Indian Patents. 256987:"NOVEL SPIRO-1,2,4-TRIOXANES AS ANTIMICROBIAL AGENTS AND PROCESS FOR THE PREPARATION THEREOF"

Title of Invention	"NOVEL SPIRO-1,2,4-TRIOXANES AS ANTIMICROBIAL AGENTS AND PROCESS FOR THE PREPARATION THEREOF"
Abstract	The present invention provides novel spiro trioxane series. This invention also provides a process for the preparation of novel spiro trioxane series. These novel spiro-trioxane cmpounds useful as anti-malarial agents .The structural formula of these novel compounds is given below: where in, Ar = aryl groups, R = hydrogen or alkyl group.

Full Text	FIELD OF THE INVENTION The present invention relates to novel spiro 1,2,4-trioxanes of general formula 4. This invention more particularly relates to a process for the preparation of a series of novel spiro 1,2,4-trioxanes. (Formula removed) wherein, Ar represents aryl groups such as phenyl, 4-biphenyl, 4-chlorophenyl, 4-methoxyphenyl, 4-methylphenyl, 4-cyclohexylphenyl, 1-naphthyl, 2-naphthyl and the like and R represents hydrogen or the alkyl group such as methyl, ethyl and the like. Several of these novel compounds show high order of antimalarial activity against multidrug-resistant malaria in mice and thus hold promise as antimalarial agents against multidrug-resistant malaria. BACKGROUND OF INVENTION Malaria is a parasitic disease which is caused by various species of Plasmodium protozoa. Together with AIDS and TB, malaria is responsible for largest number of deaths annually. The high rate of mortality associated with malaria can be attributed to the increasing cases of resistance of Plasmodium falciparum, the most deadly of the four human infecting malarial parasites, to the contemporary antimalarial drugs. Chloroquine is one of the most inexpensive, readily available, and probably most prescribed drugs for the chemotherapy of malaria, it has been rendered ineffective in many parts of the world, due to the emergence of multidrug-resistant P. falciparum. Against this background, discovery of artemisinin as the active principle of Chinese traditional drug against malaria, Artemisia annua, is an important milestone in malaria chemotherapy. Artemisinin is active against both chloroquine sensitive and chloroquine resistant malaria. (Formula removed) Semisynthetic derivatives of artemisinin such as arteether, artemether and artesunic acid, are several times more potent than the parent compound. The limited availability of artemisinin from malaria such as cerebral malaria [For reviews on artemisinin and its analogues see: (a) Klayman, D. L Science 1985, 228, 1049. (b) Bhattacharya, A. K.; Sharma, R. P. Heterocycles 1999, 57, 1681. (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].natural source and recognition of endoperoxide linkage in the form of a 1,2,4-trioxane ring system as the antimalarial pharmacophore of these compounds, has led to the present efforts to develop structurally simple synthetic trioxanes as substitutes of artemisinin derivatives. Several of these synthetic 1,2,4-trioxanes have shown promising antimalarial activity [(a) Bhattacharya, A. K.; Sharma, R. P. Heterocycles 1999, 51, 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. 1995, 5, 1913. (d) Singh, C.; Puri, S. K. U.S. Patent 6316493 Bl, 2001. (e) Singh, C; Malik, H.; Puri, S. K. Bioorg. Med. Chem. Lett. 2004, 14, 459. (f) Singh, C; Gupta, N.; Puri, S. K. Bioorg. Med. Chem. 2004, 12, 5553. (g) Singh, C; Tiwari, P.; Puri, S. K. PCT Patent application No. PCT/1N02/00093, dated 28.3.2002. (h) Singh, C. Malik, H.; Puri, S. K. PCT Patent application No. PCT/1N04/00413, dated 27.12.04]. OBJECTIVES OF THE INVENTION The main objective of the present invention is to provide a novel spiro 1,2,4-trioxanes with a potential to be used for the treatment of malaria. The objective of the present invention is also to provide a process for the preparation of novel spiro 1,2,4-trioxanes of general formula 4, a new series of antimalarial agents. Another objective of the present invention is to provide a pharmaceutical composition for the treatment of malaria. Still another objective of the present invention is to provide the novel compounds which are useful for the treatment of multidrug resistance malaria. SUMMARY OF THE INVENTION Accordingly, the present invention provides a novel spiro 1,2,4-trioxanes of general formula 4, wherein the structural formula of the compound is given below: (Formula removed) Wherein, the Ar represents aryl groups, R represents hydrogen or alkyl group. In an embodiment of the present invention the compound of general 4 is selected from [3-(l-Phenyl-vinyl)-l,2,5-trioxa-spiro[5.5]undec-9-ylidene]-acetic acid ethyl ester 4aa,2-[3-(l -Phenyl-vinyl)-1,2,5-trioxa-spiro[5.5]undec-9-ylidene]-propionic acid ethyl 4ba,2-[3-(l-Phenyl-vinyl)-1,2,5-trioxa-spiro[5.5]undec-9-ylidene]-butyric acid ethyl ester 4ca,[3-(l-Biphenyl-4-yl-vinyl)-l,2,5-trioxa-spiro[5.5]undec-9-ylidene] -acetic acid ethyl ester 4ab,2-[3-(l-Biphenyl-4-yl-vinyl)-l,2,5-trioxa-spiro[5.5]undec-9-ylidene]-propionic acid ethyl ester 4bb,{3-[l-(4-Chloro-phenyl)-vinyl]-l,2,5-trioxa-spiro[5.5]undec-9-ylidene}-acetic acid ethyl ester 4ac,2-{3-[l-(4-Chloro-phenyl)-vinyl]-1,2,5-trioxa-spiro[5.5]undec-9-ylidene} -propionic acid ethyl ester 4bc,{3-[l-(4-Methoxy-phenyl)-vinyl]-l,2,5-trioxa-spiro[5.5]undec-9-ylidene}-acetic acid ethyl ester 4ad,2-{3-[l-(4-Methoxy-phenyl)-vinyl]-l,2,5-trioxa-spiro[5.5]undec-9-ylidene}-propionic acid ethyl ester 4bd,[3-(l-p-Tolyl-vinyl)-l,2,5-trioxa-spiro[5.5]undec-9-ylidene]-acetic acid ethyl ester 4ae,2-[3-(l-p-Tolyl-vinyl)- l,2,5-trioxa-spiro[5.5]undec-9-ylidene]-propionic acid ethyl ester 4be,{3-[l-(4- Cyclohexyl-phenyl)-vinyl]-l,2,5-trioxa-spiro[5.5]undec-9-ylidene}-acetic acid ethyl ester 4af,2-{3-[l-(4-Cyclohexyl-phenyl)-vinyl]-l,2,5-trioxa-spiro[5.5]undec-9- ylidene}-propionic acid ethyl ester 4bf, [3-(l-Naphthalen-l-yl-vinyl)-1,2,5-trioxa-spiro[5.5]undec-9-ylidene]-acetic acid ethyl ester 4ag,2-[3-(l-Naphthalen-l-yl-vinyl)-l,2,5-trioxa-spiro[5.5]undec-9-ylidene]-propionic acid ethyl ester 4bg, [3-(l-Naphthalen-2-yl-vinyl)-l,2,5-trioxa-spiro[5.5]undec-9-ylidene]-acetic acid ethyl ester 4ah,2-[3-(l-Naphthalen-2-yl-vinyl)-l,2,5-trioxa-spiro[5.5]undec-9-ylidene]-propionic acid ethyl ester 4bh. In yet another embodiment of the invention a novel spiro 1,2,4-trioxanes wherein the aryl group is selected from the groups consisting of phenyl, 4-biphenyl, 4-chlorophenyl, 4-methoxyphenyl, 4-methylphenyl, 4-cyclohexylphenyl, 1-naphthyl, 2-naphthyl. In yet another embodiment of the invention a novel spiro 1,2,4-trioxanes a novel spiro trioxane wherein the alkyl group is selected from methyl, ethyl, propyl. In still another embodiment of the invention a novel spiro 1,2,4-trioxanes wherein the structural formula of said compounds is given below: (Formula removed) wherein, the compound obtained is represented by a group of following compounds: 4aa=[3-(l-Phenyl-vinyl)-l,2,5-trioxa-spiro[5.5]undec-9-ylidene]-aceticacid ethyl ester, 4ab=[3-(l-Biphenyl-4-yl-vinyl)-l,2,5-trioxa-spiro[5.5]undec-9-ylidene]-acetic acid ethyl ester, 4ac={3-[l-(4-Chloro-phenyl)-vinyl]-l,2,5-trioxa-spiro[5.5]undec-9-ylidene}-acetic acid ethyl ester, 4ad={3-[l-(4-Methoxy-phenyl)-vinyl]-l,2,5-trioxa-spiro[5.5]undec-9-ylidene}-aceticacid ethyl ester, 4ae=[3-(l-p-Tolyl-vinyl)-l,2,5-trioxa-spiro[5.5]undec-9-ylidene]-aceticacid ethyl ester, 4af= {3 - [ 1 -(4-Cyclohexyl-phenyl)-vinyl]-1,2,5-trioxa-spiro [5.5] undec-9-ylidene}-acetic acid ethyl ester, 4ag=[3-( 1-Naphthalen-1-yl-vinyl)-1,2,5-trioxa-spiro [5.5]undec-9-ylidene]-acetic acid ethyl ester, 4ah=[3-(l-Naphthalen-2-yl-vinyl)-l,2,5-trioxa-spiro[5.5]nndec-9-ylidene]-acetic acid ethyl ester. In still another embodiment of the invention a novel spiro 1,2,4-trioxanes wherein the structural formula of said compounds is given below: (Formula removed) wherein, the compound obtained is represented by a group of following compounds: 4ba=2-[3-(1 -Phenyl-vinyl)-1,2,5-trioxa-spiro[5.5]undec-9-ylidene]-propionic acid ethyl, 4bb=2-[3-(l-Biphenyl-4-yl-vinyl)-l,2,5-trioxa-spiro[5.5]undec-9-ylidene]-propionic acid ethyl ester, 4bc=2-{3-[l-(4-Chloro-phenyl)-vinyl]-l,2,5-trioxa-spiro[5.5]undec-9-ylidene}-propionic acid ethyl ester, 4bd=2-{3-[l-(4-Methoxy-phenyl)-vinyl]-l,2,5-trioxa-spiro[5.5]undec-9-ylidene}-propionic acid ethyl ester, 4be=2-[3-(l -p-Tolyl-vinyl) 1,2,5-trioxa-spiro[5.5]undec-9-ylidene]-propionic acid ethyl ester, 4bf=2-{3-[l-(4-Cyclohexyl-phenyl)-vinyl]-l,2,5-trioxa-spiro[5.5]undec-9-ylidene}-propionic acid ethyl ester, 4bg=2-[3-(l-Naphthalen-l-yl-vinyl)-l,2,5-trioxa-spiro[5.5]undec-9-ylidene]-propionic acid ethyl ester, 4bh=2-[3-(l-Naphthalen-2-yl-vinyl)-l,2,5-trioxa-spiro[5.5]undec-9-ylidene]-propionic acid ethyl ester. In still another embodiment of the invention a novel spiro 1,2,4-trioxanes wherein the structural formula of 4ca is given below: (Formula removed) In yet another embodiment of the invention a novel compound of general formula 4 as claimed in claim 1, wherein the compound is effective against parasitaemia upto 100%. In yet another embodiment of the invention of compound of formula 4 is used for the treatment of malaria. Accordingly, the present invention provides a process for the preparation of novel ;piro 1,2,4-trioxanes series of general formula 4 (Formula removed) vherein, Ar represents aryl groups R represents hydrogen or the alkyl group. In an embodiment of the invention is a novel process for the preparation of a series of spiro 1,2,4-trioxanes of general formula 4 comprising of :(a) photooxygenation of allylic alcohols of formula 1 in presence of a sensitizer and a light source which provides visible light, in an organic solvent at temperature ranging from -10°C to 0°C to obtain P-hydroxyhydroperoxide of formula 2, (Formula removed) 2 (b) reacting p-hydroxyhydroperoxide of formula2in situ with 1,4-cyclohexanedione in the presence of an acid catalyst at temperature 0°C to for 18 hours to obtain keto trioxanes of general formula 3, (Formula removed) (c) reacting the keto trioxanes of step (b) with triethylphosphonoacetate or substituted triethylphosphonoacetate in the presence of a base in an organic solvent at a temperature ranging from 0°C to 50°C to obtain spiro 1,2,4-trioxanes of formula 4, (Formula removed) (d) isolating and purifying by conventional methods to furnish spiro 1,2,4- trioxanes of formula 4. In yet another embodiment of the invention wherein the organic solvent in step (a) is selected from the aprotic solvent such as acetonitrile. In yet another embodiment of the invention wherein the substituted triethylphosphonoacetate is selected from triethylphosphono-2-propionate, triethylphosphono-2-butyrate. In yet another embodiment of the invention wherein the base in step (c) is selected from sodium hydride, n-butyl lithium. In yet another embodiment of the invention wherein the organic solvent used in step (c) is selected from tetrahydrofuran, dimethoxyetthane, diethyl ether. In still another embodiment of the invention wherein the acid catalyst used in step (d) is selected from hydrogen chloride. In still another embodiment of the invention wherein the compound obtained is represented by a group of following compounds: 4aa=[3-(l-Phenyl-vinyl)-l,2,5-trioxa-spiro[5.5]undec-9-ylidene]-acetic acid ethyl ester, 4ba=2-[3-(l-Phenyl-vinyl)-l,2,5-trioxa-spiro[5.5]undec-9-ylidene]-propionic acid ethyl ester, 4ca=2-[3-(l-Phenyl-vinyl)-l,2,5-trioxa-spiro[5.5]undec-9-ylidene]-butyric acid ethyl ester, 4ab=[3-(l-Biphenyl-4-yl-vinyl)-l,2,5-trioxa-spiro[5.5]undec-9-ylidene]-acetic acid ethyl ester, 4bb=2-[3-(l-Biphenyl-4-yl-vinyl)-l,2,5-trioxa-spiro[5.5]undec-9-ylidene]-propionic acid ethyl ester, 4ac={3-[l-(4-Chloro-phenyl)-vinyl]-l,2,5-trioxa-spiro[5.5]undec-9-ylidene}-acetic acid ethyl ester, 4bc=2-{3-[l-(4-Chloro-phenyl)-vinyl]-l,2,5-trioxa-spiro[5.5]undec-9-ylidene}-propionic acid ethyl ester, 4ad= {3 -[ 1 -(4-Methoxy-phenyl)-vinyl] -1,2,5-trioxa-spiro [5.5]undec-9-ylidene} -acetic acid ethyl ester, 4bd=2-{3-[l-(4-Methoxy-phenyl)-vinyl]-l,2,5-trioxa-spiro[5.5]undec-9-ylidene}- propionic acid ethyl ester, 4bd=[3-(l-p-Tolyl-vinyl)-l,2,5-trioxa-spiro[5.5]undec-9-ylidene]-acetic acid ethyl ester, 4be=2-[3-(l-p-Tolyl-vinyl)-l,2,5-trioxa-spiro[5.5]undec-9-ylidene]-propionic acid ethyl ester, 4af={3-[l-(4-Cyclohexyl-phenyl)-vinyl]-l,2,5-trioxa-spiro[5.5]undec-9-ylidene}- acetic acid ethyl ester, 4af=2- {3 -[ 1 -(4-Cyclohexyl-phenyl)-vinyl] -1,2,5-trioxa-spiro [5.5]undec-9-ylidene} - propionic acid ethyl ester, 4ag=[3-(l-Naphthalen-l-yl-vinyl)-l,2,5-trioxa-spiro[5.5]undec-9-ylidene]-acetic acid ethyl ester, 4ag=2-[3-(l-Naphthalen-l-yl-vinyl)-l,2,5-trioxa-spiro[5.5]undec-9-ylidene]-propionic acid ethyl ester, 4ah=[3-(l-Naphthalen-2-yl-vinyl)-l,2,5-trioxa-spiro[5.5]undec-9-ylidene]-acetic acid ethyl ester, 4bh=2-[3-(l-Naphthalen-2-yl-vinyl)-l,2,5-trioxa-spiro[5.5]undec-9-ylidene]-propionic acid ethyl ester. One of the feature of the present invention is a pharmaceutical composition comprising a pharmaceutically effective amount of compound of formula 4 -optionally along with pharmaceutically acceptable diluents and /or carrier. In an embodiment of the present invention is a composition wherein the composition is useful in the treatment of malaria. In an embodiment of the present invention is a composition wherein the dose of composition is ranging the dose of composition is ranging between 24 to 96 mg/kg/day. In still another embodiment of the invention wherein the composition is useful for treatment of multidrug resistance malaria. In still another embodiment of the invention wherein the composition is administered intramuscularly, oral route or intraperitoneally. In still another embodiment of the invention wherein the composition is effective against parasaitemia upto 100%. Another feature of the invention is a method of treating a subject having malaria, comprising administering to the subject a pharmaceutically effective amount of a composition containing compound of formula 4, (Formula removed) t wherein ,Ar represents aryl groups such as phenyl, 4-biphenyl, 4-chlorophenyl, 4-methoxyphenyl, 4-methylphenyl, 4-cyclohexylphenyl, 1-naphthyl, 2-naphthyl and a pharmaceutically acceptable salt. R represents hydrogen or the alkyl group such as methyl, ethyl, propyl. In yet another embodiment of the inevntion wherein the composition is administered intramuscularly, intraperitoneally, or orally. In yet another embodiment of the inevntion wherein the pharmaceutically acceptable amount of compound of formula 4 is in the range of 24 to 96 mg of compound of formula 4 per kilogram of body weight of subject per day. In still another embodiment of the invention wherein the subject is a human being. DETAILED DESCRIPTION OF THE INVENTION In the process allylic alcohols of formula 1 are prepared by known procedures [(a) Singh, C. Tetrahedron Lett. 1990, 31, 6901. (b) Singh, C; Tiwari, P.; Puri, S. K. PCT Patent application No. PCT/1N02/00093, 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]. In the process photooxygenation of allylic alcohols of formula 1 may be be effected by passing oxygen gas or air in the solution of the alcohol in an organic solvent and in the presence of a dye and a light source which provides visible light, to furnish {}-hydroxyhydroperoxide of formula 2. These p-hydroxyhydroperoxide of formula 2 are known compounds as they have been prepared earlier [(a) Singh, C. Tetrahedron Lett. 1990,31, 6901. (b) Singh, C; Tiwari, P.; Puri, S. K. PCT Patent application No. PCT/1N02/00093, 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]. In the process reaction of ß-hydroxyhydroperoxide of formula 2 with 1,4-cyclohexanedione in presence of an acid catalyst such as coned HC1, p-toluene sulphonic acid (p-TSA) and the like at temperature ranging from 0°C to r.t. furnish keto 1,2,4-trioxanes of formula 3. These trioxanes of formula 3 can be isolated and purified by standard laboratory methods such as column chromatography or crystallization. These compounds have been tested against malaria parasites in mice and show only moderate order of activity. Keto trioxanes 3a, 3b, 3c, 3d, 3e are known compounds [ (a) Singh, C; Malik, H.; Puri, S. K. Bioorg. Med. Chem. Lett. 2004, 14, 459. (b) Singh, C; Malik, H.; Puri, S. K. PCT Patent application No. PCT/1N04/00413, dated 27.12.04] while compounds 3f, 3g, 3h are new compounds. In the process Wittig olefination of keto trioxanes of formula 3 by reaction with triethylphosphonoacetate or substituted triethylphosphonoacetate such as triethylphosphono-2-propionate, triethylphosphono-2-butyrate in the presence of a base such as NaH, n-BuLi and the like, in an organic solvent such as dimethoxyethane, tetrahydrofuran and the like at temperature ranging from 0°C to room temperature furnish spiro 1,2,4-trioxanes of formula 4. These spiro 1,2,4-trioxanes of formula 4 can be isolated and purified by standard laboratory methods such as column chromatography and crystallization. These spiro 1,2,4-trioxanes of formula 4 are new chemical entities and they have not been prepared earlier. These 1,2,4-trioxanes of formula 4 have been tested against malaria parasites in mice and have shown high order of antimalarial activity. This invention is further illustrated by the following examples which should not, however, be construed to limit the scope of the present invention. Example 1 3-(l-Phenyl-vinyl)-l,2,5-trioxaspiro[5.5]undec-9-one (compound 3a, Ar = phenyl). Allylic alcohol. A solution of allylic alcohol of la (lg) and methylene blue (lOmg) in MeCN (50 mL) was photooxygenated at -10°C to 0°C for 4h to give (3-hydroxyhydroperoxide 2a which was reacted in situ with 1,4-cyclohexanedione (1.15g) in presence of coned HC1 (5 drops) for 18h at 0°C. Reaction mixture was concentrated under reduced pressure and residue taken up in diethylether (100 mL) was washed with sat. aq NaHCCh (30 mL). The aqueous layer was extracted with diethylether (2x20 mL), combined organic layer was dried over anhyd. Na2SO4 and concentrated. The crude product was purified by column chromatography on silica gel to furnish trioxane 3a (0.94 g, 51% yield, based on allylic alcohol la used), m.p. 70-71°C. Trioxane 3a was obtained in 53% yield when P-hydroxyhydroperoxide 2a was reacted with 1,4-cyclohexanedione at r.t. for 8h using p-toluene sulphonic acid (p-TSA) as acid catalyst. [3-(l-Phenyl-vinyl)-l,2,5-trioxa-spiro[5.5]undec-9-yIidene]-acetic acid ethyl ester (compound 4aa, Formula 4, Ar = phenyl, R = H). To a stirred and cooled (0°C) mixture of NaH (0.2g) in dry dimethoxyethane (15 mL) was added triethyl phosphonoacetate (1.2g) and the reaction mixture was stirred at 0°C for lh. To the solution thus obtained was added dropwise a solution of keto trioxane 3a (lg) in dry dimethoxyethane (15 mL), while maintaining the temperature of the flask at 0°C. After the addition was complete the resulting solution was stirred for additional twenty minutes at 0°C. The reaction mixture was diluted with water (40 mL) and extracted with diethylether (2x75 mL). The combined organic layer was washed successively with water (2x15 mL) and brine, dried over anhyd Na2SO4, concentrated and purified by column chromatography over silica gel to furnish spiro trioxane 4aa (oil, 1.16g, 92.8% yield) as a mixture of £ and Z isomers. The compound 4aa was also prepared using different reaction conditions. Table 1 gives the conditions used and the yield of compound 4aa. Table 1 (Table removed) Example 2 2-[3-(l-Phenyl-viny 1)-1,2,5-trioxa-spiro[5.5]undec-9-ylidene]-propionic acid ethyl ester (compound 4ba, Formula 4, Ar = phenyl, R = CH3). To a stirred and cooled (0°C) mixture of NaH (0.13g) in dry dimethoxyethane (20 mL) was added triethylphosphono-2-propionate (0.9g) and the reaction mixture was stirred at 0°C for lh. To the solution thus obtained was added dropwise a solution of keto trioxane 3a (0.6g) in dry dimethoxyethane (10 mL), while maintaining the temperature of the flask at 0°C. After the addition was complete the resulting solution was stirred for additional half an hour at 0°C. The reaction mixture was worked up as above and concentrated. The crude product was purified by column chromatography on silica gel to furnish spiro trioxane 4ba (oil, 0.66g, 84% yield) as a mixture of E and Z isomers. Example 3 2-[3-(l-Phenyl-vinyl)-l,2,5-trioxa-spiro[5.5]undec-9-ylidene]-butyric acid ethyl ester (compound 4ca, Formula 4, Ar = phenyl, R = CH2CH3). To a stirred and cooled (0°C) mixture of NaH (0.04g) in dry dimethoxyethane (15 mL) was added triethylphosphono-2-butyrate (0.3g) and the reaction mixture was stirred at 0°C for lh. To the solution thus obtained was added dropwise a solution of keto trioxane 3a (0.2g) in dry dimethoxyethane (8 mL), while maintaining the temperature of the flask at 0°C. After the addition was complete the resulting solution was. stirred for additional half an hour at 0°C. The reaction mixture was worked up as above and concentrated. The crude product was purified by column chromatography on silica gel to furnish spiro trioxane 4ca (oil, 0.22g, 81% yield) as a mixture of £ and Z isomers. Example 4 3-(l-Biphenyl-4yl-vinyl)-l,2,5-trioxaspiro[5.5]undec-9-one (compound 3b, Ar = biphenyl). Allylic alcohol lb was prepared according to the reported procedure (Singh, C; Tiwari, P.; Puri, S. K. PCT Patent application No. PCT/1N02/00093, dated 28.3.2002). A solution of allylic alcohol of lb (lg) and methylene blue (10 mg) in CH2C12: MeCN (1:4, 50 mL) was photooxygenated at -10°C to 0°C for 4h to give (3-hydroxyhydroperoxide 2b which was reacted in situ with 1,4-cyclohexanedione (lg) in presence of coned HC1 (5 drops) for 18h at 0°C. The reaction mixture was worked up as above and concentrated. The crude product was purified by column chromatography on silica gel to furnish trioxane 3b (0.65 g, 42% yield, based on allylic alcohol lb used), m.p. 104-105°C. [3-(l-Biphenyl-4-yl-vinyl)-l,2,5-trioxa-spiro[5.5]undec-9-ylidene]-acetic acid ethyl ester (compound 4ab, Formula 4, Ar = 4-biphenyl, R = H). To a stirred and cooled (0°C) mixture of NaH (0.12g) in dry dimethoxyethane (20 mL) was added triethylphosphonoacetate (0.8g) and the reaction mixture was stirred at 0°C for lh. To the solution thus obtained was added dropwise a solution of keto trioxane 3b (0.80g) in dry dimethoxyethane (15 mL), while maintaining the temperature of the flask at 0°C. After the addition was complete the resulting solution was stirred for additional half an hour at 0°C. The reaction mixture was worked up as above and concentrated. The crude product was purified by column chromatography on silica gel to furnish spiro trioxane 4ab (0.89g, 92.6% yield) as a mixture of E and Z isomers, m.p. 143-145°C. Example 5 2-[3-(l-Biphenyl-4-yl-vinyl)-l,2,5-trioxa-spiro[5.5]undec-9-ylidene]-propionic acid ethyl ester (compound 4bb, Formula 4, Ar = 4-biphenyl, R = CH3). ethyl ester (compound 4bb, Formula 4, Ar = 4-biphenyl, R = CH3). To a stirred and cooled (0°C) mixture of NaH (0.08 g) in dry dimethoxyethane (20 mL) was added triethylphosphono-2-propionate (0.6g) and the reaction mixture was stirred at 0°C for lh. To the solution thus obtained was added dropwise a solution of keto trioxane 3b (0.50g) in dry dimethoxyethane (10 mL), while maintaining the temperature of the flask at 0°C. After the addition was complete the resulting solution was stirred for additional half an hour at 0°C. The reaction mixture was worked up as above and concentrated. The crude product was purified by column chromatography on silica gel to furnish spiro trioxane 4bb (0.52 g, 83.7% yield) as a mixture of £ and Z isomers, m.p. 68-70°C. Example 6 3-[l-(4-Chloro-phenyI)-vinyl]-l,2,5-trioxa-spiro[5.5]undecan-9-one (compound 3c, Ar = 4-chlorophenyl). Allylic alcohol lc was prepared according to the reported procedure (Singh, C. Tetrahedron Lett. 1990, 31, 6901). A solution of allylic alcohol of lc (1 g) and methylene blue (10 mg) in MeCN (50 mL) was photooxygenated at -10°C to 0°C for 4h to give p-hydroxyhydroperoxide 2c which was reacted in situ with 1,4-cyclohexanedione (1.22 g) in presence of coned HC1 (5 drops) for 18h at 0°C. The reaction mixture was worked up as above and concentrated. The crude product was purified by column chromatography on silica gel to furnish trioxane 3c (0.64 g, 38% yield, based on allylic alcohol lc used), m.p. 72-74°C. {3-[l-(4-ChIoro-phenyl)-vinyl]-l,2,5-trioxa-spiro[5.5]undec-9-ylidene}-acetic acid ethyl ester (compound 4ac, Formula 4, Ar = 4-chlorophenyl, R = H). To a stirred and cooled (0°C) mixture of NaH (0.09g) in dry dimethoxyethane (15 mL) was added triethylphosphonoacetate (0.6g) and the reaction mixture was stirred at 0°C for lh. To the solution thus obtained was added dropwise a solution of keto trioxane 3c (0.50g) in dry dimethoxyethane (10 mL), while maintaining the temperature of the flask at 0°C. After the addition was complete the resulting solution was stirred for additional half an hour at 0°C. The reaction mixture was worked up as above and concentrated. The crude product was purified by column chromatography on silica gel to furnish spiro trioxane 4ac (0.56g, 91.2% yield) as a mixture of £ and Z isomers, m.p. 78-80°C. Example 7 2-{3-[l-(4-Chloro-phenyl)-vinyl]-l,2,5-trioxa-spiro[5.5]undec-9-ylidene}-propionic acid ethyl ester (compound 4bc, Formula 4, Ar = 4-chlorophenyl, R = CH3). To a stirred and cooled (0°C) mixture of NaH (0.05 g) in dry dimethoxyethane (20 mL) was added triethylphosphono-2-propionate (0.5g) and the reaction mixture was stirred at 0°C for lh. Tp the solution thus obtained was added drop wise a solution of keto trioxane 3c (0.30g) in dry dimethoxyethane (10 mL), while maintaining the temperature of the flask at 0°C. After the addition was complete the resulting solution was stirred for additional half an hour at 0°C. The reaction mixture was worked up as above and concentrated. The crude product was purified by column chromatography on silica gel to furnish spiro trioxane 4bc (oil, 0.33 g, 85.4% yield) as a mixture of £ and Z isomers. Example 8 3-[l-(4-Methoxy-phenyl)-vinyI]-l,2,5-trioxa-spiro[5.5]undecan-9-one (compound 3d, Ar = 4-methoxyphenyl). Ally lic alcohol Id was prepared according to the reported procedure (Singh, C. Tetrahedron Lett. 1990, 31, 6901). A solution of allylic alcohol of Id (lg) and methylene blue (10 mg) in MeCN (50 mL) was photooxygenated at -10°C to 0°C for 4h to give p-hydroxyhydroperoxide 2d which was reacted in situ with 1,4-cyclohexanedione (1.25g) in presence of coned HC1 (5 drops) for 18h at 0°C. The reaction mixture was worked up as above and concentrated. The crude product was purified by column chromatography on silica gel to furnish trioxane 3d (0.48 g, 28.1% yield, based on allylic alcohol Id used) m.p. 74-76°C. {3-[l-(4-Methoxy-phenyl)-vinyl]-l,2,5-trioxa-spiro[5.5]undec-9-ylidene}-acetic acid ethyl ester (compound 4ad, Formula 4, Ar = 4-methoxyphenyl, R = H). To a stirred and cooled (0°C) mixture of NaH (0.09g) in dry dimethoxyethane (15 mL) was added triethylphosphonoacetate (0.6g) and the reaction mixture was stirred at 0°C for lh. To the solution thus obtained was added dropwise a solution of keto trioxane 3d (0.50g) in dry dimethoxyethane (15 mL), while maintaining the temperature of the flask at 0°C. After the addition was complete the resulting solution was stirred for additional half an hour at 0°C. The reaction mixture was worked up as above and concentrated. The crude product was purified by column chromatography on silica gel to furnish spiro trioxane 4ad (oil, 0.56g, 91.0% yield) as a mixture of E and Z isomers. Example 9 2-{3-[l-(4-Methoxy-phenyl)-vmyl]-l,2,5-trioxa-spiro[5.5]undec-9-ylidene}-propionic acid ethyl ester (compound 4bd, Formula 4, Ar = 4-methoxyphenyl, R = CH3). To a stirred and cooled (0°C) mixture of NaH (0.06 g) in dry dimethoxyethane (20 mL) was added triethylphosphono-2-propionate (0.4g) and the reaction mixture was stirred at 0°C for lh. To the solution thus obtained was added dropwise a solution of keto trioxane 3d (0.30g) in dry dimethoxyethane (10 mL), while maintaining the temperature of the flask at 0°C. After the addition was complete the resulting solution was stirred for additional half an hour at 0°C. The reaction mixture was worked up as above and concentrated. The crude product was purified by column chromatography on silica gel to furnish spiro trioxane 4bd (oil, 0.32 g, 84.2% yield) as a mixture of E and Z isomers. Example 10 3-(l-p-Tolyl-vinyl)-l,2,5-trioxa-spiro[5.5]undecan-9-one (compound 3e, Ar = 4-methylphenyl). Allylic alcohol le was prepared according to the reported procedure (Singh, C. Tetrahedron Lett. 1990, 31, 6901). A solution of allylic alcohol of le (1 g) and methylene blue (10 mg) in MeCN (50 mL) was photooxygenated at -10°C to 0°C for 4h to give (3-hydroxyhydroperoxide 2e which was reacted in situ with 1,4-cyclohexanedione (1.38 g) in presence of coned HC1 (5 drops) for 18h at 0°C. The reaction mixture was worked up as above and concentrated. The crude product was purified by column chromatography on silica gel to furnish trioxane 3e (0.58 g, 32.7% yield, based on allylic alcohol le used), m.p. 66-68°C. [3-(l-p-Tolyl-vinyl)-l,2,5-trioxa-spiro[5.5]undec-9-ylidene]-acetic acid ethyl ester (compound 4ae, Formula 4, Ar = 4-methylphenyl, R = H). To a stirred and cooled (0°C) mixture of NaH (0.09g) in dry dimethoxyethane (15 mL) was added tnethylphosphonoacetate (0.6g) and the reaction mixture was stirred at 0°C for lh. To the solution thus obtained was added dropwise a solution of keto trioxane 3e (0.50g) in dry dimethoxyethane (15 mL), while maintaining the temperature of the flask at 0°C. After the addition was complete the resulting solution was stirred for additional half an hour at 0°C. The reaction mixture was worked up as above and concentrated. The crude product was purified by column chromatography on silica gel to furnish spiro trioxane 4ae (0.56g, 91.1% yield) as a mixture of £ and Z isomers, m.p. 64-66°C. Example 11 2- [3-(l -p-Tolyl-vinyl)-l ,2,5-trioxa-spiro [5.5] undec-9-ylidene] -propionic acid ethyl ester (compound 4be, Formula 4, Ar = 4-methylphenyl, R = CH3). To a stirred and cooled (0°C) mixture of NaH (0.09 g) in dry dimethoxyethane (20 mL) was added triethylphosphono-2-propionate (0.7g) and the reaction mixture was stirred at 0°C for lh. To the solution thus obtained was added dropwise a solution of keto trioxane 3e (0.50g) in dry dimethoxyethane (10 mL), while maintaining the temperature of the flask at 0°C. After the addition was complete the resulting solution was stirred for additional half an hour at 0°C. The reaction mixture was worked up as above and concentrated. The crude product was purified by column chromatography on silica gel to furnish spiro trioxane 4be (oil, 0.53 g, 86.2% yield) as a mixture of E and Z isomers. Example 12 3- [ 1 -(4-Cy clohexy 1-pheny l)-viny 1] -1,2,5-trioxa-spiro [5.5] undecan-9-one (compound 3f, Ar = 4-cyclohexylphenyl). Allylic alcohol If was prepared according to the reported procedure (Singh, C; Tiwari, P.; Puri, S. K. PCT Patent application No. PCT/1N02/00093, dated 28.3.2002). A solution of allylic alcohol of If (2 g) and methylene blue (20 mg) in MeCN (80 mL) was photooxygenated at -10°C to 0°C for 4h to give (3-hydroxyhydroperoxide 2f which was reacted in situ with 1,4-cyclohexanedione (1.94 g) in presence of coned HC1 (5 drops) for 18h at 0°C. The reaction mixture was worked up as above and concentrated. The crude product was purified by column chromatography on silica gel to furnish trioxane 3f (0.98 g, 31.7% yield, based on allylic alcohol If used)), m.p. 56-58°C. {3-[l-(4-Cyclohexyl-phenyl)-vinyI]-l,2,5-trioxa-spiro[5.5]undec-9-ylidene}-acetic acid ethyl ester (compound 4af, Formula 4, Ar = 4-cyclohexylphenyl, R = H). To a stirred and cooled (0°C) mixture of NaH (0.06g) in dry dimethoxyethane (15 mL) was added triethylphosphonoacetate (0.4g) and the reaction mixture was stirred at 0°C for lh. To the solution thus obtained was added dropwise a solution of keto trioxane 3f (0.40g) in dry dimethoxyethane (15 mL), while maintaining the temperature of the flask at 0°C. After the addition was complete the resulting solution was stirred for additional half an hour at 0°C. The reaction mixture was worked up as above and concentrated. The crude product was purified by column chromatography on silica gel to furnish spiro trioxane 4af (oil, 0.43g, 89.9% yield) as a mixture of E and Z isomers. Example 13 2- {3- [ 1 -(4-Cy clohexy I-pheny l)-viny 1] -1,2,5-trioxa-spiro [5.5] undec-9-y lidene}-propionic acid ethyl ester (compound 4bf, Formula 4, Ar = 4-cyclohexylphenyl, R = CH3). To a stirred and cooled (0°C) mixture of NaH (0.05 g) in dry dimethoxyethane (20 mL) was added triethylphosphono-2-propionate (0.4g) and the reaction mixture was stirred at 0°C for lh. To the solution thus obtained was added dropwise a solution of keto trioxane 3f (0.30g) in dry dimethoxyethane (10 mL), while maintaining the temperature of the flask at 0°C. After the addition was complete the resulting solution was stirred for additional half an hour at 0°C. The reaction mixture was worked up as above and concentrated. The crude product was purified by column chromatography on silica gel to furnish spiro trioxane 4bf (oil, 0.30 g, 82.6% yield) as a mixture of E and Z isomers. Example 14 3-(l-Naphthalen-l-yl-vinyl)-l,2,5-trioxa-spiro[5.5]undecan-9-one (compound 3g, Ar = 1-naphthyl). Allylic alcohol lg was prepared according to the reported procedure (Singh, C; Kanchan, R.; Chandra, S. and Puri, S.K. Indian patent application no. 0909/DEL/2003 dated 18/07/2003). A solution of allylic alcohol of lg (2g) and methylene blue (20 mg) in MeCN (80 mL) was photooxygenated at -10°C to 0°C for 4h to give P-hydroxyhydroperoxide 2g which was reacted in situ with 1,4-cyclohexanedione (2.26 g) in presence of coned HC1 (5 drops) for 18h at 0°C. The reaction mixture was worked up as above and concentrated. The crude product was purified by column chromatography on silica gel to furnish trioxane 3g (0.72 g, 22% yield, based on allylic alcohol lg used). [3-(l-Naphthalen-l-yl-vinyl)-l,2,5-trioxa-spiro[5.5]undec-9-ylidene]-acetic acid ethyl ester (compound 4ag, Formula 4, Ar = 1-naphthyl, R = H). To a stirred and cooled (0°C) mixture of NaH (0.07g) in dry dimethoxyethane (15 mL) was added triethylphosphonoacetate (0.4g) and the reaction mixture was stirred at 0°C for lh. To the solution thus obtained was added dropwise a solution of keto trioxane 3g (0.40g) in dry dimethoxyethane (15 mL), while maintaining the temperature of the flask at 0°C. After the addition was complete the resulting solution was stirred for additional half an hour at 0°C. The reaction mixture was worked up as above and concentrated. The crude product was purified by column chromatography on silica gel to furnish spiro trioxane 4ag (oil, 0.44g, 90.7% yield) as a mixture of E and Z isomers. Example 15 2-[3-(l-Naphthalen-l-yl-vinyl)-l,2,5-trioxa-spiro[5.5]undec-9-ylidene]-propionic acid ethyl ester (compound 4bg, Formula 4, Ar = 1-naphthyl, R = CH3). To a stirred and cooled (0°C) mixture of NaH (0.05 g) in dry dimethoxyethane (15 mL) was added triethylphosphono-2-propionate (0.4g) and the reaction mixture was stirred at 0°C for lh. To the solution thus obtained was added dropwise a solution of keto trioxane 3g (0.3g) in dry dimethoxyethane (10 mL), while maintaining the temperature of the flask at 0°C. After the addition was complete the resulting solution was stirred for additional half an hour at 0°C. The reaction mixture was worked up as above and concentrated. The crude product was purified by column chromatography on silica gel to furnish spiro trioxane 4bg (0.30 g, 80.7% yield) as a mixture of £ and Z isomers. Example 16 3-(l-Naphthalen-2-yl-vinyl)-l,2,5-trioxa-spiro[5.5]undecan-9-one (compound 3h, Ar = 2-naphthyl). Allylic alcohol lh was prepared according to the reported procedure (Singh, C; Kanchan, R.; Chandra, S. and Puri, S.K. Indian patent application no. 0909/DEL/2003 dated 18/07/2003). A solution of allylic alcohol of lh (lg) and methylene blue (10 mg) in MeCN (50 mL) was photooxygenated at -10°C to 0°C for 4h to give p-hydroxyhydroperoxide 2h which was reacted in situ with 1,4-cyclohexanedione (1.13 g) in presence of coned HC1 (5 drops) for 18h at 0°C. The reaction mixture was worked up as above and concentrated. The crude product was purified by column chromatography on silica gel to furnish trioxane 3h (0.58 g, 32.7% yield, based on allylic alcohol lh used), m.p. 58-60°C. [3-(l-Naphthalen-2-yl-vmyl)-l,2,5-trioxa-spiro[5.5]undec-9-ylidene]-acetic acid ethyl ester (compound 4ah, Formula 4, Ar = 2-naphthyl, R = H). To a stirred and cooled (0°C) mixture of NaH (0.08g) in dry dimethoxyethane (15 mL) was added triethylphosphonoacetate (0.5g) and the reaction mixture was stirred at 0°C for lh. To the solution thus obtained was added dropwise a solution of keto trioxane 3h (0.50g) in dry dimethoxyethane (15 mL), while maintaining the temperature of the flask at 0°C. After the addition was complete the resulting solution was stirred for additional half an hour at 0°C. The reaction mixture was worked up as above and concentrated. The crude product was purified by column chromatography on silica gel to furnish spiro trioxane 4ah (0.56g, 92.1% yield)) as a mixture of E and Z isomers, m.p. 54-56°C. Example 17 2-[3-(l-Naphthalen-2-yl-vinyl)-l,2,5-trioxa-spiro[5.5]undec-9-ylidene]-propionic acid ethyl ester (compound 4bh, Formula 4, Ar = 2-naphthyl, R = CH3). To a stirred and cooled (0°C) mixture of NaH (0.09 g) in dry dimethoxyethane (20 mL) was added triethylphosphono-2-propionate (0.6g) and the reaction mixture was stirred at 0°C for lh. To the solution thus obtained was added dropwise a solution of keto trioxane 3h (0.50g) in dry dimethoxyethane (10 mL), while maintaining the temperature of the flask at 0°C. After the addition was complete the resulting solution was stirred for additional half an hour at 0°C. The reaction mixture was worked up as above and concentrated. The crude product was purified by column chromatography on silica gel to furnish spiro trioxane 4bh (0.52 g, 82.6% yield) as a mixture of E and Z isomers. The antimalarial activity of the test compounds was evaluated in rodent using multidrug resistant strain of Plasmodium yoelii Nigeriensis in Swiss mice. Random bred Swiss mice of either sex (20 ±2 gm) were inoculated intraperitoneally with lxlO5 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 24-96 mg/ kg/day. The treatment was administered in groundnut oil intramuscularly and orally 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 vehicle control group and the percent suppression of parasitaemia in treated groups was calculated. For determining the curative dose of a compound the treated mice were observed till day 28. The dose at which no parasitaemia develop during the observation period has been reported as the curative dose. The antimalarial activity data is summarized in Table 2. (Table removed) Scheme 1 Reagents and reaction conditions (a) hv, 02, methylene blue, MeCN, We claim 1. A spirol ,2,4-trioxane of general formula 4, wherein, Ar represents an aryl groups, and R represents hydrogen or an alkyl group. (Formula Removed) 2. The spiro 1,2,4-trioxane as in claim 1, wherein the aryl group is an unsubstiruted or substituted aromatic hydrocarbon, wherein the substituted aromatic hydrocarbon group is substituted with at least one substituent selected from the group consisting of a C1-C6 alkyl, a C3-C8 cycloalkyl, a C1-C6 alkoxy, a halogen and an aromatic hydrocarbon group. 3. The spiro 1,2,4-trioxane as in claim 1, wherein the aryl group is selected from the group consisting of phenyl, 4-biphenyl, 4-chlorophenyl, 4-methoxyphenyl, 4-methylphenyl, 4-cyclohexylphenyl, 1-naphthyl and 2-naphthyl. 4. The spiro trioxane as in claim 1, wherein the alkyl group is selected from the group consisting of methyl, ethyl and propyl. 5. The spiro 1,2,4-trioxanes as in claim 1, wherein the compounds are selected from the group consisting of Structure 4aa-4ah (Structure Removed) 4aa=[3-(l-Phenyl-vinyl)-l,2,5-trioxa-spiro[5.5]undec-9-ylidene]-acetic acid ethyl ester, 4ab=[3-(1-Biphenyl-4-yl-vinyl)-l,2,5-trioxa-spiro[5.5]undec-9-ylidene]-ac- etic acid ethyl ester, 4ac={3-[l-(4-Chloro-phenyl)-vinyl]-l ,2,5-trioxa-spiro[5.5]undec-9-ylidene- }-acetic acid ethyl ester, 4ad={3-[l-(4-Methoxy-phenyl)-vinyl]-l,2,5-trioxa-spiro[5.5]undec-9-yliden- e}-acetic acid ethyl ester, 4ae=[3-(l-p-Tolyl-vinyl)-1,2,5-trioxa-spiro[5.5]undec-9-ylidene]-acetic acid ethyl ester, 4af={3-[l-(4-Cyclohexyl-phenyl)-vinyl]-l,2,5-trioxa-spiro[5.5]undec-9-yli- dene}-acetic acid ethyl ester, 4ag=[3-(1 -Naphthalen-1 -yl-vinyl)-1,2,5-trioxa-spiro[5.5]undec-9-ylidene]~ acetic acid ethyl ester, and 4ah=[3-(l-Naphthalen-2-yl-vinyl)-l,2,5-trioxa-spiro[5.5]undec-9-ylidene]— acetic acid ethyl ester. 6. The spiro 1,2,4-trioxanes as claimed in claim 1, wherein the compounds are selected from the group consisting of structural formulas 4ba-4bh: (Formula Removed) 4ba=2-[3-(l-Phenyl-vinyl)-l,2,5-trioxa-spiro[5.5]undec-9-ylidene]-propion- ic acid ethyl, 4bb=2-[3-(l-Biphenyl-4-yl-vinyl)-l,2,5-trioxa-spiro[5.5]undec-9- ylidene]-propionic acid ethyl ester, 4bc=2-{3-[l-(4-Chloro-phenyl)-vinyl]-l,2,5-trioxa-spiro[5.5]undec-9-ylide~ ne}-propionic acid ethyl ester, 4bd=2-{3-[l-(4-Methoxy-phenyl)-vinyl]-l,2,5-trioxa-spiro[5.5]undec-9-ylid- ene}-propionic acid ethyl ester, 4be=2-[3-(l-p-Tolyl-vinyl)-l,2,5-trioxa-spiro[5.5]undec-9-ylidene]-propio- nic acid ethyl ester, 4bf=2-{3-[l-(4-Cyclohexyl-phenyl)-vinyl]-l,2,5-trioxa-spiro[5.5]undec-9-y- lidene}-propionic acid ethyl ester, 4bg=2-[3-(l-Naphthalen-l-yl-vinyl)-l,2,5-trioxa-spiro[5.5]undec-9-ylidene- ]-propionic acid ethyl ester, and 4bh=2-[3-(l-Naphthalen-2-yl-vinyl)-l,2,5-trioxa-spiro[5.5]undec-9-ylidene- ]-propionic acid ethyl ester. 7. The Spiro 1,2,4-trioxane as in claim 1, wherein the compound has the structural formula of 4ca: 8. A process for the preparation of a spiro 1,2,4-trioxane of general formula 4 comprising the steps of: a) photooxygenating of allylic alcohols of formula 1 in presence of a sensitizer and a light source which provides visible light, in an organic solvent at temperature ranging from -10 C to 0°C to obtain .beta.-hydroxyhydroperoxide of formula 2 (Formula Removed) b) reacting beta.-hydroxyhydroperoxide of formula 2 in-situ with 1,4- cyclohexanedione in the presence of an acid catalyst at temperature 0°C for 18 hrs to obtain keto trioxanes of general formula 3, (Formula Removed) c) reacting the keto trioxanes of step (b) with triethylphosphonoacetate or substituted triethylphosphonoacetate in the presence of a base in an organic solvent at a temperature ranging from 0°C. to 50°C. to obtain spiro 1,2,4-trioxanes of formula 4, (Formula Removed) d) isolating and purifying by conventional methods to furnish a spiro 1,2,4-trioxane of formula 4. (Formula Removed) 9. The process as in claim 8, wherein the aryl group is an unsubstituted or substituted aromatic hydrocarbon, wherein the substituted aromatic hydrocarbon group is substituted with at least one substituent selected from the group consisting of a C1-C6 alkyl, a C3-C8 cycloalkyl, a C1-C6 alkoxy, a halogen and an aromatic hydrocarbon group. 10. The process as in claim 8, wherein the aryl is selected from the group consisting of phenyl, 4-biphenyl, 4-chlorophenyl, 4-methoxyphenyl, and 4-methylphenyl. 11. The process as in claim 8, wherein the sensitizer is methylene blue. 12. The process as in claim 8, wherein the organic solvent in step (a) is selected from the group consisting of aprotic solvents. 13. The process as in claim 13, wherein the aprotic solvent is acetonitrile. 14. The process as in claim 9, wherein the substituted triethylphosphonoacetate is selected from the group consisting of triethylphosphono-2-propionate, and triethylphosphono-2-butyrate. 15. The process as in claim 9, wherein the base in step (c) is selected from sodium hydride, and n-butyl lithium. 16. The process as in claim 9, wherein the organic solvent used in step (c) is selected from the group consisting of tetrahydrofuran, dimethoxyethane, and diethyl ether. 17. The process as in claim 9, wherein the acid catalyst used in step (d) is hydrogen chloride. 18. The process as in claim 9, wherein the compound obtained is selected from the group consisting of the following compounds: 4aa=[3-(l-Phenyl-vinyl)-l,2,5-trioxa-spiro[5.5]undec-9-ylidene]-acetic acid ethyl-ester, 4ba=2-[3-(l-Phenyl-vinyl)-1,2,5-trioxa-spiro[5.5]undec-9-ylidene]- propionic acid ethyl ester, 4ca=2-[3-(l-Phenyl-vinyl)-l,2,5-trioxa-spiro[5.5]undec-9-ylidene]-butyric acid ethyl ester, 4ab=[3-(l-Biphenyl-4-yl-vinyl)-l,2,5-trioxa-spiro[5.5]undec-9-ylidene]-ac- etic acid ethyl ester, 4bb=2- [3 -(1 -Biphenyl-4-yl-vinyl)-1,2,5 -trioxa-spiro [5.5]undec-9-ylidene] — propionic acid ethyl ester, 4ac={3-[l-(4-Chloro-phenyl)-vinyl]-l,2,5-trioxa-spiro[5.5]undec-9-ylidene- }-acetic acid ethyl ester, 4bc=2-{3-[l-(4-Chloro-phenyl)-vinyl]-l,2,5-trioxa-spiro[5.5]undec-9-ylide- ne}-propionic acid ethyl ester, 4ad={3-[l-(4-Methoxy-phenyl)-vinyl]-l,2,5-trioxa-spiro[5.5]undec-9-yliden- e}-acetic acid ethyl ester, 4bd=2-{3-[l-(4-Methoxy-phenyl)-vinyl]-l,2,5-trioxa-spiro[5.5]undec-9-ylid- ene}-propionic acid ethyl ester, 4bd=[3-(l-p-Tolyl-vinyl)-l,2,5-trioxa-spiro[5.5]undec-9-ylidene]-acetic acid ethyl ester, 4be=2-[3-(l-p-Tolyl-vinyl)-l,2,5-trioxa-spiro[5.5]undec-9-ylidene]-propio- nic acid ethyl ester, 4af={3-[l-(4-Cyclohexyl-phenyl)-vinyl]-l,2,5-trioxa-spiro[5.5]undec-9-yli- dene}-acetic acid ethyl ester, 4af=2-{3-[l-(4-Cyclohexyl-phenyl)-vinyl]-l,2,5-trioxa-spiro[5.5]undec-9-y- lidene}-propionic acid ethyl ester, 4ag=[3-(l-Naphthalen-l-yl-vinyl)-l,2,5-trioxa-spiro[5.5]undec-9-ylidene]~ acetic acid ethyl ester, 4ag=2-[3-(l-Naphthalen-l-yl-vinyl)-l,2,5-trioxa-spiro[5.5]undec-9-ylidene- ]-propionic acid ethyl ester, 4ah=[3-(l-Naphthalen-2-yl-vinyl)-l,2,5-trioxa-spiro[5.5]undec-9-ylidene]- acetic acid ethyl ester, and 4bh=2-[3-(l-Naphthalen-2-yl-vinyl)-l,2,5-trioxa-spiro[5.5]undec-9-ylidene- ]-propionic acid ethyl ester.

Full Text

FIELD OF THE INVENTION
The present invention relates to novel spiro 1,2,4-trioxanes of general formula 4. This invention more particularly relates to a process for the preparation of a series of novel spiro 1,2,4-trioxanes.
(Formula removed)

wherein, Ar represents aryl groups such as phenyl, 4-biphenyl, 4-chlorophenyl, 4-methoxyphenyl, 4-methylphenyl, 4-cyclohexylphenyl, 1-naphthyl, 2-naphthyl and the like and R represents hydrogen or the alkyl group such as methyl, ethyl and the like. Several of these novel compounds show high order of antimalarial activity against multidrug-resistant malaria in mice and thus hold promise as antimalarial agents against multidrug-resistant malaria. BACKGROUND OF INVENTION
Malaria is a parasitic disease which is caused by various species of Plasmodium protozoa. Together with AIDS and TB, malaria is responsible for largest number of deaths annually. The high rate of mortality associated with malaria can be attributed to the increasing cases of resistance of Plasmodium falciparum, the most deadly of the four human infecting malarial parasites, to the contemporary antimalarial drugs. Chloroquine is one of the most inexpensive, readily available, and probably most prescribed drugs for the chemotherapy of malaria, it has been rendered ineffective in many parts of the world, due to the emergence of multidrug-resistant P. falciparum. Against this background, discovery of artemisinin as the active principle of Chinese traditional drug against malaria, Artemisia annua, is an important milestone in malaria chemotherapy. Artemisinin is active against both chloroquine sensitive and chloroquine resistant malaria.
(Formula removed)

Semisynthetic derivatives of artemisinin such as arteether, artemether and artesunic acid, are several times more potent than the parent compound. The limited availability of artemisinin from malaria such as cerebral malaria [For reviews on artemisinin and its analogues see: (a) Klayman, D. L Science 1985, 228, 1049. (b) Bhattacharya, A. K.; Sharma, R. P. Heterocycles 1999, 57, 1681. (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].natural source and recognition of endoperoxide linkage in the form of a 1,2,4-trioxane ring system as the antimalarial pharmacophore of these compounds, has led to the present efforts to develop structurally simple synthetic trioxanes as substitutes of artemisinin derivatives. Several of these synthetic 1,2,4-trioxanes have shown promising antimalarial activity [(a) Bhattacharya, A. K.; Sharma, R. P. Heterocycles 1999, 51, 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. 1995, 5, 1913. (d) Singh, C.; Puri, S. K. U.S. Patent 6316493 Bl, 2001. (e) Singh, C; Malik, H.; Puri, S. K. Bioorg. Med. Chem. Lett. 2004, 14, 459. (f) Singh, C; Gupta, N.; Puri, S. K. Bioorg. Med. Chem. 2004, 12, 5553. (g) Singh, C; Tiwari, P.; Puri, S. K. PCT Patent application No. PCT/1N02/00093, dated 28.3.2002. (h) Singh, C. Malik, H.; Puri, S. K. PCT Patent application No. PCT/1N04/00413, dated 27.12.04]. OBJECTIVES OF THE INVENTION
The main objective of the present invention is to provide a novel spiro 1,2,4-trioxanes with a potential to be used for the treatment of malaria.
The objective of the present invention is also to provide a process for the preparation
of novel spiro 1,2,4-trioxanes of general formula 4, a new series of antimalarial
agents.
Another objective of the present invention is to provide a pharmaceutical composition
for the treatment of malaria.
Still another objective of the present invention is to provide the novel compounds
which are useful for the treatment of multidrug resistance malaria.
SUMMARY OF THE INVENTION
Accordingly, the present invention provides a novel spiro 1,2,4-trioxanes of general formula 4, wherein the structural formula of the compound is given below:
(Formula removed)

Wherein, the Ar represents aryl groups, R represents hydrogen or alkyl group. In an embodiment of the present invention the compound of general 4 is selected from [3-(l-Phenyl-vinyl)-l,2,5-trioxa-spiro[5.5]undec-9-ylidene]-acetic acid ethyl ester 4aa,2-[3-(l -Phenyl-vinyl)-1,2,5-trioxa-spiro[5.5]undec-9-ylidene]-propionic acid ethyl 4ba,2-[3-(l-Phenyl-vinyl)-1,2,5-trioxa-spiro[5.5]undec-9-ylidene]-butyric acid ethyl ester 4ca,[3-(l-Biphenyl-4-yl-vinyl)-l,2,5-trioxa-spiro[5.5]undec-9-ylidene] -acetic acid ethyl ester 4ab,2-[3-(l-Biphenyl-4-yl-vinyl)-l,2,5-trioxa-spiro[5.5]undec-9-ylidene]-propionic acid ethyl ester 4bb,{3-[l-(4-Chloro-phenyl)-vinyl]-l,2,5-trioxa-spiro[5.5]undec-9-ylidene}-acetic acid ethyl ester 4ac,2-{3-[l-(4-Chloro-phenyl)-vinyl]-1,2,5-trioxa-spiro[5.5]undec-9-ylidene} -propionic acid ethyl ester 4bc,{3-[l-(4-Methoxy-phenyl)-vinyl]-l,2,5-trioxa-spiro[5.5]undec-9-ylidene}-acetic acid ethyl ester 4ad,2-{3-[l-(4-Methoxy-phenyl)-vinyl]-l,2,5-trioxa-spiro[5.5]undec-9-ylidene}-propionic acid ethyl ester 4bd,[3-(l-p-Tolyl-vinyl)-l,2,5-trioxa-spiro[5.5]undec-9-ylidene]-acetic acid ethyl ester 4ae,2-[3-(l-p-Tolyl-vinyl)-
l,2,5-trioxa-spiro[5.5]undec-9-ylidene]-propionic acid ethyl ester 4be,{3-[l-(4-
Cyclohexyl-phenyl)-vinyl]-l,2,5-trioxa-spiro[5.5]undec-9-ylidene}-acetic acid ethyl
ester 4af,2-{3-[l-(4-Cyclohexyl-phenyl)-vinyl]-l,2,5-trioxa-spiro[5.5]undec-9-
ylidene}-propionic acid ethyl ester 4bf, [3-(l-Naphthalen-l-yl-vinyl)-1,2,5-trioxa-spiro[5.5]undec-9-ylidene]-acetic acid ethyl ester 4ag,2-[3-(l-Naphthalen-l-yl-vinyl)-l,2,5-trioxa-spiro[5.5]undec-9-ylidene]-propionic acid ethyl ester 4bg, [3-(l-Naphthalen-2-yl-vinyl)-l,2,5-trioxa-spiro[5.5]undec-9-ylidene]-acetic acid ethyl ester 4ah,2-[3-(l-Naphthalen-2-yl-vinyl)-l,2,5-trioxa-spiro[5.5]undec-9-ylidene]-propionic acid ethyl ester 4bh.
In yet another embodiment of the invention a novel spiro 1,2,4-trioxanes wherein the aryl group is selected from the groups consisting of phenyl, 4-biphenyl, 4-chlorophenyl, 4-methoxyphenyl, 4-methylphenyl, 4-cyclohexylphenyl, 1-naphthyl, 2-naphthyl.
In yet another embodiment of the invention a novel spiro 1,2,4-trioxanes a novel spiro trioxane wherein the alkyl group is selected from methyl, ethyl, propyl. In still another embodiment of the invention a novel spiro 1,2,4-trioxanes wherein the structural formula of said compounds is given below:
(Formula removed)

wherein, the compound obtained is represented by a group of following
compounds: 4aa=[3-(l-Phenyl-vinyl)-l,2,5-trioxa-spiro[5.5]undec-9-ylidene]-aceticacid ethyl ester,
4ab=[3-(l-Biphenyl-4-yl-vinyl)-l,2,5-trioxa-spiro[5.5]undec-9-ylidene]-acetic acid ethyl ester,
4ac={3-[l-(4-Chloro-phenyl)-vinyl]-l,2,5-trioxa-spiro[5.5]undec-9-ylidene}-acetic acid ethyl ester,
4ad={3-[l-(4-Methoxy-phenyl)-vinyl]-l,2,5-trioxa-spiro[5.5]undec-9-ylidene}-aceticacid ethyl ester,
4ae=[3-(l-p-Tolyl-vinyl)-l,2,5-trioxa-spiro[5.5]undec-9-ylidene]-aceticacid ethyl ester,
4af= {3 - [ 1 -(4-Cyclohexyl-phenyl)-vinyl]-1,2,5-trioxa-spiro [5.5] undec-9-ylidene}-acetic acid ethyl ester,
4ag=[3-( 1-Naphthalen-1-yl-vinyl)-1,2,5-trioxa-spiro [5.5]undec-9-ylidene]-acetic acid ethyl ester,
4ah=[3-(l-Naphthalen-2-yl-vinyl)-l,2,5-trioxa-spiro[5.5]nndec-9-ylidene]-acetic acid ethyl ester.
In still another embodiment of the invention a novel spiro 1,2,4-trioxanes wherein the structural formula of said compounds is given below:
(Formula removed)

wherein, the compound obtained is represented by a group of following
compounds: 4ba=2-[3-(1 -Phenyl-vinyl)-1,2,5-trioxa-spiro[5.5]undec-9-ylidene]-propionic acid ethyl,
4bb=2-[3-(l-Biphenyl-4-yl-vinyl)-l,2,5-trioxa-spiro[5.5]undec-9-ylidene]-propionic acid ethyl ester,
4bc=2-{3-[l-(4-Chloro-phenyl)-vinyl]-l,2,5-trioxa-spiro[5.5]undec-9-ylidene}-propionic acid ethyl ester,
4bd=2-{3-[l-(4-Methoxy-phenyl)-vinyl]-l,2,5-trioxa-spiro[5.5]undec-9-ylidene}-propionic acid ethyl ester,
4be=2-[3-(l -p-Tolyl-vinyl) 1,2,5-trioxa-spiro[5.5]undec-9-ylidene]-propionic acid ethyl ester,
4bf=2-{3-[l-(4-Cyclohexyl-phenyl)-vinyl]-l,2,5-trioxa-spiro[5.5]undec-9-ylidene}-propionic acid ethyl ester,
4bg=2-[3-(l-Naphthalen-l-yl-vinyl)-l,2,5-trioxa-spiro[5.5]undec-9-ylidene]-propionic acid ethyl ester,
4bh=2-[3-(l-Naphthalen-2-yl-vinyl)-l,2,5-trioxa-spiro[5.5]undec-9-ylidene]-propionic acid ethyl ester.
In still another embodiment of the invention a novel spiro 1,2,4-trioxanes wherein the structural formula of 4ca is given below:
(Formula removed)

In yet another embodiment of the invention a novel compound of general
formula 4 as claimed in claim 1, wherein the compound is effective against
parasitaemia upto 100%.
In yet another embodiment of the invention of compound of formula 4 is used for
the treatment of malaria. Accordingly, the present invention provides a process for the preparation of novel ;piro 1,2,4-trioxanes series of general formula 4
(Formula removed)

vherein, Ar represents aryl groups R represents hydrogen or the alkyl group. In an embodiment of the invention is a novel process for the preparation of a series of spiro 1,2,4-trioxanes of general formula 4 comprising of :(a) photooxygenation of allylic alcohols of formula 1 in presence of a sensitizer and a
light source which provides visible light, in an organic solvent at temperature ranging from -10°C to 0°C to obtain P-hydroxyhydroperoxide of formula 2,
(Formula removed)

2 (b) reacting p-hydroxyhydroperoxide of formula2in situ with 1,4-cyclohexanedione in the presence of an acid catalyst at temperature 0°C to for 18 hours to obtain keto trioxanes of general formula 3,
(Formula removed)

(c) reacting the keto trioxanes of step (b) with triethylphosphonoacetate or substituted triethylphosphonoacetate in the presence of a base in an organic solvent at a temperature ranging from 0°C to 50°C to obtain spiro 1,2,4-trioxanes of formula 4,
(Formula removed)

(d) isolating and purifying by conventional methods to furnish spiro 1,2,4-
trioxanes of formula 4.
In yet another embodiment of the invention wherein the organic solvent in step
(a) is selected from the aprotic solvent such as acetonitrile.
In yet another embodiment of the invention wherein the substituted
triethylphosphonoacetate is selected from triethylphosphono-2-propionate,
triethylphosphono-2-butyrate.
In yet another embodiment of the invention wherein the base in step (c) is selected
from sodium hydride, n-butyl lithium.
In yet another embodiment of the invention wherein the organic solvent used in
step (c) is selected from tetrahydrofuran, dimethoxyetthane, diethyl ether.
In still another embodiment of the invention wherein the acid catalyst used in
step (d) is selected from hydrogen chloride.
In still another embodiment of the invention wherein the compound obtained is
represented by a group of following compounds:
4aa=[3-(l-Phenyl-vinyl)-l,2,5-trioxa-spiro[5.5]undec-9-ylidene]-acetic acid ethyl
ester,
4ba=2-[3-(l-Phenyl-vinyl)-l,2,5-trioxa-spiro[5.5]undec-9-ylidene]-propionic acid
ethyl ester, 4ca=2-[3-(l-Phenyl-vinyl)-l,2,5-trioxa-spiro[5.5]undec-9-ylidene]-butyric acid ethyl ester,
4ab=[3-(l-Biphenyl-4-yl-vinyl)-l,2,5-trioxa-spiro[5.5]undec-9-ylidene]-acetic acid ethyl ester,
4bb=2-[3-(l-Biphenyl-4-yl-vinyl)-l,2,5-trioxa-spiro[5.5]undec-9-ylidene]-propionic acid ethyl ester,
4ac={3-[l-(4-Chloro-phenyl)-vinyl]-l,2,5-trioxa-spiro[5.5]undec-9-ylidene}-acetic acid ethyl ester,
4bc=2-{3-[l-(4-Chloro-phenyl)-vinyl]-l,2,5-trioxa-spiro[5.5]undec-9-ylidene}-propionic acid ethyl ester,
4ad= {3 -[ 1 -(4-Methoxy-phenyl)-vinyl] -1,2,5-trioxa-spiro [5.5]undec-9-ylidene} -acetic acid ethyl ester,
4bd=2-{3-[l-(4-Methoxy-phenyl)-vinyl]-l,2,5-trioxa-spiro[5.5]undec-9-ylidene}-
propionic acid ethyl ester,
4bd=[3-(l-p-Tolyl-vinyl)-l,2,5-trioxa-spiro[5.5]undec-9-ylidene]-acetic acid ethyl
ester,
4be=2-[3-(l-p-Tolyl-vinyl)-l,2,5-trioxa-spiro[5.5]undec-9-ylidene]-propionic acid
ethyl ester,
4af={3-[l-(4-Cyclohexyl-phenyl)-vinyl]-l,2,5-trioxa-spiro[5.5]undec-9-ylidene}-
acetic acid ethyl ester,
4af=2- {3 -[ 1 -(4-Cyclohexyl-phenyl)-vinyl] -1,2,5-trioxa-spiro [5.5]undec-9-ylidene} -
propionic acid ethyl ester,
4ag=[3-(l-Naphthalen-l-yl-vinyl)-l,2,5-trioxa-spiro[5.5]undec-9-ylidene]-acetic acid ethyl ester,
4ag=2-[3-(l-Naphthalen-l-yl-vinyl)-l,2,5-trioxa-spiro[5.5]undec-9-ylidene]-propionic acid ethyl ester,
4ah=[3-(l-Naphthalen-2-yl-vinyl)-l,2,5-trioxa-spiro[5.5]undec-9-ylidene]-acetic acid ethyl ester,
4bh=2-[3-(l-Naphthalen-2-yl-vinyl)-l,2,5-trioxa-spiro[5.5]undec-9-ylidene]-propionic acid ethyl ester.
One of the feature of the present invention is a pharmaceutical composition comprising a pharmaceutically effective amount of compound of formula 4 -optionally along with pharmaceutically acceptable diluents and /or carrier. In an embodiment of the present invention is a composition wherein the composition is useful in the treatment of malaria.
In an embodiment of the present invention is a composition wherein the dose of composition is ranging the dose of composition is ranging between 24 to 96 mg/kg/day.
In still another embodiment of the invention wherein the composition is useful for
treatment of multidrug resistance malaria.
In still another embodiment of the invention wherein the composition is administered
intramuscularly, oral route or intraperitoneally.
In still another embodiment of the invention wherein the composition is effective
against parasaitemia upto 100%.
Another feature of the invention is a method of treating a subject having malaria,
comprising administering to the subject a pharmaceutically effective amount of a
composition containing compound of formula 4,
(Formula removed)

t wherein ,Ar represents aryl groups such as phenyl, 4-biphenyl, 4-chlorophenyl, 4-methoxyphenyl, 4-methylphenyl, 4-cyclohexylphenyl, 1-naphthyl, 2-naphthyl and a pharmaceutically acceptable salt. R represents hydrogen or the alkyl group such as methyl, ethyl, propyl.
In yet another embodiment of the inevntion wherein the composition is administered intramuscularly, intraperitoneally, or orally.
In yet another embodiment of the inevntion wherein the pharmaceutically acceptable amount of compound of formula 4 is in the range of 24 to 96 mg of compound of formula 4 per kilogram of body weight of subject per day. In still another embodiment of the invention wherein the subject is a human being.
DETAILED DESCRIPTION OF THE INVENTION
In the process allylic alcohols of formula 1 are prepared by known procedures [(a) Singh, C. Tetrahedron Lett. 1990, 31, 6901. (b) Singh, C; Tiwari, P.; Puri, S. K. PCT Patent application No. PCT/1N02/00093, 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].
In the process photooxygenation of allylic alcohols of formula 1 may be be effected by passing oxygen gas or air in the solution of the alcohol in an organic solvent and in the presence of a dye and a light source which provides visible light, to furnish {}-hydroxyhydroperoxide of formula 2. These p-hydroxyhydroperoxide of formula 2 are known compounds as they have been prepared earlier [(a) Singh, C. Tetrahedron Lett. 1990,31, 6901. (b) Singh, C; Tiwari, P.; Puri, S. K. PCT Patent application No. PCT/1N02/00093, 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]. In the process reaction of ß-hydroxyhydroperoxide of formula 2 with 1,4-cyclohexanedione in presence of an acid catalyst such as coned HC1, p-toluene sulphonic acid (p-TSA) and the like at temperature ranging from 0°C to r.t. furnish keto 1,2,4-trioxanes of formula 3. These trioxanes of formula 3 can be isolated and purified by standard laboratory methods such as column chromatography or crystallization. These compounds have been tested against malaria parasites in mice and show only moderate order of activity. Keto trioxanes 3a, 3b, 3c, 3d, 3e are known compounds [ (a) Singh, C; Malik, H.; Puri, S. K. Bioorg. Med. Chem. Lett. 2004, 14, 459. (b) Singh, C; Malik, H.; Puri, S. K. PCT Patent application No. PCT/1N04/00413, dated 27.12.04] while compounds 3f, 3g, 3h are new compounds. In the process Wittig olefination of keto trioxanes of formula 3 by reaction with triethylphosphonoacetate or substituted triethylphosphonoacetate such as triethylphosphono-2-propionate, triethylphosphono-2-butyrate in the presence of a base such as NaH, n-BuLi and the like, in an organic solvent such as dimethoxyethane, tetrahydrofuran and the like at temperature ranging from 0°C to room temperature furnish spiro 1,2,4-trioxanes of formula 4. These spiro 1,2,4-trioxanes of formula 4 can be isolated and purified by standard laboratory methods such as column chromatography and crystallization. These spiro 1,2,4-trioxanes of formula 4 are new chemical entities and they have not been prepared earlier. These 1,2,4-trioxanes of formula 4 have been tested against malaria parasites in mice and have shown high order of antimalarial activity.
This invention is further illustrated by the following examples which should not, however, be construed to limit the scope of the present invention.
Example 1 3-(l-Phenyl-vinyl)-l,2,5-trioxaspiro[5.5]undec-9-one (compound 3a, Ar = phenyl). Allylic alcohol. A solution of allylic alcohol of la (lg) and methylene blue (lOmg) in MeCN (50 mL) was photooxygenated at -10°C to 0°C for 4h to give (3-hydroxyhydroperoxide 2a which was reacted in situ with 1,4-cyclohexanedione (1.15g) in presence of coned HC1 (5 drops) for 18h at 0°C. Reaction mixture was concentrated under reduced pressure and residue taken up in diethylether (100 mL) was washed with sat. aq NaHCCh (30 mL). The aqueous layer was extracted with diethylether (2x20 mL), combined organic layer was dried over anhyd. Na2SO4 and concentrated. The crude product was purified by column chromatography on silica gel to furnish trioxane 3a (0.94 g, 51% yield, based on allylic alcohol la used), m.p. 70-71°C.
Trioxane 3a was obtained in 53% yield when P-hydroxyhydroperoxide 2a was reacted with 1,4-cyclohexanedione at r.t. for 8h using p-toluene sulphonic acid (p-TSA) as acid catalyst.
[3-(l-Phenyl-vinyl)-l,2,5-trioxa-spiro[5.5]undec-9-yIidene]-acetic acid ethyl ester (compound 4aa, Formula 4, Ar = phenyl, R = H).
To a stirred and cooled (0°C) mixture of NaH (0.2g) in dry dimethoxyethane (15 mL) was added triethyl phosphonoacetate (1.2g) and the reaction mixture was stirred at 0°C for lh. To the solution thus obtained was added dropwise a solution of keto trioxane 3a (lg) in dry dimethoxyethane (15 mL), while maintaining the temperature of the flask at 0°C. After the addition was complete the resulting solution was stirred for additional twenty minutes at 0°C. The reaction mixture was diluted with water (40 mL) and extracted with diethylether (2x75 mL). The combined organic layer was washed successively with water (2x15 mL) and brine, dried over anhyd Na2SO4, concentrated and purified by column chromatography over silica gel to furnish spiro trioxane 4aa (oil, 1.16g, 92.8% yield) as a mixture of £ and Z isomers. The compound 4aa was also prepared using different reaction conditions. Table 1 gives the conditions used and the yield of compound 4aa. Table 1
(Table removed)

Example 2 2-[3-(l-Phenyl-viny 1)-1,2,5-trioxa-spiro[5.5]undec-9-ylidene]-propionic acid ethyl ester (compound 4ba, Formula 4, Ar = phenyl, R = CH3).
To a stirred and cooled (0°C) mixture of NaH (0.13g) in dry dimethoxyethane (20 mL) was added triethylphosphono-2-propionate (0.9g) and the reaction mixture was stirred at 0°C for lh. To the solution thus obtained was added dropwise a solution of keto trioxane 3a (0.6g) in dry dimethoxyethane (10 mL), while maintaining the temperature of the flask at 0°C. After the addition was complete the resulting solution was stirred for additional half an hour at 0°C. The reaction mixture was worked up as above and concentrated. The crude product was purified by column chromatography on silica gel to furnish spiro trioxane 4ba (oil, 0.66g, 84% yield) as a mixture of E and Z isomers.
Example 3 2-[3-(l-Phenyl-vinyl)-l,2,5-trioxa-spiro[5.5]undec-9-ylidene]-butyric acid ethyl ester (compound 4ca, Formula 4, Ar = phenyl, R = CH2CH3). To a stirred and cooled (0°C) mixture of NaH (0.04g) in dry dimethoxyethane (15 mL) was added triethylphosphono-2-butyrate (0.3g) and the reaction mixture was stirred at 0°C for lh. To the solution thus obtained was added dropwise a solution of keto trioxane 3a (0.2g) in dry dimethoxyethane (8 mL), while maintaining the temperature of the flask at 0°C. After the addition was complete the resulting solution was. stirred for additional half an hour at 0°C. The reaction mixture was worked up as above and concentrated. The crude product was purified by column chromatography on silica gel to furnish spiro trioxane 4ca (oil, 0.22g, 81% yield) as a mixture of £ and Z isomers.
Example 4 3-(l-Biphenyl-4yl-vinyl)-l,2,5-trioxaspiro[5.5]undec-9-one (compound 3b, Ar = biphenyl).
Allylic alcohol lb was prepared according to the reported procedure (Singh, C; Tiwari, P.; Puri, S. K. PCT Patent application No. PCT/1N02/00093, dated 28.3.2002). A solution of allylic alcohol of lb (lg) and methylene blue (10 mg) in CH2C12: MeCN (1:4, 50 mL) was photooxygenated at -10°C to 0°C for 4h to give (3-hydroxyhydroperoxide 2b which was reacted in situ with 1,4-cyclohexanedione (lg) in presence of coned HC1 (5 drops) for 18h at 0°C. The reaction mixture was worked up as above and concentrated. The crude product was purified by column chromatography on silica gel to furnish trioxane 3b (0.65 g, 42% yield, based on allylic alcohol lb used), m.p. 104-105°C.
[3-(l-Biphenyl-4-yl-vinyl)-l,2,5-trioxa-spiro[5.5]undec-9-ylidene]-acetic acid ethyl ester (compound 4ab, Formula 4, Ar = 4-biphenyl, R = H). To a stirred and cooled (0°C) mixture of NaH (0.12g) in dry dimethoxyethane (20 mL) was added triethylphosphonoacetate (0.8g) and the reaction mixture was stirred at 0°C for lh. To the solution thus obtained was added dropwise a solution of keto trioxane 3b (0.80g) in dry dimethoxyethane (15 mL), while maintaining the temperature of the flask at 0°C. After the addition was complete the resulting solution was stirred for additional half an hour at 0°C. The reaction mixture was worked up as above and concentrated. The crude product was purified by column chromatography on silica gel to furnish spiro trioxane 4ab (0.89g, 92.6% yield) as a mixture of E and Z isomers, m.p. 143-145°C.
Example 5 2-[3-(l-Biphenyl-4-yl-vinyl)-l,2,5-trioxa-spiro[5.5]undec-9-ylidene]-propionic acid ethyl ester (compound 4bb, Formula 4, Ar = 4-biphenyl, R = CH3). ethyl ester (compound 4bb, Formula 4, Ar = 4-biphenyl, R = CH3). To a stirred and cooled (0°C) mixture of NaH (0.08 g) in dry dimethoxyethane (20 mL) was added triethylphosphono-2-propionate (0.6g) and the reaction mixture was stirred at 0°C for lh. To the solution thus obtained was added dropwise a solution of keto trioxane 3b (0.50g) in dry dimethoxyethane (10 mL), while maintaining the
temperature of the flask at 0°C. After the addition was complete the resulting solution was stirred for additional half an hour at 0°C. The reaction mixture was worked up as above and concentrated. The crude product was purified by column chromatography on silica gel to furnish spiro trioxane 4bb (0.52 g, 83.7% yield) as a mixture of £ and Z isomers, m.p. 68-70°C.
Example 6 3-[l-(4-Chloro-phenyI)-vinyl]-l,2,5-trioxa-spiro[5.5]undecan-9-one (compound 3c, Ar = 4-chlorophenyl).
Allylic alcohol lc was prepared according to the reported procedure (Singh, C. Tetrahedron Lett. 1990, 31, 6901). A solution of allylic alcohol of lc (1 g) and methylene blue (10 mg) in MeCN (50 mL) was photooxygenated at -10°C to 0°C for 4h to give p-hydroxyhydroperoxide 2c which was reacted in situ with 1,4-cyclohexanedione (1.22 g) in presence of coned HC1 (5 drops) for 18h at 0°C. The reaction mixture was worked up as above and concentrated. The crude product was purified by column chromatography on silica gel to furnish trioxane 3c (0.64 g, 38% yield, based on allylic alcohol lc used), m.p. 72-74°C.
{3-[l-(4-ChIoro-phenyl)-vinyl]-l,2,5-trioxa-spiro[5.5]undec-9-ylidene}-acetic acid ethyl ester (compound 4ac, Formula 4, Ar = 4-chlorophenyl, R = H). To a stirred and cooled (0°C) mixture of NaH (0.09g) in dry dimethoxyethane (15 mL) was added triethylphosphonoacetate (0.6g) and the reaction mixture was stirred at 0°C for lh. To the solution thus obtained was added dropwise a solution of keto trioxane 3c (0.50g) in dry dimethoxyethane (10 mL), while maintaining the temperature of the flask at 0°C. After the addition was complete the resulting solution was stirred for additional half an hour at 0°C. The reaction mixture was worked up as above and concentrated. The crude product was purified by column chromatography on silica gel to furnish spiro trioxane 4ac (0.56g, 91.2% yield) as a mixture of £ and Z isomers, m.p. 78-80°C.
Example 7 2-{3-[l-(4-Chloro-phenyl)-vinyl]-l,2,5-trioxa-spiro[5.5]undec-9-ylidene}-propionic acid ethyl ester (compound 4bc, Formula 4, Ar = 4-chlorophenyl, R = CH3).
To a stirred and cooled (0°C) mixture of NaH (0.05 g) in dry dimethoxyethane (20 mL) was added triethylphosphono-2-propionate (0.5g) and the reaction mixture was stirred at 0°C for lh. Tp the solution thus obtained was added drop wise a solution of keto trioxane 3c (0.30g) in dry dimethoxyethane (10 mL), while maintaining the temperature of the flask at 0°C. After the addition was complete the resulting solution was stirred for additional half an hour at 0°C. The reaction mixture was worked up as above and concentrated. The crude product was purified by column chromatography on silica gel to furnish spiro trioxane 4bc (oil, 0.33 g, 85.4% yield) as a mixture of £ and Z isomers.
Example 8 3-[l-(4-Methoxy-phenyl)-vinyI]-l,2,5-trioxa-spiro[5.5]undecan-9-one (compound 3d, Ar = 4-methoxyphenyl).
Ally lic alcohol Id was prepared according to the reported procedure (Singh, C. Tetrahedron Lett. 1990, 31, 6901). A solution of allylic alcohol of Id (lg) and methylene blue (10 mg) in MeCN (50 mL) was photooxygenated at -10°C to 0°C for 4h to give p-hydroxyhydroperoxide 2d which was reacted in situ with 1,4-cyclohexanedione (1.25g) in presence of coned HC1 (5 drops) for 18h at 0°C. The reaction mixture was worked up as above and concentrated. The crude product was purified by column chromatography on silica gel to furnish trioxane 3d (0.48 g, 28.1% yield, based on allylic alcohol Id used) m.p. 74-76°C. {3-[l-(4-Methoxy-phenyl)-vinyl]-l,2,5-trioxa-spiro[5.5]undec-9-ylidene}-acetic acid ethyl ester
(compound 4ad, Formula 4, Ar = 4-methoxyphenyl, R = H).
To a stirred and cooled (0°C) mixture of NaH (0.09g) in dry dimethoxyethane (15 mL) was added triethylphosphonoacetate (0.6g) and the reaction mixture was stirred at 0°C for lh. To the solution thus obtained was added dropwise a solution of keto trioxane 3d (0.50g) in dry dimethoxyethane (15 mL), while maintaining the temperature of the flask at 0°C. After the addition was complete the resulting solution was stirred for additional half an hour at 0°C. The reaction mixture was worked up as above and concentrated. The crude product was purified by column chromatography
on silica gel to furnish spiro trioxane 4ad (oil, 0.56g, 91.0% yield) as a mixture of E and Z isomers.
Example 9 2-{3-[l-(4-Methoxy-phenyl)-vmyl]-l,2,5-trioxa-spiro[5.5]undec-9-ylidene}-propionic acid ethyl ester (compound 4bd, Formula 4, Ar = 4-methoxyphenyl, R = CH3).
To a stirred and cooled (0°C) mixture of NaH (0.06 g) in dry dimethoxyethane (20 mL) was added triethylphosphono-2-propionate (0.4g) and the reaction mixture was stirred at 0°C for lh. To the solution thus obtained was added dropwise a solution of keto trioxane 3d (0.30g) in dry dimethoxyethane (10 mL), while maintaining the temperature of the flask at 0°C. After the addition was complete the resulting solution was stirred for additional half an hour at 0°C. The reaction mixture was worked up as above and concentrated. The crude product was purified by column chromatography on silica gel to furnish spiro trioxane 4bd (oil, 0.32 g, 84.2% yield) as a mixture of E and Z isomers.
Example 10 3-(l-p-Tolyl-vinyl)-l,2,5-trioxa-spiro[5.5]undecan-9-one (compound 3e, Ar = 4-methylphenyl).
Allylic alcohol le was prepared according to the reported procedure (Singh, C. Tetrahedron Lett. 1990, 31, 6901). A solution of allylic alcohol of le (1 g) and methylene blue (10 mg) in MeCN (50 mL) was photooxygenated at -10°C to 0°C for 4h to give (3-hydroxyhydroperoxide 2e which was reacted in situ with 1,4-cyclohexanedione (1.38 g) in presence of coned HC1 (5 drops) for 18h at 0°C. The reaction mixture was worked up as above and concentrated. The crude product was purified by column chromatography on silica gel to furnish trioxane 3e (0.58 g, 32.7% yield, based on allylic alcohol le used), m.p. 66-68°C. [3-(l-p-Tolyl-vinyl)-l,2,5-trioxa-spiro[5.5]undec-9-ylidene]-acetic acid ethyl ester (compound 4ae, Formula 4, Ar = 4-methylphenyl, R = H). To a stirred and cooled (0°C) mixture of NaH (0.09g) in dry dimethoxyethane (15 mL) was added tnethylphosphonoacetate (0.6g) and the reaction mixture was stirred at 0°C for lh. To the solution thus obtained was added dropwise a solution of keto
trioxane 3e (0.50g) in dry dimethoxyethane (15 mL), while maintaining the temperature of the flask at 0°C. After the addition was complete the resulting solution was stirred for additional half an hour at 0°C. The reaction mixture was worked up as above and concentrated. The crude product was purified by column chromatography on silica gel to furnish spiro trioxane 4ae (0.56g, 91.1% yield) as a mixture of £ and Z isomers, m.p. 64-66°C.
Example 11
2- [3-(l -p-Tolyl-vinyl)-l ,2,5-trioxa-spiro [5.5] undec-9-ylidene] -propionic acid
ethyl ester (compound 4be, Formula 4, Ar = 4-methylphenyl, R = CH3).
To a stirred and cooled (0°C) mixture of NaH (0.09 g) in dry dimethoxyethane (20 mL) was added triethylphosphono-2-propionate (0.7g) and the reaction mixture was stirred at 0°C for lh. To the solution thus obtained was added dropwise a solution of keto trioxane 3e (0.50g) in dry dimethoxyethane (10 mL), while maintaining the temperature of the flask at 0°C. After the addition was complete the resulting solution was stirred for additional half an hour at 0°C. The reaction mixture was worked up as above and concentrated. The crude product was purified by column chromatography on silica gel to furnish spiro trioxane 4be (oil, 0.53 g, 86.2% yield) as a mixture of E and Z isomers.
Example 12
3- [ 1 -(4-Cy clohexy 1-pheny l)-viny 1] -1,2,5-trioxa-spiro [5.5] undecan-9-one
(compound 3f, Ar = 4-cyclohexylphenyl).
Allylic alcohol If was prepared according to the reported procedure (Singh, C; Tiwari, P.; Puri, S. K. PCT Patent application No. PCT/1N02/00093, dated 28.3.2002). A solution of allylic alcohol of If (2 g) and methylene blue (20 mg) in MeCN (80 mL) was photooxygenated at -10°C to 0°C for 4h to give (3-hydroxyhydroperoxide 2f which was reacted in situ with 1,4-cyclohexanedione (1.94 g) in presence of coned HC1 (5 drops) for 18h at 0°C. The reaction mixture was worked up as above and concentrated. The crude product was purified by column chromatography on silica gel to furnish trioxane 3f (0.98 g, 31.7% yield, based on allylic alcohol If used)), m.p. 56-58°C.
{3-[l-(4-Cyclohexyl-phenyl)-vinyI]-l,2,5-trioxa-spiro[5.5]undec-9-ylidene}-acetic acid ethyl ester (compound 4af, Formula 4, Ar = 4-cyclohexylphenyl, R = H). To a stirred and cooled (0°C) mixture of NaH (0.06g) in dry dimethoxyethane (15 mL) was added triethylphosphonoacetate (0.4g) and the reaction mixture was stirred at 0°C for lh. To the solution thus obtained was added dropwise a solution of keto trioxane 3f (0.40g) in dry dimethoxyethane (15 mL), while maintaining the temperature of the flask at 0°C. After the addition was complete the resulting solution was stirred for additional half an hour at 0°C. The reaction mixture was worked up as above and concentrated. The crude product was purified by column chromatography on silica gel to furnish spiro trioxane 4af (oil, 0.43g, 89.9% yield) as a mixture of E and Z isomers.
Example 13
2- {3- [ 1 -(4-Cy clohexy I-pheny l)-viny 1] -1,2,5-trioxa-spiro [5.5] undec-9-y lidene}-propionic acid ethyl ester (compound 4bf, Formula 4, Ar = 4-cyclohexylphenyl, R = CH3).
To a stirred and cooled (0°C) mixture of NaH (0.05 g) in dry dimethoxyethane (20 mL) was added triethylphosphono-2-propionate (0.4g) and the reaction mixture was stirred at 0°C for lh. To the solution thus obtained was added dropwise a solution of keto trioxane 3f (0.30g) in dry dimethoxyethane (10 mL), while maintaining the temperature of the flask at 0°C. After the addition was complete the resulting solution was stirred for additional half an hour at 0°C. The reaction mixture was worked up as above and concentrated. The crude product was purified by column chromatography on silica gel to furnish spiro trioxane 4bf (oil, 0.30 g, 82.6% yield) as a mixture of E and Z isomers.
Example 14 3-(l-Naphthalen-l-yl-vinyl)-l,2,5-trioxa-spiro[5.5]undecan-9-one (compound 3g, Ar = 1-naphthyl).
Allylic alcohol lg was prepared according to the reported procedure (Singh, C; Kanchan, R.; Chandra, S. and Puri, S.K. Indian patent application no. 0909/DEL/2003 dated 18/07/2003). A solution of allylic alcohol of lg (2g) and
methylene blue (20 mg) in MeCN (80 mL) was photooxygenated at -10°C to 0°C for 4h to give P-hydroxyhydroperoxide 2g which was reacted in situ with 1,4-cyclohexanedione (2.26 g) in presence of coned HC1 (5 drops) for 18h at 0°C. The reaction mixture was worked up as above and concentrated. The crude product was purified by column chromatography on silica gel to furnish trioxane 3g (0.72 g, 22% yield, based on allylic alcohol lg used).
[3-(l-Naphthalen-l-yl-vinyl)-l,2,5-trioxa-spiro[5.5]undec-9-ylidene]-acetic acid ethyl ester (compound 4ag, Formula 4, Ar = 1-naphthyl, R = H). To a stirred and cooled (0°C) mixture of NaH (0.07g) in dry dimethoxyethane (15 mL) was added triethylphosphonoacetate (0.4g) and the reaction mixture was stirred at 0°C for lh. To the solution thus obtained was added dropwise a solution of keto trioxane 3g (0.40g) in dry dimethoxyethane (15 mL), while maintaining the temperature of the flask at 0°C. After the addition was complete the resulting solution was stirred for additional half an hour at 0°C. The reaction mixture was worked up as above and concentrated. The crude product was purified by column chromatography on silica gel to furnish spiro trioxane 4ag (oil, 0.44g, 90.7% yield) as a mixture of E and Z isomers.
Example 15
2-[3-(l-Naphthalen-l-yl-vinyl)-l,2,5-trioxa-spiro[5.5]undec-9-ylidene]-propionic acid ethyl ester (compound 4bg, Formula 4, Ar = 1-naphthyl, R = CH3). To a stirred and cooled (0°C) mixture of NaH (0.05 g) in dry dimethoxyethane (15 mL) was added triethylphosphono-2-propionate (0.4g) and the reaction mixture was stirred at 0°C for lh. To the solution thus obtained was added dropwise a solution of keto trioxane 3g (0.3g) in dry dimethoxyethane (10 mL), while maintaining the temperature of the flask at 0°C. After the addition was complete the resulting solution was stirred for additional half an hour at 0°C. The reaction mixture was worked up as above and concentrated. The crude product was purified by column chromatography on silica gel to furnish spiro trioxane 4bg (0.30 g, 80.7% yield) as a mixture of £ and Z isomers.
Example 16 3-(l-Naphthalen-2-yl-vinyl)-l,2,5-trioxa-spiro[5.5]undecan-9-one (compound 3h,
Ar = 2-naphthyl).
Allylic alcohol lh was prepared according to the reported procedure (Singh, C; Kanchan, R.; Chandra, S. and Puri, S.K. Indian patent application no. 0909/DEL/2003 dated 18/07/2003). A solution of allylic alcohol of lh (lg) and methylene blue (10 mg) in MeCN (50 mL) was photooxygenated at -10°C to 0°C for 4h to give p-hydroxyhydroperoxide 2h which was reacted in situ with 1,4-cyclohexanedione (1.13 g) in presence of coned HC1 (5 drops) for 18h at 0°C. The reaction mixture was worked up as above and concentrated. The crude product was purified by column chromatography on silica gel to furnish trioxane 3h (0.58 g, 32.7% yield, based on allylic alcohol lh used), m.p. 58-60°C. [3-(l-Naphthalen-2-yl-vmyl)-l,2,5-trioxa-spiro[5.5]undec-9-ylidene]-acetic acid ethyl ester (compound 4ah, Formula 4, Ar = 2-naphthyl, R = H). To a stirred and cooled (0°C) mixture of NaH (0.08g) in dry dimethoxyethane (15 mL) was added triethylphosphonoacetate (0.5g) and the reaction mixture was stirred at 0°C for lh. To the solution thus obtained was added dropwise a solution of keto trioxane 3h (0.50g) in dry dimethoxyethane (15 mL), while maintaining the temperature of the flask at 0°C. After the addition was complete the resulting solution was stirred for additional half an hour at 0°C. The reaction mixture was worked up as above and concentrated. The crude product was purified by column chromatography on silica gel to furnish spiro trioxane 4ah (0.56g, 92.1% yield)) as a mixture of E and Z isomers, m.p. 54-56°C.
Example 17 2-[3-(l-Naphthalen-2-yl-vinyl)-l,2,5-trioxa-spiro[5.5]undec-9-ylidene]-propionic acid ethyl ester (compound 4bh, Formula 4, Ar = 2-naphthyl, R = CH3). To a stirred and cooled (0°C) mixture of NaH (0.09 g) in dry dimethoxyethane (20 mL) was added triethylphosphono-2-propionate (0.6g) and the reaction mixture was stirred at 0°C for lh. To the solution thus obtained was added dropwise a solution of keto trioxane 3h (0.50g) in dry dimethoxyethane (10 mL), while maintaining the temperature of the flask at 0°C. After the addition was complete the resulting solution
was stirred for additional half an hour at 0°C. The reaction mixture was worked up as above and concentrated. The crude product was purified by column chromatography on silica gel to furnish spiro trioxane 4bh (0.52 g, 82.6% yield) as a mixture of E and Z isomers.
The antimalarial activity of the test compounds was evaluated in rodent using multidrug resistant strain of Plasmodium yoelii Nigeriensis in Swiss mice. Random bred Swiss mice of either sex (20 ±2 gm) were inoculated intraperitoneally with lxlO5 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 24-96 mg/ kg/day. The treatment was administered in groundnut oil intramuscularly and orally 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 vehicle control group and the percent suppression of parasitaemia in treated groups was calculated.
For determining the curative dose of a compound the treated mice were observed till day 28. The dose at which no parasitaemia develop during the observation period has been reported as the curative dose. The antimalarial activity data is summarized in Table 2.
(Table removed)

Scheme 1 Reagents and reaction conditions (a) hv, 02, methylene blue, MeCN,

We claim
1. A spirol ,2,4-trioxane of general formula 4, wherein, Ar represents an aryl groups,
and R represents hydrogen or an alkyl group.
(Formula Removed)
2. The spiro 1,2,4-trioxane as in claim 1, wherein the aryl group is an unsubstiruted or substituted aromatic hydrocarbon, wherein the substituted aromatic hydrocarbon group is substituted with at least one substituent selected from the group consisting of a C1-C6 alkyl, a C3-C8 cycloalkyl, a C1-C6 alkoxy, a halogen and an aromatic hydrocarbon group.
3. The spiro 1,2,4-trioxane as in claim 1, wherein the aryl group is selected from the group consisting of phenyl, 4-biphenyl, 4-chlorophenyl, 4-methoxyphenyl, 4-methylphenyl, 4-cyclohexylphenyl, 1-naphthyl and 2-naphthyl.
4. The spiro trioxane as in claim 1, wherein the alkyl group is selected from the group consisting of methyl, ethyl and propyl.
5. The spiro 1,2,4-trioxanes as in claim 1, wherein the compounds are selected from the group consisting of
Structure 4aa-4ah
(Structure Removed)
4aa=[3-(l-Phenyl-vinyl)-l,2,5-trioxa-spiro[5.5]undec-9-ylidene]-acetic acid ethyl ester, 4ab=[3-(1-Biphenyl-4-yl-vinyl)-l,2,5-trioxa-spiro[5.5]undec-9-ylidene]-ac- etic acid ethyl ester, 4ac={3-[l-(4-Chloro-phenyl)-vinyl]-l ,2,5-trioxa-spiro[5.5]undec-9-ylidene- }-acetic acid ethyl ester, 4ad={3-[l-(4-Methoxy-phenyl)-vinyl]-l,2,5-trioxa-spiro[5.5]undec-9-yliden- e}-acetic acid ethyl ester, 4ae=[3-(l-p-Tolyl-vinyl)-1,2,5-trioxa-spiro[5.5]undec-9-ylidene]-acetic acid ethyl ester, 4af={3-[l-(4-Cyclohexyl-phenyl)-vinyl]-l,2,5-trioxa-spiro[5.5]undec-9-yli- dene}-acetic acid ethyl ester, 4ag=[3-(1 -Naphthalen-1 -yl-vinyl)-1,2,5-trioxa-spiro[5.5]undec-9-ylidene]~ acetic acid ethyl ester, and 4ah=[3-(l-Naphthalen-2-yl-vinyl)-l,2,5-trioxa-spiro[5.5]undec-9-ylidene]— acetic acid ethyl ester.
6. The spiro 1,2,4-trioxanes as claimed in claim 1, wherein the compounds are selected
from the group consisting of structural formulas 4ba-4bh:
(Formula Removed)
4ba=2-[3-(l-Phenyl-vinyl)-l,2,5-trioxa-spiro[5.5]undec-9-ylidene]-propion- ic acid ethyl, 4bb=2-[3-(l-Biphenyl-4-yl-vinyl)-l,2,5-trioxa-spiro[5.5]undec-9- ylidene]-propionic acid ethyl ester, 4bc=2-{3-[l-(4-Chloro-phenyl)-vinyl]-l,2,5-trioxa-spiro[5.5]undec-9-ylide~ ne}-propionic acid ethyl ester, 4bd=2-{3-[l-(4-Methoxy-phenyl)-vinyl]-l,2,5-trioxa-spiro[5.5]undec-9-ylid- ene}-propionic acid ethyl ester, 4be=2-[3-(l-p-Tolyl-vinyl)-l,2,5-trioxa-spiro[5.5]undec-9-ylidene]-propio- nic acid ethyl ester, 4bf=2-{3-[l-(4-Cyclohexyl-phenyl)-vinyl]-l,2,5-trioxa-spiro[5.5]undec-9-y- lidene}-propionic acid ethyl ester, 4bg=2-[3-(l-Naphthalen-l-yl-vinyl)-l,2,5-trioxa-spiro[5.5]undec-9-ylidene- ]-propionic acid ethyl ester, and 4bh=2-[3-(l-Naphthalen-2-yl-vinyl)-l,2,5-trioxa-spiro[5.5]undec-9-ylidene- ]-propionic acid ethyl ester.
7. The Spiro 1,2,4-trioxane as in claim 1, wherein the compound has the structural formula of 4ca:
8. A process for the preparation of a spiro 1,2,4-trioxane of general formula 4 comprising the steps of: a) photooxygenating of allylic alcohols of formula 1 in presence of a sensitizer and a light source which provides visible light, in an organic solvent at temperature ranging from -10 C to 0°C to obtain .beta.-hydroxyhydroperoxide of formula 2

(Formula Removed)
b) reacting beta.-hydroxyhydroperoxide of formula 2 in-situ with 1,4-
cyclohexanedione in the presence of an acid catalyst at temperature 0°C for 18 hrs to
obtain keto trioxanes of general formula 3,
(Formula Removed)
c) reacting the keto trioxanes of step (b) with triethylphosphonoacetate or substituted
triethylphosphonoacetate in the presence of a base in an organic solvent at a
temperature ranging from 0°C. to 50°C. to obtain spiro 1,2,4-trioxanes of formula 4,
(Formula Removed)
d) isolating and purifying by conventional methods to furnish a spiro 1,2,4-trioxane of
formula 4.
(Formula Removed)
9. The process as in claim 8, wherein the aryl group is an unsubstituted or substituted
aromatic hydrocarbon, wherein the substituted aromatic hydrocarbon group is
substituted with at least one substituent selected from the group consisting of a C1-C6
alkyl, a C3-C8 cycloalkyl, a C1-C6 alkoxy, a halogen and an aromatic hydrocarbon
group.
10. The process as in claim 8, wherein the aryl is selected from the group consisting of phenyl, 4-biphenyl, 4-chlorophenyl, 4-methoxyphenyl, and 4-methylphenyl.
11. The process as in claim 8, wherein the sensitizer is methylene blue.
12. The process as in claim 8, wherein the organic solvent in step (a) is selected from the group consisting of aprotic solvents.
13. The process as in claim 13, wherein the aprotic solvent is acetonitrile.
14. The process as in claim 9, wherein the substituted triethylphosphonoacetate is selected from the group consisting of triethylphosphono-2-propionate, and triethylphosphono-2-butyrate.
15. The process as in claim 9, wherein the base in step (c) is selected from sodium hydride, and n-butyl lithium.
16. The process as in claim 9, wherein the organic solvent used in step (c) is selected from the group consisting of tetrahydrofuran, dimethoxyethane, and diethyl ether.
17. The process as in claim 9, wherein the acid catalyst used in step (d) is hydrogen chloride.
18. The process as in claim 9, wherein the compound obtained is selected from the group consisting of the following compounds: 4aa=[3-(l-Phenyl-vinyl)-l,2,5-trioxa-spiro[5.5]undec-9-ylidene]-acetic acid ethyl-ester, 4ba=2-[3-(l-Phenyl-vinyl)-1,2,5-trioxa-spiro[5.5]undec-9-ylidene]- propionic acid ethyl ester, 4ca=2-[3-(l-Phenyl-vinyl)-l,2,5-trioxa-spiro[5.5]undec-9-ylidene]-butyric acid ethyl ester, 4ab=[3-(l-Biphenyl-4-yl-vinyl)-l,2,5-trioxa-spiro[5.5]undec-9-ylidene]-ac- etic acid ethyl ester, 4bb=2- [3 -(1 -Biphenyl-4-yl-vinyl)-1,2,5 -trioxa-spiro [5.5]undec-9-ylidene] — propionic acid ethyl ester, 4ac={3-[l-(4-Chloro-phenyl)-vinyl]-l,2,5-trioxa-spiro[5.5]undec-9-ylidene- }-acetic acid ethyl ester, 4bc=2-{3-[l-(4-Chloro-phenyl)-vinyl]-l,2,5-trioxa-spiro[5.5]undec-9-ylide- ne}-propionic acid ethyl ester, 4ad={3-[l-(4-Methoxy-phenyl)-vinyl]-l,2,5-trioxa-spiro[5.5]undec-9-yliden- e}-acetic acid ethyl ester, 4bd=2-{3-[l-(4-Methoxy-phenyl)-vinyl]-l,2,5-trioxa-spiro[5.5]undec-9-ylid- ene}-propionic acid ethyl ester, 4bd=[3-(l-p-Tolyl-vinyl)-l,2,5-trioxa-spiro[5.5]undec-9-ylidene]-acetic acid ethyl ester, 4be=2-[3-(l-p-Tolyl-vinyl)-l,2,5-trioxa-spiro[5.5]undec-9-ylidene]-propio- nic acid ethyl ester, 4af={3-[l-(4-Cyclohexyl-phenyl)-vinyl]-l,2,5-trioxa-spiro[5.5]undec-9-yli- dene}-acetic acid ethyl ester, 4af=2-{3-[l-(4-Cyclohexyl-phenyl)-vinyl]-l,2,5-trioxa-spiro[5.5]undec-9-y- lidene}-propionic acid ethyl ester, 4ag=[3-(l-Naphthalen-l-yl-vinyl)-l,2,5-trioxa-spiro[5.5]undec-9-ylidene]~ acetic acid ethyl ester, 4ag=2-[3-(l-Naphthalen-l-yl-vinyl)-l,2,5-trioxa-spiro[5.5]undec-9-ylidene- ]-propionic acid ethyl ester, 4ah=[3-(l-Naphthalen-2-yl-vinyl)-l,2,5-trioxa-spiro[5.5]undec-9-ylidene]- acetic acid ethyl ester, and 4bh=2-[3-(l-Naphthalen-2-yl-vinyl)-l,2,5-trioxa-spiro[5.5]undec-9-ylidene- ]-propionic acid ethyl ester.

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Patent Number

256987

Indian Patent Application Number

3516/DEL/2005

PG Journal Number

34/2013

Publication Date

23-Aug-2013

Grant Date

22-Aug-2013

Date of Filing

30-Dec-2005

Name of Patentee

COUNCIL OF SCIENTIFIC & INDUSTRIAL RESEARCH

Applicant Address

ANUSANDHAN BHWAN, RAFI MARG, NEW DELHI-110 001, INDIA.

Inventors:

#	Inventor's Name	Inventor's Address
1	SINGH, CHANDAN	CENTRAL DRUG RESEARCH INSTITUTE CHATTAR MANZIL PLACE, POST BOX NO. 173, LUCKNOW 226 001, INDIA.
2	PURI SUNIL KUMAR	CENTRAL DRUG RESEARCH INSTITUTE CHATTAR MANZIL PLACE, POST BOX NO. 173, LUCKNOW 226 001, INDIA.
3	MALIK, HEETIKA	CENTRAL DRUG RESEARCH INSTITUTE CHATTAR MANZIL PLACE, POST BOX NO. 173, LUCKNOW 226 001, INDIA.

PCT International Classification Number

C07D 323/00

PCT International Application Number

N/A

PCT International Filing date

PCT Conventions:

#	PCT Application Number	Date of Convention	Priority Country
1			NA