VERMA VED PRAKASH (IN)
PURI SUNIL KUMAR (IN)
SINGH CHANDAN (IN)
VERMA VED PRAKASH (IN)
PURI SUNIL KUMAR (IN)
| WO2003082852A1 | 2003-10-09 | |||
| WO2008099415A1 | 2008-08-21 |
SINGH C ET AL: "Synthesis of new 6-alkylvinyl/arylalkylvinyl substituted 1,2,4-trioxanes active against multidrug-resistant malaria in mice", BIOORGANIC & MEDICINAL CHEMISTRY, ELSEVIER SCIENCE LTD, GB, vol. 12, no. 21, 1 November 2004 (2004-11-01), pages 5553 - 5562, XP004588158, ISSN: 0968-0896
| We claim:
1. Novel hydroxy functionalized 1, 2, 4-trioxanes of general formula 7 and their derivatives wherein Ri and R 2
represent methyl group or the part of cyclic ring systems like cyclohexane, cyclopentane, cycloheptane and adamantane, A is a spacer such as oxygen substituted aromatic moieties and R3 is CH 2
CH 2
OH or CH 2
CH 2
OCOCH 2
CH 2
COOH.
R 3 = CH 2 C ,2OH 1 CH 2 CH 2 OCOCH 2 CH 2 COOH
2. Novel hydroxy functionalized 1, 2, 4-trioxanes according to claim 1 wherein the said compounds having structural formula 7aa, 7ab, 7ac and 7ae as shown below:
7aa, R 1 , R 2 = -CH 2 CH 2 CH 2 CH 2 - 7ab, R 1 , R 2 = -CH 2 CH 2 CH 2 CH 2 CH 2 - 7ac, R 1 , R 2 = Methyl, Methyl 7ae, R 1 , R 2 = -CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 -
3. Novel hydroxy functionalized 1, 2, 4-trioxanes according to claim 1 wherein the said compounds having structural formula 7ad as shown below:
4. Novel hydroxy fimctionalized 1, 2, 4-trioxanes according to claim 1 wherein the said compounds having structural formula 7aaa.7abb, 7acc and 7aee as shown below:
7aaa, R 1 , R 2 = -CH 2 CH 2 CH 2 CH 2 - 7abb, R 1 , R 2 = -CH 2 CH 2 CH 2 CH 2 CH 2 - 7acc, R 1 , R 2 = Methyl, Methyl 7aee, R 1 , R 2 = -CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 -
5. Novel hydroxy functionalized 1, 2, 4-trioxane according to claim 1 wherein the said compounds having structural formula 7add as shown below:
7add
6. Novel hydroxy functionalized 1, 2, 4-trioxanes according to claim 1 wherein the said compounds having structural formula 7ba, 7bb and 7bc as shown below:
7ba, R 1 , R 2 = -CH 2 CH 2 CH 2 CH 2 - 7bb, R 1 , R 2 = -CH 2 CH 2 CH 2 CH 2 CH 2 - 7bc, R 1 , R 2 = Methyl, Methyl
7. Novel hydroxy functionalized 1, 2, 4-trioxane according to claim 1 wherein the said compounds having structural formula 7 bd as shown below:
8. Novel hydroxy functionalized 1, 2, 4-trioxanes according to claim 1 wherein the said compounds having structural formula 7baa, 7bbb and 7bcc as shown below:
7baa, R 1 , R 2 = -CH 2 CH 2 CH 2 CH 2 - 7bbb, R 1 , R 2 = -CH 2 CH 2 CH 2 CH 2 CH 2 - 7bcc, R 1 , R 2 = Methyl, Methyl
9. Novel hydroxy functionalized 1, 2, 4-trioxane according to claim 1 wherein the said compounds having structural formula 7bdd as shown below:
10. Novel hydroxy functionalized 1, 2, 4-trioxanes according to claim 1 wherein the said compounds having structural formula 7ca and 7cb as shown below:
7ca, R 1 , R 2 = -CH 2 CH 2 CH 2 CH 2 - 7cb, R 1 , R 2 = -CH 2 CH 2 CH 2 CH 2 CH 2 -
11. Novel hydroxy functionalized 1, 2, 4-trioxane according to claim 1 wherein the said compounds having structural formula 7cc as shown below:
12. Novel hydroxy functionalized 1, 2, 4-trioxanes according to claim 1 wherein the said compounds having structural formula 7caa and 7cbb as shown below:
7caa, R 1 , R 2 = -CH 2 CH 2 CH 2 CH 2 - 7cbb, R 1 , R 2 = -CH 2 CH 2 CH 2 CH 2 CH 2 -
13. Novel hydroxy functionalized 1, 2, 4-trioxane according to claim 1 wherein the said compounds having structural formula 7ccc as shown below:
14. Novel hydroxy functionalized 1, 2, 4-trioxane according to claim 1 wherein the representative compound of formula 7 comprises:
• 2-(7- {4-[ 1 -(6,7, 10-Trioxa-spiro[4.5]dec-8-yl)-vinyl]-phenoxy} -naphthalen-2-yloxy)-ethanol (7aa).
• 2-(7-{4-[l-(l,2,5-Trioxa-spiro[5.5]undec-3-yl)-vinyl]-phenoxy}-naphthalen-2-yloxy)-ethanol (7ab).
• 2-(7-{4-[l-(3,3-Dimethyl-[l,2,4]trioxan-6-yl)-vinyl]-phenoxy}-naphthalen-2-yloxy)-ethanol (7ac).
• Adamentyl substituteted trioxane compound 7ad
• 2-(7- {4-[ 1 -( 1 ,2,5-Trioxa-spiro[5.6]dodec-3 -yl)-vinyl]-phenoxy } -naphthalen-2-yloxy)-ethanol (7ae).
• Succinic acid mono-[2-(7-{4-[l-(6,7,10-trioxa-spiro[4.5]dec-8-yl)-vinyl]-phenoxy}- naphthalen-2-yloxy)-ethyl] ester (7aaa).
• Succinic acid mono-[2-(7-{4-[l-(l,2,5-trioxa-spiro[5.5]undec-3-yl)-vinyl]-phenoxy}- naphthalen-2-yloxy)-ethyl] ester (7abb). • Succinic acid mono-[2-(7-{4-[l-(3,3-dimethyl-[l,2,4]trioxan-6-yl)-vinyl]-phenoxy}- naphthalen-2-yloxy)-ethyl] ester (7acc).
• Adamentyl substituteted trioxane compound 7add.
• Succinic acid mono-[2-(7-{4-[l-(l,2,5-trioxa-spiro[5.6]dodec-3-yl)-vinyl]-phenoxy}- naphthalen-2-yloxy)-ethyl] ester (7aee).
• 2-(5-{4-[l-(6,7,10-Trioxa-spiro[4.5]dec-8-yl)-vinyl]-phenoxy}-naphthalen-l-yloxy)-etlianol (7ba).
• 2-(5- {4-{ 1 -( 1 ,2,5-Trioxa-spiro[5.5]undec-3 -yl)-vinyl]-phenoxy}-naphthalen- l-yloxy)-ethanol (7bb).
• 2-(5- {4- [ 1 -(3 ,3 -Dimethyl-[ 1 ,2,4]trioxan-6-yl)-vinyl]-phenoxy } -naphthalen- 1 -yloxy)-ethanol (7bc).
• Adamentyl substituteted trioxane compound 7bd .
• Succinic acid mono-[2-(5-{4-[l-(6,7,10-trioxa-spiro[4.5]dec-8-yl)-vinyl]-phenoxy}- naphthalen-l-yloxy)-ethyl] ester (7baa).
• Succinic acid mono-[2-(5-{4-[l-(l,2,5-trioxa-spiro[5.5]undec-3-yl)-vinyl]-phenoxy}- naphthalen-l-yloxy)-ethyl] ester (7bbb).
• Succinic acid me i-[2-(5-{4-[l-(3,3-dimethyl-[l,2,4]trioxan-6-yl)-vinyl]-phenoxy}- naphthalen-l-yloxy)-ethyl] ester (7bcc).
• 7bdd. Adamentyl substituteted trioxane compound
• 2-(4-{4-[l-(6,7,10-Trioxa-spiro[4.5]dec-8-yl)-vinyl]-phenoxy}-phenoxy)-ethanol (7ca).
• 2-(4-{4-[l-(l,2,5-Trioxa-spiro[5.5]undec-3-yl)-vinyl]-phenoxy}-phenoxy)-ethanol (7cb).
• Adamentyl substituteted trioxane compound 7cc.
• Succinic acid mono-[2-(4-{4-[l-(6,7,10-trioxa-spiro[4.5]dec-8-yl)-vinyl]-phenoxy}- phenoxy)-ethyl] ester (7caa).
• Succinic acid mono-[2-(4-{4-[l-(l,2,5-trioxa-spiro[5.5]undec-3-yl)-vinyl]-phenoxy}- phenoxy)-ethyl] ester (7cbb).
• Adamentyl substituteted trioxane compound 7ccc.
15. A process for the preparation of novel hydroxyl functionalised 1, 2, 4-trioxanes of general formula 7 wherein Ri and R 2 represents methyl, or part of a cyclic system such as cyclopentane, cyclohexane, cycloheptane, adamantane and A is a spacer such as oxygen substituted aiyl group and R3 is CH 2 CH 2 OH or CH 2 CH 2 OCOCH 2 CH 2 COOH and the said process comprising the steps of: i.) reacting/?- fluoroacetophenone with a dihydroxy aromatic hydrocarbon selected from the group consisting of as 2,7-dihydroxynaphthalene of formula Ia, 1,5- dihydroxynaphthalene of formula Ib, quinol of formula Ic, in presence of anhyd. K 2 Cθ 3 in an aprotic organic solvent such as dimethylsulfoxide (DMSO), N, N dimethylacetamide at a temperature in the range of 140 0 C to 160 0 C, to obtain hydroxy functionalized keto compounds of general formula 2,
ii) reacting the hydroxy functionalized ketones of formula 2, obtained in step (a) with ethyl chloroacetate in the presence of anhydrous K 2 CO 3 in an aprotic organic solvent at a temperature ranging between 50-70 0 C to refluxing to give keto esters of formula 3
iii) reacting keto esters of general formula 3, obtained in step (b) with triethylphosphonoacetate in presence of sodium hydride in aprotic organic solvents selected from the group consisting of THF, DME at room temperature(20-35 0 C) to give α, β-unsaturated esters of general formula 4,
iv) reducing α, β-esters of general formula 4, with LiAlELt in solvents selected from the group consisting of THF, diethyl ether at 0-5 0 C to give allylic alcohols of general formula 5, and then photooxygenating the said allylic alcohols, in presence of a photo-sensitizer selected from the group consisting of methylene blue, Rose Bengal in a solvent selected from the group consisting of CH 3 CN, THF, MeOH, CHCl 3 at a temperature ranging between O 0 C to -10 0 C for a period ranging between 6-8 h to furnish β- hydroxyhydroperoxides of general formula 6,
v) reacting the β-hydroxyhydroperoxides of general formula 6, obtained in step (d) in situ with ketones selected from the group consisting of acetone, cyclopentanone, cyclohexanone, cycloheptanone, adamantanone in presence of an acid catalyst at temperature in the range of O 0 C to room temperature(20- 35 0 C) to furnish hydroxy functionalized 1,2,4-trioxanes of general formula 7 wherein Ri and R 2 represents methyl, or a part of a cyclic system such as cyclopentane, cyclohexane, adamantane and A is a spacer such as oxygen substituted aryl group and R 3 is CH 2 CH 2 OH,
R 3 = CH 2 CH 2 OH 1 CH 2 CH 2 OCOCH 2 CH 2 COOH 7
vi) reacting the hydroxyl functionalised 1,2,4-trioxanes as obtained in step (e) with succinic anhydride, triethyl amine and DMAP in a solvent selected from a group consisting of DCM, CHCI 3 or any other nonprotic solvent like ether THF, benzene under stirring for a period ranging between 3h-6h, further quenching the reaction mixture and isolating the hydroxy functionalized 1,2,4-trioxanes of general formula 7 wherein Ri and R 2 represents methyl, or a part of a cyclic system such as cyclopentane, cyclohexane, adamantane and A is a spacer such as oxygen substituted aryl group and R 3 is CH 2 CH 2 OCOCH 2 CH 2 COOH,
R 3 = CH 2 CH 2 OCOCH 2 CH 2 COOH
vii) purifying the products by column chromatography using silica gel and ethyl acetate: hexane as eluant.
16. A pharmaceutical composition comprising an effective amount of the compound of general formula 7 according to claim 1, wherein R 1 and R 2 represent methyl group or the part of cyclic ring systems like cyclohexane, cyclopentane, cycloheptane and adamantane A is a spacer such as oxygen or oxygen substituted aromatic moieties and R 3 is CH 2 CH 2 OH or CH 2 CH 2 OCOCH 2 CH 2 COOH optionally adding with the pharmaceutically acceptable additive, carrier.
R 3 = CH 2 CH 2 OH 1 CH 2 CH 2 OCOCH 2 CH 2 COOH
7
Fig l
17. A composition according to claim 16 wherein the composition is administered through oral or intramuscular route.
18. A composition according to claim 16, wherein diluent is selected from the group consisting of edible oils such as groundnut oil or aqueous bicarbonate solution.
19. A composition according to claim 16, wherein the composition is effective to suppress parasitaemia upto 100% at a dose ranging between 12-96mg/kg body wt.
20. A method of treating malaria comprising the steps of administrating the effective amount of the composition according to claim 16 optionally along with the diluents or carrier to the subject in need thereof. |
NOVEL HYDROXY FUNCTIONALIZED 1, 2, 4-TRIOXANES AS ANTIMALARIAL AGENTS AND A PROCESS FOR THE PREPARATION THEREOF
FIELD OF INVENTION
The present invention relates to a novel series of antimalarial hydroxy functionalized 1, 2, 4-trioxanes of general formula 7.
BACKGROUND OF INVENTION
Malaria is still one of the world's most deadly disease that threatens nearly 40% yield of the world's population and infects approximately 300 to 500 million people annually mainly in tropical and subtropical areas. It is estimated that there are between 1 to 3 million deaths every year due to malaria.
In Africa alone, more than 1 million children under the age of 5 die of malaria each year.
Malaria is a vector borne disease and human infection is caused by four distinct species of a protozoan
Plasmodium, namely P. vivax, P. falciparum, P. ovale, P. malariae. Malaria is transmitted by the 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 18 th 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 liver. Later on several synthetic analogues of quinine Le.chloroquine, mefloquine, primaquine 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 this regard, isolation of artemisinin, a sesquiterpene lactone endoperoxide, from the Chinese traditional medicinal herb Artemisia annua is a landmark in malaria chemotherapy, artemisinin and its semisynthetic derivatives like arteether and artemether have shown tremendous potential as novel antimalarials. These drugs are effective against both chloroquine-sensitive and chloroquine-resistant strains of Plasmodium falciparum, and are presently the drugs of choice for the treatment of multidrug resistant malaria [For reviews and background knowledge of artemisinin ■ and its semisynthetic derivatives see: (a) Klayman, D. L Science 1985, 225, 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 Trop. 2004, 89, 329. (e) O'Neill, P. M.; Posner, G. H. J. Med. Chem. 2004, 47, 2945.]
Primaquine
The limited availability of artemisinin from the natural sources and the fact that it is actually the endoperoxide linkage in the form of 1, 2, 4- trioxane system which is responsible for its antimalarial activity, has led to the present worldwide efforts to develop new structurally simple 1, 2, 4- 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, R. P.; Heterocycles.1999, 51, 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 6316493B1, 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. (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].
The main object of the present invention is to provide novel hydroxy functionalized 1, 2, 4- trioxanes useful as antimalarial agents.
The objective of the present invention is also to provide a process for the preparation of novel hydroxy functionalized 1, 2, 4-trioxanes useful as antimalarial agents.
Summary of the invention:
The present invention provides the novel hydroxy functionalized 1, 2, 4-trioxanes and their derivatives of general formula 7 wherein Ri and R 2 represents methyl, or part of a cyclic system such as cyclopentane, cyclohexane, cycloheptane, adamantane and A is a spacer such as oxygen substituted aryl group and R 3 is CH 2 CH 2 OH or CH 2 CH 2 OCOCH 2 CH 2 COOH useful as antimalarial agents. The invention also provides the process for preparing the said novel compounds. These compounds have been tested for there antimalarials activities against multidrug resistant strain of Plasmodium yoelii Nigeriensis using in Swiss mice.
Accordingly, the present invention provides a novel hydroxy functionalized 1, 2, 4-trioxanes of general formula 7 wherein Ri and R 2 represent methyl group or the part of cyclic ring systems like cyclohexane, cyclopentane, cycloheptane and adamantane, A is a spacer such as oxygen substituted aromatic moieties and R 3 is CH 2 CH 2 OH or CH 2 CH 2 OCOCH 2 CH 2 COOH.
R 3 ' CH 2 CH 2 OH 1 CH 2 CH 2 OGOCH 2 CH 2 COOH
Fig l
In one embodiment of the present invention the novel hydroxy functionalized 1, 2, 4-trioxanes have structural formula 7aa, 7ab, 7ac and 7ae as shown below:
7aa, R 1 , R 2 = -CH 2 CH 2 CH 2 CH 2 - 7ab, R-|, R 2 = -CH 2 CH 2 CH 2 CH 2 CH 2 - 7ac, R 1 , R 2 = Methyl, Methyl 7ae, R 1 , R 2 = -CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 -
In another embodiment of the present invention the Novel hydroxy functionalized 1, 2, 4-trioxane has structural formula 7ad as shown below:
In another embodiment of the present invention the Novel hydroxy functionalized 1, 2, 4-trioxanes have structural formula 7aaa.7abb, 7acc and 7aee as shown below:
7aaa, R 1 , R2 = -CH2CH2CH2CH2- 7abb, R 1 , R 2 = -CH 2 CH 2 CH 2 CH 2 CH 2 - 7acc, Ri, R 2 = Methyl, Methyl 7aββ, R 1 , R 2 = -CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 -
In yet another embodiment of the present invention the Novel hydroxy functionalized 1, 2, 4-trioxane has structural formula 7add as shown below:
7add
In still another embodiment of the present invention the Novel hydroxy functionalized 1, 2, 4- trioxanes have structural formula 7ba, 7bb and 7bc as shown below:
7ba, R 1 , R 2 = -CH 2 CH 2 CH 2 CH 2 - 7bb, R 1 , R 2 = -CH 2 CH 2 CH 2 CH 2 CH 2 - 7bc, R 1 , R 2 = Methyl, Methyl
In another embodiment of the present invention the Novel hydroxy functionalized 1, 2, 4-trioxane has structural formula 7 bd as shown below:
In another embodiment of the present invention the novel hydroxy functionalized 1, 2, 4-trioxanes have structural formula 7baa, 7bbb and 7bcc as shown below:
7baa, R 1 , R 2 = -CH 2 CH 2 CH 2 CH 2 - 7bbb, R 1 , R 2 = -CH 2 CH 2 CH 2 CH 2 CH 2 - 7bcc, R 1 , R 2 = Methyl, Methyl
In yet another embodiment of the present invention the novel hydroxy functionalized 1, 2, 4-trioxane has structural formula 7bdd as shown below:
In still another embodiment of the present invention the novel hydroxy functionalized 1, 2, 4- trioxanes as claimed in claim 1 wherein the said compounds having structural formula 7ca and 7cb as shown below:
7ca, R 1 , R 2 = -CH 2 CH 2 CH 2 CH 2 - 7cb, Rt, R 2 -CH 2 CH 2 CH 2 CH 2 CH 2 -
In still another embodiment of the present invention the novel hydroxy functionalized 1, 2, 4-trioxane has structural formula 7cc as shown below:
In still another embodiment of the present invention the novel hydroxy functionalized 1, 2, 4- trioxanes have structural formula 7caa and 7cbb as shown below:
7caa, R 1 , R 2 = -CH 2 CH 2 CH 2 CH 2 - 7cbb, R 1 , R 2 = -CH 2 CH 2 CH 2 CH 2 CH 2 -
In another embodiment of the present invention the novel hydroxy functionalized 1, 2, 4-trioxane has structural formula 7ccc as shown below:
In yet another embodiment of the present invention the novel hydroxy functionalized 1, 2, 4-trioxane as herein described have the representative compound of formula 7 comprising:
• 2-(7-{4-[l-(6,7,10-Trioxa-spiro[4.5]dec-8-yl)-vinyl]-phenoxy }-naphthalen-2-yloxy)-ethanol (7aa).
• 2-(7- {4-[ 1 -( 1 ,2,5-Trioxa-spiro[5.5]undec-3 -yl)-vinyl]-phenoxy } -naphthalen-2-yloxy)-ethanol (7ab).
• 2-(7- {4-[ 1 -(3 ,3-Dimethyl-[ 1 ,2,4]trioxan-6-yl)-vinyl]-phenoxy} -naphthalen-2-yloxy)-ethanol (7ac).
• Adamentyl substituteted trioxane compound 7ad.
• 2-(7-{4-[l-(l,2,5-Trioxa-spiro[5.6]dodec-3-yl)-vinyl]-phenox y}-naphthalen-2-yloxy)-ethanol (7ae).
• Succinic acid mono-[2-(7-{4-[l-(6,7,10-trioxa-spiro[4.5]dec-8-yl)-vinyl]-p henoxy}- naphthalen-2-yloxy)-ethyl] ester (7aaa).
• Succinic acid mono-[2-(7-{4-[l-(l,2,5-trioxa-spiro[5.5]undec-3-yl)-vinyl]- phenoxy}- naphthalen-2-yloxy)-ethyl] ester (7abb).
• Succinic acid mono-[2-(7-{4-[l-(3,3-dimethyl-[l,2,4]trioxan-6-yl)-vinyl]-p henoxy}- naphthalen-2-yloxy)-ethyl] ester (7acc).
• Adamentyl substituteted trioxane compound 7add.
• Succinic acid mono-[2-(7-{4-[l-(l,2,5-trioxa-spiro,[5.6]dodec-3-yl)-vinyl] -phenoxy}- naphthalen-2-yloxy)-ethyl] ester (7aee).
• 2-(5-{4-[l-(6,7,10-Trioxa-spiro[4.5]dec-8-yl)-vinyl]-phenoxy }-naphthalen-l-yloxy)-ethanol (7ba).
• 2-(5-{4-[l-(l,2,5-Trioxa-spiro[5.5]undec-3-yl)-vinyl]-phenox y}-naphthalen-l-yloxy)-ethanol (7bb).
• 2-(5- {4- [ 1 -(3 ,3 -Dimethyl-[ 1 ,2,4]trioxan-6-yl)-vinyl]-phenoxy} -naphthalen- 1 -yloxy)-ethanol 7bc.
• Adamentyl substituteted trioxane compound 7bd.
• Succinic acid mono-[2-(5-{4-[l-(6,7,10-trioxa-spiro[4.5]dec-8-yl)-vinyl]-p henoxy}- naphthalen-l-yloxy)-ethyl] ester (7baa).
• Succinic acid mono-[2-(5-{4-[l-(l,2,5-trioxa-spiro[5.5]undec-3-yl)-vinyl]- phenoxy}- naphthalen-l-yloxy)-ethyl] ester (7bbb).
• Succinic acid mono-[2-(5-{4-[l-(3,3-dimethyl-[l,2,4]trioxan-6-yl)-vinyl]-p henoxy}- naphthalen-l-yloxy)-ethyl] ester (7bcc).
• Adamentyl substituteted trioxane compound 7bdd.
• 2-(4-{4-[l-(6,7,10-Trioxa-spiro[4.5]dec-8-yl)-vinyl]-phenoxy }-phenoxy)-ethanol (7ca).
• 2-(4- {4-[ 1 -( 1 ,2,5-Trioxa-spiro[5.5]undec-3-yl)-vinyl]-phenoxy} -phenoxy)-ethanol (7cb).
• Adamentyl substituteted trioxane compound 7cc.
• Succinic acid mono-[2-(4-{4-[l-(6,7,10-trioxa-spiro[4.5]dec-8-yl)-vinyl]-p henoxy}- phenoxy)-ethyl] ester (7caa).
• Succinic acid mono-[2-(4-{4-[l-(l,2,5-trioxa-spiro[5.5]undec-3-yl)-vinyl]- phenoxy}- phenoxy)-ethyl] ester (7cbb).
• Adamentyl substituteted trioxane compound 7ccc.
Further A process for the preparation of novel hydroxyl functionalised 1, 2, 4-trioxanes of general formula 7 wherein Ri and R 2 represents methyl, or part of a cyclic system such as cyclopentane, cyclohexane, cycloheptane, adamantane and A is a spacer such as oxygen substituted aryl group and R 3 is CH 2 CH 2 OH or CH 2 CH 2 OCOCH 2 CH 2 COOH of formula as shown in Fig 1, and the said process comprising the steps of: a) reacting p- fluoroacetophenone with a dihydroxy aromatic hydrocarbon selected from the group consisting of as 2,7-dihydroxynaphthalene of formula Ia, 1,5- dihydroxynaphthalene of foπnula Ib, quinol of formula Ic, in presence of anhyd. K 2 CO 3 in an aprotic organic solvent such as dimethylsulfoxide (DMSO), N, N dimethylacetamide at a temperature in the range of 140 0 C to 160 0 C, to obtain hydroxy functionalized keto compounds of general formula 2,
b) reacting the hydroxy functionalized ketones of formula 2, obtained in step (a) with ethyl chloroacetate in the presence of anhydrous K 2 CO 3 in an aprotic organic solvent at a temperature ranging between 50-70 0 C to refluxing temperature to give keto esters of formula 3,
c) reacting keto esters of general formula 3, obtained in step (b) with triethylphosphonoacetate in presence of sodium hydride in aprotic organic solvents selected from the group consisting of THF, DME at room temperature (20-35 0 C) to give α, β-unsaturated esters of general formula 4,
d) reducing α, β-esters of general formula 4, with LiAlH 4 in solvents selected from the group consisting of THF, diethyl ether at 0-5 0 C to give allylic alcohols of general formula 5, and then photooxygenating the said allylic alcohols, in presence of a photo-sensitizer selected from the group consisting of methylene blue, Rose Bengal in
a solvent selected from the group consisting of CH 3 CN, THF, MeOH, CHCl 3 at a temperature ranging between 0 0 C to -10 0 C for a period ranging between 6-8 hr to furnish β-hydroxyhydroperoxides of general formula 6,
e) reacting the β-hydroxyhydroperoxides of general formula 6, obtained in step (d) in situ with ketonr -', selected from the group consisting of acetone, cyclopentanone, cyclohexanone, cycloheptanone, adamantanone in presence of an acid catalyst at temperature in the range of 0 0 C to 35 0 C to furnish hydroxy functionalized 1,2,4- trioxanes of general formula 7 wherein Ri and R 2 represents methyl, or a part of a cyclic system such as cyclopentane, cyclohexane, adamantane and A is a spacer such as oxygen substituted aryl group and R 3 is CH 2 CH 2 OH
R 3 = CH 2 CH 2 OH 1 CH 2 CH 2 OCOCH 2 CH 2 COOH
7 f) reacting the hydroxyl functionalised 1,2,4-trioxanes as obtained in step (e) with succinic anhydride, triethyl amine and DMAP in DCM, CHCl 3 or any nonprotic solvent like ether THF, benzene etc. under stirring for a period ranging between 3h- 6h, further quenching the reaction mixture and isolating the hydroxy functionalized 1,2,4-trioxanes of general formula 7 wherein Ri and R 2 represents methyl, or a part of a cyclic system such as cyclopentane, cyclohexane, cycloheptane and adamantane and A is a spacer such as oxygen substituted aryl group and R 3 is CH 2 CH 2 OCOCH 2 CH 2 COOH.
g) purifying the products by column chromatography using silica gel and ethyl acetate: hexane as eluant.
In an embodiment of the present invention a pharmaceutical composition comprising an effective amount of the compound of general formula 7 as claimed in claim 1 wherein Ri and R 2 represent methyl group or the part of cyclic ring systems like cyclohexane, cyclopentane, cycloheptane and adamantane A is a spacer such as oxygen or oxygen substituted aromatic moieties and R3 is CH 2 CH 2 OH or CH 2 CH 2 OCOCH 2 CH 2 COOH. optionally adding with the pharmaceutically acceptable additive, carrier.
R 3 = CH 2 CH 2 OH 1 CH 2 CH 2 OCOCH 2 CH 2 COOH
7
Fig l
In another embodiment of the present invention the composition is administered through oral or intramuscular route.
In yet another embodiment of the present invention the diluent is selected from the group consisting of edible oils such as groundnut oil or aqueous bicarbonate solution.
In still another embodiment of the present invention a composition as claimed in claim 20, wherein the composition is effective to suppress parasitaemia upto 100% at a dose ranging between 12-96 mg/kg body wt.
Further, in an embodiment of the present invention the method of treating malaria comprising the steps of administrating the effective amount of the composition optionally along with the diluents or carrier to the subject in need thereof.
DETAILED DESCRD7TION OF THE INVENTION
This present invention relates to novel hydroxy functionalized 1, 2, 4-trioxanes and their derivatives of general formula 7 useful as antimalarial agents.
R 3 = CH 2 CH 2 OH 1 CH 2 CH 2 OCOCH 2 CH 2 COOH
Fig l
This invention also relates to a process for the preparation of novel 1, 2, 4-trioxanes. More particularly the present invention provides a process for the preparation of 1, 2, 4-trioxanes of general formula 7 wherein Ri and R 2 represents methyl, or part of a cyclic system such as cyclopentane, cyclohexane, cycloheptane, adamantane and A is a spacer such as oxygen substituted aryl group and R 3 is CH 2 CH 2 OH or CH 2 CH 2 OCOCH 2 CH 2 COOH of formula as shown in Fig 1, which comprises reaction of p- fluoroacetophenone with a dihydroxy aromatic hydrocarbon such as 2,7-dihydroxynaphthalene of formula Ia, 1,5-dihydroxynaphthalene of formula Ib, quinol of formula Ic, in presence of anhyd. K 2 CO 3 in an aprotic organic solvent such as dimethylsulfoxide (DMSO), N, N dimethylacetamide in the temperature range of 140 0 C to 160 0 C, to give hydroxy functionalized keto compounds of general formula 2, Fig 2, reacting these hydroxy functionalized ketones of formula 2, Fig 2, with ethyl chloroacetate in the presence of anhydrous K 2 CO 3 in an aprotic organic solvent in the temperature range of room temperature to refluxing temperature to give keto esters of formula 3, Fig 3, reacting keto esters of general formula 3, Fig 3, with triethylphosphonoacetate in presence of sodium hydride in aprotic organic solvents such as THF, DME at room temperature to give α, β-unsaturated esters of general formula 4, Fig 4, reducing α, β-esters of general formula 4, Fig 4, with LiAlH 4 in solvents such as THF, diethyl ether at O 0 C to give allylic alcohols of general formula 5, Fig 5, photooxygenating the allylic alcohols of general formula 5, Fig 5, in presence of a photo-sensitizer such as methylene blue ,Rose Bengal in solvents such as CH 3 CN, THF, MeOH,
CHCl 3 in the temperature range from O 0 C to -10 0 C to furnish β-hydroxyhydroperoxides of general formula 6, Fig 6, reacting β-hydroxyhydroperoxides of general formula 6, Fig 6, in situ with ketones such as acetone, cyclopentanone, cyclohexanone, cycloheptanone, adamantanone in presence of an acid catalyst in the temperature range of 0 0 C to room temperature to furnish hydroxy functionalized 1,2,4-trioxanes of general formula 7 wherein Ri and R 2 represents methyl, or a part of a cyclic system such as cyclopentane, cyclohexane, cycloheptane, adamantane and A is a spacer such as oxygen substituted aryl group and R 3 is CH 2 CH 2 OH or CH 2 CH 2 OCOCH 2 CH 2 COOH of formula as shown in Fig 1, purifying the products by column chromatography using silica gel ( 60-120 mesh ) and ethyl acetate: hexane as eluant.
In the process the reactions of /?- fluoroacetophenone with 2, 7-dihydroxynaphthalene Ia, 1, 5- dihydroxynaphthalene Ib, quinol Ic, is accomplished in presence of anhyd. K 2 CO 3 in aprotic organic solvents such as dimethylsulfoxide (DMSO), in the temperature range of 140 0 C-IoO 0 C to give hydroxy functionalized keto compounds of general formula 2, Fig 2, These hydroxy functionalized keto compounds of general formula 2, Fig 2, were isolated and purified by standard laboratory methods such as column chromatography or crystallization.
A hydroxy functionalized keto compound of formula 2c is known compound (J. Chem. Soc, 1942, 347-352) whereas hydroxy functionalized keto compounds of formula 2a-b are new compounds and have not been prepared earlier.
In the process, hydroxy functionalized keto compounds of general formula 2, Fig 2, are reacted with ethyl chloroacetate in the presence of anhydrous K 2 CO 3 in an aprotic organic solvent like acetone in the temperature range of room temperature to refluxing temperature to give keto esters compounds of formula 3, Fig 3. These keto esters compounds of formula 3, Fig 3, were isolated and purified by standard laboratory methods such as column chromatography or crystallization.
Keto esters compounds of formula 3, Fig 3, are new compounds and have not been prepared earlier
In the process, reaction of keto esters compounds of general formula 3, Fig 3, with triethylphosphonoacetate is accomplished in the presence of a base such as sodium hydride in aprotic organic solvent such as dry THF, dry DME etc .at room temperature to furnish α, β-unsaturated esters of general formula 4, Fig 4.
These α, β-unsaturated esters of general formula 4, Fig 4, were isolated and purified by standard laboratory methods such as column chromatography or crystallization.
These α, β-unsaturated esters of general formula 4, Fig 4, are new compounds and have not been prepared earlier.
In the process α, β-unsaturated esters of general formula 4, Fig 4, were reduced with LiAlH 4 in solvents such as dry THF, diethyl ether at O 0 C to furnish allylic alcohols of general formula 5, Fig 5,
were isolated and purified by standard laboratory methods such as column chromatography or crystallization.
These allylic alcohols of general formula 5, Fig 5, are new compounds and have not been prepared earlier.
In the process, the photooxygenation of the allylic alcohols of general formula 5, Fig 5, was effected by passing oxygen or air in the solution of the allylic alcohols in organic solvents such as CH 3 CN
,THF, MeOH, CHCl 3 in the presence of a photo sensitizer such as methylene blue ,Rose Bengal and light source which provided visible light for a period in the range of 6 to 8 h, to furnish β- hydroxyhydroperoxides of general formula 6,Fig 6, which on in situ condensation with ketones such as acetone, cyclopentanone, cyclohexanone, cycloheptanone, adamantanone in presence of an acid catalyst in the temperature range of O 0 C to room temperature furnished hydroxy functionalized 1, 2, 4- trioxanes of general formula 7 wherein Rj and R 2 represents methyl, or part of a cyclic system such as cyclopentane, cyclohexane, cycloheptane,adamantane and A is a spacer such as oxygen substituted aryl group and R 3 is CH 2 CH 2 OH or CH 2 CH 2 OCOCH 2 CH 2 COOH of formula as shown in Fig 1. These hydroxy functionalized 1, 2, 4-trioxanes of formula 7 were purified by column chromatography using silica gel (60-120 mesh) and ethyl acetate: hexane as eluant.
These hydroxy functionalized 1, 2, 4-trioxanes of general formula 7 are new chemical entities and have not been prepared earlier.
These novel hydroxy functionalized 1, 2, 4-trioxanes and their derivatives of general formula 7 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 construed to limit the scope of present invention.
EXAMPLE-I l.l-[4-(7-Hydroxy-naphthalen-2-yloxy)-phenyl]- ethanone, 2a (general formula 2, Fig 2)
A mixture of 4-fluόroacetophenone (17 niL) and 2, 7-dihydroxynaphthalene Ia (39.42 g, 2 equivalent), and anhyd.K 2 CO 3 (136.38 g, 4 equivalent) in DMSO (50 mL) was refluxed for 1.25 h. with continuous stirring. The reaction mixture was cooled to room temperature, diluted with water (100 mL) and extracted with ether (3 x 200 mL). The organic layer was dried over anhyd. Na 2 SO 4 and concentrated to furnish a crude mixture, which was purified by column chromatography over 60-120 mesh silica gel using EtOAc/Hexane (2:98) as eluant, furnished 14 g (40.88 % yield) of pure product l-[4-(7-Hydroxy-naphthalen-2-yloxy)-phenyl]- ethanone 2a as a white solid m.p. 140 0 C.
EXAMPLE-2
2. [7-(4-Acetyl-phenoxy)-naphthalen-2-yloxy]-acetic acid ethyl ester, 3a (general formula
3, Fig 3)
A mixture of 8 g l-[4-(7-Hydroxy-naphthalen-2-yloxy)-phenyl]- ethanone 2a, ethyl chloro acetate (5.12 mL, 1.5 equivalent) and anhydrous K 2 CO 3 (13.46 g, 3 equivalent ) in acetone (50 mL) was refluxed for 8 h. Reaction mixture was concentrated to 20 mL, diluted with water (100 mL) and extracted with ethyl acetate (3 x 50 mL). Combined organic was washed with saturated brine solution, dried over anhydrous Na 2 SC^ and concentrated and the crude product was chromatographed on silica gel using ethyl acetate/hexane (2:98) as eluant, furnished 9 g (85.95% yield) of pure product [7-(4- Acetyl-phenoxy)-naphthalen-2-yloxy] -acetic acid ethyl ester 3a as a white solid m.p. 115-120
0 C.
EXAMPLE-3
3. 3- [4-(7-Ethoxycarbonylmethoxy-naphthalen-2-yloxy)-phenyl] -but-2-enoic acid)ethyl ester, 4a (general formula 4, Fig 4)
To a stirred slurry of NaH (60 % dispersion in mineral oil, 3.18 g, 2 equivalent), in dry THF (20 mL) kept at O 0 C under N 2 atmosphere, a solution of triethylphosphonoacetate (15.24 mL, 2 equivalent) in dry THF (50 mL) was added, and the reaction mixture was allowed to stir at room temperature for 1 h. To this reaction mixture [7-(4-Acetyl-phenoxy)-naphthalen-2-yloxy] -acetic acid ethyl ester 3a (14 g) dissolved in dry THF (100 mL) was added and the reaction mixture was further stirred at room temperature for 20 h. The reaction mixture was quenched with water (100 mL), extracted with ether (3 x 200 mL). The organic layer was dried over anhyd. Na 2 SO 4, concentrated and purified by column chromatography over silica gel (60-120 mesh) using EtOAc/Hexane (1:99) as eluant to furnish as oil 9 g cis-trans α, β-unsaturated ester (83.87 % yield) of pure product 3-[4-(7- Ethoxycarbonylmethoxy-naphthalen-2-yloxy)-phenyl]-but-2-enoi c acid) ethyl ester 4a as an oil.
EXAMPLE-4
4. 3-{4-[7-(2-Hydroxy-ethoxy)-naphthalen-2-yloxy]-phenyl}-but-2 -en-l-ol, 5a (general formula 5, Fig 5)
To a magnetically stirred, ice-cooled mixture of LiAlH t (3.5 g, 4equivalent) in dry THF (100 mL) 3- [4-(7-Ethoxycarbonylmethoxy-naphthalen-2-yloxy)-phenyl]-but- 2-enoic acid) ethyl ester 4a (10 g) was added under nitrogen atmosphere and the reaction mixture was allowed to stir for 1 h at O 0 C. The reaction mixture was quenched with water (10 mL) and 5% aqueous NaOH (5 mL). The organic layer was decanted and dried over anhyd. Na 2 SO 4 , concentrated to furnish a crude mixture
which on crystallization in hot ethyl acetate to furnish 5.98 g (74.19 % yield) of pure product 3-{4- [7-(2-Hydroxy-ethoxy)-naphthalen-2-yloxy]-phenyl}-but-2-en-l -ol 5a as a white solid m.p.120
0 C.
EXAMPLE-5
5. 2-(7-{4-[l-(6,7,10-Trioxa-spiro[4.5]dec-8-yl)-vinyl]-phenoxy }-naphthalen-2-yloxy)- ethanol,7aa (general formula 7, Fig 7)
A solution of allyl alcohol 5a (0.7 g) and methylene blue (5 mg), in a mixture of acetonitrile (100 mL) and THF (100 mL) was irradiated with 500 W tungsten -halogen lamp at 0 0 CtO -10 0 C, while a slow stream of O 2 was bubbled into the reaction mixture for 6 h. The reaction mixture consisting of β- hydroxyhydroperoxide 6a (general formula 6, Fig 6) was concentrated on a rotatory evaporator at room temperature, dissolved in acetonitrile (100 mL). Cyclopentanone (1.68 mL, 4 equivalent) and cone. HCl (0.5 mL) were added and the reaction mixture was stirred for Ih at room temperature. The reaction mixture was concentrated, and the crude product was purified by column chromatography over silica gel (60-120 mesh) using EtOAc/Hexane (5:95) as eluant furnished 480 mg (53.93 % yield) of pure product 2-(7-{4-[l-(6,7,10-Trioxa-spiro[4.5]dec-8-yl)-vinyl]-phenoxy }-naphthalen-2- yloxy)-ethanol 7aa as a white solid m.p.76-80 0 C.
EXAMPLE-6
6. 2-(7-{4-[l-(l,2,5-Trioxa-spiro[5.5]undec-3-yl)-vinyl]-phenox y}-naphthalen-2-yloxy)- ethanol,7ab (general formula 7, Fig 7)
A solution of allyl alcohol 5a (0.7 g) and methylene blue (5 mg), in a mixture of acetonitrile (100 mL) and THF (100 mL) was irradiated with 500 W tungsten -halogen lamp at 0 0 CtO -10 0 C, while a slow stream of O 2 was bubbled into the reaction mixture for 6 h. The reaction mixture consisting of β- hydroxyhydroperoxide 6a (general formula 6, Fig 6) was concentrated on a rotatory evaporator at room temperature, dissolved in acetonitrile (100 mL). Cyclohexanone (1.9 mL, 4 equivalent) and cone. HCl (0.5 mL) were added and the reaction mixture was stirred for Ih at room temperature. The reaction mixture was concentrated, and the crude product was purified by column chromatography over silica gel (60-120 mesh) using EtOAc/Hexane (5:95) as eluant furnished 550 mg (59.52% yield) of pure product 2-(7-{4-[l-(l,2 5 5-Trioxa-spiro[5.5]undec-3-yl)-vinyl]-phenoxy}-naphthalen-2- yloxy)-ethanol 7ab as a white solid m.ρ.107-109 0 C.
EXAMPLE-7
7. 2-(7-{4-[l-(3,3-Dimethyl-[l,2,4]trioxan-6-yl)-vinyl]-phenoxy }-naphthalen-2-yloxy)- ethanol,7ac (general formula 7, Fig 7)
A solution of allyl alcohol 5a (0.5 g) and methylene blue (5 mg), in a mixture of acetonitrile (100 mL) and THF (100 mL) was irradiated with 500 W tungsten -halogen lamp at 0 0 C to -10 0 C, while a slow stream of O 2 was bubbled into the reaction mixture for 6 h. The reaction mixture consisting of β- hydroxyhydroperoxide 6a (general formula 6, Fig 6) was concentrated on a rotatory evaporator at room temperature, dissolved in acetonitrile (100 mL). Acetone (20 mL) and cone. HCl (0.5 mL) were added and the reaction mixture was stirred for Ih at room temperature. The reaction mixture was concentrated, and the crude product was purified by column chromatography over silica gel (60-120 mesh) using EtOAc/Hexane (5:95) as eluant furnished 360 mg (59.69 % yield) of pure product 2-(J- {4-[l-(3,3-Dimethyl-[l,2,4]trioxan-6-yl)-vinyl]-plienoxy}-na phthalen-2-yloxy)-ethanol 7ac as a white solid m.p.l 12-115 0 C.
EXAMPLE-8
8. Trioxane 7ad (general formula 7, Fig 7, R 1 , R 2 = part of adamantyl)
A solution of allyl alcohol 5a (0.7 g) and methylene blue (5 mg) in a mixture of acetonitrile (100 mL) and THF (100 mL) was irradiated with 500 W tungsten -halogen lamp at 0 0 CtO -10 0 C, while a slow stream of O 2 was bubbled into the reaction mixture for 6 h. The reaction mixture consisting of β- hydroxyhydroperoxide 6a (general formula 6, Fig 6) was concentrated on a rotatory evaporator at room temperature, dissolved in acetonitrile (100 mL). Adamantanone (1.71 g, 4 equivalent) and cone. HCl (0.5 mL) were added and the reaction mixture was stirred for Ih at room temperature. The reaction mixture was concentrated, and the crude product was purified by column chromatography over silica gel (60-120 mesh) using EtOAc/Hexane (5:95) as eluant furnished 634 mg (61.67 % yield) of pure product 7ad as a white solid m.p.60-63°C.
EXAMPLE-9
9.2-(7-{4-[l-(l,2,5-Trioxa-spiro[5.6]dodec-3-yl)-vinyl]-p henoxy}-naphthalen-2-yloxy)- ethanol,7ae (general formula 7, Fig 7)
A solution of allyl alcohol 5a (1.2 g) and methylene blue (5 mg), in a mixture of acetonitrile (150 mL) and THF (100 mL) was irradiated with 500 W tungsten -halogen lamp at 0 0 CtO -10 0 C, while a slow stream of O 2 was bubbled into the reaction mixture for 6 h. The reaction mixture consisting of β- hydroxyhydroperoxide 6a (general formula 6, Fig 6) was concentrated on a rotatory evaporator at room temperature, dissolved in acetonitrile (100 mL). Cycloheptanone (3.2 mL, 5 equivalents) and
cone. HCl (0.5 mL) were added and the reaction mixture we ■:. stirred for Ih at room temperature. The reaction mixture was concentrated, and the crude product was purified by column chromatography over silica gel (60-120 mesh) using EtOAc/Hexane (5:95) as eluant furnished 675 mg (42.18 % yield) of pure product 2-(7-{4-[l-(l,2,5-Trioxa-spiro[5.6]dodec-3-yl)-vinyl]-phenox y}-naphthalen-2- yloxy)-ethanol 7ae as an oil.
EXAMPLE-10
10.Succinic acid mono-[2-(7-{4-[l-(6,7,10-trioxa-spiro[4.5]dec-8-yl)-vinyl]-p henoxy}- naphthalen-2-yloxy)-ethyI] ester,7aaa (general formula 7, Fig 7)
A solution of 7aa (150 mg), Et 3 N (0.09 mL, 2 equivalent), succinic anhydride (100 mg, 3 equivalent) and DMAP (2 mg) in DCM (20 mL) was stirred for 3h. Reaction mixture was quenched by adding 10% HCl solution and extracted with DCM (2 x 25 mL). Solvent was evaporated and crude product was isolated and purified by the column chromatography over silica gel (60-120 mesh) using EtOAc/Hexane (50:50) as eluant furnished 160 mg (87.43 % yield) of pure product Succinic acid mono-[2-(7-{4-[l-(6,7,10-trioxa-spiro[4.5]dec-8-yl)-vinyl]-p henoxy}-naphthalen-2-yloxy)- ethyl] ester 7aaa as a white solid m.p.85-90 0 C.
EXAMPLE-Il
11. Succinic acid mono-[2-(7-{4-[l-(l,2,5-trioxa-spiro[5.5]undec-3-yl)-vinyI]- phenoxy}- naphthalen-2-yloxy)-ethyl] ester,7abb (general formula 7, Fig 7)
A solution of 7ab (200 mg), Et 3 N (0.12 mL, 2 equivalent), succinic anhydride (129 mg, 3 equivalent) and DMAP (2 mg) in DCM (20 mL) was stirred for 3 h. Reaction mixture was quenched by adding 10% HCl solution and extracted with DCM (2 x 25 mL). Solvent was evaporated and crude product was isolated and purified by the column chromatography over silica gel (60-120 mesh) using EtOAc/ Hexane (50:50) as eluant furnished 190 mg (78.18 % yield) of pure product Succinic acid mono-[2- (7- {4- [ 1 -(1 ,2,5-trioxa-spiro [5.5]undec-3 -yl)-vinyl] -phenoxy } -naphthalen-2-yloxy)-ethyl] ester 7abb as a white solid m.p.115-120 0 C.
EXAMPLE-12
12. Succinic acid mono-[2-(7-{4-[l-(3,3-dimethyl-[l,2,4]trioxan-6-yl)-vinyl]-p henoxy}- naphthalen-2-yloxy)-ethyl] ester, 7acc (general formula 7, Fig 7)
A solution of 7ac (150 mg), Et 3 N (0.097 mL, 2 equivalent), succinic anhydride (106 mg, 3 equivalent) and DMAP (2 mg) in DCM (20 mL) was stirred for 3h. Reaction mixture was quenched by adding 10% HCl solution and extracted with DCM (2 x 25 mL). Solvent was evaporated and crude product was isolated and purified by the column chromatography over silica gel (60-120 mesh) using EtOAc/
Hexane (50:50) as eluant furnished 150 mg (81.08 % yield) of pure product Succinic acid mono-[2^ (7- {4- [ 1 -(3 ,3-dimethyl- [ 1 ,2,4]trioxan-6-yl)-vinyl]-phenoxy } -naphthalen-2-yloxy)-ethyl] ester 7acc as a white solid m.p.l 18-120 0 C.
EXAMPLE-13
13. Trioxane 7add (general formula 7, Fig 7, R 1 , R 2 = part of adamantyl)
A solution of 7ad (150 mg), Et 3 N (0.813 mL, 2 equivalent), succinic anhydride (116 mg, 3 equivalent) and DMAP (2 mg) in DCM (20 mL) was stirred for 3h. Reaction mixture was quenched by adding 10% HCl solution and extracted with DCM (2 x 25 mL). Solvent was evaporated and crude product was isolated and purified by the column chromatography over silica gel (60-120 mesh) using EtOAc/Hexane (50:50) as eluant furnished 180 mg (75.63 % yield) of pure product 7add as an oil.
EXAMPLE-14
14. Succinic acid mono-[2-(7-{4-[l-(l,2,5-trioxa-spiro[5.6]dodec-3-yl)-vinyl]- phenoxy}- naphthalen-2-yloxy)-ethyl] ester, 7aee (general formula 7, Fig 7)
A solution of 7ae (100 mg), Et 3 N (0.087 mL, 2 equivalent), succinic anhydride (63 mg, 3 equivalent) and DMAP (2 mg) in DCM (20 mL) was stirred for 5 h. Reaction mixture was quenched by adding 10% HCl solution and extracted with DCM (2 x 25 mL). Solvent was evaporated and crude product was isolated and purified by the column chromatography over silica gel (60-120 mesh) using EtOAc/ Hexane (50:50) as eluant furnished 110 mg (90.90 % yield) of pure product Succinic acid mono-[2- (7-{4-[l-(l ,2,5-trioxa-spiro [5.6]dodec-3 -yl)- vinyl] -phenoxy } -naphthalen-2-yloxy)-ethyl] ester 7aee as an oil.
EXAMPLE-15
15. l~[4-(5-Hydroxy-naphthalen-l-yloxy)-phenyl]-ethanone, 2b (general formula 2, Fig
2)
A mixture of 4-fluoroacetophenone (17 mL) and 1, 5-dihydroxynaphthalene Ib (39.42 g, 2 equivalent) and anhyd.K 2 CO 3 (136.38 g, 4 equivalent) in DMSO (50 mL) was refluxed for 2 h. with continuous stirring. The reaction mixture was cooled to room temperature, diluted with water (100 mL) and extracted with ether (3 x 200 mL). The organic layer was dried over anhyd. Na 2 SO 4 and concentrated to furnish a crude mixture, which was purified by column chromatography over 60-120 mesh silica gel using EtOAc/Hexane (2:98) as eluant furnished 10 g (31.07 % yield) of pure product l-[4-(5-Hydroxy-naphthalen-l-yloxy)-phenyl]-ethanone 2b as a white solid m.p. 175-177 0 C.
EXAMPLE-16
16. [5-(4-Acetyl-phenoxy)-naphthalen-l-yloχy]-acetic acid ethyl ester, 3b (general formula 3, Fig 3)
A mixture of 1 g l-[4-(5-Hydroxy-naphthalen-l-yloxy)-phenyl]-ethanone 2b, ethyl chloro acetate (0.8 mL, 2 equivalent) and anhydrous K 2 CO 3 (0.99 g, 2 equivalent) in acetone (50 mL) was refluxed for 8 h. Reaction mixture was concentrated to 20 mL, diluted with water (100 mL) and extracted with ethyl acetate (3 x 50 mL). Combined organic was washed with saturated brine solution, dried over anhydrous Na 2 SC^ and concentrated and the crude product was chromatographed on silica gel using EtOAc/Hexane (2:98) as eluant furnished 1.2 g (92.30% yield) of pure product [5- (4-Acetyl-phenoxy)-naphthalen-l-yloxy]-acetic acid ethyl ester 3b as a white solid m.p. 95-98 0 C.
EXAMPLE-17
17. 3-[4-(5-Ethoxycarbonylmethoxy-naphthalen-l-yloxy)-phenyl]-bu t-2-enoic acid ethyl ester, 4b (general formula 4, Fig 4)
To a stirred slurry of NaH (60 % dispersion in mineral oil, 2.30 g, 2 equivalent) in dry THF (20 mL) kept at O 0 C under N 2 atmosphere, a solution of triethylphosphonoacetate (11.44 mL, 2 equivalent) in dry THF (50 mL) was added, and the reaction mixture was allowed to stir at rt for 1 h. To this reaction mixture [5 -(4-Acetyl-phenoxy)-naphthalen-l-yloxy] -acetic acid ethyl ester 3b (10.5 g) dissolved in dry THF (100 mL) was added and the reaction mixture was further stirred at room temperature for 21 h. The reaction mixture was quenched with water (100 mL), extracted with ether (3 x 200 mL). The organic layer was dried over anhyd. Na 2 SO^ concentrated and purified by column chromatography over 60-120 mesh silica gel using (2:98) EtOAc/Hexane as eluant to furnish 11.5 g cis-trans α, β-unsaturated ester (92.00 % yield) of pure product 3-[4-(5-Ethoxycarbonylmethoxy- naphthalen-l-yloxy)-phenyl]-but-2-enoic acid ethyl ester 4b as an oil.
EXAMPLE-18
18. 3-{4-[5-(2-Hydroxy-ethoxy)-naphthalen-l-yloxy]-phenyl}-but-2 -en-l-ol, 5b (general formula 5, Fig 5)
To a magnetically stirred, ice-cooled mixture of LiAlH t (2.62 g, 3 equivalent) in dry THF (100 mL) 3-[4-(5-Ethoxycarbonylmethoxy-naphthalen-l-yloxy)-phenyl]-bu t-2-enoic acid ethyl ester 4b (10 g) was added under nitrogen atmosphere and the reaction mixture was allowed to stir for 1 h at O 0 C. The reaction mixture was quenched with water (10 mL) and 5% aqueous NaOH (5 mL). The organic layer was decanted and dried over anhyd. Na 2 Sθ4, concentrated to furnish a crude mixture
which on crystallization in hot ethyl acetate to furnish 6.88 g (85.27 % yield) of pure product 3-{4- [5-(2-Hydroxy-ethoxy)-naphthalen-l-yloxy]-phenyl}-but-2-en-l -ol 5b as a white solid m.p.ll4-117 °C.
EXAMPLE-19
19.2-(5-{4-[l-(6,7,10-Trioxa-spiro[4.5]dec-8-yl)-vmyl]-ph enoxy}-naphthalen-l-yloxy)- ethanol, 7ba (general formula 7, Fig 7)
A solution of allyl alcohol 5b (1 g) and methylene blue (5 mg) in a mixture of acetonitrile (100 mL) and THF (100 mL) was irradiated with 500 W tungsten -halogen lamp at 0 0 C to -10 0 C, while a slow stream of O 2 was bubbled into the reaction mixture for 8 h. The reaction mixture consisting of β- hydroxyhydroperoxide 6b (general formula 6, Fig 6) was concentrated on a rotatory evaporator at room temperature, dissolved in acetonitrile (100 mL). Cyclopentanone (1.20 mL, 5 equivalent) and cone. HCl (0.5 mL) were added and the reaction mixture was stirred for Ih at room temperature. The reaction mixture was concentrated and the crude product was purified by column chromatography over silica gel (60-120 mesh) using EtOAc/Hexane (5:95) as eluant furnished 744 mg (58.12 % yield) of pure product 2-(5-{4-[l-(6,7,10-Trioxa-spiro[4.5]dec-8-yl)-vinyl]-phenoxy }-naphthalen-l- yloxy)-ethanol 7ba as an oil.
EXAMPLE-20
20. 2-(5-{4-[l-(l,2,5-Trioxa-spiro[5.5]undec-3-yl)-vinyl]-phenox y}-naphthalen-l-yloxy)- ethanol, 7bb (general formula 7, Fig 7)
A solution of allyl alcohol 5b (1 g) and methylene blue (5 mg) in a mixture of acetonitrile (150 mL) and THF (100 mL) was irradiated with 500 W tungsten -halogen lamp at 0 0 C to -10 0 C, while a slow stream of O 2 was bubbled into the reaction mixture for 8 h. The reaction mixture consisting of β- hydroxyhydroperoxide 6b (general formula 6, Fig 6 ) was concentrated on a rotatory evaporator at room temperature, dissolved in acetonitrile (100 mL).Cyclohexanone (2.8 mL, 10 equivalent) and cone. HCl (0.5 mL) were added and the reaction mixture was stirred for Ih at room temperature. The reaction mixture was concentrated and the crude product was purified by column chromatography over silica gel (60-120 mesh) using EtOAc/Hexane (15:85) as eluant furnished 630 mg (47.72 % yield) of pure product 2-(5-{4-[l-(l,2,5-Trioxa-spiro[5.5]undec-3-yl)-vinyl]-phenox y}- naphthalen-l-yloxy)-ethanol 7bb as an oil.
EXAMPLE-21
21. 2-(5-{4-[l-(3,3-Dimethyl-[l,2,4]trioxan-6-yl)-vinyl]-phenoxy }-naphthaIen-l-yloxy)- ethanol, 7bc (general formula 7, Fig 7)
A solution of allyl alcohol 5b (1 g) and methylene blue (5 mg) in a mixture of acetonitrile (150 mL). and THF (100 mL) was irradiated with 500 W tungsten -halogen lamp at 0 0 CtO -10 0 C, while a slow
stream of O 2 was bubbled into the reaction mixture for 8 h. The reaction mixture consisting of β- hydroxyhydroperoxide 6b (general formula 6, Fig 6 ) was concentrated on a rotatory evaporator at room temperature, dissolved in acetonitrile (100 mL).Acetone (20 mL) and cone. HCl (0.5 mL) were added and the reaction mixture was stirred for Ih at room temperature. The reaction mixture was concentrated and the crude product was purified by column chromatography over silica gel (60-120 mesh) using EtOAc/ Hexane (10:90) as eluant furnished 674 mg (56.16 % yield) of pure product 2- (5-{4-[l-(3 5 3-Dimethyl-[l 5 2,4]trioxan-6-yl)-vinyl]-phenoxy}-naphthalen-l-yloxy)-ethano l 7bc as an oil.
EXAMPLE-22
22. Trioxane 7bd (general formula 7, Fig 7, Ri, R 2 = part of adamantyl)
A solution of allyl alcohol 5b (1 g) and methylene blue (5 mg) in a mixture of acetonitrile (150 mL) and THF (100 mL) was irradiated with 500 W tungsten -halogen lamp at 0 0 C to -10 0 C, while a slow stream of O 2 was bubbled into the reaction mixture for 8 h. The reaction mixture consisting of β- hydroxyhydroperoxide 6b (general formula 6, Fig 6) was concentrated on a rotatory evaporator at room temperature, dissolved in acetonitrile (100 mL). Adamantanone (2.68 g, 5 equivalent) and cone. HCl (0.5 mL) were added and the reaction mixture was stirred for Ih at room temperature. The reaction mixture was concentrated and the crude product was purified by column chromatography over silica gel (60-120 mesh) using EtOAc/Hexane (10:90) as eluant furnished 950 mg (65.06 % yield) of pure product 7bd as an oil.
EXAMPLE-23
23. Succinic acid mono-[2-(5-{4-[l-(6,7,10-trioxa-spiro[4.5]dec-8-yl)-vinyl]-p henoxy}- naphthalen-l-yloxy)-ethyl] ester, 7baa (general formula 7, Fig 7)
A solution of 7ba (500 mg), Et 3 N (0.3099 mL, 2 equivalent), succinic anhydride (333 mg, 3 equivalent) and DMAP (2 mg) in DCM (20 mL) was stirred for 6 h. Reaction mixture was quenched by adding 10% HCl solution and extracted with DCM (2 x 25 mL). Solvent was evaporated and crude product was isolated and purified by the column chromatography over silica gel (60-120 mesh) using EtOAc/Hexane (50:50) as eluant furnished 520 mg (85.24 % yield) of pure product Succinic acid mono-[2-(5-{4-[l-(6,7,10-trioxa-spiro[4.5]dec-8-yl)-vinyl]-p henoxy}-naphthalen-l-yloxy)- ethyl 7baa as an oil.
EXAMPLE-24
24. Succinic acid mono-[2-(5-{4-[l-(l,2,5-trioxa-spiro[5.5]undec-3-yl)-vinyl]- phenoxy}- naphthalen-l-yloxy)-ethyl] ester, 7bbb (general formula 7, Fig 7)
A solution of 7bb (200 mg), Et 3 N (0.180 mL, 2 equivalent), succinic anhydride (129 mg, 3 equivalent) and DMAP (2 mg) in DCM (20 mL) was stirred for 6 h. Reaction mixture was quenched
by adding 10% HCl solution and extracted with DCM (2 x 25 mL). Solvent was evaporated and crude product was isolated and purified by the column chromatography over silica gel (60-120 mesh) using EtOAc/Hexane (50:50) as eluant furnished 208 mg (85.59 % yield) of pure product Succinic acid mono-[2-(5-{4-[l-(l,2 5 5-trioxa-spiro[5.5]undec-3-yl)-vinyl]-phenoxy}-naphthalen-l- yloxy)- ethyl] ester 7bbb as an oil.
EXAMPLE-25
25. Succinic acid mono-[2-(5-{4-[l-(3,3-dimethyl-[l,2,4]trioxan-6-yl)-vinyl]-p henoxy}- naphthalen-l-yloxy)-ethyl] ester, 7bcc (general formula 7, Fig 7)
A solution of 7bc (200 mg), Et 3 N (0.1317 mL, 2 equivalent), succinic anhydride (94 mg, 2 equivalent) and DMAP (2 mg) in DCM (20 mL) was stirred for 6 h. Reaction mixture was quenched by adding 10% HCl solution and extracted with DCM (2 x 25 mL). Solvent was evaporated and crude product was isolated and purified by the column chromatography over silica gel (60-120 mesh) using EtOAc/Hexane (50:50) as eluant furnished 224 mg (90.68 % yield) of pure product Succinic acid mono-[2-(5- {4- [ 1 -(3 ,3-dimethyl-[ 1 ,2,4]trioxan-6-yl)-vinyl]-phenoxy } -naphthalen- 1 -yloxy)- ethyl] ester 7bcc as an oil.
EXAMPLE-26
26. Trioxane 7bdd (general formula 7, Fig 7, R 1 , R 2 = part of adamantyl)
A solution of 7bd (200 mg), Et 3 N (0.162 mL, 2 equivalent), succinic anhydride (116 mg, 3 equivalent) and DMAP (2 mg) in DCM (20 mL) was stirred for 6 h. Reaction mixture was quenched by adding 10% HCl solution and extracted with DCM (2 x 25 mL). Solvent was evaporated and crude product was isolated and purified by the column chromatography over silica gel (60-120 mesh) using EtOAc/Hexane (50:50) as eluant furnished 312 mg (97.50 % yield) of pure product 7bdd as an oil.
EXAMPLE-27
27. l-[4-(4-Hydroxy-phenoxy)-phenyl]-ethanone, 2c (general formula 2, Fig 2)
A mixture of 4-fluoroacetophenone (25 mL) and quinol Ic (39.85 g, 2 equivalent) and anhyd.K 2 CO 3 (99.98 g, 2 equivalent) in DMSO (100 mL) was refluxed for 3 h. with continuous stirring. The reaction mixture was cooled to room temperature, diluted with water (100 mL) and extracted with ether (3 x 200 mL). The organic layer was dried over anhyd. Na 2 Sθ 4 and concentrated to furnish a crude mixture, which was purified by column chromatography over 60-120 mesh silica gel using EtOAc/Hexane( 10:90) as eluant, furnished 18.5 g (30.56 % yield) of pure product l-[4-(4-Hydroxy- phenoxy)-phenyl]-ethanone 2c as a white solid m.p. 150 0 C.
EXAMPLE-28
28. [4-(4-AcetyI-phenoxy)-phenoxy]-acetic acid ethyl ester, 3c (general formula 3, Fig 3)
A mixture of 1.87 g l-[4-(4-Hydroxy-phenoxy)-phenyl]-ethanone 2c, ethyl chloro acetate (1.8 mL, 2 equivalent) and anhydrous K 2 CO 3 (2.26 g, 2 equivalent ) in acetone (50 mL) was refluxed for 8 h. Reaction mixture was concentrated to 20 mL, diluted with water (100 mL) and extracted with ethyl acetate (3 x 50 mL). Combined organic was washed with saturated brine solution, dried over anhydrous Na 2 SO 4 and concentrated and the crude product was chromatographed on silica gel using EtOAc/Hexane (2:98) as eluant, furnished 2.2 g (85.56 % yield) of pure product [4-(4-Acetyl- phenoxy)-phenoxy] -acetic acid ethyl ester 3c as an oil.
EXAMPLE-29
29. 3-[4-(4-Ethoxycarbonylmethoxy-phenoxy)-phenyl]-but-2-enoic acid ethyl ester, 4c (general formula 4, Fig 4)
To a stirred slurry of NaH (60 % dispersion in mineral oil, 5.35 g, 2 equivalent) in dry THF (50 mL) kept at O 0 C under N 2 atmosphere, a solution of triethylphosphonoacetate (26.75 mL, 2 equivalent) in dry THF (50 mL) was added and the reaction mixture was allowed to stir at rt for 1 h. To this reaction mixture [4-(4-Acetyl-phenoxy)-phenoxy] -acetic acid ethyl ester 3c (14 g) dissolved in dry THF (100 mL) was added and the reaction mixture was further stirred at room temperature for 20 h. The reaction mixture was quenched with water (100 mL), extracted with ether (3 x 200 mL). The organic layer was dried over anhyd. Na 2 SO 4> concentrated and purified by column chromatography over 60- 120 mesh silica gel using EtOAc/Hexane(2:98) as eluant to furnish 19.06 g cis-trans α, β-unsaturated ester (74.22 % yield) of pure product 3-[4-(4-Ethoxycarbonylmethoxy-phenoxy)-phenyl]-but-2- enoic acid ethyl ester 4c as an oil.
EXAMPLE-30
30. 3-{4-[4-(2-Hydroxy-ethoxy)-phenoxy]-phenyl}-but-2-en-l-ol, 5c (general formula 5,
Fig 5)
To a magnetically stirred, ice-cooled mixture Of LiAlH 4 (1.78 g, 3 equivalent) in dry THF (100 mL) 3-[4-(4-Ethoxycarbonylmethoxy-phenoxy)-phenyl]-but-2-enoic acid ethyl ester 4c (6 g) was added under nitrogen atmosphere and the reaction mixture was allowed to stir for 1 h at O 0 C. The reaction mixture was quenched with water (10 mL) and 5% aqueous NaOH (5 mL). The organic layer was decanted and dried over anhyd. Na 2 SO 4 , concentrated to furnish a crude mixture which on crystallization in hot ethyl acetate to furnish 4.68 g (83.76 % yield) of pure product 3-{4-[4-(2- Hydroxy-ethoxy)-phenoxy] -phenyl} -but-2-en-l-ol 5c as a white solid m.p.90 0 C.
EXAMPLE-31
31. 2-(4-{4-[l-(6,7,10-Trioxa-spiro[4.5]dec-8-yl)-vinyI]-phenoxy }-phenoxy)-ethanoI, 7ca (general formula 7, Fig 7)
A solution of allyl alcohol 5c (1 g) and methylene blue (5 mg) in a mixture of acetonitrile (100 mL) and THF (100 mL) was irradiated with 500 W tungsten -halogen lamp at 0 0 C to -10 0 C, while a slow stream of O 2 was bubbled into the reaction mixture for 8 h. The reaction mixture consisting of β- hydroxyhydroperoxide 6c (general formula 6, Fig 6) was concentrated on a rotatory evaporator at room temperature, dissolved in acetonitrile (100 mL). Cyclopentanone (2.8 mL, 10 equivalent) and cone. HCl (0.5 mL) were added and the reaction mixture was stirred for Ih at room temperature. The reaction mixture was concentrated and the crude product was purified by column chromatography over silica gel (60-120 mesh) using EtOAc/Hexane (5:95) as eluant furnished 822 mg (62.22 % yield) of pure product 2-(4-{4-[l-(6,7,10-Trioxa-spiro[4.5]dec-8-yl)-vinyl]-phenoxy }-phenoxy)- ethanol 7ca as an oil.
EXAMPLE-32
32. 2-(4-{4-[l-(l,2,5-Trioxa-spiro[5.5]undec-3-yl)-vinyl]-phenox y}-phenoxy)-ethanol , 7cb (general formula 7, Fig 7)
A solution of allyl alcohol 5c (1 g) and methylene blue (5 mg) in a mixture of acetonitrile (100 mL) and THF (100 mL) was irradiated with 500 W tungsten -halogen lamp at 0 0 CtO -10 0 C, while a slow stream of O 2 was bubbled into the reaction mixture for 8 h. The reaction mixture consisting of β- hydroxyhydroperoxide 6c (general formula 6, Fig 6) was concentrated on a rotatory evaporator at room temperature, dissolved in acetonitrile (100 mL). Cyclohexanone (3.2 mL, 10 equivalent) and cone. HCl (0.5 mL) were added and the reaction mixture was stirred for Ih at room temperature. The reaction mixture was concentrated and the crude product was purified by column chromatography over silica gel (60-120 mesh) using EtOAc/Hexane (5:95) as eluant furnished 937 mg (68.83 % yield) of pure product 2-(4-{4-[l-(l,2,5-Trioxa-spiro[5.5]undec-3-yl)-vinyl]-phenox y}-phenoxy)- ethanol 7cb as an oil.
EXAMPLE-33
33. Trioxane 7cc (general formula 7, Fig 7, R 1 , R 2 = part of adamantyl)
A solution of allyl alcohol 5c (1 g) and methylene blue (5 mg) in a mixture of acetonitrile (100 mL) and THF (100 mL) was irradiated with 500 W tungsten -halogen lamp at 0 0 CtO-IO 0 C, while a slow stream of O 2 was bubbled into the reaction "mixture for 8 h. The reaction mixture consisting of β- hydroxyhydroperoxide 6c (general formula 6, Fig 6) was concentrated on a rotatory evaporator at room temperature, dissolved in acetonitrile (100 mL). Adamantanone (4 g, equivalent) and cone. HCl (0.5 mL) were added and the reaction mixture was stirred for Ih at room temperature. The reaction
mixture was concentrated and the crude product was purified by column chromatography over silica gel (60-120 mesh) using EtOAc/Hexane (5:95) as eluant furnished 980 mg (52.40 % yield) of pure product 7cc as a white solid m.p.95-98°C.
EXAMPLE-34
34. Succinic acid mono-[2-(4-{4-[l-(6,7,10-trioxa-spiro[4.5]dec-8-yl)-vinyl]-p henoxy}- phenoxy)-ethyl] ester, 7caa (general formula 7, Fig 7)
A solution of 7ca (160 mg), Et 3 N (0.11 mL, 2 equivalent), succinic anhydride (121 mg, 1.5 equivalent) and DMAP (2 mg) in DCM (20 mL) was stirred for 7 h. Reaction mixture was quenched by adding 10% HCl solution and extracted with DCM (2 x 25 mL). Solvent was evaporated and crude product was isolated and purified by the column chromatography over silica gel (60-120 mesh) using EtOAc/Hexane (50:50) as eluant furnished 179 mg (89.5 % yield) of pure product Succinic acid mono-[2-(4-{4-[l-(6,7,10-trioxa-spiro[4.5]dec-8-yl)-vinyl]-p henoxy}-phenoxy)-ethyl] ester 7caa as a white solid m.p.72-75°C.
EXAMPLE-35
35. Succinic acid mono-[2-(4-{4-[l-(l,2,5-trioxa-spiro[5.5]undec-3-yl)-vinyl]- phenoxy}- phenoxy)-ethyl] ester, 7cbb (general formula 7, Fig 7)
A solution of 7cb (400 mg), Et 3 N (0.276 mL, 2 equivalent), succinic anhydride (145 mg, 1.5 equivalent) and DMAP (2 mg) in DCM (20 mL) was stirred for 7 h. Reaction mixture was quenched by adding 10% HCl solution and extracted with DCM (2 x 25 mL). Solvent was evaporated and crude product was isolated and purified by the column chromatography over silica gel (60-120 mesh) using EtOAc/Hexane (50:50) as eluant furnished 420 mg (84.5 % yield ) of pure product Succinic acid mono-[2-(4-{4-[l-(l,2,5-trioxa-spiro[5.5]undec-3-yl)-vinyl]- phenoxy}-phenoxy)-ethyl] ester 7cbb as a white solid m.p.52-55°C.
EXAMPLE-36
36. Trioxane 7ccc (general formula 7, Fig 7, Ri, R 2 = part of adamantyl)
A solution of 7cc (400 mg), Et 3 N (0.276 mL, 2 equivalent), succinic anhydride (145 mg, 1.5 equivalent) and DMAP (2 mg) in DCM (20 mL) was stirred for 7 h. Reaction mixture was quenched by adding 10% HCl solution and extracted with DCM (2 x 25 mL). Solvent was evaporated and crude product was isolated and purified by the column chromatography over silica gel (60-120 mesh) using EtOAc/ Hexane (50:50) as eluant furnished 530 mg (94.81 % yield) of pure product 7ccc as an oil.
Following the above procedure, the following trioxanes were prepared:
Table 1.
ANTIMALARIAL ACTIVITY
The antimalarials activity of the test compounds was evaluated in rodent using multidrug resistant strain of Plasniodium yoelii Nigeήensis in Swiss mice.
General Procedure:-
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 and i.m. route for 4 consecutive days (day 0-3). β-Arteether and α-Arteether was 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 determine 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 2.
Table 2: Blood Schizontocidal Activity of 1, 2, 4-trioxanes 7aa-7ccc.
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