Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2002-08-30
2004-03-23
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...
C514S452000, C549S349000, C549S368000
Reexamination Certificate
active
06710074
ABSTRACT:
TECHNICAL FIELD
The present invention relates to a novel compound having antimalarial activity and an antimalarial agent containing the novel compound as an active component.
BACKGROUND ART
Malaria is spread from person to person by the bite of a mosquito, Anopheles spp. A malaria parasite, being injected into a human body as a sporozoite together with saliva of a mosquito, enters into a hepatocyte and multiplies as an exoerythrocytic form (tissue form) parasite, and 10 to 14 days later, the parasite becomes a schizozoite and enters into the bloodstream to cause an infection, then multiplies through asexual reproduction wherein the parasite grows to a trophozoite, and to a schizont. A schizozoite, which corresponds to a seed of a plant, is produced in a mature schizont, and this schizozoite (merozoite) spills and enters into another erythrocyte, and then repeats its asexual reproduction. Although some of the schizozoites become male or female gametocytes without asexual reproduction, schizozoites cannot proliferate further in a human body, and schizozoites do not become male or female gametes and mate for sexual reproduction until they enter into the body of a mosquito. After several stages, such gamete matures and becomes a sporangium which has numerous sporozoites inside, and when a mosquito sucks the blood of human, such sporozoites are transfused into the human body together with saliva of the mosquito. There are four kinds of malaria parasites that infect human:
Plasmodium falciparum, Plasmodium vivax, Plasmodium ovale
and
Plasmodium malariae
, and it is estimated that 200 to 300 million people are infected with malaria in the world, and that two to three million people die from malaria every year. In recent years, there emerge insecticide-resistant mosquitoes and chloroquine-resistant malaria parasites, and it is becoming difficult to deal with these organisms.
As an antimalarial agent or an antimalarial compound, the following are conventionally known: a novel compound of ortho-condensation system containing two heterocycles as described in Japanese Laid-Open Patent Application No. 2000-7673; an antimalarial agent containing a compound having ICAM-1 expression suppressing activity as an active component as described in Japanese Laid-Open Patent Application No. 11-228446; an antimalarial agent containing a nucleoside derivative and the like such as 5′-o-sulfamoyl-2-chloroadenosine or the like as an active component as described in Japanese Laid-Open Patent Application No. 11-228422; an antimalarial agent containing tricothecenes and the like as an active component as described in Japanese Laid-Open Patent Application No. 11-228408; an antimalarial agent containing cycloprodigiosin and the like as an active component as described in Japanese Laid-Open Patent Application No. 10-265382; a drug for preventing or treating malaria containing riminophenazine as an active component as described in Japanese Laid-Open Patent Application No. 8-231401; an agent for overcoming antimalarial drug resistance containing a quinoline derivative and the like as an active component as described in Japanese Laid-Open Patent Application No. 8-73355; an antimalarial agent containing 5-fluoroorotic acid and sulfamonomethoxyne as an active component as described in Japanese Laid-Open Patent Application No. 8-59471; an antimalarial agent containing
Astragalus membranaceus, Cinnamomum cassia, Rehmanniae Radix, Paeonia lactiflora, Cnidii Rhizoma, Atractylodis Lanceae Rhizoma, Angelicae Radix, Panax ginseng, Poria cocos
and
Glycyrrhizae Radix
, or extracts thereof as an active component as described in Japanese Laid-Open Patent Application No. 7-82165; an antimalarial agent containing a tetrapyrrole derivative and the like as an active component as described in Japanese Laid-Open Patent Application No. 6-157308; an antimalarial agent containing 15-deoxyspergualin and the like as an active component as described in Japanese Laid-Open Patent Application No. 5-97665.
Malaria is a serious infection. 200 to 300 million people are infected with malaria and two to three million people die from malaria every year. Further, the emergence of a malaria parasite resistant to chloroquine, which is a drug heavily used as a panacea of malaria, has become a serious problem, and therefore, there is an urgent need to develop an effective remedy. Artemisinin, which is isolated from plants that belong to Asteraceae and has a trioxa structure, is effective to chloroquine-resistant malaria parasites, and this nature derived compound is currently used as a remedy. However, a malaria parasite which shows resistance also to artemisinin has already emerged as well, and it is causing a more serious problem. An object of the present invention is to provide a novel compound having antimalarial activity and an antimalarial agent containing the novel compound as an active component.
DISCLOSURE OF THE INVENTION
The inventors of the present invention have conducted intensive study as to synthesis of artemisinin analogues in order to attain the above-mentioned object, and found that 12-hidroxy-2-(1-methoxycarbonylethyl)-5-oxo-10,11,13-trioxatricyclo[7.2.0.0
1,6
]tridecane synthesized by utilizing photooxidation reaction, from bicyclic olefin synthesized by intramolecular Diels-Alder reaction, shows extremely high antimalarial activity and selective toxicity, and the present invention has been thus completed.
The present invention relates to a compound represented by a following general formula (I) [wherein R
1
represents a hydrogen atom or an optionally branched C1-C6 alkyl group, R
2
represents a hydrogen atom, an optionally branched C1-C6 alkyl group or an optionally substituted aryl group, R
3
represents an oxygen atom, a sulfur atom, NR
4
(R
4
represents a hydrogen atom or an optionally branched C1-C6 alkyl group) or CR
5
2
(R
5
each independently represents a hydrogen atom or an optionally branched C1-C6 alkyl group)](claim
1
),
Chemical Formula 1
and the compound according to claim
1
, wherein the compound represented by the general formula (1) is 12-hidroxy-2-(1-methoxycarbonylethyl)-5-oxo-10,11,13-trioxatricyclo[7.2.0.0
1,6
]tridecane represented by a following formula (II) (claim
2
).
Chemical Formula 2
The present invention further relates to an antimalarial agent containing a compound represented by a following general formula (I) [wherein R
1
represents a hydrogen atom or an optionally branched C1-C6 alkyl group, R
2
represents a hydrogen atom, an optionally branched C1-C6 alkyl group or an optionally substituted aryl group, R
3
represents an oxygen atom, a sulfur atom, NR
4
(R
4
represents a hydrogen atom or an optionally branched C1-C6 alkyl group) or CR
5
2
(R
5
each independently represents a hydrogen atom or an optionally branched C1-C6 alkyl group)] as an active component (claim
3
),
Chemical Formula 3
and the antimalarial agent according to claim 3, wherein the compound represented by the general formula (I) is 12-hidroxy-2-(1-methoxycarbonylethyl)-5-oxo-10,11,13-trioxatricyclo[7.2.0.0
1,6
]tridecane represented by a following formula (II) (claim
4
).
Chemical Formula 4
BEST MODE TO CARRY OUT THE INVENTION
In the compound represented by the general formula (I) according to the present invention, R
1
represents a hydrogen atom or an optionally branched C1-C6 alkyl group, and specific examples of such optionally branched C1-C6 alkyl group include a methyl group, an ethyl group, an isopropyl group and a t-butyl group. R
2
represents a hydrogen atom, an optionally branched C1-C6 alkyl group or an optionally substituted aryl group, and specific examples of such optionally branched C1-C6 alkyl group include a methyl group, an ethyl group, an isopropyl group and a t-butyl group, and those of the optionally substituted aryl group include a phenyl group, a tolyl group and a naphthyl group, respectively. In addition, as a substituent in the aryl group, an optionally branched C1-C6 alkyl group, an optionally branched C1-C6 alkoxy group and the
Ihara Masataka
Kim Hye-Sook
Takasu Kiyosei
Wataya Yusuke
Covington Raymond
Japan Science and Technology Corporation
Kinberg Robert
Rotman Alan L.
Venable LLP
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