Title of Invention

A NOVEL SUBSTITUTED 1,2,4 TRIOXANE USEFUL AS ANTIMALARIAL AGENT

Abstract

This invention relates to novel substituted 1,2,4-trioxane useful as an antimalarial agent. More particularly this invention relates to novel 6-[(cycloalkylphenyl)vinyl]-l,2,4-trioxane of general formula 7 wherein R is a cycloalkyl group selected from the group consisting of cyclohexyl, cyclopentyl, cycloheptyl and cyclooctyl ; R1 and R2 is selected from the group consisting of hydrogen, alkyl group selected from the group consisting of methyl, ethyl, propyl and decyl and aryl such as phenyl; R1R2 together is a part of a cyclic system selected from the group consisting of cyclopentane, cyclohexane, substituted cyclohexanes, bicyclo (2.2.1) heptane and adamantine. Some of these compounds have been tested against multi-drug resistance malaria in mice and have shown promising antimalarial activity. The trioxanes of the general formula 7 are new chemical entities and they have not been prepared earlier and are useful as antimalarial agents. 29

Full Text

This invention relates to novel substituted 1,2,4-trioxane useful as an antimalarial agent. More particularly this invention relates to novel 6-[(cycloalkylphenyl)vinyl]-l,2,4-trioxane of general formula 7 wherein R is a cycloalkyl group selected from the group consisting of cyclohexyl, cyclopentyl, cycloheptyl and cyclooctyl ; R[ and R2 is selected from the group consisting of hydrogen, alkyl group selected from the group consisting of methyl, ethyl, propyl and decyl and aryl such as phenyl; RjR2 together is a part of a cyclic system selected from the group consisting of cyclopentane, cyclohexane, substituted cyclohexanes, bicyclo (2.2.1) heptane and adamantine. Some of these compounds have been tested against multi-drug resistance malaria in mice and have shown promising antimalarial activity. The trioxanes of the general formula 7 are new chemical entities and they have not been prepared earlier and are useful as antimalarial agents. The main objective of the present invention is to provide novel substituted 1,2,4-trioxane of general formula 7, a new series of antimalarial agents. Accordingly, the present invention provides a novel substituted 1,2,4-trioxane of general formulae 7 useful as an antimalarial agent wherein R is a cycloalkyl group selected from the group consisting of cyclohexyl, cyclopentyl, cycloheptyl and cyclooctyl ; RI and Ra is selected from the group consisting of hydrogen, alkyl group selected from the group consisting of methyl, ethyl, propyl and decyl and aryl such as phenyl; RiR2 together is a part of a cyclic system selected from the group consisting of cyclopentane, cyclohexane, substituted cyclohexanes, bicyclo (2.2.1) heptane and adamantine. In an embodiment of the present invention the novel substituted 1,2,4-trioxane of general formulae 7 is selected from a group comprising 8-[(4-cyclopentylphenyl)vinyl]-6,7,10-trioxaspiro-[4,5]- decane trioxane 7aa, 7ab, 3-[(4-cyclopentylphenyl)vinyl]-l,2,5-trioxaspiro(5,5)undecane 7ac, 3- [(4-cyclopentylphenyl)vinyl-l,2,5-trioxaspira (5,6)dodecane 7ad, 8-(t-amyl)-3-[(4- cyclopentylphenyl)vinyl]- l,2,5-trioxaspira(5,5) undecane 7ae, 3,3-dimethyl-6-[4- cyclohexylphenyljvinyl-1,2,4-trioxane 7ba, 3-decyl,3-methyl-6-[(4-cyclohexylphenyl)vinyl]-1,2,4- trioxane 7bb, 6-[(4-cyclohexylphenyl)vinyl]-3-phenyl-1,2,4-trioxane 7bc, 3-[(4- cyclohexylphenyl)vinyl]-l,2,5-trioxaspiro(5,5)undecane 7bd, 7be, 3-ethyl-3-methyl-6-[4- cyclohexylphenyl)vinyl]-1,2,4-trioxane 7bf, 3-Methyl-3-propyl-6-[4-cyclohexyl phenyl) vinyl] - 1,2,4-trioxane 7bg, 8-[(4-cyclohexylphenyl)vinyl]-6,7,10- trioxaspiro (4,5) decane 7bh, 9-(t-amyl)- 3-[(4-cyclohexylphenyl)vinyl]-l,2,5-trioxaspiro(5,5)undecane7bi, 3-[(4- cycloheptylphenyl)vinyl]-l,2,5-trioxaspiro-[5,5]-undecane 7ca, 7cb, 8-[(4- cycloheptylphenyl)vinyl]-6,7,10-trioxaspiro(4,5)decane 7cc, 3-[(4-cycloheptylphenyl)vinyl]-8- phenyl-l,2,5-trioxaspiro(5,5)undecane7cd, 3-ethyl-3-methyl-6-[(4-cyclooctylphenyl)vinyl]-1,2,4- trioxane 7da, 3-[(4-cyclooctylphenyl)vinyl]-l,2,5-trioxaspiro-(5,5)-undecane 7db, 3-[(4- cyclooctylphenyl)vinyl]-l,2,5-trioxaspiro-(6,5)-dodecane 7dc, 7dd, 8-[(4-cyclooctylphenyl)vinyl]- 6,7jlO-trioxaspiro(4,5)undecane7de, 8-(t-amyl)-3-[(4-cyclooctylphenyl)vinyl]-1,2,5- trioxaspiro(5,5)undecane 7df, 8a,8b,8c,9a, 9b and 9c. The invention is further illustrated by the following examples which should not, however, be construed to limit the scope of the present invention. EXAMPLE 1 ETHYL 3-HYDROXY-3-(4-CYCLOPENTYLPHENYL)-BUTANOATE (COMPOUND 2a, FORMULA 2, R = CYCLOPENTYL) To a refluxing mixture ofp-cyclopentylacetophenone (17 g), I2 (5 mg) and Zn dust (12 g) in benzene (150 ml) was added ethylbromoacetate (11 ml) dropwise over 30 minutes. The mixture was refluxed for next 45 min and then cooled to room temperature. It was acidified with 10% HC1 solution (150 ml), benzene layer was separated out. The organic layer was washed with water, dried (Na2SO4) and concentrated. The crude product was purified by column chromatography on silica gel to furnish 22 g (88.1% yield) of ethyl 3-hydroxy-3-(4-cyclopentylphenyl)-butanoate (2a) as oil. ETHYL 3-(4-CYCLOPENTYLPHENYL)-BUT-2-ENOATE (COMPOUND 3a, FORMULA 3, R = CYCLOPENTYL) To a solution of ethyl 3-hydroxy-(4-cyclopentylphenyl)-butanoate (2a, 12 g) in benzene (150 ml) was added p-toluenesulfonic acid and refluxed for 1 h. The mixture was diluted with sat. NaHCOs (100 ml) and benzene layer was separated. The organic phase was washed with water, dried (NaaSC^) and concentrated. The crude product was purified by column chromatography on silica gel to give 8.9 g (79.4% yield) of ethyl 3-(4-cyclopentylphenyl)-but-2-enoate (3a, formula 3, R = cyclopentyl) as oil. 3-(4-CYCLOPENTYLPHENYL)-2-BUTENOL (COMPOUND 4a, FORMULA 4, R = CYCLOPENTYL) To an ice cooled slurry of LiAlFLt (2.7 g) in dry ether (150 ml) was added a solution of ethyl 3-(4-cyclopentylphenyl)-but-2-enoate (3a, 8.2 g) in dry ether (50 ml) dropwise. The mixture was stirred at 0°C for 3 h. The reaction mixture was quenched with water (10 ml). A solution of 10% NaOH (5 ml) was added and then ether layer was decanted. The precipitate was washed with ether and combined organic layer was concentrated. The crude product was purified by column chromatography on silica gel to give 5.6 g (82.3% yield) of 3-(4-cyclopentylphenyl)-2-butenol (4a, formula 4, R = cyclopentyl) as oil. 3-(4-CYCLOPENTYLPHENYL)-l-HYDROXY-BUT-3-EN-2-HYDROPEROXIDE (COMPOUND 5a, FORMULA 5, R = CYCLOPENTYL) A solution of 3-(4-cyclopentylphenyl)-2-butenol (4a, 500 mg) and methylene blue (5 mg) in CH2C12 (30 ml) was irradiated with a 250 watt tungston-halogen lamp at -10°C while oxygen was passed through the reaction mixture for 5 h. The reaction mixture was concentrated under reduced pressure at r.t. and purified by column chromatography on silica gel to furnish 0.29 g (51.7% yield) of hydroperoxide 5a as a solid m.p. 95-97°C. 8-[(4-CYCLOPENTYLPHENYL)VINYL]-6,7,10-TRIOXASPIRO-[4,5]-DECANE (TRIOXANE 7aa, FORMULA 7, R = CYCLOPENTYL; R, R2 = -CH2CH2CH2CH2) A solution of 3-(4-cyclopentylphenyl)-2-butenol (4a, 500 mg) and methylene blue (5 mg) in CHsCN (30 ml) was photooxygenated at -10°C for 3 h. Cyclopentanone (1.5 ml) and ptoluenesulfonic acid (50 mg) were added and reaction mixture was left at r.t. for 20 h. Reaction mixture was concentrated to remove CHaCN under reduced pressure, diluted with NaHCOa (5 ml) and water (50 ml), extracted with ether (3 x 50 ml), dried over Na2SO4 and concentrated. The crude product was purified by chromatotron on silica gel to furnish 0.38 g (52.7% yield based on allylic alcohol, 4a used) of trioxane 7aa as oil. EXAMPLE 2 TRIOXANE 8a, FORMULA 8, R = CYCLOPENTYL A solution of 3-(4-cyclopentylphenyl)-2-butenol (4a, 320 mg) and methylene blue (5 mg) in CHsCN (25 ml) was photooxygenated at -10°C for 4 h. Norcamphor (800 mg) and ptoluenesulfonic acid (60 mg) were added and reaction mixture was stirred for 20 h at r.t. The reaction mixture was worked up as above and concentrated. Crude product was purified by chromatotron on silica gel to furnish 0.14 g (28% yield based on allylic alcohol 4a, used) of trioxane 8a, m.p. 91-93°C. EXAMPLE 3 TRIOXANE 9a, FORMULA 9, R = CYCLOPENTYL A solution of 3-(4-cyclopentylphenyl)-2-butenol (4a, 500 mg) and methylene blue (5 mg) in CH3CN (30 ml) was photooxygenated at -10°C for 3 h. 2-Adamantanone (500 mg) andptoluenesulfonic acid (50 mg) were added and reaction mixture was stirred for 3.5 h at r.t. The reaction mixture was worked up as above and concentrated. Crude product was purified by chromatotron on silica gel to furnish 430 mg (49.4% yield, based on allylic alcohol, 4a used) of trioxane 9a, m.p. 74-76°C. EXAMPLE 4 TRIOXANE 7ab, FORMULA 7, R = CYCLOPENTYL ; RI R2 = -CH2CH2CH(Ph)CH2CH2- A solution of 3-(4-cyclopentylphenyl)-2-butenol (4a, 500 mg) and methylene blue (5 mg) in CH3CN (30 ml) was photooxygenated at -10°C for 3 h. 4-Phenylcyclohexanone (1 g) andptoluenesulfonic acid (50 mg) were added and reaction mixture was stirred for 20 h at r.t. Reaction mixture was worked up as above and concentrated. Crude product was purified by chromatotron on silica gel to furnish 500 mg (60.2% yield, based on allylic alcohol, 4a used) of trioxane 7ab, m.p. 98-100°C. EXAMPLE 5 ETHYL 3-HYDROXY-3-(4-CYCLOHEXYLPHENYL)-BUTANOATE (COMPOUND 2b, FORMULA 2, R * CYCLOHEXYL) To a refluxing mixture of /?-cyclohexylacetophenone (25 g), \2 (5 mg) and Zn (17 g) in benzene (150 ml) was added ethylbromoacetate (20.7 ml) dropwise during 30 minutes. The mixture was refluxed for 2 h and then cooled to room temperature. It was acidified with 10% HC1 (200 ml), benzene layer separated out. The organic phase was washed with water, dried (Na2SO4) and concentrated. The crude product was purified by column chromatography using SiCh as adsorbent and hexane-ethylacetate mixture as eluant to give 28 g (80% yield) of ethyl 3-hydroxy-3-(4- cyclohexylphenyl)-butanoate (2b, formula 2, R = cyclohexyl) m.p. 45°C. The above compound was also prepared using different reaction condition. Table 1 gives the condition used and yield of compound 2b. ETHYL 3-(4-CYCLOHEXYLPHENYL)-BUT-2-ENOATE (COMPOUND 3b, R = CYCLOHEXYL) To a solution of ethyl 3-hydroxy-3-(4-cyclohexylphenyl)-butanoate (2b, 29.5 g) in benzene (80 ml) was added/?-toluenesulfonic acid (1.8 g) and was refluxed for 2 h. The reaction mixture was diluted with sat. NaHCCh, benzene layer separated out. The organic layer was washed with water, dried (Na2S04) and concentrated. The crude product was purified by column chromatography on silica gel to give 12.7 g (46.01% yield) of ethyl 3-hydroxy-3-(4- cyclohexylphenyl)-but-2-enoate (3b, formula 3, R = cyclohexyl) as oil. The compound 3b was also prepared using different reaction condition. Table 2 gives the conditions used and the yield of compound 3b. 3-(4-CYCLOHEXYLPHENYL)-2-BUTENOL (COMPOUND 4b, FORMULA 4, R = CYCLOHEXYL) To an ice-cooled slurry of LiA1H4 (3.8 g) in dry ether (200 ml) was added a solution of ester 3-(4-cyclohexylphenyl)-but-2-enoate (3b,12.7 g) in dry ether (50 ml) dropwise. The reaction mixture was stirred for 3 h at O°C. The reaction mixture was quenched with water (20 ml). A solution of 10% NaOH (10 ml) was added and the ether layer was decanted. The precipitate was washed with ether and combined extracts were concentrated. The crude product was purified by column chromatography on silica gel as adsorbent and hexane/ethylacetate as eluant to furnish 9.5 g (88.7% yield) of 3-(4-cyclohexylphenyl)-2-butenol (4b) m.p. 54-55°C. The LAH reduction of 3- (4-cyclohexylphenyl)-2-butenol (3b) using THF as solvent under refluxing conditions did not provide the desired compound. 3-(4-CYCLOHEXYLPHENYL)-l-HYDROXY-BUT-3-EN-2-HYDROPEROXIDE (COMPOUND 5b, FORMULA 5, R =CYCLOHEXYL) A solution of 3-(4-cyclohexylphenyl)-2-butenol (4b, 600 mg) and methylene blue (20 mg) in acetonjtrile (35 ml) was irradiation with a 250 watt tungston-halogen lamp at -6°C while oxygen was passed through the reaction mixture for 5 h. The crude product obtained by usual aqueous workup was crystallized from ClfcCh to give 80 mg of hydroperoxide 5b. The filtrate was chromatographed on silica gel to give 400 mg of hydroperoxide 5b. The combined yield of hydroperoxide (compound 5b, formula 5, R = cyclohexyl) was 480 mg (70% yield), m.p. 95- 97°C. Photooxygenation of 3-(4-cyclohexylphenyl)-2-butenol (4b) in benzene at -6°C using tetraphenylphorphine as sensitizer furnish the above hydroperoxide 5b in 85.2% yield. 3,3-DIMETHYL-6-[4-CYCLOHEXYLPHENYL]VINYL-l,2,4-TRIOXANE (TRIOXANE 7ba, FORMULA 7, R = CYCLOHEXYL) A solution of 3-(4-cyclohexylphenyl)-2-butenol (4b, 500 mg) and methylene blue (50 mg) in acetone (30 ml) was photooxygenated at -6°C for 3 h to give compound 5b (as shown by TLC). To the mixture was added p-toluenesulfonic acid (60 mg) and stirred for 3 h at r.t. The reaction mixture was worked up as above and concentrated. The crude product was purified by column chromatography on silica gel to furnish 500 mg (76.9% yield based on allylic alcohol, 4b used) of trioxane 7ba, m.p. 54-55°C. EXAMPLE 6 3-DECYL,3-METHYL-6-[(4-CYCLOHEXYLPHENYL)VINYL]-l,2,4-TRIOXANE (TRIOXANE 7bb, FORMULA 7, R = CYCLOHEXYL) A solution of 3-(4-cyclohexylphenyl)-2-butenol (4b, 500 mg) and methylene blue (5 mg) in CHsCN (30 ml) was photooxygenated at -6°C for 3 h. 2-Dodecanone (1 ml) and ptoluenesulfonic acid were added and reaction mixture was stirred at r.t for 18 h. The reaction mixture was worked up as above and concentrated. The crude product was purified by chromatotron on silica gel to furnish 290 mg (31.1% yield, based on allylic alcohol, 4b used) of trioxane 7bb as oil. 6-[(4-CYCLOHEXYLPHENYL)VINYL]-3-PHENYL-l,2,4-TRIOXANE (TRIOXANE 7bc, FORMULA 7, R = CYCLOHEXYL] A solution of 3-(4-cyclohexylphenyl)-2-butenol (4b, 500 mg) and methylene blue (5 mg) in CHsCN (25 ml) was photooxygenated at -6°C for 2.5 h. Benzaldehyde (1 ml) and ptoluenesulfonic acid (50 mg) were added and the mixture was left at r.t. for 18 h. Reaction mixture was worked up and crude product was purified by flash column chromatography on silica gel to furnish 340 mg (44.7% yield based on allylic alcohol, 4b used) of trioxane 7bc, m.p. 86-88°C. EXAMPLE 7 3-[(4-CYCLOHEXYLPHENYL)VINYL]-l,2,5-TRIOXASPIRO(5,5)UNDECANE (TRIOXANE 7bd, FORMULA 7, R= CYCLOHEXYL, RiR2 = -CH2CH2CH2CH2CH2-) A solution of 3-(4-cyclohexylphenyl)-2-butenol (4b, 500 mg) and methylene blue (5 mg) CHsCN (30 ml) was photooxygenated at -6°C for 3 h. Cyclohexane (1.5 ml) and p-toluenesulfonic acid (50 mg) were added and the mixture was stirred for 4 h. The reaction mixture was worked up and crude product was purified by flash column chromatography on silica gel to furnish 550 mg (74.3% yield based on allylic alcohol, 4b used) of trioxane 7bd, m.p. 60-62°C. EXAMPLE 8 TRIOXANE 8b, FORMULA 8, R = CYCLOHEXYL A solution of 3-(4-cyclohexylphenyl)-2-butenol (4b, 500 mg) and methylene blue (5 mg) in CH3CN (30 ml) was photooxygenated at -8°C for 4 h. Norcamphor (1 g) and/?-toluenesulfonic acid (50 mg) were added and the mixture was left at 5°C for 16 h. The reaction mixture was worked up and the crude product was purified by flash column chromatography on silica gel to furnish 300 mg (40.8% yield based on allylic alcohol, 4b used) of trioxane 8b, m.p. 70-71°C. EXAMPLE 9 TRIOXANE 9b, FORMULA 9, R = CYCLOHEXYL A solution of 3-(4-cyclohexylphenyl)-2-butenol (4b, 500 mg) and methylene blue (5 mg) in CH3CN (50 ml) was photooxygenated at -6°C for 3 h. 2-Adamantanone (1 g) and ptoluenesulfonic acid (50 mg) were added and reaction mixture was stirred at r.t. for 2 h. and then left unstirred at 5°C for 15 h. Reaction mixture was worked up and crude product was purified by column chromatography on silica gel to furnish 500 mg (58.8% yield based on allylic alcohol,4b used) of trioxane 9b, m.p. 75-76°C. Trioxane 9b was also prepared by the following method using purified hydroperoxide 5a. 10 To a solution of hydroperoxide 5b (290 mg) and 2-adamantanone(300 mg) in CHCh ( 20 ml) was added one drop cone. H2SO4 and the reaction was kept for 14 h. The reaction mixture was diluted with sat. NaHCO3 (5 ml) and water (10 ml), extracted with ether (2 x 20 ml), dried over Na2S04 and concentrated. The crude product was purified by chromatotron on silica gel to furnish 250 mg (49.0% yield) of trioxane 9b, m.p. 75-76°C. The above trioxane was also prepared using different reaction conditions. Table 3 gives the conditions used and the yields of the trioxane 9b. EtOH was removed under reduced pressure after photooxygenation and replaced by CH2C12 in the second step before the addition of 2-Adamantanone. EXAMPLE 10 TRIOXANE 7be, FORMULA 7, R = CYCLOHEXYL, RiR2=-CH2-CH2-CH(Ph)CH2CH2- A solution of 3-(4-cyclohexylphenyl)-2-butenol (4b, 500 mg) and methylene blue (5 mg) in CHaCN (30 ml) was photooxygenated at -10°C for 2.5 h. 4-Phenylcyclohexanone (1 g) andptoluenesulfonic acid (50 mg) were added and the reaction mixture was left at r.t. for 20 h. The reaction mixture was worked up as above and concentrated. The crude product was purified by column chromatography on silica gel to furnish 570 mg (63.3% yield based on allylic alcohol 4b, used) of trioxane 7be as a mixture of two stereoisomers m.p. 107-109°C. 11 EXAMPLE 11 ETHYL 3-HYDROXY-3-(4-CYCLOHEPTYLPHENYL)-BUTANOATE (COMPOUND 2c, FORMULA 2, R = CYCLOHEPTYL) To a refluxing mixture of p-cycloheptylacetophenone (25 g), I2 (5 mg) and Zn (15 g) in benzene (200 ml) was added ethylbromoacetate (15 ml) dropwise during 1 h. The mixture was refluxed for 4.5 h and then cool to room temperature. It was acidified with 10% HC1 (200 ml) and benzene layer separated out. The organic layer was washed with water, dried (Na2SO4) and concentrated. The crude product was purified by column chromatography on silica gel to give 30.9 g (87.8% yield) of ethyl 3-hydroxy-3-(4-cycloheptylphenyl)-butanoate as viscous oil. ETHYL 3-(4-CYCLOHEPTYLPHENYL)-BUT-2-ENOATE (COMPOUND 3c, FORMULA 3, R = CYCLOHEPTYL) To a solution of ethyl 3-hydroxy-3-(4-cycloheptylphenyl)-butanoate (2c, 28.75 g) in benzene (175 ml) was added p-toluenesulfonic acid and was refluxed for 1 h. The reaction mixture was diluted with NaHCOs and benzene layer was separated out. The organic layer was washed with water, dried (Na2SO4) and concentrated. The crude product was purified by column chromatography on silica gel to give 11.6 g (42.9% yield) of ethyl 3-(4-cycloheptylphenyl)-but-2- enoate (3c, formula 3, R = cycloheptyl) as viscous oil. 3-(4-CYCLOHEPTYLPHENYL)-2-BUTENOL (COMPOUND 4c, FORMULA 4, R = CYCLOHEPTYL) To an ice cooled slurry of LiAlH4 (2.7 g) in dry ether (175 ml) was added a solution of ethyl 3-(4-cycloheptylphenyl)-but-2-enoate (3c, 9.5 g) in dry ether (50 ml) dropwise. The mixture was stirred for 4 h. at 0°C. The reaction mixture was quenched with water (7 ml). A solution of 10% NaOH (3 ml) was added. The precipitate was washed with ether and combined ether extracted was dried (Na2SO4) and concentrated. Crude product was purified by column chromatography on silica gel to give 6.1 g (75.3% yield) of allylic alcohol (4c, formula 4, R = cycloheptyl) as oil. 12 3-(4-CYCLOHEPTYLPHENYL)-l-HYDROXY-BUT-3-EN-2-HYDROPEROXIDE (COMPOUND 5c, FORMULA 5, R = CYCLOHEPTYL) A solution of 3-(4-cycloheptylphenyl)-2-butenol (4c, 150 mg) and methylene blue (2 mg) in acetonitrile (10 ml) was irradiated with a 250 watt tungston-halogen lamp at -6°C for 2.5 h. The reaction mixture was concentrated and crude product was purified by column chromatography on silica gel to furnish 120 mg (75% yield) of hydroperoxide 5c, m.p. 106-108°C. 3-[(4-CYCLOHEPTYLPHENYL)VINYL]-l,2,5-TRIOXASPIRO-[5,5]-UNDECANE (TRIOXANE 7ca, FORMULA 7, R = CYCLOHEPTYL; RI R2 = -C^CHaC^C^CHj-) A solution of 3-(4-cycloheptylphenyl)-2-butenol (4c, 1 g) and methylene blue (5 mg) in CHsCN (50 ml) was photooxygenated at -10°C for 3 h. Cyclohexanone (3 ml) and ptoluenesulfonic acid (50 mg) were added and reaction mixture was stirred for 18 h at r.t. The reaction mixture was worked up as above and concentrated. Crude product was purified by chromatography on silica gel to give 700mg (50% yield, based on allylic alcohol, 4c used) of trioxane 7ca m.p. 55-57°C. EXAMPLE 12 TRIOXANE 8c, FORMULA 8, R = CYCLOHEPTYL A solution of 3-(4-cycloheptylphenyl)-2-butenol (4c, 500 mg) and methylene blue (5 mg) in CHsCN (30 ml) was photooxygenated at -6°C for 3.5 h. Norcamphor (500 mg) and ptoluenesulfonic acid (30 mg) were added and reaction mixture was stirred for 18 h. at r.t. The reaction mixture was worked up as above and concentrated. Crude product was purified by chromatotron on silica gel to furnish 290 mg (38.6% yield, based on allylic alcohol, 4c used) of trioxane 8c m.p. 65-68°C. 13 EXAMPLE 13 TRIOXANE 9c, FORMULA 9, R = CYCLOHEPTYL A solution of 3-(4-cycloheptylphenyl)-2-butenol (4c, 500 mg) and methylene blue (5 mg) in CHsCN (30 ml) was photooxygenated at -6°C for 2 h 15 minutes. 2-Adamantanone (600 mg) andp-toluenesulfonic acid (50 mg) were added and reaction mixture was stirred for 22 h. at r.t. The reaction mixture was worked up as above and concentrated. Crude product was purified by chromatotron on silica gel to furnish 420 mg (50.6% yield, based on allylic alcohol, 4c used) of trioxane 9c as an oil. EXAMPLE 14 TRIOXANE 7cb, FORMULA 7, R = CYCLOHEPTYL ; R,R2 =-CH2-CH2- CH(C(CH3)2CH2CH3)-CH2CH2. A solution of 3-(4-cycloheptylphenyl)-2-butenol (4c, 500 mg) and methylene blue (5 mg) in CHsCN (30 ml) was photooxygenated at -6°C for 3 h. 4-f-Amylcyclohexanone (1.5 ml) andptoluenesulfonic acid (50 mg) were added stirred for 18 h. at r.t. The reaction mixture was worked up as above and concentrated. Crude product was purified by chromatotron on silica gel to furnish 400 mg (45.9% yield, based on allylic alcohol, 4c, used) of trioxane 7cb m.p. 58-60°C. EXAMPLE 15 ETHYL 3-HYDROXY-3-(4-CYCLOOCTYLPHENYL)-BUTANOATE (COMPOUND 2d, FORMULA 2, R = CYCLOOCTYL) To a refluxing mixture of /?-cyclooctylacetophenone (30 g), I2 (5 mg) and Zn (17.2 g) in benzene (300 ml) was added ethylbromoacetate (18 ml) dropwise during 30 minutes. The mixture was refluxed for 2 h and then cooled to room temperature. It was acidified with 10% HCI (200 ml), benzene layer was separated out. The organic layer was washed with water, dried (NaiSC^) and concentrated. The crude product was purified by column chromatography on silica gel to give 39.4 g (95% yield) of ethyl 3-hydroxy-3-(4-cyclooctylphenyl)-butanoate (2d, formula 2, R = cyclooctyl) as viscous oil. 14 ETHYL 3-(4-CYCLOOCTYLPHENYL)-BUT-2-ENOATE (COMPOUND 3d, FORMULA 3,R = CYCLOOCTYL) To a solution of ethyl 3-hydroxy-3-(4-cyclooctylphenyl)-butanoate (2d, 36 g) in benzene (350 ml) was added p-toluenesulfonic acid and refluxed for 2.5 h. The mixture was diluted with saturated NaHCCh solution (20 ml) and water (50 ml) and benzene layer was separated out. Aqueous layer was extracted with benzene (2 x 200 ml) combined organic layer was washed with water (2 x 20 ml), dried over Na2S04 and concentrated. Crude product was purified by column chromatography to furnish 27.5 g (81.1% yield) of ethyl 3-(4-cyclooctylphenyl)-but-2-enoate (3d, formula 3, R = cyclooctyl) as oil. 3-(4-CYCLOOCTYLPHENYL)-2-BUTENOL (COMPOUND 4d, FORMULA 4, R = CYCLOOCTYL) To an ice cooled slurry of LiAlFLi (2.9 g) in dry ether (200 ml) was added a solution of ethyl 3-(4-cyclooctylphenyl)-but-2-enoate (3d, 10 g) in dry ether (50 nil) dropwise. The reaction mixture was stirred at O°C for 2 h. The reaction mixture was quenched with water (11 ml). A solution of 10% NaOH (10 ml) was added and ether layer was decanted. The precipitate was washed with ether and combined extracts were concentrated. The crude product was purified by column chromatography on silica gel to give 6.82 g (79.3% yield) of 3-(4-cyclooctylphenyl)-2- butenol (4d, formula 4, R = cyclooctyl) m.p. 40-44°C. 3-(4-CYCLOOCTYLPHENYL)-l-HYDROXY-BUT-3-EN-2-HYDROPEROXIDE (COMPOUND 5d, FORMULA 5, R = CYCLOOCTYL) A solution of 3-(4-cyclooctylphenyl)-2-butenol (4d, 500 mg) and methylene blue (5 mg) in CHsCN (30 ml) was irradiation with a 250 watt tungston-halogen lamp at -6°C while oxygen was passed through the reaction mixture. After 2.5 h the reaction mixture was concentrated and crude product was purified by column chromatography on silica gel to furnished 400 mg (71.4% yield), m.p.83-85°C. 16 3-ETHYL-3-METHYL-6-[(4-CYCLOOCTYLPHENYL)VINYL]-l,2,4-TRIOXANE (COMPOUND 7da, FORMULA 7, R = CYCLOOCTYL) A solution of 3-(4-cyclooctylphenyl)-2-butenol (4d, 500 mg) and methylene blue (5 mg) in CH3CN (30 ml) was photooxygenatcd at -6°C for 3 h. Ethyl methyl ketone (1 ml) and HC1 (1 drop) were added and the reaction mixture was left at r.t. for 18 h. The reaction mixture was concentrated to remove CH3CN, diluted with NaHCO3 and water and extracted with ether (3 x 30 ml). The organic layer was dried over NaaSC^ and concentrated. The crude product was purified by chromatotron over silica gel to give 190 mg (28.7% yield based on allylic alcohol, 4d, used) of trioxane 7da as oil. EXAMPLE 16 3-[(4-CYCLOOCTYLPHENYL)VINYL]-l,2,5-TRIOXASPIRO-(5,5)-UNDECANE (TRIOXANE 7db, FORMULA 7, R = CYCLOOCTYL; R, R2 = -CHaCI^CHiCHzCHz-) A solution of 3-(4-cyclooctylphenyl)-2-butenol (4d, 500 mg) and methylene blue (5 mg) in CH3CN (30 ml) was photooxygenated at -6°C for 2.5 h. Cyclohexanone (1.5 ml) and ptoluenesulfonic acid (50 mg) were added and reaction mixture was left at r.t. for 18 h. The reaction mixture was worked up as above and concentrated. The crude product was purified by chromatron on silica gel to give 340 mg (47.8% yield, based on allylic alcohol, 4d used) of trioxane 7db as solid m.p. 58-60°C. EXAMPLE 17 3-[(4-CYCLOOCTYLPHENYL)VINYL]-l,2,5-TRIOXASPIRO-(6,5)-DODECANE (TRIOXANE 7dc, R = CYCLOOCTYL; R, R2 = -CHzCHzCHzCHjCHiCHz-) A solution of 3-(4-cyclooctylphenyl)-2-butenol (4d, 500 mg) and methylene blue (5 mg) in CH3CN (30 ml) was photooxygenated at -6°C for 2.5 h. Cycloheptanone (1.5 ml) and ptoluenesulfonic acid (50 mg) were added and reaction mixture was left at r.t. for 18 h. The reaction mixture was worked up as above and concentrated. The crude product was purified by chromatotron on silica gel to furnish 210 mg (28.3% yield, based on allylic alcohol, 4d used) of trioxane 7dc as oil. 17 EXAMPLE 18 TRIOXANE 7dd, FORMULA 7, R = CYCLOOCTYL; RI R2 = -CH2CH2CH(Ph)CH2CH2-) A solution of 3-(4-cyclooctylphenyl)-2-butenol (4d, 500 mg) and methylene blue (5 mg) in CHaCN (30 ml) was photooxygenated at -8°C for 2.5 h. 4-Phenylcyclohexanone (1 g) and ptoluenesulfonic acid (50 mg) were added and reaction mixture was left at r.t. for 18 h. The reaction mixture was worked up as above and concentrated. The crude product was purified by chromatotron on silica gel to furnish 340 mg (39.5% yield, based on allylic alcohol, 4d used) of trioxane 7dd as solid m.p. 95-97°C. EXAMPLE 19 TRIOXANE 8d, FORMULA 8, R = CYCLOOCTYL A solution of 3-(4-cyclooctylphenyl)-2-butenol (4d, 500 mg) and methylene blue (5 mg) in CHsCN (30ml) was photooxygenated at -6°C for 2.5 h. Norcamphor (500 mg) and ptoluenesulfonic acid (50 mg) were added and reaction mixture was kept at 10°C for 48 h. Reaction mixture was worked up as above and concentrated. Crude product was purified by chromatotron on silica gel to furnish 350mg (47.5 % yield, based on allylic alcohol 4d, used) of trioxane 8d as an oil. EXAMPLE 20 TRIOXANE 9d, FORMULA 9, R = CYCLOOCTYL A solution of 3-(4-cyclooctylphenyl)-2-butenol (4d, 500 mg) and methylene blue (5 mg) in CHsCN (30ml) was photooxygenated at -10°C for 3h. 2-Adamantanone (500 mg) and ptoluenesulfonic acid (80 mg) were added and reaction mixture was stirred at r.t. for 4 h and then left at r.t. for 14h. Reaction mixture was worked up as above and concentrated. Crude product was purified by chromatotron on silica gel to furnish 360mg (44.4% yield, based on allylic alcohol 4d, used) of trioxane 9d as an oil. 18 FOLLOWING THE ABOVE PROCEDURE THE FOLLOWING TRIOXANES WERE PREPARED : S.NO. Trioxane m.p. % yield 1. 3-[(4-cyclopentylphenyl)vinyl]-1,2,5- trioxaspiro(5,5)undecane (7ac, formula 7, R = cyclopentyl. RI R2= -CH2CH2CH2CH2CH2-) 57-58°C 50.6 2. 3-[(4-cyclopentylphenyl)vinyl-1,2,5- trioxaspira (5,6)dodecane (7ad, formula 7, R=cyclopentyl, RiR2=-CH2CH2CH2CH2CH2 CH2-) Oil 29.1 3. 8-(t-amyl)-3-[(4-cyclopentylphenyl)vinyl]- l,2,5-trioxaspira(5,5) undecane (7ae, formula 7, R = cyclopentyl, RI R2 = CH2-CH2- CH(C(CH3)2CH2CH3)-CH2CH2- 95-97°C 47.8 4. 3-ethyl-3-methyl-6-[4-cyclohexyl phenyl)vinyl]-l,2,4-trioxane (7bf, formula 7, R = cyclohexyl, Rt , R2= CH3> -CH2CH3) Oil 20 5. 3-Methyl-3-propyl-6-[4-cyclohexyl phenyl)vinyl]-l,2,4-trioxane (7bg, formula 7, R = cyclohexyl, Rt. R2= CH3. -CH2CH2CH3) Oil 28.1 6. 8-[(4-cyclohexylphenyl)vinyl]-6,7,10- trioxaspiro (4,5) decane (7bh, formula 7, R=cyclohexyl, RI R2=-CH2-CH2-CH2-CH2-) 43-45°C 39.4 7. 9-(t-amyl)-3-[(4-cyclohexylphenyl)vinyl]- l,2,5-trioxaspiro(5,5)undecane (7bi, formula 7, R = cyclohexyl, R, R2 = CH2-CH2- CH(C(CH3)2CH2CH3)-CH2CH2- 90-92°C 50.5 8. 8-[(4-cycloheptylphenyl)vinyl]-6,7,10- trioxaspiro(4,5)decane (7cc,formula 7, R = cycloheptyl, Rt R2 = CH2-CH2-CH2-CH2- Oil 65 9. 3-[(4-cycloheptylphenyl)vinyl]-8-phenyll, 2,5-trioxaspiro(5,5)undecane (7cd, formula 7, R = cycloheptyl, RiR2 = CH2-CH2-CH(Ph)- CH2-CH2-) 92-95°C 44 10. 8-[(4-cyclooctylphenyl)vinyl]-6,7,10- trioxaspiro(4,5)undecane (7de, formula 7, R = cycloheptyl, RiR2 = CH2-CH2-CH2-CH2-) Oil 45.5 11. 8-(t-amyl)-3-[(4-cyclooctylphenyl)vinyl]- l,2,5-trioxaspiro(5,5)undecane (7df, formula 7, R= cyclooctyl, R,R2 = CH2-CH2- CH(C(CH3)2CH2CH3)-CH2CH2- 89-91°C 51.7 19 ANTIMALARIAL ACTIVITY The antimalarial activity of the test compounds was evaluated in rodent using multidrug resistant strain ofPlasmodium yoelii Nigeriensis in swiss mice. General Procedure: Random bred swiss mice of either sex (20±2gm) were inoculated intraperitoneally with IxlO5 P. yoelii (MDR) parasites on day zero. The treatment with test compounds were administered to group of 5 mice each at different dose levels ranging between 24- 96 mg/kg/day. The treatment was administered via intramuscular route for 4 consecutive days (day 0-3). Blood smears from experimental mice were observed on day 4 and 7, day 10 and thereafter at regular intervals till day 28 or death of the animal. The parasitaemia level on day 4 was compared with the vehicle control group and the present 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 anti-malarial data is summarized in table 4.(Table Remove) We Claim: 1. A novel substituted 1,2,4-trioxane useful as an antimalarial agent of general formulae 7 (Formula Removed) wherein R is a cycloalkyl group selected from the group consisting of cyclohexyl, cyclopentyl, cycloheptyl and cyclooctyl; R1 and R2 is selected from the group consisting of hydrogen, alkyl group selected from the group consisting of methyl, ethyl, propyl and decyl and aryl such as phenyl; R1R2 together is a part of a cyclic system selected from the group consisting of cyclopentane, cyclohexane, substituted cyclohexanes, bicycle (2.2.1) heptane and adamantine. 2. A novel substituted 1,2,4-trioxane of general formulae 7 as claimed in claim 1 is selected from a group comprising 8-[(4-cyclopentylphenyl)vinyl]- 6,7,10-trioxaspiro-[4,5]-decane trioxane 7aa, 7ab, 3-[(4-cyclopentylphenyl) vinyl ]-1,2,5-trioxaspiro (5,5) undecane 7ac, 3-[(4-cyclopentylphenyl)vinyl- 1,2,5-trioxaspiro(5,6) dodecane 7ad , 8-(t-amyl)-3-[(4- cyclopentylphenyl)vinyl]-1,2,5-trioxapiro( 5,5) undecane 7ae, 3,3-dimethyl- 6-[4-cyclohexyphenyl]vinyl]-1,2,4-trioxane 7ba, 3-decyl, 3-methyl-6-[(4- cyclohexylphenyl)vinyl]-1,2,4-trioxane 7bb, 6-[(4-cyclohexylphenyl)vinyl]-3- phenyl-1,2,4-trioxane 7bc,3-[(4-cyclohexylphenyl)vinyl]-1,2,5- trioxaspiro(5,5)undecane 7bd, 7be, 3-ethyl-3-methyl-6-[4-cyclohexyphenyl)vinyl]- 1,2,4-trioxane 7bf, 3- Methyl -3- propyl-6-[4-cyclohexyl phenyl)vinyl] -1,2,4- trioxane 7bg, 8-[(4-cyclohexylphenyl)vinyl]-6,7,10-trioxaspiro (4,5) decane 7bh, 9-( t-amyl) -3- [(4-cyclohexylphenyl)vinyl]-1,2,5-trioxaspiro(5,5)undecane 7bi, 3- [(4-cycloheptylphenyl)vinyl]-1,2,5-trioxaspiro-[5,5]-undecane 7ca, 7cb, 8-[(4- cycloheptylphenyl )vinyl]-6,7,10-trioxaspiro(4,5)decane 7cc, 3-[(4- cycloheptylphenyl]-8-phenyl-1,2,5-trioxaspiro(5,5)undecane 7cd, 3-ethyl-3- methyl-6-[(4-cyclooctylphenyl)vinyl]-1,2,4-trioxane 7da, 3-[(4- cyclooctylphenyl)vinyl]-1,2,5-trioxaspiro-(5,5)-undecane 7db, 3-[(4- cyclooctylphenyl)vinyl]-1,2,5-trioxaspiro-(6,5)-dodecane 7dc, 7dd, 8-[(4-cyclooctylphenyl)vinyl]-6,7,10-trioxaspiro(4,5)undecane 7de,8-(t-amyl)-3-[(4-cyclooctylphenyl)vinyl]-1,2,5-trioxaspiro(5,5)undecane 7df, 8a,8b,8c,9a,9b and 9c. 3. A novel substituted 1,2,4-trioxane useful as an antimalarial agent substantially as herein described with reference to the examples and drawing accompanying this specification.

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1311-del-2001-abstract.pdf

1311-DEL-2001-Claims-24-11-2008.pdf

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1311-del-2001-correspondence-others.pdf

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