Title of Invention

A METHOD FOR PREPARATION OF SUBSTITUTED AMINO-FUNCTIONALIZED1,2,4-TRIOXANES USEFUL AS ANTI-MALARIAL AGENTS

Abstract The present invention relates to a method for preparation of amino-functionalized 1,2,4-trioxanes useful as anti-malarial agent, wherein Ar represents aryl groups such as phenyl, 4-biphenyl, 4-chlorophenyl, 4-methoxyphenyl, 4-methylphenyl and R represents phenyl, 4-methoxyphenyl, 4-chlorophenyl, 3,5-dichlorophenyl, 4-acetylaminophenyl, 1-naphthyl, 2-biphenyl, 4-biphenyl, 2-fluorene, 4-fluorophenyl, 2-trifluoromethylphenyl, 3-trifluoromethylphenyl and 4-trifluoromethylphenyl and the like.
Full Text A METHOD FOR PREPARATION OF SUBSTITUTED AMINO-FUNCTIONALIZED 1, 2, 4-TRIOXANES USEFUL AS ANTI-MALARIAL AGENTS
Field of the invention
The present invention relates to a novel amino functionalized 1, 2, 4-trioxanes useful as antimalarial agents and process for preparation thereof of formula 4
(Formula Removed)
wherein Ar represents aryl groups such as phenyl, 4-biphenyl, 4-chlorophenyl, 4-methoxyphenyl, 4-methylphenyl and R represents phenyl, 4-methoxyphenyl, 4-chlorophenyl, 3,5-dichlorophenyl, 4-acetylaminophenyl, 1-naphthyl, 2-biphenyl, 4-biphenyl, 2-fluorene, 4-fluorophenyl, 2-trifluoromethylphenyl, 3-trifluoromethylphenyl and 4-trifluoromethylphenyl and the like. Several of these novel compounds show promising antimalarial activity against multidrug-resistant malaria in mice and thus hold promise as antimalarial agents against multidrug-resistant malaria. Background of the invention
Malaria is one of the most deadly diseases affecting third world countries, claiming more than one million lives annually. While various classes of antimalarial agents are available, chloroquine remains the main stay of therapy against malaria. Increasing resistance of Plasmodium falciparum, the most dangerous of the four malaria parasites that infect humans, to the common drugs such as chloroquine has heightened concern about malaria. Extensive programs are underway to screen natural products and synthetic derivatives for new agents. Against this background, isolation of artemisinin as the active principle of Chinese herb Artemisia annua has opened new possibilities in malaria chemotherapy.
(Formula Removed)
Semisynthetic derivatives of artemisinin such as arteether, artemether and artesunic acid, are currently the drugs of choice for the treatment of complicated cases of malaria such as cerebral malaria [For reviews on artemisinin and its analogues see: (a) Klayman, D. L Science 1985, 228, 1049. (b) Bhattacharya, A. K.; Sharma, R. P. Hetcrocycles 1999, 57, 1681. (c) Borstnik, K.; Paik, I.; 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].
The limited availability of artemisinin from natural sources and the fact that endoperoxide linkage present in the form of a 1,2,4-trioxane ring system is the antimalarial pharmacophore of these compounds, has led to the present efforts to develop structurally simple synthetic trioxanes. Several structurally simple synthetic 1,2,4-trioxanes have shown promising antimalarial activity [(a) Bhattacharya, A. K.; Sharma, R. P. Heterocydes 1999, 57, 1681. (b) Borstnik, K.; Paik, I.; Shapiro, T. A.; Posner, G. H. Int. J. Parasitol. 2002, 32, 1661. (c) Singh, C.; Misra, D.; Saxena, G.; Chandra, S. Bioorg. Med.-Chem. Lett. 1995, 5, 1913. (d) Singh, C.; Puri, S. K. U.S. Patent 6316493 Bl, 2001. (e) Singh, C.; Gupta, N.; Puri, S. K. Bioorg. Med. Chem. Lett. 2003, 13, 3445. (f) Singh, C.; Tiwari, P.; Puri, S. K. PCT Patent application No. PCT/1N02/00093, dated 28.3.2002].
Singh ct al. have developed a novel photooxygenation route for the preparation of 1,2,4-trioxanes. p-Hydroxyhydroperoxide prepared by regiospecific photooxygenation of ally lie alcohols on condensation with aldehydes or ketone in the presence of acid catalyst furnish 1,2,4-trioxane. [(a) Singh, C.; Misra, D.; Saxena, G.; Chandra, S. Bioorg. Med. Chem. Lett. 1992, 2, 497. (b) Singh, C.; Misra, D.; Saxena, G.; Chandra, S. Bioorg. Med. Chem. Lett. 1995, 5, 1913. (c) Singh, C.; Puri, S, K. U.S. Patent 6316493 Bl, 2001. (d) Singh, C.; Gupta, N.; Puri, S. K. Bioorg. Med. Chem. Lett. 2002, 12, 1913. (e) Singh, C.; Gupta, N.; Puri, S. K. Bioorg. Med. Chem. Lett. 2003, 13, 3445. (0 Singh, C.; Tiwari, P.; Puri, S. K. PCT Patent application No. PCT/1N02/00093, dated 28.3.2002]. This method has been extended for the preparation of several amino functionalized 1,2,4-trioxanes, some of which have shown moderate antimalarial activity against multidrug resistant P. yoelii in mice [Singh, C.; Malik, H.; Puri, S. K. Bioorg. Med. Chem. Lett. 2004, 14, 459].It is desirable to develop new compounds with show high degrees of anti-malarial activity in order to overcome the problems associated with the prior art compounds including the problem of drug-resistance in the malarial virus. Objects of the invention
The main objective of the present invention is to provide novel amino functionalized 1,2,4-trioxanes with a potential to be used for the treatment of malaria.
It is another object of the invention to provide a process for the preparation of novel amino functionalized 1,2,4-trioxanes of formula 4, a new series of antimalarial agents. Summary of the invention
Accordingly the present invention provides a method for preparation of substituted amino functionalized-1,2,4-trioxanes useful as antimalarial agents of formula 4
(Formula Removed)
wherein Ar is an aryl group selected from the group consisting of phenyl, 4-biphenyl, 4-
chlorophenyl, 4-methoxyphenyl and 4-methylphenyl and R represents phenyl, 4-
methoxyphenyl, 4-chlorophenyl, 3,5-dichlorophenyl, 4-acetylaminophenyl, 1-naphthyl, 2-
biphenyl, 4-biphenyl, 2-fluorene, 4-fluorophenyl, 2-trifluoromethylphenyl, 3-
trifluoromethylphenyl and 4-trifluoromethylphenyl, the method comprising:
(i) photooxygenating an allylic alcohol of formula 1 by passing oxygen gas or air in a
solution of the alcohol in an organic solvent and in the presence of a dye and a light
source which provides visible light, for a period of 4 h, to obtain α ß-
hydroxyhydroperoxide of formula 2
(Formula Removed)
(ii) reacting the hydroperoxides of formula 2 in situ with 1,4-cyclohexanedione in the presence of an acid catalyst to give a trioxane of formula 3;
(Formula Removed)
reacting the keto trioxane of formula 3 with an aromatic amine in the presence of NaBH(OAc)3 in CH2Cl2 to obtain amino functionalized 1,2,4-trioxane of formula 4.
In one embodiment of the invention, the compound of formula 4 has structural formula 4aa-4ai shown below:
(Formula Removed)
In another embodiment of the invention, the compound of formula 4 has structural formulae 4ba-4bi shown below:
(Formula Removed)
In another embodiment of the invention, the compound of formula 4 has structural formulae 4ca-4cp shown below:
(Formula Removed)
4ba R = 4-chlorophenyl
4bb R = 2-biphenyl (upper Rf) 4bc R = 2-biphenyl (lower Rf) 4bd R = 4-biphenyl 4be R = 2-fluorene 4bf R = 4-fluorophenyl 4bg R = 2-trifluoromethylphenyl 4bh R = 3-trifluoromethylphenyl 4bi R = 4-trifluoromethylphenyl
In another embodiment of the invention, the compound of formula 4 has
structural formulae 4ca-4cp shown below:
(Formula Removed)
4ca R = phenyl
4cb R = 4-methoxyphenyl
4cc R = 4-chlorophenyl (upper Rf)
4cd R = 4-chlorophenyl (lower Rf)
4ce R = 3,5-dichlorophenyl (upper Rf)
4cf R = 3,5-dichlorophenyl (lower Rf)
4cg R = 4-acetylaminophenyl
4ch R = 1-naphthyl
4ci R = 2-biphenyl (upper Rf)
4cj R = 2-biphenyl (lower Rf)
4ck R = 4-biphenyl
4cl R = 2-fluorene
4cmR = 4-fluorophenyl
4cn R = 2-trifluoromethylphenyl
4co R = 3-trifluoromethylphenyl
4cp R = 4-trifluoromethylphenyl
In another embodiment of the invention, the compound of formula 4 has structural formulae 4da-4dn shown below:
(Formula Removed)
4da R = phenyl
4db R = 4-methoxyphenyl
4dc R = 4-chlorophenyl
4dd R = 3,5-dichlorophenyl
4de R = 4-acetylaminophenyl
4df R = 1-naphthyl
4dg R = 2-biphenyl (upper Rf)
4dh R = 2-biphenyl (lower Rf)
4di R = 4-biphenyl
4dj R = 2-fluorene
4dk R = 4-fluorophenyl
4dl R = 2-trifluoromethylphenyl
4dm R = 3-trifIuoromethylphenyl
4dn R = 4-trifluoromethylphenyl
In another embodiment of the invention, the compound of formula 4 lias structural formulae 4ea-4eo shown below:
(Formula Removed)

4ea R = phenyl
4eb R = 4-methoxyphenyl
4ec R = 4-chlorophenyl
4ed R = 3,5-dichlorophenyl (upper Rf)
4ee R = 3,5-dichlorophenyl (lower Rf)
4ef R = 4-acetylaminophenyl
4eg R = 1-naphthyl
4eh R = 2-biphenyl (upper R,,
4el R = 2-biphenyl (lower Rf)
4«j R = 4-biphenyl
4ek R = 2-fluorene
4el R = 4-fluorophenyl
4emR = 2-trifluoromethylphenyl
4en R = 3-trifluoromethylphenyl
4eo R = 4-trifluoromethylphenyl
The present invention also provides a method for the preparation of a substituted amino functionalized-l,2,4-trioxanes of formula 4
(Formula Removed)
wherein Ar represents aryl groups selected from the groups consisting of phenyl, 4-biphenyl, 4-chlorophenyl, 4-methoxyphenyl and 4-methylphenyl and R represents phenyl, 4-methoxyphenyl, 4-chlorophenyl, 3,5-dichlorophenyl, 4-acetylaminophenyl, 1-naphthyl, 2-biphenyl, 4-biphenyl, 2-fluorene, 4-fluorophenyl, 2-trifluoromethylphenyl, 3-trifluoromethylphenyl and 4-trifluoromethylphenyl and the like, the process comprising reacting a keto trioxane of formula 3
(Formula Removed)
with an aromatic amine in the presence of NaBH(OAc)3 in CH2Cl2 to furnish ami no functionalized 1,2,4-trioxanes of formula 4.
In one embodiment of the invention, the aromatic amine is selected from the group consisting of aniline, 4-methoxyaniline, 4-chloroaniline, 3,5-dichloroaniline, 4-aminoacetanilide, 1-naphthylamine, 2-aminobiphenyl, 4-aminobiphenyl, 2-aminofluorene, 4-fluoroaniline, 2-trifluoromethylaniline, 3-trifluoromethylaniline and 4-trifluoromethylaniline.
In another embodiment of the invention, the compound of formula 4 is obtained by: (i) Photooxygenating an allylic alcohol of formula 1 by passing oxygen gas or air
in a solution of the alcohol in an organic solvent and in the presence of a dye
and a light source which provides visible light, for a period of 4 h, to obtain a
p-hydroxyhydroperoxide of formula 2
(Formula Removed)
1a; Ar = Phenyl 1 b; Ar = 4-Biphenyl 1c; Ar = 4-chlorophenyl 1d; Ar = 4-methoxyphenyl 1e; Ar = 4-methylphenyl
(Formula Removed)
2a; Ar = Phenyl 2b; Ar = 4-Biphenyl 2c; Ar = 4-chlorophenyl 2d; Ar = 4-methoxyphenyl 2e; Ar = 4-methylphenyl
2
(ii) reacting the hydroperoxides of formula 2 in situ with 1,4-cyclohexanedione in the presence of an acid catalyst to give a trioxane of formula 3;
(Formula Removed)
3a; Ar = Phenyl
3b; Ar = 4-Biphenyl
3c; Ar = 4-chlorophenyl
3d; Ar = 4-methoxyphenyl
3e; Ar = 4-methylphenyl
(iii) reacting the keto trioxane of formula 3 with an aromatic amine in the presence
of NaBH(OAc)3 in CH2Cl2 to obtain amino functionalized 1,2,4-trioxane of
formula 4.
In one embodiment of the invention, the aromatic amines is selected from the group consisting of aniline, 4-methoxyaniline, 4-chloroaniline, 3,5-dichloroaniline, 4-aminoacetanilide, 1-naphthylamine, 2-aminobiphenyl, 4-aminobiphenyl, 2-aminofluorene, 4-fluoroaniline, 2-trifluoromethylaniline, 3-trifluoromethylaniline and 4-trifluoromethylaniline.
The present invention also provides a method of treating a subject having malaria, comprising administering to the subject a pharmaceutically effective amount of a composition containing substituted amino functionalized-1,2,4-trioxanes of formula 4,
wherein Ar represents aryl groups selected from the groups consisting of phenyl, 4-biphenyl, 4-chlorophenyl, 4-methoxyphenyl and 4-methylphenyl and R represents
phenyl, 4-methoxyphenyl, 4-chlorophenyl, 3,5-diclilorophcnyl, 4-acetylaminophcnyl, 1-naphthyl, 2-biphenyl, 4-biphenyl, 2-fluorene, 4-fluorophenyl, 2-trifluoromethylphenyl, 3-trifluoromethylphenyl and 4-trifluoromethylphenyl and a phamiaceutically acceptable carrier.
In one embodiment of the invention, the composition is administered intramuscularly or orally.
In another embodiment of the invention, the pharmaceutically acceptable amount of compound of formula 4 is in the range of 12 to 96 mg of compound of formula 4 per kilogram of body weight of subject per day. Detailed description of the invention
The present invention provides a process for the preparation of amino functionalized 1,2,4-trioxanes of formula 4 given above.
Our SAR studies on amino functionalized 1,2,4-trioxanes have resulted in several novel amino functionalized 1,2,4-trioxanes which show a very high order of antimalarial activity against rodent malaria and disclose here the structures and activity of these novel compounds. The order of activity of amino functionalized 1,2,4-trioxanes reported here is much higher than amino functionalized 1,2,4-trioxanes reported earlier by us [Singh, C.; Malik, H.; Puri, S. K. Bioorg. Med. Chem. Lett. 2004,14, 459].
The present invention therefore also relates to the preparation of novel amino functionalized 1,2,4-trioxanes of formula 4 with high order of antimalarial activity. The present invention particularly relates to the preparation of amino functionalized 1,2,4-trioxanes of formula 4 wherein Ar represents phenyl, 4-biphenyl, 4-chlorophenyl, 4-methoxyphenyl, 4-methylphenyl and the like and R represents phenyl, 4-methoxyphenyl, 4-chlorophenyl, 3,5-dichlorophenyl, 4-acetylaminophenyl, 1-naphthyl, 2-biphenyl, 4-biphenyl, 2-fluorene, 4-fluorophenyl, 2-trifluoromethylphenyl, 3-trifluoromethylphenyl and 4-trifluoromethylphenyl and the like. These trioxanes are new compounds and are useful as antimalarial agents. These compounds have been tested against multidrug-resistant malaria in mice and have shown high order of antimalarial activity.
These trioxanes, thus have a promise of use for the treatment of malaria, a highly prevalent parasitic disease. The invention thus relates to pharmaceutical industry.
The amino functionalized 1,2,4-trioxanes of formula 4 arc new chemical entities and they have not been prepared earlier.
The nrocess of the invention follows the pene.ral sr.hftmp shown hflnw
(Formula Removed)
1a;Ar = Phenyl 2a; Ar = Phenyl
1 b; Ar = 4-Biphenyl 2b- Ar = 4-Biphenyl
1 c; Ar = 4-chlorophenyl 2c; Ar = 4-chlorophenyl
1d; Ar = 4-methoxyPhenyl 2d; Ar = 4-methoxyphenyl
1e; Ar = 4-methylphenyl 2e= Ar = 4-methylphenyl
(Formula Removed)
3a; Ar = Phenyl
3b; Ar = 4-Biphenyl 4
3c; Ar = 4-chlorophenyl
3d; Ar = 4-methoxyphenyl
3e; Ar = 4-methylphenyl
Scheme 1 Reagents and conditions: (a) hv, 02, methylene blue, MeCN, -10 to 0°C, 4 h. (b) 1,4-cycIohexanedione, coned HC1, 5°C, 18 h. (c) RNH2, NaBH(OAc)3, CH2C12, rt, 3.5 h.
In the process of the invention allylic alcohol of formula 1 were prepared by known procedure [(a) Singh, C. Tetrahedron Lett. 1990, 31, 6901. (b) Singh, C.; Tiwari, P.; Puri, S. K. PCT Patent application No. PCT/1N02/00093, dated 28.3.2002].
In the process photooxygenation of allylic alcohols of formula 1 is effected by passing oxygen gas or air in the solution of alcohol in an organic solvent and in the presence of a dye and a light source which provides visible light, for a period of 4 h, to furnish p-hydroxyhydroperoxide of formula 2. These hydroperoxides of formula 2 are known compounds and have been prepared by us earlier [(a) Singh, C.; Misra, D.; Saxena, G.; Chandra, S. Bioorg. Med. Chern. Lett. 1992, 2, 497. (b) Singh, C.; Misra,
D.; Saxena, G.; Chandra, S. Bioorg. Med. Cliem. Lett. 1995, 5, 1913. (e) Singh, C.; Tiwari, P.; Puri, S. K. PCT Patent application No. PCT/1N02/00093, dated 28.3.2002]. The dye acts as a sensitizer, i.e., converts 3O2 to highly reactive 'O2. Hydroperoxides of formula 2 are reacted in situ with 1,4-cyclohexanedione in the presence of an acid catalyst to give trioxanes of formula 3. These 1,2,4-trioxanes of formula 3 have been tested against malaria parasites in mice and show only moderate order of activity. Keto trioxanes 3a, 3b are known compounds as they have been prepared earlier by us [Singh, C.; Malik, H.; Puri, S. K. Bioorg. Med. Chem. Lett. 2004, 14, 459] while 3c, 3d, 3e are new compounds and have not been prepared earlier.
The keto trioxanes of formula 3 are reacted with aromatic amines in the presence of NaBH(OAc)3 in CtbCh to furnish amino functionalized 1,2,4-trioxanes of formula 4. Aromatic amines used may be aniline, 4-methoxyaniline, 4-chloroaniline, 3,5-dichloroaniline, 4-aminoacetanilide, 1-naphthylamine, 2-aminobiphenyl, 4-aminobiphenyl, 2-aminofluorene, 4-fluoroaniline, 2-trifluoromethylaniline, 3-trifluoromethylaniline and 4-trifluoromethylaniline and the like. All of these amino functionalized 1,2,4-trioxanes are new chemical entities and they have not been prepared earlier. These amino functionalized 1,2,4-trioxanes of formula 4 have been tested against malaria parasites in mice and have shown high order of antimalarial activity.
This invention is further illustrated by the following examples which should not, however, be construed to limit the scope of the present invention. Example 1: 3-(l-Phenyl-vinyl)-l,2,5-trioxaspiro[5.5]undec-9-one (compound 3a, Ar = phenyl).
Solution of allylic alcohol la (Ig, 6.75mmol) and methylene blue (30mg) in acetonitrile (100ml) maintained at 0°C, was irradiated with 500W tungsten-halogen lamp while oxygen was bubbled slowly into reaction mixture for 4h. 1,4-Cyclohexanedione (1.15 g, 10.13mmol) and coned. HC1 (5 drops) were added and reaction mixture was left at 5°C overnight. Reaction mixture was concentrated under reduced pressure and residue taken up in ether (100ml) was washed with sat. aq NaMCOa (30ml). Aqueous layer was extracted with ether (2 x 75ml), combined ether layer dried over anhyd. Na2SC>4 and concentrated. Crude product was purified by
column chromatography on silica gel using EtOAc-hexane (5:95) as eluant to furnish trioxane 3a (0.94g, 51% yield, based on allylic alcohol la used), m.p. 70-71°C. Example 2: (4-chloro-phenyI)-[3-(l-phenyl-vinyl)-l,2,5-trioxa-spiro[5.51undec-9-yl|-aminc (compound 4aa, Formula 4, Ar = phenyl, R = 4-chlorophenyl).
To a mixture of trioxane 3a (0.40 g, 1.45 mmol) and 4-chloroaniline (0.23 g, 1.82 mmol) in dichloromethane (20 ml) was added acetic acid (1 ml) and reaction mixture was stirred at room temp for half an hour. Sodium triacetoxyborohydride (0.46 g, 3.63 mmol) was added slowly and was stirred for 3 h at room temperature. The reaction mixture was then poured into water and extracted with CP^Cfe (2 x 20 ml). Combined organic layer was dried over anhyd. Na2SC>4, concentrated under vacuum and crude product was chromatographed over silica gel using benzene-hexane (50:50) as eluant to furnish amino functionalized 1,2,4-trioxane 4aa as an inseparable mixture of diastereomers as oil (0.40 g, 71.7 % yield). Example 3: Biphenyl-2-yl-[3-(l -phenyl-vinyl)-! ,2,5-trioxa-spiro [5.5] undec-9-yljamine (compound 4ab and 4ac, Formula 4, Ar = phenyl, R = 2-biphenyl).
To a mixture of trioxane 3a (0.50 g, 1.82 mmol) and 2-aminobiphenyl (0.38 g, 2.27 mmol) in dichloromethane (20 ml) was added acetic acid (1 ml) and reaction mixture was stirred at room temp for half an hour. Sodium triacetoxyborohydride (0.58 g, 2.73 mmol) was added slowly and it was stirred for 3 h at room temperature. The reaction mixture was then poured into water and extracted with Ct^Ch (2 x 20 ml). Combined organic layer was dried over anhyd. Na2SO4, concentrated under vacuum and crude product was chromatographed over silica gel using benzene-hexane (50:50) as eluant to furnish amino functionalized 1,2,4-trioxane 4ab as oil (upper Rf, 0.17 g, 21.8 % yield) and 4ac (lower Rf, 0.25 g, 32.6 % yield), m.p. 74-76°C.
Example 4: Biphenyl-4-yl-[3-(l-phenyl-vinyl)-l,2,5-trioxa-spiro[5.51undec-9-yljamine (compound 4ad, Formula 4, Ar = phenyl, R = 4-biphenyl).
To a mixture of trioxane 3a (0.40g, 1.45mmol) and 4-aminobiphenyl (0.30g, 1.82 mmol) in dichloromethane (20 ml) acetic acid (1ml) was added and reaction mixture was stirred at room temp for half an hour. Sodium triacetoxyborohydride (0.46g, 3.63mmol) was added slowly and it was stirred for 3h at room temperature. Reaction mixture was then poured into water and extracted with Cl^Ch (2 x 20ml). Combined organic layer was dried over anhyd. Na2SO4, concentrated under vacuum
and crude product was chromatographed over silica gel using benzcnc-hexane (50:50) as eluant to furnish amino functionalized 1,2,4-trioxane 4ad as an inseparable mixture of diastercomers (0.44g, 70.5% yield), m.p. 118-120°C.
Example 5: (9H-Fluoren-3-yl)-[l-phenyI-vinyl)-l,2,5-trioxa-spiro[5.51undec-9-yl|-amine (compound 4ae, Formula 4, Ar = phenyl, R = 2-fluorene).
To a mixture of trioxane 3a (0.30 g, 1.09 mmol) and 2-aminofluorene (0.24 g, 1.36 mmol) in dichloromethane (20 ml) was added acetic acid (1 ml) and reaction mixture was stirred at room temp for half an hour. Sodium triacetoxyborohydride (0.35 g, 1.64 mmol) was added slowly and it was stirred for 3 h at room temperature. The reaction mixture was then poured into water and extracted with CH2Cl2 (2x15 ml). Combined organic layer was dried over anhyd. Na2SO4, concentrated under vacuum and the crude product was chromatographed over silica gel using benzene-hexane (50:50) as eluant to furnish amino functionalized 1,2,4-trioxane 4ae as an inseparable mixture of diastereomers (0.30 g, 63.5 % yield), m.p. 144-146°C. Example 6: (4-Fluoro-ph'enyl)-[3-(l-phenyl-vinyl)-l,2,5-trioxa-spiro[5.5]undec-9-yl|-amine (compound 4af, Formula 4, Ar = phenyl, R = 4-fluorophenyl).
To a mixture of trioxane 3a (0.30 g, 1.09 mmol) and 4-fluoroaniline (0.15 g,
1.34 mmol) in dichloromethane (20 ml) was added acetic acid (1 ml) and reaction
mixture was stirred at room temp for half an hour. Sodium triacetoxyborohydride
(0.35 g, 1.65 mmol) was added slowly and it was stirred for 3 h at room temperature.
The reaction mixture was then poured into water and extracted with CH2Cl2 (2 x 20
ml). Combined organic layer was dried over anhyd. Na2SO4, concentrated under
vacuum and the crude product was chromatographed over silica gel using benzene-
hexane (50:50) as eluant to furnish amino functionalized 1,2,4-trioxane 4af as an
inseparable mixture of diastereomers as oil (0.34 g, 84.1 % yield).
Example 7: [3-(l -Phenyl-vinyl)-! ,2,5-trioxa-spiro [5.5] undec-9-yl j-(3-
trifluoromethyl-phenyl)-aniine (compound 4ah, Formula 4, Ar = phenyl, R = 3-trifluoromethylphenyl).
To a mixture of trioxane 3a (0.50 g, 1.82 mmol) and 3-trifluoromethylaniline (0.37 g, 2.27 mmol) in dichloromethane (20 ml) was added acetic acid (1 ml) and reaction mixture was stirred at room temp for half an hour. Sodium triacetoxyborohydride (0.60 g, 2.73 mmol) was added slowly and it was stirred for 3 h at room temperature. The reaction mixture was then poured into water and extracted
with CH2Cl2 (2 x 20 ml). Combined organic layer was dried over anhyd. Na2SO4,
concentrated under vacuum and the crude product was chromatographed over silica
gel using benzene-hexane (50:50) as eluant to furnish amino functionalized 1,2,4-
trioxane 4ah as an inseparable mixture of diastereomers as oil (0.49 g, 64.1 % yield).
Example 8: [3-(l-Phenyl-vinyl)-l,2,5-trioxa-spiro[5.5]undec-9-yl]-(4-
trifluoromethyl-pheny1)-amine (compound 4ai, Formula 4, Ar = phenyl, R = 4-trifluoromethylphenyl).
To a mixture of trioxane 3a (0.30 , 1.09 mmol) and 4-trifluoromethylaniline
(0.22, 1.36 mmol) dichloromethane (20 ml) was added acetic acid (1 ml) and reaction
mixture was stirred at room temp for half an hour. Sodium triacetoxyborohydride
(0.34 g, 1.60 mmol) was added slowly and it was stirred for 3 h at room temperature.
The reaction mixture was then poured into water and extracted with CH2Cl2 (2 x 20
ml). Combined organic layer was dried over anhyd. Na2SO4, concentrated under
vacuum and the crude product was chromatographed over silica gel using benzene-
hexane (50:50) as eluant to furnish amino functionalized 1,2,4-trioxane 4ai as an
inseparable mixture of diastereomers as oil (0.26 g, 58.7 % yield).
Example 9: 3-(l-Biphenyl-4yl-vinyl)-l,2,5-trioxaspiro[5.5]undec-9-one
(compound 3b, Ar = biphenyl).
A solution of allylic alcohol Ib (1 g, 6.75 mmol) and methylene blue (30 mg) in acetonitrile (100 ml) maintained at 0°C, was irradiated with a 500 W tungsten-halogen lamp while oxygen was bubbled slowly into the reaction mixture for 4 h. 1,4-Cyclohexanedione (1.15 g, 10.13 mmol) and coned HC1 (5 drops) were added and the reaction mixture was left at 5°C overnight. Reaction mixture was concentrated under reduced pressure and residue taken up in ether (100 ml) was washed with sat. aq NaHCO3 (30 ml). The aqueous layer was extracted with ether (2 x 75 ml), combined ether layer dried over anhyd. Na2SO4 and concentrated. The crude product was purified by column chromatography on silica gel using EtOAc-hexane (5:95) as eluant to furnish trioxane 3b (0.65 g, 42 % yield, based on allylic alcohol Ib used), m.p. 104-105°C.
Example 10: [3-(l-Biphenyl-4-yl-vinyl)-l,2,5-trioxa-spiro[5.5]undec-9-yll-(4-chloro-phenyl)-amine (compound 4ba, Formula 4, Ar = 4-biphenyl, R = 4-chlorophenyl).
To a mixture of trioxane 3b (0.40 g, 1.14 mmol) and 4-chloroanilinc (0.18 g,
1.42 mmol) in dichloromethane (20 ml) was added acetic acid (1 ml) and reaction
mixture was stirred at room temp for half an hour. Sodium triacetoxyborohydride
(0.36 g, 1.71 mmol) was added slowly and it was stirred for 3 h at room temperature.
The reaction mixture was then poured into water and extracted with CH2Cl2 (2x15
nil). Combined organic layer was dried over anhyd. Na2SO4, concentrated under
vacuum and the crude product was chromatographed over silica gel using benzene-
hexane (50:50) as eluant to furnish amino functionalized 1,2,4-trioxane 4ba as an
inseparable mixture of diastereomers (0.38 g, 72.1 % yield), m.p. 148-150°C.
Example 11: Biphenyl-2-yl-[3-(l-biphenyl-4-yl-vinyI)-l,2,5-
trioxaspiro[5.5]undec-9-yl]-amine (compound 4bb and 4bc, Formula 4, Ar = 4-biphenyl, R = 2-biphenyl).
To a mixture of trioxane 3b (0.60 g, 1.71 mmol) and 2-aminobiphenyl (0.36 g, 2.14 mmol) in dichloromethane (25 ml) was added acetic acid (1 ml) and reaction mixture was stirred at room temp for half an hour. Sodium triacetoxyborohydride (0.54 g, 2.57 mmol) was added slowly and it was stirred for 3 h at room temperature. The reaction mixture was then poured into water and extracted with CH2Cl2 (2 x 25 ml). Combined organic layer was dried over anhyd. Na2SO4, concentrated under vacuum and the crude product was chromatographed over silica gel using benzene-hexane (50:50) as eluant to furnish amino functionalized 1,2,4-trioxane 4bb (upper Rf, 0.19 g, 21.7 % yield), m.p. 105-106°C and 4bc (lower Rf, 0.28 g, 32.4 % yield), m.p. 148-150°C.
Example 12: Biphenyl-4-yl-[3-(l-biphenyl-4-yl-vinyl)-1,2,5-
trioxaspiro[5.5]undec-9-yll-amine (compound 4bd, Formula 4, Ar = 4-biphenyl, R = 4-biphenyl).
To a mixture of trioxane 3b (0.50 g, 1.42 mmol) and 4-aminobiphenyl (0.30 g, 1.78 mmol) in dichloromethane (20 ml) was added acetic acid (1 ml) and reaction mixture was stirred at room temp for half an hour. Sodium triacetoxyborohydride (0.45 g, 2.14 mmol) was added slowly and it was stirred for 3 h at room temperature. The reaction mixture was then poured into water and extracted with CH2Cl2 (2 x 20 ml). Combined organic layer was dried over anhyd. Na2SO4, concentrated under vacuum and the crude product was chromatographed over silica gel using benzene-
hcxanc (50:50) as eluaiit to furnish aniino functionalizcd 1,2,4-lrioxanc 4hd as an inseparable mixture of diastereomers (0.53 g, 73.8 % yield), m.p. 158-160°C. Example 13: [3-(l-Biphenyl-4-yl-vinyl)-l,2,5-trioxa-spiro[5.5]undec-9-ylj-(9H-fluoren-3-yl)-amine (compound 4be, Formula 4, Ar = 4-biphenyl, R = 2-fluorene).
To a mixture of trioxane 3b (0.30 g, 0.85 mmol) and 2-aminofluorene (0.19 g, 1.07 mmol) in dichloromethane (20 ml) was added acetic acid (1 ml) and reaction mixture was stirred at room temp for half an hour. Sodium triacetoxyborohydride (0.27 g, 1.64 mmol) was added slowly and it was stirred for 3 h at room temperature. The reaction mixture was then poured into water and extracted with CH2Cl2 (2x15 ml). Combined organic layer was dried over anhyd. Na2SO4, concentrated under vacuum and the crude product was chromatographed over silica gel using benzene-hexane (50:50) as eluant to furnish amino functionalized 1,2,4-trioxane 4be as an inseparable mixture of diastereomers (0.28 g, 65.04 % yield), m.p. 170-172°C. Example 14: 3-[l-(4-Chloro-phenyl)-vinylJ-l,2,5-trioxa-spiro[5.5]undecan-9-one (compound 3c, Ar = 4-chlorophenyl).
A solution of allylic alcohol Ic (1 g, 5.47 mmol) and methylene blue (30 mg) in acetonitrile (100 ml) maintained at 0°C, was irradiated with a 500 W tungsten-halogen lamp while oxygen was bubbled slowly into the reaction mixture for 4 h. 1,4-Cyclohexanedione (1.22 g, 10.95 mmol) and coned HCI (5 drops) were added and the reaction mixture was left at 5°C overnight. Reaction mixture was concentrated under reduced pressure and residue taken up in ether (100 ml) was washed with sat. aq NaHCO3 (30 ml). The aqueous layer was extracted with ether (2 x 75 ml), combined ether layer dried over anhyd. Na2SO4 and concentrated. The crude product was purified by column chromatography on silica gel using EtOAc-hexane (5:95) as eluant to furnish trioxane 3c (0.64 g, 38 % yield, based on allylic alcohol Ic used), m.p. 72-74°C.
Example 15: {3-|l-(4-Chloro-phenyl)-vinyl]-l,2,5-trioxa-spiro[5.5]undec-9-yl}-phenyl-amine (compound 4ca, Formula 4, Ar = 4-chlorophenyl, R = phenyl).
To a mixture of trioxane 3c (0.50 g, 1.62 mmol) and aniline (0.19 g, 2.02 mmol) in dichloromethane (20 ml) was added acetic acid (1 ml) and reaction mixture was stirred at room temp for half an hour. Sodium triacetoxyborohydride (0.51 g, 2.43 mmol) was added slowly and it was stirred for 3 h at room temperature. The reaction mixture was then poured into water and extracted with CH2Cl2 (2 x 20 ml).
Combined organic layer was dried over anhyd. Na2SO4, concentrated under vacuum
and the crude product was chromatographed over silica gel using benzene-hexane
(50:50) as eluant to furnish amino functionalized 1,2,4-trioxane 4ca as an inseparable
mixture of diastereomers as oil (0.45 g, 73.4 % yield).
Example 16: {3-[l-(4-Chloro-phenyl)-vinyl]-l,2,5-trioxa-spiro[5.5]undec-9-yl}-p-
tolyl-amine (compound 4cb, Formula 4, Ar = 4-chlorophenyl, R = 4-
methoxyphenyl).
To a mixture of trioxane 3c (0.50 g, 2.27 mmol) and 4-methoxyaniline (0.25 g,
2.02 mmol) in dichloromethane (20 ml) was added acetic acid (1 ml) and reaction
mixture was stirred at room temp for half an hour. Sodium triacetoxyborohydride
(0.51 g, 2.43 mmol) was added slowly and it was stirred for 3 h at room temperature.
The reaction mixture was then poured into water and extracted with CH2Cl2 (2 x 20
ml). Combined organic layer was dried over anhyd. NaaSO4, concentrated under
vacuum and the crude product was chromatographed over silica gel using benzene-
hexane (50:50) as eluant to furnish amino functionalized 1,2,4-trioxane as an
inseparable mixture of diastereomers 4cb (0.54 g, 80.2 % yield), m.p. 148-150°C.
Example 17: Biphenyl-2-yl-{3-[l-(4-chIoro-phenyl)-vinyl]-l,2,5-trioxa-
spiro|5.5|undcc-9-yl}-amine (compound 4ci and 4cj, Formula 4, Ar = 4-chlorophenyl, R = 2-biphenyl).
To a mixture of trioxane 3c (0.50 g, 1.62 mmol) and 2-aminobiphenyl (0.34 g,
2.02 mmol) in dichloromethane (20 ml) was added acetic acid (1 ml) and reaction
mixture was stirred at room temp for half an hour. Sodium triacetoxyborohydride
(0.51 g, 2.43 mmol) was added slowly and it was stirred for 3 h at room temperature.
The reaction mixture was then poured into water and extracted with CH2Cl2 (2 x 20
ml). Combined organic layer was dried over anhyd. Na2SO4, concentrated under
vacuum and the crude product was chromatographed over silica gel using benzene-
hexane (50:50) as eluant to furnish amino functionalized 1,2,4-trioxane 4ci (upper Rf,
0.21 g, 28.8 % yield) and 4cj (lower Rf, 0.32 g, 43.2 % yield) as oil.
Example 18: Biphenyl-4-yl-{3-[l-(4-chloro-phenyl)-vinyl]-l,2,5-trioxa-
spiro[5.51undec-9-yl}-amine (compound 4ck, Formula 4, Ar = 4-chlorophenyl, R = 4-biphenyl).
To a mixture of trioxane 3c (0.50 g, 1.62 mmol) and 4-aminobiphenyl (0.34 g, 2.02 mmol) in dichloromethane (20 ml) was added acetic acid (1 ml) and reaction
mixture was stirred at room temp for half an hour. Sodium triacetoxyborohydride (0.51 g, 2.43 mmol) was added slowly and it was stirred for 3 h at room temperature. The reaction mixture was then poured into water and extracted with CH2Cl2 (2 x 20 ml). Combined organic layer was dried over anhyd. Na2SO4, concentrated under vacuum and the crude product was chromatographed over silica gel using benzene-hexane (50:50) as eluant to furnish amino functionalized 1,2,4-trioxane 4ck as an inseparable mixture of diastereomers as oil (0.37 g, 49.4 % yield). Example 19: {3-[l-(4-Chloro-phenyl)-vinyl]-l,2,5-trioxa-spiro[5.5]undec-9-yI}-(9H-fluoren-3-yl)-amine (compound 4cl, Formula 4, Ar = 4-chlorophenyl, R = 2-fluorene).
To a mixture of trioxane 3c (0.30 g, 0.97 mmol) and 2-aminofluorene (0.22 g, 1.21 mmol) in dichloromethane (20 ml) was added acetic acid (1 ml) and reaction mixture was stirred at room temp for half an hour. Sodium triacetoxyborohydride (0.30 g, 1.46 mmol) was added slowly and it was stirred for 3 h at room temperature. The reaction mixture was then poured into water and extracted with CH2Cl2 (2x15 ml). Combined organic layer was dried over anhyd. Na2SO4, concentrated under vacuum and the crude product was chromatographed over silica gel using benzene-hexane (50:50) as eluant to furnish amino functionalized 1,2,4-trioxane 4cl as an inseparable mixture of diastereomers (0.19 g, 42.3 % yield), m.p. 162-164°C. Example 20: {3-[l-(4-Chloro-phenyl)-vinyl]-l,2,5-trioxa-spiro[5.5]undec-9-yl}-(4-trifluoromethyl-phenyl)-amine (compound 4cp, Formula 4, Ar = 4-chlorophenyl, R = 4-trifluoromethylphenyl).
To a mixture of trioxane 3c (0.30 g, 0.97 mmol) and 4-trifluoromethylaniline (0.19 g, 1.21 mmol) in dichloromethane (20 ml) was added acetic acid (1 ml) and reaction mixture was stirred at room temp for half an hour. Sodium triacetoxyborohydride (0.30 g, 1.46 mmol) was added slowly and it was stirred for 3 h at room temperature. The reaction mixture was then poured into water and extracted with CH2Cl2 (2x15 ml). Combined organic layer was dried over anhyd. Na2SO4, concentrated under vacuum and the crude product was chromatographed over silica gel using benzene-hexane (50:50) as eluant to furnish amino functionalized 1,2,4-trioxane 4cp as an inseparable mixture of diastereomers as oil (0.21 g, 47.6 % yield). Example 21: 3-[l-(4-Methoxy-phenyl)-vinyl]-l,2,5-trioxa-spiro[5.5]undecan-9-one (compound 3d, Ar = 4-methoxyphenyl).
A solution of allylic alcohol Id (1 g, 5.61 mmol) and mcthylcnc blue (30 nig) in acetonitrile (100 ml) maintained at 0°C, was irradiated with a 500 W tungsten-halogen lamp while oxygen was bubbled slowly into the reaction mixture for 4 h. 1,4-Cyclohexanedione (1.25 g, 11.22 mmol) and coned HC1 (5 drops) were added and the reaction mixture was left at 5°C overnight. Reaction mixture was concentrated under reduced pressure and residue taken up in ether (100 ml) was washed with sat. aq NaHCOs (30 ml). The aqueous layer was extracted with ether (2 x 75 ml), combined ether layer dried over anhyd. Na2SO4 and concentrated. The crude product was purified by column chromatography on silica gel using EtOAc-hexane (5:95) as eluant to furnish trioxane 3d as oil (0.48 g, 28.1 % yield, based on allylic alcohol Id used).
Example 22: {3-[l-(4-Methoxy-phenyl)-vinyl]-l,2,5-trioxa-spiro[5.5]undec-9-yl}-phcnyl-amine (compound 4da, Formula 4, Ar = 4-methoxyphenyl, R = phenyl).
To a mixture of trioxane 3d (0.50 g, 1.62 mmol) and aniline (0.19 g, 2.05 mmol) in dichloromethane'(20 ml) was added acetic acid (1 ml) and reaction mixture was stirred at room temp for half an hour. Sodium triacetoxyborohydride (0.52 g, 2.46 mmol) was added slowly and it was stirred for 3 h at room temperature. The reaction mixture was then poured into water and extracted with CH2Cl2 (2 x 20 ml). Combined organic layer was dried over anhyd. Na2SO4, concentrated under vacuum and the crude product was chromatographed over silica gel using benzene-hexane (50:50) as eluant to furnish amino functionalized 1,2,4-trioxane 4da as an inseparable mixture of diastereomers as oil (0.47 g, 74.9 % yield).
Example 23: (4-Methoxy-phenyl)-{3-[l-(4-methoxy-phenyl)-vinyl]-l,2,5-trioxa-spiro|5.5|undcc-9-yl}-amine (compound 4db, Formula 4, Ar = 4-methoxyphenyl, R = 4-methoxyphenyl).
To a mixture of trioxane 3d (0.50 g, 1.64 mmol) and 4-methoxyaniline (0.25 g, 2.05 mmol) in dichloromethane (20 ml) was added acetic acid (1 ml) and reaction mixture was stirred at room temp for half an hour. Sodium triacetoxyborohydride (0.52 g, 2.46 mmol) added slowly and it was stirred for 3 h at room temperature. The reaction mixture was then poured into water and extracted with CH2Cl2 (2 x 20 ml). Combined organic layer was dried over anhyd. Na2SO4, concentrated under vacuum and the crude product was chromatographed over silica gel using benzene-hexane
(50:50) as eluant to furnish amino functionalized 1,2,4-trioxane 4db as an inseparable mixture of diastereomers (0.53 g, 79.2 % yield), m.p. 126-128°C. Example 24: (4-Chloro-phenyI)-{3-[l-(4-methoxy-phenyl)-vinyl]-l,2,5-trioxa-spiro|5.5|undec-9-yl}-aniine (compound 4dc, Formula 4, Ar = 4-methoxyphenyl, R = 4-chlorophenyl).
To a mixture of trioxane 3d (0.50 g, 1.62 mmol) and 4-chloroaniline (0.19 g, 2.05 mmol) in dichloromethane (20 ml) was added acetic acid (1 ml) and reaction mixture was stirred at room temp for half an hour. Sodium triacetoxyborohydride (0.52 g, 2.46 mmol) was added slowly and it was stirred for 3 h at room temperature. The reaction mixture was then poured into water and extracted with CH2Cl2 (2 x 20 ml). Combined organic layer was dried over anhyd. Na2SO4, concentrated under vacuum and the crude product was chromatographed over silica gel using benzene-hexane (50:50) as eluant to furnish amino functionalized 1,2,4-trioxane 4dc as an inseparable mixture of diastereomers (0.47 g, 74.9 % yield), m.p. 104-106°C. Example 25: (3,5-Dichloro-phenyl)-{3-[l-(4-methoxy-phenyl)-vinyl]-l,2,5-trioxa-spiro[5.51undec-9-yl}-amine (compound 4dd, Formula 4, Ar = 4-methoxyphenyl, R = 3,5-dichlorophenyl).
To a mixture of trioxane 3d (0.50 g, 1.64 mmol) and 3,5-dichloroaniline (0.33 g, 2.05 mmol) in dichloromethane (20 ml) was added acetic acid (1 ml) and reaction mixture was stirred at room temp for half an hour. Sodium triacetoxyborohydride (0.52 g, 2.46 mmol) was added slowly and it was stirred for 3 h at room temperature. The reaction mixture was then poured into water and extracted with CH2Cl2 (2 x 20 ml). Combined organic layer was dried over anhyd. Na2SO4, concentrated under vacuum and the crude product was chromatographed over silica gel using benzene-hexane (50:50) as eluant to furnish amino functionalized 1,2,4-trioxane 4dd as an inseparable mixture of diastereomers (0.38 g, 51.3 % yield), m.p. 85-86°C. Example 26: N-(4-{3-[l-(4-Methoxy-phenyl)-vinyl]-l,2,5-trioxa-spiro[5.5]undec-9-ylamino}-phenyl)-acetamide (compound 4de, Formula 4, Ar = 4-methoxyphenyl, R = 4-acetylaminophenyl).
To a mixture of trioxane 3d (0.50 g, 1.64 mmol) and 4-aminoacetanilide (0.30 g, 2.05 mmol) in dichloromethane (20 ml) was added acetic acid (1 ml) and reaction mixture was stirred at room temp for half an hour. Sodium triacetoxyborohydride (0.52 g, 2.46 mmol) was added slowly and it was stirred for 3 h at room temperature.
The reaction mixture was then poured into water and extracted with CH2Cl2 (2 x 20 ml). Combined organic layer was dried over anhyd. Na2SO4, concentrated under vacuum and the crude product was chromatographed over silica gel using EtOAc-hexane (50:50) as eluant to furnish amino functionalized 1,2,4-trioxane 4de as an inseparable mixture of diastereomers (0.60 g, 83.3 % yield), m.p. 70-72°C. Example 27: {3-[l-(4-Methoxy-phenyl)-vinyl]-l,2,5-trioxa-spiro[5.51undec-9-yl}-(3-trifluoroinethyl-phenyl)-amine (compound 4dm, Formula 4, Ar = 4-methoxyphenyl, R = 3-trifluoromethylphenyl).
To a mixture of trioxane 3d (0.30 g, 0.98 mmol) and 3-trifluoromethylaniline (0.20 g, 1.21 mmol) in dichloromethane (20 ml) was added acetic acid (1 ml) and reaction mixture was stirred at room temp for half an hour. Sodium triacetoxyborohydride (0.31 g, 1.47 mmol) was added slowly and it was stirred for 3 h at room temperature. The reaction mixture was then poured into water and extracted with CH2Cl2 (2x15 ml). Combined organic layer was dried over anhyd. Na2SO4, concentrated under vacuum and the crude product was chromatographed over silica gel using EtOAc-hexane (50:50) as eluant to furnish amino functionalized 1,2,4-trioxane 4dm as an inseparable mixture of diastereomers as oil (0.27 g, 60.9 % yield). Example 28: 3-(l-p-ToIyl-vinyl)-l,2,5-trioxa-spiro[5.5]undecan-9-one (compound 3e, Ar = 4-methylphenyl).
A solution of allylic alcohol le (1 g, 6.16 mmol) and methylene blue (30 mg) in acetonitrile (100 ml) maintained at 0°C was irradiated with a 500 W tungsten-halogen lamp while oxygen was bubbled slowly into the reaction mixture for 4 h. 1,4-Cyclohexanedione (1.15 g, 10.13 mmol) and coned HC1 (5 drops) were added and the reaction mixture was left at 5°C overnight. Reaction mixture was concentrated under reduced pressure and residue taken up in ether (100 ml) was washed with sat. aq NaHCCl2 (30 ml). The aqueous layer was extracted with ether (2 x 75 ml), combined ether layer dried over anhyd. Na2SO4 and concentrated. The crude product was purified by column chromatography on silica gel using EtOAc-hexane (5:95) as eluant to furnish trioxane 3e (0.58 g, 32.7 % yield, based on allylic alcohol le used), m.p. 66-68°C.
Example 29: Phenyl-[3-(l-p-tolyl-vinyl)-l,2,5-trioxa-spiro[5.5]undec-9-yl]-amine (compound 4ea, Formula 4, Ar = 4-methylphenyl, R = phenyl).

To a mixture of trioxane 3e (0.30 g, 1.04 mmol) and aniline (0.12 g, 1.30 mmol) in dichloromethane (20 ml) was added acetic acid (1 ml) and reaction mixture was stirred at room temp for half an hour. Sodium triacetoxyborohydride (0.33 g, 1.56 mmol) was added slowly and it was stirred for 3 h at room temperature. The reaction mixture was then poured into water and extracted with CH2C12 (2 x 20 ml). Combined organic layer was dried over anhyd. Na2SO4, concentrated under vacuum and the crude product was chromatographed over silica gel using ben/ene-hexane (50:50) as eluant to furnish amino functionalized 1,2,4-trioxane 4ea as an inseparable mixture of diastereomers as oil (0.29 g, 76.3 % yield).
Example 30: (4-Methoxy-phenyl)-[3-(l-p-tolyl-vinyI)-l,2,5-trioxa-
spiro|5.5]undec-9-yl|-amine (compound 4eb, Formula 4, Ar = 4-methylphenyl, R = 4-methoxyphenyl).
To a mixture of trioxane 3e (0.30 g, 1.04 mmol) and 4-methoxyaniline (0.16 g, 1.30 mmol) in dichloromethane (20 ml) was added acetic acid (1 rnl) and reaction mixture was stirred at roorn temp for half an hour. Sodium triacetoxyborohydride (0.33 g, 1.56 mmol) was added slowly and it was stirred for 3 h at room temperature. The reaction mixture was then poured into water and extracted with CH2Cl2 (2x15 ml). Combined organic layer was dried over anhyd. Na2SO4, concentrated under vacuum and the crude product was chromatographed over silica gel using benzene-hexane (50:50) as eluant to furnish amino functionalized 1,2,4-trioxane 4eb as an inseparable mixture of diastereomers as oil (0.33g, 80.2 % yield). Example 31: (4-Chloro-phenyl)-[3-(l-p-tolyl-vinyl)-l,2,5-trioxa-spiro[5.5]undec-9-yl)-amine (compound 4ec Formula 4, Ar = 4-methylphenyl, R = 4-chlorophenyl).
To a mixture of trioxane 3e (0.30 g, 1.04 mmol) and 4-chloroaniline (0.16 g, 1.30 mmol) in dichloromethane (20 ml) was added acetic acid (1 ml) and reaction mixture was stirred at room temp for half an hour. Sodium triacetoxyborohydride (0.33 g, 1.56 mmol) was added slowly and it was stirred for 3 h at room temperature. The reaction mixture was then poured into water and extracted with CH2Cl2 (2x15 ml). Combined organic layer was dried over anhyd. Na2SO4, concentrated under vacuum and the crude product was chromatographed over silica gel using benzene-hexane (50:50) as eluant to furnish amino functionalized 1,2,4-trioxane 4ec as an inseparable mixture of diastereomers (0.26 g, 62.6 % yield), m.p. 110-112°C.
Example 32: (3,5-Dichloro-phcnyl)-[3-(l-p-tolyl-vinyI)-l,2,5-trioxa-
spiru[5.5]undec-9-yl]-amine (compound 4ed (upper Rf) and 4ee (lower Rf), Fonuula 4, Ar = 4-methylphenyl, R = 3,5-dichlorophenyl).
To a mixture of trioxane 3e (0.50 g, 1.62 mmol) and 3,5-dichloroaniline (0.19 g, 2.05 mmol) in dichloromethane (20 ml) was added acetic acid (1 ml) and reaction mixture was stirred at room temp for half an hour. Sodium triacetoxyborohydride (0.52 g, 2.46 mmol) was added slowly and it was stirred for 3 h at room temperature. The reaction mixture was then poured into water and extracted with CH2C12 (2 x 20 ml). Combined organic layer was dried over anhyd. Na2SO4, concentrated under vacuum and the crude product was chromatographed over silica gel using benzene-hexane (50:50) as eluant to furnish amino functionalized 1,2,4-trioxane 4ed (upper Rf, 0.19 g, 25.20 % yield), m.p.!40-142°C and 4ee (lower Rf) 0.28 g, 37.1 % yield), m.p. 112-114°C.
Example 33: N-{4-[3-(l-p-TolyI-vinyl)-l,2,5-trioxa-spiro[5.5]undec-9-ylamino|-phenylj-acetamide (compound 4ef, Formula 4, Ar = 4-methylphenyl, R = 4-acetylaminophenyl).
To a mixture of trioxane 3e (0.50 g, 1.62 mmol) and 4-aminoacetanilide (0.19 g, 2.05 mmol) in dichloromethane (20 ml) was added acetic acid (1 ml) and reaction mixture was stirred at room temp for half an hour. Sodium triacetoxyborohydride (0.52 g, 2.46 mmol) was added slowly and it was stirred for 3 h at room temperature. The reaction mixture was then poured into water and extracted with CH2Cl2 (2 x 20 ml). Combined organic layer was dried over anhyd. NaaSO4, concentrated under vacuum and the crude product was chromatographed over silica gel using EtOAc-hexane (50:50) as eluant to furnish amino functionalized 1,2,4-trioxane 4ef as an inseparable mixture of diastereomers (0.47 g, 76.2 % yield), m.p. 83-85°C. Example 34: Naphthalen-l-yl-[3-(l-p-tolyl-vinyl)-l,2,5-trioxa-spiro[5.5]undec-9-yl]-amine (compound 4eg, Formula 4, Ar = 4-methylphenyl, R = 1-naphthyl).
To a mixture of trioxane 3e (0.50 g, 1.64 mmol) and 1-naphthylamine (0.30 g, 2.05 mmol) in dichloromethane (20 ml) was added acetic acid (1 ml) and reaction mixture was stirred at room temp for half an hour. Sodium triacetoxyborohydride (0.52 g, 2.46 mmol) was added slowly and it was stirred for 3 h at room temperature. The reaction mixture was then poured into water and extracted with CH2Cl2 (2 x 20 ml). Combined organic layer was dried over anhyd. Na2SO4, concentrated under
vacuum and the crude product was chromatographed over silica gel using benzene-hexane (50:50) as eluant to furnish amino functionalized 1,2,4-trioxane 4eg as an inseparable mixture of diastereomers (0.52 g, 72.2 % yield), m.p. 70-72°C. Example 35: Biphenyi-2-yl-[3-(l-p-tolyl-vinyl)-l,2,5-trioxa-spiro[5.5]undec-9-yl|-aininc (compound 4eh and 4ei, Formula 4, Ar = 4-methylphenyl, R = 2-biphenyl).
To a mixture of trioxane 3e (0.80 g, 2.59 mmol) and 2-aminobiphenyl (0.41 g,
3.24 mmol) in dichloromethane (30 ml) was added acetic acid (1 ml) and reaction
mixture was stirred at room temp for half an hour. Sodium triacetoxyborohydride
(0.82 g, 3.89 mmol) was added slowly and it was stirred for 3 h at room temperature.
The reaction mixture was then poured into water and extracted with CH2Cl2 (2 x 25
ml). Combined organic layer was dried over anhyd. Na2SO4, concentrated under
vacuum and the crude product was chromatographed over silica gel using benzene-
hexane (50:50) as eluant to furnish amino functionalized 1,2,4-trioxane 4eh (upper Rf,
0.29 g, 26.60 % yield) and 4ei (lower Rf, 0.44 g, 40.3 % yield) as oil.
Example 36: (4-Fluoro-phenyl)-[3-(l-p-tolyl-vinyl)-l,2,5-trioxa-spiro[5.5]undec-9-yl]-amine (compound 4el, Formula 4, Ar = 4-methylphenyl, R = 4-fluorophenyl).
To a mixture of trioxane 3e (0.30 g, 1.04 mmol) and 4-fluoroaniline (0.14 g,
1.25 mmol) in dichloromethane (20 ml) was added acetic acid (1 ml) and reaction
mixture was stirred at room temp for half an hour. Sodium triacetoxyborohydride
(0.33 g, 1.55 mmol) was added slowly and it was stirred for 3 h at room temperature.
The reaction mixture was then poured into water and extracted with CH2Cl2 (2 x 20
ml). Combined organic layer was dried over anhyd. Na2SO4, concentrated under
vacuum and the crude product was chromatographed over silica gel using benzene-
hexane (50:50) as eluant to furnish amino functionalized 1,2,4-trioxane 4el as an
inseparable mixture of diastereomers as oil (0.30 g, 75.1 % yield).
Example 37: |3-(l-p-Tolyl-vinyl)-l,2,5-trioxa-spiro[5.5]undec-9-yll-(4-
trifluoromethyl-phenyl)-amine (compound 4eo, Formula 4, Ar = 4-methylphenyl, R = 4-trifluoromethylphenyl).
To a mixture of trioxane 3e (0.30 g, 1.04 mmol) and 4-trifluoromethyloaniline (0.21 g, 1.30 mmol) in dichloromethane (20 ml) was added acetic acid (1 ml) and reaction mixture was stirred at room temp for half an hour. Sodium triacetoxyborohydride (0.33 g, 1.55 mmol) was added slowly and it was stirred for 3 h at room temperature. The reaction mixture was then poured into water and extracted
with CH2C12 (2 x 20 ml). Combined organic layer was dried over anhyd. Na2SO4, concentrated under vacuum and the crude product was chromatographed over silica gel using benzene-hexane (50:50) as eluant to furnish amino functionalized 1,2,4-trioxane 4eo as an inseparable mixture of diastereomers (0.22 g, 48.7 % yield), m.p. 104-106°C.
Following the above procedure the following amino functionalized 1,2,4-trioxanes 4ag, 4bf, 4bg, 4bh, 4bi, 4cc, 4cd, 4ce, 4cf, 4cg, 4ch, 4cm, 4cn, 4co, 4df, 4dg, 4dh, 4di, 4dj, 4dk, 4dl, 4dn, 4ej, 4ek, 4em and 4en were prepared (Scheme 1, Table 1). Table
(Table Removed)

Antimalarial Activity
The antimalarial activity of the test compounds was evaluated in rodent using multidrug resistant strain of Plasmodium yoelii Nigeriensis in Swiss mice. General Procedure
Random bred Swiss mice of either sex (20 ±2 gm) were inoculated intraperitoneally with 1 x 105 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 treatment was administered in groundnut oil intramuscularly and orally for 4 consecutive days (day 0-3). Blood smears from experimental mice were observed on day 4 and 7, day 10 and thereafter at regular intervals till day 28 or death of the animal. The parasitaemia level on day 4 was compared with vehicle control group and percent suppression of parasitaemia in treated groups was calculated.
For determining the curative dose of a compound the treated mice were observed till day 28. The dose at which no parasitaemia develop during the observation period has been reported as the curative dose. The antimalarial data is summarized in Table 2.
Table 2: ANTIMALARIAL ACTIVITY OF TRIOXANES AGAINST P. Yoelii IN MICE.
(Formula Removed)
4aa R = 4-chlorophenyl 4ab R = 2-biphenyl (upper R,) 4ac R = 2-biphenyl (lower R() 4ad R = 4-biphenyl 4ae R = 2-fluorene 4af R = 4-fluorophenyl 4ag R = 2-trifluoromethylphenyl 4ah R = 3-trifluoromethylphenyl 4al R = 4-trifluoromethylphenyl
(Formula Removed)
4ba R = 4-chlorophenyl 4bb R = 2-biphenyl (gpper R,) 4bc R = 2-biphenyl (lower Rf) 4bd R = 4-biphenyl 4be R = 2-fluorene 4bf R = 4-fluorophenyl 4bg R = 2-trifluoromethylphenyl 4bh R = 3-trifluoromethylphenyl 4bl R = 4-trifluoromethylphenyl

(Formula Removed)
4ca R = phenyl
4cb R = 4-methoxyphenyl
4cc R = 4-chlorophenyl (upper R()
4cd R = 4-chlorophenyl (lower R()
4ce R = 3,5-dichtorophenyl (upper Rf)
4cf R = 3,5-dichlorophenyl (lower R()
4cg R = 4-acetylamlnophenyl
4chR=1-naphthyl
4cl R = 2-blphenyl (upper R()
4cj R = 2-biphenyl (lower R()
4ck R = 4-biphenyl
4cl R = 2-fluorene
4cm R = 4-fluorophenyl
4cn R = 2-trifluoromethylphenyl
4co R = 3-trifluoromethylphenyl
4cp R = 4-trifluoromethylphenyl

(Formula Removed)

4da R = phenyl 4db R = 4-methoxyphenyl 4dc R = 4-chlorophenyl 4dd R = 3,5-dichlorophenyl 4de R = 4-acetylaminophenyl 4df R=1-naphthyl 4dg R = 2-biphenyl (upper R() 4dh R = 2-biphenyl (lower R,) 4dl R = 4-biphenyl 4dJ R = 2-fluorene 4dk R = 4-fluorophenyl 4dl R = 2-trifluoromethylphenyl 4dm R = 3-trifluoromethylphenyl
4dnR = d-trifli inrnmflthvlnhnnul
(Formula Removed)
4ea R = phenyl
4eb R = 4-methoxyphenyl
4ec R = 4-chlorophenyl
4ed R = 3,5-dichlorophenyl (upper R,)
4ee R = 3,5-dichlorophenyl (lower Rf)
4ef R = 4-acetylaminophenyl
4eg R = 1-naphthyl
4eh R = 2-biphenyl (upper R,)
4ei R = 2-biphenyl (lower Rf)
4ej R = 4-biphenyl
4ek R = 2-fluorene
4el R = 4-fluorophenyl
4emR = 2-trifluoromethylphenyl
4en R = 3-trifluordmethylphenyl
4eo R = 4-trifluoromethylphenyl



















We claim:
1. A method for preparation of substituted amino functionalized-l,2,4-trioxanes useful as antimalarial agents of formula 4
(Formula Removed)
wherein Ar is an aryl group selected from the group consisting of phenyl, 4-biphenyl, 4-chlorophenyl, 4-methoxyphenyl and 4-methylphenyl and R represents phenyl, 4-methoxyphenyl, 4-chlorophenyl, 3,5-dichlorophenyl, 4-acetylaminophenyl, 1-naphthyl, 2-biphenyl, 4-biphenyl, 2-fluorene, 4-fluorophenyl, 2-trifluoromethylphenyl, 3-trifluoromethylphenyl and 4-trifluoromethylphenyl, the method comprising:
(i) photooxygenating an allylic alcohol of formula 1 by passing oxygen gas or air in a solution of the alcohol in an organic solvent and in the presence of a dye and a light source which provides visible light, for a period of 4 h, to obtain a P-hydroxyhydroperoxide of formula 2
(Formula Removed)
(ii) reacting the hydroperoxides of formula 2 in situ with 1,4-cyclohexanedione in the presence of an acid catalyst to give a trioxane of formula 3;
(Formula Removed)
reacting the keto trioxane of formula 3 with an aromatic amine in the presence of NaBH(OAc)3 in CH2Cl2 to obtain amino functionalized 1,2,4-trioxane of formula 4.
2. A method as claimed in claim 1, wherein the aromatic amine is selected from the
group consisting of aniline, 4-methoxyaniline, 4-chloroaniline, 3,5-dichloroaniline, 4-
aminoacetanilide, 1-naphthylamine, 2-aminobiphenyl, 4-aminobiphenyl, 2-
aminofluorene, 4-fluoroaniline, 2-trifluoromethylaniline, 3-trifluoromethylaniline and
4-trifiuoromethylaniline.
3. A method for preparation of substituted amino functionalized-1, 2, 4-trioxanes useful
as antimalarial agents substantially as herein described with reference to examples
accompanying this specification.

Documents:

1282-DELNP-2005-Abstract-(18-12-2009).pdf

1282-DELNP-2005-Abstract-(22-03-2010).pdf

1282-delnp-2005-abstract.pdf

1282-DELNP-2005-Claims-(18-12-2009).pdf

1282-DELNP-2005-Claims-(22-03-2010).pdf

1282-delnp-2005-claims.pdf

1282-DELNP-2005-Correspondence-Others-(18-12-2009).pdf

1282-DELNP-2005-Correspondence-Others-(22-03-2010).pdf

1282-delnp-2005-correspondence-others.pdf

1282-DELNP-2005-Description (Complete)-(18-12-2009).pdf

1282-DELNP-2005-Description (Complete)-(22-03-2010).pdf

1282-delnp-2005-description (complete).pdf

1282-DELNP-2005-Form-1-(18-12-2009).pdf

1282-DELNP-2005-Form-1-(22-03-2010).pdf

1282-delnp-2005-form-1.pdf

1282-delnp-2005-form-18.pdf

1282-DELNP-2005-Form-2-(18-12-2009).pdf

1282-DELNP-2005-Form-2-(22-03-2010).pdf

1282-delnp-2005-form-2.pdf

1282-DELNP-2005-Form-3-(18-12-2009).pdf

1282-delnp-2005-form-3.pdf

1282-delnp-2005-form-5.pdf

1282-DELNP-2005-Petition-137-(18-12-2009).pdf

abstract.jpg


Patent Number 240677
Indian Patent Application Number 1282/DELNP/2005
PG Journal Number 22/2010
Publication Date 28-May-2010
Grant Date 26-May-2010
Date of Filing 31-Mar-2005
Name of Patentee COUNCIL OF SCIENTIFIC & INDUSTRIAL RESEARCH
Applicant Address ANUSANDHAN BHAWAN, RAFI MARG, NEW DELHI 110 001, INDIA.
Inventors:
# Inventor's Name Inventor's Address
1 SINGH, CHANDAN CENTRAL DRUG RESEARCH INSTITUE, CHATTAR MANZIL PLALCE, POST BOX NO 173, LUCKNOW 226 001, INDIA.
2 HEETIKA MALIK CENTRAL DRUG RESEARCH INSTITUE, CHATTAR MANZIL PLALCE, POST BOX NO 173, LUCKNOW 226 001, INDIA.
3 PURI,SUNIL KUMAR CENTRAL DRUG RESEARCH INSTITUE, CHATTAR MANZIL PLALCE, POST BOX NO 173, LUCKNOW 226 001, INDIA.
PCT International Classification Number C07D 323/06
PCT International Application Number PCT/IN04/00413
PCT International Filing date 2004-12-27
PCT Conventions:
# PCT Application Number Date of Convention Priority Country
1 PCT/IN04/00413 2004-12-23 U.S.A.