Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
1999-07-06
2001-06-05
Criares, Theodore J. (Department: 1617)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S232800, C544S147000, C549S551000
Reexamination Certificate
active
06242484
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Cross Reference to Related Applications
Expressly incorporated herein by reference are U.S. Pat. No. 5,801,193, and co-pending applications, U.S. Ser. Nos. 09/006,946; 09/007,308; 09/298,653; and PCT WO 98/46222.
2. Field of the Invention
This invention relates to the use of diterpene compounds, in particular hypoestoxides, derivatives and agonists thereof for anti-parasitic therapy and prophylaxis, wherein unexpected and beneficial results have been noted against nucleated infectious agents, among other things.
3. Background Art
Almost a third of the world's population lives in areas at risk of malaria, and according to estimates by World Health Organization (WHO), one to two million children in Sub-Saharan Africa die from the disease each year (WHO, Wkly Epidemiol Rec. 1997; 72: 269-76). This long-standing problem has not been addressed by conventional disclosures and remains a pressing issue in most of the developing nations of the world, in addition to demanding instant clinical study.
Malaria is caused by the protozoan parasites
Plasmodium falciparum, P. vivax, P. ovale
and
P. malariae
in humans and by
P. berghei, P. chabaudi, P. yoelii, P. vinckei
in rodents;
P. knowlesi, P. cynomolgi
in primates and
P. Iophurae
in avian. Malaria is the most deadly protozoan infection of humans. Hundreds of millions of cases of malaria occur annually and infections with
P. falciparum
the most virulent human malaria parasite, leads to millions of deaths each year (Walsh J. A. Annals of the New York Acad. Sciences 1989; 569: 1-16). Despite extensive control efforts, the incidence of malaria is not decreasing in most endemic areas of the world, and in some areas, it is clearly increasing (Oaks et al, eds. 1991: Washington, D.C.: National Academy Press). A major reason for the persistence of the severe malaria problem is the increasing resistance of parasites to available chemotherapeutic agents. Resistance to chloroquine, the most widely used antimalarial in the last 50 years, is now very common, and other available antimalarials are limited by resistance, high cost and toxicity (Olliaro et al; JMA 1996, 275:230-233).
Other antimalarials such as atrabrine dihydrochloride (quinacrine hydrochloride) produces a number of undesirable side effects, such as jaundice and gastrointestinal disturbances (Bogitsh, B. J. and Chen, T. C. eds. Human Parasitology, 2nd edition, 1998:Academic Press, San Diego, London, Boston, New York, etc.). Thus, the development of antimalarial drugs must be a continuous process, and requires both theoretical and clinical attention urgently.
SUMMARY OF THE INVENTION
To provide a solution to this longstanding need an unexpected use of the instant compounds has generated the teaching of the present invention, which overcome the drawbacks of the prior art.
Applicants' invention rests on their finding that a select group of hypoestoxide analogs possess unexpected prophylactic and therapeutic effectiveness as growth inhibiting agents against harmful organisms including the known protozoan parasite of the genus, Plasmodium, among others having similar status as nucleated infectious agents.
In particular, the present invention comprises a method for inhibiting and/or delaying the growth of these parasites in subjects. The method comprises administering to a subject in need of antiparasitic therapy or prophylaxis, a pharmaceutical composition comprising a therapeutically effective amount of a compound of the formula I.
In another aspect, the invention provides a method of treating a subject to alleviate pathological effects of the growth of parasites of numerous other members of the Protozoan family and related microorganisms (e.g Plasmodia, Trypanosoma, Theileria, Babesia and Coccidia).
According to a feature of the present invention there is provided a therapeutic method for treating a subject having a disease caused by infection with a protozoan parasite, comprising inhibiting the growth of said parasite by administering to said subject an effective amount of at least one compound, or a pharmaceutically acceptable prodrug of said compound, said compound having the structural formula I:
wherein R is:
a) H,
b) P(O)(OH)
2
,
c) P(O)(OH)(OM), wherein M is an alkali metal salt, or an alkaline earth metal salt,
d) P(O)OM
2
wherein M is each independently selected from the group consisting of alkali metal salts and alkaline earth metal salts,
e) Alkyl of 1 to 12 carbon atoms substituted or unsubstituted, straight chain or branched, 0 to 6 double bonds, (CH
2
)
n
morpholine where n=1-4, morpholinomethylphenyl, ortho-aminophenyl, ortho-hydroxyphenyl, (CH
2
)
n
COOR
2
where n=1-4;
wherein R
2
is H, an alkali metal salt, an alkaline earth metal salt, NH
4
+, N+(R
3
)
4
wherein R
3
is each independently selected from the group consisting of H and alkyl of 1 to 4 carbon atoms,
f) COR
1
wherein R
1
is selected from the group consisting of H, (CH
2
)
n
CH
3
wherein n=0-6, (CH
2
)
n
COOR
2
wherein n=1-4 and R
2
is as previously defined, and (CH
2
)
n
N+(R
3
)
3
, wherein n=1-4,
wherein the effective amount is sufficient to ameliorate at least one symptom of said disease.
Likewise, according to a further feature of the present invention there is provided a prophylactic method for protecting a subject in danger of contracting disease caused by infection with a protozoan parasite, comprising inhibiting the growth of said parasite by administering to said subject an effective amount of at least one compound, or pharmaceutically acceptable prodrug of said compound, said compound having the structural formula I:
wherein R is:
a) H,
b) P(O)(OH)
2
,
c) P(O)OH)(OM), wherein M is an alkali metal salt, or an alkaline earth metal salt,
d) P(O)OM
2
wherein M is each independently selected from the group consisting of alkali metal salts and alkaline earth metal salts,
e) alkyl of 1 to 12 carbon atoms substituted or unsubstituted, straight chain or branched, 0 to 6 double bonds, (CH
2
)
n
morpholine where n=1-4, morpholinomethylphenyl, ortho-aminophenyl, ortho-hydroxyphenyl, (CH
2
)
n
COOR
2
where n=1-4;
f) wherein R
2
is H, an alkali metal salt, an alkaline earth metal salt, NH
4
+, N+(R
3
)
4
wherein R
3
is each independently selected from the group consisting of H and alkyl of 1 to 4 carbon atoms,
g) COR
1
wherein R
1
is selected from the group consisting of H, (CH
2
)
n
CH
3
wherein n=0-6, (CH
2
)
n
COOR
2
wherein n=1-4 and R
2
is as previously defined, and (CH
2
)
n
N+(R
3
)
3
, wherein n=1-4,
wherein the effective amount is sufficient to ameliorate the manifestation of at least one symptom of said disease.
These, and other objects, features and advantages of the present invention will become apparent when read in conjunction with the accompanying figures.
REFERENCES:
patent: 5801193 (1998-09-01), Ojo-Amaize
WHO. World malaria situation in 1994. Wkly Epidemiol Rec. 1997; 72 269-76.
Walsh, J.A. Disease problems in the Third World. Annals of the New York Academy of Sciences 1989; 569:1-16.
Oaks, S.C; Mitchell, V.S.; Pearson, G.W. and Carpenter, C.C.J; eds,. 1991. Malaria: Obstacles and Opportunities. Washington D C.: National Academy Press.
Olliaro, P., Cattani J and Wirth, D. Malaria, the submerged disease. JAMA 1996; 275: 230-233.
Bogitsh, B.J. and Chen, T.C, eds. Human Parasitology 2nd edition, 1998: Academic Press, San Diego, London, Boston, New York.
Miller, L.H; Pino J.A, McKelvey, Jr., J.J. eds. Immunity to blood parasites of animals and man. (Advances in experimental Medicine and Biology vol. 93), 1997: Plenum Press, New York and London.
Baker, J.R.; Muller, R, and Rollinson, D. eds. Advances in Parasitology vol. 43, 1999: Academic Press.
Murray, P.K. et al. eds. Medical Microbiology. Third edition, Mosby, St. Louis, MO. 1998.
Ojo-Amaize, E.A. et al. Plasmodium berghei sporozoites are mitogenic for murine T cells, induce interferon and activate natural killer cells. J. Immunol 1984, 133: 1005-1009.
Ojo-Amaize, E.A. et al.
Nchekwube Emeka J.
Ojo-Amaize Emmanuel A.
Okogun Joseph I.
Criares Theodore J.
Paraquest, Inc.
Pillsbury & Winthrop LLP
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