Field of Invention

This invention deals with iodine catalyzed synthesis of symmetrically and asymmetrically substituted tetraoxanes as an antimalarial agents.

Background of Invention

Malaria affects over 40% of world's population, causing deaths of 1-3 million people every year [Haynes, R: K. Acc. Chem. Res. 1997, 30, 73; Meunier, B. Acc. Chem. Res. 2002, 35, 167; O'Neill, P. M.; J. Med Chem. 2004, 47, 2945; Jam, R. Med Res. Rev.
2007, 27, 65; Vennerstrom, J. L. Med Res. Rev. 2004, 24, 425; Schlitzer, M. Angew. Chem. mt. Ed Engi. 2003, 42, 5274; Vennerstrom, J. L. Nature 2004, 430, 900; White,
:. J. Science 2008, 320, 330]. The incidence of malaria has become a matter of concern because of many Plasmodium falciparum strains have developed resistance to most widely used drugs [Greenwood, B. Nature 2002, 415, 670]. Endoperoxide class of compounds have received considerable amount of attention of chemist and biologist due to their potent activity against Plasmodiumfalciparum [Haynes, R. K. Curr. Topics-Med Chem. 2006. 6, 509, Vennerstrom, J. L. EP1414813, 2004]. Artemisinin, a natural product isolated from Chinese plant Artemisia annua, and its semi synthetic derivatives have been most effective antimalarials against Plasmodiumfalciparum [O'Neill, P. M. J. Med Chem. 2002, 45, 1052, White, N. J. Am. J. Trop. Med Hyg. 2004, 71, 179]. However limited availability, high cost, and poor bioavailability of artemisinin has been the major drawback [Malenga, G. A. BMJ 2005, 331, 706]. Other semi-synthetic derivatives such as artesunate and artemether, also shows poor pharmacokinetic properties [Klayman, D. L. Science 1985, 228, 1049]. Further studies confirmed that the peroxide linkage is the most crucial pharmacophore in these molecules [Meshnick, S. R. mt. J. Parasitol. 2002, 32, 1655, Junxia, W. EP19l 1761, 2008, Li, Y. PCT/CNO6/00182, 2007]. This discovery was the beginning of a significant effort to identify synthetically accessible antimalarial peroxides and dispiro-tetraoxane is one such class of compounds which was found to be equally potent as artimisinin [Vennerstrom, J. L.: J. Med Chem.

1992, 35, 3023, O'Neill, P. M. W02008038030, 2008, Solaja, B. W003068736, 2003, Vennerstrom, J. L. W093071 19, 1993]. The most common method of synthesis of symmetrical tetraoxane is acid catalyzed cyclocondensation of hydrogen peroxide with ketones or aldehydes [McCullough, K. J. Med Chem. 2001, 44, 2357; Solaja, B. A.; .1. Med Chem. 2002, 45, 3331; Hetz, W. Tetrahedron 1971, 27, 3629; Adam, W.; Tetrahedron Lett. 1992, 33, 5833], ozonolysis of olefins [Keul, H. Chem. Ber. 1975, 108, 1198], enol ethers [Kuczkowski, R. L. J. Org. Chem. 1989, 54, 115; Kusabayashi, S. .1 Am. Chem. Soc. 1987, 109, 4969], 0-ether oxime [Matsuura, T. Bull. Chem. Soc. Jpn. 1980, 53, 2407], and cyclocondensation of bis(trimethylsilyl) peroxide with carbonyl compounds catalyzed by trimethylsilyl trifluoromethanesulfonate (TMSOTf) [Jefford, C. W.; Synthesis 1988, 391; Solaja, B. A. .J Med Chem. 2000, 43, 3274]. A number of other methods have also been reported for the synthesis of these compounds [Berkessel, A.; Angew. Chem. mt. Ed. 2002, 41, 4481]. The unsymmetrical tetraoxanes have been synthesized by cyclocondensation of ketones and aldehydes with steroidal gem-hishydroperoxides (H2S04 catalyst) (lskra, J.; Bonnet-Delpan, D.; Begue, J.-P. Tetrahedron Lett. 2003, 44, 6309], aliphatic and alicyclic gem-hydroperoxides (MeReO3-HBF4 catalyst) [Iskra, J.; Tetrahedron Lett. 2003, 44, 6309], and gembis(trimethylsilyldioxy)alkanes (TMSOTf catalyst) [McCullough, K. £ Chem. Soc., Perkin Trans 1, 1999, 1867]. All of these methods are highly dependent on several factors, such as the structure of the carbonyl compounds, temperature, concentration, pH, mode of addition, solvent, and the equilibrium between ketone and the precursors of cyclic peroxides [McCullough, K. J. M.; J. Chem. Res. (5). 1980, 42, 601], which leads variable yield of the tetraoxanes. As part of our ongoing efforts towards the synthesis of biologically active compounds [Rawat, D. S. Bioorg. Med Chem. Le#. 2007, 17, 3226; Rawat, D. S. J. Heterocyclic Chem. 2008, 45, 737; Rawat, D. S. Bioorg Med Chem. Lea. 2008, 18, 1446; Rawat, D. S. Patent Application No: 1462/DEL/2008], we disclose herein an efficient, cost effective, iodine catalyzed simple one pot synthesis of symmetrically and asymmetrically substituted tetraoxanes as an antimalarial agents.

In spite of huge medicinal potential limited number of tetraoxanes have been evaluated for their antimalarial activity, and little over 25 tetraoxanes having aromatic ring as a part of the active pharmacophore have been reported. We speculated that tetraoxanes with aromatic ring would offer more opportunity for incorporation of various functional groups on the tetraoxane scaffold. Very recently we have reported synthesis and antimalarial activity of symmetrically and asymmetrically substituted tetraoxanes which have been prepared by using substituted benzaldehydes as a starting material. Some of the compounds especially tolyl based tetraoxanes exhibit good antimalarial activity [Rawat, D. S. Bioorg. Med Chem. Lett. 2008, 18, 1446]. So, it was necessary to synthesize more tetraoxanes with varying alkyl chain in the aromatic ring. During the course of this study we observed that the MTO catalyzed reaction has many limitations as MTO/TFE system is uneconomical, non-selective for various functional groups, and poor yield. So there is a great scope to develop an easy, practical, and economical method for the synthesis of this class of compounds. In most of the cases gem-hydroperoxide has been used as an intermediate for the preparation of tetraoxanes, and it has been prepared via various methods [Terentev, A. 0. I. Synthesis 2004, 2356; Kim, H.-S. J. Chem. Soc., Perkin Trans 1, 1999, 1867; Jefford, C. Synth. Comm un. 1990, 20, 2589; Tevent'ev, A.
0. Synthesis 2005, 2215; Ledaal, T. Acta Chem. Scand. 1967, 21, 1658; Solaja, B. A. Steroids 1996, 61, 688; Hamann, H. J. Synlett 2001, 96]. Encouraged by a recent publication of Iskra et al [Iskra, J. Org. Lett. 2006, 8, 2491; Iskra, J. .1. Org. Chem. 2007, 72, 6534] that deals with the iodine catalyzed synthesis of bis-hydroperoxides, we speculated iodine can catalyze the reaction of bis-hydroperxides and carbonyl compounds that can lead tetraoxanes. The present synthetic methodology allows to prepare these compounds in good yield with the use of readily accessible and inexpensive substituted aromatic aldehydes. Furthermore, the reaction requires catalytic amount of iodine, and acetonitrile as a solvent instead of TFE or HFIP as a solvent and MTO as a catalyst, which are very expensive.

Objects Qf Invention
The object of this invention is to develop a novel method for the synthesis of symmetrically and asynimetrically substituted tetraoxane derivatives possessing a mono or poly substituted aromatic/hetero cyclic/cyclic/acyclic/aminoacid/peptide/sugar side chain as an antimalarial agents.
Detailed description of Invention

Inventors have synthesized various symmetrically and asymmetrically substituted tetraoxanes under milder reaction conditions. Accordingly, the present invention provide compounds with general formula I as depicted below.
(Formula Removed)

Wherein compound I:

R = R' = Mono, di, tri, poly substituted aromatic/heteroaromatic/cyclic/acyclic/polycyclic side chains.
This invention also covers the asymmetrical products with general structure as depicted above, where R and R' are two different functionalities.
Functionality R and R' can be attached to amino acods, peptides sugurs, and stereoids which can act as a carrier molecules.
The compound of the formula I can also be converted, if required, to the corresponding salts with pharmaceutically acctptable acids/bases.
In a typical reaction conditions, 0.1 equivalent 12 and 4.0 equivalent of H202 was taken in 10 mL of acetonitrile. Substituted benzaldehyde (1.0 equivalent) was added to the above

solution, and reaction mixture was stirred at room temperature for 6.0 hr. After this, 1.0 equivalent of same or different aldehyde was added followed by 1.0 mL of HBF4.Et2O. The reaction mixture was stirred for 2.0 hr and solvent from the reaction mixture was removed under vacuum. The crude product was quenched with NaHCO3, and compound was extracted by CHCl3. Finally the crude product was purified by flash chromatography, and characterized spectroscopically. The reaction condition works well for all kinds of substituted benzenes having electron donating, electron withdrawing or neutral functional groups.

Likewise asymmetrical tetraoxanes were prepared using different starting aldehydes. This is of particular interest, as wide variety of tetraoxanes with variety of functional groups that can be further manipulated chemically, if required, can be prepared. The use of 12 as a catalyst and acetonitrile as a solvent offers many advantage as they are commercially chief, easily available, and excess of H202, and aldehydes are not required in this reaction, which has been one of the major drawback of the existing methods. Furthermore, this synthetic methodology offers a great opportunity for the structure activity relationship studies on these compounds. These compounds holds good promise for the treatment of deadly diseases such as malaria, cancer, microbial infections etc.

Spectral data of selected compounds:

3,6-Bis-(4-ethyI-phenyI)-~1,2,4,5Jtetroxane:
mp: 190-192 0C; IR (KBr, cm'): 2969,1610, 1512, 1458, 1422, 1362, 1181, 1117, 1022, 1003, 909, 840; 'H NMR (300 MHz,
CDClj): 1.26 (t, J = 6 Hz, 6H), 2.66-2.94(m,4H), 6.91 (s, 2H), 7.28(m,J = 8 Hz, 4H),
7.53 (m, J = 8 Hz, 4H); MS-ESI (mlz): 300.2 (Mt); Anal. calcd. for C,8H2004: C, 71.98;
H, 6.71. Found: C, 71.77; H, 6.53.
3,6-Bis-(4-n-propyl-phenyl)-[1,2,4,5]tetroxane: mp: 165-166 0C; IR (KBr, cm-1): NMR
(300 MHz, CDCl3): 0.94 (t, 6H), 1.60-1.70(m,4H), 2.62 (t, 4H), 6.88 (s, 2H), 7.26 (d, J= 8Hz, 4H), 7.43 (d, J = 8Hz, 4H); MS-ESI (m/z): 320.2 (Me).

3,6-Bis-(4-isopropyl-phenyl)-[1,2,4,5]tetroxane: mp: 156-157 0C; IR (KBr, cm'): 2959,

2932, 1611, 1510, 1462, 1411,1362,1182, 1021, 909, 841; 'HNMR(300MHz,CDCl3):

1.28 (d, J = 6Hz, 12H), 2.95 (sept, 2H), 6.91 (s, 2H), 7.30 (d, J = 8Hz, 4H), 7.44 (d, J =

8Hz, 4H); MS-ES! (in/z): 328.2 (M~); Anal. calcd. for C20H2404: C, 73.15; H, 7.37.

Found: C, 73.39; H, 7.70.

3,6-Bis-(4-tert-butyl-phenyl)-[1,2,4,5]tetroxane: mp: 222-224 0C; IR (KBr, cm'):

2924, 1614, 1461, 1370, 1312, 1267, 1187, 1021, 1003, 911, 838, 803; 'H NMR (300

MHz, CDC13): 1.31 (s, 18H), 6.92 (s, 2H), 7.50-7.62(m,8H); '3C NMR (75.5 MHz,

CDCl3): 31.16 (CH3), 34.91 (CH3), 108.10 (CH), 125.76 (CH), 127.57 (CH), 128.06 (C),

154.67 (CH); MS-ES! (mlz): 356.4 (Me); Anal. calcd. for C22H2804: C, 74.13; H, 7.92.

Found: C, 74.37; H, 7.73.

3,6-Bis-(4-butyl-phenyl)-[1,2,4,Sltetroxane: mp: 145 0C; 'H NMR (300 MHz, CDC13):

0.94 (t, 6H), 1.30-1.43(m,4H), 1.57-1.67(m,4H), 2.66 (t, 4H), 6.90 (s, 2H), 7.24 (d, J

8Hz, 4H), 7.42 (d, J = 8Hz, 4H); MS-ES! (inlz): 356.2 (Me); Anal. calcd. for C22H2804:

C, 74.13; H, 7.92. Found: C, 74.37; H, 7.73.

3-(4-tert-Butyl-phenyl)-6-p-tolyl-[1,2,4,5]tetroxane: mp: 188-190 0C; 'H NMR (300

MHz, CDCl3): 1.35 (s, 9H), 2.41 (s, 3H), 6.90 (s, 1H), 6.93 (s, 1H), 7.28 (d, 4H), 7.42 (d,

41-1); ~ NMR (75.5 MHz, CDCl3): 21.49, 31.17, 34.93, 108.14, 125.77, 127.57, 127.77,

128.11, 129.46, 141.61; MS-ES! (mlz): 314.2 (Mt); Anal. calcd. for C,9H2204: C, 72.59;

H, 7.05. Found: C, 72.27; H, 7.33.

3-0-Tolyl-6-p-tolyl-[1,2,4,5]tetroxane: mp: 205 0C; IR (KBr, cm-1): 2953, 1608, 1512,

1459, 1361, 1311, 1198, 1181, 1018, 910, 828, 792; 'H NMR (300 MHz, CDCl3): 2.38

(s, 6H), 6.87 (s, 2H), 7.22-7.41(m,8H); MS-ESI (in/z): 272.1 (Me); Anal. calcd. for

C,6H,604: C, 70.57; H, 5.92. Found: C, 70.79; H, 6.23.

3-n-Tolyl-6-p-tolyl-[1,2,4,5]tetroxane: mp: 208 0C; JR (KBr, cm-1): 2925, 1610, 1459,

1359, 1181, 1017, 909, 827, 789; 'H NMR (300 MHz, CDCl3): 2.38 (s, 6H), 6.87 (s, 2H),

7.22-7.41 (m, 8H); MS-ES! (m/z): 272.1 (Me).

3-(4-tert-Butyl-phenyl)-6-o-tolyl-[1,2,4,5] tetroxane: mp: 2 18-220 0C; JR (KBr, cm-1):

2957, 1612, 1510, 1459, 1360, 1312, 1182, 1108, 1021, 911, 836; 'H NMR (300 MHz,

CDCl3): 1.35 (s, 9H), 2.44 (s, 3H), 6.90 (s, 1H), 6.92 (s, 1H), 7.27-7.30(m,4H), 7.41-

7.50(m,4H); ~ NMR (75.5 MHz, CDC13): 21.49, 31.17, 34.93, 108.14, 125.77, 127.57,

127.77, 128.11, 129.46, 141.61, 154.70; MS-ES! (m/z): 314.4 (Me); Anal. calcd. for

C,9H2204: C, 72.59; H, 7.05. Found: C, 72.47; H, 7.19.

3-(4-Methoxy-phenyl)-6-m-tolyl-[1,2,4,5]tetroxane: mp: 120 0C; JR (KBr, cm-1): 2954,

1611, 1583, 1516, 1462, 1363, 1309, 1261, 1175, 1033, 1014, 839, 786; 'H NMR (300

MHz, CDCl3): 2.38 (3H), 3.82 (s, 3H), 6.83 (s, lH), 6.92 (s, lH), 7.3 1-7.35(m,6H), 7.42

(d, 2H), MS-ES! (in/z): 288.2 (Me).

3-(4-Methoxy-phenyl)-6-p-tolyl-[1,2,4,5]tetroxane: mp: 206 0C; JR (KBr, cm'): 2950,

1701, 1609, 1582, 1513, 1460, 1362, 1309, 1258, 1174, 1017, 907, 843, 824, 791; 'H

NMR (300 MHz, CDCl3): 2.38 (3H), 3.82 (s, 3H), 6.84 (s, 1H), 6.92 (s, 1H)~ 7.27 (m,

4H), 7.38(m,4H); MS-ES! (mlz): 288.2 (Me).

3-(4-tert-Butyl-phenyl)-6-(4-methoxy-phenyl)-I1 ,2,4,5J tetroxane: mp: 168 0C; IR

(KBr, cin'): 2963, 1610, 1584, 1516, 1463, 1366, 1189, 1020, 799; 'H NMR (300 MHz,

CDCI3): 1.32 (s, 9H), 3.83 (s, 3H), 6.85 (s, 1H), 6.92 (s, lH), 7.29-7.41(m,8H); MS-ES!

(in/z): 330.2 (M+); Anal. calcd. for C,9H2205: C, 69.07; H, 6.71. Found: C, 69.37; H,

6.99.

3-(4-Isopropyl-phenyl)-6-(4-methoxy-phenyl)-[ 1 ,2,4,5J tetroxane: mp: 176 0C; 'H

NMR (300 MHz, CDCl3): 1.26 (d, 6H), 2.29 (sept, 1H), 3.83 (s, 3H), 6.83 (s, 1H), 6.92

(s, 1H), 7.28-7.30(m,4H), 7.42-7.46 (s, 4H); MS-ES! (M/z): 316.1 (M+).

-9-

3-(4-Isopropyl-phenyl)-6-p-tolyl-[1,2,4,5]tetroxane: mp: 215-216 0C; 'H NMR (300

MHz, CDCl3): 1.28 (d, J = 6Hz, 6H), 2,40 (s, 3H), 2.92 (septet, IH), 6.89 (s, 2H), 7.27-

7.32 (m, 4H), 7.40-7.46(m,4H); MS-ES! (mlz): 314.4 (Me); Anal. calcd. for C,8H2004:

C, 71.98; H, 6.71. Found: C, 71.77; H, 6.59.

3-(4-Ethyl-phenyl)-6-p-tolyl-[1 ,2,4,SJtetroxane: mp: 205-208 0C; IR (KBr, cm-1): 2949,

1610, 1361, 1180, 1021, 909, 840; 'H NMR (300 MHz, CDCl3): 1.26 (t, J = 6Hz, 3H),

2.40 (s, 3H), 2.69 (q, J = 6Hz, 2H), 6.90 (s, 1H), 6.91 (s, 1H), 7.27-7.30(m,4H), 7.41-

7.47 (m, 4H); MS-ES! (inlz): 286.1 (M~); Anal. calcd. for C17H,804: C, 71.31; H, 6.34.

Found: C, 71.61; H, 6.54.

3-(4-Ethyl-phenyl)-6-m-tolyl-[1,2,4,5]tetroxane: mp: 180-183 0C; JR (KBr, cm-1):

2952, 1653, 1543, 1510, 1437, 1360, 1281, 1181, 1009, 887; 'H NMR (300 MHz,

CDCl3): 1.23 (t, J = 6H, 3H), 2.38 (s, 3H), 2.66 (q, J = 6Hz, 2H), 6.88 (s, 2H), 7.26-7.28

(m, 4H), 7.41-7.43(m,4H); MS-ES! (mlz): 314.4 (Me); Anal. calcd. for C,7H,804: C,

71.31; H, 6.34. Found: C, 71.57; H, 6.69.
3-(4-Ethyl-phenyl)-6-m-tert-butyl-phenyl-I1,2,4,51 tetroxane: mp: 206 0C; JR (KBr, cm'): 2960, 2867, 1614, 1360, 1108, 1022, 1004, 911, 838; 'H NMR (300 MHz, CDCl3):
1.21-1.32(m,12H), 2.66 (q, 2H), 6.89 (s, 21-1), 7.41-7.45(m,8H); MS-ES! (m/z): 320.2 (Me).

4-(6-p-Tolyl-[1,2,4,5]tetroxan-3-yl)-benzoic acid methyl ester: mp: 207-208 0C; 'H

NMR (300 MHz, CDCl3): 2.39 (s, 3H), 3.94 (s, 3H), 6.87 (s, 1H), 6.89 (s, 1H), 7.22-7.26

(m, 2H), 7.40(m,2H), 7.58 (d, 2H), 8.11 (d, 2H); MS-ES! (mlz): 316.2 (M~); Anal.

calcd. for C17H,606: C, 64.55; H, 5.10. Found: C, 64.87; H, 5.49.

3-(4-Ethyl-phenyl)-6-(4-isopropyl-phenyl)- 11,2,4,51 tetroxane: mp: 165 0C; JR (KBr,

cm'): 2966, 2365, 1610, 1511, 1460, 1361, 1181, 1021, 909, 838; 'H NMR (300 MHz,

CDC13): 1.23-1.28(m,9H), 2.71 (q, 2H, CH2CH3), 2.95 (sept, 1H, CH(CH3)2), 6.91 (s,

2H), 7.29-7.32(m,4H), 7.43-7.47(m,4H); MS-ES! (in/z): 314.1 (M~); Anal. calcd. for

C19H2204: C, 72.59; H, 7.05. Found: C, 72.77; H, 7.39.

3-Phenyl-6-m-tolyl-[1,2,4,5]tetroxane: mp: 198 0C; 'H NMR (300 MHz, CDCl3): 2.38

(s, 3H), 6.89 (s, IH), 6.93 (s, 1H), 7.28-7.31(m,5H), 7.41-7.53(m,4H); MS-ES! (m/z):

258.2 (Ml).

3,6-Dicyclohexyl-[1,2,4,5]tetroxane: mp: 128-130 0C; 'H NMR (300 MHz, CDCl3):

0.97-1.12(m,8H), 1.48-1.77(m,14H), 4.43 (d, J = 6Hz, 2H); MS-ES! (m!z): 256.1 (Me);

Anal. calcd. for C14H2404: C, 65.60; H, 9.44. Found: C, 65.89; H, 9.66.

We Claim

1. The compound represented by general formula I, a known anti material, anticancer pharmacophore, and a pharmaceutical composition comprising the compound represented by the formula (I) a salt thereof, a solvate thereof, or a prodrug thereof; in combination with one, two or more kinds selected drugs from an antimalarial, wherein R and R' is a mono, di, tri, tetra, penta, or hexa symmetrically or asymmetrically substituted benzene, which may be substituted with Cl-cl 2 alkyl chain, cyclic or acyclic groups or any other fiinctiQnal group like, Cl, Br, F, CF3. NO2, OMe, NH2, CHO, CO. COOR.

2. The compound represented by formula I as claimed in claim 1 wherein R and R' is acyclic chain, cyclic group or substituted N, 0, S heterocycle.

3. The compound represented by formula I as claimed in claim 1 wherein R and R' functionality is attached with amino acid, peptide and stereoidal side cl~in which can act as a carrier molecule.

4. The compound represented by formula as claimed above, where R = any group of claim 1-3, and R' is a stereoid or any other. molecule that can act as a carrier molecule of tetraoxane based antimalarials.

5. The compound represented by formula I as claimed in claim 1 wherein R=R', and more precisely it can be a combination of claim 1-4.

6. The compound represented by formula I as claimed in claim 1 wher0in R is a mono, di, tri, or poly substituted aromatic/hetero-aromatic ring and substituted by an electron donating, electron withdrawing or neutral group or atom such as Cl, Br, F, CF3, NO2, OMe, NH2, CHO, CO, COOR, and R' is a steroid, sugar, peptides etc.