Indian Patents. 255359:NOVEL HYDROXY FUNCTIONALIZED ADAMANTYL SUBSTITUTED 6-ARYLVINYL-1,2,4-TRIOXANES AND THEIR HEMISUCCINATES, USEFUL AS ANTIMALARIAL AGENTS, AND A PROCESS FOR THE PREPARATION THEREOF

Title of Invention	NOVEL HYDROXY FUNCTIONALIZED ADAMANTYL SUBSTITUTED 6-ARYLVINYL-1,2,4-TRIOXANES AND THEIR HEMISUCCINATES, USEFUL AS ANTIMALARIAL AGENTS, AND A PROCESS FOR THE PREPARATION THEREOF
Abstract	NOVEL HYDROXY FUNCTIONALIZED ADAMANTYL SUBSTITUTED 6-ARYLVINYL-1,2,4-TRIOXANES AND THEIR HEMISUCCINATES, USEFUL AS ANTIMALARIAL AGENTS, AND A PROCESS FOR THE PREPARATION THEREOF

Full Text	Field of invention The present invention relates to novel hydroxy functionalized adamantyl substituted 6-arylvinyl-1,2,4-trioxanes the present invention particularly relates to a novel series of antimalarial 1,2,4-trioxanes analogues of general formula 8 (Formula Removed) wherein X represents the groups like OCH2CH2OH, OC2CH2OCOCH2CH2COOH whereas R1 and R2 represents the alkyl group selected from methyl or part of a cyclic systems such as cyclopentane, cyclohexane and adamantane and the preparation thereof; several of these novel compounds show promising antimalarial activity against multi-drug resistant malaria in mice. BACKGROUND OF INVENTION Malaria, endemic in many parts of the tropical countries, with approximately 300-500 million episodes of clinical infection and nearly 2 million deaths per year worldwide, is a serious health problem. The rapid emergence of resistance by Plasmodium falciparum to existing therapies has added new dimensions to this problem. Against this background discovery of artemisinin, a sesquiterpene lactone Endoperoxide, isolated from the Chinese traditional herbal remedy against malaria, Artemisia annua, has been a welcome development in the chemotherapy of malaria. Some of the semisynthetic derivatives of artemisinin e.g. artemether, arteether and artesunic acid are more active than artemisinin and are currently being used clinically. These drugs are effective against both cholroquin sensitive and chloroquine resistant strains of Plasmodium falciparum. [For background literature on artemisinin and its derivatives see: (a) Klayman, D. L Science 1985, 225, 1049. (b) Zaman, s. s.; Sharma, R.P. Heterocycles 1991,32,1593. (c) Jung, M. Curr. Med. Chem. 1994, 1, 35. (d) /efford, C. W. Advances in drug research; vol. 29, p 272. (e) Avery, M. A. Curr. Pharm. Design. 1995, 5, 101. (f) Bhattacharya, A. K.; Sharma, R. P. Heterocycles 1999, 51, 1651. (g) Borstnik, K.; Paik, I.; Shapiro, T. A.; Posner, G. H. Int. J. Parasitol. 2002, 32, 1661. (h) Ploypradith, P. Ada Trap. 2004, 89, 329. (i) O'Neill, P. M.; Posner, G. H. J. Med. Chem. 2004, 47, 2945] (Formula Removed) The limited availability of artemisinin from natural sources and the realization that 1,2,4-trioxane is the pharmacophore for the antimalarial activity of artemisinin and its analogues, has inspired major efforts towards the preparation and bioevaluation of structurally simple synthetic 1,2,4-trioxanes. As a result of these efforts, a number of methodologies have been developed by various workers for the preparation of 1,2,4-trioxanes . Several of these synthetic trioxanes have shown promising antimalarial activities both in vitro and in vivo [(a) Peters, W.; Robinson, B. L.; Tovey, G.; Rossier, J. C.; Jefford, C. W. Ann. Trap. Med. Parasitol. 1993, 87, 1-7. (b) Peters, W.; Robinson, B. L.; Rossier, J. C.; Jefford, C. W. Ann. Trap. Med. Parasitol. 1993, 87, 9-16. (c) Peters, W.; Robinson, B. L.; Tovey, G.; Rossier, J. C.; Jefford, C. W. Ann. Trop. Med. Parasitol. 1993, 87, 111-123. (d) Kepler, J. A.; Philip, A.; Lee, Y. W.; Matthew C. Morey, M. C.; and F. Ivy Carroll, F. I. J. Med Chem. 1988, 31, 713-716. (e) Posner, G. H.; Maxwell, J. P.; O'Dowd, H.; Krasavin, M.; Xie, S.; Shapiro, T. A. Bioorg. Med. Chem. 2000, 8, 1361-1370. (0 Posner, G. H.; Jeon, H. B.; Parker, M. H.; Krasavin, M.; Paik, I.-K; Shapiro, T. A. J. Med Chem. 2001, 44, 3054-3058. (g) Posner, G. H.; Jeon, H. B.; Polypradith, P.; Paik, I.-H.; Borstnik, K.; Xie, S.; Shapiro, T. A. J. Med. Chem. 2002, 45, 3824-3828. (h) Griesbeck, A. G.; El-Idreesy, T. T.; Fiege, M.; Brun, R Org. Lett. 2002, 24, 4193-4195. (i) O'Neill, P. M.; Mukhtar, A.; Ward, S. A.; Bickley, J. F.; Davies, J.; Bachi, M. D.; Stocks, P. A. Org. Lett. 2004,75,3035-3038.] Singh et al have prepared 1,2,4-trioxanes by regiospecific photooxygenation of allylic alcohols to furnish hydroperoxide, which on condensation with aldehydes or ketones in the presence of an acid catalyst furnish 1,2,4-trioxane [(a) Singh, C. Tetrahedron Lett. 1990, 31, 901-6902. (b) Singh, C.; Gupta, N.; Puri, S. K. Tetrahedron Lett. 2005, 39, 405. (c) Singh, C.; Misra, D.; Saxena, G.; Chandra, S. Bioorg. & Med. Chem. Lett. 1992, 2, 497-500. (d) Singh, C.; Misra, D.; Saxena, G.; Chandra, S. Bioorg. & Med. Chem. Lett. 1995, 5, 1913-1916. (e) Singh, C.; Gupta, N.; Puri, S. K. Bioorg. & Med. Chem. 2004, 12, 5553-5562. (f) Singh, C.; Srivastav, N. C.; Puri, S. K.; Bioorg. & Med. Chem. 2004, 12, 5745-5752. (g) Singh, C.; Gupta, N.; Puri, S. K. Bioorg. & Med. Chem. Lett. 2003, 13, 3447-3450. (h) Singh, C.; Malik, H.; Puri, S. K.. Bioorg. & Med. Chem. 2004, 12, 1177-1182. (i). Singh, C.; Malik, H.; Puri, S. Kioorg. & Med. Chem.Lett. 2005, 15, 4484-4487. (k) Singh, C.; Malik, H.; Puri, S. K... Bioorg. & Med. Chem.Lett. 2004, 14, 459-462. (j) Singh, C.; Malik, H.; Puri, S. K.. B. J. Med. Chem. 2006, 49, 2794-2803. Object of the Invention The main object of the present invention is to provide novel hydroxy functionalized adamantyl substituted 6-arylvinyl-1,2,4-trioxanes. Another object of the present invention is to provide the composition for the treatment of malaria. Further object of the present invention is to provide the composition effect given for the treatment of multi drug resistance malaria. Another object of the present invention is to provide the composition effective up to 100% suppression of parasitaemia Accordingly, the present invention is provides a novel substituted 1,2,4-trioxanes of general formula 8 (Formula Removed) wherein X is selected from OCH2CH2OH, OCH2CH2OCOCH2CH2COOH and RI & R2 represents alkyl group such as methyl or a part of cyclic system selected from cyclopentane, cyclohexane or adamantane and their hemisuccinate derivatives, or salts thereof. In an embodiment of the present invention, the said compound 8 having structural formula 8aa-a, 8aa-b and 8aa-d as shown below: (Formula Removed) 8aa 8aa-a : R,, R2 = -CH2CH2CH2CH2-8aa-b : R,, R2 = -CH2CH2CH2CH2CH2- 8aa-d : R, = R2 = methyl In another embodiment of the present invention, the said compound 8 having structural formula 8aa-c as shown below: (Formula Removed) 8aa-c In yet another embodiment of the present invention, the said compound 8 having structural formula 8ba-a, 8ba-b as shown below: (Formula Removed) 8ba 8ba-a : R,, R2 = -CH2CH2CH2CH2- 8ba-b : RI, R2 = -CH2CH2CH2CH2CH2- One more embodiment of the present invention, the said compound 8 having structural formula 8ba-c as shown below: (Formula Removed) 8ba-c Further embodiment of the present invention, Novel substituted 1,2,4-trioxanes as claimed in claim 1 wherein the said compound 8 having structural formula 8ab-a, 8ab-b and 8ab-d shown below: (Formula Removed) 8ab 8ab-a : R,, R2 = -CH2CH2CH2CH2-8ab-b : R,, R2 = -CH2CH2CH2CH2CH2- 8ab-d : RI = R2 = methyl One of the embodiments of the present invention, the said compound 8 having structural formula 8ab-c shown below: (Formula Removed) 8ab-c Other embodiment of the present invention, the said compound 8 having structural formula 8bb-a and 8bb-b as shown below: (Formula Removed) 8bb 8bb-a : R,, R2 = -CH2CH2CH2CH2-8bb-b : R,, R2 = -CH2CH2CH2CH2CH2- Further embodiment of the present invention, the said compound 8 having structural formula 8bb-c as shown below: (Formula Removed) 8bb-c In another embodiment of the present invention, the salt of compound 8 (X is OCH2CH2OCOCH2CH2COOH) may be selected from sodium or potassium. The compound of general formula 8 and their hemisuccinate derivatives or salts thereof are useful for the treatment of malaria. The dose of the compound 8 may be ranging between 48 to 96 mg/kg body weight. One more embodiment of the present invention, the compound may be administered through oral or intramuscular route. Accordingly, the present invention provides a process for the preparation of novel substituted 1,2,4-trioxanes of general formula 8, (Formula Removed) Wherein X is selected from OCH2CH2OH, OCfyCfyOCOCfyC^COOH and R, & R2 represents alkyl group such as methyl or a part of cyclic system selected from cyclopentane, cyclohexane or adamantane which comprises: (i) reacting aryl methyl ketones of formula 1 with 1-adamantanol in the presence of an acid catalyst in an organic solvent at a temperature ranging between room temperature to refluxing to give adamantyl substituted aryl methyl ketones of formula 2; (Formula Removed) (ii) reacting aryl methyl ketones of formula 2 with ethyl chloroacetate in the presence of anhydrous KjCOa in an aprotic organic solvent in the temperature range of room temperature to refluxing temperature to give esters of formula 3; (Formula Removed) (iii) reacting esters of formula 3 with ethyl bromoacetate and Zn in the presence of catalytic amount of I2 in an aprotic organic solvent in the temperature range of room temperature to refluxing temperature to give /2-hydroxyesters of formula 4; (Formula Removed) (iv) dehydrating the /?-hydroxyesters of formula 4 using a catalytic amount of/?-TSA in an aprotic organic solvent at a temperature ranging between room temperature to refluxing temperature to give or,/?-unsaturated esters of formula 5; (FormulaRemoved) (v) reducing the esters of formula 5 with LiAlHj in diethyl ether at a temperature ranging between -5°C to 0°C to give allylic alcohols of formula 6; (Formula Removed) (vi) photooxygenating the allylic alcohols of formula 6 in the presence of a sensitizer in an organic solvent at a temperature ranging between -10°C to room temperature to give ft-hydroxyhydroperoxides of formula 7; (Formula Removed) (vii) reacting >3-hydroxyhydroperoxide of formula 7 in situ with ketones of formula 9wherein RI and Ra represents, methyl, the part of cyclic system such as cyclopentane, cyclohexane or adamantane in the presence of an acid catalyst in an aprotic organic solvent in the temperature range of 3°C to room temperature, followed by isolation and purification by known methods to furnish the trioxanes of general formula 8, wherein X is OCHjCI^OH, RI, R2 have the same meaning as above; (Formula Removed) 8 X = OCH2CH2OH (viii) reacting trioxanes of formula 8 (X = OCfyCFkOH) with succinic anhydride and triethylamine in presence of catalytic amount of dimethylaminopyridine (DMAP) in a low boiling chlorinated solvent to furnish their hemisuccinates of formula 8 (X = OC^CfyOCOCHjCfyCOOH) and RI, R2 represents, methyl, the part of cyclic system such as cyclopentane, cyclohexane or adamantane, (Formula Removed) 8 X = OCH2CH2OCOCH2CH2COOH In another embodiment of the present invention, the acid catalyst in step (i) may be selected from H2S04, H3PO4and amberlyst-15. In yet another embodiment of the present invention, the organic solvent in step (i) is selected from CH3COOH, CfiHe, THF. In a further embodiment of the invention , wherein adamantyl substituted m/p-hydroxy] acetophenone of formula 2 is prepared by reacting aryl methyl ketone of formula 1 with 1-admantanol in acetic acid in the presence of coned. H2SO4, or in acetic acid in the presence of H3PO4, or in acetic acid in the presence of amberlyst-15 , or in benzene in the presence of amberlyst-15 , or in THF in the presence of amberlyst-15. In an embodiment of the present invention, the adamantyl substituted esters of formula 3 are prepared by reacting adamantyl substituted m/p-hydro\y acetophenone of formula 2 with ethyl 2-chloroacetate and K.2CC>3 in acetone. In another embodiment of the present invention, the /?-hydroxyesters of formula 4 are prepared by reacting adamantyl substituted esters of formula 3 with ethyl 2-bromoacetate and Zn in the presence of catalytic amount of I2 in an aprotic solvent such as benzene. In yet another embodiment of the present invention, the o;/?-unsaturated esters of formula 5 are prepared by dehydrating /2-hydroxyesters of formula 4 using catalytic amount of/?-TSA in an aprotic organic solvent like benzene. Other embodiment of the present invention, the allylic alcohols of formula 6 are prepared by reducing o;/?-unsaturated esters of formula 5 in ethereal solvent like diethyl ether. One more embodiment of the present invention, the organic solvent used in step (vi) and (viii) is selected from the group consisting of CHCI3, THF, CHsCN. Further embodiment of the present invention, the adamantyl substituted hydroxy functionalized 1,2,4- trioxanes of formula 8 are prepared by reacting yS-hydroxyhydroperoxides of formula 7 with a ketone in the presence of an acid catalyst. One of the embodiments is the present invention, the preparation of hemisuccinate derivatives of general formula 8 (X = OCH2CH2OCOCH2CH2COOH) by reacting 1,2,4-trioxanes of general formula 8 (X = OCH2CH2OH) with succinic anhydride and triethyl amine in the presence of catalytic DMAP in dichloromethane at a temperature ranging between 0°C to room temperature. Accordingly the present invention provides a pharmaceutical composition comprising an effective amount of the compound of formula 8 (Formula Removed) wherein X is selected from OCH2CH2OH, OCH2CH2OCOCH2CH2COOH and RI & R2 represents alkyl group such as methyl or a part of cyclic system selected from cyclopentane, cyclohexane or adamantane, their derivatives, isomers or salts thereof, optionally along with pharmaceutically acceptable diluents. In an embodiment of the present invention, the compounds are administered through oral or intramuscular routes. In another embodiment of the present invention, the diluent is selected from the group consisting of edible oils such as groundnut oil or aqueous bicarbonate solution. In yet another embodiment of the present invention, the curative dose of the compound is ranging between 48 to 96 mg/kg. Further embodiment of the present invention, the suppression of parasitaemia is upto 100% on day 4 at 48 mg/kg with 20% survival of the treated mice at this dose by intramuscular route. Accordingly the present invention provides a method of treating the subject suffering from malaria con.prising; administering the effective amount of composition to the subject in need wherein the composition comprises; an effective amount of the compound of formula 8, (Formula Removed) 8 wherein X is selected from OCH2CH2OH, OCH2CH2OCOCH2CH2COOH and RI & R2 represents alkyl group such as methyl or a part of cyclic system selected from cyclopentane, cyclohexane or adamantane, their derivatives, isomers or salts thereof, along with pharmaceutically acceptable additives, carriers, diluents. Detailed Description This invention relates to novel substituted 1,2,4-trioxanes. This invention also relates to a process for the preparation of novel substituted 1,2,4-trioxanes. This invention particularly relates to a process for the preparation of adamantyl substituted 6-arylvinyl-1,2,4-trioxanes as a new series of antimalarial agents. More particularly the present invention provides a process for the preparation of 1,2,4-trioxanes of general formula 8 wherein X represents the groups like OCHaCfyOH, OCH2CH2OCOCH2CH2COOH whereas RI and R2 represents the alkyl group selected from methyl or part of a cyclic systems such as cyclopentane, cyclohexane and adamantane. These trioxanes are new compounds and are useful as antimalarial agents. These compounds have been tested against multi-drug resistant malaria in mice and some of them have shown promising antimalarial activity. The invention, thus relates to pharmaceutical industry. The trioxanes of general formula 8 are new chemical entities and these have not been prepared earl'er. The objective of the present invention is to provide a new series of 1,2,4-trioxanes and a process for the preparation of novel 1,2,4-trioxanes of general formula 8. Accordingly, the present specification provides a process for the preparation of novel substituted 1, 2, 4-trioxanes of general formula 8. (Formula Removed) 8 wherein X represents the groups like OCH2CH2OH, OCH2CH2OCOCH2CH2COOH and R,, R2 represent alkyl groups selected from methyl or a part of cyclic systems such as cyclopentane, cyclohexane, adamantane and the like, which comprises reacting aryl methyl ketones of formula 1, with 1 -adamantanol in the presence of an acid catalyst in an organic solvent in the temperature range of room temperature to refluxing to give adamantyl substituted aryl methyl ketones of formula 2; reacting aryl methyl ketones of formula 2 with ethyl chloroacetate in the presence of anhydrous K2CO3 in an aprotic organic solvent in the temperature range of room temperature to refluxing temperature to give esters of formula 3; reacting esters of formula 3 with ethyl bromoacetate and Zn in the presence of catalytic amount of I2 in an aprotic organic solvent in the temperature range of room temperature to refluxing temperature to give /J-hydroxyesters of formula 4; dehydrating the ft-hydroxyesters of formula 4 using a catalytic amount of/»-TSA in an aprotic organic solvent in the temperature range of room temperature to refluxing temperature to give o;/?-unsaturated esters of formula 5; reducing the ester of formula 5 with LiAlI-Li in diethyl ether in the temperature range of -5°C to 0°C to give allylic alcohols of formula 6; photooxygenating the allylic alcohols of formula 6 in the presence of a sensitizer in an organic solvent in the temperature ranging from -10°C to room temperature to give /?-hydroxyhydroperoxides of formula 7; reacting /?-hydroxyhydroperoxide of formula 7 in situ with ketones of formula 9 wherein RI and R2 represents, methyl, the part of cyclic system such as cyclopentane, cyclohexane or adamantane in the presence of an acid catalyst in an aprotic organic solvent in the temperature range of 0°C to room temperature, followed by isolation and purification by known methods to furnish the trioxanes of general formula 8, wherein X is OCH2CH2OH, RI, RZ have the same meaning as above, reacting trioxanes of formula 8 (X = OCH2CH2OH) with succinic anhydride and triethylamine in the presence of catalytic DMAP in dichloromethane to furnish their hemisuccinates of formula 8 (X = OCH2CH2OCOCH2CH2COOH). In the process of aryl methyl ketones 1 are reacted with 1- adamantanol in the presence of acid catalysts such as H2SO4, H3PO4,/?-TSA and Amberlyst-15 in organic solvents such as benzene, THF and acetic acid to give adamantyl substituted aryl methyl ketones of formula 2. These adamantyl substituted aryl methyl ketones can be isolated and purified by the standard laboratory methods such as column chromatography or crystallization. Adamantyl substituted aryl methyl ketones of formula 2 are new compounds and these have not been prepared earlier. In the process of adamantyl substituted aryl methyl ketones of formula 2 are reacted with ethyl chlproacetate in the presence of anhydrous K2CO3 in an aprotic organic solvent like acetone in the temperature range of room temperature to refluxing temperature to give adamantyl substituted esters of formula 3. These adamantyl substituted esters of formula 3 can be isolated and purified by the standard laboratory methods such as column chromatography or crystallization. Adamantyl substituted esters of formula 3 are new compounds and these have not been prepared earlier. In the process of adamantyl substituted esters of formula 3 are reacted with ethyl 2-bromoacetate, and Zn in the presence of catalytic amount of I2 in an aprotic organic solvent such as benzene to give /3-hydroxyesters of formula 4. These /?-hydroxyesters of formula 4 can be isolated and purified by standard laboratory procedure such as column chromatography or can be used without further purification in the next step. /5-Hydroxy esters of formula 4 are new compounds and these have not been prepared earlier. In the process dehydration of yS-hydroxy esters of formula 4 is effected in aprotic organic solvent such as benzene in the presence of an acid catalyst such asp-TSA to give o;/?-unsaturated esters of formula 5. These unsaturated esters of formula 5 can be isolated and purified by the standard procedure such as column chromatography using silica gel as an adsorbent or by crystallization in suitable solvent. The o;/?-unsaturated esters of formula 5 are new compounds and have not been prepared earlier. In the process reduction of o;/?-unsaturated esters of formula 5 is effected with LiAlH4 in an ether solvent such as diethyl ether to furnish allylic alcohol of formula 6. These allyl alcohols can be isolated and purified by standard laboratory procedures such as crystallization or column chromatography on silica gel. The allylic alcohols of formula 6 are new compounds and have not been prepared earlier. In the process of photooxygenation of allylic alcohols of formula 6 is effected by passing oxygen gas in the solution of the alcohol in an organic solvent such as THF, CHC13, CH3CN and in the presence of a sensitizer dye such as methylene blue and a light source which provides visible light to furnish /3-hydroxyhydroperoxides of formula 7 which are used in the next step without further purification. The dye that acts as sensitizer converts 3O2 to highly reactive 'O2. In the process >S-hydroxyhydroperoxides of formula 7 are reacted in situ with ketones of formula 9 in an aprotic solvent in the presence of an acid catalyst such as HC1 to furnish trioxanes of formula 8 wherein X is OCH2CH2OH. The ketones can be selected from acetone, cyclopentanone, cyclohexanone or tricyclic ketones such as 2-adamantanone and the like. These trioxanes of formula 8 can be purified by the standard laboratory procedures such as column chromatography and crystallization. The trioxanes of formula 8 (X = OCH2CH2OH) are the new chemical entities and these have not been prepared earlier. In the process for preparing hemisuccinate derivatives of formula 8 (X = OCH2CH2OCOCH2CH2COOH) by reacting trioxanes of formula 8 (X = OCH2CH2OH) with succinic anhydride and triethylamine in the presence of catalytic DMAP in dichloromethane. These hen .isuccinate derivatives can be purified by the standard laboratory procedures such as column chromatography and crystallization. The hemisuccinate derivatives of formula 8 (X = OCH2CH2OCOCH2CH2COOH) are the new chemical entities and these have not been prepared earlier. (Scheme-1). Some of these trioxanes have been tested against malarial parasite in mice and show promising antimalarial activity. The present invention is further illustrated by the following examples, which however should not be construed to limit the scope of the present invention. EXAMPLE-1 l-(3-Adamantan-l-yl-4-hydroxy-phenyI)-ethanone (2a) To a solution of p-hydro\y acetophenone la (10 g) and 1-adamantanol (10 g) in Acetic acid (100 mL) was added coned. H2SO4 (15 mL) dropwise and stirred for two days at room temperature. Reaction mixture was poured into ice-cooled water (300 mL) and extracted with ethyl acetate (3 x 100 mL). Combined organic layer was washed with water followed by saturated sodium bicarbonate solution and brine solution Dried over anhydrous Na2SO4 and concentrated. Crude product was isolated and purified by column chromatography on silica gel using a mixture of ethyl acetate and hexane as eluant to furnish 2a (10.12 g, 51% yield). Aryl methyl ketone la was also reacted with 1-adamantanol in the presence of other acid catalysts such as H3PO4, p-TSA and Amberlyst-15 in an organic solvents such as acetic acid, benzene and THF to give adamantyl substituted aryl methyl ketones of formula 2 in 50-72% yields. (Results are summarized in Table 1) Table 1. (Table Removed) (4-Acetyl-2-adamantan-l-yl-phenoxy)-acetic acid ethyl ester (3a) A solution of 2a (5 g), ethyl chloro acetate (3.38 g) and anhydrous K2CO3 (3.85 g) in dry acetone (50 mL) was refluxed for 8 h. Reaction mixture was concentrated to 20 mL, diluted with water (100 mL) and extracted with ethyl acetate (3 x 50 mL). Combined organic was washed with saturated brine solution, dried over anhydrous Na2SC>4 and concentrated and the crude product was chromatographed on silica gel using ethyl acetate-hexane as eluant to furnish 3a (6 g, 91% yield). 3-(3-Adamantan-l-yl-4-ethoxycarbonylmethoxy-phenyl)-3-hydroxy-butyric acid ethyl ester (4a) To i refluxing mixture of adamantyl-substituted aryl methyl ketone 3a (3 g), and Zn (1.09 g) and I2 (10 mg) in benzene (100 mL), was added a solution of ethyl bromoacetate (2.1 g) in benzene (30 mL) dropwise over 20 min. The reaction mixture was refluxed for 4 h and then cooled to room temperature with stirring. It was acidified with 10% HC1 (50 mL), benzene layer was separated out. The organic phase was washed with water, dried over anhydrous Na2SC»4 and concentrated. The crude product was purified by chromatography using silica gel as adsorbent and ethyl acetate-hexane mixture as eluant to give 4a (3 g, 80% yield). 3-(3-Adamantan-l-yl-4-ethoxycarbonylmethoxy-phenyl)-but-2-enoic acid ethyl ester (5a) A solution of 4a (3 g) in benzene (75 mL) and /^-toluene sulphonic acid (240 mg) was refluxed for 2 h. Solvent was distilled off and again refluxed the reaction mixture in dried benzene (75 mL), repeated the procedure twice. Reaction mixture was quenched with saturated NaHCO3 (15 mL) and benzene layer was separated, organic phase was washed with water, dried over anhydrous Na2SO4 and concentrated and the crude product was purified by chromatography using silica gel as adsorbent and a mixture of ethyl acetate-hexane mixture as eluant to give 5a (2.5 g, 87% yield). 3-[3-Adamantan-l-yl-4-(2-hydroxy-ethoxy)-phenyl]-but-2-en-l-ol(6a) To an ice cooled slurry of LiAIRt (500 mg.) in dry ether (50 mL) was added a solution of 5a (2.8 g) in dry ether (30 mL) dropwise over 15 min and stirred for 1 h at 0°C. The reaction mixture was quenched with water (20 mL) and added a solution of 10% NaOH (5 mL), ether layer was decanted. The precipitate was washed with ether (2 x 30 mL), combined ether extracts were concentrated and the crude product was purified by crystallization with dichloromethane-acetone to give 6a (1.9 g, 85% yield). 2-{2-Adamantan-l-yl-4-[l-(6,7,10-trioxa-spiro[4.5]dec-8-yl)-vinyl]-phenoxy}-ethanol (Compound 8aa-a, Formula 8aa) Compound 6a (1 g) and methylene blue (5 mg) was taken in a mixture of THF (25 mL) and CHsCN (25 mL) and photooxygenated at 0°C for 4 h to give a compound 7a (as shown by TLC). Cyclopentanone (0.25 g) and coned. HC1 (0.4 mL) was added to the reaction mixture and stirred for 2 h at room temp. Reaction mixture was concentrated and the crude product was purified by column chromatography using silica gel as adsorbent and a mixture of ethyl acetate as eluant to furnish trioxane 8aa-a (210 mg, 33% yield based on allylic alcohol used), mp 120°C. Succinic acid mono-(2-{2-adamantan-l-yl-4-[l-(6,7,10-trioxa-spiro[4.5]dec-8-yl)-vinyl]- phenoxyj-ethyl) (Compound 8ab-a, Formula Sab) A solution of 8aa-a (100 mg), Et3N (0.07 mL, 3 eq), succinic anhydride (68 mg, 3 eq) and DMAP (2 mg) in DCM (20 mL) was stirred for 1 h. Reaction mixture was quenched by adding 10% HCI solution and extracted with DCM (2 x 25 mL). Solvent was evaporated and the crude product was purified by the column chromatography using a mixture of methanol-chloroform as eluant to furnish 8ab-a (oil, 100 mg, 82% yield). EXAMPLE-2 Following the same procedure as for trioxane 8aa-a and 8ab-a, compounds 8aa-b 8aa-c, 8aa-d, Sab-fa, 8ab-c and 8ab-d were prepared. 2-{2-Adamantan-l-yI-4-[l-(l,2,5-trioxa-spiro[5.5]undec-3-yl)-vinyIJ-phenoxy}-ethanol (Compound 8aa-b, Formula 8aa) Allylic alcohol 6a (500 mg) and methylene blue (5 mg) was taken in a mixture of THF (25 mL) and ACN (25 mL) and photooxygenated at 0°C for 4 h to give compound 7a, which was reacted in situ witn cyclohexanone (290 mg) in the presence of coned. HC1 (0.2 mL) room temp. The reaction mixture was concentrated and the crude product was purified by column chromatography to furnish trioxane 8aa-b (250 mg, 38% yield based on allylic alcohol used) as white solid, mp 132°C. Trioxane 8aa-c, Formula 8aa Allylic alcohol 6a (500 mg) and methylene blue (5 mg) was taken in a mixture of THF (25 mL) and ACN (25 mL) and photooxygenated at 0°C for 4 h to give a compound 7a, which was condensed in situ 2-admantanone (440 mg) in the presence of coned. HC1 (0.5 mL) at room temp. The reaction mixture was concentrated and crude product was purified by column chromatography on silica gel to furnish 8aa-c 200 mg (27% yield based on allylic alcohol used) as white solid, mp 126°C. 2-{2-Adamantan-l-yl-4-[l-(3,3-dimethyl-[l,2,4]trioxan-6-yl)-vinyl]-phenoxy}-ethanol (Compound 8aa-d, Formula 8aa) Allylic alcohol 6a (500 mg) and methylene blue (5 mg) was taken in a mixture of THF (25 ml) and ACN (25 mL) and 30 ml acetone and photooxygenated at 0°C for 4 h to give a compound 7a, To the reaction mixture was added coned. HC1 (0.3 mL) and stirred for 2 h at room temp. Reaction mixture was concentrated and the crude product was purified by column chromatography on silica gel to furnish 8aa-d 200 mg (oil, 27% yield based on allylic alcohol used). Succinic acid mono-(2-{2-adamantan-l-yl-4-\|l-(l,2,5-trioxa-spiro[5.5]undec-3-yl)-vinyl\|-phenoxy}-ethyl) (Compound 8ab-b, Formula Sab) A solution of 8aa-b (100 mg), Et3N (0.07 mL, 3 eq), succinic anhydride (68 mg, 3 eq) and DMAP (2 mg) in DCM (20 mL) was stirred for 1 h. Reaction mixture was quenched by adding 10% HC1 solution and extracted with DCM (2 x 25 mL). Solvent was evaporated and crude product was isolated and purified by the column chromatography on silica gel using a mixture of methanol- chloroform as eluant to furnish 8ab-b (oil, 100 mg, 82% yield). Trioxane 8ab-c, Formula Sab A solution of 8aa-c (100 mg), Et3N (0.06 mL, 3 eq), succinic anhydride (60 mg, 3 eq) and DMAP (2 mg) in DCM (20 mL) was stirred for 1 h. Reaction mixture was quenched by adding 10% HC1 solution and extracted with DCM (3 x 25 mL). Solvent was evaporated and crude product was isolated and purified by the column chromatography on silica gel using a mixture of methanol- chloroform as eluant to furnish 8ab-c (oil, 100 mg, 84% yield). Succinic acid mono-(2-{2-adamantan-l-yI-4-[l-(33-dimethyl-[l,2,4]trioxan-6-yl)-vinyl]- phenoxy}-ethyl) ester (Compound 8ab-d, Formula Sab) A solution of 8aa-d (100 mg), Et3N (0.08 mL, 3 eq), succinic anhydride (73 mg, 3 eq) and DMAP (2 mg) in DCM (20 mL) was stirred for 1 h. Reaction mixture was quenched by adding 10% HCI solution and extracted with DCM (3 x 25 mL). Solvent was evaporated and crude product was isolated and purified by the column chromatography on silica gel using a mixture of methanol- chloroform as eluant to furnish 8ab-d (oil, 100 mg, 81% yield). EXAMPLE -3 l-(2-adamantan-yl-3-hydroxy-phenyl)-ethanone (2b) To a solution of w-hydroxy acetophenone Ib (10 g) and 1-adamantanol (10 g) in acetic acid (100 mL) was added coned. H2SO4 (15 mL) dropwise and stirred for two days at rt. Reaction mixture was poured into ice-cooled water (300 mL) and extracted with ethyl acetate (3 x 100 mL). Combined organic layer was washed with water followed by saturated sodium bicarbonate solution and brine solution Dried over anhydrous Na2SO4 and concentrated, and the crude product was purified by column chromatography on silica gel using a mixture of ethyl acetate-hexane as eluant to furnish 2b (6 g, 30% yield). (3-Acetyl-2-adamantan-l-yl-phenoxy)-acetic acid ethyl ester (3b) A solution of 2b (6 g), ethyl chloro acetate (5.4 g) and anhydrous K.2CO3 (12.26 g) in dry acetone (50 mD was refluxed for 8 h. Reaction mixture was concentrated to 20 ml, diluted with water (100 ml) and extracted with ethyl acetate (3 x 75 mL). Combined organic phase was washed with saturated brine solution, dried over anhydrous Na2SC>4 and concentrated; the crude product was chromatographed on silica gel using a mixture of ethyl acetate-hexane as eluant to furnish 3b. (6 g, 76% yield). 3-(2-adamantan-yl-3-ethoxycarbonymethoxy-phenyl)-3-hydroxy-butyric acid ethyl ester (4b) To a refluxing mixture of adamantyl-substituted aryl methyl ketone 3b (6 g), Zn (1.7 g) and la (10 mg) in benzene (100 mL) was added a solution of ethyl bromoacetate (3.5 g) in benzene (30 mL) dropwise over 20 min. The reaction mixture was refluxed for 4 h and acidified with 10% solution HC1 (50 mL) at room temperature, benzene layer was separated, and organic phase was washed with water, dried over anhydrous Na2SO4 and concentrated. The crude product was purified by chromatography using silica gel as an adsorbent and ethyl acetate-hexane mixture as eluant to give 4b 5.6 g (72% yield) 3-(l-adamantan-l-yI-3-ethoxycarbonylmethoxy-phenyl)-but-2-enoic acid ethyl ester (5b) A solution of 4b (5 g) andp-toluene sulphonic acid (560 mg) in benzene (100 mL) was refluxed for 2 h. Benzene was distilled off and again refluxed the reaction mixture in dried benzene (75 mL) for 1 h, repeated the procedure twice. Reaction mixture was quenched with saturated NaHCOa (15 mL), and benzene layer was separated. Organic phase was washed with water and dried over anhydrous Na2SO4 and concentrated, and the crude product was purified by chromatography using silica gel as adsorbent and ethyl acetate-hexane mixture as eluant to give 5b (3.53 g, 74% yield). 3-[2-adamantan-yl-3-(2-hydroxy-ethoxy)-phenyl]-but-2-en-l-ol (6b) To an ice cooled slurry of LiAlH4 (800 mg) in dry ether (50 mL) was added a solution of 5b (3.53 g) in dry ether (100 mL) dropwise over 15 min. The mixture was stirred for 1 h at this temperature, reaction mixture was quenched with water (20 mL) and a solution of 10% NaOH (10 mL) was added; ether layer was decanted. The precipitate was washed with ether (3 x 50 mL), combined ether extracts were concentrated, the crude product was purified by crystallization with dichloromethane-acetone to give 6b (2.5 g, 89% yields). 2-{2-Adamantan-l-yI-5-[l-(6,7,10-trioxa-spiro[4.5]dec-8-yl)-vinyl]-phenoxy}-ethanol (Compound 8ba-a, Formula 8ba) A solution of 6b (1 g) and methylene blue (10 mg) in THF-ACN (50:50, 100 mL) was photooxygenated at 0°C for 4 h to furnish /0-hydroxyhydroperoxide 7b (as shown by TLC) was not isolated but reacted in situ with cyclopentanone (740 mg) in the presence of coned. HC1 (0.4 mL) at it. The reaction mixture was concentrated and crude product was purified by column chromatography on silica gel to furnish trioxane 8ba-a (300 mg, 23% yield based on allylic alcohol used), mp 110°C. Succinic acid mono-(2-{2-adamantan-l-yl-5-[l-(6,7,10-trioxa-spiro[4.5]dec-8-yl)-vinyl]-phenoxyj-ethyl) ester (Compound 8bb-a, Formula 8bb) A sjlution of 8ba-a (200 mg), Et3N (0.14 mL, 3 eq), succinic anhydride (136 mg, 3 eq) and DMAP (2 mg) in DCM (20 mL) was stirred for 1 h. Reaction mixture was quenched by adding 10% HCI solution (10 mL) and extracted with DCM (2 x 25 mL). Solvent was evaporated and crude product was isolated and purified by the column chromatography using methanol-chloroform mixture as eluant to furnish 8bb-a (oil, 190 mg, 77% yield). EXAMPLE-4 Following the same procedure as for trioxanes 8ba-a and 8bb-a, compounds 8ba-b, 8ba-c, 8bb-b and 8bb-c were prepared. 2-{2-Adamantan-l-yl-5-[l-(l,2,5-trioxa-spiro[5.5]undec-3-yl)-vinyl]-phenoxy}-ethanol (Compound 8ba-b, Formula ba) Allylic alcohol 6b (940 mg) and methylene blue (10 mg) in THF-ACN (50:50, 100 mL) was photooxygenated at 0°C for 4 h to furnish /?-hydroxyhydroperoxide 7b, which was reacted in situ with cyclohexanone (1.08 g) in the presence of coned. HC1 (0.4 mL) at rt. The reaction mixture was concentrated and crude product was purified by column chromatography on silica gel to furnish trioxane 8ba-b (400 mg, 32% yield based on allylic alcohol used), mp 115°C Trioxane 8ba-c, Formula 8ba Allylic alcohol 6b (450 mg) and methylene blue (5 mg) in THF-ACN (50:50, 50 mL) was photo oxygenated at 0°C for 4 h to furnish /?-hydroxyhydroperoxide 7b, which was reacted in situ with 2-admantanone (290 mg) in the presence of coned. HC1 (0.4 mL) at rt. The reaction mixture was concentrated and the crude product was purified by column chromatography on silica gel to furnish compound 8ba-c 180 mg (27% yield based on allylic alcohol used) mp 125°C. Succinic acid mono-(2-{2-adamantan-l-yl-5-[l-(l,2,5-trioxa-spiro[5.5]undec-3-yl)-vinyl]-phenoxy}-ethyl) ester (Compound 8bb-b, Formula 8bb) A solution of 8ba-b (300 mg), Et3N (0.2 mL, 3 eq), succinic anhydride (198 mg, 3 eq) and DMAP (2 mg) in DCM (20 mL) was stirred for 1 h. Reaction mixture was quenched by adding 10% HCI (20 mL) solution and extracted with DCM (3 x 25 mL). Solvent was evaporated and crude product was isolated and purified by the column chromatography using methanol-chloroform mixture as eluant to furnish 8bb-b (oil, 300 mg, 82% yield). Trioxane 8bb-c, Formula 8bb A solution of 8ba-c (200 mg), Et3N (0.123 mL, 3 eq), succinic anhydride (120 mg, 3 eq) and DMAP (2 mg) in DCM (20 mL) was stirred for 1 h. Reaction mixture was quenched by adding 10% HCI (10 mL) and extracted with DCM (3 x 20 mL). Solvent was evaporated and crude product was isolated and purified by the column chromatography using methanol-chloroform mixture as eluant to furnish 8bb-c (oil, 200 mg, 84% yield). Following the above procedure, following trioxanes were prepared. Table 2. (Table Removed)Compound No. 8ab-a, 8ab-b, 8ab-c, 8ab-d, 8bb-a, 8bb-b & 8bb-c which are hemisuccinates, can be converted into their corresponding Na/K-salts. Salts of compounds No 8ab-a, 8ab-b, 8ab-c, 8ab-d, 8bb-a, 8bb-b & 8bb-c may be prepared by dissolving compounds into CO3--/HCO3- solution. AatUMlarial activity: The antimalarial activity of the test compounds were evaluated in rodent using multi-drug resistant strain of Plasmodium yoelii nigeriensis in Swiss mice. Random bred Swiss mice of either sex (20 + 2 g) were inoculated intraperitoneally with 1 x 10s P. yoelii (MDR) parasites on day zero. The treatment with test compounds were administered to group of 5 mice at different dose levels ranging between 48-96 mg/kg/day. The treatment was administered via intramuscular route for 4 consecutive days (day 0-3). Blood smears from the experimental mice were observed on day 4, 7 and day 10, and thereafter at regular intervals till day 28 or death of the animal. The parasitaemia level on day 4 was compared with vehicle control group and the percent suppression of parasitaemia in treated groups was calculated. For determining the curative dose of a compound the treated mice were observed till day 28. The dose at which no parasitaemia develop during the observation period has been reported as the curative dose. The biological efficacy data is summarized in Table 3. Table 3. Antimalarial activity of trioxancs against P. yoelii in mice (Table Removed) In vivo test procedure: The colony of bred Swiss mice (25 ± Ig) were inoculated with 1 X 106 parasitized RBC on day zero and treatment was administered to a group of five mice at each dose, from day 0 to 3, in two divided doses daily. The drug dilutions of compounds of general formula 8 were prepared in groundnut oil so as to contain the required amount of the compound (1.2 mg for a dose of 96 mg/kg, 0.6 mg for a dose of 48 mg/kg) in 0.1 ml and administered orally/intramuscularly for each dose. Parasitaemia level were recorded from thin blood smears between day 4-28. The trea ed mice surviving beyond day 28 were recorded as the mice protected by the drug. Mice treated with y9-Arteether served as positive controls. Compound 8ab-c was found to be most active with 100% suppression at 48 mg/kg on day 4 and 20% of the treated mice survived on day 28. Activity data of all the trioxanes are summarized in Table 3. Scheme 1. (Scheme Removed) X = OCH2CH2OH X = OCH2CH2OCOCH2CH2COOH Reagents and conditions: a. 1-adamantanol, coned. H2SO4, Acetic acid, rt, 2 days; b. ClCH2COOEt, K2CO3, Acetone, reflux, 8 h; c. BrCH2COOEt, Zn, I2, Benzene, reflux, 8 h; d.p-TSA, Benzene, reflux, 4-7 h; i. LiAlH4, dry ether, 0°C, 2 h; f. '02, MB, hv, 0°C, rt, 5 h; g. ketone, conc.HCl, rt, 4-5 h; h. succinic anhydride, triethyl amine, DMAP (cat), CH2C12, rt, 0.5 h We claim 1. A compound [2-adamantyl-4-halo phenyl]-6-ethyl-3-dialkyl-l,2,4-trioxane of general formula 8 (Formula Removed) wherein X is selected from OCH2CH2OH, OCH2CH2OCOCH2CH2COOH and R1 & R2 represents alkyl group such as methyl or a part of cyclic system selected from cyclopentane, cyclohexane or adamantane, and their derivatives or salts thereof. 2. The compound as claimed in claim 1 wherein the said compound 8 having structural formula 8aa-a, 8aa-b and 8aa-d as shown below: (Formula Removed) 3. The compound as claimed in claim 1 wherein the said compound 8 having structural formula 8aa-c as shown below: (Formula Removed) 4. The compound as claimed in claim 1 wherein the said compound 8 having structural formula 8ba-a, 8ba-b as shown below: (Formula Removed) 5. The compound as claimed in claim 1 wherein the said compound 8 having structural formula 8ba-c as shown below: (Formula Removed) 6. The compound as claimed in claim 1 wherein the said compound 8 having structural formula 8ab-a, 8ab-b and 8ab-d shown below: (Formula Removed) 7. The compound as claimed in claim 1 wherein the said compound 8 having structural formula 8ab-c shown below: (Formula Removed) 8. The compound as claimed in claim 1 wherein the said compound 8 having structural formula 8bb-a and 8bb-b as shown below: (Formula Removed) 9. The compound as claimed in claim 1 wherein the said compound 8 having structural formula 8bb-c as shown below: (Formula Removed) 10. The compound as claimed in claim 1 wherein the salt of compound 8 is selected from sodium or potassium. 11. A process for the preparation of novel substituted 1,2,4-trioxanes of general formula 8, (Formula Removed) wherein X is selected from OCH2CH2OH, OCH2CH2OCOCH2CH2COOH and R1 & R2 represents alkyl group such as methyl or a part of cyclic system selected from cyclopentane, cyclohexane or adamantane which comprises: (i) reacting aryl methyl ketones of formula 1 with 1-adamantanol in the presence of an acid catalyst in an organic solvent at a temperature ranging between room temperature to refluxing to give adamantyl substituted aryl methyl ketones of formula 2; (Formula Removed) (ii) reacting aryl methyl ketones of formula 2 with ethyl chloroacetate in the presence of anhydrous K2CO3 in an aprotic organic solvent in the temperature range of room temperature to refluxing temperature to give esters of formula 3; (Formula Removed) (iii) reacting esters of formula 3 with ethyl bromoacetate and Zn in the presence of catalytic amount of I2 in an aprotic organic solvent in the temperature range of room temperature to refluxing temperature to give ß-hydroxyesters of formula 4; (Formula Removed) (iv) dehydrating the ß-hydroxyesters of formula 4 using a catalytic amount of p-TSA in an aprotic organic solvent at a temperature ranging between room temperature to refluxing temperature to give α,ß-unsaturated esters of formula 5; (Formula Removed) (v) reducing the esters of formula 5 with LiAlH4 in diethyl ether at a temperature ranging between -5°C to 0°C to give allylic alcohols of formula 6; (Formula Removed) (vi) photooxygenating the allylic alcohols of formula 6 in the presence of a sensitizer in an organic solvent at a temperature ranging between -10°C to room temperature to give ß-hydroxyhydroperoxides of formula 7; (Formula Removed) (vii) reacting ß-hydroxyhydroperoxide of formula 7 in situ with ketone compounds of formula 9 wherein R1 and R2 represents, methyl, the part of cyclic system such as cyclopentane, cyclohexane or adamantane in the presence of an acid catalyst in an aprotic organic solvent in the temperature range of 0°C to room temperature, followed by isolation and purification by known methods to furnish the trioxanes of general formula 8, wherein X is OCH2CH2OH, Rb R2 have the same meaning as above; (Formula Removed) (viii) reacting trioxanes of formula 8 (X = OCH2CH2OH) with succinic anhydride and triethylamine in presence of catalytic amount of dimethylaminopyridine (DMAP) in a low boiling chlorinated solvent to furnish their hemisuccinates of formula 8 (X = OCH2CH2OCOCH2CH2COOH) and Rh R2 represents, methyl, the part of cyclic system such as cyclopentane, cyclohexane or adamantane, (Formula Removed) 12. The process as claimed in 11 wherein the acid catalyst in step (i) is selected from H2SO4, H3PO4 and amberlyst-15. 13. The process as claimed in 11 wherein the organic solvent in step (i) is selected from CH3COOH, C6H6, THF. 14. The process as claimed in claim 11 wherein adamantyl substituted m/p-hydroxyl acetophenone of formula 2 is prepared by reacting aryl methyl ketone of formula 1 with 1- admantanol in acetic acid in the presence of coned. H2SO4, or in acetic acid in the presence of H3PO4, or in acetic acid in the presence of amberlyst-15 , or in benzene in the presence of amberlyst-15 , or in THF in the presence of amberlyst-15. 15. The process as claimed in claim 11 wherein adamantyl substituted esters of formula 3 are prepared by reacting adamantyl substituted m/p-hydroxy acetophenone of formula 2 with ethyl 2-chloroacetate and K2CO3 in acetone. 16. The process as claimed in claim 11 wherein ß-hydroxyesters of formula 4 are prepared by reacting adamantyl substituted esters of formula 3 with ethyl 2-bromoacetate and Zn in the presence of catalytic amount of I2 in an aprotic solvent such as benzene. 17. The process as claimed in claim 11 wherein α,ß-unsaturated esters of formula 5 are prepared by dehydrating ß-hydroxyesters of formula 4 using catalytic amount of p-TSA in an aprotic organic solvent like benzene. 18. The process as claimed in claim 11 wherein the allylic alcohols of formula 6 are prepared by reducing α,ß-unsaturated esters of formula 5 in ethereal solvent like diethyl ether. 19. The process as claimed in claim 11 wherein the organic solvent used in step (vi) and (viii) is selected from the group consisting of CHC13, THF, CH3CN. 20. The process as claimed in claim 11 in step (viii) wherein adamantyl substituted hydroxy functionalized 1,2,4-trioxanes of formula 8 are prepared by reacting ß- hydroxyhydroperoxides of formula 7 with a ketone in the presence of an acid catalyst. 21. The process as claimed in claim 11 for the preparation of hemisuccinate derivatives of general formula 8 (X = OCH2CH2OCOCH2CH2COOH) by reacting 1,2,4-trioxanes of general formula 8 (X = OCH2CH2OH) with succinic anhydride and triethyl amine in the presence of catalytic DMAP in dichloromethane at a temperature ranging between 0°C to room temperature.

Full Text

Field of invention
The present invention relates to novel hydroxy functionalized adamantyl substituted 6-arylvinyl-1,2,4-trioxanes the present invention particularly relates to a novel series of antimalarial 1,2,4-trioxanes analogues of general formula 8

(Formula Removed)
wherein X represents the groups like OCH2CH2OH, OC2CH2OCOCH2CH2COOH whereas R1 and R2 represents the alkyl group selected from methyl or part of a cyclic systems such as cyclopentane, cyclohexane and adamantane and the preparation thereof; several of these novel compounds show promising antimalarial activity against multi-drug resistant malaria in mice.
BACKGROUND OF INVENTION
Malaria, endemic in many parts of the tropical countries, with approximately 300-500 million
episodes of clinical infection and nearly 2 million deaths per year worldwide, is a serious health problem. The rapid emergence of resistance by Plasmodium falciparum to existing therapies has added new dimensions to this problem. Against this background discovery of artemisinin, a sesquiterpene lactone Endoperoxide, isolated from the Chinese traditional herbal remedy against malaria, Artemisia annua, has been a welcome development in the chemotherapy of malaria. Some of the semisynthetic derivatives of artemisinin e.g. artemether, arteether and artesunic acid are more active than artemisinin and are currently being used clinically. These drugs are effective against both cholroquin sensitive and chloroquine resistant strains of Plasmodium falciparum. [For background literature on artemisinin and its derivatives see: (a) Klayman, D. L Science 1985, 225, 1049. (b) Zaman, s. s.; Sharma, R.P. Heterocycles 1991,32,1593. (c) Jung, M. Curr. Med. Chem. 1994, 1, 35. (d) /efford, C. W. Advances in drug research; vol. 29, p 272. (e) Avery, M. A. Curr. Pharm. Design. 1995, 5, 101. (f) Bhattacharya, A. K.; Sharma, R. P. Heterocycles 1999, 51, 1651. (g) Borstnik, K.;
Paik, I.; Shapiro, T. A.; Posner, G. H. Int. J. Parasitol. 2002, 32, 1661. (h) Ploypradith, P. Ada Trap. 2004, 89, 329. (i) O'Neill, P. M.; Posner, G. H. J. Med. Chem. 2004, 47, 2945]
(Formula Removed)
The limited availability of artemisinin from natural sources and the realization that 1,2,4-trioxane
is the pharmacophore for the antimalarial activity of artemisinin and its analogues, has inspired major
efforts towards the preparation and bioevaluation of structurally simple synthetic 1,2,4-trioxanes. As
a result of these efforts, a number of methodologies have been developed by various workers for the
preparation of 1,2,4-trioxanes . Several of these synthetic trioxanes
have shown promising antimalarial activities both in vitro and in vivo [(a) Peters, W.; Robinson, B. L.; Tovey, G.; Rossier, J. C.; Jefford, C. W. Ann. Trap. Med. Parasitol. 1993, 87, 1-7. (b) Peters, W.; Robinson, B. L.; Rossier, J. C.; Jefford, C. W. Ann. Trap. Med. Parasitol. 1993, 87, 9-16. (c) Peters, W.; Robinson, B. L.; Tovey, G.; Rossier, J. C.; Jefford, C. W. Ann. Trop. Med. Parasitol. 1993, 87, 111-123. (d) Kepler, J. A.; Philip, A.; Lee, Y. W.; Matthew C. Morey, M. C.; and F. Ivy Carroll, F. I. J. Med Chem. 1988, 31, 713-716. (e) Posner, G. H.; Maxwell, J. P.; O'Dowd, H.; Krasavin, M.; Xie, S.; Shapiro, T. A. Bioorg. Med. Chem. 2000, 8, 1361-1370. (0 Posner, G. H.; Jeon, H. B.; Parker, M. H.; Krasavin, M.; Paik, I.-K; Shapiro, T. A. J. Med Chem. 2001, 44, 3054-3058. (g) Posner, G. H.; Jeon, H. B.; Polypradith, P.; Paik, I.-H.; Borstnik, K.; Xie, S.; Shapiro, T. A. J. Med. Chem. 2002, 45, 3824-3828. (h) Griesbeck, A. G.; El-Idreesy, T. T.; Fiege, M.; Brun, R Org. Lett. 2002, 24, 4193-4195. (i) O'Neill, P. M.; Mukhtar, A.; Ward, S. A.; Bickley, J. F.; Davies, J.; Bachi, M. D.; Stocks, P. A. Org. Lett. 2004,75,3035-3038.]
Singh et al have prepared 1,2,4-trioxanes by regiospecific photooxygenation of allylic
alcohols to furnish hydroperoxide, which on condensation with aldehydes or ketones in the
presence of an acid catalyst furnish 1,2,4-trioxane [(a) Singh, C. Tetrahedron Lett. 1990, 31, 901-6902. (b) Singh, C.; Gupta, N.; Puri, S. K. Tetrahedron Lett. 2005, 39, 405. (c) Singh, C.; Misra, D.; Saxena, G.; Chandra, S. Bioorg. & Med. Chem. Lett. 1992, 2, 497-500. (d) Singh, C.; Misra, D.; Saxena, G.; Chandra, S. Bioorg. & Med. Chem. Lett. 1995, 5, 1913-1916. (e) Singh, C.; Gupta, N.; Puri, S. K. Bioorg. & Med. Chem. 2004, 12, 5553-5562. (f) Singh, C.; Srivastav, N. C.; Puri, S. K.; Bioorg. & Med. Chem. 2004, 12, 5745-5752. (g) Singh, C.; Gupta, N.; Puri, S. K. Bioorg. & Med. Chem. Lett. 2003, 13, 3447-3450. (h) Singh, C.; Malik, H.; Puri, S. K.. Bioorg. & Med. Chem. 2004, 12, 1177-1182. (i). Singh, C.; Malik, H.; Puri, S. Kioorg. & Med. Chem.Lett. 2005, 15, 4484-4487. (k) Singh, C.; Malik, H.; Puri, S. K... Bioorg. & Med. Chem.Lett. 2004, 14, 459-462. (j) Singh, C.; Malik, H.; Puri, S. K.. B. J. Med. Chem. 2006, 49, 2794-2803. Object of the Invention
The main object of the present invention is to provide novel hydroxy functionalized adamantyl substituted 6-arylvinyl-1,2,4-trioxanes.
Another object of the present invention is to provide the composition for the treatment of
malaria.
Further object of the present invention is to provide the composition effect given for the
treatment of multi drug resistance malaria.
Another object of the present invention is to provide the composition effective up to 100%
suppression of parasitaemia
Accordingly, the present invention is provides a novel substituted 1,2,4-trioxanes of general
formula 8
(Formula Removed)
wherein X is selected from OCH2CH2OH, OCH2CH2OCOCH2CH2COOH and RI & R2 represents alkyl group such as methyl or a part of cyclic system selected from cyclopentane, cyclohexane or adamantane and their hemisuccinate derivatives, or salts thereof.
In an embodiment of the present invention, the said compound 8 having structural formula 8aa-a, 8aa-b and 8aa-d as shown below:
(Formula Removed)
8aa
8aa-a : R,, R2 = -CH2CH2CH2CH2-8aa-b : R,, R2 = -CH2CH2CH2CH2CH2-
8aa-d : R, = R2 = methyl
In another embodiment of the present invention, the said compound 8 having structural formula 8aa-c as shown below:
(Formula Removed)
8aa-c
In yet another embodiment of the present invention, the said compound 8 having structural formula 8ba-a, 8ba-b as shown below:
(Formula Removed)
8ba 8ba-a : R,, R2 = -CH2CH2CH2CH2-
8ba-b : RI, R2 = -CH2CH2CH2CH2CH2-
One more embodiment of the present invention, the said compound 8 having structural formula 8ba-c as shown below:

(Formula Removed)
8ba-c
Further embodiment of the present invention, Novel substituted 1,2,4-trioxanes as claimed in claim 1 wherein the said compound 8 having structural formula 8ab-a, 8ab-b and 8ab-d shown below:

(Formula Removed)
8ab
8ab-a : R,, R2 = -CH2CH2CH2CH2-8ab-b : R,, R2 = -CH2CH2CH2CH2CH2-
8ab-d : RI = R2 = methyl
One of the embodiments of the present invention, the said compound 8 having structural formula 8ab-c shown below:

(Formula Removed)
8ab-c
Other embodiment of the present invention, the said compound 8 having structural formula 8bb-a and 8bb-b as shown below:
(Formula Removed)
8bb
8bb-a : R,, R2 = -CH2CH2CH2CH2-8bb-b : R,, R2 = -CH2CH2CH2CH2CH2-
Further embodiment of the present invention, the said compound 8 having structural formula 8bb-c as shown below:
(Formula Removed)
8bb-c
In another embodiment of the present invention, the salt of compound 8 (X is OCH2CH2OCOCH2CH2COOH) may be selected from sodium or potassium.
The compound of general formula 8 and their hemisuccinate derivatives or salts thereof are useful for the treatment of malaria.
The dose of the compound 8 may be ranging between 48 to 96 mg/kg body weight.
One more embodiment of the present invention, the compound may be administered through oral or intramuscular route.
Accordingly, the present invention provides a process for the preparation of novel substituted 1,2,4-trioxanes of general formula 8,

(Formula Removed)
Wherein X is selected from OCH2CH2OH, OCfyCfyOCOCfyC^COOH and R, & R2 represents alkyl group such as methyl or a part of cyclic system selected from cyclopentane, cyclohexane or adamantane which comprises:
(i) reacting aryl methyl ketones of formula 1 with 1-adamantanol in the presence of an acid catalyst in an organic solvent at a temperature ranging between room temperature to refluxing to give adamantyl substituted aryl methyl ketones of formula 2;
(Formula Removed)
(ii) reacting aryl methyl ketones of formula 2 with ethyl chloroacetate in the presence of anhydrous KjCOa in an aprotic organic solvent in the temperature range of room temperature to refluxing
temperature to give esters of formula 3;
(Formula Removed)
(iii) reacting esters of formula 3 with ethyl bromoacetate and Zn in the presence of catalytic amount of I2 in an aprotic organic solvent in the temperature range of room temperature to refluxing temperature to give /2-hydroxyesters of formula 4;
(Formula Removed)
(iv) dehydrating the /?-hydroxyesters of formula 4 using a catalytic amount of/?-TSA in an aprotic organic solvent at a temperature ranging between room temperature to refluxing temperature to give or,/?-unsaturated esters of formula 5;
(FormulaRemoved)
(v) reducing the esters of formula 5 with LiAlHj in diethyl ether at a temperature ranging between -5°C to 0°C to give allylic alcohols of formula 6;

(Formula Removed)
(vi) photooxygenating the allylic alcohols of formula 6 in the presence of a sensitizer in an organic solvent at a temperature ranging between -10°C to room temperature to give ft-hydroxyhydroperoxides of formula 7;

(Formula Removed)
(vii) reacting >3-hydroxyhydroperoxide of formula 7 in situ with ketones of formula 9wherein RI and Ra represents, methyl, the part of cyclic system such as cyclopentane, cyclohexane or adamantane in the presence of an acid catalyst in an aprotic organic solvent in the temperature range of 3°C to room temperature, followed by isolation and purification by known methods to furnish the trioxanes of general formula 8, wherein X is OCHjCI^OH, RI, R2 have the same meaning as above;
(Formula Removed)
8
X = OCH2CH2OH
(viii) reacting trioxanes of formula 8 (X = OCfyCFkOH) with succinic anhydride and triethylamine in presence of catalytic amount of dimethylaminopyridine (DMAP) in a low boiling chlorinated solvent to furnish their hemisuccinates of formula 8 (X = OC^CfyOCOCHjCfyCOOH) and RI, R2 represents, methyl, the part of cyclic system such as cyclopentane, cyclohexane or adamantane,
(Formula Removed)
8
X = OCH2CH2OCOCH2CH2COOH
In another embodiment of the present invention, the acid catalyst in step (i) may be selected from
H2S04, H3PO4and amberlyst-15.
In yet another embodiment of the present invention, the organic solvent in step (i) is selected from
CH3COOH, CfiHe, THF.
In a further embodiment of the invention , wherein adamantyl substituted m/p-hydroxy] acetophenone
of formula 2 is prepared by reacting aryl methyl ketone of formula 1 with 1-admantanol in acetic acid
in the presence of coned. H2SO4, or in acetic acid in the presence of H3PO4, or in acetic acid in the
presence of amberlyst-15 , or in benzene in the presence of amberlyst-15 , or in THF in the presence
of amberlyst-15.
In an embodiment of the present invention, the adamantyl substituted esters of formula 3 are prepared
by reacting adamantyl substituted m/p-hydro\y acetophenone of formula 2 with ethyl 2-chloroacetate
and K.2CC>3 in acetone.
In another embodiment of the present invention, the /?-hydroxyesters of formula 4 are prepared by
reacting adamantyl substituted esters of formula 3 with ethyl 2-bromoacetate and Zn in the presence
of catalytic amount of I2 in an aprotic solvent such as benzene.
In yet another embodiment of the present invention, the o;/?-unsaturated esters of formula 5 are
prepared by dehydrating /2-hydroxyesters of formula 4 using catalytic amount of/?-TSA in an aprotic
organic solvent like benzene.
Other embodiment of the present invention, the allylic alcohols of formula 6 are prepared by reducing
o;/?-unsaturated esters of formula 5 in ethereal solvent like diethyl ether.
One more embodiment of the present invention, the organic solvent used in step (vi) and (viii) is
selected from the group consisting of CHCI3, THF, CHsCN.
Further embodiment of the present invention, the adamantyl substituted hydroxy functionalized 1,2,4-
trioxanes of formula 8 are prepared by reacting yS-hydroxyhydroperoxides of formula 7 with a ketone
in the presence of an acid catalyst.
One of the embodiments is the present invention, the preparation of hemisuccinate derivatives of
general formula 8 (X = OCH2CH2OCOCH2CH2COOH) by reacting 1,2,4-trioxanes of general
formula 8 (X = OCH2CH2OH) with succinic anhydride and triethyl amine in the presence of catalytic
DMAP in dichloromethane at a temperature ranging between 0°C to room temperature.
Accordingly the present invention provides a pharmaceutical composition comprising an effective
amount of the compound of formula 8
(Formula Removed)
wherein X is selected from OCH2CH2OH, OCH2CH2OCOCH2CH2COOH and RI & R2 represents
alkyl group such as methyl or a part of cyclic system selected from cyclopentane, cyclohexane or
adamantane, their derivatives, isomers or salts thereof, optionally along with pharmaceutically
acceptable diluents.
In an embodiment of the present invention, the compounds are administered through oral or
intramuscular routes.
In another embodiment of the present invention, the diluent is selected from the group consisting of
edible oils such as groundnut oil or aqueous bicarbonate solution.
In yet another embodiment of the present invention, the curative dose of the compound is ranging
between 48 to 96 mg/kg.
Further embodiment of the present invention, the suppression of parasitaemia is upto 100% on day 4
at 48 mg/kg with 20% survival of the treated mice at this dose by intramuscular route.
Accordingly the present invention provides a method of treating the subject suffering from malaria
con.prising; administering the effective amount of composition to the subject in need wherein the
composition comprises; an effective amount of the compound of formula 8,
(Formula Removed)
8
wherein X is selected from OCH2CH2OH, OCH2CH2OCOCH2CH2COOH and RI & R2 represents alkyl group such as methyl or a part of cyclic system selected from cyclopentane, cyclohexane or adamantane, their derivatives, isomers or salts thereof, along with pharmaceutically acceptable additives, carriers, diluents. Detailed Description
This invention relates to novel substituted 1,2,4-trioxanes. This invention also relates to a process for the preparation of novel substituted 1,2,4-trioxanes. This invention particularly relates to
a process for the preparation of adamantyl substituted 6-arylvinyl-1,2,4-trioxanes as a new series of antimalarial agents.
More particularly the present invention provides a process for the preparation of 1,2,4-trioxanes of general formula 8 wherein X represents the groups like OCHaCfyOH, OCH2CH2OCOCH2CH2COOH whereas RI and R2 represents the alkyl group selected from methyl or part of a cyclic systems such as cyclopentane, cyclohexane and adamantane. These trioxanes are new compounds and are useful as antimalarial agents. These compounds have been tested against multi-drug resistant malaria in mice and some of them have shown promising antimalarial activity. The invention, thus relates to pharmaceutical industry.
The trioxanes of general formula 8 are new chemical entities and these have not been prepared earl'er. The objective of the present invention is to provide a new series of 1,2,4-trioxanes and a process for the preparation of novel 1,2,4-trioxanes of general formula 8.
Accordingly, the present specification provides a process for the preparation of novel substituted 1, 2, 4-trioxanes of general formula 8.
(Formula Removed)
8
wherein X represents the groups like OCH2CH2OH, OCH2CH2OCOCH2CH2COOH and R,, R2 represent alkyl groups selected from methyl or a part of cyclic systems such as cyclopentane, cyclohexane, adamantane and the like, which comprises reacting aryl methyl ketones of formula 1, with 1 -adamantanol in the presence of an acid catalyst in an organic solvent in the temperature range of room temperature to refluxing to give adamantyl substituted aryl methyl ketones of formula 2; reacting aryl methyl ketones of formula 2 with ethyl chloroacetate in the presence of anhydrous K2CO3 in an aprotic organic solvent in the temperature range of room temperature to refluxing temperature to give esters of formula 3; reacting esters of formula 3 with ethyl bromoacetate and Zn
in the presence of catalytic amount of I2 in an aprotic organic solvent in the temperature range of
room temperature to refluxing temperature to give /J-hydroxyesters of formula 4; dehydrating the ft-hydroxyesters of formula 4 using a catalytic amount of/»-TSA in an aprotic organic solvent in the temperature range of room temperature to refluxing temperature to give o;/?-unsaturated esters of formula 5; reducing the ester of formula 5 with LiAlI-Li in diethyl ether in the temperature range of -5°C to 0°C to give allylic alcohols of formula 6; photooxygenating the allylic alcohols of formula 6 in the presence of a sensitizer in an organic solvent in the temperature ranging from -10°C to room temperature to give /?-hydroxyhydroperoxides of formula 7; reacting /?-hydroxyhydroperoxide of formula 7 in situ with ketones of formula 9 wherein RI and R2 represents, methyl, the part of cyclic system such as cyclopentane, cyclohexane or adamantane in the presence of an acid catalyst in an aprotic organic solvent in the temperature range of 0°C to room temperature, followed by isolation and purification by known methods to furnish the trioxanes of general formula 8, wherein X is OCH2CH2OH, RI, RZ have the same meaning as above, reacting trioxanes of formula 8 (X = OCH2CH2OH) with succinic anhydride and triethylamine in the presence of catalytic DMAP in dichloromethane to furnish their hemisuccinates of formula 8 (X = OCH2CH2OCOCH2CH2COOH).
In the process of aryl methyl ketones 1 are reacted with 1- adamantanol in the presence of acid catalysts such as H2SO4, H3PO4,/?-TSA and Amberlyst-15 in organic solvents such as benzene, THF and acetic acid to give adamantyl substituted aryl methyl ketones of formula 2. These adamantyl substituted aryl methyl ketones can be isolated and purified by the standard laboratory methods such as column chromatography or crystallization. Adamantyl substituted aryl methyl ketones of formula 2 are new compounds and these have not been prepared earlier.
In the process of adamantyl substituted aryl methyl ketones of formula 2 are reacted with ethyl chlproacetate in the presence of anhydrous K2CO3 in an aprotic organic solvent like acetone in the temperature range of room temperature to refluxing temperature to give adamantyl substituted esters of formula 3. These adamantyl substituted esters of formula 3 can be isolated and purified by the standard laboratory methods such as column chromatography or crystallization. Adamantyl substituted esters of formula 3 are new compounds and these have not been prepared earlier.
In the process of adamantyl substituted esters of formula 3 are reacted with ethyl 2-bromoacetate, and Zn in the presence of catalytic amount of I2 in an aprotic organic solvent such as benzene to give /3-hydroxyesters of formula 4. These /?-hydroxyesters of formula 4 can be isolated and purified by standard laboratory procedure such as column chromatography or can be used without further purification in the next step. /5-Hydroxy esters of formula 4 are new compounds and these have not been prepared earlier.
In the process dehydration of yS-hydroxy esters of formula 4 is effected in aprotic organic solvent such as benzene in the presence of an acid catalyst such asp-TSA to give o;/?-unsaturated esters of formula 5. These unsaturated esters of formula 5 can be isolated and purified by the standard procedure such as column chromatography using silica gel as an adsorbent or by crystallization in suitable solvent. The o;/?-unsaturated esters of formula 5 are new compounds and have not been prepared earlier.
In the process reduction of o;/?-unsaturated esters of formula 5 is effected with LiAlH4 in an ether solvent such as diethyl ether to furnish allylic alcohol of formula 6. These allyl alcohols can be isolated and purified by standard laboratory procedures such as crystallization or column chromatography on silica gel. The allylic alcohols of formula 6 are new compounds and have not been prepared earlier.
In the process of photooxygenation of allylic alcohols of formula 6 is effected by passing oxygen gas in the solution of the alcohol in an organic solvent such as THF, CHC13, CH3CN and in the presence of a sensitizer dye such as methylene blue and a light source which provides visible light to furnish /3-hydroxyhydroperoxides of formula 7 which are used in the next step without further purification. The dye that acts as sensitizer converts 3O2 to highly reactive 'O2.
In the process >S-hydroxyhydroperoxides of formula 7 are reacted in situ with ketones of formula 9 in an aprotic solvent in the presence of an acid catalyst such as HC1 to furnish trioxanes of formula 8 wherein X is OCH2CH2OH. The ketones can be selected from acetone, cyclopentanone, cyclohexanone or tricyclic ketones such as 2-adamantanone and the like. These trioxanes of formula
8 can be purified by the standard laboratory procedures such as column chromatography and crystallization. The trioxanes of formula 8 (X = OCH2CH2OH) are the new chemical entities and these have not been prepared earlier.
In the process for preparing hemisuccinate derivatives of formula 8 (X = OCH2CH2OCOCH2CH2COOH) by reacting trioxanes of formula 8 (X = OCH2CH2OH) with succinic anhydride and triethylamine in the presence of catalytic DMAP in dichloromethane. These hen .isuccinate derivatives can be purified by the standard laboratory procedures such as column chromatography and crystallization. The hemisuccinate derivatives of formula 8 (X = OCH2CH2OCOCH2CH2COOH) are the new chemical entities and these have not been prepared earlier. (Scheme-1).
Some of these trioxanes have been tested against malarial parasite in mice and show promising antimalarial activity.
The present invention is further illustrated by the following examples, which however should not be construed to limit the scope of the present invention.
EXAMPLE-1
l-(3-Adamantan-l-yl-4-hydroxy-phenyI)-ethanone (2a)
To a solution of p-hydro\y acetophenone la (10 g) and 1-adamantanol (10 g) in Acetic acid (100 mL) was added coned. H2SO4 (15 mL) dropwise and stirred for two days at room temperature. Reaction mixture was poured into ice-cooled water (300 mL) and extracted with ethyl acetate (3 x 100 mL). Combined organic layer was washed with water followed by saturated sodium bicarbonate solution and brine solution Dried over anhydrous Na2SO4 and concentrated. Crude product was isolated and purified by column chromatography on silica gel using a mixture of ethyl acetate and hexane as eluant to furnish 2a (10.12 g, 51% yield).
Aryl methyl ketone la was also reacted with 1-adamantanol in the presence of other acid catalysts such as H3PO4, p-TSA and Amberlyst-15 in an organic solvents such as acetic acid, benzene and
THF to give adamantyl substituted aryl methyl ketones of formula 2 in 50-72% yields. (Results are summarized in Table 1) Table 1.

(Table Removed) (4-Acetyl-2-adamantan-l-yl-phenoxy)-acetic acid ethyl ester (3a)
A solution of 2a (5 g), ethyl chloro acetate (3.38 g) and anhydrous K2CO3 (3.85 g) in dry acetone (50 mL) was refluxed for 8 h. Reaction mixture was concentrated to 20 mL, diluted with water (100 mL) and extracted with ethyl acetate (3 x 50 mL). Combined organic was washed with saturated brine solution, dried over anhydrous Na2SC>4 and concentrated and the crude product was chromatographed on silica gel using ethyl acetate-hexane as eluant to furnish 3a (6 g, 91% yield). 3-(3-Adamantan-l-yl-4-ethoxycarbonylmethoxy-phenyl)-3-hydroxy-butyric acid ethyl ester (4a) To i refluxing mixture of adamantyl-substituted aryl methyl ketone 3a (3 g), and Zn (1.09 g) and I2 (10 mg) in benzene (100 mL), was added a solution of ethyl bromoacetate (2.1 g) in benzene (30 mL) dropwise over 20 min. The reaction mixture was refluxed for 4 h and then cooled to room temperature with stirring. It was acidified with 10% HC1 (50 mL), benzene layer was separated out. The organic phase was washed with water, dried over anhydrous Na2SC»4 and concentrated. The crude product was purified by chromatography using silica gel as adsorbent and ethyl acetate-hexane mixture as eluant to give 4a (3 g, 80% yield).
3-(3-Adamantan-l-yl-4-ethoxycarbonylmethoxy-phenyl)-but-2-enoic acid ethyl ester (5a) A solution of 4a (3 g) in benzene (75 mL) and /^-toluene sulphonic acid (240 mg) was refluxed for 2
h. Solvent was distilled off and again refluxed the reaction mixture in dried benzene (75 mL),
repeated the procedure twice. Reaction mixture was quenched with saturated NaHCO3 (15 mL) and
benzene layer was separated, organic phase was washed with water, dried over anhydrous Na2SO4
and concentrated and the crude product was purified by chromatography using silica gel as adsorbent
and a mixture of ethyl acetate-hexane mixture as eluant to give 5a (2.5 g, 87% yield).
3-[3-Adamantan-l-yl-4-(2-hydroxy-ethoxy)-phenyl]-but-2-en-l-ol(6a)
To an ice cooled slurry of LiAIRt (500 mg.) in dry ether (50 mL) was added a solution of 5a (2.8 g)
in dry ether (30 mL) dropwise over 15 min and stirred for 1 h at 0°C. The reaction mixture was
quenched with water (20 mL) and added a solution of 10% NaOH (5 mL), ether layer was decanted.
The precipitate was washed with ether (2 x 30 mL), combined ether extracts were concentrated and
the crude product was purified by crystallization with dichloromethane-acetone to give 6a (1.9 g,
85% yield).
2-{2-Adamantan-l-yl-4-[l-(6,7,10-trioxa-spiro[4.5]dec-8-yl)-vinyl]-phenoxy}-ethanol
(Compound 8aa-a, Formula 8aa)
Compound 6a (1 g) and methylene blue (5 mg) was taken in a mixture of THF (25 mL) and CHsCN
(25 mL) and photooxygenated at 0°C for 4 h to give a compound 7a (as shown by TLC).
Cyclopentanone (0.25 g) and coned. HC1 (0.4 mL) was added to the reaction mixture and stirred for 2
h at room temp. Reaction mixture was concentrated and the crude product was purified by column
chromatography using silica gel as adsorbent and a mixture of ethyl acetate as eluant to furnish
trioxane 8aa-a (210 mg, 33% yield based on allylic alcohol used), mp 120°C.
Succinic acid mono-(2-{2-adamantan-l-yl-4-[l-(6,7,10-trioxa-spiro[4.5]dec-8-yl)-vinyl]-
phenoxyj-ethyl) (Compound 8ab-a, Formula Sab)
A solution of 8aa-a (100 mg), Et3N (0.07 mL, 3 eq), succinic anhydride (68 mg, 3 eq) and DMAP (2
mg) in DCM (20 mL) was stirred for 1 h. Reaction mixture was quenched by adding 10% HCI
solution and extracted with DCM (2 x 25 mL). Solvent was evaporated and the crude product was
purified by the column chromatography using a mixture of methanol-chloroform as eluant to furnish
8ab-a (oil, 100 mg, 82% yield).
EXAMPLE-2
Following the same procedure as for trioxane 8aa-a and 8ab-a, compounds 8aa-b 8aa-c, 8aa-d, Sab-fa, 8ab-c and 8ab-d were prepared.
2-{2-Adamantan-l-yI-4-[l-(l,2,5-trioxa-spiro[5.5]undec-3-yl)-vinyIJ-phenoxy}-ethanol (Compound 8aa-b, Formula 8aa)
Allylic alcohol 6a (500 mg) and methylene blue (5 mg) was taken in a mixture of THF (25 mL) and ACN (25 mL) and photooxygenated at 0°C for 4 h to give compound 7a, which was reacted in situ witn cyclohexanone (290 mg) in the presence of coned. HC1 (0.2 mL) room temp. The reaction mixture was concentrated and the crude product was purified by column chromatography to furnish trioxane 8aa-b (250 mg, 38% yield based on allylic alcohol used) as white solid, mp 132°C. Trioxane 8aa-c, Formula 8aa
Allylic alcohol 6a (500 mg) and methylene blue (5 mg) was taken in a mixture of THF (25 mL) and ACN (25 mL) and photooxygenated at 0°C for 4 h to give a compound 7a, which was condensed in situ 2-admantanone (440 mg) in the presence of coned. HC1 (0.5 mL) at room temp. The reaction mixture was concentrated and crude product was purified by column chromatography on silica gel to furnish 8aa-c 200 mg (27% yield based on allylic alcohol used) as white solid, mp 126°C. 2-{2-Adamantan-l-yl-4-[l-(3,3-dimethyl-[l,2,4]trioxan-6-yl)-vinyl]-phenoxy}-ethanol (Compound 8aa-d, Formula 8aa)
Allylic alcohol 6a (500 mg) and methylene blue (5 mg) was taken in a mixture of THF (25 ml) and ACN (25 mL) and 30 ml acetone and photooxygenated at 0°C for 4 h to give a compound 7a, To the reaction mixture was added coned. HC1 (0.3 mL) and stirred for 2 h at room temp. Reaction mixture was concentrated and the crude product was purified by column chromatography on silica gel to furnish 8aa-d 200 mg (oil, 27% yield based on allylic alcohol used).
Succinic acid mono-(2-{2-adamantan-l-yl-4-|l-(l,2,5-trioxa-spiro[5.5]undec-3-yl)-vinyl|-phenoxy}-ethyl) (Compound 8ab-b, Formula Sab)
A solution of 8aa-b (100 mg), Et3N (0.07 mL, 3 eq), succinic anhydride (68 mg, 3 eq) and DMAP (2
mg) in DCM (20 mL) was stirred for 1 h. Reaction mixture was quenched by adding 10% HC1
solution and extracted with DCM (2 x 25 mL). Solvent was evaporated and crude product was
isolated and purified by the column chromatography on silica gel using a mixture of methanol-
chloroform as eluant to furnish 8ab-b (oil, 100 mg, 82% yield).
Trioxane 8ab-c, Formula Sab
A solution of 8aa-c (100 mg), Et3N (0.06 mL, 3 eq), succinic anhydride (60 mg, 3 eq) and DMAP (2
mg) in DCM (20 mL) was stirred for 1 h. Reaction mixture was quenched by adding 10% HC1
solution and extracted with DCM (3 x 25 mL). Solvent was evaporated and crude product was
isolated and purified by the column chromatography on silica gel using a mixture of methanol-
chloroform as eluant to furnish 8ab-c (oil, 100 mg, 84% yield).
Succinic acid mono-(2-{2-adamantan-l-yI-4-[l-(33-dimethyl-[l,2,4]trioxan-6-yl)-vinyl]-
phenoxy}-ethyl) ester (Compound 8ab-d, Formula Sab)
A solution of 8aa-d (100 mg), Et3N (0.08 mL, 3 eq), succinic anhydride (73 mg, 3 eq) and DMAP (2
mg) in DCM (20 mL) was stirred for 1 h. Reaction mixture was quenched by adding 10% HCI
solution and extracted with DCM (3 x 25 mL). Solvent was evaporated and crude product was
isolated and purified by the column chromatography on silica gel using a mixture of methanol-
chloroform as eluant to furnish 8ab-d (oil, 100 mg, 81% yield).
EXAMPLE -3
l-(2-adamantan-yl-3-hydroxy-phenyl)-ethanone (2b)
To a solution of w-hydroxy acetophenone Ib (10 g) and 1-adamantanol (10 g) in acetic acid (100 mL) was added coned. H2SO4 (15 mL) dropwise and stirred for two days at rt. Reaction mixture was poured into ice-cooled water (300 mL) and extracted with ethyl acetate (3 x 100 mL). Combined organic layer was washed with water followed by saturated sodium bicarbonate solution and brine solution Dried over anhydrous Na2SO4 and concentrated, and the crude product was purified by
column chromatography on silica gel using a mixture of ethyl acetate-hexane as eluant to furnish 2b
(6 g, 30% yield).
(3-Acetyl-2-adamantan-l-yl-phenoxy)-acetic acid ethyl ester (3b)
A solution of 2b (6 g), ethyl chloro acetate (5.4 g) and anhydrous K.2CO3 (12.26 g) in dry acetone (50
mD was refluxed for 8 h. Reaction mixture was concentrated to 20 ml, diluted with water (100 ml)
and extracted with ethyl acetate (3 x 75 mL). Combined organic phase was washed with saturated
brine solution, dried over anhydrous Na2SC>4 and concentrated; the crude product was
chromatographed on silica gel using a mixture of ethyl acetate-hexane as eluant to furnish 3b. (6 g,
76% yield).
3-(2-adamantan-yl-3-ethoxycarbonymethoxy-phenyl)-3-hydroxy-butyric acid ethyl ester (4b)
To a refluxing mixture of adamantyl-substituted aryl methyl ketone 3b (6 g), Zn (1.7 g) and la (10
mg) in benzene (100 mL) was added a solution of ethyl bromoacetate (3.5 g) in benzene (30 mL)
dropwise over 20 min. The reaction mixture was refluxed for 4 h and acidified with 10% solution
HC1 (50 mL) at room temperature, benzene layer was separated, and organic phase was washed with
water, dried over anhydrous Na2SO4 and concentrated. The crude product was purified by
chromatography using silica gel as an adsorbent and ethyl acetate-hexane mixture as eluant to give 4b
5.6 g (72% yield)
3-(l-adamantan-l-yI-3-ethoxycarbonylmethoxy-phenyl)-but-2-enoic acid ethyl ester (5b)
A solution of 4b (5 g) andp-toluene sulphonic acid (560 mg) in benzene (100 mL) was refluxed for 2 h. Benzene was distilled off and again refluxed the reaction mixture in dried benzene (75 mL) for 1 h, repeated the procedure twice. Reaction mixture was quenched with saturated NaHCOa (15 mL), and benzene layer was separated. Organic phase was washed with water and dried over anhydrous Na2SO4 and concentrated, and the crude product was purified by chromatography using silica gel as adsorbent and ethyl acetate-hexane mixture as eluant to give 5b (3.53 g, 74% yield). 3-[2-adamantan-yl-3-(2-hydroxy-ethoxy)-phenyl]-but-2-en-l-ol (6b)
To an ice cooled slurry of LiAlH4 (800 mg) in dry ether (50 mL) was added a solution of 5b (3.53 g) in dry ether (100 mL) dropwise over 15 min. The mixture was stirred for 1 h at this temperature, reaction mixture was quenched with water (20 mL) and a solution of 10% NaOH (10 mL) was added; ether layer was decanted. The precipitate was washed with ether (3 x 50 mL), combined ether extracts were concentrated, the crude product was purified by crystallization with dichloromethane-acetone to give 6b (2.5 g, 89% yields).
2-{2-Adamantan-l-yI-5-[l-(6,7,10-trioxa-spiro[4.5]dec-8-yl)-vinyl]-phenoxy}-ethanol (Compound 8ba-a, Formula 8ba)
A solution of 6b (1 g) and methylene blue (10 mg) in THF-ACN (50:50, 100 mL) was photooxygenated at 0°C for 4 h to furnish /0-hydroxyhydroperoxide 7b (as shown by TLC) was not isolated but reacted in situ with cyclopentanone (740 mg) in the presence of coned. HC1 (0.4 mL) at it. The reaction mixture was concentrated and crude product was purified by column chromatography on silica gel to furnish trioxane 8ba-a (300 mg, 23% yield based on allylic alcohol used), mp 110°C. Succinic acid mono-(2-{2-adamantan-l-yl-5-[l-(6,7,10-trioxa-spiro[4.5]dec-8-yl)-vinyl]-phenoxyj-ethyl) ester (Compound 8bb-a, Formula 8bb)
A sjlution of 8ba-a (200 mg), Et3N (0.14 mL, 3 eq), succinic anhydride (136 mg, 3 eq) and DMAP (2 mg) in DCM (20 mL) was stirred for 1 h. Reaction mixture was quenched by adding 10% HCI solution (10 mL) and extracted with DCM (2 x 25 mL). Solvent was evaporated and crude product was isolated and purified by the column chromatography using methanol-chloroform mixture as eluant to furnish 8bb-a (oil, 190 mg, 77% yield).
EXAMPLE-4
Following the same procedure as for trioxanes 8ba-a and 8bb-a, compounds 8ba-b, 8ba-c, 8bb-b and 8bb-c were prepared.
2-{2-Adamantan-l-yl-5-[l-(l,2,5-trioxa-spiro[5.5]undec-3-yl)-vinyl]-phenoxy}-ethanol (Compound 8ba-b, Formula ba)
Allylic alcohol 6b (940 mg) and methylene blue (10 mg) in THF-ACN (50:50, 100 mL) was photooxygenated at 0°C for 4 h to furnish /?-hydroxyhydroperoxide 7b, which was reacted in situ with cyclohexanone (1.08 g) in the presence of coned. HC1 (0.4 mL) at rt. The reaction mixture was concentrated and crude product was purified by column chromatography on silica gel to furnish trioxane 8ba-b (400 mg, 32% yield based on allylic alcohol used), mp 115°C Trioxane 8ba-c, Formula 8ba
Allylic alcohol 6b (450 mg) and methylene blue (5 mg) in THF-ACN (50:50, 50 mL) was photo oxygenated at 0°C for 4 h to furnish /?-hydroxyhydroperoxide 7b, which was reacted in situ with 2-admantanone (290 mg) in the presence of coned. HC1 (0.4 mL) at rt. The reaction mixture was concentrated and the crude product was purified by column chromatography on silica gel to furnish compound 8ba-c 180 mg (27% yield based on allylic alcohol used) mp 125°C. Succinic acid mono-(2-{2-adamantan-l-yl-5-[l-(l,2,5-trioxa-spiro[5.5]undec-3-yl)-vinyl]-phenoxy}-ethyl) ester (Compound 8bb-b, Formula 8bb)
A solution of 8ba-b (300 mg), Et3N (0.2 mL, 3 eq), succinic anhydride (198 mg, 3 eq) and DMAP (2 mg) in DCM (20 mL) was stirred for 1 h. Reaction mixture was quenched by adding 10% HCI (20 mL) solution and extracted with DCM (3 x 25 mL). Solvent was evaporated and crude product was isolated and purified by the column chromatography using methanol-chloroform mixture as eluant to furnish 8bb-b (oil, 300 mg, 82% yield). Trioxane 8bb-c, Formula 8bb
A solution of 8ba-c (200 mg), Et3N (0.123 mL, 3 eq), succinic anhydride (120 mg, 3 eq) and DMAP (2 mg) in DCM (20 mL) was stirred for 1 h. Reaction mixture was quenched by adding 10% HCI (10 mL) and extracted with DCM (3 x 20 mL). Solvent was evaporated and crude product was isolated and purified by the column chromatography using methanol-chloroform mixture as eluant to furnish 8bb-c (oil, 200 mg, 84% yield). Following the above procedure, following trioxanes were prepared.
Table 2.
(Table Removed)Compound No. 8ab-a, 8ab-b, 8ab-c, 8ab-d, 8bb-a, 8bb-b & 8bb-c which are hemisuccinates, can be converted into their corresponding Na/K-salts. Salts of compounds No 8ab-a, 8ab-b, 8ab-c, 8ab-d, 8bb-a, 8bb-b & 8bb-c may be prepared by dissolving compounds into CO3--/HCO3- solution. AatUMlarial activity:
The antimalarial activity of the test compounds were evaluated in rodent using multi-drug resistant
strain of Plasmodium yoelii nigeriensis in Swiss mice.
Random bred Swiss mice of either sex (20 + 2 g) were inoculated intraperitoneally with 1 x 10s P. yoelii (MDR) parasites on day zero. The treatment with test compounds were administered to group of 5 mice at different dose levels ranging between 48-96 mg/kg/day. The treatment was administered via intramuscular route for 4 consecutive days (day 0-3).
Blood smears from the experimental mice were observed on day 4, 7 and day 10, and thereafter at regular intervals till day 28 or death of the animal. The parasitaemia level on day 4 was compared with vehicle control group and the percent suppression of parasitaemia in treated groups was calculated.
For determining the curative dose of a compound the treated mice were observed till day 28. The dose at which no parasitaemia develop during the observation period has been reported as the curative dose. The biological efficacy data is summarized in Table 3.
Table 3. Antimalarial activity of trioxancs against P. yoelii in mice
(Table Removed)
In vivo test procedure: The colony of bred Swiss mice (25 ± Ig) were inoculated with 1 X 106 parasitized RBC on day zero and treatment was administered to a group of five mice at each dose, from day 0 to 3, in two divided doses daily. The drug dilutions of compounds of general formula 8 were prepared in groundnut oil so as to contain the required amount of the compound (1.2 mg for a dose of 96 mg/kg, 0.6 mg for a dose of 48 mg/kg) in 0.1 ml and administered orally/intramuscularly for each dose. Parasitaemia level were recorded from thin blood smears between day 4-28. The trea ed mice surviving beyond day 28 were recorded as the mice protected by the drug. Mice treated with y9-Arteether served as positive controls. Compound 8ab-c was found to be most active
with 100% suppression at 48 mg/kg on day 4 and 20% of the treated mice survived on day 28. Activity data of all the trioxanes are summarized in Table 3.
Scheme 1.

(Scheme Removed)

X = OCH2CH2OH

X = OCH2CH2OCOCH2CH2COOH

Reagents and conditions: a. 1-adamantanol, coned. H2SO4, Acetic acid, rt, 2 days; b. ClCH2COOEt, K2CO3, Acetone, reflux, 8 h; c. BrCH2COOEt, Zn, I2, Benzene, reflux, 8 h; d.p-TSA, Benzene, reflux, 4-7 h; i. LiAlH4, dry ether, 0°C, 2 h; f. '02, MB, hv, 0°C, rt, 5 h; g. ketone, conc.HCl, rt, 4-5 h; h. succinic anhydride, triethyl amine, DMAP (cat), CH2C12, rt, 0.5 h

We claim
1. A compound [2-adamantyl-4-halo phenyl]-6-ethyl-3-dialkyl-l,2,4-trioxane of general
formula 8
(Formula Removed)
wherein X is selected from OCH2CH2OH, OCH2CH2OCOCH2CH2COOH and R1 & R2 represents alkyl group such as methyl or a part of cyclic system selected from cyclopentane, cyclohexane or adamantane, and their derivatives or salts thereof.
2. The compound as claimed in claim 1 wherein the said compound 8 having
structural formula 8aa-a, 8aa-b and 8aa-d as shown below:
(Formula Removed)
3. The compound as claimed in claim 1 wherein the said compound 8 having structural
formula 8aa-c as shown below:
(Formula Removed)
4. The compound as claimed in claim 1 wherein the said compound 8 having structural
formula 8ba-a, 8ba-b as shown below:
(Formula Removed)
5. The compound as claimed in claim 1 wherein the said compound 8 having structural
formula 8ba-c as shown below:
(Formula Removed)
6. The compound as claimed in claim 1 wherein the said compound 8 having structural
formula 8ab-a, 8ab-b and 8ab-d shown below:
(Formula Removed)
7. The compound as claimed in claim 1 wherein the said compound 8 having structural
formula 8ab-c shown below:
(Formula Removed)
8. The compound as claimed in claim 1 wherein the said compound 8 having structural
formula 8bb-a and 8bb-b as shown below:
(Formula Removed)
9. The compound as claimed in claim 1 wherein the said compound 8 having structural
formula 8bb-c as shown below:
(Formula Removed)
10. The compound as claimed in claim 1 wherein the salt of compound 8 is selected from
sodium or potassium.
11. A process for the preparation of novel substituted 1,2,4-trioxanes of general formula 8,
(Formula Removed)
wherein X is selected from OCH2CH2OH, OCH2CH2OCOCH2CH2COOH and R1 & R2 represents alkyl group such as methyl or a part of cyclic system selected from cyclopentane, cyclohexane or adamantane which comprises:
(i) reacting aryl methyl ketones of formula 1 with 1-adamantanol in the presence of an acid catalyst in an organic solvent at a temperature ranging between room temperature to refluxing to give adamantyl substituted aryl methyl ketones of formula 2;
(Formula Removed)
(ii) reacting aryl methyl ketones of formula 2 with ethyl chloroacetate in the presence of anhydrous K2CO3 in an aprotic organic solvent in the temperature range of room temperature to refluxing temperature to give esters of formula 3;
(Formula Removed)
(iii) reacting esters of formula 3 with ethyl bromoacetate and Zn in the presence of catalytic amount of I2 in an aprotic organic solvent in the temperature range of room temperature to refluxing temperature to give ß-hydroxyesters of formula 4;
(Formula Removed)
(iv) dehydrating the ß-hydroxyesters of formula 4 using a catalytic amount of p-TSA in an aprotic organic solvent at a temperature ranging between room temperature to refluxing temperature to give α,ß-unsaturated esters of formula 5;
(Formula Removed)
(v) reducing the esters of formula 5 with LiAlH4 in diethyl ether at a temperature ranging between -5°C to 0°C to give allylic alcohols of formula 6;
(Formula Removed)
(vi) photooxygenating the allylic alcohols of formula 6 in the presence of a sensitizer in an organic solvent at a temperature ranging between -10°C to room temperature to give ß-hydroxyhydroperoxides of formula 7;
(Formula Removed)
(vii) reacting ß-hydroxyhydroperoxide of formula 7 in situ with ketone compounds of formula 9
wherein R1 and R2 represents, methyl, the part of cyclic system such as cyclopentane, cyclohexane or adamantane in the presence of an acid catalyst in an aprotic organic solvent in the temperature range of 0°C to room temperature, followed by isolation and purification by
known methods to furnish the trioxanes of general formula 8, wherein X is OCH2CH2OH, Rb R2 have the same meaning as above;
(Formula Removed)
(viii) reacting trioxanes of formula 8 (X = OCH2CH2OH) with succinic anhydride and triethylamine in presence of catalytic amount of dimethylaminopyridine (DMAP) in a low boiling chlorinated solvent to furnish their hemisuccinates of formula 8 (X = OCH2CH2OCOCH2CH2COOH) and Rh R2 represents, methyl, the part of cyclic system such as cyclopentane, cyclohexane or adamantane,
(Formula Removed)
12. The process as claimed in 11 wherein the acid catalyst in step (i) is selected from H2SO4, H3PO4 and amberlyst-15.
13. The process as claimed in 11 wherein the organic solvent in step (i) is selected from CH3COOH, C6H6, THF.
14. The process as claimed in claim 11 wherein adamantyl substituted m/p-hydroxyl
acetophenone of formula 2 is prepared by reacting aryl methyl ketone of formula 1 with 1-
admantanol in acetic acid in the presence of coned. H2SO4, or in acetic acid in the presence of
H3PO4, or in acetic acid in the presence of amberlyst-15 , or in benzene in the presence of
amberlyst-15 , or in THF in the presence of amberlyst-15.
15. The process as claimed in claim 11 wherein adamantyl substituted esters of formula 3 are
prepared by reacting adamantyl substituted m/p-hydroxy acetophenone of formula 2 with
ethyl 2-chloroacetate and K2CO3 in acetone.
16. The process as claimed in claim 11 wherein ß-hydroxyesters of formula 4 are prepared by reacting adamantyl substituted esters of formula 3 with ethyl 2-bromoacetate and Zn in the presence of catalytic amount of I2 in an aprotic solvent such as benzene.
17. The process as claimed in claim 11 wherein α,ß-unsaturated esters of formula 5 are prepared by dehydrating ß-hydroxyesters of formula 4 using catalytic amount of p-TSA in an aprotic organic solvent like benzene.
18. The process as claimed in claim 11 wherein the allylic alcohols of formula 6 are prepared by reducing α,ß-unsaturated esters of formula 5 in ethereal solvent like diethyl ether.
19. The process as claimed in claim 11 wherein the organic solvent used in step (vi) and
(viii) is selected from the group consisting of CHC13, THF, CH3CN.
20. The process as claimed in claim 11 in step (viii) wherein adamantyl substituted hydroxy
functionalized 1,2,4-trioxanes of formula 8 are prepared by reacting ß-
hydroxyhydroperoxides of formula 7 with a ketone in the presence of an acid catalyst.
21. The process as claimed in claim 11 for the preparation of hemisuccinate derivatives of general formula 8 (X = OCH2CH2OCOCH2CH2COOH) by reacting 1,2,4-trioxanes of general formula 8 (X = OCH2CH2OH) with succinic anhydride and triethyl amine in the presence of catalytic DMAP in dichloromethane at a temperature ranging between 0°C to room temperature.

Documents:

2157-DEL-2006-Claims-(25-06-2012).pdf

2157-del-2006-claims.pdf

2157-DEL-2006-Correspondence Others-(25-06-2012).pdf

2157-del-2006-correspondence-others (17-03-2008).pdf

2157-del-2006-correspondence-others.pdf

2157-del-2006-description (complete).pdf

2157-del-2006-form-1.pdf

2157-del-2006-form-18 (17-03-2008).pdf

2157-del-2006-form-2.pdf

2157-del-2006-form-3.pdf

2157-del-2006-form-5.pdf

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Patent Number

255359

Indian Patent Application Number

2157/DEL/2006

PG Journal Number

08/2013

Publication Date

22-Feb-2013

Grant Date

14-Feb-2013

Date of Filing

29-Sep-2006

Name of Patentee

COUNCIL OF SCIENTIFIC & INDUSTRIAL RESEARCH

Applicant Address

ANUSANDHAN BHAWAN, RAFI MARG, NEW DELHI-110001, INDIA.

Inventors:

#	Inventor's Name	Inventor's Address
1	CHANDAN SINGH	CENTRAL DRUG RESEARCH INSTITUTE, CHATTAR MANZIL PALACE, POST BOX NO 173, LUCKNOW 226001, INDIA
2	SUNIL KUMAR PURI	CENTRAL DRUG RESEARCH INSTITUTE, CHATTAR MANZIL PALACE, POST BOX NO 173, LUCKNOW 226001, INDIA
3	UPASANA SHARMA	CENTRAL DRUG RESEARCH INSTITUTE, CHATTAR MANZIL PALACE, POST BOX NO 173, LUCKNOW 226001, INDIA
4	NA	NA
5	NA	NA

PCT International Classification Number

C07D

PCT International Application Number

N/A

PCT International Filing date

PCT Conventions:

#	PCT Application Number	Date of Convention	Priority Country
1			NA