WO1997018800A1

WO1997018800A1 - Use of naphthoquinone compounds as antiprotozoal agents

Info

Publication number: WO1997018800A1
Application number: PCT/GB1996/002872
Authority: WO
Inventors: Bhupinder Pall Singh Khambay; Monique Sheelagh Jacquard Simmonds
Original assignee: British Technology Group Ltd
Current assignee: BTG International Ltd
Priority date: 1995-11-21
Filing date: 1996-11-21
Publication date: 1997-05-29
Anticipated expiration: 1998-05-21
Also published as: GB9523801D0; AU7632796A

Abstract

The use of a compound of general formula (I) or a salt thereof as a medicament is provided, in which n represents an integer from 0 to 4; m represents an integer 0 or 1; each R independently represents a halogen atom or a nitro, cyano, hydroxyl, alkyl, alkenyl, haloalkyl, haloalkenyl, alkoxy, haloalkoxy, haloalkenoxy, amino, alkylamino, dialkylamino, alkoxycarbonyl, carboxyl, alkanoyl, alkylthio, alkylsulphinyl, alkylsulphonyl, carbamoyl, alkylamido, cycloalkyl, aryl or aralkyl group; R?1 and R2¿ each independently represent an optionally substituted alkoxy group or together represent a group =O, =S or =N-OR9, where R9 represents a hydrogen atom or an optionally substituted alkyl group; R3 represents a hydroxyl group, or a group-OL where L is a leaving group, or a group which in vivo is transformed into a group -OL1 where L1 is a leaving group; R6 represents an optionally substituted alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, alkoxy, alkenyloxy, alkynyloxy, cycloalkyloxy, cycloalkenyloxy or aryloxy group; R?7 and R8¿ independently represent an optionally substituted alkoxy group or together represent a group =O, =S or =N-OR9, where R9 is as previously defined; wherein R¿4? and R5 independently represent a halogen atom or an optionally substituted alkyl or alkenyl group, or together with the interjacent carbon atom represent an optionally substituted cycloalkyl or cycloalkenyl group; and A represents a straight or branched chain alkyl or alkenyl group, which may be optionally substituted, preferably with halogen, an acyclic carbon chain of which links the 3 position of the naphthalene ring shown and the moiety -CR?4R5R6¿.

Description

USE OF NAPHTHOQUINONE COMPOUNDS AS ANTIPROTOZOAL AGENTS

The present invention relates to the use of certain naphthoquinone compounds as medicaments, particularly medicaments for internal use against parasitic microorganisms, and more particularly as anti -protozoan agents, to compositions containing these and to methods for carrying out such use.

It has been known for many years that 2-substituted-3-hydroxy-naphthalene-l ,4- diones have anti-protozoan properties. Fieser et al. JACS Vol. 70 (1948) J_0 pages 3151 -3165 describe a great many of such compounds together with their activity against Plasmodium lophurae wherein the 2-substituent is alkyl. This document also teaches that the 3-hydroxy group may be esterified with a variety of acids or in the form of a salt with a suitable cation and the antiplasmodial activity retained.

Since the work of Fieser et al. , a number of patent documents have been published which relate to 2-substituted-3-hydroxy-naphthalene-l ,4-diones useful in treating protozoan diseases. Typical of these are US 339321 1. EP 002228, EP 077551, EP 0123238, EP 0123239, EP 0362996, WO 9104021, WO 9307156, WO 931 1756 and

WO 9320044. Particular organisms against which the naphthalene- 1 ,4-diones

(naphthoquinones) have been shown to have activity include coccidosis and toxoplasmosis causing organisms and malaria.

In particular EP 0077550 discloses compounds of general formula (Pl)

in which R is an alkyl group of from 1 to 10 carbon atoms and describes their use in veterinary formulations, particularly for prophylaxis against protozoan infection including Plasmodium species. The applicants^" copending international application WO 95/32176 relates to naturally occurring compounds of the general formula (P2)

in which R represents a hydrogen atom or a hydroxyl or an ethanoyloxy group, and relates to their use as pesticides, especially fungicides, insecticides and/or acaricides. These compounds were previously disclosed as plant metabolites by Cha y et al. , (1993) Bol. Soc. Chil. Quim. 38 187-190. In further work Chamy et al. (1995) Comp. Biochem. Physiol. Vol. 1 12C No. 2 pp 1 19-128 describe work where it is confirmed that these compounds also have growth inhibitory effect on protozoans, particularly Trypanosoma cruzi.

The present inventors have also developed synthetic naphthoquinones that have advantageous pesticidal properties as compared to those already known in the art, particularly as applied to the treatment of specific pests of fungal, insect and/or acarid nature: these being claimed per se in copending WO 9621355. They have now determined that these compounds, and their naturally occuring analogues described in WO 95/32176, are surprisingly effective as agents for treatment of infection with Plasmodium and Giardia organisms, being especially effective against organisms resistant to known anti-protozoan agents.

According to a first aspect of the present invention there is provided a compound of general formula (I)

or a salt thereof, in which n represents an integer from 0 to 4; m represents an integer 0 or 1 ;

.1. each R independently represents a halogen atom or a nitro. cyano. hydroxyl, alkyl, alkenyl, haloalkyl, haloalkenyl, alkoxy, haloalkoxy, haloalkenoxy, amino, alkylamino, dialkylamino. alkoxycarbonyl, carboxyl, alkanoyl, alkylthio. alkylsulphinyl, alkylsulphonyl, carbamoyl. alkylamido, cycloalkyl, aryl or aralkyl group; R* and R^ each independently represent an optionally substituted alkoxy group or together represent a group =0, =S or =N-ORj where R^ represents a hydrogen atom or an optionally substituted alkyl group;

R3 represents a hydroxyl group, or a group -OL where L is a leaving group, or a group which in vivo is transformed into a group -OL* where L ^ is a leaving group; R" represents an optionally substituted alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, alkoxy, alkenyloxy, alkynyloxy, cycloalkyloxy, cycloalkenyloxy or aryloxy group;

R' and R° independently represent an optionally substituted alkoxy group or together represent a group =0, =S or =N-OR J where R" is as previously defined; wherein R4 and R5 independently represent a halogen atom or an optionally substituted alkyl or alkenyl group, or together with the interjacent carbon atom represent an optionally substituted cylcoalkyl or cycloakenyl group; and A represents a straight or branched chain alkyl or alkenyl group, which may be optionally susbtituted, preferably with halogen, an acyclic carbon chain of which links the 3 position ofthe naphthalene ring shown and the moiety -CR^R^R" for use as a medicament for the treatment of malaria or giardial infection.

More preferably the use is as a medicament to be administered internally to a human or animal body; e.g. by mouth, parenterally or by absorption through the skin, particularly by mouth where suitable prodrug protecting groups are in place, e.g. on the 3 -hydroxy group.

When the compounds of formula I contain a group defmed as an alkyl. alkenyl or alkynyl substituent group otherwise undefined, this may be linear or branched and may contain up to 12, preferably up to 6 and especially up to 4, carbon atoms. A cycloalkyl or cycloalkenyl group may contain from 3 to 10, but most preferably contains 5 to 8 carbon atoms. An aryl group may be any aromatic hydrocarbon group. especially a phenyl or naphthyl group. An aralkyl group may be any alkyl group as defined above which is substituted by an aryl group as defined above, especially a benzyl group, or may be an aryl group substituted by an alkyl group.

When any ofthe foregoing substituents are designated as being optionally substituted, the substituent groups which are optionally present may be any one or more of those customarily employed in the development of therapeutic compounds and/or the modification of such compounds to influence their activity, pharmacokinetics or other property. Specific examples of such substituents include, for example, halogen atoms, nitro, cyano, hydroxyl, alkyl, alkenyl, haloalkyl, haloalkenyl, alkoxy, haloalkoxy, amino, alkylamino, dialkylamino, alkoxycarbonyl, carboxyl, alkanoyl, alkylthio, alkylsulphinyl, alkylsulphonyl, carbamoyl, alkyiamido, cycloalkyl, phenyl and benzyl groups. Typically, 0-3 substituents may be present. When any of the foregoing substituents represents or contains an alkyl substituent group, this may be linear or branched and may contain up to 12, preferably up to 6, and most preferably up to 4, carbon atoms. When any of the foregoing substituents represents or contains an aryl or cycloalkyl moiety, the aryl or cycloalkyl moiety may itself be substituted by one or more halogen atoms, nitro, cyano, alkyl, alkenyl, haloalkyl, haloalkenyl, alkoxy or haloalkoxy groups. Preferably, the aryl moiety is a phenyl moiety and the cycloalkyl moiety contains from 3 to 8, preferably 4 to 7, carbon atoms.

It is preferred that R, if present, represents a halogen atom or a nitro, cyano, hydroxyl, C_j _4 alkyl, C_j _4 haloalkyl, C2_.4 alkenyl, C2.4 haloalkyl, C_j_4 alkoxy, ^Cl-4 haloalkoxy ^C2-4 haloalkenyl, Cj_₄ alkylamino. di-Cj_ alkylamino, C_j_4 alkoxycarbonyl, C_j_4 alkylthio, Cι _4 alkylsulphinyl or C 1.4 alkylsulphonyl group.

More preferably, R, if present, represents a halogen atom or a C_j_ alkyl, C _j _ haloalkoxy, C .4 haloalkenyl, C _j _₄ alkoxy or C _j .4 haloalkoxy group. Preferably, n is 0. 1 or 2 and it is especially preferred that n is 0. It is also preferred that R* and R^ each independently represent a C ι _4 alkoxy, especially a methoxy, group or together represent a group =0 or =N-OR j where R" represents a hydrogen atom or a C 1_..4 alkyl, especially a methyl, group. It is especially preferred that R^ and R- are both methoxy or together represent a group =0. When R^J is a group -OL where L is a leaving group, or a group which in vivo is transformed into a group -OL, the leaving group may be any group customarily employed as a leaving group. It is preferred that the leaving group is such that the pK_a value of the acid LOH in water is from 1 to 7, more preferably from 1 to 6 and especially from 1 to 5.

When R^J represents a group which in vivo is transformed into a group -OL where L is a leaving group, it is preferred that the transformation is carried out in the body to be protected or the microbe to be combated, preferably by action of enzymes within the microorganism. For instance, if R³ represents a β-acid group, such as - 0-CH₂CH₂CO-OH where -CH₂CH₂CO-OH is not a leaving group, it may be subjected to enzymatic oxidation in vivo to form a group -0-CO-CH₂CH₂-CO-OH, e.g. by a β-oxidase, where -CO-CH₂-CO-OH is a leaving group.

Preferably, R-³ represents an optionally substituted alkyl group or a group -OR¹ where R^{ι υ} represents a hydrogen atom, an optionally substituted alkyl. alkenyl, aryl or aralkyl group or a group -CO-R^{1 1} , -CO-O-R¹ , -SOR^{1 ]} . -S0₂-R^{1 ]} ,

-P(X)(OR¹²)(OR¹³), -P(X)(R¹²)(OR¹³), -P(OR¹²)(OR¹³) or -P(R¹²)(OR¹³) where R represents a hydrogen atom, an optionally substituted alkyl, alkenyl, aryl or aralkyl group or a group -NR¹ R , R and R¹³ independently representing a hydrogen atom or an optionally substituted alkyl group and X represents an oxygen or sulphur atom. Where R^{ι υ} or R' ' represents an optionally substituted aryl or aralkyl group, it is preferred that the aryl group or moiety is a phenyl group or moiety and that the optional substituents are selected from halogen atoms, nitro and C 1. alkyl groups. Substitution at the 4-position ofthe phenyl ring is particularly preferred. For the purposes of R³, the term optionally substituted includes, e.g. substitution with silicon contaimng groups, e.g. trialkylsilyl groups such as trimethylsilyl, as a preferred substituent on R , R¹ ' or R¹².

Preferably R^J represents a hydroxyl group or a group -O-CO-R¹ , -O-CO-OR * where R represents a hydrogen atom or a C_j__j alkyl, C_j_ haloalkyl. C __|2 hydroxyalkyl, C_j_ carboxy lalkyl. phenyl or benzyl group.

-S- It is particularly preferred that R^J represents a group -OH or -O-CO-R ' ^! . where R¹ represents a hydrogen atom or a C_j _, g alkyl, C_|__{j 2} haloalkyl, phenyl or benzyl group. Most preferred for R¹ is a methyl, ethyl, propyl or butyl group.

Preferably R⁶ represents a C_j .₁₆ alkyl, C₂__{J 6} alkenyl, C_j_ι ₆ haloalkyl. C₂_i6 haloalkenyl, C_j __{j 6} alkanoyialkyl, C_j._jg alkoxyalkyl, C_j ._{1 6} alkoxy, C_]__j^ haloalkoxy or C _j__jg alkoxyalkoxy group. More preferably these groups are of C_]_6 in length, or C₂.g in length in the case of alkenyls.

Still more preferably, R^ represents a C_j_^ alkyl, especially methyl or ethyl, C_j_6 haloalkyl, eg. trifluoromethyl, difluoromethyl or monofluoromethyl group, or C- _g alkenyl or C _g haloalkenyl.

Preferably, R⁷ and R° independently represent a C_]_ alkoxy group or together represent a group =O or =N-OR j where R" represents a hydrogen atom or a C _j _^ alkyl group, but it is especially preferred that R' and R° are both methoxy or together represent a group =0. It will be realised by those skilled in the art that compounds wherein R¹ and R², and R' and R° are =S or a group NOR^ will be potential biological precursors for the corresponding naphthoquinones; the naphthoquinones being the preferred compounds ofthe invention.

Preferably, R^ and R-^> represent a C_j_4 alkyl, C₂_4 alkenyl group or, together with the interjacent carbon atom, represent a cycloalkyl or cycloalkenyl group which is optionally substituted with halogen. Most efficaciously for the treatment of plasmodium R^ and R-> are both methyl, and R" is alkenyl, preferably ethenyl.

The compounds of formula I may form salts, e.g. when R³ represents a hydroxyl group. Suitable bases for forming such salts include inorganic bases, such as sodium hydroxide, potassium hydroxide or sodium carbonate, and organic bases, especially tertiary amines such as triethylamine and pyrrolidine.

It will be appreciated by those skilled in the art that many of the compounds provided for the use ofthe present invention will exist as different geometric isomers and diastereomers. The invention thus includes use of both the individual isomers and mixtures of these. The present inventors have determined that the compounds provided for the use of the present invention are of particular interest in so far as they show activity against internal parasitic microorganisms, and particularly show anti-protozoan activity against species and strains that have developed resistance to currently used commercial anti-protozoans. Thus the compounds ofthe present invention will have particular application against species that are resistant to other commercially available anti-microbials.

In a first preferred group of compounds for the use of the present invention there are provided compounds of general formula (II)

or salts thereof in which R, R , R², R³, R^, R⁷ and R° and n are as defined for formula I and R^ and R represent a halogen or an optionally substituted alkyl or alkenyl group for use as a medicament as described above. More preferred compounds of the general formula (II) are those where n is

0, Rl and R², and R' and R° are both =0; wherein R^ and R^ each independently represent a C_j_4 alkyl or C _j. haloalkyl group and R^ represents a C^_{. j}g alkyl, C_j._jg haloalkyl, C_{j . j}g alkoxyalkyl, C_|__j^ alkoxy, C_j._jg alkoxyalkoxy, C->_ιg alkenyl, C₂-C^g haloalkenyl or C- C_j^ alkoxyalkenyl group. R³ is preferably -OH, -O-CO-CH3, -OCO-C₂H₅ or -OCOC3H7, most preferably -OH. Still more preferably R" represents a Ci .i g alkyl, C₂.16 alkenyl or Cpl6 haloalkyl group and most preferably R" represents a C 1.1 ^ alkyl, C _j _g haloalkyl, C- _^ alkenyl or C _g haloalkenyl group.

It is found by the inventors that compounds of this first preferred group generally have exceptionally high activity against both protozoans, and particularly against plasmodium. In a second preferred group of compounds for the use of the invention there are provided a second distinct group of compounds of the first aspect of he invention the quaternary carbon atom is provided as part of a cycloalkyl or cycloalkenyl ring and thus this second group of preferred compounds of formula (I) are of preferred formula (III)

wherein

n, A, R, R¹, R², R³, R⁶, R⁷ and R⁸ are as defined for general formula (I); m represents an integer 0 to 1 ; and R^ and R^ together with the interjacent carbon atom represent an optionally substituted cycloalkyl or cycloalkenyl group for use as a medicament as described above.

More preferably the compounds of this group are of formula (III) wherein R^ and R², and R⁷ and R*^> are both =0; n and m are 0; R^ and R^ together with the interjacent carbon atom represent a fully saturated cycloalkyl ring which is optionally substituted; and R" represents a C_j._jg alkyl or C₂_16 alkenyl group optionally substituted by halogen.R³ is preferably OH, -O-CO-CH3, -OCO-C₂H₅ or -OCOC₃H₇, most preferably OH.

Still more preferably R^ and R-> together with the interjacent carbon atom represent a C3 n saturated cycloalkyl ring optionally substituted with halogen, most preferably chlorine or fluorine, still more preferably a C^_ cycloalkyl ring, and R" is a C_j _g alkyl, C₂_g alkenyl. C_j_g haloalkyl group, C->^ haloalkenyl group or a halogen. Most preferably R^ and R^D together with the interjacent carbon atom represent a cyclohexyl ring. In a third preferred group of compounds for the use of the invention there are provided compounds of formula (IV)

wherein n, A, R, R¹ , R², R³, R⁶, R⁷ and R⁸ are as defined for general formula (1); and

R^ and R-^> each independently represent a halogen or optionally substituted alkyl or alkenyl group for use as a medicament as described above.

More preferred compounds of this group are of formula (IV) wherein R¹ and Rj and R⁷ and R⁸ are both =0; m is i , A is a C_β_g alkyl or alkenyl chain, which may be substituted by a halogen or a branch chain which may be halogenated. Preferably R

R-> and R" are Ci . alkyl or haloalkyl or C .6 alkenyl or haloalkenyl. R³ is preferably

OH, -O-CO-CH3, -OCO-C₂H₅ or -OCOC3H7, most preferably OH.

Preferred compounds of this group are those where A is a group ~(CH₂)_a- or -(CH )_a-CH=CH-(CH₂)b- where a and b are integers which add up to 0 to 6, and analogues of these wherein one or more of the carbon atoms in the these groups are substituted by alkyl. haloalkyl, alkenyl, haloalkenyl or halogen.

A second aspect ofthe present invention provides a method of treating microbial infections, particularly protozoan infections, in a human or animal body, which comprises treating the body internally with a compound ofthe general formula (I), preferably of general formula (II), (III) or (IV).

In a third aspect of the present invention a composition is provided which comprises a compound of formula (I) and preferably of formula (II), (III) or (IV), as defined above, in association with at least one pharmaceutically acceptable carrier. Such a composition may contain a single compound or a mixture of several compounds of the present invention. It is also envisaged that different isomers or mixtures of isomers may have different levels or spectra of activity and thus compositions may comprise individual isomers or mixture of isomers.

The compositions of the invention typically contain from 0.001 to 95% by weight of the active ingredient of formula I. Preferably the compositions contain from 0.001 to 25% by weight of the active ingredient when they are in ready-to-use form. However, higher concentrations, for instance, up to 95%, may be present in compositions to be sold as concentrates for dilution before use.

The compositions of the invention may be mixed with a variety of appropriate inert pharmaceutically acceptable carriers such as solvents, diluents and/or surface- active agents. Suitable carriers are described in the prior art patent specifications referred to above.

In addition to these inert carriers, the compositions of the invention may also contain one or more further active ingredients. These further active ingredients may be other compounds which exhibit anti-parasitic activity and these other compounds may exhibit a synergistic effect with the compounds of the present invention. Typical of these will be synergistic agents such as those 4-pyridinol compounds and their alkanoic esters described in EP 0123239.

Compounds for use in the present invention may be readily synthesized from known starting materials as described in copending PCT applications WO 96/21355 and WO 95/31276.

Methods of treatment of humans and animals susceptible to and suffering from malarial and giardial infection are also provided comprising administering the compounds of the use of the invention thereto.

Typical dosage rates of compound of formula (I) for such treatments preferably fall in the range 0.1 to 200 mg/kg/day, more preferably 5 to 100 mg/kg/day. most preferably 25 to 50 mg/kg day.

The present invention will now be described further by way of illustration only by reference to the following non-limiting Examples and Comparative Examples. Further embodiments of the invention will occur to those skilled in the art in the light of these. EXAMPLES

Examples 1 and 2 relate to the activity of compounds for the use ofthe invention against Plasmodium falciparum and Giardia respectively.

Anti-malarial activitv of compounds The test organisms used were of Plasmodium falciparum: both multi-drug resistant strain KI and a non-resistant strain.

Standards chloroquine diphosphate and quinine dihydrochloride were obtained from Sigma Chemical Company.

The activity of the compounds was studied using the method outlined in Ekong et al.. (1990) Bioassay measures the inhibnition of [3H] hypoxanthine into infected erythrocytes. Compounds were tested 2-4 times at 2-7 different concentrations and the results compared with those from chloroquine diphosphate and quinine dihydrochloride. The data from the different tests were accumulated and the mean LC5_Q calculated. Results are shown in Table 1 beiow.

TABLE 1 Anti-plasmodium activitv

Example 1 is 2-(l .l-dimethylpropyl)-3-hydroxynaphthalenc- l ,4-dione. Example 2 is 2-( l , l -dimethylpropyl)-3-ethanoyloxynaphthalene- l ,4-dione. Example 3 is 2-hydroxy-3-(l -methylcyclohexyl)-naphthalene- 1.4-dione. The natural compounds are designated Example 4 (2-hydroxy- 3-(l .l-dimethyl- propan-2-enyl)-napthalene-l ,4-dione) and Example 5 (2-ethanoyloxy-3-(l , l -dimethyl- propan-2-enyl)-naphthalene-l ,4-dione), in these tables: these compounds corresponding to formula II wherein R^ and R^ are methyl, R^ i ethenenyl and R³ is -OH and -O-acetyl respectively.

The method employed was that as described by Ekong, R.M., Kirby, G.C.,

Patel, G., Warhurst, D.C. & Phillipson, J.D. (1990) Comparison of the in vitro activities of quassinoids with activity against Plasmodium falciparum anisomycin and some other inhibitors of eukaryotic protein synthesis. Biochemical Pharmacology 40, 297-301. Anti-giardial activitv

The anti-giardial activity assay used was based on that of * Wright et al. (1992). Giardia trophozoites (BV-M) arc grown in 96 well multiwell plates in TYI-S-33 and various concentrations of drug. Controls on each plate include medium without cells, cells in medium -no drug and cells in medium + DMSO (5 μl). Total reaction volumes are 200 μl. The plates are incubated at 37°C for 72 hours. After this time, spent medium is removed and the cells washed three times. The cells are then resuspended in 200 μl of phosphate buffered saline containing 20 mM glucose and 0.2 mg/ml XTT. The plate is then incubated for 4 hours at 37°C under N₂ and the formulation of soluble formazan measured at 405 nm.

TABLE 2 Anti-giardial activitv

Compound Example No. LCc DnU u ^r ε ^Π/ml ± SEM determined from 8 data sets)

Example 4 < 1

Example 5 < 1

Example 6 < 1

Example 7 2 ± 1

Example 6 is the benzoyl ester of 2-hydroxy-3-(l,l-dimethylpropan-2-enyl)- naphthalene- 1.4-dione.

Example 7 is 2-hydroxy-3-(l-phenyl-cyclopropyl)-naphthalene dione.

*Wright. CW. et al. ( 1992) Transactions of the Royal Society of Tropical Medicine and Hygiene 86: 517-519.

Claims

CLAIMS.

1. A compound of general formula (I)

or a salt thereof, in which n represents an integer from 0 to 4; m represents an integer 0 or 1 : each R independently represents a halogen atom or a nitro, cyano. hydroxyl, alkyl, alkenyl, haloalkyl, haloalkenyl, alkoxy, haloalkoxy, haloalkenoxy, amino, alkylamino, dialkylamino. alkoxycarbonyl, carboxyl, alkanoyl, alkylthio, alkylsulphinyl, alkylsulphonyl, carbamoyl, alkyiamido, cycloalkyl, aryl or aralkyl group; Rl and R^ each independently represent an optionally substituted alkoxy group or together represent a group =0, =S or =N-OR j where R^ represents a hydrogen atom or an optionally substituted alkyl group;

R^J represents a hydroxyl group, or a group -OL where L is a leaving group, or a group which in vivo is transformed into a group -OL ' where L s a leaving group; R" represents an optionally substituted alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl. alkoxy. alkenyloxy, alkynyloxy, cycloalkyloxy, cycloalkenyloxy or aryloxy group; R⁷ and R⁸ independently represent an optionally substituted alkoxy group or together represent a group =0, =S or =N-OR , where R" is as previously defined; wherein R4 and R5 independently represent a halogen atom or an optionally substituted alkyl or alkenyl group, or together with the interjacent carbon atom represent an optionally substituted cylcoalkyl or cycloakenyl group; and

A represents a straight or branched chain alkyl or alkenyl group, which may be optionally susbtituted, preferably with halogen, an acyclic carbon chain of which links the 3 position of the naphthalene ring shown and the moiety -CR^R-'R" for use as a medicament for the treatment of malaria or siardia.

2. A compound for use as claimed in claim 1 wherein the use is as a medicament to be administered internally to a human or animal body.

3. A compound for use as claimed in claim 1 or 2 characterised in that the compound is of general formula (II)

or a salt thereof in which R, R , R~, R-\ R , R⁷ and R⁸ and n are as defined for formula I and R^ and

R represent a halogen or an optionally substituted alkyl or alkenyl group.

4. A compound for use as claimed in claim 1 or 2 wherein the compound is of formula (III)

wherein n, A, R, R , R², R³, R^, R⁷ and R⁸ are as defmed for general formula (I); m represents an integer 0 to 1 ; and R^ and R^ together with the interjacent carbon atom represent an optionally substituted cycloalkyl or cycloalkenyl group.

5. A compound for use as claimed in claim 1 or 2 wherein the compound is of formula (IV)

wherein n, A, R, R¹ , R², R³, R⁶, R⁷ and R⁸ are as defined for general formula (I); and

R^ and R^ each independently represent a halogen or optionally substituted alkyl or alkenyl group for use as a medicament as described above.

6. A method of treating malarial or giardial infections in a human or animal body comprising treating the body internally with a compound of the general formula (I). (II), (III) or (IV).

7. A pharmaceutical composition comprising a compound of formula (I) in association with at least one pharmaceutically acceptable carrier with the proviso that the compound is not 2-hydroxy-3-(l.l-dimethylpropan-2-enyl)-naphthalene-1.4-dione or its 2-ethanoyl ester.

8. A composition as claimed in claim 7 being sterile and pyrogen free.

9. Use of a compound of formula (I), (II), (III) or (IV) for the preparation of a medicament for the treatment of malaria or giardia.