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WO2008038299A1 - Substituted 6-(1-aryl ethyl)-i, 2, 4-trioxanes - Google Patents

Substituted 6-(1-aryl ethyl)-i, 2, 4-trioxanes Download PDF

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WO2008038299A1
WO2008038299A1 PCT/IN2007/000375 IN2007000375W WO2008038299A1 WO 2008038299 A1 WO2008038299 A1 WO 2008038299A1 IN 2007000375 W IN2007000375 W IN 2007000375W WO 2008038299 A1 WO2008038299 A1 WO 2008038299A1
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phenyl
napthyl
trioxanes
formula
substituted
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Chandan Singh
Ajit Shankar Singh
Sunil Kumar Puri
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Council of Scientific and Industrial Research CSIR
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D323/00—Heterocyclic compounds containing more than two oxygen atoms as the only ring hetero atoms
    • C07D323/04—Six-membered rings
    • C07D323/06—Trioxane
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P33/00—Antiparasitic agents
    • A61P33/02—Antiprotozoals, e.g. for leishmaniasis, trichomoniasis, toxoplasmosis
    • A61P33/06—Antimalarials
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D323/00—Heterocyclic compounds containing more than two oxygen atoms as the only ring hetero atoms
    • C07D323/04—Six-membered rings
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • This present invention relates to substituted I 5 2, 4-trioxanes useful as antimalarial agents having general formula 2.
  • This invention also relates to a process for the preparation of these novel substituted 1, 2, A- trioxanes.
  • This invention particularly relates to a process for the preparation of 6-(l-aryl ethyl)-l, 2, A- trioxanes, as a new series of antimalarial agents. More particularly the present invention provides a process for the preparation of 1,2,4-trioxanes of general formula 2 wherein Ar represents the aryl groups like phenyl , j?Me-phenyl, pCl-phenyl 5 /MeO- phenyl, pF-phenyl, biphenyl, 2- napthyl, />-Br-phenyl,l-napthyl, /p-Cyclohexyl-phenyl, 2-Flurenyl, whereas R 1 and R 2 represent the part of.
  • trioxanes are new compounds and are useful as antimalarial agents. Some of these compounds have been tested against multi-drug resistant malaria in mice and have shown promising antimalarial activity.
  • the invention thus relates to pharmaceutical industry.
  • Malaria is still one of the world's most deadly disease that threatens nearly 40% of the world's population and infects approximately 300 to 500 million people annually world wide mainly in tropical and subtropical areas. It is estimated that there are between 1 million to 3 million deaths every year due to malaria. In Africa alone, more than 1 million children under the age of 5 die from malaria each year.
  • Malaria is a parasite borne disease and human infection is caused by four distinct species of the protozoon Plasmodium, namely P. vivax, P. falciparum, P. ovale, P. malariae. Malaria is transmitted by bite of a vector the female Anopheles mosquito which is responsible for its global epidemics.
  • artemisinin a sesquiterpene lactone endoperoxide, isolated from Chinese traditional medicinal herb Artemisia annua and its semisynthetic derivatives like arteether and artemether have shown tremendous potential and are presently the drugs of choice for the treatment of multidrug resistant malaria. These drugs are effective against both chloroquine sensitive and chloroquine resistant strains of Plasmodium falciparum, [For reviews and background knowledge of artemisinin and its semisynthetic derivatives see: (a) Klayman, D. L Science 1985, 228, 1049. (b) Bhattacharya, A. K.; Sharma, R. P. Heterocycles 1999, 51, 1651.
  • Singh C; Misra, D.; Saxena, G.; Chandra, S. Bioorg. Med. Chem. Lett. 1992, 2, 497.
  • Singh C; Misra, D.; Saxena, G.; Chandra, S. Bioorg. Med. Chem. Lett. 1995, 5, 1913.
  • Singh C; Puri S. K. U.S. Patent 6316493B 1,2001.
  • Singh C; Gupta, N.; Puri, S. K. Bioorg. Med. Chem. Lett. 2003, 13, 3447.
  • Singh C; Malik, H.; Puri, S. K. Bioorg. Med. Chem. Lett.
  • Singh C; Srivastav,N.C; Puri, S. K. Bioorg. Med. Chem. Lett. 2004, 12, 5745-5752.
  • Singh C; Tiwari, P.; Puri, S. K.
  • the present invention deals with the preparation of a novel series of 1,2,4-trioxanes, some of which have shown high order of antimalarial activity against multidrug resistant strain, Plasmodium yoelii in mice.
  • This present invention relates to novel substituted 1, 2, 4-trioxanes useful as antimalarial agents having general formula 2.
  • This invention also relates to a process for the preparation of these novel substituted 1, 2, 4-trioxanes.
  • This invention particularly relates to a process for the preparation of 6-(l-aryl ethyl)-l, 2, 4- trioxanes, as a new series of antimalarial agents.
  • the present invention provides a process for the preparation of 1,2,4-trioxanes of general formula 2 wherein Ar represents the aryl groups like phenyl, pMe-phenyl, joCl-phenyl, pMeO- phenyl, pF-phenyl, biphenyl, 2-napthyl, />-Br-phenyl,l-napthyl, p-Cyclohexyl-phenyl, 2-Flurenyl and the like, whereas R 1 and R 2 represent the part of cyclic ring system like cyclohexane, cyclopentane and adamantane and the like.
  • These trioxanes are new compounds and are useful as antimalarial agents. Some of these compounds have been tested against multi-drug resistant malaria in mice and have shown high order of antimalarial activity.
  • trioxanes thus have the potential to be used for the treatment of malaria, a highly prevalent parasitic disease.
  • the invention thus relates to pharmaceutical industry.
  • trioxanes of the general formula 2 are new chemical entities and they have not been prepared earlier.
  • the main objective of the present invention is to provide novel substituted 1, 2, 4-trioxanes of formula 2 and a process for the preparation of these novel substituted 1, 2, 4-trioxanes of general formula 2, a new series of antimalarial agents.
  • the present invention provides substituted 1, 2, 4-trioxanes of general formula 2 , and their isomers of formula 3 and 4
  • Ar is selected from the group comprising of phenyl , />Me-phenyl, />Cl-phenyl, £>MeO- phenyl,£>F -phenyl, biphenyl, 2-napmyl,/>-Br-phenyl,l-napthyl,£>-Cyclohexyl-phenyl, 2-Flurenyl, wherein R 1 and R 2 represent the part of cyclic ring system like cyclohexane, cyclopentane and adamantane.
  • the diastereoisomers of compound of formula 2 is represented by structural formula 3 and 4 as shown below, wherein Ar is selected from the group consisting of phenyl , pMe-phenyl, ⁇ pCl-phenyl, />MeO- phenyl, />F-phenyl, biphenyl, 2-napthyl, ⁇ -Br-phenylJ-napthyl j p-Cyclohexyl-phenyl, 2-Flurenyl, whereas R 1 and R 2 represent the part of cyclic ring system like cyclohexane, cyclopentane and adamantane.
  • Ar is selected from the group consisting of phenyl , pMe-phenyl, ⁇ pCl-phenyl, />MeO- phenyl, />F-phenyl, biphenyl, 2-napthyl, ⁇ -Br-pheny
  • the dose of test compounds is ranging between 12- 96 mg/kg/day.
  • the compounds are administered as solutions in oil via oral route for 4 consecutive days (day 0-3).
  • the present invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising an effective amount of the compound of formula 2, and their isomers of formula 3 and 4.
  • Ar is selected from the group comprising of phenyl , />Me-phenyl, /?Cl-phenyl, /MeO- phenyl, pF-phenyl, biphenyl, 2-napthyl, /i-Br-phenylJ-napthyl, p-Cyclohexyl-phenyl, 2- Flurenyl, whereas R 1 and R 2 represent the part of cyclic ring system like cyclohexane, cyclopentane and adamantine optionally along with pharmaceutically acceptable diluents.
  • the isomer of the formula 2 is selected from the compound of general formula 3 or 4.
  • test compounds are administered at different dose levels ranging between 12-96 mg/kg/day.
  • composition is administered through oral route for 4 consecutive days (day 0-3).
  • diluent is selected from the group of oils such as groundnut oil, olive oil, or any edible oil. Accordingly the present invention provides a method of treating the subject suffering from malaria, the said method comprising; administering the effective amount of composition to the subject in need wherein the composition comprises; an effective amount of the compound of formula 2, and their isomers of formula 3 and 4;
  • Ar is selected from the group comprising of phenyl , />Me-phenyl, />Cl-phenyl, pMsO- phenyl, />F-phenyl, biphenyl, 2-napthyl, p-Br-phenyl,l-napthyl, j?-Cyclohexyl-phenyl, 2- Flurenyl, whereas R 1 and R 2 represent the part of cyclic ring system like cyclohexane, cyclopentane and adamantane optionally along with pharmaceutically acceptable additives, carriers, diluents.
  • the route of administration may be oral, im or intraperitoneal.
  • the dose of the composition is ranging between 12 to 96 mg/kg.
  • percent suppression of parasitaemia is up to 100% on day 4 of administration of the composition.
  • the subject is selected from animals including human.
  • the present invention provides a process for the preparation of novel substituted 1,2,4-trioxanes of formula 2 and their isomers of general formula 3 and 4; wherein Ar is selected from the group consisting of phenyl , j?Me-phenyl, _pCl-phenyl, pMeO- phenyl, /?F-phenyl, biphenyl, 2-napthyl, p-Br-phenyl, l-napthyl,/>-Cyclohexyl-phenyl, 2-Flurenyl,
  • R 1 and R 2 represents the part of cyclic ring system like cyclohexane, cyclopentane and adamantane, which comprises reaction of 6-(l-aryl vinyl)- 1, 2, 4-trioxanes of formula 1
  • Ar is selected from the group consisting of phenyl , />Me-phenyl, j?Cl-phenyl, pMeO- phenyl, pF '-phenyl, biphenyl, 2-napthyl, />-Br-phenyl, 1-napthyl, p-Cyclohexyl-phenyl, 2- Flurenyl whereas R 1 and R 2 represent the part of cyclic ring system like cyclohexane, cyclopentane and adamantane, with diimide, generated in situ, by reacting H 2 O 2 with N 2 H 4 -H 2 O or CO 2 neutralized N 2 H 4 -H 2 O in a water miscible organic solvent at a temperature ranging between O 0 C to room temperature for a period ranging between 2 to 29 days, to furnish trioxanes of formula 2 as a mixture of diastereomers, separating the diastereomers by chromatid
  • the water miscible organic solvent is selected from a group consisting of tetrahydrofuran, ethyl alcohol, methyl alcohol, CH 3 CN or a mixture thereof,
  • the chromatography to separate the compounds of formula 3 and 4 is carried out using solvent selected from EtOAc: Hexane.
  • the chromatography is carried out on silica gel.
  • the invention provides a process for the preparation of novel substituted 1, 2, 4-trioxanes of general formula 2 which comprises the reduction of the 6- (1-aryl vinyl)- 1, 2, 4-trioxanes of formula 1 with diimide, generated in situ, by the reaction of H 2 O 2 with N 2 H 4 -H 2 O or CO 2 neutralized N 2 H 4 -H 2 O in a water miscible organic solvent such as tetrahydrofuran, ethyl alcohol, methyl alcohol, CH 3 CN or a mixture of these solvents at a temperature range of O 0 C to room temperature to furnish trioxanes of formula 2 as a mixture of diastereomers, separation of the diastereomers by chromatography to give pure isomers of the formula 3 and 4 wherein Ar, R 1 and R 2 have the same meaning as above.
  • a water miscible organic solvent such as tetrahydrofuran, ethyl alcohol, methyl alcohol, CH 3 CN or a mixture of these solvents at a
  • trioxanes of the formula 1 are reduced with diimide.generated by the reaction of hydrogen peroxide and hydrazine hydrate in a water miscible organic solvent such as THF, ethanol, methanol, CH 3 CN or a mixture of these solvents at ambient temperature to furnish a mixture of diastereomers of the formula 2. Separation of the isomers by chromatography gave pure isomers of formula 3 and 4 where in Ar, R 1 and R 2 have the same meanings as stated above.
  • trioxanes having general formula 3 and 4 are new chemical entities and have not been prepared earlier.
  • trioxanes of formula 3 and 4 have been tested against malarial parasite in mice and have shown promising antimalarial activity.
  • TRIOXANE 2a7 FORMULA 2a, Ar 2-NapthyI-
  • reaction mixture was evaporated on a rota- vapour and then diluted with water (20 ml) and then extracted with ether (3x100 ml ).
  • the ethereal layer was neutralized with 10% HCl (20 ml) and washed with saturated NaHCCb and brine solution and evaporated on a rota-vapour and the crude product was purified by column chromatography on silica gel using 1.0% EtOAc: Hexane as eluant to yield 1.95g of compound 2alO as a mixture of diastereomers (97.01 % yield) in approx.
  • reaction mixture was evaporated on a rotavapour and then diluted with water (40 ml) and extracted with ether (3x100 ml).
  • the ethereal layer was neutralized with 10% HCl (20 ml) and washed with saturated NaHCO 3 and brine solution and evaporated on a rotavapour and the crude product was purified by column chromatography on silica gel using 1.0% EtOAc: Hexane as eluant to yield 636 mg of compound 2b2 as a mixture of diastereomers (31.56 % yield) in approx.
  • reaction mixture was evaporated on a rotavapour and then diluted with water (40 ml) and extracted with ether (3x100 ml).
  • the ethereal layer was neutralized with 10% HCl (20 ml) and washed with saturated NaHCO 3 and brine solution and evaporated on a rotavapour and the crude product was purified by column chromatography on silica gel using 1.0% EtOAc: Hexane as eluant to yield 1.040 gm of compound 2b3 as a mixture of diastereomers (51.63 % yield) in approx.
  • reaction mixture was evaporated on a rotavapour and then diluted with water (40 ml) and extracted with ether (3x100 ml).
  • the ethereal layer was neutralized with 10% HCl (20 ml) and washed with saturated NaHCU 3 and brine solution and evaporated on a rotavapour and the crude product was purified by column chromatography on silica gel using 1.0% EtOAc: Hexane as eluant to yield 1.34 gm of compound 2b4 as a mixture of diastereomers (66.5 % yield) in approx.
  • reaction mixture was evaporated on a rotavapour and then diluted with water (40 ml) and extracted with ether (3x100 ml).
  • the ethereal layer was neutralized with of 10% HCl (20 ml) and washed with saturated NaHCO 3 and brine solution and evaporated on a rotavapour and the crude product was purified by column chromatography on silica gel using 1.0% EtOAc: Hexane as eluant to yield 1.29 gm of compound 2b5 as a mixture of diastereomers (64.04 % yield) in approx.
  • reaction mixture was evaporated on a rotavapour and then diluted with water (20 ml) and extracted with ether (3x50 ml).
  • the ethereal layer was neutralized with 10% HCl (20 ml) and washed with saturated NaHCO 3 and brine solution and evaporated on a rotavapour and the crude product was purified by column chromatography on silica gel using 1.0% EtOAc: Hexane as eluant to yield 437 mg of compound 2b6 as a mixture of diastereomers (43.44 % yield) in approx.
  • reaction mixture was evaporated on a rotavapour and then diluted with water (40 ml) and extracted with ether (3x100 ml).
  • the ethereal layer was neutralized with 10% HCl (20 ml) and washed with saturated NaHCO 3 and brine solution and evaporated on a rotavapour and the crude product was purified by column chromatography on silica gel using 1.0% EtOAc: Hexane as eluant to yield 1.310 gm of compound 2b7 as a mixture of diastereomers (65.06% yield) in approx.
  • reaction mixture was evaporated on a rotavapour and then diluted with water (40 ml) and extracted with ether (3x100 ml).
  • the ethereal layer was neutralized with 10% HCl (20 ml) and washed with saturated NaHCO 3 and brine solution and evaporated on a rotavapour and the crude product was purified by column chromatography on silica gel using 1.0% EtOAc: Hexane as eluant to yield 1.174 gm of compound 2cl as a mixture of diastereomers (58.25 % yield) in approx.
  • reaction mixture was evaporated on a rotavapour and then diluted with water (40 ml) and extracted with ether (3x100 ml).
  • the ethereal layer was neutralized with of 10% HCl (20 ml) and washed with saturated NaHCO 3 and brine solution and evaporated on a rotavapour and the crude product was purified by column chromatography on silica gel using 1.0% EtOAc: Hexane as eluant to yield 1.790 gm of compound 2c2 as a mixture of diasteriomers (88.80 % yield) in approx.
  • reaction mixture was evaporated on a rotavapour and then diluted with water (40 ml) and extracted with ether (3x100ml).
  • the ethereal layer was neutralized with 10% HCl (20 ml) and washed with saturated NaHCO 3 and brine solution and evaporated on a rotavapour and the crude product was purified by column chromatography on silica gel using 1.0% EtOAc: Hexane as eluant to yield 1.50 gm of compound 2c3 as a mixture of diasteriomers (74.49 % yield) in approx.
  • reaction mixture was evaporated on a rotavapour and then diluted with water (40 ml) and extracted with ether (3x100 ml).
  • the ethereal layer was neutralized with 10% HCl (20 ml ) and washed with saturated NaHCO 3 and brine solution and evaporated on a rotavapour and the crude product was purified by column chromatography on silica gel using 1.0% EtOAc: Hexane as eluant to yield 1.395 gm of compound 2c4 as a mixture of diasteriomers (69.25 % yield) in approx.
  • reaction mixture was evaporated on a rotavapour and then diluted with water (40 ml) and extracted with ether (3x100 ml).
  • the ethereal layer was neutralized with 10% HCl (20 ml) and washed with saturated NaHCO 3 and brine solution and evaporated on a rotavapour and the crude product was purified by column chromatography on silica gel using 1.0% EtOAc: Hexane as eluant to yield 1.82 gm of compound 2c5 as a mixture of diasteriomers (90.38 % yield) in approx.
  • reaction mixture was evaporated on a rotavapour and then diluted with water (40 ml) and extracted with ether (3x100 ml).
  • the ethereal layer was neutralized with 10% HCl (20 ml) and washed with saturated NaHCO 3 and brine solution and evaporated on a rotavapour and the crude product was purified by column chromatography on silica gel using 1.0% EtOAc: Hexane as eluant to yield 1.750 gm of compound 2c6 as a mixture of diastereomers (86.98 % yield) in approx.
  • reaction mixture was evaporated on a rotavapour and then diluted with water (40 ml) and extracted with ether (3x100 ml).
  • the ethereal layer was neutralized with of 10% HCl (20 ml) and washed with saturated NaHCO 3 and brine solution and evaporated on a rotavapour and the crude product was purified by column chromatography on silica gel using 1.0% EtOAc: Hexane as eluant to yield 1.745 gm of compound 2c7 as a mixture of diasteriomers (86.686 % yield) in approx.
  • the antimalarial activity of the test compounds was evaluated against multidrug resistant strain of Plasmodium yoelii nigeriensis in Swiss mice.
  • Random bred Swiss mice of either sex (20 + 2 g) were inoculated intraperitoneally with 1x10 5 P. yoelii (MDR) parasites on day zero.
  • the treatments with test compounds were administered to group of 5 mice each at different dose levels ranging between 12-96 mg/kg/day.
  • the compounds were administered as solutions in oil via oral route for 4 consecutive days (day 0-3).
  • ⁇ -Arteether and ⁇ -Arteether were used as positive control.
  • the drug dilutions of compounds were prepared in ground oil and administered to a group of mice at each dose via oral route, from day 0-3 in two divided doses daily.
  • trioxanes of the present invention having formula 3al, 3a2, 3a3, 3a4, 3a5 and several others are active at a lower dose (12 to 48mg/kg) as compared to their parent counterpart trioxanes which are known compounds having formula IaI, Ia2, Ia3, Ia4, Ia5 are not even active at 96mg/kg dose.

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Abstract

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

Description

"SUBSTITUTED 6-(1-ARYL ETHYL)-I5 2, 4-TRIOXANES"
FIELD OF INVENTION
This present invention relates to substituted I5 2, 4-trioxanes useful as antimalarial agents having general formula 2.
Figure imgf000002_0001
This invention also relates to a process for the preparation of these novel substituted 1, 2, A- trioxanes.
This invention particularly relates to a process for the preparation of 6-(l-aryl ethyl)-l, 2, A- trioxanes, as a new series of antimalarial agents. More particularly the present invention provides a process for the preparation of 1,2,4-trioxanes of general formula 2 wherein Ar represents the aryl groups like phenyl , j?Me-phenyl, pCl-phenyl5 /MeO- phenyl, pF-phenyl, biphenyl, 2- napthyl, />-Br-phenyl,l-napthyl, /p-Cyclohexyl-phenyl, 2-Flurenyl, whereas R1 and R2 represent the part of. cyclic ring system like cyclohexane, cyclopentane and adamantane. These trioxanes are new compounds and are useful as antimalarial agents. Some of these compounds have been tested against multi-drug resistant malaria in mice and have shown promising antimalarial activity. The invention, thus relates to pharmaceutical industry.
BACKGROUND OF INVENTION Malaria is still one of the world's most deadly disease that threatens nearly 40% of the world's population and infects approximately 300 to 500 million people annually world wide mainly in tropical and subtropical areas. It is estimated that there are between 1 million to 3 million deaths every year due to malaria. In Africa alone, more than 1 million children under the age of 5 die from malaria each year.
Malaria is a parasite borne disease and human infection is caused by four distinct species of the protozoon Plasmodium, namely P. vivax, P. falciparum, P. ovale, P. malariae. Malaria is transmitted by bite of a vector the female Anopheles mosquito which is responsible for its global epidemics.
Quite a number of natural products isolated from various plants and micro-organisms have shown potent antimalarial activity, thus acting as lead for further drug development. Natural products as lead for malaria chemotherapy dates back to the early 18th century when bark of Cinchona tree was used in the treatment of fever by the natives of South America. It was in 1820 that quinine was isolated as active principle of the bark. Quinine is active against the trophozoites present in the erythrocytes but has no effect on exo-erythrocytic stages that develop in lever. Later on taking quinine as lead several synthetic analogues like chloroquine, mefloquin, primaquine etc, were developed as antimalarial drugs and are still being used.
Unfortunately due to indiscriminate use of chloroquine and its analogues the parasite developed resistance towards these drugs. Indeed the re-emergence of the malaria as a world wide epidemic can be largely attributed due to rapid development of parasite resistance towards conventional drugs. Thus there is an urgent need to develop new drugs which are novel both in terms of mechanism of action and pharmacophore.
In that regard, discovery of artemisinin, a sesquiterpene lactone endoperoxide, isolated from Chinese traditional medicinal herb Artemisia annua and its semisynthetic derivatives like arteether and artemether have shown tremendous potential and are presently the drugs of choice for the treatment of multidrug resistant malaria. These drugs are effective against both chloroquine sensitive and chloroquine resistant strains of Plasmodium falciparum, [For reviews and background knowledge of artemisinin and its semisynthetic derivatives see: (a) Klayman, D. L Science 1985, 228, 1049. (b) Bhattacharya, A. K.; Sharma, R. P. Heterocycles 1999, 51, 1651. (c) Borstnik, K.; Paik, L; Shapiro, T. A.; Posner, G. H. Int. J. Parasitol. 2002, 32, 1661. (d) Ploypradith, P. Acta Trap. 2004, 89, 329. (e) O'Neill, P. M.; Posner, G. H. J. Med. Chem. 2004, 47, 2945.]
Figure imgf000003_0001
Figure imgf000003_0002
Primaquine
Figure imgf000004_0001
Artemisinin
Figure imgf000004_0002
er
The limited availability of artemisinin from the natural sources and taking into account of the fact, that it is actually the endoperoxide linkage in the form of 1,2,4- trioxane ring system which is responsible for its antimalarial activity, has led to the present efforts to develop new structurally simple trioxanes which are easily accessible, relatively cheap and active against multidrug resistant strains. Several structurally simple synthetic trioxanes have shown promising antimalarial activity [(a) Bhattacharya,A K.,Sharma,i?.P.; Hetrocycles.1999 57,1681. (b) Borstnik, K.; Paik, L; Shapiro, T.A.; Posner, G. H. Int. J. Parasitol. 2002, 32, 1661. (c) Singh, C; Misra, D.; Saxena, G.; Chandra, S. Bioorg. Med. Chem. Lett. 1992, 2, 497. (d) Singh, C; Misra, D.; Saxena, G.; Chandra, S. Bioorg. Med. Chem. Lett. 1995, 5, 1913. (e) Singh, C; Puri S. K. U.S. Patent 6316493B 1,2001. (f) Singh, C; Gupta, N.; Puri, S. K. Bioorg. Med. Chem. Lett. 2003, 13, 3447. (g) Singh, C; Malik, H.; Puri, S. K. Bioorg. Med. Chem. Lett. 2004, 14, 459. (h) Singh, C; Srivastav,N.C; Puri, S. K. Bioorg. Med. Chem. Lett. 2004, 12, 5745-5752. (i) Singh, C; Tiwari, P.; Puri, S. K.
PCT Patent application No. PCT/IN02/00093, dated 28.3.2002. (J) Singh, C; Malik, H.; Puri, S. K. Patent application No. PCT/IN04/00413, dated 27.12.04. (k) Singh, C; Malik, H.; Puri, S. K.: J. Med. Chem., 2006. 49 (9), 2794 -2803].
Figure imgf000004_0003
The present invention deals with the preparation of a novel series of 1,2,4-trioxanes, some of which have shown high order of antimalarial activity against multidrug resistant strain, Plasmodium yoelii in mice.
SUMMARY OF THE PRESENT INVENTION
This present invention relates to novel substituted 1, 2, 4-trioxanes useful as antimalarial agents having general formula 2. This invention also relates to a process for the preparation of these novel substituted 1, 2, 4-trioxanes. This invention particularly relates to a process for the preparation of 6-(l-aryl ethyl)-l, 2, 4- trioxanes, as a new series of antimalarial agents. More particularly, the present invention provides a process for the preparation of 1,2,4-trioxanes of general formula 2 wherein Ar represents the aryl groups like phenyl, pMe-phenyl, joCl-phenyl, pMeO- phenyl, pF-phenyl, biphenyl, 2-napthyl, />-Br-phenyl,l-napthyl, p-Cyclohexyl-phenyl, 2-Flurenyl and the like, whereas R1 and R2 represent the part of cyclic ring system like cyclohexane, cyclopentane and adamantane and the like. These trioxanes are new compounds and are useful as antimalarial agents. Some of these compounds have been tested against multi-drug resistant malaria in mice and have shown high order of antimalarial activity.
These trioxanes thus have the potential to be used for the treatment of malaria, a highly prevalent parasitic disease. The invention, thus relates to pharmaceutical industry.
These trioxanes of the general formula 2 are new chemical entities and they have not been prepared earlier.
The main objective of the present invention is to provide novel substituted 1, 2, 4-trioxanes of formula 2 and a process for the preparation of these novel substituted 1, 2, 4-trioxanes of general formula 2, a new series of antimalarial agents.
DETAILED DESCRIPTION OF THE INVENTION
Accordingly, the present invention provides substituted 1, 2, 4-trioxanes of general formula 2 , and their isomers of formula 3 and 4
Figure imgf000005_0001
wherein Ar is selected from the group comprising of phenyl , />Me-phenyl, />Cl-phenyl, £>MeO- phenyl,£>F -phenyl, biphenyl, 2-napmyl,/>-Br-phenyl,l-napthyl,£>-Cyclohexyl-phenyl, 2-Flurenyl, wherein R1 and R2 represent the part of cyclic ring system like cyclohexane, cyclopentane and adamantane.
In one of the embodiment of the invention wherein the representative compounds of general formula 2a, being defined as follows;
Figure imgf000006_0001
2a1 Ar=C6H5- 2a7 Ar=2-Napthyl-
2a2 Ar=PMe-C6H4- 2a8 Ar=P-Br-C6H4-
2a3 Ar=pCI-C6H4- 2a9 Ar=1-Napthyl-
2a4 Ar=PF-C6H4- 2a10 Ar=p-Cyclohexyl-phenyl-
2a5 Ar=pMeO-C6H4- 2a11 Ar=2-Flurenyl-
2a6 Ar=pPh-C6H4-
In another embodiment of the invention wherein the representative compounds of general formula 2b, being defined as follows;
Figure imgf000006_0002
2b1 Ar=C6H5- 2b5 Ar=pMeO-C6H4- 2b2 Ar=PMe-C6H4- 2b6 Ar=pPri-C6H4- 2b3 Ar=PCI-C6H4- 2b7 Ar=2-Napthyl- 2b4 Ar=pF-C6H4-
In yet another embodiment of the invention wherein the representative compounds of general formula 2c, being defined as follows;
Figure imgf000007_0001
2c
2c1 Ar=C6H5- 2c5 Ar=pMeO-C6H4
2c2 Ar=PMe-C6H4- 2c6 Ar=PPh-C6H4-
2c3 Ar=PCI-C6H4- 2c7 Ar=2-Napthyl-
2c4 Ar=PF-C6H4-
In a further embodiment of the invention, the diastereoisomers of compound of formula 2 is represented by structural formula 3 and 4 as shown below, wherein Ar is selected from the group consisting of phenyl , pMe-phenyl, ^pCl-phenyl, />MeO- phenyl, />F-phenyl, biphenyl, 2-napthyl, ^-Br-phenylJ-napthyljp-Cyclohexyl-phenyl, 2-Flurenyl, whereas R1 and R2 represent the part of cyclic ring system like cyclohexane, cyclopentane and adamantane.
Figure imgf000007_0002
In still another embodiment of the invention wherein the representative compounds of general formula 3a, being defined as follows;
Figure imgf000007_0003
3a
3a1 Ar=C6H5- 3a7 Ar=2-Napthyl-
3a2Ar=PMe-C6H4- 3a8 Ar=P-Br-C6H4-
3a3 Ar=PCl-C6H4- 3a9 Ar=1-Napthyl-
3a4Ar=PF-C6H4- 3a10 Ar=p-Cyclohexyl-phenyl-
3a5 Ar=PMeO-C6H4- 3a11 Ar=2-Flurenyl-
3a6 Ar=pPh-C6H4- In yet another embodiment of the invention wherein the representative compounds of general formula 4al-4all, being defined as follows;
Figure imgf000008_0001
4a1 Ar=C6H5- 4a7 Ar=2-Napthyl- 4a2 Ar=pMe-C6H4- 4a8 Ar=P-Br-C6H4- 4a3 Ar=PCI-C6H4- 4a9 Ar=1-Napthyl- 4a4Ar=PF-C6H4- 4a10 Ar=p-Cyclohexyl-phenyl- 4a5 Ar=PMeO-C6H4- 4a11 Ar=2-Flurenyl- 4a6 Ar=pPh-C6H4-
In one of the embodiment of the invention wherein the representative compounds of general formula 3bl-3b7 being defined as follows;
Figure imgf000008_0002
3b1 Ar=C6H5- 3b5 Ar=pMeO-C6H4-
3b2 Ar=pMe-C6H4- 3b6 Ar=pPh-C6H4-
3b3 Ar=PCI-C6H4- 3b7 Ar=2-Napthyl- 3b4 Ar=p F-C6 H4-
In a further embodiment of the invention wherein the representative compounds of general formula 4bl-4b7 being defined as follows;
Figure imgf000009_0001
4b1 Ar=C6H5- 4b5 Ar=pMeO-C6H4-
4b2 Ar=PMe-C6H4- 4b6 Ar=pPh-C6H4- 4b3Ar=pCI-C6H4- 4b7 Ar=2-Napthyl-
4b4 Ar=PF-C6H4-
In still another embodiment of the invention wherein the representative compounds of general formula 3cl-3c7 being defined as follows;
Figure imgf000009_0002
3d Ar=C6H5- 3c5 Ar=pMeO-C6H4- 3c2 Ar=PMe-C6H4- 3c6 Ar=pPh-C6H4- 3c3 Ar=PCI-C6H4- 3c7 Ar=2-Napthyl 3c4 Ar=pF-C6H4-
In a further embodiment of the invention wherein the representative compounds of general formula 4cl-4c7 being defined as follows;
Figure imgf000009_0003
4c1 Ar=C6H5- 4c5 Ar=pMeO-C6H4- 4c2 Ar=PMe-C6H4- 4c6 Ar=pPh-C6H4- 4c3Ar=pCI-C6H4- 4c7 Ar=2-Napthyl- 4c4 Ar=pF-C6H4- In a further embodiment of the invention, the said compounds are useful for the treatment of malaria.
In still further embodiment of the invention, the dose of test compounds is ranging between 12- 96 mg/kg/day.
In one of the embodiment of the invention, the compounds are administered as solutions in oil via oral route for 4 consecutive days (day 0-3).
Accordingly the present invention relates to a pharmaceutical composition comprising an effective amount of the compound of formula 2, and their isomers of formula 3 and 4.
Figure imgf000010_0001
2 3 4 wherein Ar is selected from the group comprising of phenyl , />Me-phenyl, /?Cl-phenyl, /MeO- phenyl, pF-phenyl, biphenyl, 2-napthyl, /i-Br-phenylJ-napthyl, p-Cyclohexyl-phenyl, 2- Flurenyl, whereas R1 and R2 represent the part of cyclic ring system like cyclohexane, cyclopentane and adamantine optionally along with pharmaceutically acceptable diluents.
In yet another embodiment of the invention, the isomer of the formula 2 is selected from the compound of general formula 3 or 4.
Figure imgf000010_0002
In one of the embodiment of the invention, the test compounds are administered at different dose levels ranging between 12-96 mg/kg/day.
In another embodiment of the invention composition, the composition is administered through oral route for 4 consecutive days (day 0-3).
In yet another embodiment of the invention, diluent is selected from the group of oils such as groundnut oil, olive oil, or any edible oil. Accordingly the present invention provides a method of treating the subject suffering from malaria, the said method comprising; administering the effective amount of composition to the subject in need wherein the composition comprises; an effective amount of the compound of formula 2, and their isomers of formula 3 and 4;
Figure imgf000011_0001
2 3 4 wherein Ar is selected from the group comprising of phenyl , />Me-phenyl, />Cl-phenyl, pMsO- phenyl, />F-phenyl, biphenyl, 2-napthyl, p-Br-phenyl,l-napthyl, j?-Cyclohexyl-phenyl, 2- Flurenyl, whereas R1 and R2 represent the part of cyclic ring system like cyclohexane, cyclopentane and adamantane optionally along with pharmaceutically acceptable additives, carriers, diluents.
Ia one of the embodiment of the invention the route of administration may be oral, im or intraperitoneal.
In still another embodiment of the invention, the dose of the composition is ranging between 12 to 96 mg/kg.
In yet another embodiment of the invention, percent suppression of parasitaemia is up to 100% on day 4 of administration of the composition.
In one of the embodiment of the invention, the subject is selected from animals including human.
Accordingly the present invention provides a process for the preparation of novel substituted 1,2,4-trioxanes of formula 2 and their isomers of general formula 3 and 4; wherein Ar is selected from the group consisting of phenyl , j?Me-phenyl, _pCl-phenyl, pMeO- phenyl, /?F-phenyl, biphenyl, 2-napthyl, p-Br-phenyl, l-napthyl,/>-Cyclohexyl-phenyl, 2-Flurenyl,
Figure imgf000011_0002
wherein R1 and R2 represents the part of cyclic ring system like cyclohexane, cyclopentane and adamantane, which comprises reaction of 6-(l-aryl vinyl)- 1, 2, 4-trioxanes of formula 1
Figure imgf000012_0001
1 where in Ar is selected from the group consisting of phenyl , />Me-phenyl, j?Cl-phenyl, pMeO- phenyl, pF '-phenyl, biphenyl, 2-napthyl, />-Br-phenyl, 1-napthyl, p-Cyclohexyl-phenyl, 2- Flurenyl whereas R1 and R2 represent the part of cyclic ring system like cyclohexane, cyclopentane and adamantane, with diimide, generated in situ, by reacting H2O2 with N2H4-H2O or CO2 neutralized N2H4-H2O in a water miscible organic solvent at a temperature ranging between O0C to room temperature for a period ranging between 2 to 29 days, to furnish trioxanes of formula 2 as a mixture of diastereomers, separating the diastereomers by chromatography to give pure isomers of the formula 3 and 4 wherein Ar, R1 and R2 have the same meaning as above for compound of formula 2.
In one of the embodiment of the invention, the water miscible organic solvent is selected from a group consisting of tetrahydrofuran, ethyl alcohol, methyl alcohol, CH3CN or a mixture thereof, hi further embodiment of the invention, the chromatography to separate the compounds of formula 3 and 4 is carried out using solvent selected from EtOAc: Hexane.
hi one of the embodiment of the invention, the chromatography is carried out on silica gel.
In one of the feature of the invention, the invention provides a process for the preparation of novel substituted 1, 2, 4-trioxanes of general formula 2 which comprises the reduction of the 6- (1-aryl vinyl)- 1, 2, 4-trioxanes of formula 1 with diimide, generated in situ, by the reaction of H2O2 with N2H4-H2O or CO2 neutralized N2H4-H2O in a water miscible organic solvent such as tetrahydrofuran, ethyl alcohol, methyl alcohol, CH3CN or a mixture of these solvents at a temperature range of O 0C to room temperature to furnish trioxanes of formula 2 as a mixture of diastereomers, separation of the diastereomers by chromatography to give pure isomers of the formula 3 and 4 wherein Ar, R1 and R2 have the same meaning as above.
Figure imgf000012_0002
Figure imgf000013_0001
1a1 Ar=C6H5- 1b1 Ar=C6H5- . 1c1 Ar=C6H5- 1a2 Ar=PMe-C6H4- 1b2 Ar=PMe-C6H4- 1c2 Ar=pMe-C6H4- 1a3 Ar=PCI-C6H4- 1 b3 Ar=PCI-C6H4- 1c3 Ar=PCI-C6H4- 1a4 Ar=pF-C6H4- 1b4 Ar=PF-C6H4- 1c4 Ar=PF-C6H4- 1a5 Ar=PMeO-C6H4- 1b5 Ar=pMeO-C6H4- 1c5 Ar=PMeO-C6H4- 1a6 Ar=PPh-C6H4- 1b6 Ar=PPh-C6H4- 1c6 Ar=pPh-C6H4- 1a7 Ar=2-Napthyl- 1b7 Ar=2-Napthyl- 1c7 Ar=2-Napthyl- 1a8 Ar=P-Br-C6H4-
1a9 Ar=1-Napthyl-
1a10 Ar=p-Cyclohexyl-phenyl-
1a11 Ar=2-Flurenyl-
Trioxanes having formula 1
In the process the 6-Aryl vinyl substituted 1, 2, 4-trioxanes of the formula 1 were prepared by the known procedure [(a) Singh.C; Tetrahedron. Lett. 1990, 31, 6901. (b) Singh, C; Tiwari, P.; Puri, S. K. PCT Patent application No. PCT/IN02/00093, dated 28.3.2002. (c) Singh, C; Kanchan, R.; Chandra, S. and Puri, S.K. Indian patent application no. 0909/DEL/2003 dated 18/07/2003]. These trioxanes of formula 1 have been prepared earlier in our laboratory and are known compounds. In the process trioxanes of the formula 1 are reduced with diimide.generated by the reaction of hydrogen peroxide and hydrazine hydrate in a water miscible organic solvent such as THF, ethanol, methanol, CH3CN or a mixture of these solvents at ambient temperature to furnish a mixture of diastereomers of the formula 2. Separation of the isomers by chromatography gave pure isomers of formula 3 and 4 where in Ar, R1 and R2 have the same meanings as stated above.
Figure imgf000013_0002
These trioxanes having general formula 3 and 4 are new chemical entities and have not been prepared earlier.
Some of the trioxanes of formula 3 and 4 have been tested against malarial parasite in mice and have shown promising antimalarial activity.
The invention is further illustrated by the following examples which should not, however, be constructed to limit the scope of present invention.
EXAMPLE: - 1
TRIOXANE 2al, FORMULA 2a, Ar=C6H5-
To a stirred solution of unsaturated trioxane IaI (formula Ia, Ar=CeHs-) (1.00 gm, 3.205 mmol.) and N2H4-H2O (3.2 ml) in 1:1 mixture of EtOH/THF (50 ml), cooled to 0 0C, was added 30% H2O2 (10.9 ml) dropwise and the reaction mixture was kept at the same temperature for 3 days. The reaction mixture was evaporated on a rota-vapour and then diluted with water (20 ml) and extracted with ether (3x50 ml). The ethereal layer was neutralized with 10% HCl (20 ml) and washed with saturated NaHCO3 and brine solution and evaporated on a rota-vapour and the crude product was purified by column chromatography on silica gel using 1.0% EtOAc: Hexane as eluant to yield 440 mg of compound 2al as a mixture of diastereomers (43.7 % yield) in approx. 2:3 ratio which were separated by column chromatography using 0.1% EtOAc: Hexane as eluant to furnish the two isomers, 3al (higher Rf.) as oil and, 4al (lower Rf.) as white solid (m.p. 84-85 0C) respectively. The above reaction was also carried out using different solvents. (Table 1)
TABLE 1
Figure imgf000014_0001
EXAMPLE: - 2 TRIOXANE 2a2, FORMULA 2a, Ar=pMe-C6H4-
To a stirred solution of unsaturated trioxane Ia2 (formula Ia, Ar=JpMe-CeELr) (1.9 gm, 5.828 mmol) and N2H4-H2O (5.8 ml) in 1: 1 mixture of EtOHZTHF (100 ml), cooled to 0° C, was added 30% H2O2 (19.8 ml) dropwise and the reaction mixture was kept at same temp for 3 days. The reaction mixture was evaporated on a rota-vapour and then diluted with water (40 ml) and extracted with ether (3x100 ml). The ethereal layer was neutralized with 10% HCl (20 ml) and washed with saturated NaHCO3 and brine solution and evaporated on a rota-vapour and the crude product was purified by column chromatography on silica gel using 1.0% EtOAc: Hexane as eluant to yield 717 mg of compound 2a2 as a mixture of diastereomers (35.8 % yield) in approx. 2:3 ratio which were separated by column chromatography using 0.1% EtOAc: Hexane as eluant to furnish the two isomers, 3a2 (higher Rf) as oil and 4a2 (lowerRf) as white solid (m.p.74-76 0C) respectively.
EXAMPLE:- 3 TRIOXANE 2a3, FORMULA 2a, Ar =pCl-C6H4-
To a stirred solution of unsaturated trioxane Ia3 (formula Ia, Ar= pCl-CβΑr) (2.0 gm, 5.780 mmol) and N2H4-H2O (6ml) in 1:1 mixture of EtOH/THF (100 ml), cooled to 0° C, was added 30% H2O2 (20 ml) dropwise and the reaction mixture was kept at same temp for 2 days. The reaction mixture was evaporated on a rota-vapour and then diluted with water (40 ml) and then extracted with ether (3x100 ml). The ethereal layer was neutralized with 10% HCl (20 ml) and washed with saturated NaHCO3 and brine solution and evaporated on a rota-vapour and the crude product was purified by column chromatography on silica gel using 1.0% EtOAc: Hexane as eluant to yield 710 mg of compound 2a3 as a mixture of diastereomers (35.3 % yield) in approx. 2:3 ratio which were separated by column chromatography using 0.1% EtOAc: Hexane as eluant to furnish the two isomers 3a3 (higher Rf) as white solid (m.p. 92°-94° C) and 4a3 (lower Rf) as solid as well (m.p. 114°-115° C) respectively.
EXAMPLE:- 4 TRIOXANE 2a4, FORMULA 2a, Ar =pF-C6H4- To a stirred solution of unsaturated trioxane Ia4 (formula Ia, Ar= JsF-C6H4-) (2.00 gm, 6.060 mmol) and N2H4-H2O (6 ml) in 1: 1 mixture of EtOH/THF (100 ml), cooled to 0° C, was added 30% H2O2 (20 ml) dropwise and the reaction mixture was kept at same for 2 days. The reaction mixture was evaporated on a rota-vapour and then diluted with water (40 ml) and extracted with ether (3x100 ml). The ethereal layer was neutralized with 10% HCl (20 ml) and washed with saturated NaHCO3 and brine solution and evaporated on a rota-vapour and the crude product was purified by column chromatography on silica gel using 1.0% EtOAc: Hexane as eluant to yield 735 mg of compound 2a4 as a mixture of diastereomers (36.5 % yield) in approx. 2:3 ratio which were separated by column chromatography using 0.1% EtOAc: Hexane as eluant to furnish the two isomers 3a4 (higher Rf) as oil and 4a4 (lower Rf) as white solid (m.p. 80°-81° C) respectively. EXAMPLE: - 5 TRIOXANE 2a5, FORMULA 2a, Ar =pMeO-C6H4-
To a stirred solution of unsaturated trioxane Ia5 (formula Ia, Ar=^MeO-C6ELt-) (2.00 gm, 5.548 mmol) and N2H4-H2O (6ml) in 1:1 mixture of EtOH/THF (100 ml), cooled to 0° C, was added 30% H2O2 (20 ml) dropwise and the reaction mixture was kept at same temp for 2 days. The reaction mixture was evaporated on a rotavapour and then diluted with water (40 ml) and extracted with ether (3x100ml). The ethereal layer was neutralized with 10% HCl (20 ml) and washed with saturated NaHCO3 and brine solution and evaporated on a rotavapour and the crude product was purified by column chromatography on silica gel using 1.0% EtOAc: Hexane as eluant to yield 730 mg of compound 2a5 as a mixture of diastereomers (36.5 % yield) in approx. 2:3 ratio which were separated by column chromatography using 0.1% EtOAc: Hexane as eluant to furnish the two isomers 3a5 (higher Rf) as oil and 4a5 (lower Rf) as white solid (m.p. 60-62 0C) respectively.
EXAMPLE: - 6 TRIOXANE 2a6, FORMULA 2a, Ar =pPh-C6H4-
To a stirred solution of unsaturated trioxane Ia6 (formula Ia, Ar= ^Ph-C6H4-) (1.00 gm, 2.577 mmol) and N2H4-H2O (6ml) in 1:1 mixture of EtOH/THF (50ml), cooled to 0° C, was added 30% H2O2 (20 ml) dropwise and the reaction mixture was kept at same temp for 2 days and then at room temperature for 2 days. The reaction mixture was evaporated on a rota-vapour and then diluted with water (20 ml) and extracted with ether (3x50 ml). The ethereal layer was neutralized with 10% HCl (20 ml) and washed with saturated NaHCO3 and brine solution and evaporated on a rota-vapour and the crude product was purified by column chromatography on silica gel using 1.0% EtOAc: Hexane as eluant to yield 590 mg of compound 2a6 as a mixture of diastereomers (58.7 % yield) in approx. 2:3 ratio which were separated by column chromatography using 0.1% EtOAc: Hexane as eluant to furnish the two isomers 3a6 (higher Rf) as white solid (m.p. 138°- 140° C) and 4a6 (lower Rf) as white solid (m.p. 145°-147° C) as well, respectively.
EXAMPLE: - 7
TRIOXANE 2a7 FORMULA 2a, Ar =2-NapthyI- To a stirred solution of unsaturated trioxane Ia7 (formula Ia, Ar=2-Napthyl-) (2.00 gm, 5.525 mmol) and N2H4-H2O (2.8 ml) in 1:1 mixture of EtOH/THF (100 ml), cooled to 0° C, was added 30% H2O2 (9.4 ml) dropwise and the reaction mixture was kept at same temp for 2 days and then stirred at room temperature, for 13 days, The reaction mixture was evaporated on a rota-vapour and then diluted with water (20 ml) and extracted with ether (3x100 ml). The ethereal layer was neutralized with 10% HCl (20 ml) and washed with saturated NaHCO3 and brine solution and evaporated on a rota-vapour and the crude product was purified by column chromatography on silica gel using 1.0% EtOAc: Hexane as eluant to yield 680 mg of compound 2a7 as a mixture of diastereomers (67.6 % yield) in approx. 2:3 ratio which were separated by column chromatography using 0.1% EtOAc: Hexane as eluant to furnish the two isomers 3a7 (higher Rf) as white solid (m.p. 120-121 0C) and 4a7 (lower Rf) as white solid (m.p. 135-137 0C) respectively. EXAMPLE: - 8
TRIOXANE 2a8 FORMULA 2a, Ar =/>Br-C6H4
To a stirred solution of unsaturated trioxane Ia8 (formula Ia, Ar= ^Br-C6H4-) (2.3 gm, 5.897 mmol) and N2H4-H2O (2.5 ml) (neutralized with CO2) in 1:1 mixture of EtOH/THF (100 ml), cooled to 0° C, was added 30% H2O2 (8.5 ml) dropwise and the reaction mixture was stirred at room temperature, for 10 days. The reaction mixture was evaporated on a rota-vapour and then diluted with water (20 ml) and extracted with ether (3x100 ml). The ethereal layer was neutralized with of 10% HCl (20 ml) and washed with saturated NaHCO3 and brine solution and evaporated on a rota-vapour and the crude product was purified by column chromatography on silica gel using 1.0% EtOAc: Hexane as eluant to yield 2.19 g of compound 2a8 as a mixture of diastereomers (94.8 % yield) in approx. 2:3 ratio which were separated by column chromatography using 0.1% EtOAc: Hexane as eluant to furnish the two isomers 3a8 (higher Rf) as white solid (m.p. 115°-116° C) and 4a8 (lower Rf) as white solid (m.p. 130-131 0C) respectively.
EXAMPLE: - 9 TRIOXANE 2a9 FORMULA 2a, Ar =1-Napthyl-
To a stirred solution of unsaturated trioxane Ia9 (formula Ia, Ar=l-Napthyl-) (1.00 gm, 2.762 mmol) and N2H4-H2O (2.7 ml) (neutralized with CO2) in 1:1 mixture of EtOH/THF (50ml), cooled to 0° C, was added 30% H2O2 (9.4 ml) dropwise and the reaction mixture was stirred at room temperature, for 29 days. The reaction mixture was evaporated on a rota-vapour and then diluted with water (20 ml) and extracted with ether (3x50 ml). The ethereal layer was neutralized with 10% HCl (20 ml) and washed with saturated NaHCO3 and brine solution and evaporated on a rota-vapour and the crude product was purified by column chromatography on silica gel using 1.0% EtOAc: Hexane as eluant to yield 350mg of compound 2a9 as a mixture of diastereomers (34.82 % yield) in approx. 2:3 ratio which were separated by column chromatography using 0.1% EtOAc: Hexane as eluant to furnish the two isomers 3a9 (higher Rf) as semisolid and 4a9 (lower Rf) as white solid (m.p. 120-122 0C) respectively.
EXAMPLE: - 10
TRIOXANE 2alO FORMULA 2a, Ar =p-Cyclohexyl-C6H4- To a stirred solution of unsaturated trioxane lalO (formula Ia, Ar= p-Cyclohexyl-QELt-) (2.00 gm, 5.076 mmol) and N2H4-H2O (5.05 ml) (neutralized with CO2) in 1:1 mixture of EtOH/THF (100 ml), cooled to 0° C , was added of 30% H2O2 (17.26 ml ) dropwise and the reaction mixture was stirred at room temperature for 7 days. The reaction mixture was evaporated on a rota- vapour and then diluted with water (20 ml) and then extracted with ether (3x100 ml ). The ethereal layer was neutralized with 10% HCl (20 ml) and washed with saturated NaHCCb and brine solution and evaporated on a rota-vapour and the crude product was purified by column chromatography on silica gel using 1.0% EtOAc: Hexane as eluant to yield 1.95g of compound 2alO as a mixture of diastereomers (97.01 % yield) in approx. 2:3 ratio which were separated by column chromatography using 0.1% EtOAc: Hexane as eluant to furnish the two isomers 3alO (higher Rf) as white solid (m.p. 141°-143° C) and 4alO (lower Rf) as white solid (m.p. 117-118 0C) respectively. EXAMPLE: - 11
TRIOXANE 2all FORMULA 2a, Ar =2-FIurenyl-
To a stirred solution of unsaturated trioxane lall (formula Ia, Ar=2-Flurenyl-) (1.00 gm, 2.50 mmol) and N2H4-H2O (2.5 ml) in 1:1 mixture of EtOH/THF (50 ml), cooled to 0° C, was added 30% H2O2 (8.5 ml) (neutralized with CO2) dropwise and the reaction mixture was stirred at room temperature for 10 days. The reaction mixture was evaporated on a rota-vapour and then diluted with water (20 ml) and extracted with ether (3x50 ml). The ethereal layer was neutralized with 10% HCl (20 ml) and washed with saturated NaHCO3 and brine solution and evaporated on a rota-vapour and the crude product was purified by column chromatography on silica gel using 1.0% EtOAc: Hexane as eluant to yield 900mg of compound 2all as a mixture of diastereomers (89.5 % yield) in approx. 2:3 ratio which were separated by column chromatography using 0.1% EtOAc: Hexane as eluant to furnish the two isomers 3all (higher Rf) as white solid (m.p. 133- 135 0C) and 4all (lower Rf) as white solid (m.p. 136-138 0C) respectively.
EXAMPLE: - 12 8-(l-PHENYL-ETHYL)-6, 7, 10-TRIOXA-SPIRO [4, 5] DECANE (TRIOXANE 2bl, FORMULA 2b, Ar =C6H5-)
To a stirred solution of unsaturated trioxane (IbI) 8-(l-Phenyl-vinyl)-6,7,10-trioxa- spiro[4.5]decane (formula Ib, Ar=C6H5-) (2.00 gm, 8.130 mmol) and N2H4-H2O (8.1 ml) in 1:1 mixture of EtOH/THF (200 ml), cooled to 0° C, was added 30% H2O2 (27.6 ml) dropwise and the reaction mixture was kept at same temp for 2 days. The reaction mixture was evaporated on a rotavapour and then diluted with water (40 ml) and extracted with ether (3x100 ml ) . The ethereal layer was neutralized with 10% HCl (20 ml) and washed with saturated NaHCO3 and brine solution and evaporated on a rotavapour and the crude product was purified by column chromatography on silica gel using 1.0% EtOAc: Hexane as eluant to yield 740 mg of compound 2bl as a mixture of diastereomers (36.67 % yield) in approx. 2:3 ratio which were separated by column chromatography using 0.1% EtOAc: Hexane as eluant to furnish the two isomers 3bl (higher Rf) as oil and 4b2 (lower Rf) as oil as well, respectively. EXAMPLE: - 13
8-(l-TOLYL-ETHYL)-6,7,10-TRlOXA-SPIRO[4,5]DECANE (TRIOXANE 2b2,
FORMULA 2b, Ar ^pMe-C6H4-)
To a stirred solution of unsaturated trioxane (Ib2) 8~(l-p-Tolyl-vinyl)-6,7,10-trioxa- spiro[4.5]decane (formula Ib, Ar=^pMe-C6H5-) (2.00 gm, 7.692 mmol) and N2H4-H2O (7.7 ml) in 1 :1 mixture of EtOH/THF (200 ml), cooled to 0° C, was added 30% H2O2 (26.16 ml) dropwise and the reaction mixture was kept at same temp for 2 days. The reaction mixture was evaporated on a rotavapour and then diluted with water (40 ml) and extracted with ether (3x100 ml). The ethereal layer was neutralized with 10% HCl (20 ml) and washed with saturated NaHCO3 and brine solution and evaporated on a rotavapour and the crude product was purified by column chromatography on silica gel using 1.0% EtOAc: Hexane as eluant to yield 636 mg of compound 2b2 as a mixture of diastereomers (31.56 % yield) in approx. 2:3 ratio which were separated by column chromatography using 0.1% EtOAc: Hexane as eluant to furnish the two isomers 3b2 (higher Rf) as oil and 4b2 (lower Rf) as oil as well, respectively. EXAMPLE: - 14
8-[l-(4-CBQLORO-PHENYL)-ETHYL]-6,7,10-TRIOXA-SPIRO[4,5]DECA]NE (TRIOXANE 2b3, FORMULA 2b, Ar ^Cl-C6H4-)
To a stirred solution of unsaturated trioxane (Ib3) 8-[l-(4-Chloro-phenyl)-vinyl]-6,7,10-trioxa- spiro[4.5]decane (formula Ib, Ar= ^Cl-C6H4-) (2.00 gm, 7.143 mmol) and N2H4-H2O (7.15 ml) in 1:1 mixture of EtOH/THF (200 ml), cooled to 0° C, was added 30% H2O2 (24.3 ml) dropwise and the reaction mixture was kept at same for 2 days and then stirred at room temperature for 1 day. The reaction mixture was evaporated on a rotavapour and then diluted with water (40 ml) and extracted with ether (3x100 ml). The ethereal layer was neutralized with 10% HCl (20 ml) and washed with saturated NaHCO3 and brine solution and evaporated on a rotavapour and the crude product was purified by column chromatography on silica gel using 1.0% EtOAc: Hexane as eluant to yield 1.040 gm of compound 2b3 as a mixture of diastereomers (51.63 % yield) in approx. 2:3 ratio which were separated by column chromatography using 0.1% EtOAc: Hexane as eluant to furnish the two isomers 3b3 (higher Rf) as oil and 4b3 (lower Rf) as oil as well, respectively. EXAMPLE: - 15
8-[l-(4-FLUORO-PHENYL)-ETHYL]-6,7,10-TRIOXA-SPIRO[4,5]DECANE (TRIOXANE 2b4, FORMULA 2b, Ar =pF-C6H4-)
To a stirred solution of unsaturated trioxane (Ib4) 8-[l-(4-Fluoro-phenyi)-vinyl]-6,7,10-trioxa- spiro[4.5]decane (formula Ib, Ar=^F-C6H4-) (2.00 gm, 7.576 mmol) and N2H4-H2O (7.6 ml) in 1:1 mixture of EtOH/THF (200 ml), cooled to 0° C, 20 was added 30% H2O2 (25.8 ml) dropwise and the reaction mixture was kept at same temp for 2 days and then stirred at room temperature for 1 day. The reaction mixture was evaporated on a rotavapour and then diluted with water (40 ml) and extracted with ether (3x100 ml). The ethereal layer was neutralized with 10% HCl (20 ml) and washed with saturated NaHCU3 and brine solution and evaporated on a rotavapour and the crude product was purified by column chromatography on silica gel using 1.0% EtOAc: Hexane as eluant to yield 1.34 gm of compound 2b4 as a mixture of diastereomers (66.5 % yield) in approx. 2:3 ratio which were separated by column chromatography using 0.1% EtOAc: Hexane as eluant to furnish the two isomers 3b4 (higher Rf) as oil and 4b4 (lower Rf) as oil as well, respectively.
EXAMPLE: - 16 8-[l-(4-METHOXY-PHE]>reX)-ETHYL]-6,7,10-TRIOXA-SPIRO[4,5]DECANE (TRIOXANE 2b5, FORMULA 2b, Ar =pMeO-C6H4-)
To a stirred solution of unsaturated trioxane (Ib5) 8-[l-(4-Methoxy-phenyl)-vinyl]-6,7,10-trioxa- spiro[4.5]decane (formula Ib, Ar= /PMeO-C6H4-) (2.00 gm, 7.246 mmol) and N2H4-H2O ( 7.25 ml ) in 1:1 mixture of EtOH/THF ( 200 ml), cooled to 0° C, 20 was added 30% H2O2 ( 24.6 ml ) dropwise and the reaction mixture was kept at same temp for 2 days and then stirred at room temperature for 12 days. The reaction mixture was evaporated on a rotavapour and then diluted with water (40 ml) and extracted with ether (3x100 ml). The ethereal layer was neutralized with of 10% HCl (20 ml) and washed with saturated NaHCO3 and brine solution and evaporated on a rotavapour and the crude product was purified by column chromatography on silica gel using 1.0% EtOAc: Hexane as eluant to yield 1.29 gm of compound 2b5 as a mixture of diastereomers (64.04 % yield) in approx. 2:3 ratio which were separated by column chromatography using 0.1% EtOAc: Hexane as eluant to furnish the two isomers 3b5 (higher Rf) as white solid (m.p. 84°-86° C) and 4b5 (lower Rf) as oil, respectively.
EXAMPLE: - 17 8-(l-BIPHNYL-4-YL-ETHYL)-6,7,10-TRIOXA-SPIRO[4,5]DECANE (TRIOXANE 2b6 FORMULA 2b, Ar =pPh-C6H4-)
To a stirred solution of unsaturated trioxane (Ib6) 8-(l-Biphenyl-4-yl-vinyl)-6,7,10-trioxa- spiro[4.5]decane (formula Ib, Ar= ^Ph-C6H4-) (1.00 gm, 3.105 mmol) and N2H4-H2O (3 ml) in 1:1 mixture of EtOH/THF (100 ml), cooled to 0° C, 20 was added 30% H2O2 (10.18 ml) dropwise and the reaction mixture was kept at same temp for 2 days. The reaction mixture was evaporated on a rotavapour and then diluted with water (20 ml) and extracted with ether (3x50 ml). The ethereal layer was neutralized with 10% HCl (20 ml) and washed with saturated NaHCO3 and brine solution and evaporated on a rotavapour and the crude product was purified by column chromatography on silica gel using 1.0% EtOAc: Hexane as eluant to yield 437 mg of compound 2b6 as a mixture of diastereomers (43.44 % yield) in approx. 2:3 ratio which were separated by column chromatography using 0.1% EtOAc: Hexane as eluant to furnish the two isomers 3b6 (higher Rf) as white solid (m.p. 74°-76° C) and 4b6 (lower Rf) as white solid (m.p. 82°-84° C) as well, respectively.
EXAMPLE: - 18
8-(l-NAPTHALEN-2-YL-ETHYL)-6,7,10-TRIOXA-SPIRO[4,5]DECANE (TRIOXANE 2b7 FORMULA 2, Ar =2-Napthyl-)
To a stirred solution of unsaturated trioxane (Ib7) 8-(l-Naphthalen-2~yl-vmyl>6,7,10-trioxa- spiro[4.5]decane (formula Ib, Ar=2-Napthyl-) (2.00 gm, 6.757 mmol) and N2H4-H2O (7.25 ml) in 1:1 mixture of EtOH/THF (200 ml), cooled to 0° C, was added 30% H2O2 (22.98 ml) dropwise and the reaction mixture was kept at same temp for 2 days and then stirred at room temperature for 8 days. The reaction mixture was evaporated on a rotavapour and then diluted with water (40 ml) and extracted with ether (3x100 ml). The ethereal layer was neutralized with 10% HCl (20 ml) and washed with saturated NaHCO3 and brine solution and evaporated on a rotavapour and the crude product was purified by column chromatography on silica gel using 1.0% EtOAc: Hexane as eluant to yield 1.310 gm of compound 2b7 as a mixture of diastereomers (65.06% yield) in approx. 2:3 ratio which were separated by column chromatography using 0.1% EtOAc: Hexane as eluant to furnish the two isomers 3b7 (higher Rf) as white solid m.p.70°-72°C and 4b7 (lower Rf) as oil, respectively.
EXAMPLE: - 19 3-(1-PHENYL-ETHYL)-I^5S-TMOXA-SPIRO[S5S]UNDECANE (TRIOXANE 2cl, FORMULA 2c, R=C6H5-)
To a stirred solution of unsaturated trioxane (IcI) 3-(l-Phenyl-vinyl)-l,2,5-trioxa- spiro[5.5]undecane (formula Ic, Ar=C6H5-) (2.00 gm, 7.692 mmol) and N2H4-H2O (8.1 ml) in 1:1 mixture of EtOH/THF (200 ml), cooled to 0° C, was 30% H2O2 (26.05 ml) dropwise and the reaction mixture was kept at same temp for 2 days and then stirred at room temperature for 8 days. The reaction mixture was evaporated on a rotavapour and then diluted with water (40 ml) and extracted with ether (3x100 ml). The ethereal layer was neutralized with 10% HCl (20 ml) and washed with saturated NaHCO3 and brine solution and evaporated on a rotavapour and the crude product was purified by column chromatography on silica gel using 1.0% EtOAc: Hexane as eluant to yield 1.174 gm of compound 2cl as a mixture of diastereomers (58.25 % yield) in approx. 2:3 ratio which were separated by column chromatography using 0.1% EtOAc: Hexane as eluant to furnish the two isomers 3cl (higher Rf) as oil and 4cl (lower Rf) as oil as well, respectively.
EXAMPLE: - 20 3-(l-p-TOLYL-ETHYL)-l,2,5-TRIOXA-SPIRO[555]UNDECANE (TRIOXANE 2c2, FORMULA 2c, R=pMe-C6H4- , R1R2= CYCLOHEXYL) To a stirred solution of unsaturated trioxane (Ic2) 3-(l-p-Tolyl-vinyl)-l,2,5-trioxa- spiro[5.5]undecane (formula Ic, Ar= /Me-C6H5-) (2.00 gm, 7.299 mmol) and N2H4-H2O (7.3 ml) in 1:1 mixture of EtOH/THF (200 ml), cooled to 0° C, was added 30% H2O2 (24.8 ml) dropwise and the reaction mixture was kept at same temp for 2 days and then stirred at room temperature for 5 days. The reaction mixture was evaporated on a rotavapour and then diluted with water (40 ml) and extracted with ether (3x100 ml). The ethereal layer was neutralized with of 10% HCl (20 ml) and washed with saturated NaHCO3 and brine solution and evaporated on a rotavapour and the crude product was purified by column chromatography on silica gel using 1.0% EtOAc: Hexane as eluant to yield 1.790 gm of compound 2c2 as a mixture of diasteriomers (88.80 % yield) in approx. 2:3 ratio which were separated by column chromatography using 0.1% EtOAc: Hexane as eluant to furnish the two isomers 3c2 (higher Rf) as oil and 4c2 (lower Rf) as oil as well, respectively.
EXAMPLE: - 21 3-[1-(4-CHLORO-PHENYL)-I^5S-TRIOXA-SPIRO[S5S]UNDECANE (TRIOXANE 2c3, FORMULA 2, R=pCl-C6H4-)
To a stirred solution of unsaturated trioxane (Ic3) 3-[l-(4-Chloro-phenyl)-vinyl]-l,2,5-trioxa- spiro[5.5]undecane (formula Ic, Ar=^Cl-C6H4-) (2.00 gm,6.803 mmol) and N2H4-H2O ( 6.8 ml ) in 1:1 mixture of EtOH/THF ( 200 ml ), cooled to 0° C, was added 30% H2O2 ( 23.1 ml ) dropwise and the reaction mixture was kept at same temp for 2 days and then stirred at room temperature for 9 days. The reaction mixture was evaporated on a rotavapour and then diluted with water (40 ml) and extracted with ether (3x100ml). The ethereal layer was neutralized with 10% HCl (20 ml) and washed with saturated NaHCO3 and brine solution and evaporated on a rotavapour and the crude product was purified by column chromatography on silica gel using 1.0% EtOAc: Hexane as eluant to yield 1.50 gm of compound 2c3 as a mixture of diasteriomers (74.49 % yield) in approx. 2:3 ratio which were separated by column chromatography using 0.1% EtOAc: Hexane as eluant to furnish the two isomers 3c3 (higher Rf) as oil and 4c3 (lower Rf) as oil as well, respectively.
EXAMPLE: - 22 3-[1-(4-FLUORO-PHENYL)-I^9S-TRIOXA-SPIRO[S5S]UNDECANE (TRIOXANE 2c4, FORMULA 2c, R=pF-C6H4-)
To a stirred solution of unsaturated trioxane (Ic4) 3-[l-(4-Fluoro-phenyl)-vinyl]-l,2,5-trioxa- spiro[5.5]undecane (formula Ic, Ar=JpF-C6H4-) (1.00 gm, 7.194 mmol) and N2H4-H2O (7.2 ml) in 1:1 mixture of EtOH/THF (200 ml), cooled to 0° C, 20 was added 30% H2O2 (24.46 ml) dropwise and the reaction mixture was kept at same temp for 2 days and then stirred at room temperature for 5 days. The reaction mixture was evaporated on a rotavapour and then diluted with water (40 ml) and extracted with ether (3x100 ml). The ethereal layer was neutralized with 10% HCl (20 ml ) and washed with saturated NaHCO3 and brine solution and evaporated on a rotavapour and the crude product was purified by column chromatography on silica gel using 1.0% EtOAc: Hexane as eluant to yield 1.395 gm of compound 2c4 as a mixture of diasteriomers (69.25 % yield) in approx. 2:3 ratio which were separated by column chromatography using 0.1% EtOAc: Hexane as eluant to furnish the two isomers 3c4 (higher Rf) as white solid (m.p. 56°-58° C) and 4c4 (lower Rf) as oil, respectively.
EXAMPLE: - 23
3-[1-(4-METHOXY-PHENYL)-I^S-TWOXA-SPIRO[S5S]UNDECANE (TRIOXANE 2C5, FORMULA 2c, R=pMeO-C6H4-) To a stirred solution of unsaturated trioxane (Ic5) 3-[l-(4-Methoxy-phenyl)-vinyl]-l,2,5-trioxa- spiro[5.5]undecane (formula Ic, Ar= ^MeO-C6H4-) (2.00 gm, 6.896 mmol) and N2H4-H2O (6.9 ml ) in 1:1 mixture of EtOH/THF ( 200 ml ), cooled to 0° C, was added 30% H2O2 (23.45 ml) dropwise and the reaction mixture was kept at same temp for 2 days and then stirred at room temperature for 9 days. The reaction mixture was evaporated on a rotavapour and then diluted with water (40 ml) and extracted with ether (3x100 ml). The ethereal layer was neutralized with 10% HCl (20 ml) and washed with saturated NaHCO3 and brine solution and evaporated on a rotavapour and the crude product was purified by column chromatography on silica gel using 1.0% EtOAc: Hexane as eluant to yield 1.82 gm of compound 2c5 as a mixture of diasteriomers (90.38 % yield) in approx. 2:3 ratio which were separated by column chromatography using 0.1% EtOAc: Hexane as eluant to furnish the two isomers 3c5 (higher Rf) as white solid (m.p. 65-67 0C) and 4c5 (lower Rf) as oil, respectively.
EXAMPLE: - 24
3-(l-BIPHENYL-4-YL-ETHYL)-l,2,5-TRIOXA-SPIRO[5,5]UNDECANE (TRIOXANE 2c6 FORMULA 2c, R=/>Ph-C6H4-) To a stirred solution of unsaturated trioxane (Ic6) 3-(l-Biphenyl-4-yl-vinyl)-l,2,5-trioxa- spiro[5.5]undecane (formula Ic, Ar= ^Ph-C6H4-) (2.00 gm, 5.952 mmol) and N2H4-H2O (5.95 ml) in 1:1 mixture of EtOH/THF (200 ml), cooled to 0° C, was added 30% H2O2 (20.24 ml) dropwise and the reaction mixture was kept at same temp for 2 days, and then stirred at room temperature for 18 days. The reaction mixture was evaporated on a rotavapour and then diluted with water (40 ml) and extracted with ether (3x100 ml). The ethereal layer was neutralized with 10% HCl (20 ml) and washed with saturated NaHCO3 and brine solution and evaporated on a rotavapour and the crude product was purified by column chromatography on silica gel using 1.0% EtOAc: Hexane as eluant to yield 1.750 gm of compound 2c6 as a mixture of diastereomers (86.98 % yield) in approx. 2:3 ratio which were separated by column chromatography using 0.1% EtOAc: Hexane as eluant to furnish the two isomers 3c6 (higher Ri) as white solid (m.p. 80°-81° C) and 4c6 (lower Rf) as white solid (m.p. 85°-86° C) as well, respectively. EXAMPLE: - 25
3-(l-NAPHTHALEN-2-YL-ETHYL)-l, 2,5-TRIOXA-SPIRO [5, 5] UNDECANE (TRIOXANE 2c7, FORMULA 2c, R=2-Napthyl-)
To a stirred solution of unsaturated trioxane (Ic7) 3-(l-Naphthalen-2-yl-vinyl)-l,2,5-trioxa- spiro[5.5]undecane (formula Ic, Ar=2-Napthyl-) (2.00 gm, 6.452 mmol) and N2H4-H2O (6.46 ml) in 1:1 mixture of EtOH/THF (200 ml), cooled to 0° C, was added 30% H2O2 (21.9 ml) dropwise and the reaction mixture was kept at same temp for 2 days and then stirred at room temperature for 15 days. The reaction mixture was evaporated on a rotavapour and then diluted with water (40 ml) and extracted with ether (3x100 ml). The ethereal layer was neutralized with of 10% HCl (20 ml) and washed with saturated NaHCO3 and brine solution and evaporated on a rotavapour and the crude product was purified by column chromatography on silica gel using 1.0% EtOAc: Hexane as eluant to yield 1.745 gm of compound 2c7 as a mixture of diasteriomers (86.686 % yield) in approx. 2:3 ratio which were separated by column chromatography using 0.1% EtOAc: Hexane as eluant to furnish the two isomers 3c7 (higher Rf) as white solid (m.p. 85°-87° C) and 4c7 (lower Rf) as white solid (m.p. 92°-94° C) respectively.
FOLLOWING THE ABOVE PROCEDURE, THE FOLLOWING TRIOXANES WERE ALSO PREPARED: (TABLE 2)
Figure imgf000024_0001
Figure imgf000025_0001
Figure imgf000026_0001
Figure imgf000027_0001
ANTIMALARIAL ACTIVITY
The antimalarial activity of the test compounds was evaluated against multidrug resistant strain of Plasmodium yoelii nigeriensis in Swiss mice.
General Procedure:-
Random bred Swiss mice of either sex (20 + 2 g) were inoculated intraperitoneally with 1x105 P. yoelii (MDR) parasites on day zero. The treatments with test compounds were administered to group of 5 mice each at different dose levels ranging between 12-96 mg/kg/day. The compounds were administered as solutions in oil via oral route for 4 consecutive days (day 0-3). β-Arteether and α-Arteether were used as positive control.
Blood smears from experimental mice were observed on day 4 and 7, day 10 and thereafter at regular interval till day 28 or death of the animal. The parasitaemia level on day 4 was compared with the vehicle control group and the percent suppression of parasitaemia in treated groups was calculated. The compounds which showed more than 90% suppression were identified for further screening.
For determining the curative dose of a compound the treated mice were observed till day 28. The dose at which no parasitaemia develops during the observation period has been recorded as the curative dose. The results are shown in table given below: ANTIMALARIAL ACTIVITY OF TRIOXANES AGAINST Plasmodium yoelii nigeriensis m MICE (TABLE 3)
Figure imgf000028_0001
Figure imgf000029_0001
Figure imgf000030_0001
Figure imgf000031_0001
Percent suppression^ [(C - T) / C] XlOO; where C '= parasitaemia in control group, and T — parasitaemia in treated group
The drug dilutions of compounds were prepared in ground oil and administered to a group of mice at each dose via oral route, from day 0-3 in two divided doses daily.
We observed a great deal of increment in terms of activity of these trioxanes against multidrug resistant Plasmodium yoelii nigeriensis in mice via oral route, as some of the trioxanes was several fold active in comparison to some of the known trioxanes whose activity is shown in table given below. ANTIMALARIAL ACTIVITY OF SOME KNOWN TRIOXANES AGAINST Plasmodium yoelii nigeriensis IN MICE (TABLE 4)
Figure imgf000032_0002
As it can be seen from the tables given above that trioxanes of the present invention having formula 3al, 3a2, 3a3, 3a4, 3a5 and several others are active at a lower dose (12 to 48mg/kg) as compared to their parent counterpart trioxanes which are known compounds having formula IaI, Ia2, Ia3, Ia4, Ia5 are not even active at 96mg/kg dose. ( Singh, C; Misra, D.; Saxena, G.; Chandra, S. Bioorg. Med. Chem. Lett. 1992, 2, 497.)
A SCHEME FOR PREPRATION OF TRIOXANES OF GENERAL FORMULA 2
Figure imgf000032_0001
O°-rt

Claims

1. Substituted 1, 2, 4-trioxanes of general formula 2 , and their isomers of formula 3 and 4
Figure imgf000033_0001
2 3 4 wherein Ar is selected from the group comprising of phenyl , pMe-phenyl, ^Cl-phenyl, ^MeO- phenyl, pΕ -phenyl, biphenyl, 2-napthyl,/?-Br-phenyl,l-napthyl,/>-Cyclohexyl-phenyl, 2-Flurenyl, wherein R1 and R2 represents the part of cyclic ring' system like cyclohexane, cyclopentane and adamantane.
2. Substituted 1, 2, 4-trioxanes according to claim 1, wherein the representative compounds of general formula 2a, being defined as follows;
Figure imgf000033_0002
2a1 Ar=C6H5- 2a7 Ar=2-Napthyi- 2a2 Ar=pMe-C6H4- 2a8 Ar=P-Br-C6H4- 2a3 Ar=PCI-C6H4- 2a9 Ar=1-Napthyl- 2a4 Ar=PF-C6H4- 2a10 Ar=p-Cyclohexyl-phenyl- 2a5 Ar=PMeO-C6H4- 2a11 Ar=2-Flurenyl- 2a6 Ar=pPh-C6H4-
3. Substituted 1, 2, 4-trioxanes according to claim 1, wherein the representative compounds of general formula 2b, being defined as follows;
Figure imgf000034_0001
2b1 Ar=C6H5- 2b5 Ar=pMeO-C6H4- 2b2 Ar=pMe-C6H4- 2b6 Ar=pP/7-C6H4- 2b3 Ar=PCI-C6H4- 2b7 Ar=2-Napthyl- 2b4 Ar=pF-C6H4-
4. Substituted 1, 2, 4-trioxanes according to claim 1, wherein the representative compounds of general formula 2c, being defined as follows;
Figure imgf000034_0002
2c1 Ar=C6H5- 2c5 Ar=pMeO-C6H4- 2c2 Ar=PMe-C6H4- 2c6 Ar=PPh-C6H4- 2c3 Ar=PCI-C6H4- 2c7 Ar=2-Napthyl- 2c4 Ar=PF-C6H4-
5. Substituted 1, 2, 4-trioxanes according to claim 1, wherein the diastereoisomers of compound of formula 2 is represented by structural formula 3 and 4 as shown below wherein Ax is selected from the group consisting of phenyl , /»Me-phenyl, j^Cl-phenyl, pMeO- phenyl, j?F-phenyl, biphenyl, 2-napthyl, p-Br-phenyl,l-napthyl, />-Cyclohexyl-phenyl, 2-Flurenyl, whereas R1 and R2 represents the part of cyclic ring system like cyclohexane, cyclopentane and adamantane.
Figure imgf000034_0003
6. Substituted 1, 2, 4-trioxanes according to claims 1-5, wherein the representative compounds of general formula 3a, being defined as follows;
Figure imgf000035_0001
3a
3a1 Ar=C6H5- 3a7 Ar=2-Napthyl-
3a2 Ar=PMe-C6H4- 3a8 Ar=P-Br-C6H4-
3a3 Ar=PCI-C6H4- 3a9 Ar=1-Napthyl-
3a4Ar=PF-C6H4- 3a10 Ar=p-Cyclohexyl-phenyl-
3a5 Ar=pMeO-C6H4- 3a11 Ar=2-Flurenyl-
3a6 Ar=pPh-C6H4-
7. Substituted 1, 2, 4-trioxanes according to claims 1-5, wherein the representative compounds of general formula 4al-4all, being defined as follows;
wherein the said compounds having the structural formula as shown below:
Figure imgf000035_0002
4a1 Ar=C6H5- 4a7 Ar=2-Napthyl-
4a2 Ar=PMe-C6H4- 4a8 Ar=P-Br-C6H4-
4a3 Ar=PCI-C6H4- 4a9 Ar=1-Napthyl-
4a4Ar=pF-C6H4- 4a10 Ar=p-Cyclohexyl-phenyl
4a5 Ar=pMeO-C6H4- 4a11 Ar=2-Flurenyl-
4a6 Ar=pPh-C6H4-
8. Substituted 1, 2, 4-trioxanes according to claims 1-5, wherein the representative compounds of general formula 3bl-3b7 being defined as follows;
Figure imgf000036_0001
3b1 Ar=C6H5- 3b5 Ar=pMeO-C6H4-
3b2 Ar=PMe-C6H4- 3b6 Ar=pPh-C6H4-
3b3 Ar=PCI-C6H4- 3b7 Ar=2-Napthyl- 3b4 Ar=PF-C6H4-
9. Substituted 1, 2, 4-trioxanes according to claims 1-5, wherein the representative compounds of general formula 4bl-4b7 being defined as follows;
Figure imgf000036_0002
4b1 Ar=C6H5- 4b5 Ar=PMeO-C6H4- 4b2 Ar=pMe-C6H4- 4b6 Ar=PPh-C6H4- 4b3Ar=pCI-C6H4- 4b7 Ar=2-Napthyl- 4b4 Ar=pF-C6H4-
10. Substituted 1, 2, 4-trioxanes according to claims 1-5, wherein the representative compounds of general formula 3cl-3c7 being defined as follows;
Figure imgf000036_0003
3d Ar=C6H5- 3c5 Ar=PMeO-C6H4- 3c2 Ar=PMe-C6H4- 3c6 Ar=PPh-C6H4- 3c3 Ar=PCI-C6H4- 3c7 Ar=2-Napthyl 3c4 Ar=pF-C6H4-
11. Substituted 1, 2, 4-trioxanes according to claims 1-5, wherein the representative compounds of general formula 4cl-4c7 being defined as follows;
Figure imgf000037_0001
4c1 Ar=C6H5- 4c5 Ar=pMeO-C6H4-
4c2 Ar=pMe-C6H4- 4c6 Ar=pPh-C6H4-
4c3Ar=pCI-C6H4- 4c7 Ar=2-Napthyl- 4c4 Ar=pF-C6H4-
12. Substituted 1,2,4-trioxanes according to claims 1-11, useful for the treatment of malaria.
13. Substituted 1, 2, 4-trioxanes according to claims 1-11, wherein the dose of test compounds is ranging between 12-96 mg/kg/day.
14. Substituted 1, 2, 4-trioxanes according to claims 1-11, wherein the compounds were administered as solutions in oil via oral route for 4 consecutive days (day 0-3).
15. A pharmaceutical composition comprising an effective amount of the compound of formula 2, and their isomers of formula 3 and 4.
Figure imgf000037_0002
2 4 wherein Ar is selected from the group comprising of phenyl , /?Me-phenyl, /O-phenyl, pMeO- phenyl, pF-phenyl, biphenyl, 2-napthyl, p-Br-phenyl,l-napthyl, p-Cyclohexyl-phenyl, 2- Flurenyl, whereas R1 and R2 represents the part of cyclic ring system like cyclohexane, cyclopentane and adamantine optionally along with pharmaceutically acceptable diluents.
16. A composition according to claim 15, wherein the isomer of the formula 2 is selected from the compound of general formula 3 or 4.
Figure imgf000038_0001
2 3 4
17. A composition according to claim 15, wherein the test compounds were administered at different dose levels ranging between 12-96 mg/kg/day.
18. A composition according to claim 15, wherein the composition is administered through oral route for 4 consecutive days (day 0-3).
19. A composition according to claim 15, wherein diluent is any edible oil such as groundnut oil, olive oil.
20. A method of treating the subject suffering from malaria, the said method comprising; administering the effective amount of composition to the subject in need wherein the composition comprises; an effective amount of the compound of formula 2, and their isomers of formula 3 and 4;
Figure imgf000038_0002
3 4 wherein Ar is selected from the group comprising of phenyl , ^Me-phenyl, pCl-phenyl, pMeO- phenyl, />F-phenyl, biphenyl, 2-napthyl, ^-Br-phenyl,l-napthyl, />-Cyclohexyl-phenyl, 2- Flurenyl, whereas R1 and R2 represents the part of cyclic ring system like cyclohexane, cyclopentane and adamantine, optionally along with pharmaceutically acceptable additives, carriers, diluents.
21. A method according to claim 20, wherein the route of administration is oral, im or intraperitoneal.
22. A method according to claim 20, wherein the dose of the composition is ranging between 12 to 96 mg/kg.
23 A method according to claim 20, wherein percent suppression of parasitaemia is up to 100% on day 4 of administration of the composition.
24. A method according to claim 20, wherein the subject is selected from animal including human.
25. A process for the preparation of novel substituted 1,2,4-trioxanes of formula 2 and their isomers of general formula 3 and 4; wherein Ar is selected from the group consisting of phenyl , />Me-phenyl, pCl-phenyl, pMsO- phenyl, pΕ '-phenyl, biphenyl, 2-napthyl, p-Br-phenyl, 1- napthyl, />-Cyclohexyl-phenyl, 2-Flurenyl,
Figure imgf000039_0001
2 3 4 wherein R1 and R2 represent the part of cyclic ring system like cyclohexane, cyclopentane and adamantane, which comprises reaction of 6-(l-aryl vinyl)- 1, 2, 4-trioxanes of formula 1
Figure imgf000039_0002
1 where in Ar is selected from the group consisting of phenyl , pMe-phenyl, pCl-phenyl, pMeO- phenyl, /?F-phenyl, biphenyl, 2-napthyl, p-Br-phenyl, 1-napthyl, p-Cyclohexyl-phenyl, 2- Flurenyl whereas R1 and R2 represent the part of cyclic ring system like cyclohexane, cyclopentane and adamantane, with diimide, generated in situ, by reacting H2O2 with N2H4.H2O or CO2 neutralized N2H4-H2O in a water miscible organic solvent at a temperature ranging between 0 0C to room temperature for a period ranging between 2 to 29 days, to furnish trioxanes of formula 2 as a mixture of diastereomers, separating the diastereomers by chromatography to give pure isomers of the formula 3 and 4 wherein Ar, R1 and R2 have the same meaning as above for compound of formula 2.
26. A process according to claim 15, wherein the water miscible organic solvent is selected from a group consisting of tetrahydrofuran, ethyl alcohol, methyl alcohol, CH3CN or a mixture thereof.
27. A process according to claim 15, wherein the chromatography to separate the compounds of formula 3 and 4 is carried out using solvent selected from EtOAc Hexane.
28. A process according to claim 15, wherein the chromatography is carried out on silica gel.
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