GB2400033A - Use of fluoroquinolone antibiotics for the treatment of Q fever - Google Patents

Abstract

Use of a compound of formula (I) in the treatment of Q fever and related diseases: <EMI ID=1.1 HE=46 WI=109 LX=522 LY=782 TI=CF> <PC>in which R<1> is a hydrogen atom or a C1-C6 alkyl group, R<2> is a hydrogen atom or a C1-C6 alkoxy group and R<3> is a C1-C6 alkyl, C1-C6 alkenyl, C1-C6 alkynyl group or salt thereof. Alternatively, the use of a compound of formula (II) in the treatment of Q fever and related diseases: <EMI ID=1.2 HE=47 WI=114 LX=481 LY=1771 TI=CF> <PC>in which R<1> is a hydrogen atom or a C1-C6 alkyl group, R<2> is a hydroxyl group, a C1-C6 alkoxy group or an amino group, and R<3> is a is a hydrogen atom, a C1-C6 alkyl, C1-C6 alkenyl, C1-C6 alkynyl, C1-C6 aminoalkyl group or salt thereof.

Description

USE OF FLUOROQUINOLONE ANTIBIOTICS FOR THE TREATMENT OF

Q FEVER.

The present invention is generally concerned with the use of certain fluoroquinolones for the treatment of Q fever.

Q fever is a zoonosis, which is endemic throughout the world. The infectious organism, the rikettsia Coxiella burnetti, (C. burnetti) is an obligate intracellular bacterium found in lice and ticks. Infection in humans, by bite, can be asymptomatic, acute or chronic. Acute Q fever is often associated with atypical pneumonia whilst chronic Q fever often manifests as endocarditis.

C. burnetti has been shown to be susceptible to tetracycline antibiotics, in particular, doxycycline, which form the basis of present treatment of Q fever. A number of recent studies have focused on the possible use of fluoroquinolone antibiotics, which are known to have broad spectrum activity, for the treatment of Q fever and infection by other rickettsia. In particular, so called first generation fluoroquinolones, ofloxacin and pefloxacin have been shown to be effective against C. burnetti in ovo (D. Raoult et al., Antimicrobial Agents and Chemotherapy, 1989, 33, 621-623). First generation fluoroquinolones ciprofloxacin, sparfloxacin, oflaxacin, pefloxacin and levofloxacin have been shown as bacteriostatic at concentrations of 0.5 to 1.0 mg/1 against C. burnetti (Nine Mile strain) in L929 cells (idem, ibid, 1991, 35, 88-91 and 2070-2077; Journal of Antimicrobial Chemotherapy, 1991, 39, 725-730). More recently, minimum inhibitory concentration (MIC) values of 0.5 to 1.0 mg/1 have been reported for the second generation fluoroquinolone, moxifloxacin against acute and chronic disease causing strains of C. burnetti (idem, Antimicrobial Agents and Chemotherapy, 2001, 45, 301-302). In addition a MIC value of 1.0 mg/1 has been reported for trovafloxacin against C. burnetti.

The present invention has found that certain second generation, fluoroquinolones have surprising efficacy against C. burnetti. In particular, it has been surprisingly found to that gatifloxacin is 20 times more effective than ciprofloxacin and ten times more effective than other second generation fluoroquinolones. Further, the efficacy of gatifloxacin approaches that of doxycycline.

The surprising efficacy of these fluoroquinolones offers increased possibilities for the effective treatment of Q fever and other rickettsia infections including the treatment of patients in whom doxycycline or other treatment is contraindicated. Further, they reduce the possibility of doxycycline resistant strains whilst offering alternative treatments therefor or in times of high demand.

The present invention generally aims to provide an alternative, effective treatment of Q fever and other rickettsia infections. The present invention also aims to provide fluoroquinolones suitable for the effective treatment of Q fever and other rickettsia infections.

Accordingly, in one aspect, the present invention provides compounds of formula (I) Rl o (I) in which Ret is hydrogen atom or a Cal to C6 alkyl group, R2 is a hydrogen atom or a Cat to C6 alkoxy group, and R3 is a Cat to C6 alkyl, Cat to C6 alkenyl or C' to C6 alkynyl group or a pharmaceutically acceptable salt thereof in the preparation of a medicament for the treatment of Q fever and other rickettsia diseases.

As used herein the term "C' to C6 alkyl" refers to a branched or straight chain alkyl group having 1 to 6 carbon atoms. Examples include methyl, ethyl, propyl, isopropyl, n-butyl, s-butyl, n-pentyl, neopentyl, n-hexyl and the like. Optionally the groups may be substituted by simple substituents such as a halogen atom (fluorine, chlorine or bromine). Examples include chloromethyl, dichloromethyl, trichloromethyl, trifluoromethyl and the like.

Further, the term "Cal to C6 alkoxy" is used herein to refer to a ROradical where R is a Cal to C6 alkyl group defined above.

As used herein, the term "Cat to C6 alkenyl" means a branched or straight chain group, substituted or unsubstituted, having 1 to 6 carbon atoms and comprising one or more double carbon-carbon bonds. Examples include ethenyl, 2-propenyl, 1-propenyl and the like.

The term "Cat to C6 alkynyl, as used herein, means a branched or straight chain group, substituted or unsubstituted, having I to 6 carbon atoms and comprising one or more triple carbon-carbon bonds. Examples include ethynyl, 2-propynyl, 1-propynyl and the like.

In one embodiment of the present invention, Ret is a hydrogen atom or a methyl group and R2 is a methoxy group. Preferably, R' is a hydrogen atom.

In an alternative embodiment, Rt is a Cat to C6 alkyl group and R2 is a hydrogen atom.

Preferably Ri is a methyl group.

In either embodiment, R3 is preferably a methyl group. It will be apparent that R3 confers on compounds of the present invention an asymmetrically substituted carbon atom at the three position of the 1- piperazinyl ring. The medicaments or compositions of the present invention may, in particular, comprise a racemate or an optically pure stereoisomer. Preferably, the medicament or composition comprises the stereoisomer in which the asymmetric carbon has an S configuration (as determined by the IUPAC standards).

In one specific embodiment of the present invention, the compound of formula (I) is (+/-)-1 -cyclopropyl-6-fluoro- 1,4-dihydro-8-methoxy-7-(3 -methyl- 1 - piperazinyl)-4 oso-3-quinolinecarboxylic acid. This compound, commonly known as gatifloxacin, is commercially available in the form of the sesquihydrate under the name Tequin_ (Bristol Meyers Squibb, New Jersey, USA).

In an alternative specific embodiment of the present invention, the compound of formula (I) is (S)- 1 -cyclopropyl-6-fluoro- 1,4-dihydro-5methyl-7-(3 -methyl- 1 -piper azinyl)-4-oxo-3-quinoline carboxylic acid. This compound, commonly known as grepafloxacin, is commercially available in the form of the hydrochloride salt under the name Raxar_ (Bayer, UK).

In a second aspect, the present invention provides a method of treatment for Q fever and other rickettsia infections comprising the step of administering to a patient in need thereof a pharmaceutically effective amount of a compound of formula (I)

D I

TO r ' J R7 (I) in which R' is hydrogen atom or a Cal to C6 alkyl group, R2 is a hydrogen atom or a C' to C6 alkoxy group, and R3 is a Cal to C6 alkyl, Cat to C6 alkenyl or Cal to C6 alkynyl group or a pharmaceutically acceptable salt thereof.

It is preferred that the method comprises administering a dose of between I mg to 1000 mg of the compound of formula (I) daily. Preferably, the method comprises administering a dose of between 1 to 500 mg daily. Most preferably, the method comprises administering gatifloxacin in a dose of 1 to 500 mg daily.

In a third aspect, the present invention provides a pharmaceutical composition for use in the treatment of Q fever and other rickettsia infections comprising a compound of formula (I) A\ O 3: (I) in which R' is hydrogen atom or a Cal to C6 alkyl group, R2 is a hydrogen atom or a C' to C6 alkoxy group, and R3 is a Cat to C6 alkyl, Cal to C6 alkenyl or Cat to C6 alkynyl group or a pharmaceutically acceptable salt thereof.

The medicarnents or compositions of the present invention may comprise a combination of more than one compound formula (I). Alternatively, compounds of formula (I) may be administered as medicaments or compositions formulated for simultaneous or sequential use thereof. The medicaments or compositions may also comprise a compound of formula (I) and another active agent, such as doxycycline, known for the treatment of Q fever and other rickettsia infections.

The medicaments or compositions of the present invention may comprise a compound of formula (I) in zwitterionic form or in the form of a pharmaceutically acceptable salt. Suitable salts include salts of organic acids, for example acetate, adipate, alginate, aspartate, benzoate, benzene sulphonate, bisulphate, butyrate, camphorate, camphor sulphonate, citrate, carbonate, digluconate, cyclopentane propionate, dodecylsulphate, ethane sulphonate, glucoheptanoate, glycerophosphate, hemisulphate, heptanoate, hexanoate, fumarate, 2-hydroxyethane sulphonate, lactate, maleate, methane sulphonate, nicotinate, 2-napthalene sulphonate, oxalate, palmoate, pectinate, persulphate, 3-phenylpropionate, picrate, pivalate, propionate succinate, tartrate, thiocyanate, p-toluene sulphonate, and salts of inorganic acids such as hydrochloride, hydrobromide, hydroiodide, sulphate, phosphate.

Pharmaceutically acceptable salts may also comprise cations based on the alkali or alkaline earth metals such as sodium, lithium, potassium, calcium, magnesium, aluminium and the like. In addition they may include salts formed by quaternisation of suitable basic nitrogen containing groups with short chain alkyl halides such as methyl, ethyl, propyl and butyl chlorides, bromides or iodides or long chain alkyl halides such as decyl, lauryl, myristyl, and stearyl chlorides, bromides or iodides.

Further, such salts may also be formed from dialkyl sulphonates such as dimethyl, diethyl, dibutyl or diamyl sulphates or from aralkyl halides such as benzyl bromides and the like.

The medicaments or compositions of the present invention may be administered orally, parenterally, sublingually, by inhalation, rectally or topically. They may comprise dosage formulations containing conventional pharmaceutical carriers, adjuvants and other vehicles as desired. Topical administration may involve the use of transdermal patches or ionospheresis devices. The term "parenteral" as used herein includes subcutaneous injection, intravenous, intramuscular, intrasternal injection or infusion techniques. The choice of the method of administration will depend on a number of factors including the nature of the formulation, the strain of the bacterium, the manifestation and severity of the infection, the patient and the like.

It is preferred that the medicament or composition of the present invention is in solid dosage form although liquid dosage forms may also be used. Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules. In such solid dosage forms the fluoroquinolone may be admixed with at least one inert diluent such as sucrose, lactose or starch or mixtures thereof. The dosage forms may also comprise, in accordance with normal practice, additional substances such as lubricating agents, for example, magnesium stearate. For capsules, tablets and pills the dosage forms may also comprise buffer agents. Tablets and pills may also be prepared with enteric coatings.

Liquid dosage forms for oral administration may comprise pharmaceutically acceptable emulsions, solutions, suspensions, syrups and elixirs containing such inert diluents as are common to the art. Such dosage forms may also comprise adjuvants such as wetting agents, emulsifying and suspending agents as well as sweetening, flavour and/or perfume agents.

Injectable preparations may be formulated in accordance with the known art using suitable dispersing or wetting agents and suspending agents. The preparation may be formulated as a sterile injectable solution or suspension in a parenterally acceptable diluent or solvent, for example, as a solution in propanedioVwater (1:3). Acceptable vehicles and solutions include Ringer's solution and isotonic sodium chloride..

Sterile fixed oils, including synthetic mono- or all-glycerides may also be employed as a solvent or suspending medium. Injectable preparations may also include fatty acids, such as oleic acid.

The medicaments and pharmaceutical compositions of the present invention may also include other ingredients necessary to achieve optimum formulation, for example, preservatives, stabilisers, excipients and natural or synthetic lecithins. They may also comprise liposomes derived, for example, from phospholipids or other lipid substances. The liposomes may comprise multi-lamellar, hydrated liquid crystals dispersed in an aqueous medium. Any pharmaceutically acceptable and metabolisable lipid capable of forming liposomes may be used.

In a fourth aspect the present invention provides use of a compound of formula (II) \ R. (II) in which Rat is hydrogen atom or a C' to C6 alkyl group, R2 is a hydroxyl group, a Cal to C6 alkoxy group or an amino group, and R3 is a hydrogen atom or a Cat to C6 alkyl, Cat to C6 alkenyl, Cal to C6 alkynyl, or C' to C6 aminoalkyl group or a pharmaceutically acceptable salt thereof in the preparation of a medicament for the treatment of Q fever and other rickettsia infections.

As used herein the term Cal to C6 aminoalkyl refers to a straight or branched carbon chain radical, having 1 to 6 carbon atoms, in which the terminal part is the amino radical -NR4R5, in which R4 and R5 independently are a hydrogen atom, a Cat to C6 alkyl group or a Cat to C6 ester group.

In a preferred embodiment, R' is a hydrogen atom and R2 is a methoxy group. In this embodiment R3 is preferably a Cal to C6 aminoalkyl group. Still more preferably, the aminoalkyl group is a Cat aminoalkyl and R4 and R5 are both hydrogen atoms.

It will be apparent that compounds according to the fourth aspect of the present invention comprise an asymmetrically substituted carbon atom at the 3 position of the pyrolidinyl ring. In addition the oxime moiety on the pyrolidinyl ring can lead to E, Z diastereoisomers or mixtures thereof. The medicaments or compositions of the present invention may therefore comprise a mixture of stereoisomers and in particular 15, a racemate of E, Z diastereoisomers or a racemate of a single E or Z diastereoisomer.

Preferably, the medicaments or compositions comprise a single optically pure stereoisomer. Still more preferably, the medicaments or compositions comprise an optically pure Z stereosiomer in which the asymmetric carbon atom has a S configuration (as determined by the IUPAC standards).

In one specific embodiment of the present invention, the compound of formula (II) is (+/-) 7-[3-(aminomethyl)-4-oxo- 1 -pyrolidinyl]- 1 -cyclopropyl-6-fluoro- 1,4-dihydro-4- oxo-1,8-napththyridine-3-carboxylic acid, 74-(Z)-(O-methyloxime). This compound, commonly known as gemifloxacin, is commercially available under the trade name FactiveTM (Smith Kline Beecham, UK) as a mesylate salt.

In a fifth aspect the present invention provides a method of treatment of Q fever and other rickettsia infections comprising the step of administering to a patient in need thereof a pharmaceutically effective amount of a compound of formula (II) Al R\ MEL R3 (II) in which Ret is hydrogen atom or a Cal to C6 alkyl group, R2 is a hydroxyl group, a Cat to C6 alkoxy group or an amino group, and R3 is a hydrogen atom or a Cal to C6 alkyl, Cal to C6 alkenyl, Cal to C6 alkynyl Cat to C6 aminoalkyl group or a pharmaceutically acceptable salt thereof.

In a sixth aspect, the present invention provides for a pharmaceutical composition for the treatment of Q fever and other rickettsia infections comprising a pharmaceutically effective amount of a compound of formula (II) R. (II) in which R' is hydrogen atom or a Cal to C6 alkyl group, R2 is a hydroxyl group, a C' to C6 alkoxy group or an amino group, and R3 is a hydrogen atom or a Cal to C6 alkyl, Cat to C6 alkenyl, Cal to C6 alkynyl or Cal to C6 arninoalkyl group or a pharmaceutically acceptable salt thereof.

It will be understood that the medicaments or compositions of the present invention comprising compounds of formula (II) may be formulated or used as described for compounds of formula (I).

The present invention is illustrated by reference to the following examples: Materials and Methods C. burnetti strain Nine Mile, a strain associated with acute Q fever in humans, was obtained from the American Type Culture Collection (ATCC) and inoculated into yolk sacs of 6 day old embryonated hen eggs under the Association for Classifiation of Dangerous Pathogens (ACDP) containment level 3 conditions. When 50% mortality had occurred (9 days post inoculation), yolk sacs from surviving eggs were harvested. The yolk sacs were homogenized in sterile phosphate buffered saline (PBS, pH 7.4) and pooled to create a 30% v/v homogenate stock. All stocks were aliquoted and frozen at-70 C.

Tissue culture flasks (12.5 cm2) were primed with 4.5 ml of Vero cells suspended in Leibovitz (L15) growth medium (Gibco Lid), with 5% foetal calf serum (FCS) at 5.0 x 105 cells per ml. The mixture was incubated overnight at 37 C to achieve confluent cell growth. The incubation medium was then replaced with 200,ul of C. burnetti containing yolk sac homogenate at 10- dilution in sterile PBS. After incubation for lh at 37 C, the inoculum was removed and the cells were twice washed with 4.0 ml PBS. A L15 medium (2% FCS) was added and the flasks incubated at 37 C for 10 mine prior to assay.

Similar control flasks were prepared except that the inoculation step was omitted or a non-infected egg homogenate was used.

An immunofluorescent assay (IFA, Maurin et al., Journal of Antimicrobial Chemotherapy, 1997, 45, 301-302) was used to confirm that the cells had become enlarged through incorporation of C. burnetti. The monolayer of cells was broken up by the addition of 1% trypsin-EDTA. Aliquots of the resulting suspension (501) were dotted on microscope slides, excess liquid removed after lOs and the cells air dried and fixed in acetone (at -20 C) for 10 mine. Rabbit anti-C. burnetti serum was added to the cells at 1/100 dilution PBS and incubated at 37 C for lh. After washing three times in PBS, goat anti-rabbit immunoglobulin (Sigma, UK) was added at 1/1000 dilution in PBS with Evans blue and incubated at 37 C for Ih. The cells were subsequently viewed using fluorescent microscopy.

Extracellular C. burnetti was detected in culture supernatants from flasks inoculated with 10- dilution of stock 3 days post inoculation. Intracellular C. burnetti was detected only from day 4 onwards.

Condonation of infection of the cells was also confirmed using scanning and transmission electron microscopy. Glutaraldehyde (I ml of a 2.5% solution w/v) was added to each flask and the mixture incubated at 37 C for 30 mine. After removal of the supernatant the cell sheet was scaped off and suspended in I ml of a 2.5% glutaraldehyde solution for 4 h at 48OC. The cells were pelleted by gentle centrifugation (500 g for 15 mine.) and resuspended in 0.1 M phosphate buffer (pH 7.0) at room temperature for 4 h. Samples were post fixed in 1% osmium tetroxide in phosphate buffer (pH 7.0) at room temperature for 4 h. The cells were then dehydrated through a graded ethanol series and embedded in araldite resin. Ultra-thin sections of the impregnated resin were prepared, stained with uranium and lead salts and examined under a Phillips CM100 transmission electron microscope operating at 80kV.

Scanning electron microscopy was performed by fixation of cells grown as before in shell vials containing 2 ml L15 media (Gipco Ltd). The cells were fixed and dehydrated as described before and air dried with hexamethyldisilazane. The cells were mounted on SEM stubs, coated with gold by ion beam sputtering and examined under a Phillips XL30FEG scanning electron microscope.

Enlarged rounded Vero cells were observed 8 days post infection using scanning electron microscopy. Transmission electron microscopy confirmed intracellular C. burnetti.

Stock solutions (lmg/ml) of antibiotics, including compounds of the present invention, were prepared in sterile PBS (pH 7.4) and diluted to the required concentration in L15 media (Gibco Ltd) for susceptibility studies.

Antibiotic susceptibility was examined by preparing infected cells as described above except that the final step involved the addition of the L15 medium (2% FCS) containing the test antibiotic in concentrations ranging from 0.001 to 8 mg/1 and incubating at 37 C for 6 days.

At 6 days post infection, the flasks were viewed by phase contrast microscopy (Olympus). Enlarged, infected cells were counted using an eyepiece graticule at 100 times magnification, which gave a defined field of view (FV). The number of infected cells was counted per FV. Ten FVs were counted per flask in a set pattern: three FVs across the top, four across the middle and three across the bottom of the flask. A mean number of infected cells per FV was then derived.

Examples 1 to 3 and Comparative Examples The activity of eight antibiotics was determined by inspection of the number of cells compared to controls after addition of a predetermined concentration of antibiotic stock solution using phase contrast microscopy. Table 1 summarises the results obtained with three embodiments of the present invention compared to those obtained for antibiotics known as bacteriostatics for C. bur7etti. The mean number of infected cells in the antibiotic treated groups is expressed in Table 1 as a percentage of infected cells in non- antibiotic treated controls for a particular concentration.

The minimum inhibitory concentration (MIC) of an antibiotic is defined as the lowest antibiotic concentration in the incubation medium which inhibits intracellular growth of C. burnetti (determined by the presence of enlarged cells) to less than or equal to 10% of the antibiotic free control. Each experiment was carried out in duplicate.

As may be seen, gatifloxacin (Compound 3) has a surprising low MIC value (0.1 mg/1) and has the lowest number of infected cells in all concentrations compared to the other fluoroquinolones tested. Thus gatifloxacin is at least 20 times active as ciprofloxacin (2.0 mg/1). Grepafloxacin (Compound 1) and gemifloxacin (Compound 2) have a MIC value (1.0 mg/1) at least two times lower than ciprofloxacin.

Antibiotic Concentration (mall) | 8.0 4.0 2.0 1.0 0.5 0.1 0.05.01.005.00 Doxycycline 0 0 0 0 0 0 25 85 Ciprofloxacin 0 7 41 48 83 90 Trovafloxacin 0 0 23 39 52 Moxifloxacin 0 0 24 42 46 52 Azimthromycin 38 34 16 23 51 39 56 40 Compound 1 0 0 12 29 43 63 (Grepafloxacin) Compound 2 0 2 17 46 59 52 (Gemifloxacin) Compound 3 0 0 2 32 38 27 (Gatifloxacin)

Table 1

Claims (33)

1. Use of a compound of formula (I)

R R3

in which Ret is hydrogen atom or a C' to C6 alkyl group, R2 is a hydrogen atom or a C' to C6 alkoxy group, and R3 is a C, to C6 alkyl, C, to C6 alkenyl, or C, to C6 alkynyl group or a pharmaceutically acceptable salt thereof in the preparation of a medicament for the treatment of Q fever and related diseases.

2. Use according to Claim 1, in which Ret is a methyl group and R2 is a methoxy group.

3. Use according to Claim 1, in which Rat is a Cat to C6 alkyl group and R2 is hydrogen atom.

4. Use according to Claim 3, in which R' is a methyl group.

5. Use according to any preceding Claim, in which R3 is a methyl group.

6. Use according to Claim 5, in which the compound is the S stereoisomer.

7. A method of treatment for Q fever and other rickettsia infections comprising the step of administering to a patient in need thereof a pharmaceutically effective amount of a compound of formula (I) OF = LOU (I) in which R' is hydrogen atom or a C, to C6 alkyl group, R2 is a hydrogen atom or a Cal to C6 alkoxy group, and R3 is a C, to C6 alkyl, C, to C6 alkenyl or C, to C6 alkynyl group or a pharmaceutically acceptable salt thereof.

8. A method according to Claim 7, in which R' is a methyl group and R2 is a methoxy group.

9. A method according to Claim 7, in which Ret is a Cal to C6 alkyl group and R2 is hydrogen atom.

10. A method according to Claim 9, in which Ret is a methyl group.

1 1. A method according to any of Claims 7 to 10, in which R3 is a methyl group.

12. A method according to Claim 11, in which the compound is the S stereoisomer.

13. A pharmaceutical composition for use in the treatment of Q fever and other rickettsia infections comprising a compound of formula (I) 81 o F "LR (I) in which R' is hydrogen atom or a C, to C6 alkyl group, R2 is a hydrogen atom or a Cal to C6 alkoxy group, and R3 is a Cal to C6 alkyl, C, to C6 alkenyl or Cal to C6 alkynyl group or a pharmaceutically acceptable salt thereof.

14. A composition according to Claim 13, in which R' is a methyl group and R2 is a methoxy group.

15. A composition according to Claim 13, in which R' is a C, to C6 alkyl group and R2 is hydrogen atom.

16. A composition according to Claim 15, in which Rat is a methyl group.

17. A composition according to any of Claims 13 to 16, in which R3 is a methyl group.

18. A composition according to Claim 17, in which the compound is the S stereoisomer.

19. Use of a compound of formula (II) Rat H R3 (II) in which Ret is hydrogen atom or a C' to C6 alkyl group, R2 is a hydroxyl group, a Cat to C6 alkoxy group or an amino group, and R3 is a hydrogen atom or a C' to C6 alkyl group. Cat to C6 alkenyl, C' to C6 alkynyl or Cal to C6 aminoalkyl group or a pharmaceutically acceptable salt thereof in the preparation of a medicament for the treatment of Q fever.

20. Use according to Claim 19, in which Rt is a hydrogen atom and R2 is a methoxy group.

21. Use according to Claim 19 or Claim 20, in which R3 is a Cal to C6 aminoalkyl group.

22. Use according to Claim 21, in which R3 is art aminomethyl group.

23. Use according to any of Claims 19 to 22, in which the compound comprises the S stereoisomer.

24. A method of treatment of Q fever and other rickettsia infections comprising the step of administering to a patient in need thereof a pharmaceutically effective amount of a compound of formula (II) (II) in which Rt is hydrogen atom or a C' to C6 alkyl group, R2 is a hydroxyl group, a C' to C6 alkoxy group or an amino group, and R3 is a hydrogen atom or a Cal to C6 alkyl, C' to C6 alkenyl, Cat to C6 alkynyl Cal to C6 aminoalkyl group or a pharmaceutically acceptable salt thereof.

25. A method according to Claim 24, in which Rat is a hydrogen atom and R2 is a methoxy group.

26. A method according to Claim 24 or Claim 25, in which R3 is a Cat to C6 aminoalkyl group.

27. A method according to Claim 26, in which R3 is an aminomethyl group.

28. A method according to any of Claims 24 to 27, in which the compound comprises the S stereoisomer.

29. A pharmaceutical composition for the treatment of Q fever and other rickettsia infections comprising a pharmaceutically effective amount of a compound of formula (II) 1 to Rip BILL (II) in which Ret is hydrogen atom or a Cat to C6 alkyl group, R2 is a hydroxyl group, a Cat to C6 alkoxy group or an amino group, and R3 is a hydrogen atom or a Cat to C6 alkyl, C, to C6 alkenyl, Cal to C6 alkynyl or Cat to C6 aminoalkyl group or a pharmaceutically acceptable salt thereof.

30. A composition according to Claim 29, in which R' is a hydrogen atom and R2 is a methoxy group.

31. A composition according to Claim 29 or Claim 30, in which R3 is a Cal to C6 aminoalkyl group.

32. A composition according to Claim 31, in which R3 is an aminomethyl group.

33. A composition according to any of Claims 29 to 32, in which the compound comprises the S stereoisomer.