Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2002-03-28
2004-05-18
Rotman, Alan L. (Department: 1625)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C549S333000, C549S336000, C549S368000
Reexamination Certificate
active
06737438
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to a novel series of antimalarial 1,2,4-trioxanes analogues of general formula 7,
wherein R represents cycloalkyl groups selected from the groups consisting of cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl or aryl groups selected from phenyl, 4-bromophenyl and 4-chlorophenyl, R
1
and R
2
represent hydrogen, alkyl group selected from methyl, ethyl, propyl and decyl, aryl selected from phenyl or parts of a cyclic systems such as cyclopentane, cyclohexane, substituted cyclohexane, cycloheptane bicyclo(2.2.1)heptane, adamantane and its preparation thereof; several of these novel compounds show promising antimalarial activity against multidrug resistant malaria in mice.
BACKGROUND OF INVENTION
Malaria, endemic in many parts of the tropical countries, with approximately 300-500 million episodes of clinical infection and nearly 2 million deaths per year worldwide, is a serious health problem. The rapid emergence of resistance by
Plasmodium falciparum
to the existing therapies, e.g. chloroquine, mefloquine etc, has added new dimensions to this problem. Against this background discovery of artemisinin 1, a sesquiterpene lactone endoperoxide, isolated from the Chinese traditional herbal remedy against malaria, Artemisia annua, has been a welcome development in the chemotherapy of malaria. Some of the semisynthetic derivatives of artemisinin e.g. artemether 2, arteether 3, and artesunic acid 4 are more active than artemisinin and are currently being used clinically. These drugs are effective against both chloroquine sensitive and chloroquine resistant strains of
Plasmodium falciparum
[For reviews on artemisinin and its derivatives, see: (a) Klayman, D. L.
Science,
1985, 228, 1049; (b) Luo, X. D.; Shen, C. C.
Med. Res. Rev.,
1987, 7, 29; (c) Zaman, S. S.; Sharma, R. P.
Heterocycles,
1991,32,1593; (d) Butler, A. R.; Wu, Y. Lin.
Chem. Soc. Rev.,
1993, 21,85; (e) Meshnick, S. R.; Taylor, T. E.; Kamchonwongpaisan, S.
Microbiol. Rev.,
1996, 60,301; (f) Bhattacharya, A. K.; Sharma, R. P.
Heterocycles,
1999, 51, 1681; (g) Haynes, R. K.; Vonwiller, S. C.
Acc. Chem. Res.,
1997, 73].
The limited availability of artemisinin from natural sources and the realization that 1,2,4-trioxane is the phannacophore for the antimalarial activity of artemisinin and its analogues, has inspired major efforts towards the preparation and bioevaluation of structurally simple synthetic 1,2,4-trioxanes. As a result of these efforts, a number of metho dologies have been developed by various workers for the preparation of 1,2,4-trioxanes (prototypes of these trioxanes are given in FIG.
1
). Several of these synthetic trioxanes have shown promising antimalarial activities both in vitro and in vivo [Cumming, J. M.; Ploypradith, P.; Posner, G. H.
Adv Pharmacol,
1999, 37,253].
Singh et al. have prepared 1,2,4-trioxanes by the regiospecific photooxygenation of allylic alcohols to furnish -hydroxyhydroperoxide, which on condensation with aldehyde or ketone in the presence of an acid catalyst furnish 1,2,4-trioxane [(a) Singh, C.
Tetrahedron Lett.
1990,31,6901;(b) Singh, C.; Misra, D.; Saxena, G.; Chandra, S.
Bioorg. Med. Chem. Lett.,
1992, 2, 497; Singh, C.; Misra, D.; Saxena, G.; Chandra, S.
Bioorg. Med. Chem. Lett.,
1995,17, 1913]. As an extension of this work we have prepared a new series of novel 1,2,4-trioxanes which have been found to be highly active against multi-drug resistant
P. yoelii
in mice and which are the subject matter of this patent. This invention relates to novel substituted 1,2,4-trioxanes useful as antimalarial agents.
This invention also relates to a process for the preparation of novel substituted 1,2,4-trioxanes.
This invention particularly relates to a process for the preparation of 6-[(cycloalkylphenyl/Substituted biphenyl)vinyl]-1,2,4-trioxanes, a new series of antimalarial agents. More particularly the present invention provides a process for the preparation of 1,2,4-trioxanes of general formula 7 wherein R represents cycloalkyl groups selected from the groups consisting of cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl or aryl groups selected from phenyl, 4-bromophenyl and 4-chlorophenyl, R
1
and R
2
represent hydrogen, alkyl group selected from methyl, ethyl, propyl and decyl, aryl selected from phenyl, or part of a cyclic system such as cyclopentane, cyclohexane, substituted cyclohexane, cycloheptane, cyclo(2.2.1 )heptane, adamantane. These trioxanes are new compounds and are useful as antimalarial agents. Some of these compounds have been tested against multi-drug resistant malaria in mice and have shown promising antimalarial activity. The invention, thus relates to pharmaceutical industry.
The trioxanes of the general formula 7 are new chemical entities and they have not been prepared earlier.
The main objective of the present invention is to provide novel substituted 1,2,4-trioxanes.
The objective of the present invention is also to provide a process for the preparation of novel substituted 1,2,4-trioxanes of general formula 7, a new series of antimalarial agents. Accordingly, the present invention provides a process for the preparation of novel substituted 1,2,4-trioxanes of general formula 7 as given below.
Wherein R represents cycloalkyl groups selected from the groups consisting of cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl or aryl groups selected from phenyl, 4-bromophenyl and 4-chlorophenyl, R
1
and R
2
represent hydrogen, alkyl group selected from methyl, ethyl, propyl and decyl, aryl selected from phenyl or parts of a cyclic systems such as cyclopentane, cyclohexane, substituted cyclohexane, cycloheptane, bicyclo (2.2.1)heptane, adamantane which comprises reacting aryl methyl ketone of formula 1, wherein R represents cycloalkyl groups selected from the groups consisting of cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl or aryl groups selected from phenyl, 4-bromophenyl and 4-chlorophenyl with haloacetate such as ethyl bromoacetate or ethylchloroacetate and Zn in presence of catalytic amount of I
2
in an aprotic organic solvent at a temperature range of room temperature to refluxing temperature to give &bgr;-hydroxyester of formula 2, wherein R has the same meaning as above, dehydrating the above said &bgr;-hydroxy esters of formula 2 using a catalyst selected from the group consisting of I
2
, P
2
O
5
, PTSA and cation exchanger such as Amberlyst-15, in an aprotic organic solvent at room temperature to refluxing temperature to obtain &agr;,&bgr;-unsaturated ester 3, wherein R has the same meaning as above, reducing the above said esters of formula 3 with a metal hydride such as LiAlH
4
in an ether solvent at a temperature ranging from 0° C. to refluxing temperature to give allylic alcohols of the formula 4, wherein R has the same meaning as above, photooxygenating the above said allylic alcohols of formula 4 in presence of a sensetizer in an organic solvent at temperature ranging from −10° C. to room temperature to obtain &bgr;-hydroxyhydroperoxides of formula 5, wherein R has the same meaning as above , reacting in situ or after isolating the &bgr;-hydroxyhydroperoxide of the formula 5 with an aldehyde or ketone of the general formula 6, wherein, R
1
and R
2
represent hydrogen, alkyl group such as methyl, ethyl, propyl and decyl, aryl such as phenyl and parts of a cyclic system selected from groups consisting of cyclopentane, cyclohexane, cycloheptane, substituted cyclohexanes, bicyclo(2.2.1)heptane, adamantane, in presence of an acid catalyst in an aprotic organic solvent at a temperature range of 0° C. to room temperature, followed by isolation and purification by known methods to furnish the trioxanes of general formula 7, wherein R, R
1
and R
2
have the same meaning as above.
In the process aryl methyl ketone of formula 1 are reacted with haloacetate such as ethyl bromoacetate or ethylchloroacetate and Zn in presence of catalytic amount of I
2
in an aprotic organic solvent such as benzene, toluene, diethyl ether, TH
Puri Sunil Kumar
Singh Chandan
Tiwari Pallvi
Council of Scientific and Industrial Research
Covington Raymond
Morgan & Finnegan , LLP
Rotman Alan L.
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