WO1993007119A1 - Novel antimalarial peroxides and processes for their production and use - Google Patents

Abstract

The present invention relates to new tetraoxanes useful in the treatment of malaria and to processes for the production thereof. The invention also relates to methods for the treatment of malaria and, in particular, to the treatment of chloroquine-resistant strains of malaria. The compounds of the invention have formula (I).

Description

NOVEL ANTIMALARIAL PEROXIDES AND PROCESSES FOR THEIR PRODUCTION AND USE

FIELD OF THE INVENTION

The present invention relates to antimalarial peroxides and their use in the treatment of malaria and to processes for the production thereof . The invention also relates to methods for the treatment of malaria and, in particular, to the treatment r of chloroquine resistant strains of malaria. In a preferred

embodiment, this invention relates to Dispiro-1, 2 ,4,5-tetraoxan which are active against chloroquine-resistant malaria. BACKGROUND OF THE INVENTION

In the following discussion, a number of citations from professional journals are included for the convenience of the reader. These citations are in abbreviated form in the text by author, followed by author and year only. The full citation of each is set forth in the References section at the end of the specification. While these citations more fully describe the state of the art to which the present invention pertains, the inclusion of these citations is not intended to be an admission that any of the cited publications represent prior art with respect to the present invention.

By a large margin, malaria is the most prevalent disease the world. It is estimated for the year 1986 that some 489 million people contracted malaria, 2.3 million of whom died fro the disease (Sturchler, 1989). Drug-resistance to most known antimalarial drugs has become an enormous problem (Payne, 1987). Artemisinin, a complex endoperoxide sesquiterpene lactone

isolated from Artemisia annua has been used successfully to treat drug-resistant malaria in China since 1972, although

recrudescence often occurs after the drug is discontinued

(Qinghaosu Antimalaria Coordinating Research Group, 1972).

Isolation of this promising new drug is an expensive process, however, as it is present in only small quantities (0.01 - 0.5% by dry weight) in A. annua (Klayman, 1985). Although the total synthesis of artemisinin has been accomplished (Avery et al., 1987; Xu et al., 1986; Schmid and Hofheinz, 1983), its industrial manufacture by chemical synthesis would be unreasonably expensive by orders of magnitude. Thus, there remains a need for new antimalarial agents, especially for those active against

drug-resistant malaria.

As a result of an apparent association between the peroxide functional group and antimalarial activity (Vennerstrom and

Eaton, 1988), a substantial effort has been devoted to developing new peroxide antimalarials. Our attempts (Vennerstrom et al., 1989) in this regard led us to conclude that an endoperoxide ketal is a minimum but insufficient (Bischoff and Rieche, 1969) structural requirement for an effective peroxide-containing antimalarial. Most of this work, however, has centered around artemisinin, the prototype peroxide antimalarial, in an effort to discern its structure-activity-relationships (SAR) (Acton and Klayman, 1987; Avery et al. 1989a; 1989b; 1990; Jung et al., 1990; Imakura et al., 1990). These investigations demonstrate that the 1,2,4-trioxane heterocycle in artemisinin is the critical pharmacophore. Highest activity is seen in those derivatives with an ethano bridge corresponding to carbons 4 and 5 in artemisinin. Full activity is seen with ABC ring

derivatives (Imakura et al., 1990).

Others (Jefford, 1986; Jefford et al., 1988; Kepler, et al., 1988) have synthesized simpler 1,2,4-trioxanes which have afforded mixed results when screened for antimalarial activity. For example, Jefford (1986) described excellent antimalarial activity for seventeen 1,2,4-trioxanes (IC₅₀ 0.50-25 ng/ml) against P. falciparum in vitro; the structures of these

1,2,4-trioxanes, however, were not disclosed. More recently, Jefford et al. (1988) reported that ten 1, 2 ,4-trioxanes were either inactive or much less active than was artemisinin again P. berghei in mice. Finally, Kepler et al. (1988) synthesized ten 1,2,4-trioxanes that were inactive against P. berghei ; the most active compounds in this series had IC₅₀'s of between 24. and 100 ng/ml against P. falciparum in vitro.

Artemisinin is inactive in vivo against P. berghei

(Vennerstrom et al., 1989) at a 640 mg/kg dose in the Rane screen (Osdene et al., 1967) run by the Walter Reed Army Institute of Research (WRAIR); the curative activity of artemisinin is ampl evident, however, when a multiple-dose protocol is followed (Lin et al., 1987). ??In this light, a technical report by Doorenbos and Decker (1973) that several 1,2,4,5-tetraoxanes are curative at single doses of 320 and 640 mg/kg is remarkable. To our knowledge, these 1,2,4,5-tetraoxanes are the only peroxides reported to date that have single-dose in vivo activity against P. berghei. ??

It is an object of this invention to provide novel

antimalarial peroxides and a method for the treatment of malaria with the peroxides herein after described which have single-dose in vivo activity against P. berghei and are also active against P. falciparum in vitro.

SUMMARY OF THE INVENTION

In accordance with the present invention 1,2,4,5-tetraoxanes (hereinafter tetraoxanes) and their stereoisomers and regei isomers are provided. In one embodiment, these compounds can be depicted by the following formula:

wherein n is a whole integer from 1 to about 4; R and R' can be same or different and are H or monovalent radicals derived from an acyclic or cyclic hydrocarbon by removal of one hydrogen atom from a carbon atom. Additionally, R and R' can be fluoro (F-), chloro (Cl-), bromo (Br-), trifluoromethyl (-CF₃), cyano (-CN)), or methylsulfoxide (-SOCH₃). In its acyclic form, R and R' generally contain at least two, and no more than about 12, carbon atoms and, preferably, are unsubstituted straight or branched alkanes, preferably, lower alkyls (generally containing between about 1 and about 4 carbon atoms). In their cyclic form, R and R' contain at least three and, generally, no more than about eight carbon atoms and, preferably, are cycloalkanes, which may optionally be substituted with the above specified groups.

Tetraoxanes derived from 5, 6, and 7 membered cyclic ketones, i.e., where n in the above formula is 1, 2, or 3, are preferred as antimalarials. The following tetraoxanes (1-3) are exemplary of the antimalarial activity of the compounds of thi invention. 1 and 2 were isolated as mixtures of meso and d,l stereoisomers, whereas 3 was isolated as a single meso isomer. Each of these compounds exhibits curative, single dose, in vivo activity against P. berghei (3 is as active as artemisinin in Thompson test and has a higher therapeutic index). Compound 3 (IC₅₀3-7 nM) is nearly equipotent to artemisinin (IC₅₀2-5 nM) against both drug-sensitive and -resistant strains of P.

falciparum in vitro. Significantly, these curative antimalarial properties were not accompanied by toxicity as has been observed with other peroxides (Vennerstrom et al., 1989)·

The tetraoxanes of this invention constitute a new class of peroxide antimalarial drugs. A substantial advantage of these compounds with respect to artemisinin and its derivatives

includes straightforward one-step syntheses using inexpensive starting materials vs. multistep syntheses or isolations from natural sources.

A method for the treatment of malaria constitutes another embodiment of this invention. This method comprises

administering to a host a tetraoxane of this invention in a pharmaceutically acceptable dosage form containing an amount of said tetraoxane which is effective in treating malaria. Ideally, the effective dose for treating malaria is that dose which is toxic to the malaria parasite infecting the host, but below the threshold of significant toxicity to the host. Generally, for the compounds of this invention this dose ranges from about 5 mg to about 100 mg per kilogram of host body weight. Because the compounds of this invention exhibit high therapeutic indices, it is possible, but generally not economically practical, to employ higher doses up to even 500 mg/kg and higher. Normally, because the compounds of this invention have such high antimalarial activity, doses of between about 5 and about 50 mg/kg host boddy weight are employed.

DETAILED DESCRIPTION OF THE INVENTION

a. 1,2,4,5-Tetraoxanes Derived from Unsubstituted

Cyclohexanones

Tetraoxanes A1-A5 are isolated as a single isomer.

b. 1,2,4,5-Tetraoxanes Derived from Alkyl-substituted

Cyclohexanones

In this class, the synthesis of tetraoxanes substituted the 1 and 10 positions (B1- B8) (available from 2-substituted cyclohexanones) as structural analogs of 3 are preferred. These compounds are generally isolated as a single meso stereoisomer corresponding to 3. The remaining examples in this category include tetraalkyl-substituted tetraoxanes obtained from all the isomeric dimethyl-substituted cyclohexanones and other

dialkyl-substituted cyclohexanones.

B1 1,10-diethyl B18 1,2,10, 11-tetra_ethyl

B2 1,10-dipropyl B19 1,3,10,12-tetramethyl

B3 1,10-diisopropyl B20 3,12-dimethyl-1,10-di-tert-butyl

B4 1,10-dibityl B21 1,10-dimethyl-3,12-di-tert-butyl

B5 1,10-di-tert-butyl B22 1,10-dimethyl-4,13-di-tert-butyl B6 1,10-divinyl B23 1,4,10,13-tetramethyl

B7 1,10-diallyl B24 1, 10-diisopropyl-4,13-dimethyl

B8 1,10-dibenzyl B25 4,13-diisopropyl-1,10-dimethyl

B9 2,11-dimethyl B26 1,10-diisopropenyl-4,13-dimethyl

B10 2,11-diethyl B27 4,13-diisopropenyl-1,10-dimethyl

B11 2,11-dipropyl B28 2,3,11,12-tetramethyl

B12 2,11-diisopropyl B29 1,1,10,10-tetramethyl

B13 2,11-dibutyl B30 2,2,11,11-tetramethyl

B14 3,12-diethyl B31 2,2,11,12-tetramethyl

B15 3,12-dipropyl

B16 3,12-diisopropyl

B17 3,12-dibutyl c. 1,2,4,5-Tetraoxanes Derived from Alkyl-substituted

Cyclopentanones

The following exemplify methyl-substituted derivatives of A2, in addition to several examples with larger alkyl

substituents as illustrated below.

C1 1,9-dimethyl C9 1 ,2 ,9 ,10-tetramethyl

C2 1,9-diethyl C10 1,3,9,11-tetramethyl

C3 1,9-dipropyl C11 2,3,10,11-tetramethyl

C4 1,9-diisopropyl C12 1,1,9,9-tetramethyl

C5 2,10-dimethyl C13 2,2,10,10-tetramethyl

C6 2,10-diethyl

C7 2,10-dipropyl

C8 2,10-diisopropyl d. 1,2,4,5-Tetraoxanes Derived from Alkyl-substituted

Cyclohexenoneε

These tetraoxanes and those in the following category (e.) are analogs of the two preceding classes (b. and c. ) with different geometries inherent in cyclohexene and cyclopentene rings compared with their saturated counterparts. The synthesis of olefinic tetraoxanes have been previously reported (Bailey et al., 1965). Isomeric analogs can be obtained from the

appropriate unsaturated (unconjugated) cyclohexenones and cyclopentenones. The synthesis of these compounds involves an acid-catalyzed isomerization to the more stable conjugated keton under the acidic reaction conditions, as discussed more fully hereinafter.

D1 unsubstituted D7 3 ,5,12,14-tetramethyl

D2 1,10-dimethyl D8 3,3,12,12-tetramethyl

D3 2,11-dimethyl D9 4,13-diisopropyl-1,10-dimethyl

D4 3,12-dimethyl

D5 4,13-dimethyl

D6 5,14-dimethyl

e. 1,2,4,5-Tetraoxanes Derived from Alkyl-substituted

Cyclopentenones

(see section d. above)

E1 unsubstituted

E2 1,9-dimethyl

E3 2,10-dimethyl

E4 3,11-dimethyl

E5 4,12-dimethyl

E6 3,3,11,11-tetramethyl f. 1,2,4,5-Tetraoxanes Derived from Alkyl-substituted

Cycloheptanones

Dimethyl and tetramethyl substituted tetraoxanes of this category can be synthesized from the readily accessible

cycloheptanones required as starting material.

F1 1,11-dimethyl

F2 2,12-dimethyl

F3 3,13-dimethyl

F4 3,3,13,13-tetramethyl g. 1,2,4,5-Tetraoxanes Derived from Bicyclic and Tricyclic Ketones

This class of tetraoxanes demonstrates the effects of conformational rigidity inherent in these ring systems on antimalarial activity. There is precedent for the synthesis of tetraoxanes of this type; for example - G3 (Overton and Owen, 1973). Aside from the synthesis of tetraoxanes from adamantanone (G1), thujone (G2) and ß-pinenone(G3), most of the proposed tetraoxanes will explore the effects of methyl-substitution, and unsaturation on tetraoxanes derived from bicyclic [2.2.1],

[2.2.2], [3.3.1], and [3.2.1] systems.

h. 1,2,4,5-Tetraoxanes Derived from Miscellaneous Ketones

The following tetraoxanes demonstrate halogen and ether functionality in analogs of the corresponding compounds in classes a. - c.

i. "Bridged" 1,2,4,5-Tetraoxanes Derived from

Bis-cyclohexanones

The following tetraoxanes exemplify another embodiment of this invention. Compounds I1-I8 are "bridged" analogs of A3. Tetraoxanes I1 and I5 are particularly preferred. Compounds I1-I8 may each be isolated as mixtures of meso and d,l

diastereomers.

j. "Bridged" 1,2,4,5-Tetraoxanes Derived from

Bis-cyclopentanones

This group of tetraoxanes (JI-J8) demonstrates a

cyclopentane rather than a cyclohexane spirocarbocycle (I1-I8)

k. Artemisinin ABC Ring 1,2,4,5-Tetraoxane Analogs

Tetraoxanes K1-K4 exemplify artemisinin analogs even more closely than do the "bridged" tetraoxanes of the preceding two categories. For example, K1-K4, in addition to having the

1,2,4,5-tetraoxane ring in a fixed boat conformation, each have a methyl group corresponding to the methyl at C-3 in artemisinin rather than a spiro-fused cyclohexane ring as with I1-I8. K2-K4 demonstrate methyl substitution on the cyclohexane ring

corresponding to substituted positions (C-6, C-8a) in

artemisinin.

K1 R₁=H-R₂=H

K2 R₁=CH₃,R₂=H

K3 R₁=H,R₂ =CH₃

K4 R₁=CH_3-R₂ =CH₃

Methods

a. Synthesis of 1,2,4,5-Tetraoxanes by Acid-Catalyzed

Peroxyketalization

Compounds 1-3 were obtained in yields of between 78 and 80% using a modified procedure of Braunworth and Crosby, 1963) in which acid-catalyzed (H₂SO₄) peroxyketalization occurred between a 1:1 molar ratio of the corresponding ketone and 30% hydrogen peroxide in aq. EtOH at 0º C Other methods are superior to this one for some ketones. However, either the procedure of Braunworth and Crosby, 1963) or similar procedures are suitable for the synthesis of many of the target tetraoxanes. Indeed, A2-A4 have been previously synthesized by similar methods (Groth, 1964; Milas et al., 1939; Kharasch and Sosnovsky, 1958).

Alternative peroxyketalization procedures (McCullough et al., 1980; Sanderson et al., 1975; 1976; Hawkins, 1969) have been described using different solvents (CH₃CN, CH₂Cl₂),

different concentrations of hydrogen peroxide (50-90%) and different acid catalysts (methanesulfonic acid, HCI, acetic and formic acids) or the use of bis(trimethylsilyl)peroxide in the presence of trimethylsilyl trifluoromethanesulfonate (Jefford and Boukouvalas, 1988) in an anhydrous variant on this reaction.

The synthesis of tetraoxanes I1-I8, J1-J8, and K1-K4 involves an intramolecular acid-catalyzed peroxyketalization between diketones and hydrogen peroxide rather than the

corresponding intermolecular reaction between ketones and

hydrogen peroxide in the synthesis of tetraoxanes A-H. This proposed intramolecular reaction is without precedent and may produce products resulting from intermolecular chemistry in addition to the desired products. These undesired products will, however, have substantially higher molecular weights and

different chemical/physical properties which may allow separation from the desired target compounds. b. Synthesis of 1,2,4,5-Tetraoxanes by Ozonolysis and Other Methods

Ozonolysis of tetrasubstituted olefins represents a useful alternative procedure for the synthesis of tetraoxanes (Bailey, 1978). Indeed, such olefins do not usually give ozonides

(1,2,4-trioxolanes), but rather afford diperoxides

(1,2,4,5-tetraoxanes) resulting from dimerization of the Criegee carbonyl oxide intermediate (Murray et al., 1972). Presumably, the failure to give ozonides is the result of the reduced reactivity of the ketonic carbonyl toward the Criegee carbonyl oxide zwitterion (Murray et al., 1972). This dimerization process occurs in non-participating solvents such as carbon tetrachloride. For example, Criegee and Lohaus (1953) report the synthesis of tetraoxanes A2 and A3 from ozonolysis (petroleum ether) of bis-cyclopentylidene and bis-cyclohexylidene,

respectively. It is likely that similar tetrasubstituted olefins might serve as starting materials for the successful synthesis of other target tetraoxanes, if required.

In another example, ozonation of ß-pinene afforded the corresponding diperoxide (tetraoxane G3) via dimerization of the Criegee carbonyl oxide zwitterion (Overton and Owen, 1973).

Tetraoxanes are also formed by treatment of ozonides with

antimony pentachloride or chlorosulfonic acid (Miura and Nojima, 1979; 1980). Lastly, oxidation of ketones at low temperatures using peracetic acid is reported (Lohringer and/Sixt, 1963) to give diperoxides (tetraoxanes) instead of the usual esters produced under Baeyer-Villager conditions. c. Synthesis of Unsymmetrical 1,2,4,5-Tetraoxanes

Aside from the reaction of unsymmetrical diketones with hydrogen peroxide under acidic conditions, and the ozonolysis of certain unsymmetrical tetrasubstituted olefins (product mixture) (Murray et al., 1972), no method has been developed for obtaining unsymmetrical tetraoxanes. One possible route is a condensation reaction of gem-dihydroperoxides with ketones. Using this concept, one can prepare the gera-dihydroperoxide of one ketone and condense it with a different ketone to form an unsymmetrical tetraoxane. Such a procedure would provide access to

a greatly expanded repertory of tetraoxanes. Jefford et al.

(1990) has recently reported a convenient and greatly improved method of gem-dihydroperoxide synthesis which entails the

acid-catalyzed perhydrolysis of ketals using anhydrous hydrogen peroxide and tungstic acid in acetonitrile solvent. This

convenient access to gem-dihydroperoxides provides an impetus for the development of a new synthetic method to obtain unsymmetrical tetraoxanes. d. Characterization of Target 1,2,4,5-Tetraoxanes

The target tetraoxanes can be purified by crystallization, flash column or prep HPLC chromatography and their structures and purity confirmed by analytical HPLC, Η and ¹³C NMR, IR, MS, vapor-pressure osmometry, melting point and elemental analysis. The target 1,2,4,5-tetraoxanes (thermodynamic products) and the 1,2,4,5,7,8-hexaoxonanes (kinetic products) (Story et al., 1970) produced in the acid-catalyzed peroxyketalization reaction between ketones and hydrogen peroxide must be distinguished.

Such mixtures are difficult to assess because ordinary analytical methods may not distinguish between them. For example,

1,2,4,5-tetraoxanes and 1,2,4,5,7,8-hexaoxonanes each give the same elemental analysis and very similar IR spectra (Story and Busch, 1972).

Furthermore, in accordance with the findings of Bladon et al. (1980), NMR is an unreliable technique to differentiate between the 1,2,4,5-tetraoxanes and 1,2,4,5,7,8-hexaoxonanes. Although Bertrand et al. (1968) was able to get a small molecular ion for the 1,2,4,5-tetraoxane of cyclohexanone using EI-MS, the

intensity was very low (0.2% of total ionic current). MS (even FAB-MS) appears to be an inconsistent method for MW assignment as the molecular ions are not always present. When the M+ peak is observed, it is uniformly of very low intensity.

The use of vapor-pressure osmometry for molecular weight

determination is essential to distinguish between target

1,2,4,5-tetraoxanes (thermodynamic products) and

1,2,4,5,7,8-hexaoxonanes (kinetic products) (Story et al., 1970) produced in the acid-catalyzed peroxyketalization reaction

between ketones and hydrogen peroxide. Vapor-pressure osmometry is a very useful analytical procedure as it is based on

colligative properties of solution and affords an average MW; this technique has been successfully used to determine MW's of 1,2,4,5-tetraoxanes (Bertrand et al., 1968; McGullough et al., 1980). This average MW will provide an excellent index of purity because it will reflect the relative percent of

1,2,4,5,7,8-hexaoxonane which might have been isolated along with the desired 1,2,4,5-tetraoxane. This isolation of both

1,2,4,5-tetraoxanes (thermodynamic products) and

1,2,4,5,7,8-hexaoxonanes (kinetic products) as a mixture is quite common as reported by Story and Busch (1972). Two reaction products, for example, can give identical m.p.'s but give

slightly different NMR spectra. It is believed that in the melting point determination, conversion of

1,2,4,5,7,8-hexaoxonanes (kinetic products) to

1,2,4,5-tetraoxanes (thermodynamic products) might occur.

As has already been mentioned, many reaction products will consist of mixtures of stereoisomers. When separation of a d,l pair from a meso compound using TLC or flash column

chromatography fails, the use of HPLC may allow stereoisomer separation. In some cases, however, the single d,l pair or meso isomer will be isolated for testing, as noted earlier. Differreent antimalarial activity for tetraoxanes 1 and 2, for example, is observed, depending on which synthetic method and crystallization solvents are chosen which illustrates the importance of stereochemistry and stereoisomer separation. Furthermore, chiral HPLC columns enable one to distinguish between d,l and meso isomers. Lastly, although, GC has been used successfully as an analytical method for tetraoxanes (Cafferata et al., 1991;

Sanderson et al., 1975), HPLC is a preferred procedure based on the ability to conveniently conduct preparative scale

separations. e. Commercially Available Ketones

The unsubstituted carbocyclic ketones (cyclobutanone,

cyclopentanone, cyclohexanone, cycloheptanone, cyclooctanone) required for the synthesis of A1-A5 are available from Aldrich Chemical Co. The substituted ketones 2-tert-butyl-, 3-methyl-, 4-ethyl-, 2,5-dimethyl-, and 3,4-dimethylcyclohexanone, menthone, dihydrocarvone, 2-methyl-, 3-methyl-, and

2,4-dimethylcyclopentanone, 2-cyclohexenone, 3-methyl-,

4,6-dimethyl-, and 4,4-dimethyl-2-cyclohexenone, carvone,

2-cyclopentenone, 2-methyl-, 3-methyl-, and

4,4-dimethyl-2-cyclopentenone, 2-adamantanone, (-)-thujone,

2-norbornanone, 3-chloro-2-norbornanone, camphor,

bicyclo[3.2.1]octan-2-one, bicyclo[3.3.1]nonan-9-one,

2-chlorocyclohexanone, 2-chlorocyclopentanone,

2-methoxycyclohexanone, and tetrahydro-4H-pyran-4-one required for the synthesis of B5, B9, B14, B23, B28, B24, B27, C1, C5,

C10, D1, D3, D7, D8, D9, E1, E2, E3, E6, G1, G2, G5, G6, G8, G12 G13, H1, H2, H3, and H4, respectively, can be obtained from

Aldrich Chemical Co. or from TCI American Organic Chemicals. f. Synthesis of Required Ketones

Several secondary alcohols including 2-ethyl-, 2-isopropyl-, 2,3-dimethyl-, and 4-methyl-2-tert-butyl substituted

cyclohexanols, and 7,7-dimethyl-2-norbornanol are available and can be easily oxidized by chromium reagents to the correspond ketones required for the synthesis of B1, B3, B18, B20, B26, and G4, respectively (Bowden et al., 1946; Ungnade and McLaren, 1944; Brown and Garg, 1961; Firouzabadi and Ghaderi, 1978).

Bispyridinium chlorochromate (Guziec and Luzzio, 1980) is a particularly useful reagent for this purpose.

The 2-alkyl-, 2-vinyl-, and 2-allyl-substituted cyclohexanonees and cyclopentanones required for the synthesis of B1-B4, B6, B7, B19, B21, B29, C2-C4, and C12 are accessible via a-alkylation. The literature on this important carbon-carbon bond-forming reaction is enormous and provides many options including

enantioselective procedures. 2-Alkyl-cyclopentanones and

-hexanones are formed most commonly via the lithium enolate formed by treatment with LDA or by exposure of the corresponding silyl enol ethers to methyl lithium; alkyl iodides are the preferred electrophilic agents (Larock, 1990). Both chiral and achiral enamines of cyclohexanone are also widely used for a-alkylation. 2-methyl-, 2-ethyl-, 2-propyl-, 2-allyl-, and 2-butylcyclohexanones and 2-ethyl- and 2-propylcyclopentanones may be accessed by this route (Whitesell and Felman, 1977;

Szmuskovicz, 1963; Stork et al., 1963). Alkylation of chiral lithioenamines of cyclohexanone (Meyers et al., 1981; Hashimoto and Koga, 1978) with methyl-, ethyl-, and propyl iodides to form chiral versions of 2-methyl-, 2-ethyl-, and

2-propylcyclohexanones is a useful variant on enamine chemistry. 2,2-dimethylcyclohexanone is obtained by treatment of

2-methylcyclohexenone with lithium/ammonia followed by MeI

(House, 1972). An alternative is one of the many classic blocking procedures to afford 2,2-alkylated cyclohexanones as exemplified by Boatman and Harris (1968) in an Org. Syn.

procedure. 2-vinylcyclohexanone is afforded by treatment of the lithium enolate of cyclohexanone with

dicarbonyl(cyclopentadienyl) (ethyl vinyl ether)iron

tetrafluoroborate followed by tetrafluoroboric acid etherate exposure (Chang and Rosenblum, 1987). An alternative formation of the lithium enolate by conjugate addition of lithium dialkyl cuprates to a,b-enones affords 3-alkyl-2-vinyl cyclohexanones by this procedure. 2-isopropylcyclohexanone is formed in

quantitative yield in a double conjugate addition of lithium dimethyl cuprate to 2-n-butylthiomethylenecyclohexanone (Coates, and Sowerby, 1971). Treatment of the analogous cyclopentanone derivative with lithium/ammonia followed by Mel affords

2,2-dimethylcyclopentanone (Coates and Sowerby, 1971).

2-Methyl-4-tert-butylcyclohexanone is obtained by treatment of the N,N-dimethylhydrazone of 4-tert-butylcyclohexanone with LDA followed by Mel and a sodium periodate oxidative hydrolysis to the ketone (Corey and Enders, 1976). The less stable trans isomer was isolated. This same procedure can also be used for the synthesis of 6-methyl-2-cyclohexenone and

5-methyl-2-cyclopentenone required for the synthesis of D6 and E5, respectively, which illustrates the selective a'-alkylation of a,b-unsaturated ketones under conditions of kinetic

deprotonation. 2-Methyl-5-tert-butylcyclohexanone required for the synthesis of B22 can be obtained via a Pd(0) promoted alkylation of the enol phosphate of 4-tert-butylcyclohexanone with trimethylaluminum followed by treatment with titanium tetrachloride in a

1,2-carbonyl alkylative transposition reaction (Sato et al., 1981). 4-propyl and 4-isopropylcyclohexanone required for the synthesis of B15 and B16 can be obtained in a regiospecific monoalkylation of 3-ethoxy-2-cyclohexenone followed by sequential reductive transposition (LAH), hydrolysis, and catalytic

hydrogenation (Kende and Fludzinski, 1986; Stork and Danheiser, 1973). This is useful general procedure for obtaining

4-alkyl-substituted cyclohexenones and cyclohexanones. The most generally useful method for obtaining the necessary 3-substituted cyclohexanones and cyclopentanσnes required for the synthesis of B10-B13, B18, B30, C6, C7, and C9 is the conjugate addition of lithium dialkyl cuprates to a,b-unsaturated enones (Posner, 1972). Moreover, tandem conjugate addition - a-functionalization provides a means for obtaining numerous

2,3-disubstituted cyclohexanones and cyclopentanones (Taylor, 1985; Chapdelaine and Hulse, 1990). 2,3-Dimethyl-, 3-ethyl-, 3-isopropyl-, 3-butyl-, and 3,3-dimethylcyclohexanone and

3-ethyl-, and 3-propylcyclopentanone can all be obtained by the conjugate addition of the appropriate lithium dialkyl cuprate to commercially available enones (Corey et al, 1986; Suzuki et al, 1980; House et al., 1966). Chiral versions of this reaction are available using mixed cuprates containing a chiral anionic ligand (Corey et al., 1986). Treatment of the enol acetates of

1,3-cyclohexanedione or 1,3-cyclopentanedione with lithium dialkyl cuprates provides access to 3-propyl-,

3,3-dimethylcyclohexanone, and 2,3-dimethylcyclopentanone (Piers and Nagakura, 1975; Casey et al., 1973).

Reduction of the available enones with lithium/ammonia (Caine, 1976) provides ready access to 2,4-dimethyl- and

4,4-dimethylcyclohexanone, and 2,3-dimethyl-, and

3,3-dimethylcyclopentanone, and 3-methylcycloheptanone (Ito et al., 1988) required for the synthesis of B19, B31, C9, C13, and F2 respectively. A similar reduction of 5,5-dimethyl-2-cycloheptenone (available via a selenium dioxide oxidation (Helv Chim. Acta, 1940; Rabjohn, 1949) of

4,4-dimethylcycloheptene) will afford 4,4-dimethylcycloheptenone required for the synthesis of F4. In addition, treatment of the lithium enolate formed upon lithium/ammonia reduction of

2-methyl-2-cyclopentenone with methyl iodide will afford

2,2-dimethylcyclopentanone required for the synthesis of C12.

Birch reduction of 4-methylanisole (Birch, 1944),

2,4-dimethylpyridine (Birch, 1947), 2-methylanisole (Birch, 1944), and anethole (Stork and Danheiser, 1973) affords

4-methyl-, 5-methyl-, and 6-methyl-2-cyclohexenone and

4-propylcyclohexanone (requires subsequent catalytic

hydrogenation) required for the synthesis of D4-D6, and B15, respectively.

Several miscellaneous reactions afford the alicyclic ketones required for the synthesis of B25, C11, D2, F1-F3, and H5.

Catalytic hydrogenation of dihydrocarvone affords carvomenthone. 3,4-Dimethylcyclopentanone can be formed in a [3+2] cyclocoupling reaction using 1,3-dibromoacetone, cis- or trans-2-butene, and an diiron ennecarbonyl (Noyori and Hayakawa, 1983). Other

3,4-dialkylcyσlopentanones can also be accessed by this route. 2-Methyl-2-cyclohexenone is synthesized by treatment of

2-methylcyclohexanone with sulfuryl chloride followed by

dehydrohalogenation with lithium chloride in DMF (Warnhoff, et al., 1963). 2-Methyl- and 4-methylcycloheptanone are synthes zed by treatment of 2-methyl- and 3-methylcyclohexanone,

respectively, with either diazomethane (Smith and Baer, 1960; Dauben et al., 1963) or trimethylsilyldiazomethane (Hashimoto et al., 1980). 4-Ethoxycyclohexanone is obtained via its oxime by treatment with sodium tungstate and hydrogen peroxide (Kahr and Berther, 1960).

The bicyclic ketones G7, and G9-G11 are available by diverse methodology. Bicyclo[2.2.1]hept-2-en-5-one is obtained by oxidative decarboxylation via oxygenation of its acid dianion (Wasserman and Lipshutz, 1975) whereas

bicyclo[2.2.2]oct-2-en-5-one is obtained via oxidative

decarboxylation of the corresponding a-methylthiocarboxylic acid (Trost and Tamara, 1977). 4-Methylbicyclo[2.2.1]hepten-2-one is obtained via an intramolecular alkylation of

3-(bromoethyl)-3-methylcyclopentanone which in turn is obtained in a four-step sequence from 3-methylcyclopentenone (CargilL et al., 1974). Bicyclo[2.2.2]octan-2-one is obtained by treating anion of the bicyclic Diels-Alder adduct of vinyl phenyl sulfone and 1,3-cyclohexadiene with molybdenum peroxide (Little and

Myong, 1980). Numerous other bicyclic ketones are available via intramolecular reactions of diazocarbonyl compounds as reviewed by Burke and Grieco (1979) and Smith and Dieter (1981). The diketones required for the synthesis of I1-I4, I5-I8, J1-J4, and J5-J8 will be obtained by bisalkylation of the anions (Sadler et al., 1984) of ethyl 2-cyclohexanonecarboxylate, ethyl

6-methyl-2-cyclohexanonecarboxylate, ethyl

2-cyclopentanonecarboxylate, and ethyl

5-methyl-2-cyclopentanonecarboxylate, respectively, with

1,2-dibromoethane, 1,3-dibromopropane, 1,4-dibromobutane, and cis-1,4-dichloro-2-butene followed by decarbomethoxylation with lithium chloride/DMSO (Schlessinger et al., 1983). Ethyl

6-methyl-2-cyclohexanonecarboxylate and ethyl

5-methyl-2-cyclopentanonecarboxylate are obtained via a reversed Dieckmann cleavage of ethyl 2-cyclohexanonecarboxylate and ethyl 2-cyclopentanonecarboxylate, respectively (Meyer et al., 1965; Sisido et al., 1964; Taber et al., 1987), or by a direct

methylation of their dianions formed by treatment with 2.5 equiv of LDA (Schlessinger et al., 1983).

The diketones required for the synthesis of KI and K3 will be obtained by treatment of the lithium enolates of

N,N-dimethylhydrazones of cyclohexanone and

2-methylcyclohexanone, respectively, with methyl vinyl ketone followed by a sodium periodate oxidative hydrolysis (Corey and Enders, 1976). The diketones required for the synthesis of K2 and K4 are obtained by treatment of the lithium enolates formed from lithium/ammonia reduction of 3-methyl-2-cyclohexenone and 3,6-dimethyl-2-cyclohexenone, respectively, with methyl vinyl ketone. g. Characterization of Required Ketones

The required ketones are all known compounds and are purified by distillation (bulb-to-bulb or fractional), crystallization, flash column or prep HPLC chromatography and their structures and purity confirmed by TLC or analytical HPLC, Η and ¹³C NMR, IR, and melting point analysis for solids.

Screening Methods

In vitro testing is conducted using a modification of the semiautomated microdilution technique of Desjardins et al. (1979) and Milhous et al. (1985). Two P. falciparum malaria parasite clones, designated as Sierra Leone (D-6) and Indochina (W-2), are used in susceptibility testing. The former is resistant to mefloquine, and the latter to CQ, pyrimethamine, sulfadoxine, and quinine. Test compounds are dissolved in 95% ethanol, and

serially diluted in RPMI culture medium with 10% human plasma to 400-fold. Subsequent dilution is achieved using the Cetus

Pro/Pette over a range of 1 - 100 x 10^-9 M. Erythrocytes with 0.5% parasitemia are added to each well of a 96-well

microdilution plate to give a final hematocrit of 1.0%; these parasite inocula are incubated for 24 h before addition of drug and [³H]hypoxanthine. After continued incubation for 18 h. particulate matter is harvested from each microliter well by using a Skatron automated cell harvester. Uptake of

[³H]hypoxanthine is measured using a Beckman scintillation spectrophotometer. Concentration -response data is analyzed by nonlinear regression and the IC₅₀ (ng/mL) values calculated.

In vivo antimalarial activity against a drug-sensitive strain of P. berghei (strain KBG 173) is determined using the Rane screen (Osdene et al., 1967). Mice are infected with 5.98 × 10⁵ P.

berghei parasitized cells ip on day 0. Test compounds are dissolved in peanut oil and administered sc on day 3

post-infection in doses of 20 - 640 mg/kg (n = 5 per dose).

Blood films are taken on days 6, 13, and 20. Blood

schizontocidal activity is determined by monitoring blood films for the appearance of parasites and for extended survival times compared to infected untreated controls. T-C is the mean

survival time of the treated mice beyond that of the control animals. This value must be ≥ twice the mean survival time -(6.2 days) of the control animals to be considered active (A).

Survival beyond 60 days is considered curative (C), and deaths from 0-2 days post-treatment are attributed to toxicity (T).

Pharmacological Methods

In vitro activity against P. falciparum is determined using a modification of the semiautomated microdilution technique of Desjardins et al. (1979) and Milhous et al. (1985). Two P. falciparum malaria parasite clones, designated as Sierra Leone (D-6) and Indochina (W-2), are used in susceptibility testing. The former is resistant to mefloquine, and the latter to CQ, pyrimethamine, sulfadoxine, and quinine. Test compounds are dissolved in dimethylsulfoxide, and solutions serially diluted with culture media. Erythrocytes with 0.25 to 0.5% parasitemie are added to each well of a 96-well microdilution plate to give a final hematocrit of 1.5%. Inhibition of uptake of tritiated hypoxanthine is used as an index of antimalarial activity.

Results are reported as IC₅₀ (ng/mL) values. For a complete description of this assay, see Milhous et al. (1985) and Lin et 1. (1987).

In vivo activity against P. berghei is obtained against a drug-sensitive strain of P. berghei (strain KBG 173) (Osdene et al., 1967). Each test compound is administered subcutaneous to five male mice per dilution in a single subcutaneous dose 3 days after infection. Results are expressed in T - C values which indicate the mean survival time of the treated mice beyond that of the control animals; untreated mice survive on average 6.2 days. Compounds are classified as active (A) when the mean survival time of the treated mice is twice that of the controls (>6.2 days), and curative (C) when one or more test animals live 60 days post-infection. Deaths from 0-2 days post-treatment are attributed to toxicity (T). Therapeutic doses and formulations

The compounds of this invention can be administered to the host or patient as an active ingredient in a variety of dosage forms. In addition to the active ingredient, which may be in the form of a pharmaceutically-acceptable derivative, such as a

pharmaceutically-acceptable salt, any of a number of

pharmaceutically-acceptable excipients which facilitate

processing of the active compound into suitable pharmaceutica preparations can be used to formulate these compositions. These are well known and need not be detailed here (e.g., see

Remingtons Pharmaceutical Sciences. 1985). Because the

Tetraoxanes of this invention are active orally, dosage forms designed for oral administration are preferred. Exemplary are tablets, capsules, and dragees. In some cases, for example, where the host is seriously ill and time is of the essence, it may be necessary to administer the compounds of this inventioon parenterally. In such cases intravenous administration is usually preferred. However, other dosage forms designed for parenteral administration can also be employed, e.g.,

subcutaneous or rectal (usually suppositories).

Appropriate formulations for parenteral administration include aqueous solutions of the active compound prepared in a water-soluble or water-dispersible form. Alternatively, the active compounds may be administered as suspensions in appropriate oily injection carriers, i.e., in suitable lipophilic carriers, such as fatty oils (sesame oil being an example), or synthetic fatty acid esters (ethyl oleate or triglycerides being examples).

Pharmaceutical formulations prepared for aqueous injection may contain substances which increase the viscosity or the suspension such as, for example, sodium carboxymethyl cellulose, sorbitol, and/or dextran.

The therapeutic tetraoxanes of the present invention may also be administered encapsulated in liposomes. In such pharmaceutical preparations, the active compound is contained in corpuscles which consist of concentric aqueous layers interspersed between hydrophobic lipidic layers. The bisquinolines, depending upon their solubility, may be present both in the aqueous layer and in the lipidic layer, or in what is generally termed a liposomic suspension. The hydrophobic layer, generally but not

exclusively, comprises phospholipids such as lecithin and

sphingomyelin, steroids such as cholesterol, more or less ionic surfactants such as a diacetylphosphate, stearylamine, or

phosphatidic acid, and/or other materials of a hydrophobic nature which are generally well known in the art.

To be available for use in systemic administration, the

therapeutic tetraoxanes must be formulated into suitable

pharmaceutical compositions; the protocol for systemic

administration would use a therapeutic approach compatible with the particular formulation selected. Pharmaceutical compositions within the scope of the present invention include those

compositions where the tetraoxane contained in an effective amount sufficient to kill the malaria-inducing parasite without causing unacceptable toxicity for the host or patient. The therapeutic amount which represents an effective anti-malaria dose sufficient for treatment of each of the various types of malaria remains to be determined empirically by those skilled in the art of designing and administering anti-malarials. However, it has been determined that the tetraoxanes this invention appear to have high therapeutic indices, thus presenting a wide range of effective dosage options and strategies. A preferred dosage range is from about 5 to about 100 milligrams of tetraoxanes pea milligram of host body weight, given three times a day. Doses as high as 500 mg/kg, or even higher, thrice daily can be given, but are not economically practical in the usual case of malaria encountered. As a practical matter, any dose which is sufficient to achieve an effective blood concentration of from about 0,05 to about 0.2 μg/mL can be employed.

Pharmacological Methods

In vitro activity against P. falciparum is determined using a modification of the semiautomated microdilution technique of Desjardins et al. (1979) and Milhous et al. (1985). Two P.

falciparum malaria parasite clones, designated as Sierra Leone (D-6) and Indochina (W-2), are used in susceptibility testing. The former is resistant to mefloquine, and the latter to CQ, pyrimethamine, sulfadoxine, and quinine. Test compounds are dissolved in dimethylsulfoxide, and solutions serially diluted with culture media. Erythrocytes with 0.25 to 0.5% parasitemia are added to each well of a 96-well microdilution plate to give a final hematocrit of 1.5%. Inhibition of uptake of tritiated hypoxanthine is used as an index of antimalarial activity.

Results are reported as IC₅₀ (ng/mL) values. For a complete description of this assay, see Milhous et al. (1985) and Lin et al. (1987).

In vivo activity against P. berghei is obtained against a drug-sensitive strain of P. berghei (strain KBG 173) (Osdene et al., 1967). Each test compound is administered subcutaneous to five male mice per dilution in a single subcutaneous dose 3 days after infection. Results are expressed in T - C values which indicate the mean survival time of the treated mice beyond that of the control animals; untreated mice survive on average 6.2 days. Compounds are classified as active (A) when the mean survival time of the treated mice is twice that of the controls (>6.2 days), and curative (C) when one or more test animals live 60 days post-infection. Deaths from 0-2 days post-treatment are attributed to toxicity (T). References

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Claims

WHAT IS CLAIMED IS: 1. A compound having the following formula:

wherein n is a whole integer from 1 to about 4; R and R' can be same or different and are H or monovalent radicals derived from an acyclic or cyclic hydrocarbon by removal of one hydrogen atom from a carbon atom; additionally, R and R' can be fluoro (F-) chloro (Cl-), bromo (Br-), trifluoromethyl (-CF-), cyano (-CN), or methylsulfoxide (-SOCH-); and in their acyclic form, R and R' generally contain at least two, and no more than about 12, carbon atoms, and, in their cyclic form, R and R' contain at least three and, generally, no more than about eight carbon atoms.

2. The compound of claim 1 wherein R and R' are selected from the group consisting of H, (CH₂)2, CH₂CH(CH₃), (CH₂)₃, and (CH₂)₄ 3. The compound of claim 1 wherein n is 1. 4. The compound of claim 1 wherein n is 2. 5. The compound of claim 1 wherein n is 3. 6. The compound of claim 1 wherein n is 4. 7. A method for the treatment of malaria comprising

administering to a host a compound of claim 1 in a

pharmaceutically acceptable dosage form containing an amount of said compound which is effective in treating malaria. 8. The method of claim 7 wherein the effective dose for treating malaria is that dose which is toxic to the malaria parasite infecting the host, but below the threshold of

significant toxicity to the host. 9. An antimalarial composition comprising a compound of claims

1 in a pharmaceutically acceptable dosage form.