Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2001-06-22
2003-07-01
Gerstl, Robert (Department: 1626)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S365000, C514S367000, C548S203000, C548S179000, C549S348000
Reexamination Certificate
active
06586464
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to a procedure for the production of enantiomerically pure monomeric and dimeric C-10 non-acetal derivatives of natural trioxane artemisinin having high in vitro antimalarial, antiproliferative and antitumor activities. The present invention further relates to the formation of a novel trioxane aldehyde compound produced via a chemoselective C—C bond formation at the C-10 position upon reaction of artemisinin trioxane lactone with lithiothiazole or lithiobenzothiazole. This trioxane aldehyde may then be reacted with organolithium, Grignard, and phosphorus ylide nucleophiles exclusively via carbonyl addition.
2. Description of the State of Art
Each year approximately 200-300 million people experience a malarial illness and over 1 million individuals die. In patients with severe and complicated disease, the mortality rate is between 20 and 50%.
Plasmodium is the genus of protozoan parasites which is responsible for all cases of malaria and
Plasmodium falciparum
is the species of parasite that is responsible for the vast majority of fatal malaria infections. Malaria has traditionally been treated with quinolines such as chloroquine, quinine, mefloquine, and primaquine and with antifolates such as sulfadoxine-pyrimethamine. Unfortunately, most
P. falciparum
strains have now become resistant to chloroquine, and some, such as those in Southeast Asia, have also developed resistance to mefloquine and halofantrine; multidrug resistance is developing in Africa also.
The endoperoxides are a promising class of antimalarial drugs which may meet the dual challenges posed by drug-resistant parasites and the rapid progression of malarial illness. The first generation endoperoxides include artemisinin and several synthetic derivatives, discussed in further detail below.
Artemisia annua L.
, also known as qinghao or sweet wormwood, is a pervasive weed that has been used for many centuries in Chinese traditional medicine as a treatment for fever and malaria. Its earliest mention, for use in hemorrhoids, occurs in the
Recipes for
52
Kinds of Diseases
found in the Mawangdui Han dynasty tomb dating from 168 B.C. Nearly five hundred years later Ge Hong wrote the
Zhou Hou Bei Ji Fang
(Handbook of Prescriptions for Emergency Treatments) in which he advised that a water extract of qinghao was effective at reducing fevers. In 1596, Li Shizhen, the famous herbalist, wrote that chills and fever of malaria can be combated by qinghao preparations. Finally, in 1972, Chinese chemists isolated from the leafy portions of the plant the substance responsible for its reputed medicinal action. This crystalline compound, called qinghaosu, also referred to as QHS or artemisinin, is a sesquiterpene lactone with an internal peroxide linkage.
Artemisinin is a member of the amorphane subgroup of cadinenes and has the following structure (I).
Artemisinin or QHS was the subject of a 1979 study conducted by the Qinghaosu Antimalarial Coordinating Research Group involving the treatment of 2099 cases of malaria (
P. vivax
and
P. falciparum
in a ratio of about 3:1) with different dosage forms of QHS, leading to the clinical cure of all patients. See, Qinghaosu Antimalarial Coordinating Research Group,
Chin. Med. J.,
92:811 (1979). Since that time artemisinin has been used successfully in many thousand malaria patients throughout the world including those infected with both chloroquine-sensitive and chloroquine-resistant strains of
P. falciparum
. Assay of artemisinin against
P. falciparum
in vitro revealed that its potency is comparable to that of chloroquine in two Hanian strains (Z. Ye, et al.,
J. Trad. Chin. Med.,
3:95 (1983)) and of mefloquine in the Camp (chloroquine-susceptible) and Smith (chloroquine-resistant) strains, D. L. Klayman, et al.,
J. Nat. Prod.,
47:715 (1984).
Although artemisinin is effective at suppressing the parasitemias of
P. vivax
and
P. falciparum
, the problems encountered with recrudescence, and the compound's insolubility in water, led scientists to modify artemisinin chemically, a difficult task because of the chemical reactivity of the peroxide linkage which is believed to be an essential moiety for antimalarial activity.
Reduction of artemisinin in the presence of sodium borohydride results in the production of dihydroartemisinin (II-1) or DHQHS, (illustrated in structure II below), in which the lactone group is converted to a lactol (hemiacetal) function, with properties similar to artemisinin. Artemisinin in methanol is reduced with sodium borohydride to an equilibrium mixture of &Dgr;-and E-isomers of dihydroartemisinin. The yield under controlled conditions is 79% (artemisinin, 0.85M with NaBH
4
6:34M, 7:5 equivalents in methanol, 12 L at 0-5° C. for about 3 hours followed by quenching with acetic acid to neutrality at 0-5° C. and dilution with water to precipitate dihydroartemisinin), A. Brossi, et al.,
Journal of Medicinal Chemistry,
31:645-650 (1988). Using dihydroartemisinin as a starting compound a large number of other derivatives, such as,
1 R=H
2 R=CH
3
3 R=CH
2
CH
3
4 R=COCH
2
CH
2
COONa
5 R=CH
2
C
6
H
4
COOH
6 R=CH
2
C
6
H
4
COONa
7
artemether (compound II-2), arteether (II-3), sodium artesunate (II-4), artelinic acid (II-5), soduim artelinate (II-6), dihydroartemisinin condensation by-product (II-7) and the olefinic compound structure III,
have been produced.
Artemether (II-2) is produced by reacting E-dihydroartemisinin with boron trifluoride (BF
3
) etherate or HCl in methanol:benzene (1:2) at room temperature. A mixture of E-and &Dgr;-artemether (70:30) is obtained, from which the former is isolated by colunm chromatography and recrystallized from hexane or methanol, R. Haynes,
Transactions of the Royal Society of Tropical Medicine and Hygiene,
88(1): S1/23-S1/26 (1994). For arteether (II-3), (Brossi, et al., 1988), the &Dgr;-isomer is equilibrated (epimerized) to the E-isomer in ethanol:benzene mixture containing BF
3
etherate. Treatment of dihydroartemisinin with an unspecified dehydrating agent yields both the olefinic compound, (III), and the dihydroartemisinin condensation by-product (II-7), formed on addition of dihydroartemisinin to (III), M. Cao, et al.,
Chem. Abstr.,
100:34720k (1984). Until recently, the secondary hydroxy group in dihydroartemisinin (II-1) provided the only site in an active artemisinin-related compound that had been used for derivatization. See B. Venugopalan, “Synthesis of a Novel Ring Contracted Artemisinin Derivative,”
Bioorganic
&
Medicinal Chemistry Letters,
4(5):751-752 (1994).
The potency of various artemisinin-derivatives in comparison to artemisinin as a function of the concentration at which the parasitemia is 90 percent suppressed (SD
90
) was reported by D. L. Klayman, “Qinghaosu (Artemisinin): An Antimalarial Drug from China,”
Science
228:1049-1055 (1985). Dr. Klayman reported that the olefinic compound III is inactive against
P. berghei
-infected mice, whereas the dihydroartemisinin condensation by-product (II-7) has an SD
90
of 10 mg/Kg in
P. berghei
-infected mice. Thus, the dihydroartemisinin ether dimer proved to be less potent than artemisinin, which has an SD
90
of 6.20 mg/Kg. Following, in order of their overall antimalarial efficacy, are the three types of derivatives of dihydroartemisinin (II-1) that have been produced: (artemisinin)<ethers (II, R=alkyl)<esters [II,=C(═O)-alkyl or -aryl]<carbonates [II, R=C (═O)O-alkyl or -aryl].
Other rational design of structurally simpler analogs of artemisinin has led to the synthesis of various trioxanes, some of which possess excellent antimalarial activity. Posner, G. H., et al., reported the chemistry and biology of a series of new structurally simple, easily prepared, racemic 1,2,4-trioxanes (disclosed in U.S. Pat. No. 5,225,437 and incorporated herein by reference) that are tricyclic (lacking the lactone ring present in tetracyclic artemisinin I) an
Murray Christopher
O'Dowd Hardwin
Posner Gary H.
Shapiro Theresa A.
Xie Suji
Gerstl Robert
Hogan & Hartson LLP
Johns Hopkins University
O'Rourke Sarah S.
Petersen Steven C.
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