activity. Carvedilol is indicated for the treatment of mild or moderate (NYHA class II or III) heart failure of ischemic or cardiomyopathic origin, in conjunction with digitalis, diuretics, and ACE inhibitor, to reduce the progression of disease as evidenced by cardiovascular death, cardiovascular hospitalization, or the need to adjust other heart failure medications. Carvedilol may be used in patients unable to tolerate an ACE inhibitor. Carvedilol may be used in patients who are or are not receiving digitalis, hydralazine or nitrate therapy. Carvedilol is also indicated for the management of essential hypertension. It can be used alone or in combination with other antihypertensive agents, especially thiazide-type diuretics. Carvedilol, an antihypertensive drug with activity on adrenoceptors as well as on calcium channel activity. Use of carvedilol in compositions for treatment of congestive heart failure is disclosed in US Patents 4,503,067 and 5,902,82. US Patent 4369326 discloses carbazolylmethane compounds useful as pressure sensitive or heat recording material. Also carvedilol has been explored for treatment of sexual impotence (US Patent 5,399,581). However, there is no report till date of the use of carvedilol or its derivatives for treatment of cancer. Accordingly, the Applicants undertook a study to investigate the use of carvedilol for treatment of cancer. To their surprise, the Applicants found that carvedilol caused different radio-protective results depending on the dosage and cell-line used. OBJECTS OF THE INVENTION Accordingly, the main object of the invention is to provide novel carvedilol derivatives and a method for preparation of the said derivatives. Another object of the invention is to provide pharmaceutical compositions and method for treating various types of cancer in patients using carvedilol derivatives. SUMMARY OF THE INVENTION The present invention provides novel carvedilol derivatives and pharmaceutical compositions containing such derivatives and useful in the treatment of cancer. In particular, the invention provides novel method for treating, inhibiting and/or preventing tumor or cancer growth, more particularly treating leukemia, lymphomas, lung, prostate, ovarian, melanoma, colon, pancreatic, oral, breast and laryngeal cancer. DETAILED DESCRIPTION OF THE INVENTION Accordingly, the invention provides novel carvedilol derivatives synthesized by effecting modifications in the carvedilol ring. Such modifications have resulted in the development of acyl, Benzoyl, Sulphonamide, oxo, oximino, amino, O-mesylate, phenyl hydrazino, Hydroxyethyl, N-Benzylidene and benzene sulphonate derivatives. Such novel carbazol derivatives are represented by the general formula shown in figure 1 hereunder: (Figure Removed) Fig. 2 In which R, RI and Rj independently or in combination represent the following groups Wherein R is H ; 0; CJH2n+1 (n = 1 to 7); CO(CH)nCH3 (n = 0 to 14), COC(CH3); CO(CH2)nXp (where n= 1 to 7), p = 1, X = H, Cl, Br or F); COCH2C6HnXp (n = 2to 4), p = 1 to 3); C6HnXp (n = 2 to 4), p = 1 to 3); CH2C6HnXp (n = 2 to 4, p = 1 to 3); CH2 C6HnXp (n = 2 to 6, p = 1 to 5), COC6HnXp (n = 0 to 4, p = 1 to 5) [X = H, Cl, Br, F, I, CN, NO2, NH2, CF3, CHC12, OH, OCH3, OC2H5 and/or CnH2n+1 (n =1 to 7)] Wherein R1 is H and R2 is OH, OCO(CH2)nCH3 (where n = 0 to 14), OCOC(CH3)3, OCO(CH2)nXp (where n = 1 to 7, p = 1, X = H, Cl, Br, F), OCOCH2C6HnXp [n = 2 to 4, p = 1 to 3, X = H, Cl, Br, F, I, CN, N02, NH2, CF3, CHC12, OH, OCH3, OC2H5, CHC12 or CnH2n+1 (n=l to 7)], OSO2(CH2)nXp (where n = 1 to 7, p = 1, X = H or Cl), OS02ONH2> OCOC6HnXp [n = 0 to 4, p = 1 to 5, X = H, Cl, Br, F, I, CN, NO2, NH2, CF3, OH, OCH3, OC2H5, CHC12 or CnH2n+1(n = 1 to 7)], NH2, NH(CH2)nOR [(n = 2 to 4), R = H or COCH3], NHR, N(R)2 [where R = CH3, C2H5, C3H7, C4H9], NHC6HnXp, NHCH2C6HnXp (where n = 2 to 4, p = 1 to 3), NHCH2C10HnXp (n = 2 to 6, p = 1 to 5) [X = H,C1, Br, F, I, CHC12, CN, CF3, CHC12, OH, OCH3, OC2H5 or CnH2n+1 (n = 1 to 7)], RCH2NOH (R = H,CH3,C2H5,C3H7,C4H9), NHOR [R = H, COCH3, COC6HnXp , CH2C6HnXp, C6HnXp, n = 2 to 4, p = 1 to 3, X = Cl, Br, F, I, CF3, CHC12, CN, N02, CH3, NH2, OH, OCH3, OC2H5 or CnH2n+`1(n = 1 to 7)], N=CHC6HnXp (where n = 2 to 4, p = 1 to 3), N=CHC6HnXp (n = 2 to 6, p = 1 to 5) [X = H, Cl, Br, F, I, CF3, CN, NO2, NH2, OH, OCH3, OC2H5 or CnH2n+1 (n = 1 to 3)], OCO(CH2)nNH2 (n = 1 to 8), NHCO(CH2)nXp (X = H,C1 or Br, n = 1 to 4, p = 1), NHCOC6HnXp , NHCOCH2C6HnXp (n = 2 to 4, p = 1 to 3),NHCOC6HnXp , NHCOCH2C6HnXp (n = 2 to 6, p = 1 to 5) [X = Cl, Br, F, I, CF3, CN, N02, NH2, OH, OCH3, OC2H5, CHC12 or CnH2n+1(n = 1 to 7)], NHCOC6H4COOH, NHCOC6Hn(COOH)Xp, OCOC6H4COOH, OCOC6Hn(COOH)Xp [ where n = 2 or 3, p = 1 or 2, X = H, Cl, Br, F, N02 or NH2), OCOCHRR1, (R = H, CH3 or Ph; R, = OH, Cl, Br or OCOCH3), NHNHC6HnXp , NHNHCH(OH)C6HnXp (n = 2 to 4, p = 1 to 3), NHNHC6HnXp NHNHCH(OH)C10HnXp (n = 2 to 6, p = 1 to 5)[X = Cl, Br, F, I, OH, OCH3, OC2H5, NO2, NH2, CHC12, CF3 or CnH2n+, (n = 1 to 7)], OCOCH = C(R)2 (R is H, CH3 or C2H5), O-CO-CH=CH-COOH, O-CO-C(Br)=CHCOOH, OCOCH2C(R)2COOH (R = H or CH3), OCO(CH2)nCOOH (n = 0to3), ' (Figure Removed) , -OOCCH(OH)CH(Ph)R [R = NH2, NHC6HnXp (n = 2 to 4, p = 1 to 3), NHCi0HnXp (n = 2 to 6, p = 1 to 5), NHCO(CH2)nXp (n = 1 to 16, p = 1)(X = H, Cl, F, Br), NHCOC6HnXp, NHCOCH2C6HnXp, N=CHC6HnXp, NHCH2C6HnXp, NHSO2C6HnXp (n = 2 to 4, p = 1 to 3), NHCOCioHnXp, N=CHCioHnXp, NHCH2C10HnXp (n = 2 to 6, p = 1 to 5)[X = H, Cl, Br, F, I, CN, NO2, NH2, CF3, CHC12, OCH3, OC2H5 or CnH2n+1 (n = 1 to 7)], NHS02(CH2)nXp [n = 1 to 7, p = 1, X = H, Cl, Br, F, CH3, NO2 or NH2]; amino acid and peptide residues (protected and unprotected) and their salts. Wherein R1 and R2 together are O, NNHC6HnXp , NNHCOC6HnXp (n = 2 to 4, p = 1 to 3), NNHC10HnXp, NNHCOC10HnX(n = 2 to 6, p = 1 to 5), NC6HnXp (n = 2 to 4, p = 1 to 3), NC10HnXp(n = 2 to 6, p = 1 to 5) [X = H, Cl, Br, F, I, CN, NO2, NH2, CF3, CHC12, OH, OCH3, OC2H5 or CnH2n+i (n = 1 to 7)], NNHCeHnBrXp [n = 2 or 3, p = 1 or 2, X = F, Cl, NO2, NH2, OCH3, OC2H5, CnH2n+1 (n = 1 to 7)], NOSO3H, N-OXp, NHOXp[p = 1, X = H, CH3, C2H5,COCH3,S02C6H4CH3],COC6HnXp, C6HnXp,CH2C6HnXp [n = 2 to 4, p = 1 to 3, X = H, Cl, Br, F, I, CN, NO2, NH2, OH, OCH3, OC2H3, CnH2n+1 (n = 1 to 7), CF3 or CHC12], NNHR [R is CH3, C2H5, C2H40Y, Y = H, alkyl, phenyl, benzyl or its substituted derivative with Cl, Br, F, I, N02, NH2, CF3, CHC12, OH, OCH3, OC2H5 or CnH2n+1 (n = 1 to 7)]. The preferred compounds of the invention are shown in figure 2 hereunder: (Figure Removed) Fig. 2 Wherein, R = H,CH3; R1=H; R2 = OH, OCDCH2NHCOCH2NH2, OCOCH3; R1and R2 together is O. These compounds are also represented in the Table shown herebelow: (Table Removed) The method for the preparation of the above compounds are illustrated in the examples hereunder. The procedures are either used alone or in combination to produce the derivatives of the present invention. The Applicants have tested the novel carvedilol derivatives in various cell lines for their cytotoxic activity and have found to their surprise, that these compounds can effectively be used for inhibition of tumors and for treatment of cancer. Such indications exhibited by these carvidelol derivatives are surprising as carvedilol is generally known to act as an anti-hypertensive drug and cytotoxic activity is not expected. Pharmaceutical compositions containing an effective amount of the compounds of the invention as described hereinabove may be prepared according to methods known in the art. By "effective amount", the applicants intend an amount that will produce tumor inhibiting effects or anti-cancer effects without causing undue harmful side effects. The pharmaceutical compositions may provide from about 10 mg to 1000 mg of carvidelol or its derivatives as discussed in this invention, per unit dose. The actual dosage for humans and animals will vary depending upon the body weight of the subject, stage of affliction etc. The composition may be administered either alone or as a mixture with other therapeutic agents. These compositions exhibit synergistic effect, which is unexpected and surprising. The compositions may be formulated in various physical forms such as tablets, capsules, solutions, injectibles, lozenges, powders, aqueous or oily suspensions, syrups, elixirs, implants or aqueous solutions etc. As said earlier, the compositions containing carvidelol or carvidelol derivatives of the invention as active ingredients, may be formulated as tablets, if intended for oral use, or lyophilized powders for parenteral administration. The powders may be reconstituted by adding suitable diluents or pharmaceutically acceptable carriers prior to use. Tablets containing the compounds of the invention as active ingredient, alongwith non-toxic pharmaceutically acceptable excipients. Such excipients may be for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example, corn starch, or alginic acid; binding agents, for example starch, gelatin or acacia, and lubricating agents, for example magnesium stearate, stearic acid or talc. The tablets may be uncoated or they may be coated by known techniques. Compositions for oral use may also be presented as hard gelatin capsules wherein the active ingredient comprises carvidelol or its derivatives as provided in this invention, are mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, for example peanut oil, liquid paraffin or olive oil. The pharmaceutical compositions of the invention may also be formulated as solution, when intended for systemic or parenteral administration. Systemic administration refers to oral, rectal, nasal, transdermal and parentral (i.e., intramuscular, intraperitoneal, subcutaneous or intravenous). The liquid formulation is generally buffered, isotonic or aqueous solution. Examples of suitable diluents are normal isotonic saline solution, standard 5% dextrose in water or buffered sodium or ammonium acetate solution. Such formulation suitable for parenteral administration, may also be used for oral administration or contained in a metered dose inhaler or nebulizer. It may be desirable to add excipients such as ethanol, polyvinylpyrrolidone, gelatin, hydroxy cellulose, acacia, polyethylene glycol, mannitol, sodium chloride or sodium citrate. Alternatively, the compounds of the invention may be prepared in a emulsion or syrup for oral administration. Pharmaceutically acceptable solid or liquid carriers may be added to enhance or stabilize the composition, or to facilitate preparation of the composition. Liquid carriers include syrup, peanut oil, olive oil, glycerin, saline, ethanol, and water. Solid carriers include starch, lactose, calcium sulfate dihydrate, terra alba, magnesium stearate or stearic acid, talc, pectin, acacia, agar or gelatin. The carrier may also include a sustained release material such as glyceryl monostearate or glyceryl distearate, alone or with a wax. The amount of solid carrier varies but, preferably, will be between about 20 mg to about 1 g per dosage unit. The pharmaceutical preparations are made following the conventional techniques of pharmacy involving milling, mixing, granulating, and compressing, when necessary, for tablet forms: or milling, mixing and filling for hard gelatin capsule forms. When a liquid carrier is used, the preparation will be in the form of a syrup, elixir, emulsion or an aqueous or non-aqueous suspension. Such a liquid formulation may be administered directly or filled into a soft gelatin capsule. The compositions may contain additives selected from the group consisting of sweetening agents, flavoring agents, coloring agents and preserving agents in order to provide pharmaceutically elegant and palatable preparations. The applicants have investigated as to whether carvedilol interacts with the cytotoxicity induced by irradiation in vitro as well as in vivo. A daily injection of carvedilol in clinically relevant concentrations (3 mg/kg subcutaneously), 4 days before and 3 days after a single radiation dose of 20 Gy significantly decreased the inflammatory reaction in the rat lung, evaluated as number of inflammatory cells in the peri vascular area. The density of mast cells was also slightly reduced. In vitro studies revealed that carvedilol caused different radio-protective effects, dependent on dose (1-7 Gy) used and cell line studied. The effects were especially pronounced in a malignant mesothelioma cell line (P-31), and somewhat less evident in a prostatic carcinoma cell line (PC-3). No significant effect was seen in a highly radiosensitive small cell lung cancer cell line (U-1690). Thus, carvedilol may under some circumstances interact with radiation-induced tissue reactions, most probably by a direct interaction at the cellular level. The specific explanation to the differences in sensitivity to carvedilol remains to be evaluated, but the known antioxidative properties and/or scavenging of free radicals of carvedilol may be a plausible mechanism of action. Secondary induced alterations in inflammatory response may also be considered. It is suggested that a potential interaction between drugs such as carvedilol and irradiation should be considered for clinical practice. Acquired resistance to chemotherapy is a major problem during cancer treatment. One mechanism for drug resistance is overexpression of the MDR1 (multidrug resistance) gene encoding for the transmembrane efflux pump, P-glycoprotein (P-gp). The calcium channel blocker verapamil has been shown to reverse cellular drug resistance by inhibiting P-gp drug efflux. This study evaluated whether the new antihypertensive drug carvedilol influenced doxorubicin (Dox) cytotoxicity and P-gp activity in a P-gp-expressing cell line compared to a non-expressing subline. Verapamil (10 micromol/L), and even more markedly, carvedilol (10 micromol/L) increased cellular uptake of P-gp-transported calcein of a P-gp-expressing breast cancer cell line (Hs578T-Dox). In the subline (Hs578T) not expressing P-gp, no effects of carvedilol or verapamil on calcein uptake were seen. Carvedilol and verapamil (10 micromol/L) reduced the LD50 (dose which results in the death of half the number of cells) of the Hs578T-Dox subline from 200 mg/L to approx. 10 mg/L Dox, whereas the LD50 of the Hs578T subline was only marginally affected. Carvedilol (10 micromol/L) reduced P-gp activity approximately twice as effectively as verapamil at an equimolar concentration. Carvedilol did not affect pyrogallol cytotoxicity and pyrogallol was without effect on calcein accumulation of the Hs578T-Dox cell line, indicating the lack of antioxidative properties affecting P-gp activity and associated toxicity of the drug. The results suggest that carvedilol has the clinical potential to reverse tumour MDR involving the efflux protein P-gp. The present invention also provides method for the treatment of cancer, said method comprising the steps of administering to the subject an effective amount of carvedilol or derivatives thereof as discussed hereinabove and shown in figures 1 and 2 hereinabove. The nature of pharmaceutical composition employed will, of course, depend on the desired route of administration.. The patient of the invention can be human, mammal or other animal. The dosage in human beings for treatment of cancer includes the combination of the compounds of the invention with conventional agents. The usual dosage is about 3 to 30 µg as a single dose or divided doses. The preferred and actual dosage of the compounds used in the composition of the invention will be according to the specific compositions formulated, mode of administration, the site of administration and the patients being treated. No unexpected or toxic effects were observed when the compounds of the invention were tested for treatment of cancer or inhibition of tumors. The invention is further described in detail by the following examples which are given for illustration of the invention and not intended to limit the scope thereof in any manner: Examples: A:. Preparation of carvedilol derivatives In the following examples, the substarte used was carvidelol. Example 1: Preparation of 3—o-acyl derivatives Method 1: Substrate in organic base is treated with suitable anhydride (saturated or unsaturated) at room temperature for approximately 4-16 hours. Examples of anhydrides that can be used in this process are represented by general formula (RCH2CO2)O wherein R=H, CH3, C2H5, etc. The reaction was worked by evaporation of the reaction mixture, addition of water and extraction with an organic solvent. The organic layer was dried over anhydrous sodium sulfate, evaporated and residue crystallized to yield the corresponding pure 3-0 acyl derivatives respectively. Examples of organic bases that can be used in this method are TEA, pyrdine and BMP A. Method II: Substrate in halogenated organic solvent was treated with suitable acyl chloride as in Method 1. The reaction was worked up as described in Method I to yield the corresponding 3-o-acyl derivatives in the pure form. Examples of acyl chlorides that can be used are R(CH2 )„ COCI wherein R=H, Cl, BH, I or F and n=l to 16 or RCH2 (CH)n XCOCI wherein R=H, X=OH, OCOCH3 and n=l. The halogenated solvent may be selected from CC14 CH2 C12, C6 H5CH3 or the like. Example 2: Preparation of 3-oxo-derivatives. The substrate was dissolved in an organic solvent and conventional oxidizing agent was added under normal reaction conditions. The reaction was worked up as described in Method I to yield the corresponding 3-oxo derivatives in the pure form. Example of oxidizing agents that can be used are CrO3/Py; CrO3/H2SO4; CrO3./AcOH or the like. The normal reaction condition is stirring the substrate with oxidizing agent at from 0°C to room temperature for a few hours. The organic solvent may be selected from acetone, CH2C12, AcOH, mixtures thereof or the like. Example 3: Preparation of 2, 20,29- tribro mo 3-oxo derivative A -3-oxo betulinic acid derivative prepared according to the process of Example 3 was dissolved in halogenated organic solvent. To this was added dropwise liquid bromine dissolved in the same solvent and the temperature was maintained between 0-10°C. The reaction mixture was brought to room temperature and stirred for a few hours. The reaction was worked up as described in Method I of Example 2. The organic layer was washed with 5-10% aqueous alkaline solution and evaporated. The crystallized product yielded pure 2, 20, 29-tribromo-3-oxo derivatives. Examples of halogenated solvents that can be used are CCl4,CH2Cl2, CHCl3 and the like; Examples of aqueous alkaline solution that can be used are bicarbonate or carbonate of an alkali metal in water, and the like. Example 4: Preparation of 3-oximino derivative A 3-oxo derivative of carvidelol is mixed in an alcoholic solvent such as methanol, ethanol, propanol and the like. To this was added alkyl hydroxylamine, phenyl hydroxylamine or benzyl hydroxylamine or its substituted derivatives and sodium acetate. The mixture was refluxed for a few hours. The reaction mixture was evaporated to dryness. The reaction was worked up as described in Method I of Example 2 and yielded crude-3-oximino derivative which crystallized to yield the corresponding pure 3-oximino derivative. Example 5: Preparation of phenylhydrazone of 3-oxo derivative Phenylhydrazine or alkyl hydrazine their substituted analogs or a salt thereof, and sodium acetate were added to 3-oxo derivative dissolved in alcoholic solvent such as methanol, ethanol, propanol and the like, and was refluxed for about four hours. The reaction was worked up as described in Method I of Example 2 to yield the corresponding pure phenylhydrazone derivative in pure form. Example 6: Preparation of 2-bromo-3-oxo-derivative: 3-oxo-dihydrobetulinic acid derivative was dissolved in halogenated organic solvent such as CCl4,CH2,Cl2, CHC13 or the like. Liquid bromine dissolved in the same solvent was added drop wise while maintaining the temperature between 0-10°C. The reaction mixture was brought to room temperature and maintained for a few hours. The mixture was worked up in the usual manner, the organic layer was washed with 5-10% aqueous alkaline solution followed by water. Evaporation and crystallization yielded pure 2-Bromo-3-oxo derivatives. Examples of aqueous alkaline solution that can be used are bicarbonate or carbonate of an alkali metal in water, and the like. Example 7: Preparation of dibromo derivative: Betulinic acid or its derivative (except 3-oxo-betulinic acid or its derivatives) was dissolved in halogenated organic solvent. To this liquid bromine dissolved in the same solvent was added dropwise and temperature maintained between 0-10°C. The reaction mixture was brought to room temperature and stirred for few hours. The reaction mixture was worked up as described in Method I of Example 2. The organic layer was washed in 5-10% aqueous alkaline solution and evaporated. The crystallized product yield pure 20,29-dibromo derivative. Examples of halogenated solvents that can be used are CCl4CH2Cl2,CHCl3and the like. Example 8: Preparation of amino derivatives The derivatives were prepared by the following method: a] 3-oximino derivative is dissolved in glacial acetic acid and shaken under hydrogen atmosphere (60-70psi) in presence of platinum oxide catalyst for several hours. Reaction mixture is filtered, mother liquor evaporated under vacuum to remove glacial acetic acid and the residue worked up in the usual manner to yield the corresponding 3-amino derivative. b] 3 oxo-derivative is dissolved in methanol added ammonium sulphate and sodium borohyride and refluxed for 2-4 hrs. Reaction mixture evaporated to dryness, added water, filtered the solid and crystallized to give 3-amino derivatives. Example 9: Preparation of 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 C6HnXCOCl (n= 2 to 4) C10Hn X COC1 [X = H, Cl, Br, I, F, CF3 CHC12, C6H5, OH, OCHs, OC2H, OC3H7, CnH2n + l(n= 1 to 7)]. 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 O-benzoyl derivatives respectively. Examples of organic bases that can be used are pyridine, piperidine. Example 10: reparation of 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 O- mesylate derivative. Example 11: Preparation of phenyl hydrazino or its phenyl substituted derivative Phenylhydrazone 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 12: Preparation of N-Hydroxyethyl derivative The oxo-derivative of carvidelol 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 13: Preparation of N-Benzylidene derivative Amino derivative of carvidelol is dissolved in alcoholic solvent, such as methanol / ethanol and to it added benzaldehyde or substituted beiizaldehyde 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 14: Preparation of O-benzene sulphonate derivatives These derivatives were prepared by: (a) dissolving the substrate in halogenated organic solvent, adding few drops of pyridine followed by benzene sulphonyl chloride or its benzene substituted derivative slowly keeping the temperature between 5 to 10°C. (b) stirring the mixture at an ambient temperature for few hours. (c) working up the reaction mixture by washing the organic layer with water. d) drying the organic layer over anhydrous sodium sulfate, filtering, evaporated to get a residue which is crystallized from nitrite or alcoholic solvent to yield pure 3-0- bezene sulphonate derivative Example 15: Preparation of 3-O-sulphonamide derivatives These derivatives were prepared by: a) dissolving 3-amino derivative in halogenated organic solvent adding few drops of triethylamine followed by alkyl or benzene sulphonyl chloride or its substituted derivative slowly keeping the temperature between 5 -10°C. b) stirring the mixture at an ambient temperature for few hours. c) working up the reaction mixture by washing with water. d) drying the organic layer over anhydrous sodium sulphate, filtering, evaporating to dryness to get a residue which is crystallized to yield pure 3-O-sulphonamide derivatives. B. In vitro testing of carvedilol derivatives Example 16 In vitro cytotoxic activity of carvedilol derivatives was determined by performing the MTT cytotoxicity assay. Briefly, the cultured ovarian cancer cells (PA-1) were separately seeded in a 96-well culture plate and co-incubated with carvedilol derivatives dissolved in methanol, dimethyl formamide, dimethyl sulfoxide or isopropyl alcohol with relevant controls at 37°C in a CO: incubator. After 72 hours, the assay was terminated and percent cyotoxicities calculated. The EDjo values are shown in the Table below. (Table Removed) Example 17 In vitro cytotoxic activity of carvedilol 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 carvedilol or its derivatives dissolved in methanol, dimethyl formamide, dimethyl sulfoxide or isopropyl alcohol with relevant controls at 37°C in a CO: incubator. After 72 hours, the ass.ay was terminated and percent cyotoxicities calculated. As shown in Table I, metabolic activity of leukemia cells (MOLT-4), melanoma cells (B16.F10), colon tumor cells (PTC), prostate cancer cells (DU145), Oral cancer cells (KB), ovarian cancer cells (PA-1), breast cancer cells (HBL100), glioblastoma (U87.MG), lung cancer cells (L132) and pancreatic cancer cells (MiaPaCa.2) was inhibited by carvedilol. (Table Removed) Example 18 A suitable formulation of carvidelol acid derivatives was prepared as follows. The derivatives were solubilized in a minimum volume of methanol. The 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 derivative was added in small aliquots to the denvatized 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. CLAIMS: l. Novel caridelol derivatives useful in the treatment of cancer, and represented by the general formula as shown in figure 2: (Figure Removed) In which R, RI and R2 independently or in combination represent the following groups Wherein R is H ; 0; CnH2n+1 (n = 1 to 7); CO(CH)nCH3 (n = 0 to 14), COC(CH3); CO(CH2)nXp (where n= 1 to 7), p = 1, X = H, Cl, Br or F); COCH2C6HnXp (n = 2to 4), p = 1 to 3); C6HnXp (n = 2 to 4), p = 1 to 3); CH2C6HnXp (n = 2 to 4, p = 1 to 3); CH2 C10HnXp (n = 2 to 6, p = 1 to 5), COC6HnXp (n = 0 to 4, p = 1 to 5) [X = H, Cl, Br, F, I, CN, N02, NH2, CF3, CHC12, OH, OCH3, OC2H3 and/or CnH2n+1 (n =1 to 7)] Wherein R1 is H and R2 is OH, OCO(CH2)nCH3 (where n = 0 to 14), OCOC(CH3)3, OCO(CH2)nXp (where n = 1 to 7, p = 1, X = H, Cl, Br, F), OCOCH2C6HnXp [n = 2 to 4, p = 1 to 3, X = H, Cl, Br, F, I, CN, N02, NH2, CF3, CHC12, OH, OCH3, OC2H5, CHC12 or CnH2n+1 (n=l to 7)], OSO2(CH2)nXp (where n = 1 to 7, p = 1, X = H or Cl), OS02ONH2, OCOC6HnXp [n = 0 to 4, p = 1 to 5, X = H, Cl, Br, F, I, CN, NO2, NH2, CF3, OH, OCH3, OC2H5, CHC12 or CnH2n+,(n = 1 to 7)], NH2, NH(CH2)nOR [(n = 2 to 4), R = H or COCH3], NHR, N(R)2 [where R = CH3, C2H5, C3H7, C4H9], NHC6HnXp, NHCH2C6HnXp (where n = 2 to 4, p = 1 to 3), NHCH2C10HnXp (n = 2 to 6, p = 1 to 5) [X = H,C1, Br, F, I, CHC12, CN, CF3, CHC12, OH, OCH3> OC2H3 or CnH2n+1, (n = 1 to 7)], RCH2NOH (R = H,CH3,C2H5,C3H7,C4H9), NHOR [R = H, COCH3, COC6HnXp, CH2C6HnXp, C6HnXp, n = 2 to 4, p = 1 to 3, X = Cl, Br, F, I, CF3, CHC12, CN, N02, CH3, NH2, OH, OCH3, OC2H5 or CnH2n+1(n = 1 to 7)], NOHC6HnXp (where n = 2 to 4, p = 1 to 3), N=CHC10HnXp (n = 2 to 6, p = 1 to 5) [X = H, Cl, Br, F, I, CF3, CN, NO2, NH2, OH, OCH3, OC2H3 or CnH2n+1(n = 1 to 3)], OCO(CH2)nNH2 (n = 1 to 8), NHCO(CH2)nXp (X = H,C1 or Br, n = 1 to 4, p = 1), NHCOC6HnXp, NHCOCH2C6HnXp (n = 2 to 4, p = 1 to 3),NHCOC10HnXp, NHCOCH2C10HnXp (n = 2 to 6, p = 1 to 5) [X = Cl, Br, F, I, CF3, CN, N02, NH2, OH, OCH3, OC2H5, CHC12 or CnH2n+1(n = 1 to 7)], NHCOC6H4COOH, NHCOC6Hn(COOH)Xp, OCOC6H4COOH, OCOC6Hn(COOH)Xp [ where n = 2 or 3, p = 1 or 2, X = H, Cl, Br, F, NO2 or NH2), OCOCHRR1, (R = H, CH3 or Ph; R1= OH, Cl, Br or OCOCH3), NHNHCeHnXp, NHNHCH(OH)C6HnXp (n = 2 to 4, p = 1 to 3), NHNHC10HnXp NHNHCH(OH)C10HnXp (n = 2 to 6, p = 1 to 5)[X = Cl, Br, F, I, OH, OCH3, OC2H5, N02, NH2, CHC12, CF3 or CnH2n+1 (n = 1 to 7)], OCOCH = C(R)2 (R is H, CH3 or C2H5), 0-CO-CH=CH-COOH, 0-CO-C(Br)=CHCOOH, OCOCH2C(R)2COOH (R = H or CH3), OCO(CH2)nCOOH (n = 0 to 3), (Figure Removed) , -OOCCH(OH)CH(Ph)R [R = NH2) NHC6HnXp (n = 2 to 4, p = 1 to 3), NHC10HnXp (n = 2 to 6, p = 1 to 5), NHCO(CH2)nXp (n = 1 to 16, p = 1)(X = H, Cl, F, Br), NHCOC6HnXp, NHCOCH2C6HnXp , N=CHC6HnXp , NHCH2C6HnXp , NHS02C6HnXp (n = 2 to 4, p = 1 to 3), NHCOC10HnXp, N=CHC10HnXp, NHCH2C10HnXp (n = 2 to 6, p = 1 to 5)[X = H, Cl, Br, F, I, CN, NO2, NH2, CF3, CHC12, OCH3, OC2H5 or CnH2n+1 (n = 1 to 7)], NHSO2(CH2)nXp [n = 1 to 7, p = 1 , X = H, Cl, Br, F, CH3, NO2 or NH2]; amino acid and peptide residues (protected and unprotected) and their salts. Wherein R1 and R2 together are O, NNHC6HnXp, NNHCOC6HnXp (n = 2 to 4, p = 1 to 3), NNHC10HnXp, NNHCOC10HnX(n = 2 to 6, p = 1 to 5), NC6HnXp(n = 2 to 4, p = 1 to 3), NC10HnXp (n = 2 to 6, p = 1 to 5) [X = H, Cl, Br, F, I, CN, NO2, NH2, CF3, CHC12, OH, OCH3, OC2H5 or CnH2n+1 (n = 1 to 7)], NNHC6HnBrXp [n = 2 or 3, p = 1 or 2, X = F, Cl, N02, NH2, OCH3, OC2H5, CnH2n+1 (n = 1 to 7)], NOS03H, N-OXP, NHOXp[p = 1, X = H, CH3, C2H5,COCH3,S02C6H4CH3],COC6HnXp, C6HnXpCH2C6HnXptn = 2 to 4, p = 1 to 3, X = H, Cl, Br, F, I, CN, N02, NH2, OH, OCH3, OC2H5, CnH2n+1 (n = 1 to 7), CF3 or CHC12], NNHR [R is CH3, C2H3, C2H40Y, Y = H, alkyl, phenyl, benzyl or its substituted derivative wit-h Cl, Br, F, I, N02, NH2, CF3, CHC12, OH, OCH3, OC2H5or CnH2n+, (n = 1 to 7)]. 2. Novel carvidelol derivatives as claimed in claim 1 wherein the preferred compounds are as shown in figure 2 hereunder: (Figure Removed) Wherein, R = H, CH3; R. =H; R2 = OH, OCOCH2NHCOCH2NH2, OCOCH3; RI and R2 together is O. 3 Pharmaceutical compositions containing an effective amount of the compounds as claimed in claims 1 and 2 as active ingredients together with or in combination with carriers, excipients and additives such as herindescribed and useful in the treatment of cancer or inhibition of tumours. 4. A composition as claimed in claim 3 formulated in physical forms selected from tablets, capsules, solutions, injectibles, lozenges, powders, aqueous or oily suspensions, syrups, elixirs, implants or aqueous solutions etc. 5. Compositions as claimed in claim 3 wherein the effective amount of the active ingredients ranges from 10 to 100 mg. 6. A composition as claimed in claim 3 wherein the excipients are selected from inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents such as corn starch, or alginic acid; binding agents such as starch, gelatin or acacia, and lubricating agents such as magnesium stearate, stearic acid or talc 7. A composition as claimed in claim 3 wherein the excipients further comprise ethanol, polyvinylpyrrolidone, gelatin, hydroxy cellulose, acacia, polyethylene glycol, mannitol, sodium chloride or sodium citrate. 8. A method of using novel carvidelol derivatives or a combination thereof to treat a patient with cancer by administering a pharmaceutically effective dosage of said carvidelol derivatives or its combination to the patient. 9. A method for the treatment of cancer in humans, said method comprising the steps of administering a therapeutically effective of a pharmaceutical composition containing carvidelol or its derivatives as claimed in claims 1 and 2 to a subject in need thereof. 10. A method as claimed in claim 9 wherein patient is human, mammal or other animal. 11. A method as claimed in claim 9 wherein the pharmaceutical composition contains carvidelol or its derivatives as claimed in claims 1 and 2 alone or in combination with appropriate excipients, additives and carriers. 12. A method as claimed in claim 9 wherein the carvidelol derivatives as claimed in claims 1 and 2 are administered to the patient alone or together with pharmaceutically acceptable additive, carrier, diluent, solvent, filler, lubricant, excipient, binder or stabilizer. 13. A method as claimed in claim 9 wherein the carvidelol derivatives as claimed in claims 1 and 2 is administered in the form of a tablet, lozenge, capsule, powder, aqueous or oily suspension, syrup, elixir, implant or aqueous solution. 14. A method as claimed in claim 9 wherein the carvidelol derivatives as claimed in claims 1 and 2 or a combination thereof is administered to the patient orally or systemically. 15. Novel carvidelol derivatives substantially as hereindescribed and illustrated. 16. Pharmaceutical compositions containing such carvidelol derivatives substantially as hereindescribed and illustrated. 17. Method of treatment substantially as hereindescribed and illustrated.

Documents:

1-del-2001-abstract.pdf

1-del-2001-claims.pdf

1-del-2001-correspondence-others.pdf

1-del-2001-correspondence-po.pdf

1-del-2001-description (complete).pdf

1-del-2001-form-1.pdf

1-del-2001-form-13.pdf

1-del-2001-form-19.pdf

1-del-2001-form-2.pdf

1-del-2001-form-26.pdf

1-del-2001-form-3.pdf

1-del-2001-form-5.pdf