Indian Patents. 271697:NOVEL 6-(1- ARYL ETHYL)-1, 2,4-TRIOXANES, USEFUL AS ANTIMALARIAL AGENTS, AND A PROCESS FOR THE PREPARATION THERE OF

Title of Invention	NOVEL 6-(1- ARYL ETHYL)-1, 2,4-TRIOXANES, USEFUL AS ANTIMALARIAL AGENTS, AND A PROCESS FOR THE PREPARATION THERE OF
Abstract	Novel substituted 1,2,4-trioxanes, useful as antimalarial agents, and a process for the preparation thereof.

Full Text	This present invention relates to novel substituted 1, 2, 4-trioxanes useful as antimalarial agents having general formula 2. (FIGURE REMOVE) This invention also relates to a process for the preparation of these novel substituted 1, 2, 4-trioxanes. This invention particularly relates to a process for the preparation of 6-(1-aryl ethyl)-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 2 wherein Ar represents the aryl groups like phenyl , pMe-phenyl, pCI-phenyl, pMeO- phenyl, pF-phenyl, biphenyl, 2-napthyl, p-Br-phenyl,1-napthyl, p-Cyclohexyl-phenyl, 2-Flurenyl, whereas R1 and R2 represents the part of cyclic ring system like cyclohexane, cyclopentane and adamantane. Several of these novel trioxanes have shown high order of antimalarial activity against multidrug-resistant malaria in mice and thus hold promise as antimalarial agents against multidrug-resistant malaria. FIELD OF INVENTION This present invention relates to novel substituted 1, 2, 4-trioxanes useful as antimalarial agents having general formula 2. (FIGURE REMOVE) This invention also relates to a process for the preparation of these novel substituted 1, 2, 4-trioxanes. This invention particularly relates to a process for the preparation of 6-(1-aryl ethyl)-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 2 wherein Ar represents the aryl groups like phenyl , pMe-phenyl, pCI-phenyl, pMeO- phenyl, pF-phenyl, biphenyl, 2-napthyl, p-Br-phenyl,1-napthyl, p-Cyclohexyl-phenyl, 2-Flurenyl, whereas R1 and R2 represents the part of cyclic ring system like cyclohexane, cyclopentane and adamantane. These trioxanes are new compounds and are useful as antimalarial agents. Some of these compounds have been tested against multi-drug resistant malaria in mice and have shown promising antimalarial activity. The invention, thus relates to pharmaceutical industry. BACKGROUND OF INVENTION Malaria is still one of the world's most deadly disease that threatens nearly 40% of the world's population and infects approximately 300 to 500 million people annually world wide mainly in tropical and subtropical areas. It is estimated that there are between 1 million to 3 million deaths every year due to malaria. In Africa alone, more than 1 million children under the age of 5 die from malaria each year. Malaria is a parasite borne disease and human infection is caused by four distinct species of the protozoon Plasmodium, namely P. vivax, P. falciparum, P. ovale, P. malariae. Malaria is transmitted by bite of a vector the female Anopheles mosquito which is responsible for its global epidemics. Quite a number of natural products isolated from various plants and microorganisms have shown potent antimalarial activity, thus acting as lead for further drug development. Natural products as lead for malaria chemotherapy dates back to the early 18th century when bark of Cinchona tree was used in the treatment of fever by the natives of South America. It was in 1820 that quinine was isolated as active principle of the bark. Quinine is active against the trophozoites present in the erythrocytes but has no effect on exo-erythrocytic stages that develop in lever. Later on taking quinine as lead several synthetic analogues like chloroquine, mefloquin, primaquine etc, were developed as antimalarial drugs and are still being used. Unfortunately due to indiscriminate use of chloroquine and its analogues the parasite developed resistance towards these drugs. Indeed the re-emergence of the malaria as a world wide epidemic can be largely attributed due to rapid development of parasite resistance towards conventional drugs. Thus there is an urgent need to develop new drugs which are novel both in terms of mechanism of action and pharmacophore. In that regard discovery of artemisinin, a sesquiterpene lactone endoperoxide, isolated from Chinese traditional medicinal herb Artemisia annua and its semisynthetic derivatives like arteether and artemether have shown tremendous potential and are presently the drugs of choice for the treatment of multidrug resistant malaria. These drugs are effective against both chloroquine sensitive and chloroquine resistant strains of Plasmodium falciparum, [For reviews and background knowledge of artemisinin and its semisynthetic derivatives see: (a) Klayman, D. L Science 1985, 228, 1049. (b) Bhattacharya, A. K.; Sharma, R. P. Heterocycles 1999, 51, 1651. (c) Borstnik, K.; Paik, I.; Shapiro, T. A.; Posner, G. H. Int. J. Parasitol. 2002, 32, 1661. (d) Ploypradith, P. Acta Trop. 2004, 89, 329. (e) O'Neill, P. M.; Posner, G. H. J. Med. Chem. 2004, 47, 2945.] (FIGURE REMOVE) The limited availability of artemisinin from the natural sources and taking into account of the fact, that it is actually the endoperoxide linkage in the form of 1,2,4- trioxane ring system which is responsible for its antimalarial activity, has led to the present efforts to develop new structurally simple trioxanes which are easily accessible relatively cheap and active against multidrug resistant strains. . Several structurally simple synthetic trioxanes have shown promising antimalarial activity [(a) Bhattacharya.A K.,Sharma,RP.; Hefrocyc/es.1999 57,1681. (b) Borstnik, K.; Paik, I.; Shapiro, T.A.; Posner, G. H. Int. J. Parasitol. 2002, 32, 1661. (c) Singh, C.; Misra, D.; Saxena, G.; Chandra, S. Bioorg. Med. Chem. Lett. 1992, 2, 497. (d) Singh, C.; Misra, D.; Saxena, G.; Chandra, S. Bioorg. Med. Chem. Lett. 1995, 5, 1913. (e) Singh, C.; Puri S. K. U.S. Patent 631649381,2001. (f) Singh, C.; Gupta, N.; Puri, S. K. Bioorg. Med. Chem. Lett. 2003, 13, 3447. (g) Singh, C.; Malik, H.; Puri, S. K. Bioorg. Med. Chem. Lett. 2004, 14, 459. (h) Singh, C.; Srivastav.N.C.; Puri, S. K. Bioorg. Med. Chem. Lett. 2004, 12, 5745-5752. (i) Singh, C.; Tiwari, P.; Puri, S. K. PCT Patent application No. PCT/IN02/00093, dated 28.3.2002. 0) Singh, C.; Malik, H.; Puri, S. K. Patent application No. PCT/IN04/00413, dated 27.12.04. (k) Singh, C; Malik, H.; Puri, S. K.: J. Med. Chem., 2006. 49 (9), 2794 -2803]. (FIGURE REMOVE) (FIGURE REMOVE) (FIGURE REMOVE) The present invention deals with the preparation of a novel series of 1,2,4-trioxanes, some of which have shown high order of antimalarial activity against multidrug resistant strain, Pyoelii in mice. ABOUT THE PRESENT INVENTION This present invention relates to novel substituted 1, 2, 4-trioxanes useful as antimalarial agents having general formula 2. This invention also relates to a process for the preparation of these novel substituted 1, 2, 4-trioxanes. This invention particularly relates to a process for the preparation of 6-(1-aryl ethyl)-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 2 wherein Ar represents the aryl groups like phenyl , pMe-phenyl, pCI-phenyl, pMeO- phenyl, pF-phenyl, biphenyl, 2-napthyl, p-Br-phenyl,1-napthyl, p-Cyclohexyl-phenyl, 2-Flurenyl and the like, whereas R1 and R2 represents the part of cyclic ring system like cyclohexane, cyclopentane and adamantane and the like. These trioxanes are new compounds and are useful as antimalarial agents. Some of these compounds have been tested against multi-drug resistant malaria in mice and have shown high order of antimalarial activity. These trioxanes thus have the potential to be used for the treatment of malaria, a highly prevalent parasitic disease. The invention, thus relates to pharmaceutical industry. These trioxanes of the general formula 2 are new chemical entities and they have not been prepared earlier. The main objective of the present invention is to provide novel substituted 1, 2, 4-trioxanes of formula 2 and a process for the preparation of these novel substituted 1, 2, 4-trioxanes of general formula 2, a new series of antimalarial agents. Accordingly, the present process provides a process for the preparation of novel substituted 1, 2, 4-trioxanes of general formula 2 which comprises the reduction of the 6-(1-aryl vinyl)-1, 2, 4-trioxanes of formula 1 with diimide, generated in situ, by the reaction of H2O2 with N2H4.H20 or CO2 neutralized N2H4.H2O in a water miscible organic solvent such as tetrahydrofuran, ethyl alcohol, methyl alcohol CH3CN or a mixture of these solvents at a temperature range of 0 °C to room temperature to furnish trioxanes of formula 2 as a mixture of diastereomers, separation of the diastereomers by chromatography to give pure isomers of the formula 3 and 4 wherein Ar, R1 and R2 have the same meaning as above. (FIGURE REMOVE) Ar=C6H5-1a2 Ar=pMe-C6H4-1a3Ar=pCI-C6H4-1a4Ar=pF-C6H4-1a5 Ar=pMeO-C6H4-1a6Ar=pPh-C6H4-1a7Ar=2-Napthyl-1a8 Ar=p-Br-C6H4-1a9Ar=1-Napthyl-1a10 Ar=p-Cyclohexyl-phenyl- Ar=C6H5-1b2Ar=pMe-C6H4-1b3Ar=pCI-C6H4-1b4Ar=pF-C6H4-1b5Ar=pMeO-C6H4-1b6Ar=pPh-C6H4-1b7Ar=2-Napthyl- Ar=C6H5-1c2 Ar=pMe-C6H4-1c3 Ar=pCI-C6H4-1c4Ar=pF-C6H4-1c5 Ar=pMeO-C6H4-1c6Ar=pPh-C6H4-1c7Ar=2-Napthyl- Ar=2-Flurenyl- Trioxanes having formula 1 In the process the 6-Aryl vinyl substituted 1, 2, 4-trioxanes of the formula 1 were prepared by the known procedure [(a) Singh.C.; Tetrahedron. Lett. 1990, 31, 6901. (b) Singh, C.; Tiwari, P.; Puri, S. K. PCT Patent application No. PCT/IN02/00093, dated 28.3.2002. (c) Singh, C.; Kanchan, R.; Chandra, S. and Puri, S.K. Indian patent application no. 0909/DEL/2003 dated 18/07/2003]. These trioxanes of formula 1 have been prepared earlier in our (FIGURE REMOVE) laboratory and are known compounds. In the process trioxanes of the formula 1 are reduced with diimide.generated by the reaction of hydrogen peroxide and hydrazine hydrate in a water miscible organic solvent such as THF, ethanol, methanol, CH3CN or a mixture of these solvents at ambient temperature to furnish a mixture of diastereomers of the formula 2. Separation of the isomers by chromatography gave pure isomers of formula 3 and 4 where in Ar, R1 and R2 have the same meanings as stated above. ,H These trioxanes having general formula 3 and 4 are new chemical entities and have not been prepared earlier. Some of the trioxanes of formula 3 and 4 have been tested against malarial parasite in mice and have shown promising antimalarial activity. The invention is further illustrated by the following examples which should not, however, be constructed to limit the scope of present invention. (FIGURE REMOVE) EXAMPLE: -1 TRIOXANE 2a1, FORMULA 2a, Ar=C6H5- To a stirred solution of unsaturated trioxane 1a1 (formula 1a, Ar=C6H5-) (1.00 gm, 3.205 mmol.) and N2H4.H2O (3.2 ml) in 1:1 mixture of EtOH/THF (50 ml), cooled to 0 °C, was added 30% H202 (10.9 ml) dropwise and the reaction mixture was kept at the same temperature for 3 days. The reaction mixture was evaporated on a rota-vapour and then diluted with water (20 ml) and extracted with ether (3x50 ml). The ethereal layer was neutralized with 10% HCI (20 ml) and washed with saturated NaHCO3 and brine solution and evaporated on a rota-vapour and the crude product was purified by column chromatography on silica gel to yield 440 mg of mixture of diastereomers (43.7 % yield) in approx. 2:3 ratio which were separated by column chromatography to furnish the two isomers, 3a1 (higher Rf.) as oil and, 4a1 (lower Rf.) as white solid (m.p. 84-85 °C) respectively.The above reaction was also carried out using different solvents. (TABLE REMOVE -1) EXAMPLE: - 2 TRIOXANE 2a2, FORMULA 2a, Ar=pMe-C6H4- To a stirred solution of unsaturated trioxane 1a2 (formula 1a, Ar=pMe-C6H4-) (1.9 gm, 5.828 mmol) and N2H4.H20 (5.8 ml) in 1:1 mixture of EtOH/THF (100 ml), cooled to 0° C, was added 30% H2O2 (19.8 ml) dropwise and the reaction mixture was kept at same temp for 3 days. The reaction mixture was evaporated on a rota-vapour and then diluted with water (40 ml) and extracted with ether (3x100 ml). The ethereal layer was neutralized with 10% HCI (20 ml) and washed with saturated NaHCO3 and brine solution and evaporated on a rota-vapour and the crude product was purified by column chromatography on silica gel to yield 717 mg of mixture of diastereomers (35.8 % yield) in approx. 2:3 ratio which were separated by column chromatography to furnish the two isomers, 3a2 (higher Rf) as oil and 4a2 (lowerRf) also as oil respectively. .EXAMPLE:-3 TRIOXANE 2a3, FORMULA 2a, Ar =pCI-C6H4- To a stirred solution of unsaturated trioxane 1a3 (formula 1a, Ar= pCI-CeH4-) (2.0 gm, 5.780 mmol) and N2H4.H2O (6ml) in 1:1 mixture of EtOH/THF (100 ml), cooled to 0° C, was added 30% H2C>2 (20 ml) dropwise and the reaction mixture was kept at same temp for 2 days. The reaction mixture was evaporated on a rota-vapour and then diluted with water (40 ml) and then extracted with ether (3x100 ml). The ethereal layer was neutralized with 10% HCI (20 ml) and washed with saturated NaHCOs and brine solution and evaporated on a rota-vapour and the crude product was purified by column chromatography on silica gel to yield 710 mg of mixture of diastereomers (35.3 % yield) in approx. 2:3 ratio which were separated by column chromatography to furnish the two isomers 3a3 (higher Rf) as white solid (m.p. 92°-94° C) and 4a3 (lower Rf) as solid as well (m.p. 114°-115° C) respectively. .EXAMPLE:- 4 TRIOXANE 2a4, FORMULA 2a, Ar =pF-C6H4- To a stirred solution of unsaturated trioxane 1a4 (formula 1a, Ar= pF-CeH4-) (2.00 gm, 6.060 mmol) and N2H4.H20 (6 ml) in 1:1 mixture of EtOH/THF (100 ml), cooled to 0° C, was added 30% H2O2 (20 ml) dropwise and the reaction mixture was kept at same for 2 days. The reaction mixture was evaporated on a rota-vapour and then diluted with water (40 ml) and extracted with ether (3x100 ml). The ethereal layer was neutralized with 10% HCI (20 ml) and washed with saturated NaHCO3 and brine solution and evaporated on a rota-vapour and the crude product was purified by column chromatography on silica gel to yield 735 mg of mixture of diastereomers (36.5 % yield) in approx. 2:3 ratio which were separated by column chromatography to furnish the two isomers 3a4 (higher Rf) as oil and 4a4 (lower Rf) as white solid (m.p. 80°-81° C) respectively. EXAMPLE: - 5 TRIOXANE 2a5, FORMULA 2a, Ar =pMeO-C6H4- To a stirred solution of unsaturated trioxane 1a5 (formula 1a, Ar= pMeO-C6H4-) (2.00 gm, 5.548 mmol) and N2H4.H2O (6ml) in 1:1 mixture of EtOH/THF (100 ml), cooled to 0° C, was added 30% H2O2 (20 ml) dropwise and the reaction mixture was kept at same temp for 2 days. The reaction mixture was evaporated on a rotavapour and then diluted with water (40 ml) and extracted with ether (3x100ml). The ethereal layer was neutralized with 10% HCI (20 ml) and washed with saturated NaHCOaand brine solution and evaporated on a rotavapour and the crude product was purified by column chromatography on silica gel to yield 730 mg of mixture of diastereomers (36.5 % yield) in approx. 2:3 ratio which were separated by column chromatography to furnish the two isomers 3a5 (higher Rf) as oil and 4a5 (lower Rf) as oil as well, respectively. EXAMPLE: - 6 TRIOXANE 2a6, FORMULA 2a, Ar =pPh-C6H4- To a stirred solution of unsaturated trioxane 1a6 (formula 1a, Ar= pPh-C6H4-) (1.00 gm, 2.577 mmol) and N2H4.H20 (6ml) in 1:1 mixture of EtOH/THF (50ml), cooled to 0° C, was added 30% H2O2 (20 ml) dropwise and the reaction mixture was kept at same temp for 2 days and then at r.t for 2 days. The reaction mixture was evaporated on a rota-vapour and then diluted with water (20 ml) and extracted with ether (3x50 ml). The ethereal layer was neutralized with 10% HCI (20 ml) and washed with saturated NaHCO3 and brine solution and evaporated on a rota-vapour and the crude product was purified by column chromatography to yield 590 mg of mixture of diastereomers (58.7 % yield) in approx. 2:3 ratio which were separated by column chromatography to furnish the two isomers 3a6 (higher Rf) as white solid (m.p. 138°-140° C) and 4a6 (lower Rf) as white solid (m.p. 145°-147° C) as well, respectively. EXAMPLE: - 7 TRIOXANE 2a7 FORMULA 2a, Ar =2-Napthyl- To a stirred solution of unsaturated trioxane 1a7 (formula 1a, Ar=2-Napthyl-) (2.00 gm, 5.525 mmol) and N2H4.H2O (2.8 ml) in 1:1 mixture of EtOH/THF (100 ml), cooled to 0° C, was added 30% H2O2 (9.4 ml) dropwise and the reaction mixture was kept at same temp for 2 days and then stirred at r.t. for 13 days, The reaction mixture was evaporated on a rota-vapour and then diluted with water (20 ml) and extracted with ether (3x100 ml). The ethereal layer was neutralized with 10% HCI (20 ml) and washed with saturated NaHCOs and brine solution and evaporated on a rota-vapour and the crude product was purified by column chromatography on silica gel to yield 680 mg of mixture of diastereomers (67.6 % yield) in approx. 2:3 ratio which were separated by column chromatography to furnish the two isomers 3a7 (higher Rf) as white solid (m.p. 120°-121° C) and 4a7 (lower Rf) as white solid (m.p. 135°C) respectively. EXAMPLE: - 8 TRIOXANE 2a8 FORMULA 2a, Ar = pBr-C6H4 To an stirring solution of unsaturated trioxane 1a8 (formula 1a, Ar= pBr-CeH4-) (2.3 gm, 5.897 mmol) and N2H4.H2O (2.5 ml) (neutralized with CO2) in 1:1 mixture of EtOHH-HF (100 ml), cooled to 0° C, was added 30% H2O2 (8.5 ml) dropwise and the reaction mixture was stirred at r.t. for 8 days, till no more reactant was left, the reaction mixture was evaporated on a rota-vapour and then diluted with water (20 ml) and extracted with ether (3x100 ml). The ethereal layer was neutralized with of 10% HCI (20 ml) and washed with saturated NaHCO3 and brine solution and evaporated on a rota-vapour and the crude product was purified by column chromatography on silica gel to yield 2.19 g of mixture of diastereomers (94.8 % yield) in approx. 2:3 ratio which were separated by column chromatography to furnish the two isomers 3a8 (higher Rf) as white solid (m.p. 115°-116° C) and 4a8 (lower Rf) as white solid (m.p. 130-131 °C) respectively. EXAMPLE: - 9 TRIOXANE 2a9 FORMULA 2a, Ar =1-Napthyl- To a stirred solution of unsaturated trioxane 1a9 (formula 1a, Ar=1-Napthyl-) (1.00 gm, 2.762 mmol) and N2H4.H2O (2.7 ml) (neutralized with CO2) in 1:1 mixture of EtOH/THF (50ml), cooled to 0° C, was added 30% H2O2 (9.4 ml) dropwise and the reaction mixture was stirred at r.t. for 27 days. The reaction mixture was evaporated on a rota-vapour and then diluted with water (20 ml) and extracted with ether (3x50 ml). The ethereal layer was neutralized with 10% HCI (20 ml) and washed with saturated NaHCO3and brine solution and evaporated on a rota-vapour and the crude product was purified by column chromatography on silica gel to yield 350mg of mixture of diastereomers (34.82 % yield) in approx. 2:3 ratio which were separated by column chromatography to furnish the two isomers 3a9 (higher Rf) as semisolid and 4a9 (lower Rf) as white solid (m.p. 120-122 °C) respectively. EXAMPLE:-10 TRIOXANE 2a10 FORMULA 2a, Ar =p-Cyclohexyl-C6H4- To a stirred solution of unsaturated trioxane 1a10 (formula 1a, Ar= p-Cyclohexyl-C6H4-) (2.00 gm, 5.076 mmol) and N2H4.H2O (5.05 ml) in 1:1 mixture of EtOH/THF (100 ml), cooled to 0° C , was added of 30% H2O2 (17.26 ml) dropwise and the reaction mixture was stirred at it for 5 days. The reaction mixture was evaporated on a rota-vapour and then diluted with water (20 ml) and then extracted with ether (3x100 ml ). The ethereal layer was neutralized with 10% HCI (20 ml) and washed with saturated NaHCO3 and brine solution and evaporated on a rota-vapour and the crude product was purified by column chromatography on silica gel to yield 1.95g of mixture of diastereomers (97.01 % yield) in approx. 2:3 ratio which were separated by column chromatography to furnish the two isomers 3a10 (higher Rf) as white solid (m.p. 141°-143° C) and 4a10 (lower Rf) as white solid (m.p. 117-118 °C) respectively. EXAMPLE: -11 TRIOXANE 2a11 FORMULA 2a, Ar =2-Flurenyl- To a stirred solution of unsaturated trioxane 1a11 (formula 1a, Ar=2-Flurenyl-) (1.00 gm, 2.50 mmol) and N2H4.H2O (2.5 ml) in 1:1 mixture of EtOHmHF (50 ml), cooled to 0° C, was added 30% H2O2 (8.5 ml) dropwise and the reaction mixture was stirred at it for 8 days. The reaction mixture was evaporated on a rota-vapour and then diluted with water (20 ml) and extracted with ether (3x50 ml). The ethereal layer was neutralized with 10% HCI (20 ml) and washed with saturated NaHCOs and brine solution and evaporated on a rota-vapour and the crude product was purified by column chromatography on silica gel to yield 900mg of mixture of diastereomers (89.5 % yield) in approx. 2:3 ratio which were separated by column chromatography to furnish the two isomers 3a11 (higher Rf) as white solid (m.p. 133-135 °C) and 4a11 (lower Rf) as white solid (m.p. 136-138 °C) respectively. EXAMPLE: -12 8-(1-PHENYL-ETHYL)-6, 7, 10-TRIOXA-SPIRO [4, 5] DECANE (TRIOXANE 2b1, FORMULA 2b, Ar =C6H5-) To a stirred solution of unsaturated trioxane 1b1 (formula 1b, Ar=C6H5-) (2.00 gm, 8.130 mmol) and N2H4.H2O (8.1 ml) in 1:1 mixture of EtOH/THF (200 ml), cooled to 0° C, was added 30% H202 (27.6 ml) dropwise and the reaction mixture was kept at same temp for 2 days. The reaction mixture was evaporated on a rotavapour and then diluted with water (40 ml) and extracted with ether (3x100 ml) . The ethereal layer was neutralized with 10% HCI (20 ml) and washed with saturated NaHC03 and brine solution and evaporated on a rotavapour and the crude product was purified by column chromatography on silica gel to yield 740 mg of mixture of diastereomers (36.67 % yield) in approx. 2:3 ratio which were separated by column chromatography to furnish the two isomers 3b1 (higher Rf) as oil and 4b2 (lower Rf) as oil as well, respectively. EXAMPLE: -13 8-(1-TOLYL-ETHYL)-6,7,10-TRIOXA-SPIRO[4,5]DECANE (TRIOXANE 2b2, FORMULA 2b, Ar =pMe-C6H4-) To a stirred solution of unsaturated trioxane 1b2 (formula 1b, Ar= pMe-CeHs-) (2.00 gm, 7.692 mmol) and N2H4.H20 (7.7 ml) in 1:1 mixture of EtOH/THF (200 ml), cooled to 0° C, was added 30% H2O2 (26.16 ml) dropwise and the reaction mixture was kept at same temp for 2 days. The reaction mixture was evaporated on a rotavapour and then diluted with water (40 ml) and extracted with ether (3x100 ml). The ethereal layer was neutralized with 10% HCI (20 ml) and washed with saturated NaHCOsand brine solution and evaporated on a rotavapour and the crude product was purified by column chromatography on silica gel to yield 636 mg of mixture of diasteriomers (31.56 % yield) in approx. 2:3 ratio which were separated by column chromatography to furnish the two isomers 3b2 (higher Rf) as oil and 4b2 (lower Rf) as oil as well, respectively. EXAMPLE: -14 8-[1-(4-CHLORO-PHENYL)-ETHYL]-6,7,10-TRiOXA-SPIRO[4,S]DECANE (TRIOXANE 2b3, FORMULA 2b, Ar =pCI-C6H4-) To a stirred solution of unsaturated trioxane 1b3 (formula 1b, Ar= pCI-C6H4-) (2.00 gm, 7.143 mmol) and N2H4.H20 (7.15 ml) in 1:1 mixture of EtOH/THF (200 ml), cooled to 0° C, was added 30% H2O2 (24.3 ml) dropwise and the reaction mixture was kept at same for 2 days and then stirred at rt. for 1 day. The reaction mixture was evaporated on a rotavapour and then diluted with water (40 ml) and extracted with ether (3x100 ml). The ethereal layer was neutralized with 10% HCI (20 ml) and washed with saturated NaHCO3 and brine solution and evaporated on a rotavapour and the crude product was purified by column chromatography on silica gel to yield 1.040 gm of mixture of diasteriomers (51.63 % yield) in approx. 2:3 ratio which were separated by column chromatography to furnish the two isomers 3b3 (higher Rf) as oil and 4b3 (lower Rf) as oil as well, respectively. EXAMPLE:-15 8-[1 -(4-FLUORO-PHENYL)-ETHYL]-6,7,10-TRIOXA-SPIRO[4,5]DECANE (TRIOXANE 2b4, FORMULA 2b, Ar =pF-C6H4-) To a stirred solution of unsaturated trioxane 1b4 (formula 1b, Ar= pF-C6H4-) (2.00 gm, 7.576 mmol) and N2H4.H2O (7.6 ml) in 1:1 mixture of EtOH/THF (200 ml), cooled to 0° C, 20 was added 30% H2O2 (25.8 ml) dropwise and the reaction mixture was kept at same temp for 2 days and then stirred at rt. for 1 day. The reaction mixture was evaporated on a rotavapour and then diluted with water (40 ml) and extracted with ether (3x100 ml). The ethereal layer was neutralized with 10% HCI (20 ml) and washed with saturated NaHCO3 and brine solution and evaporated on a rotavapour and the crude product was purified by column chromatography on silica gel to yield 1.34 gm of mixture of diasteriomers (66.5 % yield) in approx. 2:3 ratio which were separated by column chromatography to furnish the two isomers 3b4 (higher Rf) as oil and 4b4 (lower Rf) as oil as well, respectively. EXAMPLE:-16 8-[1-(4-METHOXY-PHENYL)-ETHYL]-6,7,10-TRIOXA-SPIRO[4,5]DECANE (TRIOXANE 2b5, FORMULA 2b, Ar =pMeO-C6H4-) To a stirred solution of unsaturated trioxane 1b5 (formula 1b, Ar= pMeO-C6H4-) (2.00 gm, 7.246 mmol) and N2H4.H2O ( 7.25 ml ) in 1:1 mixture of EtOH/THF ( 200 ml), cooled to 0° C, 20 was added 30% H2O2 ( 24.6 ml ) dropwise and the reaction mixture was kept at same temp for 2 days and then stirred at rt. for 12 days. The reaction mixture was evaporated on a rotavapour and then diluted with water (40 ml) and extracted with ether (3x100 ml). The ethereal layer was neutralized with of 10% HCI (20 ml) and washed with saturated NaHCOs and brine solution and evaporated on a rotavapour and the crude product was purified by column chromatography on silica gel to yield 1.29 gm of mixture of diasteriomers (64.04 % yield) in approx. 2:3 ratio which were separated by column chromatography to furnish the two isomers 3b5 (higher Rf) as white solid (m.p. 84°-86° C) and 4b5 (lower Rf) as oil, respectively. EXAMPLE:-17 8-(1-BIPHNYL-4-YL-ETHYL)-6,7,10-TRIOXA-SPIRO[4,5]DECANE (TRIOXANE 2b6 FORMULA 2b, Ar =pPh-C6H4-) To a stirred solution of unsaturated trioxane 1b6 (formula 1b, Ar= pPh-C6H4-) (1.00 gm, 3.105 mmol) and N2H4.H2O (3 ml) in 1:1 mixture of EtOH/THF (100 ml), cooled to 0° C, 20 was added 30% H2O2 (10.18 ml) dropwise and the reaction mixture was kept at same temp for 2 days. The reaction mixture was evaporated on a rotavapour and then diluted with water (20 ml) and extracted with ether (3x50 ml). The ethereal layer was neutralized with 10% HCI (20 ml) and washed with saturated NaHCO3 and brine solution and evaporated on a rotavapour and the crude product was purified by column chromatography on silica gel to yield 437 mg of mixture of diastereomers (43.44 % yield) in approx. 2:3 ratio which were separated by column chromatography to furnish the two isomers 3b6 (higher Rf) as white solid (m.p. 74°-76° C) and 4b6 (lower Rf) as white solid (m.p. 82°-84°C) as well, respectively. EXAMPLE:-18 8-(1-NAPTHALEN-2-YL-ETHYL)-6,7,10-TRIOXA-SPIRO[4,5]DECANE (TRIOXANE 2b7 FORMULA 2, Ar =2-Napthyl-) To a stirred solution of unsaturated trioxane 1b7 (formula 1b, Ar=2-Napthyl-) (2.00 gm, 6.757 mmol) and N2H4.H2O (7.25 ml) in 1:1 mixture of EtOH/THF (200 ml), cooled to 0° C, was added 30% H2O2 (22.98 ml) dropwise and the reaction mixture was kept at same temp for 2 days and then stirred at rt. for 8 days. The reaction mixture was evaporated on a rotavapour and then diluted with water (40 ml) and extracted with ether (3x100 ml). The ethereal layer was neutralized with 10% HCI (20 ml) and washed with saturated NaHCO3 and brine solution and evaporated on a rotavapour and the crude product was purified by column chromatography on silica gel to yield 1.310 gm of mixture of diasteriomers (65.06% yield) in approx. 2:3 ratio which were separated by column chromatography to furnish the two isomers 3b7 (higher Rf) as white solid m.p.70°-72°C and 4b7 (lower Rf) as oil, respectively. EXAMPLE:-19 3-(1-PHENYL-ETHYL)-1,2,5-TRIOXA-SPIRO[5,5]UNDECANE (TRIOXANE 2c1, FORMULA 2c, R=C6H5-) To a stirred solution of unsaturated trioxane 1c1 (formula 1c, Ar=CeH5-) (2.00 gm, 7.692 mmol) and N2H4.H2O (8.1 ml) in 1:1 mixture of EtOHmHF (200 ml), cooled to 0° C, was 30% H202 (26.05 ml) dropwise and the reaction mixture was kept at same temp for 2 days and then stirred at rt. for 8 days. The reaction mixture was evaporated on a rotavapour and then diluted with water (40 ml) and extracted with ether (3x100 ml). The ethereal layer was neutralized with 10% HCI (20 ml) and washed with saturated NaHCO3 and brine solution and evaporated on a rotavapour and the crude product was purified by column chromatography on silica gel to yield 1.174 gm of mixture of diastereomers (58.25 % yield) in approx. 2:3 ratio which were separated by column chromatography to furnish the two isomers 3d (higher Rf) as oil and 4c1 (lower Rf) as oil as well, respectively. EXAMPLE: - 20 3-(1 -p-TOLYL-ETHYL)-1,2,5-TRIOXA-SPIRO[5,5]UNDECANE (TRIOXANE 2c2, FORMULA 2c, R=pMe-C6H4-, R1R2= CYCLOHEXYL) To a stirred solution of unsaturated trioxane 1c2 (formula 1c, Ar= pMe-C6H5-) (2.00 gm, 7.299 mmol) and N2H4.H2O (7.3 ml) in 1:1 mixture of EtOH/THF (200 ml), cooled to 0° C, was added 30% H2O2 (24.8 ml) dropwise and the reaction mixture was kept at same temp for 2 days and then stirred at rt. for 5 days. The reaction mixture was evaporated on a rotavapour and then diluted with water (40 ml) and extracted with ether (3x100 ml). The ethereal layer was neutralized with of 10% HCI (20 ml) and washed with saturated NaHCO3 and brine solution and evaporated on a rotavapour and the crude product was purified by column chromatography on silica gel to yield 1.790 gm of mixture of diasteriomers (88.80 % yield) in approx. 2:3 ratio which were separated by column chromatography to furnish the two isomers 3c2 (higher Rf) as oil and 4c2 (lower Rf) as oil as well, respectively. EXAMPLE: - 21 3-[1-(4-CHLORO-PHENYL)-1,2,5-TRIOXA-SPIRO[5,5]UNDECANE (TRIOXANE 2c3, FORMULA 2, R=pCI-C6H4-) To a stirred solution of unsaturated trioxane 1c3 (formula 1c, Ar= pCI-C6H4-) (2.00 gm,6.803 mmol) and N2H4.H20 ( 6.8 ml) in 1:1 mixture of EtOH/THF ( 200 ml), cooled to 0° C, was added 30% H2O2 ( 23.1 ml) dropwise and the reaction mixture was kept at same temp for 2 days and then stirred at it for 9 days. The reaction mixture was evaporated on a rotavapour and then diluted with water (40 ml) and extracted with ether (3x100ml). The ethereal layer was neutralized with 10% HCI (20 ml) and washed with saturated NaHCO3 and brine solution and evaporated on a rotavapour and the crude product was purified by column chromatography on silica gel to yield 1.50 gm of mixture of diasteriomers (74.49 % yield) in approx. 2:3 ratio which were separated by column chromatography to furnish the two isomers 3c3 (higher Rf) as oil and 4c3 (lower Rf) as oil as well, respectively. EXAMPLE: - 22 3-[1-(4-FLUORO-PHENYL)-1,2,5-TRIOXA-SPIRO[5,5]UNDECANE (TRIOXANE 2c4, FORMULA 2c, R=pF-C6H4-) To a stirred solution of unsaturated trioxane 1c4 (formula 1c, Ar= pF-C6H4-) (1.00 gm, 7.194 mmol) and N2H4.H20 (7.2 ml) in 1:1 mixture of EtOH/THF (200 ml), cooled to 0° C, 20 was added 30% H2O2 (24.46 ml) dropwise and the reaction mixture was kept at same temp for 2 days and then stirred at it for 5 days. The reaction mixture was evaporated on a rotavapour and then diluted with water (40 ml) and extracted with ether (3x100 ml). The ethereal layer was neutralized with 10% HCI (20 ml )and washed with saturated NaHCOa and brine solution and evaporated on a rotavapour and the crude product was purified by column chromatography on silica gel to yield 1.395 gm of mixture of diasteriomers (69.25 % yield) in approx. 2:3 ratio which were separated by column chromatography to furnish the two isomers 3c4 (higher Rf) as white solid (m.p. 56°-58° C) and 4c4 (lower Rf) as oil, respectively. EXAMPLE: - 23 3-[1 -(4-METHOXY-PHENYL)-1,2,5-TRIOXA-SPIRO[5,5]UNDECANE (TRIOXANE 2c5, FORMULA 2c, R=pMeO-C6H4-) To a stirred solution of unsaturated trioxane 1c5 (formula 1c, Ar= pMeO-C6H4-) (2.00 gm, 6.896 mmol) and N2H4.H2O (6.9 ml ) in 1:1 mixture of EtOH/THF ( 200 ml ), cooled to 0° C, was added 30% H2O2 (23.45 ml) dropwise and the reaction mixture was kept at same temp for 2 days and then stirred at rt. for 9 days. The reaction mixture was evaporated on a rotavapour and then diluted with water (40 ml) and extracted with ether (3x100 ml). The ethereal layer was neutralized with 10% HCI (20 ml) and washed with saturated NaHCOa and brine solution and evaporated on a rotavapour and the crude product was purified by column chromatography on silica gel to yield 1.82 gm of mixture of diasteriomers (90.38 % yield) in approx. 2:3 ratio which were separated by column chromatography to furnish the two isomers 3c5 (higher Rf) as white solid (m.p. 65° C) and 4c5 (lower Rf) as oil, respectively. EXAMPLE: - 24 3-(1 -BIPHENYL-4-YL-ETHYL)-1,2,5-TRIOXA-SPIRO[5,5]UNDECANE (TRIOXANE 2c6 FORMULA 2c, R=pPh-C6H4-) To a stirred solution of unsaturated trioxane 1c6 (formula 1c, Ar= pPh-C6H4-) (2.00 gm, 5.952 mmol) and N2H4.H20 (5.95 ml) in 1:1 mixture of EtOHfi"HF (200 ml), cooled to 0° C, was added 30% H2O2 (20.24 ml) dropwise and the reaction mixture was kept at same temp for 2 days, and then stirred at r.t for 18 days. The reaction mixture was evaporated on a rotavapour and then diluted with water (40 ml) and extracted with ether (3x100 ml). The ethereal layer was neutralized with 10% HCI (20 ml) and washed with saturated NaHCO3 and brine solution and evaporated on a rotavapour and the crude product was purified by column chromatography on silica gel to yield 1.750 gm of mixture of diastereomers (86.98 % yield) in approx. 2:3 ratio which were separated by column chromatography to furnish the two isomers 3c6 (higher Rf) as white solid (m.p. 80°-81° C) and 4c6 (lower Rf) as white solid (m.p. 85°-86° C) as well, respectively. EXAMPLE: - 25 3-(1-NAPHTHALEN-2-YL-ETHYL)-1, 2,5-TRIOXA-SPIRO [5, 5] UNDECANE (TRIOXANE 2c7, FORMULA 2c, R=2-Napthyl-) To a stirred solution of unsaturated trioxane 1c7 (formula 1c, Ar=2-Napthyl-) (2.00 gm, 6.452 mmol) and N2H4.H20 (6.46 ml) in 1:1 mixture of EtOH/THF (200 ml), cooled to 0° C, was added 30% H2O2 (21.9 ml) dropwise and the reaction mixture was kept at same temp for 2 days and then stirred at r.t for 15 days. The reaction mixture was evaporated on a rotavapour and then diluted with water (40 ml) and extracted with ether (3x100 ml). The ethereal layer was neutralized with of 10% HCI (20 ml) and washed with saturated NaHCO3 and brine solution and evaporated on a rotavapour and the crude product was purified by column chromatography on silica gel to yield 1.745 gm of mixture of diasteriomers (86.686 % yield) in approx. 2:3 ratio which were separated by column chromatography to furnish the two isomers 3c7 (higher Rf) as white solid (m.p. 85°-87° C) and 4c7 (lower Rf) as white solid (m.p. 92°-94° C) respectively. FOLLOWING THE ABOVE PROCEDURE, THE FOLLOWING TRIOXANES WERE ALSO PREPARED: (TABLE REMOVE -2) (TABLE REMOVE -3) (TABLE REMOVE -4) (TABLE REMOVE -5) ANTIMALARIAL ACTIVITY The antimalarial activity of the test compounds was evaluated against multidrug resistant strain of Plasmodium yoelii Nigeriensis in Swiss mice. General Procedure:- Random bred Swiss mice of either sex (20 ± 2 g) were inoculated intraperitoneally with 1x105 P. yoelii (MDR) parasites on day zero. The treatments with test compounds were administered to group of 5 mice each at different dose levels ranging between 12-96 mg/kg/day. The compounds were administered as solutions in oil via oral route for 4 consecutive days (day 0-3). p-Arteether and cc-Arteether were used as positive control. Blood smears from experimental mice were observed on day 4 and 7, day 10 and thereafter at regular interval till day 28 or death of the animal. The parasitaemia level on day 4 was compared with the vehicle control group and the percent suppression of parasitaemia in treated groups was calculated. The compounds which showed more than 90% suppression were identified for further screening. For determining the curative dose of a compound the treated mice were observed till day 28.The dose at which no parasitaemia develops during the observation period has been recorded as the curative dose. The results are shown in table given below: ANTIMALARIAL ACTIVITY OF TRIOXANES AGAINST P. yoelii IN MICE (TABLE REMOVE -6) (TABLE REMOVE -7) (TABLE REMOVE -8) (TABLE REMOVE -9) A SCHEME FOR PREPRATION OF TRIOXANES OF GENERAL FORMULA (FIGURE REMOVE) WE CLAIM: 1:- Substituted 1, 2, 4-trioxanes of general formula 2 , and their isomers of formula 3 and 4 (Formula Removed) wherein Ar is selected from the group comprising of phenyl , pMe-phenyl, pCl-phenyl, pMeO- phenyl, pF-phenyl, biphenyl, 2-napthyl, p-Br-phenyl,l-napthyl, p-Cyclohexyl- phenyl, 2-Flurenyl, wherein R1 and R2 represents the part of cyclic ring system like cyclohexane, cyclopentane and adamantane. 2:- Substituted 1, 2, 4-trioxanes as claimed in claim 1 wherein the representative compounds of general formula 2a, being defined as follows; (Formula Removed) 3:- Substituted 1, 2, 4-trioxanes as claimed in claim 1 wherein the representative compounds of general formula 2a, being defined as follows; (Formula Removed) 4:- Substituted 1, 2, 4-trioxanes as claimed in claim 1 wherein the representative compounds of general formula 2a, being defined as follows; (Formula Removed) 5:- Substituted 1,2, 4-trioxanes as claimed in claim 1 wherein the diastereoisomers of compound of formula 2 is represented by structural formula 3 and 4 as shown below wherein Ar is selected from the group consisting of phenyl , pMe-phenyl, pCl-phenyl, pMeO- phenyl, pF-phenyl, biphenyl, 2-napthyl, p-Br-phenyl,l-napthyl, p-Cyclohexyl-phenyl, 2-Flurenyl, whereas R1 and R2 represents the part of cyclic ring system like cyclohexane, cyclopentane and adamantane. (Formula Removed) 6:- Substituted 1, 2, 4-trioxanes as claimed in claim 1-5 wherein the representative compounds of general formula 3a, being defined as follows; (Formula Removed) 7. :- Substituted 1, 2, 4-trioxanes as claimed in claim 1-5 wherein the representative compounds of general formula 4al-4a11, being defined as follows; wherein the said compounds having the structural formula as shown below: (Formula Removed) 8.:- Substituted 1, 2, 4-trioxanes as claimed in claim 1-5 wherein the representative compounds of general formula 3bl-3b7 being defined as follows; (Formula Removed) 9:- Substituted 1, 2, 4-trioxanes as claimed in claim 1-5 wherein the representative compounds of general formula 4bl-4b7 being defined as follows; (Formula Removed) 10:- Substituted 1, 2, 4-trioxanes as claimed in claim 1-5 wherein the representative compounds of general formula 3cl-3c7 being defined as follows; (Formula Removed) 11:- Substituted 1, 2, 4-trioxanes as claimed in claim 1-5 wherein the representative compounds of general formula 4cl-4c7 being defined as follows; (Formula Removed) 12. A process for the preparation of novel substituted 1,2,4-trioxanes of formula 2 and their isomers of general formula 3 and 4; wherein Ar is selected from the group consisting of phenyl , pMe-phenyl, pCl-phenyl, pMeO- phenyl, pF-phenyl, biphenyl, 2-napthyl, p-Br-phenyl, l-napthyl,p-Cyclohexyl-phenyl, 2-Flurenyl, (Formula Removed) wherein R and R represents the part of cyclic ring system like cyclohexane, cyclopentane and adamantane, which comprises reaction of 6-(l-aryl vinyl)-1, 2, 4-trioxanes of formula 1 (Formula Removed) where in Ar is selected from the group consisting of phenyl , pMe-phenyl, pCl-phenyl, pMcO- phenyl,pF-phenyl, biphenyl, 2-napthyl, p-Br-phenyl, 1-napthyl, p-Cyclohexyl-phenyl, 2-Flurenyl whereas R1 and R2 represents the part of cyclic ring system like cyclohexane, cyclopentane and adamantane, with diimide, generated in situ, by reacting H2O2 with N2H4.H2O or CO2 neutralized N2H4.H2O in a water miscible organic solvent at a temperature ranging between 0 °C to room temperature for a period ranging between 2 to 29 days, to furnish trioxanes of formula 2 as a mixture of diastereomers, separating the diastereomers by chromatography to give pure isomers of the formula 3 and 4 wherein Ar, R1 and R have the same meaning as above for compound of formula 2. 13:- A process as claimed in claim 12 wherein the water miscible organic solvent is selected from a group consisting of tetrahydrofuran, ethyl alcohol, methyl alcohol, CH3CN or a mixture thereof. 14:- A process as claimed in claim 12 wherein the chromatography to separate the compounds of formula 3 and 4 is carried out using solvent selected from EtOAc: Hexane. 15:- A process as claimed in claim 12 wherein the chromatography is carried out on silica gel.

Full Text

This present invention relates to novel substituted 1, 2, 4-trioxanes useful as antimalarial agents having general formula 2.
(FIGURE REMOVE)

This invention also relates to a process for the preparation of these novel substituted 1, 2, 4-trioxanes.
This invention particularly relates to a process for the preparation of 6-(1-aryl ethyl)-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 2 wherein Ar represents the aryl groups like phenyl , pMe-phenyl, pCI-phenyl, pMeO- phenyl, pF-phenyl, biphenyl, 2-napthyl, p-Br-phenyl,1-napthyl, p-Cyclohexyl-phenyl, 2-Flurenyl, whereas R1 and R2 represents the part of cyclic ring system like cyclohexane, cyclopentane and adamantane. Several of these novel trioxanes have shown high order of antimalarial activity against multidrug-resistant malaria in mice and thus hold promise as antimalarial agents against multidrug-resistant malaria.
FIELD OF INVENTION
This present invention relates to novel substituted 1, 2, 4-trioxanes useful as antimalarial agents having general formula 2.
(FIGURE REMOVE)

This invention also relates to a process for the preparation of these novel substituted 1, 2, 4-trioxanes.
This invention particularly relates to a process for the preparation of 6-(1-aryl ethyl)-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 2 wherein Ar represents the aryl groups like phenyl , pMe-phenyl, pCI-phenyl, pMeO- phenyl, pF-phenyl, biphenyl, 2-napthyl, p-Br-phenyl,1-napthyl, p-Cyclohexyl-phenyl, 2-Flurenyl, whereas R1 and R2 represents the part of cyclic ring system like cyclohexane, cyclopentane and adamantane. These trioxanes are new compounds and are useful as antimalarial agents. Some of these compounds have been tested against multi-drug resistant malaria in mice and have shown promising antimalarial activity. The invention, thus relates to pharmaceutical industry.
BACKGROUND OF INVENTION
Malaria is still one of the world's most deadly disease that threatens nearly 40% of the world's population and infects approximately 300 to 500 million people annually world wide mainly in tropical and subtropical areas. It is estimated that there are between 1 million to 3 million deaths every year due to malaria. In Africa alone, more than 1 million children under the age of 5 die from malaria each year.
Malaria is a parasite borne disease and human infection is caused by four distinct species of the protozoon Plasmodium, namely P. vivax, P. falciparum, P. ovale, P. malariae. Malaria is transmitted by bite of a vector the female Anopheles mosquito which is responsible for its global epidemics. Quite a number of natural products isolated from various plants and microorganisms have shown potent antimalarial activity, thus acting as lead for further drug development.

Natural products as lead for malaria chemotherapy dates back to the early 18th century when bark of Cinchona tree was used in the treatment of fever by the natives of South America. It was in 1820 that quinine was isolated as active principle of the bark. Quinine is active against the trophozoites present in the erythrocytes but has no effect on exo-erythrocytic stages that develop in lever. Later on taking quinine as lead several synthetic analogues like chloroquine, mefloquin, primaquine etc, were developed as antimalarial drugs and are still being used.
Unfortunately due to indiscriminate use of chloroquine and its analogues the parasite developed resistance towards these drugs. Indeed the re-emergence of the malaria as a world wide epidemic can be largely attributed due to rapid development of parasite resistance towards conventional drugs. Thus there is an urgent need to develop new drugs which are novel both in terms of mechanism of action and pharmacophore.
In that regard discovery of artemisinin, a sesquiterpene lactone endoperoxide, isolated from Chinese traditional medicinal herb Artemisia annua and its semisynthetic derivatives like arteether and artemether have shown tremendous potential and are presently the drugs of choice for the treatment of multidrug resistant malaria. These drugs are effective against both chloroquine sensitive and chloroquine resistant strains of Plasmodium falciparum, [For reviews and background knowledge of artemisinin and its semisynthetic derivatives see: (a) Klayman, D. L Science 1985, 228, 1049. (b) Bhattacharya, A. K.; Sharma, R. P. Heterocycles 1999, 51, 1651. (c) Borstnik, K.; Paik, I.; Shapiro, T. A.; Posner, G. H. Int. J. Parasitol. 2002, 32, 1661. (d) Ploypradith, P. Acta Trop. 2004, 89, 329. (e) O'Neill, P. M.; Posner, G. H. J. Med. Chem. 2004, 47, 2945.]

(FIGURE REMOVE)

The limited availability of artemisinin from the natural sources and taking into account of the fact, that it is actually the endoperoxide linkage in the form of 1,2,4- trioxane ring system which is responsible for its antimalarial activity, has led to the present efforts to develop new structurally simple trioxanes which are easily accessible relatively cheap and active against multidrug resistant strains. . Several structurally simple synthetic trioxanes have shown promising antimalarial activity [(a) Bhattacharya.A K.,Sharma,RP.; Hefrocyc/es.1999 57,1681. (b) Borstnik, K.; Paik, I.; Shapiro, T.A.; Posner, G. H. Int. J. Parasitol. 2002, 32, 1661. (c) Singh, C.; Misra, D.; Saxena, G.; Chandra, S. Bioorg. Med. Chem. Lett. 1992, 2, 497. (d) Singh, C.; Misra, D.; Saxena, G.; Chandra, S. Bioorg. Med. Chem. Lett. 1995, 5, 1913. (e) Singh, C.; Puri S. K. U.S. Patent 631649381,2001. (f) Singh, C.; Gupta, N.; Puri, S. K. Bioorg. Med. Chem. Lett. 2003, 13, 3447. (g) Singh, C.; Malik, H.; Puri, S. K. Bioorg. Med. Chem. Lett. 2004, 14, 459. (h) Singh, C.; Srivastav.N.C.; Puri,
S. K. Bioorg. Med. Chem. Lett. 2004, 12, 5745-5752. (i) Singh, C.; Tiwari, P.; Puri, S. K.
PCT Patent application No. PCT/IN02/00093, dated 28.3.2002. 0) Singh, C.; Malik, H.; Puri, S. K. Patent application No. PCT/IN04/00413, dated 27.12.04. (k) Singh, C; Malik, H.; Puri, S. K.: J. Med. Chem., 2006. 49 (9), 2794 -2803].

(FIGURE REMOVE)

(FIGURE REMOVE)
(FIGURE REMOVE)
The present invention deals with the preparation of a novel series of 1,2,4-trioxanes, some of which have shown high order of antimalarial activity against multidrug resistant strain, Pyoelii in mice.
ABOUT THE PRESENT INVENTION
This present invention relates to novel substituted 1, 2, 4-trioxanes useful as antimalarial agents having general formula 2. This invention also relates to a process for the preparation of these novel substituted 1, 2, 4-trioxanes. This invention particularly relates to a process for the preparation of 6-(1-aryl ethyl)-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 2 wherein Ar represents the aryl groups like phenyl , pMe-phenyl, pCI-phenyl, pMeO- phenyl, pF-phenyl, biphenyl, 2-napthyl, p-Br-phenyl,1-napthyl, p-Cyclohexyl-phenyl, 2-Flurenyl and the like, whereas R1 and R2 represents the part of cyclic ring system like cyclohexane, cyclopentane and adamantane and the like. These trioxanes are new compounds and are useful as antimalarial agents. Some of these compounds have been tested against multi-drug resistant malaria in mice and have shown high order of antimalarial activity.
These trioxanes thus have the potential to be used for the treatment of malaria, a highly prevalent parasitic disease. The invention, thus relates to pharmaceutical industry.
These trioxanes of the general formula 2 are new chemical entities and they have not been prepared earlier.
The main objective of the present invention is to provide novel substituted 1, 2, 4-trioxanes of formula 2 and a process for the preparation of these novel substituted 1, 2, 4-trioxanes of general formula 2, a new series of antimalarial agents.
Accordingly, the present process provides a process for the preparation of novel substituted 1, 2, 4-trioxanes of general formula 2 which comprises the reduction of the 6-(1-aryl vinyl)-1, 2, 4-trioxanes of formula 1 with diimide, generated in situ, by the reaction of H2O2 with N2H4.H20 or CO2 neutralized N2H4.H2O in a water miscible organic solvent such as tetrahydrofuran, ethyl alcohol, methyl alcohol CH3CN or a mixture of these solvents at a temperature range of 0 °C to room temperature to furnish trioxanes of formula 2 as a mixture of diastereomers, separation of the diastereomers by chromatography to give pure isomers of the formula 3 and 4 wherein Ar, R1 and R2 have the same meaning as above.
(FIGURE REMOVE)

Ar=C6H5-1a2 Ar=pMe-C6H4-1a3Ar=pCI-C6H4-1a4Ar=pF-C6H4-1a5 Ar=pMeO-C6H4-1a6Ar=pPh-C6H4-1a7Ar=2-Napthyl-1a8 Ar=p-Br-C6H4-1a9Ar=1-Napthyl-1a10 Ar=p-Cyclohexyl-phenyl-

Ar=C6H5-1b2Ar=pMe-C6H4-1b3Ar=pCI-C6H4-1b4Ar=pF-C6H4-1b5Ar=pMeO-C6H4-1b6Ar=pPh-C6H4-1b7Ar=2-Napthyl-

Ar=C6H5-1c2 Ar=pMe-C6H4-1c3 Ar=pCI-C6H4-1c4Ar=pF-C6H4-1c5 Ar=pMeO-C6H4-1c6Ar=pPh-C6H4-1c7Ar=2-Napthyl-

Ar=2-Flurenyl-
Trioxanes having formula 1
In the process the 6-Aryl vinyl substituted 1, 2, 4-trioxanes of the formula 1 were prepared by the known procedure [(a) Singh.C.; Tetrahedron. Lett. 1990, 31, 6901. (b) Singh, C.; Tiwari, P.; Puri, S. K. PCT Patent application No. PCT/IN02/00093, dated 28.3.2002. (c) Singh, C.; Kanchan, R.; Chandra, S. and Puri, S.K. Indian patent application no. 0909/DEL/2003 dated 18/07/2003]. These trioxanes of formula 1 have been prepared earlier in our
(FIGURE REMOVE)
laboratory and are known compounds. In the process trioxanes of the formula 1 are reduced with diimide.generated by the reaction of hydrogen peroxide and hydrazine hydrate in a water miscible organic solvent such as THF, ethanol, methanol, CH3CN or a mixture of these solvents at ambient temperature to furnish a mixture of diastereomers of the formula 2. Separation of the isomers by chromatography gave pure isomers of formula 3 and 4 where in Ar, R1 and R2 have the same meanings as stated above. ,H

These trioxanes having general formula 3 and 4 are new chemical entities and have not been prepared earlier.
Some of the trioxanes of formula 3 and 4 have been tested against malarial parasite in mice and have shown promising antimalarial activity. The invention is further illustrated by the following examples which should not, however, be constructed to limit the scope of present invention.
(FIGURE REMOVE)

EXAMPLE: -1
TRIOXANE 2a1, FORMULA 2a, Ar=C6H5-
To a stirred solution of unsaturated trioxane 1a1 (formula 1a, Ar=C6H5-) (1.00 gm, 3.205 mmol.) and N2H4.H2O (3.2 ml) in 1:1 mixture of EtOH/THF (50 ml), cooled to 0 °C, was added 30% H202 (10.9 ml) dropwise and the reaction mixture was kept at the same temperature for 3 days. The reaction mixture
was evaporated on a rota-vapour and then diluted with water (20 ml) and extracted with ether (3x50 ml). The ethereal layer was neutralized with 10% HCI (20 ml) and washed with saturated NaHCO3 and brine solution and evaporated on a rota-vapour and the crude product was purified by column chromatography on silica gel to yield 440 mg of mixture of diastereomers (43.7 % yield) in approx. 2:3 ratio which were separated by column chromatography to furnish the two isomers, 3a1 (higher Rf.) as oil and, 4a1 (lower Rf.) as white solid (m.p. 84-85 °C) respectively.The above reaction was also carried out using different solvents.
(TABLE REMOVE -1)

EXAMPLE: - 2
TRIOXANE 2a2, FORMULA 2a, Ar=pMe-C6H4-
To a stirred solution of unsaturated trioxane 1a2 (formula 1a, Ar=pMe-C6H4-)
(1.9 gm, 5.828 mmol) and N2H4.H20 (5.8 ml) in 1:1 mixture of EtOH/THF (100
ml), cooled to 0° C, was added 30% H2O2 (19.8 ml) dropwise and the reaction
mixture was kept at same temp for 3 days. The reaction mixture was

evaporated on a rota-vapour and then diluted with water (40 ml) and extracted with ether (3x100 ml). The ethereal layer was neutralized with 10% HCI (20 ml) and washed with saturated NaHCO3 and brine solution and evaporated on a rota-vapour and the crude product was purified by column chromatography on silica gel to yield 717 mg of mixture of diastereomers (35.8 % yield) in approx. 2:3 ratio which were separated by column chromatography to furnish the two isomers, 3a2 (higher Rf) as oil and 4a2 (lowerRf) also as oil respectively.
.EXAMPLE:-3
TRIOXANE 2a3, FORMULA 2a, Ar =pCI-C6H4-
To a stirred solution of unsaturated trioxane 1a3 (formula 1a, Ar= pCI-CeH4-) (2.0 gm, 5.780 mmol) and N2H4.H2O (6ml) in 1:1 mixture of EtOH/THF (100 ml), cooled to 0° C, was added 30% H2C>2 (20 ml) dropwise and the reaction mixture was kept at same temp for 2 days. The reaction mixture was evaporated on a rota-vapour and then diluted with water (40 ml) and then extracted with ether (3x100 ml). The ethereal layer was neutralized with 10% HCI (20 ml) and washed with saturated NaHCOs and brine solution and evaporated on a rota-vapour and the crude product was purified by column chromatography on silica gel to yield 710 mg of mixture of diastereomers (35.3 % yield) in approx. 2:3 ratio which were separated by column chromatography to furnish the two isomers 3a3 (higher Rf) as white solid (m.p. 92°-94° C) and 4a3 (lower Rf) as solid as well (m.p. 114°-115° C) respectively.
.EXAMPLE:- 4
TRIOXANE 2a4, FORMULA 2a, Ar =pF-C6H4-
To a stirred solution of unsaturated trioxane 1a4 (formula 1a, Ar= pF-CeH4-) (2.00 gm, 6.060 mmol) and N2H4.H20 (6 ml) in 1:1 mixture of EtOH/THF (100 ml), cooled to 0° C, was added 30% H2O2 (20 ml) dropwise and the reaction

mixture was kept at same for 2 days. The reaction mixture was evaporated on a rota-vapour and then diluted with water (40 ml) and extracted with ether (3x100 ml). The ethereal layer was neutralized with 10% HCI (20 ml) and washed with saturated NaHCO3 and brine solution and evaporated on a rota-vapour and the crude product was purified by column chromatography on silica gel to yield 735 mg of mixture of diastereomers (36.5 % yield) in approx. 2:3 ratio which were separated by column chromatography to furnish the two isomers 3a4 (higher Rf) as oil and 4a4 (lower Rf) as white solid (m.p. 80°-81° C) respectively.
EXAMPLE: - 5
TRIOXANE 2a5, FORMULA 2a, Ar =pMeO-C6H4-
To a stirred solution of unsaturated trioxane 1a5 (formula 1a, Ar= pMeO-C6H4-) (2.00 gm, 5.548 mmol) and N2H4.H2O (6ml) in 1:1 mixture of EtOH/THF (100 ml), cooled to 0° C, was added 30% H2O2 (20 ml) dropwise and the reaction mixture was kept at same temp for 2 days. The reaction mixture was evaporated on a rotavapour and then diluted with water (40 ml) and extracted with ether (3x100ml). The ethereal layer was neutralized with 10% HCI (20 ml) and washed with saturated NaHCOaand brine solution and evaporated on a rotavapour and the crude product was purified by column chromatography on silica gel to yield 730 mg of mixture of diastereomers (36.5 % yield) in approx. 2:3 ratio which were separated by column chromatography to furnish the two isomers 3a5 (higher Rf) as oil and 4a5 (lower Rf) as oil as well, respectively.
EXAMPLE: - 6
TRIOXANE 2a6, FORMULA 2a, Ar =pPh-C6H4-
To a stirred solution of unsaturated trioxane 1a6 (formula 1a, Ar= pPh-C6H4-) (1.00 gm, 2.577 mmol) and N2H4.H20 (6ml) in 1:1 mixture of EtOH/THF (50ml), cooled to 0° C, was added 30% H2O2 (20 ml) dropwise and the reaction mixture was kept at same temp for 2 days and then at r.t for 2 days.

The reaction mixture was evaporated on a rota-vapour and then diluted with water (20 ml) and extracted with ether (3x50 ml). The ethereal layer was neutralized with 10% HCI (20 ml) and washed with saturated NaHCO3 and brine solution and evaporated on a rota-vapour and the crude product was purified by column chromatography to yield 590 mg of mixture of diastereomers (58.7 % yield) in approx. 2:3 ratio which were separated by column chromatography to furnish the two isomers 3a6 (higher Rf) as white solid (m.p. 138°-140° C) and 4a6 (lower Rf) as white solid (m.p. 145°-147° C) as well, respectively.
EXAMPLE: - 7
TRIOXANE 2a7 FORMULA 2a, Ar =2-Napthyl-
To a stirred solution of unsaturated trioxane 1a7 (formula 1a, Ar=2-Napthyl-) (2.00 gm, 5.525 mmol) and N2H4.H2O (2.8 ml) in 1:1 mixture of EtOH/THF (100 ml), cooled to 0° C, was added 30% H2O2 (9.4 ml) dropwise and the reaction mixture was kept at same temp for 2 days and then stirred at r.t. for 13 days, The reaction mixture was evaporated on a rota-vapour and then diluted with water (20 ml) and extracted with ether (3x100 ml). The ethereal layer was neutralized with 10% HCI (20 ml) and washed with saturated NaHCOs and brine solution and evaporated on a rota-vapour and the crude product was purified by column chromatography on silica gel to yield 680 mg of mixture of diastereomers (67.6 % yield) in approx. 2:3 ratio which were separated by column chromatography to furnish the two isomers 3a7 (higher Rf) as white solid (m.p. 120°-121° C) and 4a7 (lower Rf) as white solid (m.p. 135°C) respectively.
EXAMPLE: - 8
TRIOXANE 2a8 FORMULA 2a, Ar = pBr-C6H4
To an stirring solution of unsaturated trioxane 1a8 (formula 1a, Ar= pBr-CeH4-) (2.3 gm, 5.897 mmol) and N2H4.H2O (2.5 ml) (neutralized with CO2) in 1:1

mixture of EtOHH-HF (100 ml), cooled to 0° C, was added 30% H2O2 (8.5 ml) dropwise and the reaction mixture was stirred at r.t. for 8 days, till no more reactant was left, the reaction mixture was evaporated on a rota-vapour and then diluted with water (20 ml) and extracted with ether (3x100 ml). The ethereal layer was neutralized with of 10% HCI (20 ml) and washed with saturated NaHCO3 and brine solution and evaporated on a rota-vapour and the crude product was purified by column chromatography on silica gel to yield 2.19 g of mixture of diastereomers (94.8 % yield) in approx. 2:3 ratio which were separated by column chromatography to furnish the two isomers 3a8 (higher Rf) as white solid (m.p. 115°-116° C) and 4a8 (lower Rf) as white solid (m.p. 130-131 °C) respectively.
EXAMPLE: - 9
TRIOXANE 2a9 FORMULA 2a, Ar =1-Napthyl-
To a stirred solution of unsaturated trioxane 1a9 (formula 1a, Ar=1-Napthyl-) (1.00 gm, 2.762 mmol) and N2H4.H2O (2.7 ml) (neutralized with CO2) in 1:1 mixture of EtOH/THF (50ml), cooled to 0° C, was added 30% H2O2 (9.4 ml) dropwise and the reaction mixture was stirred at r.t. for 27 days. The reaction mixture was evaporated on a rota-vapour and then diluted with water (20 ml) and extracted with ether (3x50 ml). The ethereal layer was neutralized with 10% HCI (20 ml) and washed with saturated NaHCO3and brine solution and evaporated on a rota-vapour and the crude product was purified by column chromatography on silica gel to yield 350mg of mixture of diastereomers (34.82 % yield) in approx. 2:3 ratio which were separated by column chromatography to furnish the two isomers 3a9 (higher Rf) as semisolid and 4a9 (lower Rf) as white solid (m.p. 120-122 °C) respectively.
EXAMPLE:-10
TRIOXANE 2a10 FORMULA 2a, Ar =p-Cyclohexyl-C6H4-

To a stirred solution of unsaturated trioxane 1a10 (formula 1a, Ar= p-Cyclohexyl-C6H4-) (2.00 gm, 5.076 mmol) and N2H4.H2O (5.05 ml) in 1:1 mixture of EtOH/THF (100 ml), cooled to 0° C , was added of 30% H2O2 (17.26 ml) dropwise and the reaction mixture was stirred at it for 5 days. The reaction mixture was evaporated on a rota-vapour and then diluted with water (20 ml) and then extracted with ether (3x100 ml ). The ethereal layer was neutralized with 10% HCI (20 ml) and washed with saturated NaHCO3 and brine solution and evaporated on a rota-vapour and the crude product was purified by column chromatography on silica gel to yield 1.95g of mixture of diastereomers (97.01 % yield) in approx. 2:3 ratio which were separated by column chromatography to furnish the two isomers 3a10 (higher Rf) as white solid (m.p. 141°-143° C) and 4a10 (lower Rf) as white solid (m.p. 117-118 °C) respectively.
EXAMPLE: -11
TRIOXANE 2a11 FORMULA 2a, Ar =2-Flurenyl-
To a stirred solution of unsaturated trioxane 1a11 (formula 1a, Ar=2-Flurenyl-) (1.00 gm, 2.50 mmol) and N2H4.H2O (2.5 ml) in 1:1 mixture of EtOHmHF (50 ml), cooled to 0° C, was added 30% H2O2 (8.5 ml) dropwise and the reaction mixture was stirred at it for 8 days. The reaction mixture was evaporated on a rota-vapour and then diluted with water (20 ml) and extracted with ether (3x50 ml). The ethereal layer was neutralized with 10% HCI (20 ml) and washed with saturated NaHCOs and brine solution and evaporated on a rota-vapour and the crude product was purified by column chromatography on silica gel to yield 900mg of mixture of diastereomers (89.5 % yield) in approx. 2:3 ratio which were separated by column chromatography to furnish the two isomers 3a11 (higher Rf) as white solid (m.p. 133-135 °C) and 4a11 (lower Rf) as white solid (m.p. 136-138 °C) respectively.

EXAMPLE: -12
8-(1-PHENYL-ETHYL)-6, 7, 10-TRIOXA-SPIRO [4, 5] DECANE (TRIOXANE 2b1, FORMULA 2b, Ar =C6H5-)
To a stirred solution of unsaturated trioxane 1b1 (formula 1b, Ar=C6H5-) (2.00 gm, 8.130 mmol) and N2H4.H2O (8.1 ml) in 1:1 mixture of EtOH/THF (200 ml), cooled to 0° C, was added 30% H202 (27.6 ml) dropwise and the reaction mixture was kept at same temp for 2 days. The reaction mixture was evaporated on a rotavapour and then diluted with water (40 ml) and extracted with ether (3x100 ml) . The ethereal layer was neutralized with 10% HCI (20 ml) and washed with saturated NaHC03 and brine solution and evaporated on a rotavapour and the crude product was purified by column chromatography on silica gel to yield 740 mg of mixture of diastereomers (36.67 % yield) in approx. 2:3 ratio which were separated by column chromatography to furnish the two isomers 3b1 (higher Rf) as oil and 4b2 (lower Rf) as oil as well, respectively.
EXAMPLE: -13
8-(1-TOLYL-ETHYL)-6,7,10-TRIOXA-SPIRO[4,5]DECANE (TRIOXANE 2b2, FORMULA 2b, Ar =pMe-C6H4-)
To a stirred solution of unsaturated trioxane 1b2 (formula 1b, Ar= pMe-CeHs-) (2.00 gm, 7.692 mmol) and N2H4.H20 (7.7 ml) in 1:1 mixture of EtOH/THF (200 ml), cooled to 0° C, was added 30% H2O2 (26.16 ml) dropwise and the reaction mixture was kept at same temp for 2 days. The reaction mixture was evaporated on a rotavapour and then diluted with water (40 ml) and extracted with ether (3x100 ml). The ethereal layer was neutralized with 10% HCI (20 ml) and washed with saturated NaHCOsand brine solution and evaporated on a rotavapour and the crude product was purified by column chromatography on silica gel to yield 636 mg of mixture of diasteriomers (31.56 % yield) in approx. 2:3 ratio which were separated by column chromatography to furnish the two isomers 3b2 (higher Rf) as oil and 4b2 (lower Rf) as oil as well, respectively.

EXAMPLE: -14
8-[1-(4-CHLORO-PHENYL)-ETHYL]-6,7,10-TRiOXA-SPIRO[4,S]DECANE (TRIOXANE 2b3, FORMULA 2b, Ar =pCI-C6H4-)
To a stirred solution of unsaturated trioxane 1b3 (formula 1b, Ar= pCI-C6H4-) (2.00 gm, 7.143 mmol) and N2H4.H20 (7.15 ml) in 1:1 mixture of EtOH/THF (200 ml), cooled to 0° C, was added 30% H2O2 (24.3 ml) dropwise and the reaction mixture was kept at same for 2 days and then stirred at rt. for 1 day. The reaction mixture was evaporated on a rotavapour and then diluted with water (40 ml) and extracted with ether (3x100 ml). The ethereal layer was neutralized with 10% HCI (20 ml) and washed with saturated NaHCO3 and brine solution and evaporated on a rotavapour and the crude product was purified by column chromatography on silica gel to yield 1.040 gm of mixture of diasteriomers (51.63 % yield) in approx. 2:3 ratio which were separated by column chromatography to furnish the two isomers 3b3 (higher Rf) as oil and 4b3 (lower Rf) as oil as well, respectively.
EXAMPLE:-15
8-[1 -(4-FLUORO-PHENYL)-ETHYL]-6,7,10-TRIOXA-SPIRO[4,5]DECANE
(TRIOXANE 2b4, FORMULA 2b, Ar =pF-C6H4-)
To a stirred solution of unsaturated trioxane 1b4 (formula 1b, Ar= pF-C6H4-) (2.00 gm, 7.576 mmol) and N2H4.H2O (7.6 ml) in 1:1 mixture of EtOH/THF (200 ml), cooled to 0° C, 20 was added 30% H2O2 (25.8 ml) dropwise and the reaction mixture was kept at same temp for 2 days and then stirred at rt. for 1 day. The reaction mixture was evaporated on a rotavapour and then diluted with water (40 ml) and extracted with ether (3x100 ml). The ethereal layer was neutralized with 10% HCI (20 ml) and washed with saturated NaHCO3 and brine solution and evaporated on a rotavapour and the crude product was purified by column chromatography on silica gel to yield 1.34 gm of mixture of diasteriomers (66.5 % yield) in approx. 2:3 ratio which were separated by

column chromatography to furnish the two isomers 3b4 (higher Rf) as oil and 4b4 (lower Rf) as oil as well, respectively.
EXAMPLE:-16
8-[1-(4-METHOXY-PHENYL)-ETHYL]-6,7,10-TRIOXA-SPIRO[4,5]DECANE (TRIOXANE 2b5, FORMULA 2b, Ar =pMeO-C6H4-)
To a stirred solution of unsaturated trioxane 1b5 (formula 1b, Ar= pMeO-C6H4-) (2.00 gm, 7.246 mmol) and N2H4.H2O ( 7.25 ml ) in 1:1 mixture of EtOH/THF ( 200 ml), cooled to 0° C, 20 was added 30% H2O2 ( 24.6 ml ) dropwise and the reaction mixture was kept at same temp for 2 days and then stirred at rt. for 12 days. The reaction mixture was evaporated on a rotavapour and then diluted with water (40 ml) and extracted with ether (3x100 ml). The ethereal layer was neutralized with of 10% HCI (20 ml) and washed with saturated NaHCOs and brine solution and evaporated on a rotavapour and the crude product was purified by column chromatography on silica gel to yield 1.29 gm of mixture of diasteriomers (64.04 % yield) in approx. 2:3 ratio which were separated by column chromatography to furnish the two isomers 3b5 (higher Rf) as white solid (m.p. 84°-86° C) and 4b5 (lower Rf) as oil, respectively.
EXAMPLE:-17
8-(1-BIPHNYL-4-YL-ETHYL)-6,7,10-TRIOXA-SPIRO[4,5]DECANE (TRIOXANE 2b6 FORMULA 2b, Ar =pPh-C6H4-)
To a stirred solution of unsaturated trioxane 1b6 (formula 1b, Ar= pPh-C6H4-) (1.00 gm, 3.105 mmol) and N2H4.H2O (3 ml) in 1:1 mixture of EtOH/THF (100 ml), cooled to 0° C, 20 was added 30% H2O2 (10.18 ml) dropwise and the reaction mixture was kept at same temp for 2 days. The reaction mixture was evaporated on a rotavapour and then diluted with water (20 ml) and extracted with ether (3x50 ml). The ethereal layer was neutralized with 10% HCI (20 ml)

and washed with saturated NaHCO3 and brine solution and evaporated on a rotavapour and the crude product was purified by column chromatography on silica gel to yield 437 mg of mixture of diastereomers (43.44 % yield) in approx. 2:3 ratio which were separated by column chromatography to furnish the two isomers 3b6 (higher Rf) as white solid (m.p. 74°-76° C) and 4b6 (lower Rf) as white solid (m.p. 82°-84°C) as well, respectively.
EXAMPLE:-18
8-(1-NAPTHALEN-2-YL-ETHYL)-6,7,10-TRIOXA-SPIRO[4,5]DECANE (TRIOXANE 2b7 FORMULA 2, Ar =2-Napthyl-)
To a stirred solution of unsaturated trioxane 1b7 (formula 1b, Ar=2-Napthyl-)
(2.00 gm, 6.757 mmol) and N2H4.H2O (7.25 ml) in 1:1 mixture of EtOH/THF
(200 ml), cooled to 0° C, was added 30% H2O2 (22.98 ml) dropwise and the
reaction mixture was kept at same temp for 2 days and then stirred at rt. for 8
days. The reaction mixture was evaporated on a rotavapour and then diluted
with water (40 ml) and extracted with ether (3x100 ml). The ethereal layer
was neutralized with 10% HCI (20 ml) and
washed with saturated NaHCO3 and brine solution and evaporated on a rotavapour and the crude product was purified by column chromatography on silica gel to yield 1.310 gm of mixture of diasteriomers (65.06% yield) in approx. 2:3 ratio which were separated by column chromatography to furnish the two isomers 3b7 (higher Rf) as white solid m.p.70°-72°C and 4b7 (lower Rf) as oil, respectively.
EXAMPLE:-19 3-(1-PHENYL-ETHYL)-1,2,5-TRIOXA-SPIRO[5,5]UNDECANE (TRIOXANE
2c1, FORMULA 2c, R=C6H5-)
To a stirred solution of unsaturated trioxane 1c1 (formula 1c, Ar=CeH5-) (2.00 gm, 7.692 mmol) and N2H4.H2O (8.1 ml) in 1:1 mixture of EtOHmHF (200 ml),

cooled to 0° C, was 30% H202 (26.05 ml) dropwise and the reaction mixture was kept at same temp for 2 days and then stirred at rt. for 8 days. The reaction mixture was evaporated on a rotavapour and then diluted with water (40 ml) and extracted with ether (3x100 ml). The ethereal layer was neutralized with 10% HCI (20 ml) and washed with saturated NaHCO3 and brine solution and evaporated on a rotavapour and the crude product was purified by column chromatography on silica gel to yield 1.174 gm of mixture of diastereomers (58.25 % yield) in approx. 2:3 ratio which were separated by column chromatography to furnish the two isomers 3d (higher Rf) as oil and 4c1 (lower Rf) as oil as well, respectively.
EXAMPLE: - 20
3-(1 -p-TOLYL-ETHYL)-1,2,5-TRIOXA-SPIRO[5,5]UNDECANE (TRIOXANE
2c2, FORMULA 2c, R=pMe-C6H4-, R1R2= CYCLOHEXYL)
To a stirred solution of unsaturated trioxane 1c2 (formula 1c, Ar= pMe-C6H5-) (2.00 gm, 7.299 mmol) and N2H4.H2O (7.3 ml) in 1:1 mixture of EtOH/THF (200 ml), cooled to 0° C, was added 30% H2O2 (24.8 ml) dropwise and the reaction mixture was kept at same temp for 2 days and then stirred at rt. for 5 days. The reaction mixture was evaporated on a rotavapour and then diluted with water (40 ml) and extracted with ether (3x100 ml). The ethereal layer was neutralized with of 10% HCI (20 ml) and washed with saturated NaHCO3 and brine solution and evaporated on a rotavapour and the crude product was purified by column chromatography on silica gel to yield 1.790 gm of mixture of diasteriomers (88.80 % yield) in approx. 2:3 ratio which were separated by column chromatography to furnish the two isomers 3c2 (higher Rf) as oil and 4c2 (lower Rf) as oil as well, respectively.
EXAMPLE: - 21

3-[1-(4-CHLORO-PHENYL)-1,2,5-TRIOXA-SPIRO[5,5]UNDECANE (TRIOXANE 2c3, FORMULA 2, R=pCI-C6H4-)
To a stirred solution of unsaturated trioxane 1c3 (formula 1c, Ar= pCI-C6H4-) (2.00 gm,6.803 mmol) and N2H4.H20 ( 6.8 ml) in 1:1 mixture of EtOH/THF ( 200 ml), cooled to 0° C, was added 30% H2O2 ( 23.1 ml) dropwise and the reaction mixture was kept at same temp for 2 days and then stirred at it for 9 days. The reaction mixture was evaporated on a rotavapour and then diluted with water (40 ml) and extracted with ether (3x100ml). The ethereal layer was neutralized with 10% HCI (20 ml) and washed with saturated NaHCO3 and brine solution and evaporated on a rotavapour and the crude product was purified by column chromatography on silica gel to yield 1.50 gm of mixture of diasteriomers (74.49 % yield) in approx. 2:3 ratio which were separated by column chromatography to furnish the two isomers 3c3 (higher Rf) as oil and 4c3 (lower Rf) as oil as well, respectively.
EXAMPLE: - 22
3-[1-(4-FLUORO-PHENYL)-1,2,5-TRIOXA-SPIRO[5,5]UNDECANE (TRIOXANE 2c4, FORMULA 2c, R=pF-C6H4-)
To a stirred solution of unsaturated trioxane 1c4 (formula 1c, Ar= pF-C6H4-) (1.00 gm, 7.194 mmol) and N2H4.H20 (7.2 ml) in 1:1 mixture of EtOH/THF (200 ml), cooled to 0° C, 20 was added 30% H2O2 (24.46 ml) dropwise and the reaction mixture was kept at same temp for 2 days and then stirred at it for 5 days. The reaction mixture was evaporated on a rotavapour and then diluted with water (40 ml) and extracted with ether (3x100 ml). The ethereal layer was neutralized with 10% HCI (20 ml )and washed with saturated NaHCOa and brine solution and evaporated on a rotavapour and the crude product was purified by column chromatography on silica gel to yield 1.395 gm of mixture of diasteriomers (69.25 % yield) in approx. 2:3 ratio which were

separated by column chromatography to furnish the two isomers 3c4 (higher Rf) as white solid (m.p. 56°-58° C) and 4c4 (lower Rf) as oil, respectively.
EXAMPLE: - 23
3-[1 -(4-METHOXY-PHENYL)-1,2,5-TRIOXA-SPIRO[5,5]UNDECANE
(TRIOXANE 2c5, FORMULA 2c, R=pMeO-C6H4-)
To a stirred solution of unsaturated trioxane 1c5 (formula 1c, Ar= pMeO-C6H4-) (2.00 gm, 6.896 mmol) and N2H4.H2O (6.9 ml ) in 1:1 mixture of EtOH/THF ( 200 ml ), cooled to 0° C, was added 30% H2O2 (23.45 ml) dropwise and the reaction mixture was kept at same temp for 2 days and then stirred at rt. for 9 days. The reaction mixture was evaporated on a rotavapour and then diluted with water (40 ml) and extracted with ether (3x100 ml). The ethereal layer was neutralized with 10% HCI (20 ml) and washed with saturated NaHCOa and brine solution and evaporated on a rotavapour and the crude product was purified by column chromatography on silica gel to yield 1.82 gm of mixture of diasteriomers (90.38 % yield) in approx. 2:3 ratio which were separated by column chromatography to furnish the two isomers 3c5 (higher Rf) as white solid (m.p. 65° C) and 4c5 (lower Rf) as oil, respectively.
EXAMPLE: - 24
3-(1 -BIPHENYL-4-YL-ETHYL)-1,2,5-TRIOXA-SPIRO[5,5]UNDECANE
(TRIOXANE 2c6 FORMULA 2c, R=pPh-C6H4-)
To a stirred solution of unsaturated trioxane 1c6 (formula 1c, Ar= pPh-C6H4-) (2.00 gm, 5.952 mmol) and N2H4.H20 (5.95 ml) in 1:1 mixture of EtOHfi"HF (200 ml), cooled to 0° C, was added 30% H2O2 (20.24 ml) dropwise and the reaction mixture was kept at same temp for 2 days, and then stirred at r.t for 18 days. The reaction mixture was evaporated on a rotavapour and then diluted with water (40 ml) and extracted with ether (3x100 ml). The ethereal

layer was neutralized with 10% HCI (20 ml) and washed with saturated NaHCO3 and brine solution and evaporated on a rotavapour and the crude product was purified by column chromatography on silica gel to yield 1.750 gm of mixture of diastereomers (86.98 % yield) in approx. 2:3 ratio which were separated by column chromatography to furnish the two isomers 3c6 (higher Rf) as white solid (m.p. 80°-81° C) and 4c6 (lower Rf) as white solid (m.p. 85°-86° C) as well, respectively.
EXAMPLE: - 25
3-(1-NAPHTHALEN-2-YL-ETHYL)-1, 2,5-TRIOXA-SPIRO [5, 5] UNDECANE
(TRIOXANE 2c7, FORMULA 2c, R=2-Napthyl-)
To a stirred solution of unsaturated trioxane 1c7 (formula 1c, Ar=2-Napthyl-) (2.00 gm, 6.452 mmol) and N2H4.H20 (6.46 ml) in 1:1 mixture of EtOH/THF (200 ml), cooled to 0° C, was added 30% H2O2 (21.9 ml) dropwise and the reaction mixture was kept at same temp for 2 days and then stirred at r.t for 15 days. The reaction mixture was evaporated on a rotavapour and then diluted with water (40 ml) and extracted with ether (3x100 ml). The ethereal layer was neutralized with of 10% HCI (20 ml) and washed with saturated NaHCO3 and brine solution and evaporated on a rotavapour and the crude product was purified by column chromatography on silica gel to yield 1.745 gm of mixture of diasteriomers (86.686 % yield) in approx. 2:3 ratio which were separated by column chromatography to furnish the two isomers 3c7 (higher Rf) as white solid (m.p. 85°-87° C) and 4c7 (lower Rf) as white solid (m.p. 92°-94° C) respectively.
FOLLOWING THE ABOVE PROCEDURE, THE FOLLOWING TRIOXANES WERE ALSO PREPARED:
(TABLE REMOVE -2)
(TABLE REMOVE -3)
(TABLE REMOVE -4)
(TABLE REMOVE -5)
ANTIMALARIAL ACTIVITY
The antimalarial activity of the test compounds was evaluated against multidrug resistant strain of Plasmodium yoelii Nigeriensis in Swiss mice.
General Procedure:-
Random bred Swiss mice of either sex (20 ± 2 g) were inoculated intraperitoneally with 1x105 P. yoelii (MDR) parasites on day zero. The treatments with test compounds were administered to group of 5 mice each at different dose levels ranging between 12-96 mg/kg/day. The compounds were administered as solutions in oil via oral route for 4 consecutive days (day 0-3). p-Arteether and cc-Arteether were used as positive control.

Blood smears from experimental mice were observed on day 4 and 7, day 10 and thereafter at regular interval till day 28 or death of the animal. The parasitaemia level on day 4 was compared with the vehicle control group and the percent suppression of parasitaemia in treated groups was calculated. The compounds which showed more than 90% suppression were identified for further screening.
For determining the curative dose of a compound the treated mice were observed till day 28.The dose at which no parasitaemia develops during the observation period has been recorded as the curative dose. The results are shown in table given below:
ANTIMALARIAL ACTIVITY OF TRIOXANES AGAINST P. yoelii IN MICE
(TABLE REMOVE -6)

(TABLE REMOVE -7)
(TABLE REMOVE -8)
(TABLE REMOVE -9)

A SCHEME FOR PREPRATION OF TRIOXANES OF GENERAL FORMULA

(FIGURE REMOVE)

WE CLAIM:
1:- Substituted 1, 2, 4-trioxanes of general formula 2 , and their isomers of formula 3 and 4
(Formula Removed)
wherein Ar is selected from the group comprising of phenyl , pMe-phenyl, pCl-phenyl,
pMeO- phenyl, pF-phenyl, biphenyl, 2-napthyl, p-Br-phenyl,l-napthyl, p-Cyclohexyl-
phenyl, 2-Flurenyl,
wherein R1 and R2 represents the part of cyclic ring system like cyclohexane,
cyclopentane and adamantane.
2:- Substituted 1, 2, 4-trioxanes as claimed in claim 1 wherein the representative
compounds of general formula 2a, being defined as follows;
(Formula Removed)
3:- Substituted 1, 2, 4-trioxanes as claimed in claim 1 wherein the representative compounds of general formula 2a, being defined as follows;
(Formula Removed)
4:- Substituted 1, 2, 4-trioxanes as claimed in claim 1 wherein the representative compounds of general formula 2a, being defined as follows;
(Formula Removed)
5:- Substituted 1,2, 4-trioxanes as claimed in claim 1 wherein the diastereoisomers of compound of formula 2 is represented by structural formula 3 and 4 as shown below wherein Ar is selected from the group consisting of phenyl , pMe-phenyl, pCl-phenyl,

pMeO- phenyl, pF-phenyl, biphenyl, 2-napthyl, p-Br-phenyl,l-napthyl, p-Cyclohexyl-phenyl, 2-Flurenyl, whereas R1 and R2 represents the part of cyclic ring system like cyclohexane, cyclopentane and adamantane.
(Formula Removed)
6:- Substituted 1, 2, 4-trioxanes as claimed in claim 1-5 wherein the representative compounds of general formula 3a, being defined as follows;
(Formula Removed)
7. :- Substituted 1, 2, 4-trioxanes as claimed in claim 1-5 wherein the representative compounds of general formula 4al-4a11, being defined as follows;
wherein the said compounds having the structural formula as shown below:
(Formula Removed)
8.:- Substituted 1, 2, 4-trioxanes as claimed in claim 1-5 wherein the representative
compounds of general formula 3bl-3b7 being defined as follows;
(Formula Removed)
9:- Substituted 1, 2, 4-trioxanes as claimed in claim 1-5 wherein the representative compounds of general formula 4bl-4b7 being defined as follows;
(Formula Removed)
10:- Substituted 1, 2, 4-trioxanes as claimed in claim 1-5 wherein the representative compounds of general formula 3cl-3c7 being defined as follows;
(Formula Removed)
11:- Substituted 1, 2, 4-trioxanes as claimed in claim 1-5 wherein the representative compounds of general formula 4cl-4c7 being defined as follows;

(Formula Removed)
12. A process for the preparation of novel substituted 1,2,4-trioxanes of formula 2 and their isomers of general formula 3 and 4; wherein Ar is selected from the group consisting of phenyl , pMe-phenyl, pCl-phenyl, pMeO- phenyl, pF-phenyl, biphenyl, 2-napthyl, p-Br-phenyl, l-napthyl,p-Cyclohexyl-phenyl, 2-Flurenyl,
(Formula Removed)
wherein R and R represents the part of cyclic ring system like cyclohexane, cyclopentane and adamantane, which comprises reaction of 6-(l-aryl vinyl)-1, 2, 4-trioxanes of formula 1
(Formula Removed)
where in Ar is selected from the group consisting of phenyl , pMe-phenyl, pCl-phenyl, pMcO- phenyl,pF-phenyl, biphenyl, 2-napthyl, p-Br-phenyl, 1-napthyl, p-Cyclohexyl-phenyl, 2-Flurenyl whereas R1 and R2 represents the part of cyclic ring system like cyclohexane, cyclopentane and adamantane, with diimide, generated in situ, by reacting H2O2 with N2H4.H2O or CO2 neutralized N2H4.H2O in a water miscible organic solvent at a temperature ranging between 0 °C to room temperature for a period ranging between 2 to 29 days, to furnish trioxanes of formula 2 as a mixture of diastereomers, separating the diastereomers by chromatography to give pure isomers of the formula 3 and 4 wherein Ar, R1 and R have the same meaning as above for compound of formula 2. 13:- A process as claimed in claim 12 wherein the water miscible organic solvent is selected from a group consisting of tetrahydrofuran, ethyl alcohol, methyl alcohol, CH3CN or a mixture thereof.
14:- A process as claimed in claim 12 wherein the chromatography to separate the compounds of formula 3 and 4 is carried out using solvent selected from EtOAc: Hexane. 15:- A process as claimed in claim 12 wherein the chromatography is carried out on silica gel.

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Patent Number

271697

Indian Patent Application Number

2158/DEL/2006

PG Journal Number

10/2016

Publication Date

04-Mar-2016

Grant Date

29-Feb-2016

Date of Filing

29-Sep-2006

Name of Patentee

COUNCIL OF SCIENTIFIC & INDUSTRIAL RESEARCH

Applicant Address

ANUSANDHAN BHAWAN, RAFI MARG, NEW DELHI-11001, INDIA.

Inventors:

#	Inventor's Name	Inventor's Address
1	AJIT SHANKAR 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	CHANDAN SINGH	CENTRAL DRUG RESEARCH INSTITUTE, CHATTAR MANZIL PALACE, POST BOX NO 173, LUCKNOW 226001, INDIA

PCT International Classification Number

C07D323/04

PCT International Application Number

N/A

PCT International Filing date

PCT Conventions:

#	PCT Application Number	Date of Convention	Priority Country
1			NA