CZ242994A3 - 1,4-naphthoquinone derivatives exhibiting anti-protozoic and anti-parasitic activity - Google Patents

Abstract

Compounds of general formula (II) wherein R<3> is C1-35 hydrocarbyl group optionally substituted by one to five substituents, selected from halo, C1-6alkoxy, hydroxy, amino, and mono- or di-C1-4alkyl-amino; and either the dotted line represents a double bond between the 2 and 3 positions of the naphthyl ring; R<1> and R<4> each represent = O; and R<2> represents a group (a) wherein n is 2 or 3, R<6> and R<7> which may be the same or different, each represent a hydrogen atom, a C1-6alkyl group, optionally substituted by hydroxy, C1-6alkoxy or a group (b) wherein R<9> is a C1-6alkyl group optionally substituted by an amino group optionally substituted by one or two alkyl groups, or R<6> and R<7> may each be a group (c) wherein R<8> is a C1-6alkyl group, A is an oxygen atom or a group (d) wherein R<5> represents a hydrogen atom, a C1-6alkyl group optionally substituted by hydroxy, C1-6 alkoxy or an amino group optionally substituted by one or two C1-6alkyl groups or R<5> is a group (e) wherein R<10> is a C1-6alkyl group or R<5> is a group (f) wherein p is 2 or 3 and R<11> and R<12> are as hereinbefore defined for R<6> and R<7> or, when m is 1 and n is 2 R<5> may be linked to R<6> so that (g) forms a piperazine ring; or the dotted line represents double bonds between the 1, 2 and 3, 4 positions of the naphthyl ring, and R<1>, R<2> and R<4> each represent a group (h) (wherein n, A, R<6> and R<7> are as hereinbefore defined); and physiologically acceptable salts thereof.

Description

1,4-Naphtoquinone derivatives with antiprotozoal activity and antiparasitic techniques

The present invention relates to naphthoquinones and their use in chemotherapy. In particular, the present invention relates to novel carbonate and carbamate derivatives of hydroxynaphthoquinones, processes for their preparation and pharmaceutical compositions containing them. The use of the compounds of this invention is directed to the chemotherapy of certain protozoal and parasitic infections.

BACKGROUND OF THE INVENTION

Parasitic protozoal infections are responsible for a wide variety of medical and veterinary diseases, including malaria in humans and various coccidiosis in birds, fish and mammals. Many of these diseases cause life threats to the host and cause considerable economic losses in livestock farming. Parasitic protozoa include Apicomplexa such as Eimeria, Cryptosporidium, Toxoplasma and Plasmodium. Another parasitic organism of increased interest is Pneumocystis carinii, which can cause frequent fatal pneumonia in immunocompromised hosts or including those infected with HIV. The classification of these organisms is unclear and it is still uncertain whether they are protozoa or fungi.

A wide variety of naphthoquinones are known in the art. Such compounds have been variously described as having antimalial, anticoccidial and antitheilerial activity.

Some compounds have also been reported to have activity against external parasites. Thus, Fieser et al. in J. Am. Chem. Soc. 70, 3156-3165 (1948) (and references cited in this work) disclose a large number of 2-substituted 3-hydroxy-1,4-naphthoquinone quinones as having antimalial activity. A number of these compounds are also described in U.S. Patent No. 2,553,648. Another group of 2-substituted 3-hydroxy-1,4-naphthoquinones having antimalial, anticoccidial and / or antitheilerial activity is disclosed in U.S. Pat. No. 3,367,830 and 3,347,742, GB Patent Specification No. 1,553,424 and European Patent Specifications Nos. 2,223, 77,551, 77550 and 123,233.

European Patent Application 362 996 discloses, for the treatment and / or prophylaxis of infections caused by Pneumocystis carinii, 1,4-naphtho-thionones of the general formula I

in which

R is an optionally substituted non-aromatic hydrocarbon radical having from 1 to 35 carbon atoms and

R ^b is, inter alia, -OCOR ^c , OR ^d , SR ^d or

NR ^e R ^f , which compounds are expected to act as precursors of drug compounds based on compounds wherein R ^b is hydroxy.

SUMMARY OF THE INVENTION

It has now been found that 1,4-naphthoquinones substituted in position 2 by the carbamate group exhibit good in vivo anti-malaria activity in mice infected with Plasmodium voelii.

Thus, a first aspect of the invention relates to a compound of formula II

(II) wherein it is a C 1 -C 35 hydrocarbyl group optionally substituted with one to five substituents selected from halogen, C 1 -C 6 alkoxy, hydroxy, amino, C 1 -C 4 monoalkylamino or C 1 -C 4 dialkylamino carbon atoms in each alkyl moiety; and.

any dashed bond represents a double bond between positions 2 and 3 of the naphthyl ring,

R ¹ and R ⁴ are each a group of the formula = O and

R ‘represents a group of the formula

R /

A - (CH-) n -N where n is 2 or 3 a

R ⁶ and R ⁷ , which may be the same or different, each represent a hydrogen atom, an alkyl group having from 1 to 6 carbon atoms, optionally substituted by a hydroxy group, an alkoxy group having 1 to 6 carbon atoms or a group of the formula

wherein R ⁹ is C 1 -C 6 alkyl optionally substituted with amino optionally substituted with one or two alkyl groups, or

7

R and R may each represent a group of the formula

Q wherein R represents an alkyl group having 1 to 6 carbon atoms,

A represents an oxygen atom or a group of the formula

R ⁵ \

-Nwhere R ⁵ is hydrogen, C 1 -C 6 alkyl optionally substituted by hydroxy, C 1 -C 6 alkoxy or amino optionally substituted by one or two C 1 -C 6 alkyl groups, or

R ⁵ represents a group of the formula

-COR ¹⁰ wherein R is an alkyl group sl to 6 carbon atoms or

R 0 represents a group of formula ( ^c H ₂ ) -N · ^L ? \ η ·>

Wherein p is 2 or 3 a

R ¹¹ and R ¹² have the meaning given above for R ⁶ and R ⁷ or when m is number r ¹ is 2, R ⁵ can be a bond to R ⁶ so that a group of formula

N (CH ₂ ) ₂ N forms a piperazine ring, or the dashed line represents a double bond between positions 1, 2 and 3,4 of the naphthyl ring and

Ί O

R, Ir and R ^q represent each group of formula o

: l

C (CH_) n ·, z \, ²

Wherein n, A, R ⁶ and R ⁷ are as defined above, and physiologically acceptable salts thereof.

The hydrocarbon group having 1 to 35 carbon atoms R ^{3 can} be an alkyl group having 1 to 14 carbon atoms (e.g., 1 to 8 carbon atoms), an alkenyl group having 2 to 14 carbon atoms (e.g., 2 to 8 carbon atoms), straight or branched chain, or a cycloalkyl group of 3 to 10 carbon atoms (for example of 3 to 6 carbon atoms), each of which may be substituted by a cycloalkyl group of 3 to 10 carbon atoms (for example of 3 to 6 carbon atoms), and each of the aforementioned cycloalkyl groups being optionally substituted with an alkyl group having 1 to 10 carbon atoms (e.g., 1 to 4 carbon atoms). In another embodiment, the hydrocarbon group R ³ may be a cycloalkyl group having 3 to 10 carbon atoms (e.g., 3 to 3 carbon atoms) substituted with a phenyl group optionally substituted with an alkyl group having 1 to 10 carbon atoms (eg, 1 to 4 atoms) carbon). The hydrocarbon group R ³ preferably contains from 1 to 20 carbon atoms, for example 1 to 14 carbon atoms. Suitable groups R ³ includes C3-10 cycloalkyl C1_g alkyl, C1_10al'kyl ^{C3_10cykloalkyl-c} i_io ^ai_ -alkyl-C3 _'10 cycloalkyl-C ₁ _ ₁₀ alkyl and C ₃ _ ₁₀ cycloalkyl - C ₁ _ ₃ Qcykloalkyl. R ³ can also be substituted as defined herein with one to five halogen atoms, alkoxy groups of 1 to 6 carbon atoms, or groups of the formula S (O) _m R ¹⁰ where m is 0, 1 or 2 and R 6 -θ is C1 -C6 alkyl, hydroxy, C1 -C4 monoalkylamino or C1 -C4 dialkylamino in each alkyl moiety.

Preferred R ³ groups include:

(C 1 -C 10) alkyl, (C 5 -C 7) cycloalkyl (which may be optionally substituted by straight or branched (C 1 -C 6) alkyl, (C 1 -C 6) haloalkyl, (C 1 -C 6) alkoxy) carbon or phenyl, the phenyl itself being optionally substituted by one or more substituents selected from alkyl groups having 1 to 6 carbon atoms and halogen) and

A C 1-10 alkyl-C 5-6 cycloalkyl group wherein the cycloalkyl moiety is optionally substituted as defined above for a C 5 -C 7 cycloalkyl group.

A particularly preferred group of substituents R ³ is represented by the general formula

wherein g represents zero or the number 1 a

R ¹³ represents an alkyl group having 1 to 10 carbon atoms.

Another particularly preferred group of substituents R ³ is represented by the general formula II '.

wherein r represents zero or the number 1 and either

R ¹⁴ represents a hydrogen atom and 1c

R is selected from halogen, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, arylalkoxy, C 1 -C 6 alkylalkoxy in both the alkyl and alkoxy moieties and the phenyl moiety substituted with one or two groups selected from halogen atoms and alkyl groups having 1 to 6 carbon atoms; or

R @ ¹⁴ and R @ ¹ are both C1 -C6 alkyl or phenyl.

It will be appreciated that the compounds of the general formula

I, in which R ³ contains a substituted cyclohexyl group, may exist as cis or trans isomers, so that the cyclohexyl ring may be cis or trans substituted with a naphthoquinone ring and a substituent on the cyclohexyl ring. Both cis and trans isomers and mixtures thereof in any ratio can be used according to the invention. Generally, when the compound is in the form of a mixture of isomers, the trans isomer will be present in an amount of about 50% or will be the predominant isomer, but the use of mixtures in which the cis isomer is dominant is also included within the scope of the invention. The particular ratio of isomers may vary as desired, but conventional mixtures include those in which the ratio of cis to trans isomers is about 1: 1, 40:60 and 5:95. Preferred for use herein is the trans isomer of a compound of Formula I or a mixture of cis and trans isomers containing at least 95%, for example, 99% of the trans isomer.

A particularly preferred R ³ substituent is a 4- (4-chlorophenyl) cyclohexyl group of the formula

Especially in trans form, relative to the naphthoquinone ring.

In the compounds of formula II, A is preferably a group of formula

R?

-Na R represents a carbamate group of the general formula

If any of the groups R ^5, R ^6, R ^7, R ^8, R ^10, R ¹¹ or 2 Ί Rl represents an alkyl group having 1 to 6 carbon atoms, this may be straight or branched chain and is, for example methyl, ethyl, isopropyl, tert-butyl, isopentyl or n-hexyl. Suitably, R @ 1, R @ ⁶ and R @ ⁷ are each hydrogen or C1 -C4 alkyl. Particularly preferably R ⁵ is methyl or ethyl, ^R6 is hydrogen, methyl or ethyl and R ⁷ is hydrogen or a group -CO-OR ⁸ wherein R ⁸ is alkyl of 1-4 carbon atoms, for example tert. butyl.

In compounds of formula II, R ¹ and R ⁴ preferably represent = O and the dashed line indicates the bond between positions 2 and 3 of the naphthyl ring.

A preferred group of compounds of formula II may be represented by formula III

(III) wherein

R A 7

R, R ^Q and R 'are as defined above, and physiologically acceptable salts of these compounds.

Other compounds of formula III are preferred in the form of trans isomers.

2- (trans-4- (4-Chlorophenyl) cyclohexyl) -3- [N-methyl-N- [2- (methylamino) ethyl] carbamoyloxy] -1,4-naphthoquinone is a preferred compound of formula III,

A further preferred group of compounds of formula II may be compounds of formula IV

in which

RR ⁶ and R ⁷ are as defined above.

2- [trans- (4-tert-Butylcyclohexyl) methyl] -3- [N-methyl-N- [2- (methylamino) ethyl] carbamoyloxy] -1,4-naphthoquinone is a preferred compound of Formula IV.

By hydrocarbon residue or hydrocarbon group is meant an aliphatic group, for example a straight, branched or cyclic alkyl, alkenyl or alkynyl group, a carbocyclic aryl group, an aliphatic group substituted with a carbocyclic aryl group optionally substituted by an aliphatic group, or a carbocyclic aryl group substituted. aliphatic group.

Without wishing to be bound by theory, it is believed that the carbonate or carbamate derivatives of formula (II) are precursors of the active substances corresponding to the hydroxynaphthoquinone, i.e. the carbamate or carbonate or group is cleaved in vivo to give a compound of formula (I) wherein R ^b is hydroxy.

Compounds of formula (II) are expected to exhibit activity against parasitic protozoa, particularly those organisms against which the corresponding hydroxynaphthoquinones, for example Plasmodia species, for example P. falciparum, Eimeria species, for example E. tenella and E., have been found to be active. acervulina, Theileria species, for example T. parvum and T. annulata, Cryptosporidium and Toxoplasma gondii, as well as the parasitic organism Pneumocystis carinii, and will therefore be suitable for the treatment and / or prophylaxis of parasitic infections, such as infections caused by parasitic protozoa, for example or prophylaxis of malaria, coccidiosis, cryptosporidiosis, toxoplasmosis, and against diseases caused by P. carinii, for example P. carinii pneumonia (PCP) in animals including humans.

It will be appreciated that the amount of compound of Formula II or a salt thereof required for use in the treatment or prophylaxis of the aforementioned diseases will depend, inter alia, on the particular compound administered, the route of administration, age and weight of the mammal (including human) to be treated and the nature. and the severity of the condition being treated. Generally, a suitable dosage for administration to a human to treat malaria is in the range of from 0.1 to 200 mg per kilogram of body weight per day, for example from 1 to 100 mg / kg, especially from 10 to 40 mg / kg. It should be appreciated that lower doses may be required for administration to newborns.

For prophylactic treatment, the compound of formula (II) or a salt thereof may also be administered less frequently, for example, as a single dose every other day, once or twice a week or once or twice a month. The dosage for prophylactic treatment will depend, inter alia, on the frequency of administration and, when a depot or controlled release composition is used, the dose of active ingredient released. Thus, for once-week administration, the prophylactic dose is in the range of 0.1 to 100 mg / kg, for example 0.5 to 50 mg / kg, especially 5 to 50 mg / kg.

It will be appreciated that to achieve consistency in dosing, the dosages listed above are calculated with respect to the compound of formula (II) per se and may require adjustment if a salt is used.

A method for the treatment and / or prophylaxis of parasitic infections, for example parasitic protozoal infections such as malaria, or P. carinii infections in mammals, for example humans, is to administer an effective amount of a compound of general formula to a mammal affected or susceptible to said infection. or a physiologically acceptable salt thereof.

The compound of formula (II) or a physiologically acceptable salt thereof is used in therapy, for example in the treatment and / or prophylaxis of parasitic infections as defined above.

The invention also allows the use of a compound of formula (II) or a physiologically acceptable salt thereof for the manufacture of a medicament for the treatment and / or prophylaxis of parasitic infections as defined above.

For use according to the invention, the compound of formula (II) or a physiologically acceptable salt thereof is preferably present in the form of a pharmaceutical composition. Generally, such pharmaceutical compositions will comprise a compound of Formula II or a physiologically acceptable salt thereof together with one or more pharmaceutically acceptable carriers and optionally other therapeutic and / or prophylactic agents. The carrier (s) must be acceptable in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.

The present invention therefore further provides a pharmaceutical composition comprising a compound of Formula II or a pharmaceutically acceptable salt thereof, together with at least one pharmaceutically acceptable carrier therefor, or a salt thereof.

Also provided is a method of making a pharmaceutical composition comprising contacting a compound of formula (II) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier therefor.

The compound of formula (II) or a salt thereof may conveniently be presented as a pharmaceutical composition in dosage unit form. A typical dosage unit contains from 10 mg to 1 g of a compound of formula II or a physiologically acceptable salt thereof.

Pharmaceutical compositions include compositions adapted for oral, topical (including dermal, buccal and sublingual), rectal and parenteral (including subcutaneous, intradermal, intramuscular, and instravenous) administration. If appropriate, the compositions may conveniently be presented in separate dosage units and may be prepared by any of the methods well known in the art of pharmacy. All such methods include the step of bringing into association a compound of formula (II) or a physiologically acceptable salt thereof with liquid carriers or finely divided solid carriers, or both, and, if desired, shaping the product into the desired composition.

Pharmaceutical compositions suitable for oral administration in which the carrier is a solid are most preferably present as a unit dosage formulation, such as a bolus, capsule or tablet, each containing a predetermined amount of the active agent or agents. The tablet may be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be made by compressing, in a suitable machine, the active compound or the active compounds in a free-flowing form such as powder or granules, optionally mixed with a binder, lubricant, inert diluent, glidant, surfactant or dispersing agent. Molded tablets may be made by molding in a suitable machine a powdered active ingredient or active ingredients with any suitable carrier. The tablets may optionally be coated and, if uncoated, may be scored. Capsules may be prepared by filling either the active ingredient alone or the active ingredients alone or in admixture with one or more excipients, into the capsule shell and then sealing in a conventional manner. Cassettes (drug capsules) are analogous to capsules in which the active ingredient (s) together with the excipient (s) is enclosed in a pad of rice paper. The compound of formula (II) or a physiologically acceptable salt thereof may also be formulated as dispersible granules, which may, for example, be suspended in water prior to administration or sprayed on food. The granules may also be packaged, for example, in sachets (drug pouches). Compositions suitable for oral administration in which the carrier is a liquid may be present as a solution or as a suspension in an aqueous liquid or non-aqueous liquid or as an oil-in-water emulsion, for example a syrup, elixir, emulsion or potion. A syrup may be made by adding the active ingredient (s) to a concentrated aqueous sugar solution, for example sucrose, to which any excipients may be added, including flavoring agents, sugar-crystallization-preventing agents, or agents which increase the solubility of other ingredients, such as are polyhydric alcohols such as glycerol or sorbitol.

Formulations for oral administration include controlled release dosage forms, for example, tablets in which the active ingredient is or the active ingredients are formulated into a suitable release-enabling base or coated with a release-controlling film. Such compositions may be particularly suitable for prophylatic use.

Pharmaceutical compositions suitable for rectal administration in which the carrier is a solid are most often presented as unit dose suppositories. Suitable carriers include cocoa butter and other substances commonly used in the art. Suppositories can usually be prepared by mixing the active ingredient (s) with the softened or melted carrier (s), followed by rapid cooling and molding.

Pharmaceutical compositions suitable for parenteral administration include sterile solutions or suspensions of the active ingredient (s) in aqueous or oily excipients. Injectable preparations may be adapted for administration as an injection or for continuous infusion. Such compositions are generally presented in single or multiple dose containers that are sealed upon introduction of the composition until required for use. In another embodiment, the active agent (s) may be in powder form, for example lyophilized, which is formed prior to use with a suitable excipient such as sterile pyrogen-free water.

The compound of formula (II) or a physiologically acceptable salt thereof can also be formulated as a long-acting depot preparation, which can be administered by intramuscular injection or implantation, for example subcutaneously or intramuscularly. The depot compositions can contain, for example, suitable polymeric or hydrophobic materials or ion exchange resins. Such long-acting agents are particularly suitable for prophylactic use.

While the compounds of the invention may be formulated in any known manner, for example as noted above, in view of their properties, they are particularly suitable for compositions such as aqueous solutions which may be used for injection. 2- [trans-4- (4-Chlorophenyl) cyclohexyl] -3- [N-methyl-N- [2- (methylamino) ethyl] carbamoyloxy] -1,4-naphthoquinone has improved water solubility over the base hydroxynaphthoinone.

It should be recognized that in addition to the above carriers, the pharmaceutical compositions for the various routes of administration described above may include one or more other carriers such as diluents, buffers, flavoring agents, binders, surfactants, thickeners, lubricants, preservatives (e.g. including antioxidants) and the like, and substances included to render the composition isotonic with the blood of the intended recipient.

The compounds of the invention may be administered in combination or concurrently with other therapeutic agents, for example other anti-malaria agents, such as 4-aminoquinolines, for example chloroquine and amodiachine, 8-aminoquinolines, for example primaquine, chloroquine, mefloquine, quinine, quinidine, artemesinin , artesumate, artemether, halofantrine, dihydrofolate-based reductase inhalers, for example pyrimethamine, sulfonamides, for example sulfadoxin, proguanil, chlorproguanil, dapson, hydroxynaphthoquinones, or mixtures, for example pyrimethamine and sulfadoxin, pyrimethamim, and dapsone or antibacterial agents, and sulfaroethoxazole, anticoccidial agents such as monensin, halofuginone, arprinocide, amprolium, dinitolmid, robenidine or salinomycin or antibiotics such as clindamycin, tetracycline, doxycycline or spiromycin or agents active against Pneumocystis carnii as well as pen tamidin or eflornithine.

When the compounds of Formula XI are used in combination with a second therapeutic agent, the dose of each compound may vary from that required when the compound is used alone. Appropriate dosages can be readily determined by one skilled in the art.

Compounds of formula (II) may be prepared by reacting a compound of formula (V), as defined above, and a known halogen atom, with a compound of formula (VI) wherein R7, n, A, R, and R are as defined above;

(VI) provided that if it is desired to produce a compound wherein at least one of R ⁶ and R ⁷ is hydrogen, the corresponding compound with the group -CO-OR ^{8 in} place of the hydrogen atom is produced and this group is then removed.

The reaction may conveniently be carried out in the presence of a solvent inert to the reactants. Solvents that may be used include aromatic hydrocarbons such as benzene or toluene, halogenated hydrocarbons such as chloroform or dichloromethane, dipolar aprotic solvents such as dimethylformamide or phosphoric acid hexamethylamide, ethers such as hydrofuran or dioxane, pyridine, acetonitrile, trimethyl phosphate and triethylphosphate. The reaction temperature is usually in the range of from 80 to 100 ° C, preferably from 0 to 30 ° C.

The reaction is preferably carried out in the presence of a base, which may be an organic base, for example pyridine, 4-dimethylaminopyridine, a tertiary amine such as triethylamine or

1,8-diazabicyclo [5.4.0] -7-undecene (DBU) or an inorganic base, for example an alkali metal carbonate such as potassium carbonate or sodium bicarbonate.

For the preparation of compounds of formula II in which R ¹ ,

R ² and R ⁴ each represent a carbonate or carbamate group the reaction should be carried out after reduction chinoncvěho cores which can be carried out in conventional manner.

The preparation of salts can be carried out by methods well known in the art, by reacting a compound of formula II with a suitable acid.

The deprotection of the formula -co-OR ⁸ is usually carried out by treatment with an acid, for example when R ⁸ represents a tert-butyl group, with hydrochloric acid in ether.

The compounds of formula (V) may conveniently be prepared in situ from the corresponding hydroxynaphthoquinone, for example when X is chlorine, by reacting the hydroxynaphthoquinone with phosgene in an inert solvent as described above in the presence of a base used to attach the carbamate side chain.

The reaction is carried out at a temperature of from -50 to 50 ° C and conveniently at a temperature of from -10 to 10 ° C.

The compounds of formula (IV) can be prepared according to known methods for the synthesis of hydroxynaphthoquinone derivatives as described in US Patent Nos. 2,553,648, 3,367,830 and 3,347,742, GB Patent No. 1,553,424, European Pat. For example, compounds of formula IV can be prepared by reacting 2-halo-1,4-naphthoquinone (e.g., 2-chloro-1,4-), e.g., 2,228, 77,551, 77,550 and 123,238 and European Patent Application No. 362,996. naphthoquinone) with a compound for introducing the desired R ³ group and subsequent hydrolysis under alkaline conditions. When R ³ is an optionally substituted cyclohexyl group or an optionally substituted cyclohexylmethyl group, this substituent may be introduced by reaction with an appropriately substituted cyclohexylcarboxylic acid or cyclohexylacetic acid.

DETAILED DESCRIPTION OF THE INVENTION

The invention will now be illustrated by the following non-limiting examples.

In vivo activity against Plasmodium voelii in mice

Test compounds

Compound A: 2- [trans-4- (4-chlorophenyl) cyclohexyl] -3- [N-methyl-N- [2- (methylamino) ethyl] carbamoyloxy] -1,4-naphthoquinone hydrochloride monohydrate

Compound B: 2- / trans-4- (4-chlorophenyl) cyclohexyl] -3- [N- [2- (methylamino) ethyl] carbamoyloxy] -1,4-naphthoquinone hydrochloride monohydrate

Compound C: 2- [trans-4- (4-chlorophenyl) cyclohexyl] -3- [N-methyl-N- [3- (methylamino) propyl] carbamoyloxy) -1,4-naphthoquinone

Compound D: trans-2- [4- (4-chlorophenyl) cyclohexyl] -3- [piperazine-N-carbonyloxy] -1,4-naphthoquinone hydrochloride dihydrate

Compound I: 2- [trans-4- (4-chlorophenyl) cyclohexyl] -3-hydroxy-1,4-naphthoquinone

Compounds A, B, C and I are administered orally and intravenously as described below.

Method

The test method is a modified version of the four-day suppressive test. The P. voelii YM strain is maintained in mice twice weekly by passaging. The infected blood is collected and diluted with normal saline to give an inoculum of 3x10 6 parasitized enytrocytes per milliliter. On the morning of day 1, the theatrical animals (male CD-I mice weighing 18-20 g) are intravenously infected via the tail vein with 0.1 ml of mouse inoculum.

Oral treatment (p.o.)

Test compounds A, B and I are processed in a ball mill in 0.25% celacol with stainless steel beads. The entire amount required is processed at the beginning of the test and then stored at 4 ° C.

Each test compound is administered orally (po) to four or more usually five groups of mice, each group receiving a different dose (dilution) level. Another group of mice is given only celacol as a control group (i.e., a total of 30 mice are used to achieve each ED ₅₀ value). Mice are dosed orally 24 hours after infection.

Intravenous treatment (i.v.)

Formulations for intravenous administration of test compounds A and B are prepared by dissolving the compound in water immediately before use and administering it to the tail vein as a single dose 24 hours after infection.

On the morning of day 5, blood drawn from the tail is prepared by spreading on a glass slide for each mouse and parasitemia is calculated. Data are analyzed to obtain ED _5q values that best fit the sigmoidal dose response curve. The results are shown in Table 1 below.

Table 1

Breakdown Values 1 x p. dosage ED ₅₀ mg / k 1 xi · Compound AND 0.16 0.12 Compound AND 0.15 0.12 Compound (B) 0.2 0.27 Compound C 0.4 0.29 Compound D 0.4

In vivo activity against Pneumocystis carinii in mice

Tested active substances

Septrin: Pediatric Supension (Wellcome) containing 200 mg sulfamethoxazole and 40 mg trimethoprim per 5 ml

Atovaquon: 2- [trans-4- (4-chlorophenyl) cyclohexyl] -3-hydroxy-1,4-naphthoquinone

Test compound: 2- / trans-4- (4-chlorophenyl) cyclohexyl] -3- [N-methyl-N- [2- (methylamino) ethyl] carbamoyloxy] -1,4-naphthoquinone hydrochloride monohydrate

Method A

Female SCID mice (CB-17 / lcr-scid / scid) weighing 20-25 g of uninfected Pneumocystis carinii (PC) are treated with dexamethasone (2 ml in drinking water) 7 days prior to induction of intratracheal infection with a single dose of PC obtained from mice, kept at low temperatures (dose: 2 χ 10 ⁴ cysts, equivalent to approximately 10 ⁶ trophozoites). Drugs are evaluated for prophylactic effect by continuous daily dosing of each drug from day 1 after infection to day 42 in a group of 10 mice each. Assays are terminated and all mice are sacrificed 24 hours after the last dose. The lungs are removed and the blood smear obtained by spreading on a glass slide is prepared from the appropriate lung sections of randomly selected mice. ). Slides are evaluated for the intensity of P. carinii infection by measurement at 100X magnification and high fluorescent cysts are counted. The slides are rated at one of the following stages:

O = no cysts on the slide +1 = 1 to 5 cysts on the slide +2 = 6 to 50 cysts on the slide +3 = 51 to 250 cysts on the slide +4 = more than 251 cysts on the slide

Medicinal product

Septin is diluted with drinking water and the dose is calculated on the basis that each mouse should drink at least 2.5 ml per day. An aliquot is administered as a suspension in 0.25% celacol. The test compound is dissolved in distilled water and the solution is administered within 1 hour of preparation.

The results shown in Table 2 below are based on two independent blank tests and are expressed as the average measure of infection in 10 mice in each group. Values are also expressed as a percentage of the control assay (daily dose administered orally with distilled water).

Table 2

Treatment group Mean density ±% of the control standard deviation of the assay

control group 3.6 + 0.2 100 ALIGN! Septrin (250/50 mg / kg / d) 0.1 0.1 3 Atovaquon (100 mg / kg / d p.o.) 1.5 + 0.3 43 test compound 0.1 + 0.1 3

(100 mg / kg / d p.o.)

Examples of resources

The following examples illustrate, in particular with respect to the compound of Example 2, the pharmaceutical compositions that can be used according to the invention. It will be appreciated that other compounds of Formula II may be treated in a similar manner.

A, Solution for Injection

The solution for intramuscular injection can be made by mixing:

the compound of Example 2 9.5 parts % by weight dimethylsulfoxide 19.0 parts % by weight sorbitan monooleate 4,5 parts % by weight corn oil 67.0 parts % by weight total 100.0 parts % by weight

B. Solution for injection

the compound of Example 2 5 parts % by weight N-methyl-pyrollidone 48.3 parts % by weight Tween 80 2 parts weight Sleep 80 4.7 dilú % by weight Miglyol 812 40 parts % by weight total 100.0 parts % by weight C. Tablets the compound of Example 2 25.0 mg lactose BP 48.5 mg microcrystalline cellulose BP 10.0 mg (Avicel pH 101) low-substituted hydroxy- 10.0 mg propylcellulose BP LHPC LH-11 sodium starch glycolate BP 3.0 mg (Explotab) Povidone BP (K30) 3.0 mg Magnesium stearate BP 0.5 mg total 100.0 mg

D. Lyophilized solution for intravenous administration of the compound of Example 2 50 mg water for injection to 10 ml

The naphthoquinone is dissolved in water for injection, the resulting solution is sterile filtered, filled into glass vials and lyophilized. Reconstitution is performed shortly before use with water for injection.

E. Capsules

the compound of Example 2 100 ALIGN! mg Starch 1500 150 mg magnesium stearate 2.5 mg

They are filled into hard gelatin capsules.

F. Aerosol compositions

(a) the compound of Example 2, 1.0 ng micronized aerosol ejector gas to 5.0 ml

The micronized compound is suspended in an aerosol ejector gas. The resulting suspension is filled into pre-prepared aerosol canisters, in an amount of 5 ml per canister, through a valve orifice.

b) the compound of Example 2, micronized Arlacel 85 aerosol propellant

1.0 mg

0.1% (w / v) to 5.0 ml

Arlacel 85 is dispersed in an aerosol ejector gas and then the compound of Example 4 is added. The suspension is filled into pre-prepared aerosol canisters, in an amount of 5 ml per canister, through a valve orifice.

G. Inhalation Powder Compound of Example 2, Micronized Lactose

1.0 mg

29.0 mg

The micronized compound is triturated and mixed with ε lactose. The resulting powder mixture is filled into hard gelatin casple shells in an amount of 30 mg each per capsule.

Process for the preparation of tert-butyl [N-methyl-N- [2- (methylamino) ethyl] carbamate]

This compound was prepared from N, N * -dimethylethylenediamine as described by W.S. Saari, J. E. Schwering,

P.A. Lyle, S.J. Smith and E.L. Engelhardt in J. Med. Chem.

33, 97 (1990).

A process for the preparation of bis [2 - [(tert-butoxycarbonyl) amino] ethyl] amine

To a stirred solution of 10 g (97 ml) of diethylenetriamine (Lancaster synthesis) in 5 ml of tetrahydrofuran cooled to 0 ° C was added dropwise a solution of 10.5 g (48 mmol) of di-tert-butyl dicarbonate in 50 ml of tetrahydrofuran. The mixture was allowed to warm to room temperature and stirred for 18 hours, filtered and evaporated under reduced pressure. The residue was partitioned between brine and ethyl acetate. The aqueous layer was extracted once with ethyl acetate, and the combined extracts were dried over magnesium sulfate and concentrated in vacuo to give 6.7 g of a clear oil. Chromatography on silica gel with methanol / chloroform (1: 4) gave the title compound as a clear oil (2 g). Yield 27%.

NMR δΗ (CDCl ₃ ): 3.15-3.3 (4H, m), 2.75 (4H, t, J =

Hz), 1.45 (18H, s) ppm.

Example 1

2- (trans-4- (4-chlorophenyl) cyclohexyl) -3- [N-methyl-N- [2- (N-methyl-N-tert-butoxycarbonyl) aminoethyl] carbamoyloxy] -1,4 naphthoquinone

To a stirred suspension of 3.7 g (10 mmol) of 2-hydroxy-3- [trans-4- (4-chlorophenyl) cyclohexyl] -1,4-naphthoquinone in 60 mL of dry dichloromethane, cooled to 0 ° C under a nitrogen atmosphere, 10 ml of a 1.25 molar solution of phosgene in toluene is added in one portion. Pyridine (0.8 mL, 10 mmol) was added dropwise and the solution was stirred at 0 ° C for an additional 45 min.

A mixture of 1.85 g (10.5 mmol) of tert. -butyl- [N-methyl-N- [2- (methylamino) ethyl] carbamate] and 0.8 mL (10 mmol) pyridine in 10 mL dry dichloromethane over 15 minutes and allowed to stir at room temperature for 18 hours . The mixture was diluted with 50 mL of dichloromethane, washed with water, 1M hydrochloric acid and water, dried (MgSO 4) and evaporated to give an orange oil. Chromatography on silica gel with ethyl acetate / dichloromethane (1: 9), followed by trituration with ether / hexane (1: 2) gave 3.12 g of the title compound, mp 113-115 ° C. Yield: 54%.

SH-NMR (CDC1 ₃₎ 8.0 - 8.2 (2H, m), 7.65 - 7.8 (2H, m), 7.1 - 7.3 (4H, m), 3.4 - 3.7 (4H, m), 3.15 (3H, 2xs), 3.05-3.25 (1H, m), 3.0 (3H, 2xs), 1.5-2.15 (SH, 2xs) ppm.

Example 2

Process for the preparation of 2- [trans-4- (4-chlorophenyl) cyclohexyl] -3- [N-methyl-N- [2- (methylamino) ethyl] carbamoyloxy] -1,4-naphthoquinone hydrochloride monohydrate

2.74 g (3 mmol) of 2- [trans-4- (4-chlorophenyl) cyclohexyl] -3- [N-methyl-N-] 2- (N-methyl-N-) are added to 30 ml of hydrogen-saturated ether. tert-butoxycarbonyl) aminoethyl / carbamoyloxy] -1,4-naphthoquinone and the solution was stirred at room temperature for 5 hours. The precipitate was filtered off, washed with ether and dried under reduced pressure. This gives 1.48 g of the title compound, m.p. &gt; 140 ° C (dec.). Yield: 92%.

NMR δ (CDCl ₃ ): 9.1-9.3 (1H, broad s), 7.95-8.2 (2H, m), 7.65-7.85 (2H, m), 7.1 7.35 (4H, S), 3, -7-4.0 (1H, broad s), 3.0-3.5 (6H, m), 2.8 (3H, broad s), 2, 65 (1H, m), 1.75-2.15 (8H, m), 1.4-1.75 (2H, m) ppm.

Further, the following compounds were prepared in a similar manner to Example 1:

2- [trans-4- (4-chlorophenyl) cyclohexyl] -3- [N- [2- (N-methyl-N-tert-butoxycarbonylamino) ethyl] carbamoyloxy] -1,4-naphthoquinone from tert-butyl - (N-methyl-N- (2-aminoethyl) carbamate) (WS Saari et al., J. Med. Chem. 33, 97 (1990)), m.p. 128-131 ° C, NMR δΗ (CDCl ₃₎ ): 8.05-8.15 (2H, m), 7.65-7.8 (2H, m), 7.15-7.3 (4H, m), 3.5 (4H, m), 3.0-3.2 (1H, m), 3.0 (3H, s), 2.5-2.7 (1H, m), 1.75-2.15 (6H, m), 1, 45-1.7 (11H, m) ppm,

2- [trans-4- (4-chlorophenyl) cyclohexyl] -3- [N-methyl-N- [3- (N-methyl-N-tert-butoxycarbonylamino) propyl] carbamoyloxy] -1,4-naphthoquinone from tert-butyl- [N-methyl-N- [3- (methylamino) propyl] carbamate] (WS Saari et al., J. Med. Chem. 33, 97 (1990)), oil, NMR 6H (CDCl3): 8.0-8.2 (2H, m), 7.65-7.8 (2H, m), 7.1-7.35 (4H, m), 3.25-3.6 (4H, m), 3.0-3.25 (4H, m), 2.9 (3H, s), 2.5-2.7 (1H, m), 1.75-2.15 (8H) , m),

1.4-1.7 (11H, m) ppm,

2- [trans-4- (4-chlorophenyl) cyclohexyl] -3- [N-ethyl-N- [2- (N-ethyl-N-tert-butoxycarbonylamino) ethyl] carbamoyloxy] -1,431

- naphthoquinone from tert-butyl [N-ethyl-N- [2- (ethylamino) ethyl] carbamate] (W. S. Saari et al., J. Med. Chem. 33, 97 (1990)), oil,

2- [trans-4- (4-chlorophenyl) cyclohexyl] -3- (N-tert-butoxycarbonylpiperazine-N-carbonyloxy] -1,4-naphthoquinone from N-tert-butoxycarbonylpiperazine (Carpino et al., J. Org. Chem. 48 (5), 664 (1983)), oil,

2- [trans-4- (4-chlorophenyl) cyclohexyl] -3- [[2- (N-methyl-N-tert-butoxycarbonylamino) ethoxy] carbonyloxy]-1,4-naphthoquinone from tert-butyl- / N- (2-hydroxyethyl) -N-methyl carbonate ((WS Saari et al., J. Med. Chem. 33, 97 (1990)), m.p. 110-111 ° C, NMR SH (dg-DMSO): 7, 9-8.1 (4H, m), 7.3 (4H, s), 4.35-4.45 (2H, t, J = 4Hz), 3.5-3.6 (2H, t, J = 4 Hz), 3.0-3.15 (1H, m), 2.5-2.7 (1H, ro), 1.7-2.0 (6H, m),

1.45-1.65 (2H, m), 1.4 (9H, s) ppm,

2- [trans -4- (4-chlorophenyl) cyclohexyl] -3- [N, N-bis (2-tert-butoxycarbonylamino) ethyl] carbamoyloxy] -1,4-naphthoquinone from bis- [2] (tert. -butoxycarbonyl) amino) ethyl / amine, yellow oil, NMR? H (CDC1 ₃₎ 8.0 - 8.2 (2H, m), 7.65 - 7.8 (2H, m), 7.1 - 7 3 (4H, m), 3.35-3.7 (4H, m), 3.15 (1H, m), 2.62 (1H, m), 1.8-2.1 (4H, m) m), 1.45 (9H, broad s), 1.4 (SH, broad s) ppm.

Further, the following compounds were prepared in a similar manner to Example 2 from the corresponding tert-butoxycarbonyl protected carbonates or carbamates:

2- / trans-4- (4-chlorophenyl) cyclohexyl] -3- [N- [2- (methylamino) ethyl] carbamoyloxy] -1,4-naphthochi32onone hydrochloride monohydrate, m.p. 194-197 ° C, NMR δΗ (d ₆ -DMSO): 9.1

9.3 (2H, broad s), 8.4-8.5 (1H, t), 7.3-3.1 (4H, m), 7.3 (4H, s), 3.4- 3.6 (2H, TO), 3.0-3.2 (3H, m), 2.55

- 2.75 (4H, m), 1.4 - 2.15 (8H, m) ppm, 2- / trans-4- (4-chlorophenyl) cyclohexyl] -3- [N-methyl-1-N] hydrochloride monohydrate - 3- (methylamino) propyl / carbamoyloxy] -1,4-naphthoquinone, m.p. 208-210 ° C, NMR SH (CDCl 3): 8.1-8.2 (1H, d, J = 5 Hz), 8.0-8.1 (1H, d, J =

Hz), 7.65-7.85 (2H, m), 7.15-7.3 (4H, m), 3.05-3.35 (7H, m), 2.5-2.8 ( 5H, m), 1.45-2.1 (10H, fn) ppm, 2- / trans-4- (4-chlorophenyl) cyclohexyl] -3- [N-ethyl-N- / 2- (ethylamino) hydrochloride monohydrate ) ethyl / carbamoyloxy] -1,4-naphthoquinone, melting point 197-201 ° C, NMR δΗ (CDCl ₃ ): 8.1 - 8.2 (1H, d, J = 8 Hz), 8.0 - 8 1 (1H, d, J = 8Hz), 7.65-7.8 (2H, m), 7.1-7.3 (4H, m), 3.0-4.1 (7H, m )

2.5-2.7 (1H, m), 1.25-2.15 (14H, m) ppm, 2- / trans-4- (4-chlorophenyl) cyclohexyl] -3- (piperazine hydrochloride dihydrate greater than 160) (4H, m), 7.25 (5H, m), 2.5 (2H, m) ppm,

N-carbonyloxy) -1,4-naphthoquinone, ° C (dec.), NMR δ (d 6 -DMSO): 7.8-7.4 (4H, m), 3.6-4.0 (4H) , m), 3.0 2.7 (1H, m), 1.7-2.05 (6H, m), 1.4 melting-8.1 3.5 1.7 2- / trans-4 hydrochloride - (4-chlorophenyl) cyclohexyl / -3- [2-dimethylaminoethoxy / carbonyloxy] -l, 4-naphthoquinone, mp 211-213 ° C, NMR 6H _(dg-DMSO): 7.95 - 8.05 ( 2H, m), 7.74-7.9 (2H, m), 7.33 (4H, s), 4.2-4.3 (2H, m), 3.5-3.6 (2H, m), 3.0-3.2 (1H, m), 2.75 (3H, s), 2.5-2.7 (1H, m), 2.05-2.3 (2H, m) , 1.8-2.0 (2H, m), 1.4-1.7 (4H, m) ppm, 2- [trans-4- (4-chlorophenyl) cyclohexyl] -3- (dihydrochloride) dihydrochloride dihydrate N, N-bis- (2-aminoethyl) carbamoyloxy] -1,4-naphthoquinone, m.p. 215-218 ° C, NMR SH (dg-DNSO): 8.25-8.7 (4H, broad signal), 7.85-8.15 (4H, m), 7.3-7.45 (4H, m),

3.5-4.0 (4H, m), 3.0-3.4 (5H, m), 2.7 (1H, m), 1.5-2.2 (8H, ro) ppm.

Example 3

2- (trans-(4-tert-butylcyclohexyl) methyl) -3- [N-roethyl-N- ./2- (N-methyl-N-tert-butoxycarbonylamino) ethyl] carbamoyloxy] -1 Of 4-naphthoquinone

To a stirred solution of 6.7 g (6.19 mmol) of 2- [trans- (4-tert-butylcyclohexyl) methyl] -3-hydroxy-1,4-naphthoquinone in 250 mL of dry dichloromethane under a nitrogen atmosphere was added 20 mL A 12.5% solution of phosgene in toluene was added dropwise

Pyridine (1.6 mL, 20 mmol) was added and the mixture was stirred for 1 hour.

1.6 ml (20 mmol) of pyridine and 3.7 g (21 mmol) of tert-butyl- N -methyl-N- (2- (methylamino) ethyl) carbamate are then added dropwise to the reaction mixture and the reaction mixture is stirred Evaporation of the solvents under reduced pressure gave a yellow solid which was chromatographed on silica eluting with toluene.

and then ethyl acetate. with toluene 1: 3. This gives 3.19 g of the title compound, m.p. 117-118 ° C. Yield: 31%.

SH-NMR (CDC1 ₃₎ 8.05 - 3.15 (2H, m), 7.65 - 7.75 (2H, m), 3.45 - 3.6 (4H, m), 3.2 - 3.1 (3H, 2xs), 2.95 (3H, 2XS), 2.45-2.55 (2H, ro), 1.7-1.9 (5H, m), 1.5 (9H, 2xs), 0.9

1.1 (5H, m), 0.85 (9H, s) ppm.

Example 4

2- (trans-(4-tert-butylcyclohexyl) methyl) -3- [N-methyl-N- [2- (N-methylamino) ethyl] carbamoyloxy] -1,4-naphthoquinone g 2- trans -(4- tert -butylcyclohexyl)methyl/-3- N -methyl- N - (2- (methylamino) ethyl / carbamoyloxy) -1,4-naphthoquinone was added to 20 mL of saturated ether and the solution The mixture was stirred in the dark at room temperature for 90 minutes. The ether was evaporated under reduced pressure to give a yellow oil which was dissolved in ethyl acetate and filtered, and cyclohexane was added to the filtrate resulting in precipitation of the title compound as a yellow powder. 0.43 g, having a melting point greater than 140 ° C (dec.).

Claims (21)

PATENT CLAIMS Compounds of general formula II (II) wherein: R ³ is a C 1 -C 35 hydrocarbyl group optionally substituted by one to five substituents selected from halogen, C 1 -C 6 alkoxy, hydroxy, amino, C 1 -C 4 monoalkylamino or C 1 -C 4 dialkylamino in each alkyl moiety and any dashed bond represents a double bond between positions 2 and 3 of the naphthyl ring, R ³ and R ⁴ are each a group of the formula = O and R is a radical of formula wherein n is 2 or 3 a R ⁶ and R ^7, which may be the same or different, each represents hydrogen, alkyl having 1 to 6 carbon atoms optionally substituted by hydroxyl, alkoxy having 1 to 6 carbon atoms or a group of formula wherein R ⁹ is an alkyl group having 1 to C 6 optionally substituted amino, which is optionally substituted with one or two alkyl groups, or 6 7 R a and R a can each represent a group of the formula O where R 0 represents an alkyl group having 1 to 6 carbon atoms, A represents an oxygen atom or a group of the formula - '- R ⁵ ' -Nwhere R ³ is hydrogen, C 1 -C 6 alkyl optionally substituted by hydroxy, C 1 -C 6 alkoxy or amino optionally substituted by one or two C 1 -C 6 alkyl groups, or R « R is a radical of formula Wherein R ¹⁰ represents an alkyl group having 1 to 6 carbon atoms; R 0 represents a group of the formula R '/ (CH ² ) - N ² ? λ i ₂ Wherein p is 2 or 3 a R ³ · ² · and R ³ · ² are as defined above for R 1 and R ⁷ or when A is a group of the formula R ⁵ \ - n is 2, R ⁵ can be a bond to R ⁶ so that a group of formula R ⁵ N (CH ₂ ) ₂ N forms a piperazine ring, or the dashed line represents a double bond between positions 1, 2 and 3,4 of the naphthyl ring and R ¹ , R ² and R ⁴ are each a group of the formula IN/ C (CH,) ί. π wherein n, A, R ⁶ and R ⁷ are as defined above, and their physiologically acceptable salts. Compounds according to claim 1, wherein R ³ represents a C 1 -C 10 alkyl group, a C 5 -C 7 cycloalkyl group (which may be optionally substituted by a straight or branched C 1 -C 6 alkyl group, a C 1 haloalkyl group) (C 1 -C 6) alkoxy, C 1 -C 6 alkoxy or phenyl, the phenyl itself being optionally substituted by one or more substituents selected from C 1 -C 6 alkyl and halogen) or C ^ _ ^ q alkyl-C5_7 ykloalkyl ^c ou ^o group wherein the cycloalkyl moiety is optionally substituted as defined above for a cycloalkyl group having 5-7 carbon atoms. Compounds according to claim 1 or 2, wherein R ³ is represented by the general formula wherein q is zero or the number 1 and R represents an alkyl group having 1 to 10 carbon atoms. A compound according to claim 1 or 2 wherein R ³ is represented by the general formula wherein r is zero or the number 1 and either R ³ - ⁴ represents a hydrogen atom and R ¹⁵ is selected from halogen, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, arylalkoxy, C 1 -C 6 alkylalkoxy both in the alkyl and alkoxy moiety and in the phenyl moiety substituted with one or more two groups selected from halogen atoms and alkyl groups having 1 to 6 carbon atoms; or ^R14 and ^3-5 are both alkyl of 1 to 6 carbon atoms or phenyl. Compounds according to claim 4, wherein R ³ is 4- (4-chlorophenyl) cyclohexyl group of formula Compounds according to claim 5, wherein R ³ is in trans form with respect to the naphthoquinone ring. Compounds according to claim 7, wherein A represents a group of formula II. -Na R represents a carbamate group. Compounds according to claim 7, wherein R ⁵ , R ⁸ and R ⁷ each represent a hydrogen atom or a C 1 -C 4 alkyl group. Compounds according to claim 8, wherein R ⁵ represents methyl or ethyl, R ⁶ represents hydrogen, methyl or ethyl 7 ₍ Q and R is hydrogen or -CO-OR, wherein R ⁸ is tert-butyl. Compounds according to any one of claims 1 to 10, wherein R ³ to R ⁴ represent a group of formula = O and the dashed line indicates the bond between positions 2 and 3 of the naphthyl ring. Compounds according to claim 1 represented by the general formula III in which 5 6 7 R, R and R 'are as defined above, and physiologically acceptable salts of these compounds. Compounds according to claim 11, which are in the form of a trans isomer. The compound 2- / trans-4- (4-chlorophenyl) cyclohexyl] -3- [N-methyl-N- [2- (methylamino) ethyl] carbamoyloxy] -1,4-naphthoquinone according to claim 11 and physiologically acceptable salts thereof. A hydrochloride monohydrate as a salt of a compound according to claim 13. Compounds according to claim 1 represented by the general formula IV wherein R ¹ , R ⁶ and R ⁷ are as defined above, and their physiologically acceptable salts. The compound 2- (trans- (4-tert-butylcyclohexyl) methyl) -3- [N-methyl-N- [2- (methylamino) ethyl] carbamoyloxy] -1,4-naphthoquinone according to claim 15 and physiologically acceptable salts thereof. A compound of formula (II) or a physiologically acceptable salt thereof for use in therapy. Use of a compound of formula II or a physiologically acceptable salt thereof for the manufacture of a medicament for the treatment and / or prophylaxis of parasitic infections. 19. A pharmaceutical composition comprising a compound of formula II or a physiologically acceptable salt thereof together with one or more pharmaceutically acceptable carriers and optionally other therapeutic and / or prophylactic agents. 20. A dosage unit of a composition comprising a compound of formula II or a physiologically acceptable salt thereof in an amount of from 10 mg to 1 g. 21. A process for the preparation of a compound of formula (II) and a physiologically acceptable salt thereof, which comprises reacting a compound of the formula (II)