Title of Invention

NOVEL SUBSTITUTED 1,2,4-TRIOXANES AS ANTIMALARIAL AGENTS

Abstract

Novel substituted 1,2,4-trioxanes as antimalarial agents This invention particularly relates to a process for the preparation of 6-[(fluorenyl/phenanthrenyl)vinyl]-l,2,4-trioxanes, a new series of antimalarial agents. 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.

Full Text

This invention relates to novel substituted 1,2,4-trioxanes useful as antimalarial agents. This invention also relates to a process for the preparation of novel substituted 1,2,4-trioxanes. This invention perticularly relates to a process for the preparation of 6-[(fluorenyl/phenanthrenyl)vinyl]-1,2,4-trioxanes, 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 7 wherein R represents 2-fluorenyl, 2-phenanthrenyl and 3-phenanmrenyl, R1 and R2 represent hydrogen, alkyl group like methyl, ethyl, propyl, isopropyl, aryl like phenyl, p-fluorophenyl or part of cyclic system such as cyclopentane, cyclohexane, bicyclo(2,2,l)heptane, 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. The trioxanes of the general formula 7 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. The objective of the present invention is also to provide a process for the preparation of novel substituted 1,2,4-trioxanes of general formula 7, a new series of antimalarial agents. Accordingly, the present invention provides a process for the preparation of novel substituted 1,2,4-trioxanes of general formula 7 as given below : (Formula Removed) wherein R represents 2-fluorenyl, 2-phenanthrenyl, 3-phenanthrinyl, R1 and R2 represent hydrogen, alkyl group such as methyl, ethyl, propyl, isopropyl, aryl such as phenyl, p-fluorophenyl or part of a cyclic system such cylopentane, cyclohexane, bicycle(2,2,l)heptane, adamantane which comprises i)reaction of aryl methyl ketone of formula 1 (Formula Removed) wherein R represents 2-fluorenyl, 2-phenanthrenyl or 3-phenanthrenyl, with haloacetate such as ethyl bromoacetate, ethyl chloroacetate and Zn in presence of catalytic amount of I2 in an aprotic organic solvent in the temperature range of room temperature to refluxing temperature to give (3-hydroxyesters of formula 2 (Formula Removed) wherein R has the same meaning as above, ii)dehydrating P-hydroxyesters of formula 2 using a dehydrating catalyst in an aprotic organic solvent at room temperature to refluxing temperature to give a,P-unsaturated esters of the formula 3 (Formula Removed) wherein R has the same meaning as above, iii) reducing esters of formula 3 with a metal hydride such as LiAlH4 in an ether solvent in the temperature range of 0°C to room temperature to give allylic alcohols of the formula 4 (Formula Removed) wherein R has the same meaning as above, iv) photooxygenating the allylic alcohols of formula 4 in presence of a sensitizer in an organic solvent in the temperature range of -10°C to room temperature to give b-hydroxyhydroperoxides of formula 5 (Formula Removed) wherein R has the same meaning as above, v) isolating and then reacting or reacting in situ the P-hydroxyhydroperoxides of the formula 5 with an aldehyde/ketone of the general formula 6 (Formula Removed) wherein R1 and R2 represent hydrogen, alkyl group such as methyl, ethyl, propyl, isopropyl. aryl such as phenyl, p-fluorophenyl or part of the cyclic system such as cyclopentane, cyclohexane, 2-bicyclo(2,2,l)heptane, adamantine in presence of an acid catalyst in an aprotic organic solvent in a temperature range of 0°C to room temperature, vi) isolating and purifying the trioxanes of general formula 7 wherein R, R1 and R2 have the same meaning as above, by known methods. Accordingly the invention provides a novel substituted 1,2.4-trioxanes of formula 7 wherein R is 2-fluorenyl, 2-phenanthrenyl, 3-phenanthrenyl, R1 and R2 represent Iiydrogen, alkyi groups such as methyl, ethyl, propyl, isopropyl, aryl groups such as phenyl, p-fluorophenyl, aralkyl such as benzyl, or part of a cyclic system. (Formula Removed) Novel trioxanes of the said compounds having the structural formulae 7a-c, 7j-k, as shown below. (Formula Removed) 7a R1,R2 7b R! , R2 = H, p-fluoropheny 1 7c R1R2 = -CH2CH2CH2CH,CH2- TJ R1,R2 - -CH2CH2CH2CH2 7k R1,R2--CH2CH2CH2CH2- Novel 1,2,4-trioxanes of the said compounds having the structural formulae 7d-e.71-m as given below: (Formula Removed) 7d R1,R2 = H,Ph 7e R1, R2 = -CH2CH2CH2CH2CH2- 71 R,,R2 = CH3,CH3 7m R1,R2 = -CH2CH2CH2CHr Novel 1,2,4-trioxanes of the the said compounds having the structural formulae 7f-I, 7n-o as shown below: (Formula Removed) 7f R1,R2 = CH3,CH3 7g R1,R2 = CH3,CH2CH2CH3 7h R1, R2 = -CH2CH2CH2CH2CH2- 7i R1,R2 = -CH2CH2CH2CH2- 7n R1,R2 = H,CH(Me)2 7o Rl,R2 = H,Ph 7p R1, R2 = H, p-fluorophenyl Novel 1,2,4-trioxanes of the said compounds having the structural formulae 8a-c as shown below. (Formula Removed) 8a R = 2-fluorenyl 8b R = 2-phenanthrenyl 8c R = 3-phenanthrenyl Novel 1,2,4-trioxanes of the said compounds having the structural formulae 9 a-c as shown below. 9 a R = 2-fluorenyl 9b R = 2-phenanthrenyl 9d R = 3-phenanthrenyl In the process aryl methyl ketones of formula 1 are reacted with haloacetate such as ethyl bromoacetate, ethyl chloroacetate and Zn in presence of catalytic amount of 12 in an aprotic organic solvent such as benzene,toluene,diethyl ether to gove beta-lrydroxyesters of formula 2. These beta-hydroxyesters can be isolated and purified by standard laboratory methods such as column chromatography or can be used without purification in the next step. p-Hydroxyesters of formula 2 are new compounds and they have not been prepared earlier. In the process dehydration of p-hydroxyesters of formula 2 may be effected in aprotic organic solvent such as benzene, toluene, CH2C12 in presence of a dehydrating agent such as I2, p-toluene sulfonic acid or P2O3 to give α,ß-unsaturated esters of formula 3. These unsaturated esters can be isolated and purified by standard laboratory methods such as column chromatography using silica gel as an adsorbent and hexane/ethylacetate as eluent. The α,ß-unsaturated esters of formula 3 are new compounds and they have not been prepared earlier. In the process reduction of α,ß-unsaturated esters of formula 3 is effected with a complex metal hydride such as LiAlH4 in an ether solvent such as diethyl ether, tetrahydrofuran, to give allylic alcohols of formula 4. These allylic alcohols of formula 4 can be isolated and purified by standard laboratory methods such as crystallization or column chromatography on silica gel. The allylic alcohols of formula 4 are new compounds and they have not been prepared earlier. In the process photooxygenation of allylic alcohols of formula 4 may be effected by passing oxygen gas or air in the solution of alcohol in an organic solvent and in the presence of a dye and a light source which provides visible light for a period in the range of 2 to 15 h, to give p.-hydroxyhydroperoxides of formula 5. These p-hydroxyhydroperoxides of formula 5 which are new chemical entities can be isolated and purified by standard laboratory methods such as crystallization or column chromatography or can be used in situ, without purification, in the next step. The dye which acts as a sensitizer i.e. converts 3O2 to highly reactive lO2 may be selected from methylene blue, rose bengal, tetraphenylporphine and the like. Organic solvent used may be selected from CH2C12, benzene, CH3CN, ethanol and the like. In the process reaction of ß-hydroxyhydroperoxides of formula 5 with aldehydes/ketones of formula 6 is done in an aprotic solvent in the presence of an acid catalyst to give trioxanes of formula 7. The aldehydes and ketones used may be such as isobutyraldehyde, benzaldehyde, p-fluorobenzaldehyde, acetone, ethyl methyl ketone, methyl propyl ketone, cyclopentanone, cyclohexanone, bicyclic ketone such as norcomphor and tricyclic ketone such as 2-adamantanone. The acid catalyst used may be such as HCl, H2SO4, p-toluenesulfonic acid, acidic resin like Amberlyst-15. The aprotic organic solvent used may be such as CH2C12, CHC13, benzene, CH3CN. These trioxanes of formula 7 can be isolated and purified by standard laboratory methods such as column chromatography and crystallization. These trioxanes are new chemical entities and they have not been prepared earlier. Some of the trioxanes of formula 7 have been tested against malarial parasites in mice and show promising antimalarial activity. The invention is firmer 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-(2-fluorenyl)-butanoate (Compound 2a, formula 2, R=2-fluorenyI) To a refluxing mixture of 2-acetylfluorene (3.4 gm), I2 (50 mg) and Zn (4.25 gm) in benzene (80 ml) was added ethylbromoacetate (4.1 gm) dropwise during 5 minutes. The mixture was refluxed for 1.5 h and men cooled to room temperature. It was acidified wim 10% HCl (15 ml), benzene layer separated out The organic phase was washed with water, dried (NA2SO4) and concentrated. The crude product was purified by chromatography using SiO2 as adsorbent and hexane-ethylacetate mixture as eluant to give 3.0 g (63% yield) of ethyl 3-hydroxy-3-(2-fluorenyl)-butanoate (2a, formula 2, R = 2-fluorenyl) mp. 94-95°C. Compound 2a was obtained only in 1% yield when ethyl chloroacetate was used instead of ethyl bromoacetate. Ethyl 3-(2-fluorenyl)-but-2-eneate (Compound 3a, formula 3, R=2-fluorenyl) To a solution of ethyl 3-hydroxy-3-(2-fluorenyl)-butanoate (2a, 4.0 gm), in benzene (20 ml) was added p-toluene sulphonic acid (170 mg) and refluxed for 1.5 h. The mixture was diluted with sat NaHCO3 (5 ml), benzene layer separated out. The organic layer was washed with water, dried (Na2SO4), and concentrated. The crude product was purified by chromatography on silica gel to give 3.4 gm (90% yield) of ethyl 3-(2-fluorenyl)-but-2-enoate (3a, formula 3, R=2-fluorenyl), m.p. 112-114°C. 3-(2-Fluorenyl)-2-butenol (Compound 4a, formula 4, R=2-fluorenyl) To an ice cooled slurry of LAH (1.5 gm) in dry ether (70 ml) was added a solution of ethyl 3-(2-fluorenyl)-but-2-enoate (3a, 3.4 gm) in dry ether (30 ml) dropwise. The mixture was stirred for 4 h at 0°C. The reaction mixture was quenched with water (20 ml). A solution of 10% NaOH (5 ml) was added and the ether layer was decanted. The precipitate was washed with ether and the combined ether extracts were concentrated. The crude product was purified by crystallization with ether/hexane to give 1.9 gm (66% yield) of 3-(2-fluorenyl)-2-butenol (4a, formula 4, R=2-fluorenyl), m.p. 118-120°C. The above compound was also prepared by changing reaction conditions as follows: To an ice cooled slurry of LAH (250 mg) in dry THF (20 ml) was added a solution of ethyl 3-(2-fluorenyl)-but-2-enoate (3a, 250 mg) in dry THF (5 ml) dropwise during 4 minutes. The mixture was stirred for 3.5 h at 0°C. The reaction mixture was quenched with water (3 ml) and added 10% NaOH (1 ml). Organic layer was decanted and precipitate was washed with ethyl acetate. Combined organic extracts were dried (Na2SO4) and concentrated. The crude product was purified by chromatography on silica gel to give 30 mg (14% yield) of 3-(2-fluorenyl)-2-butenol (4a). 3-(2-Fluorenyl)-l-hydroxy-but-3-en-2-hydroperoxide (Compound 5a, formula 5, R=2-fluorenyl) A solution of 3-(2-fluorenyl)-2-butenol (4a, 200 mg) and methylene blue (10 nig) in acetonitrile (30 ml) was irradiated with a 250 watt, tungston-halogen lamp at -10°C while oxygen was passed through the reaction mixture for 4.5 h. The crude product obtained by usual aqueous workup was crystallized from CH2C12 to give 40 mg of hydroperoxide 5a. The filtrate was chromatographed on silica gel to give 80 mg of hydroperoxide 5a. The combined yield of hydroperoxide (compound 5a, formula 5, R=2-fluorenyl) was 120 mg (53% yield), m.p. 79-80°C. Photooxygenation of 3-(2-fluorenyl)-2-butenol in CC14 at r.t. using tetraphenylporphine as sensitizer and air as source of oxygen furnished the above hydroperoxide 5a in 78% yield. 3,3-Dimethyl-6-[(2-fluorenyl)vinyl-1,2,4-trioxane (Trioxane 7a, formula 7, R=2-fluorenyl; R1R2=CH3, CH3) A solution of 3-(2-fluorenyl)-2-butenol (4a, 400 mg) and methylene bhie (10 mg) in a mixture of acetone (30 ml) and acetonitrile (25 ml) was photooxygenated at 0°C for 4 h. to give compound 5a (as shown by TLC). To the mixture cone. HC1 (2 drops) was added and stirred for 2 h at r.t.The reaction mixture was concentrated and the crude product was purified by column chromatography on silica gel to furnish 340 mg (65% yield based on allylic alcohol used) of trioxane 7a, m.p. 88-90°C. Example 2 6-[(2-Fluorenyl)vinyl]-3-p-fluoropheayl-l,2,4-trioxane (Trioxane 7b, formula 7, R=2-fluorenyl; R1, R2=H, p-FC6H4) A solution of 3-(2-fluorenyl)-2-butenol (4a, 300 mg) and methylene blue (10 mg) in CH3CN (40 ml) was photooxygenated at 0°C for 5 h. p-fluorobenzaldehyde (1.1 gtn) and Amberlyst-15 (100 mg) were added and the mixture was stirred for 11 h at r.t Resin was filitered off and filtrate was concentrated. The crude product was purified by column chromatography on silica gel and crystallization from hexane to give 110 mg (23% yield, based on allylic alcohol used) of trioxane 7b, m.p. 148-150°C. Example 3 3-[(2-Fraorenyl)vinyl]-l,2,5-trioxaspiro(5,5)undecane (Trioxane 7c, formula 7, R=2-fluorenyl; R,, R2 = -CH2CH2CH2CH2CH2-) A solution of 3-(2-fluorenyl)-2-butenol (4a, 100 mg) and methylene blue (10 mg) in CH3CN (30 ml) was photooxygenated at 0°C for 4 h. Cyclohexanone (500 mg) and p-toluene sulfonic acid (20 mg) were added and the reaction mixture was stirred for 4 h and left for over night 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 give 70 mg (48% yield, based on allylic alcohol used) of trioxane 7c, m.p. 102-103°C. The trioxane 7c was also prepared by using cone. HC1 as catalyst in 27% yield. Example 4 Trioxane 8a, formula 8, R=2-fluorenyl A solution of 3-(2-fluorenyl)-l-hydroxy-but-3-en-2-hydroperoxode (5a, 220 mg) and norcamphor (400 mg) in CH2C12 (20 ml) was added cone. HC1 (1 drop). The mixture was stirred for 1.5 h and kept over night at r.t Mixutre was diluted with sat NaHCO3 (1 ml) and water (5 ml), CH2C12 layer separated out Aqueous phase was extracted with ether (50 ml). Combined organic layer was washed with water, dried (Na2SO4) and concentrated.The crude product was purified by column chromatography on silica gel to give 170 mg (55% yield) of trioxane 8a. Example 5 (Trioxane 9a, formula 9, R=2-fluorenyl) A solution of 3-(2-fluorenyl)-2-butenol (4a, 400 mg) and methylene blue (20 mg) in a mixture of CH3CN (50 ml) and CH2C12 (10 ml) was photooxygenated at 0°C for 4 h. Adamantanone (900 mg) and conc. HC1 (2 drops) were added and the reaction mixture was kept for 2.5 h at r.t The reaction mixture was diluted with sat. NaHCO3 (5 ml) and water (40 ml), extracted with ether (2 x 80 ml), dried on Na2SO4 and concentrated. The crude product was purified by column chromatography on silica gel and crystallized from hexane to give 400 mg (59% yield, based on allylic alcohol used) of trioxane 9a, m.p. 98-100°C. Example 6 Trioxane 9a (formula 9, R=2-flnorenyl) To a solution of hydroperoxide 5a (50 mg) and adamantanone (60 mg) in CHC13 (10 ml) was added one drop of cone. H2SO4 and the reaction mixture was kept for 15 minutes. The reaction mixture was diluted with sat. NaHCO3 (2 ml) and water (10 ml), extracted with «ther (2 x 20 ml), dried on Na2SO4 and concentrated. The crude product was purified by column chromatography on silica gel to furnished trioxane 9a (50 mg, 59% yield). Example 7 Ethyl 3-hydroxy-3-(2-phenanthrenyl)-butanoate (Componnd 2b formula 2, R=2- phenanthrenyl) To a refluxing mixture of 2-acetylphenanthrene (4.0 gm), I2 (50 mg) and Zn (4.72 gm) in benzene (100 ml) was added ethylbromoacetate (6.1 gm) dropwise during 5 minutes. The mixture was refluxed for 5 h and then cooled to room temperature. It was acidified with 10% HC1 (20 ml), benzene layer separated out The organic layer was washed with water, dried (Na2SO4) and concentrated. The crude product was purified by chromatography on silica gel to give 4.58 g (82% yield) of ethyl 3-hydroxy-3-(2-phenanthrenyl)-butanoate (2b), tap. 64-67°C. Ethyl 3-(2-phenanthrenyl)-but-2-enoate (Compound 3b formula 3, R=2-phenanthrenyl) To a solution of ethyl 3-hydroxy-3-(2-phenanthrenyl)-butanoate (2b, 700 mg), in benzene (25 ml) was added p-toluene sulphonic acid (100 mg) and refluxed for 0.5 h. The mixture was diluted with sat. NaHCO3 (5 ml), benzene layer was separated. The organic phase was washed with water, dried (Na2SO4) and concentrated. The crude product was purified by chromatography on silica gel to give 550 nig (83% yield) of ethyl 3-(2-phenanthrenyl)-but-2-enoate (3b, formula 3, R=2-phenanthrenyl), m.p. 108-110°C. Similar yield (86%) was obtained when the dehydration was carried out with iodine in same solvent 3-(2-Phenanthrenyl)-2-butenol (Compound 4b, formula 4, R=2-phenanthrenyI) To an ice cooled slurry of LAH (500 mg) in dry ether (40 ml) was added a solution of ethyl 3-(2-phenanthrenyl)-but-2-enoate (3b, 950 mg) in dry ether (20 ml) dropwise. The mixture was stirred for 3 h at 0°C. The reaction mixture was quenched with water (5 ml). A solution of 10% NaOH (2 ml) was added stirred and then ether layer was decanted. The precipitate was washed with ether and the combined ether extracts were concentrated. The crude product was purified by chromatography on silica gel to give 600 mg (74% yield) of 3-(2-phenanthrenyl)-2-butenol (4b, formula 4, R=2-phenanthrenyl), m.p. 127-130°C. 3-(2-Phenanthrenyl)-l-hydroxy-but-3-en-2-hydroperoxide (Compound 5b, formnla 5, R=2-phenanthrenyl) A solution of 3-(2-phenanthrenyl)-2-butenol (4b, 600 mg) and methylene blue (20 mg) in methanol (60 ml) was irradiated with a 250 watt, tungston-halogen lamp at 0°C while oxygen was passed through the reaction mixture. After 13 h mixture was diluted with water (50 ml) and extracted with ether (3 x 50 ml). The ether extract was washed with water, dried (Na2SO4) and concentrated. The crude product was crystallized from CH2C12 to give 140 mg of hydroperoxide 5b. The filtrate was chromatographed on silica gel to give 200 mg of hydroperoxide 5b. The combined yield of hydroperoxide 5b was 340 mg (50% yield), m.p. 120-121°C. The above hydroperoxide was also prepared using different reaction conditions. Table 1 gives the conditions used and the yield of the hydroperoxide 5b. Tablet (Table Removed) 6-[(2-Phenanthrenyl)vinyl]-3-phenyl-1,2,4-trioxane (Trioxane 7d, formula 7, R=2-phenanthrenyl; R1,R2=H, Ph) A solution of 3-(2-phenanthrenyl)-2-butenol (4b, 400 mg) and methylene blue (10 mg) in CH2C12 (40 ml) was photooxygenated at 0°C for 5 h. Benzaldehyde (800 mg) and cone. HC1 (2 drops) were added and the reaction mixture was stirred for 4 h then kept over night at r.t The reaction mixture was diluted with sat. NaHCO3 (2 ml) and water (20 ml), extracted with ether (2 x 100 ml), dried on Na2SO4 and concentrated. Thr crude product was purified by column chromatography on silica gel to give 290 mg (49% yield, based on allylic alcohol, 4b used) of trioxane 7d, m.p. 107-108°C. Example 8 3-[(2-Phenanthrenyl)vinyl]-l,2,5-trioxaspiro(5,5)undecane (Trioxane 7e, formula 7, R-2-phenanthrenyl; R1,R2= CH2CH2CH2CH2CH2-) A solution of 3-(2-phenanthrenyl)-2-butenol (4b, 430 mg) and methylene blue (10 mg) in CH3CN (50 ml) was photooxygenated at -8°C for 5.5 h. Cyclohexanone (860 mg) and cone. HCl (2 drops) were added and the reaction mixture was kept for 2.5 h at r.t The reaction mixture was worked up as above and concentrated. The crude product was purified by column chromatography to give 190 mg (30% yield, based on allylic alcohol, 4b used) of trioxane 7e, m.p. 102-104°C. Example 9 Trioxane 8b, formula 8, R=2-phenanthrenyl A solution of 3-(2-phenanmrenyl)-2-butenol (4b, 400 mg) and methylene blue (10 mg) in CH3CN (50 ml) was photooxygenated at 0°C for 5 h. Norcamphor (800 mg) and conc. HCl (2 drops) were added to the mixture and stirred for 5.5 h at r.t. The reaction mixture was worked up and chromatographed on silica gel as above to give 230 mg (38% yield, based on allylic alcohol, 4b used) of trioxane 8b. Example 10 Trioxane 9b, formula 9, R=2-phenanthrenyl A solution of 3-(2-phenanthrenyl)-2-butenol (4b, 600 mg) and methylene blue (20 nig) in CH3CN (70 ml) was photooxygenated at 0°C for 5 h. Adamantanone (600 mg) and conc. HCl (2 drops) were added and the reaction mixture was kept for 2.5 h at r.t. The reaction mixture was diluted wim sat NaHCO3 (3 ml) and water (50 ml), extracted wim ether (3 x 80 ml), dried on Na2SO4 and concentrated. The crude product was purified by column chromatography on silica gel and crystallized from hexane to give 570 mg (57% yield, based on allylic alcohol, 4b used) of trioxane 9b, m.p. 130-133°C. The trioxanes 9b was also prepared under different reaction conditions using different acid catalysts as given in table 2. Table 2 (Table Removed) Example 11 Ethyl 3-hydroxy-3-(3-phenaothrenyI)-butanoate (Compoimd 2c formula 2, R=3- phenanthrenyr) To a refluxing mixture of 3-acetylphenanthrene (5.01 gm), I2 (70 mg) and Zn (3.0 gm) in benzene (80 ml) was added ethylbromoacetate (4.5 gm) dropwise during 10 minutes. The mixture was refluxed for 4.5 h and then cooled to room temperature. It was acidified with 10% HCl (20 ml), benzene layer separated out. The organic layer was washed with water, dried (Na2SO4) and concentrated. The crude product was purified by chromatography on silica gel to give 5.02 g (72% yield) of ethyl 3-hydroxy-3-(3-phenanthrenyl)-butanoate (2c, formula 2, R=3-phenanthrenyl) as a viscous oil. Ethyl 3-(3-phenanthrenyl)-but-2-enoate (Compound 3c formula 3, R=3-phenanthrenyl) To a solution of ethyl 3-hydroxy-3-(3-phenanthrene)-butanoate (2c, 5.02 gm), in benzene (30 ml) was added phosphorous pentaoxide (3.6 gm) and refluxed for 4 h. The benzene layer was decanted and then concentrated. The crude product was purified by chromatography on silica gel to give 2.6 gm (55% yield) of ethyl 3-(3-phenanthrenyl)-but-2-enoate (3c, formula 3, R=3-phenanthrenyl), m.p. 78-80°C. Compound 3c was also prepared using different catalyst as given in table-3. Table 3 (Table Removed) 3-(3-Phenanthrenyl)-2-butenol (Compound 4c, formula 4, R=3-pheuanthreuyI) To an ice cooled slurry of LAH (2.4 gm) in dry ether (80 ml) was added a solution of ethyl 3-(3-phenanthrenyl)-but-2-enoate (3c, 2.3 gm) in dryether (25 ml) dropwise. The reaction mixture was stirred for 2 h at 0°C. The reaction mixture was quenched with water (15 ml). A solution of 10% NaOH (5 ml) was added and the ether layer was decanted. The precipitate was washed with ether and the combined ether extracts were concentrated. The crude product was chromatographed on silica gel to give 1.2 gm(63% yield) of 3-(3-phenanthrenyl)-2-butenol (4c, formula 3, R=3-phenanthrenyl), m.p. 57-58°C. 3-(3-Phenanthrenyl)-l-hydroxy-but-3-en-2-hydroperoxide (Compound 5c, formula 5, R=3-phenanthrenyl) A solution of 3-(3-phenanthrenyl)-2-butenol (4c, 400 mg) and methylene blue (10 mg) in acetonitrile (50 ml) was irradiated with a 250 watt tungston-halogen lamp at -8°C while oxygen was passed through the reaction mixture. After 4 h the reaction mixture was diluted with water (40 ml) and extracted with ether (2 x 50 ml). The ether extract was washed wim water, dried (Na2SO4) and concentrated. The crude product was purified by chromatography and crystallized with CH2C12 to give 290 mg (65% yield) of 3-(3-phenanthrenyl)-l-hydroxy-but-3-en-2-hydroperoxide (5c, formula 5, R=3-phenanthrenyl) m.p. 116-117°C. 3,3-Dimethyl-6-[(3-phenanthienyl)vinyl]-l,2,4-trioxane (Trioxane 7f, formula 7, R=3-phenanthrenyl; R1,R2=CH3, CH3) A solution of 3-(3-phenanthrenyl)-2-butenol (4c, 200 mg) and methylene blue (10 mg) in acetone (25 ml) was photooxygenated at 0°C for 3.5 h. To the mixture, cone. HC1 (1 drops) was added and kept for 4 h. at r.t. and then concentrated. The crude product was purified by column chromatography to give 120 mg (48% yield, based on allylic alcohol, 4c used) of trioxane 7f, m.p. 59-60°C. Example 12 3-Methyl,3-n-propyl-6-[(3-phenanthrenyl)vinyl]-l,2,4-trioxane (Trioxane 7g, formola 7, R=3-phenanthrenyl; R1,R2= -CH3, n-CH2CH2CH3) A solution of 3-(3-phenanthrenyl)-2-butenol (4c, 400 mg) and methylene blue (10 mg) in CH3CN (50 ml) was photooxygenated at 0°C for 4.5 h. Methyl propyl ketone (420 mg) and cone. HC1 (2 drops) were added and the mixture was kept for 20 h at r.t. The reaction mixture was worked up as above and concentrated. The crude product was purified by column chromatography to give 220 mg (39% yield, based on allylic alcohol, 4c used) of a mixture of two isomers of trioxane 7g, as an oil. Example 13 3-[(3-Phenanthrenyl)vmyl]-l,2,5-trioxaspiro(5,5)undecane (Trioxane 7h, formola 7, R=3-phenanthrenyl; R1,R2 = - CH2CH2CH2CH2CH2-) A solution of 3-(3-phenanthrenyl)-2-butenol (4c, 300 mg) and methylene blue (10 mg) in CH3CN (30 ml) was photooxygenated at -8 to 0°C for 5 h. Cyclohexanone (360 mg) and cone. HC1 (2 drops) were added and the reaction mixture was kept for 2 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 170 mg (39% yield, based on allylic alcohol, 4c used) of trioxane 7h, m.p. 84-85 °C. Example 14 8-[(3-Phenanthrenyl)vinyl]-6,7,10-trioxaspiro(4,5)decane (Trioxane 7i, formula 7, R=3-phenanthrenyl; R1,R2 = - CH2CH2CH2CHz-) A solution of 3-(3-phenanthrenyl)-2-butenol (4c, 210 mg) and methylene blue (10 mg) in CH3CN (25 ml) was photooxygenated at 0°C for 2.5 h. Cyclopentanone (260 mg) and cone. HC1 (2 drops) were added and the mixture was stirred for 2 h at r.t The reaction mixture was diluted with sat. NaHCO3 (2 ml) and water (20 ml), extracted with ether (2 x 40 ml), dried on Na2SO4 and concentrated The crude product was purified by column chromatography on silica gel to give 110 mg (38% yield, based on allylic alcohol, 4c used) of trioxane 7i, m.p. 70-72°C. Example 15 Trioxane 9c, formula 9, R=3-phenanthrenyI A solution of 3-(3-phenanthrenyl)-2-butenol (4c, 230 mg) and methylene blue (10 mg) in CH3CN (25 ml) was photooxygenated at 0°C for 5 h. Adamantanone (300 mg) and conc. HC1 (2 drops) were added and the reaction mixture was kept for 17 h at r.t The reaction mixture was diluted with sat NaHCO3 (2 ml) and water (20 ml), extracted with ether (2 x 40 ml), dried on Na2SO4 and concentrated. The crude product was purified by column chromatography on silica gel to give 190 mg (50% yield, based on allylic alcohol, 4c used) of trioxane of formula 9c, m.p. 86-88°C. Following the above procedures the following trioxanes were prepared. (Table Removed) Antimalarial Activity The antimalarial activity of the test compounds was evaluated in rodent using multidrug resistant strain of Plasmodium yoelii Mgeriensis in Swiss mice. General Procedure : Random bred swiss mice of either sex (20 ± 2 gm) were inoculated intraperitoneally with 1 x 103 P. yoelii (MDR) parasites on day zero. The treatment with test compounds were administered to groups of 6 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 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. For determing 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 recorded as the curative dose. The antimalarial data is summarized in Table-4. Table 4 : Antimalarial activity of trioxanes against P. yoelii in mice (Table Removed) We claim 1. Novel substituted 1,2,4-trioxanes of formula 7 wherein R is 2-fluorenyl, 2-phenanthrenyl, 3-phenanthrenyl, R1 and R2 represent hydrogen, alkyl groups such as methyl, ethyl, propyl, isopropyl, aryl groups such as phenyl, p-fluorophenyl, aralkyl such as benzyl, or part of a cyclic system. (Formula Removed) 2. Novel trioxanes as claimed in claim 1 wherein the said compounds having the structural formulae 7a-c, 7j-k, as shown below. (Formula Removed) 7a R1,R2 = CH3,CH3 7b R1, R2 = H, p-fluorophenyl 7c R1, R2 = -CH2CH2CH2CH2CH2- 7j R1, R2 = CH3, CH2CH2CH3 7k R1, R2 = -CH2CH2CH2CH2- 3. Novel 1,2,4-trioxanes as claimed in claims 1-2 wherein the said compounds having the structural formulae 7d-e, 71-m as shown below. (Formula Removed) 7d R1,R2 = H,Ph 7e R1, R2 = -CH2CH2CH2CH2CH2- 71 R1, R2 — CH3, CH3 7m R1, R2 = -CH2CH2CH2CH2- 4. Novel 1,2,4-trioxanes as claimed in claims 1-3 wherein the said compounds having the structural formulae 7f-i, 7n-o, as shown below. (Formula Removed) 7f R1, R2 = CH3, CH3 7g R1, R2 - CH3, CH2CH2CH3 7h R1, R2 = -CH2CH2CH2CH2CH2- 7i R1, R2 = -CH2CH2CH2CH2- 7n R1,R2 = H,CH(Me)2 7o R1,R2 = H,Ph 7p R1, R2 = H, p-fluorophenyl Novel 1,2,4-trioxanes as claimed in claims 1-4 wherein the said compounds having the structural formulae 8a-c as shown below. (Formula Removed) 8a R = 2-fluorenyl 8b R = 2-phenanthrenyl 8c R = 3-phenanthrenyl Novel 1,2,4-trioxanes as claimed in claims 1-5 wherein the said compounds having the structural formulae 9a-c as shown below. (Formula Removed) (Formula Removed) 9a R = 2-fluorenyl 9b R = 2-phenanthrenyl 9d R = 3-phenanthrenyl A process for the preparation of novel substituted 1,2,4-trioxanes of general formulae 7 wherein R represents 2-fluorenyl, 2-phenanthrenyl. 3-phenanthrinyl, R1 and R2 represent hydrogen, alkyl group such as methyl, ethyl, propyl, isopropyl, aryl such as phenyl, p-fluorophenyl or part of a cyclic system such cylopentane, cyclohexane, bicycle(2,2,l)heptane, adamantane which comprises i)reaction of aryl methyl ketone of formula 1 (Formula Removed) wherein R represents 2-fluorenyl, 2-phenanthrenyl or 3-phenanthrenyl. with haloacetate such as ethyl bromoacetate, ethyl chloroacetate and Zn in presence of catalytic amount of h in an aprotic organic solvent in the temperature range of room temperature to refluxing temperature to give P-hydroxyesters of formula 2 (Formula Removed) wherein R has the same meaning as above, ii)dehydrating P-hydroxyesters of formula 2 using a dehydrating catalyst in an aprotic organic solvent at room temperature to refluxing temperature to give α,ß-unsaturated esters of the formula 3 (Formula Removed) wherein R has the same meaning as above, iii) reducing esters of formula 3 with a metal hydride such as LiA1H4 in an ether solvent in the temperature range of 0°C to room temperature to give allylic alcohols of the formula 4 (Formula Removed) wherein R has the same meaning as above, iv) photooxygenating the allylic alcohols of formula 4 in presence of a sensitizer in an organic solvent in the temperature range of-10°C to room temperature to give b-hydroxyhydroperoxides of formula 5 (Formula Removed) wherein R has the same meaning as above, v) isolating and then reacting or reacting in situ the ß-hydroxyhydroperoxides of the formula 5 with an aldehyde/ketone of the general formula 6 (Formula Removed) wherein R1 and R2 represent hydrogen, alkyl group such as methyl, ethyl, propyl, isopropyl, aryl such as phenyl, p-fluorophenyl or part of the cyclic system such as cyclopentane, cyclohexane, 2-bicyclo(2,2,l)heptane, adamantine in presence of an acid catalyst in an aprotic organic solvent in a temperature range of 0°C to room temperature, vi) isolating and purifying the trioxanes of general formula 7 wherein R, R1 and R2 have the same meaning as above, by known methods. 8. A process as claimed in claim 7, wherein P-hydroxyesters of formula 2 are prepared by reacting aryl methyl ketones of formula 1 with haloacetates such as ethyl bromoacetate, ethyl chloroacetate and zinc in an aprotic solvent such as diethyl ether, benzene. 9. A process as claimed in claims 7-8, wherein α,ß-unsaturated esters of formula 3 are prepared by dehydration of P-hydroesters of formula 2 in an aprotic solvent such CH2Cl2, benzene, etc., using a dehydrating catalyst such as iodine, p-toluenesulfonic acid, P2O5. 10. A process as claimed in claims 7-9 wherein allylic alcohols of formula 4 are prepared by reduction of esters of formula 3 with a metal hydride such LiAlH4 in an ether solvent such as diethyl ether, THF. 11. A process as claimed in claims 7-10 wherein P-hydroxyhydroperoxides of formula 5 are prepared by photooxygenatio of allylic alcohols of formula 4 in an organic solvent such as CH2Cl2, benzene, CHCl3, CH3CN, methanol, ethanol using a dye (as sensitizer) such as methylene blue. Rose Bengal, tetraphenylporphine. 12. A process as claimed in claims 7-11 wherein trioxanes of formula 7 ae prepared by condensation of p-hydroxyhydroperoxides of formula 5 with aldehydes/ketones of formula 6 in an organic solvent such as CH2Cl2, CHCl3, CCl4, CH3CN, benzene using an acid catalyst such as HC1, H2SO4, PTSA, acidic resin like Amberlyst-15, and isolated and purified by chromatography on silica gel using mixture of hexane and ethyl acetate as eluant. 13. A process as claimed in claims 7-12 wherein carbonyl compounds of formula 6 used are such as acetone, ethyl methyl ketone, methyl propyl ketone, isobutyraldehyde, benzaldehyde, benzaldehyde, p-fluorobenzaldehyde, cyclopentanone, cyclohexanone, norcamphor, 2-adamantanone. 14. A process for the preparation of novel substituted 1,2,4-trioxanes of general formula 7 of the drawing accompanying this specification wherein R, R1 and R2 have the meaning as stated above, substantiated as herein described with reference to the examples. 15. Novel substituted 1,2,4-trioxanes of formula 7 as claimed in claims 1-6.

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1554-del-1999-abstract.pdf

1554-del-1999-claims.pdf

1554-del-1999-complete specification (granted).pdf

1554-del-1999-correspondence-others.pdf

1554-del-1999-correspondence-po.pdf

1554-del-1999-description (complete).pdf

1554-del-1999-drawings.pdf

1554-del-1999-form-1.pdf

1554-del-1999-form-18.pdf

1554-del-1999-form-19.pdf

1554-del-1999-form-2.pdf

1554-del-1999-form-3.pdf