WO1993014752A1

WO1993014752A1 - M. fermentans infection treatment

Info

Publication number: WO1993014752A1
Application number: PCT/GB1993/000125
Authority: WO
Inventors: Peter Charles Thomas Hannan; Peter John O'hanlon
Original assignee: SmithKline Beecham Ltd
Current assignee: SmithKline Beecham Ltd
Priority date: 1992-01-22
Filing date: 1993-01-20
Publication date: 1993-08-05
Anticipated expiration: 1994-07-22
Also published as: JPH07503243A; AU3361293A; EP0621778A1; GB9201391D0

Abstract

Certain normonyl derivatives are of use in treating M. fermentans-induced infections.

Description

M. fermentans infection treatment.

This present application relates to a method for treating Mycoplasma fermentans-iaά ceά infections and to compositions for use in such treatment.

Mycoplasma fermentans has in the past been suspected of being a human pathogen, having been occasionally isolated from human urogenital tract, from bone marrow of leukaemic patients, from synovial effusions of rheumatoid patients, as well as from tissue cultures. More recently, AIDS researchers have identified a strain of mycoplasma, since identified as M. fermentans, which it is thought may act as co-factor in the pathogenesis of AIDS (Science, vol 248, 11th May 1990). In addition, these same mycoplasma have been implicated in fulminant infections of non-AIDS patients (Amer. J. Trop. Med., Hyg, 42(5), 1990, 399). The provision of a chemotherapeutic agent with activity against M. fermentans would therefore be of assistance in the treatment of such patients.

Accordingly, the present invention provides a method of treating humans infected with M. fermentans, in particular humans also infected with HIV, which method comprises treating humans in need of such therapy with an anti-mycoplasmal effective amount of a compound of formula (I):

in which R° denotes:

(a) a group R which is a 5-membered heterocyclic group having a 6π-electron system with up to four heteroatoms which may be selected from oxygen, sulphur and nitrogen, and optionally substituted with two substituents R^ and ^ which may be the same or different and is each selected from (Cι_2θ)alkyl, (C2-8)alkenyl, (C3„7)cycloalkyl, aryl(Cι_ g)alkyl, aryl or heterocyclyl, each of which may be optionally substituted; or

(b) a group -COR^ in which R4 denotes an optionally substituted phenyl group. In a further aspect, the invention provides for the use of a compound of formula (I) as hereinbefore defined in the manufacture of a medicament for treating M. fermentans - induced infection.

When used herein, the term 'aryl' includes for example phenyl and naphthyl optionally substituted with up to five, preferably up to three, groups selected from halogen, optionally substituted (Cι_g)alkyl, phenyl,

(Cι_g)alkoxy, halo(Cι_g)alkyl, hydroxy, amino, mono- or di-(Cι_ g)alkylamino, nitro, carboxy, (Cι_g)alkoxycarbonyl, optionally substituted

(Cι_g)alkoxycarbonyl(C-t_.g)alkyl, (Cι_g)alkylcarbonyloxy, (Cχ_ g)alkylcarbonyl, (Cι_g)alkylthio, (Cι_g)alkanesulphinyl, and (Cj.

6)alkanesulphonyl.

When used herein and unless otherwise defined, the term

'heterocyclyl' includes for example single or fused rings comprising up to four hetero-atoms in each ring selected from oxygen, nitrogen and sulphur and optionally substituted with up to three groups. Suitably the heterocyclic ring comprises from 4 to 7 ring atoms, preferably 5 or 6 atoms.

Suitable substituents for 'heterocyclyl' and for heterocyclyl groups specifically named herein are selected from halogen, optionally substituted (Cι_g)alkyl, (C i-.g)alkoxy, halo(C;i-.g)alkyl, hydroxy, amino, mono- or di(C-]_.g)alkylam_no, carboxy, (Cχ.g)alkoxycarbonyl, (C _ g)alkoxycarbonyl(Cι_g)alkyl, aryl or oxo.

When used herein, the term 'halogen' refers to fluorine, chlorine, bromine or iodine.

Suitable substituents for alkyl, alkenyl or cycloalkyl include for example halogen, hydroxy, (Cι_g)alkoxy, carboxy and salts thereof, (C-χ. g)alkoxycarbonyl, carbamoyl, mono- or di(C-i_L.g)alkylcarbamoyl, sulphamoyl, mono- and di-(C-L_g)alkylsulphamoyl, amino, mono- and di-

(Cχ.g)al__ylamino, (Cι.g)acylamino, ureido, (Cι.g)alkoxycarbonylamino,

2,2,2-trichloroethoxy- carbonylamino, aryl, heterocyclyl, oxo, acyl,

2-thenoyl, (Cι.g)alkylthio, arylthio, (Cι.g)alkanesulphinyl, arylsulphinyl,

(Cι.g)alkanesulphonyl, arylsulphonyl, (C-^g)alkoxyimino, hydroxyimino, hydrazono, benzohydroxyimoyl, and 2-thiophenecarbohydroxyimoyl.

Compounds of formula (I) may conveniently be named as

'(l-normon-2-yl)' derivatives. 'Normonyl' is the trivial name for the

3-[(2S,3R,4R,5S)-5-[(2S,4S,5S)-2,3- epoxy-5-hydroxy-4-methylhexyl]-3,4-dihydroxytetrahydro- pyran-2-yl]-2-methylprop-l(E)-enyl radical, as shown in formula (II):

(II)

Suitably R* denotes a group:

in which R^ and R^ are as hereinbefore defined,

X is a divalent group -Y-C=C-, and Y is oxygen or sulphur; for instance an oxazolyl, thiazolyl, isoxazolyl or isothiazolyl, preferably oxazolyl and especially oxazol-2-yl; or a group which is a trivalent, 5-membered heterocyclic group having a 6-π electron system, bonded via carbon, the five ring atoms being either one carbon atom and four atoms selected from carbon and nitrogen, two carbon atoms, two nitrogen atoms and one atom selected from oxygen and sulphur, or four carbon atoms and one atom selected from oxygen and sulphur, and R^ and R^ are as herein before defined and are each substituents on a carbon or nitrogen; for instance, a pyrrolyl, diazolyl, triazolyl, tetrazolyl, oxadiazolyl, thiadiazolyl, furyl and thiophenyl, preferably oxadiazolyl and especially 1,3,4-oxadiazolyl.

Such compounds are disclosed in EP 0 087 953 and EP 0 123 378 (Beecham Group pic).

Preferably, the group R~ denotes a group of the formula:

in which R^ denotes an optionally substituted isoxazol-5-yl, a fur-2-yl, a fur-3-yl or a pyridyl group bonded by a carbon atom thereof to the oxazolyl moiety. Preferred substituents for the isoxazol-5-yl group include (C-j.. g)alkyl, and for the fur-2-yl group include cyano. Example of such compounds are disclosed in EP 0 399 645 and WO 91/09856 (both to Beecham Group pic). Compounds of formula (I) in which R° denotes the group -CO ^ are described in WO 91/09855 (Beecham Group pic).

This invention also provides a pharmaceutical composition which comprises a compound of formula (I) (hereinafter referred to as the 'drug') together with a pharmaceutically acceptable carrier or excipient. The compositions may be formulated for administration by any route, and would depend on the disease being treated. The compositions may be in the form of tablets, capsules, powders, granules, lozenges, liquid or gel preparations, such as oral, topical or sterile parenteral suspensions.

Tablets and capsules for oral administration may be in unit dose presentation form, and may contain conventional excipients such as binding agents, for example syrup, acacia, gelatin, sorbitol, tragacanth, or polyvinyl-pyrollidone; fillers, for example lactose, sugar, maize-starch, calcium phosphate, sorbitol or glycine; tabletting lubricants, for example magnesium stearate, talc, polyethylene glycol or silica; disintegrants, for example potato starch, or acceptable wetting agents such as sodium lauryl sulphate. The tablets may be coated according to methods well known in normal pharmaceutical practice. Oral liquid preparations may be in the form of, for example, aqueous or oily suspensions, solutions, emulsions, syrups or elixirs, or may be presented as a dry product for reconstitution with water or other suitable vehicle before use. Such liquid preparations may contain conventional additives such as suspending agents, for example sorbitol, syrup, methyl cellulose, glucose syrup, gelatin, hydrogenated edible fats; emulsifying agents, for example lecithin, sorbitan monooleate, or acacia; non-aqueous vehicles (which may include edible oils), for example almond oil, fractionated coconut oil, oily esters such as glycerine, propylene glycol, or ethyl alcohol; preservatives, for example methyl or propyl p-hydroxybenzoate or sorbic acid, and if desired conventional flavouring or colouring agents.

For topical application to the skin the drug may be made up into a cream, lotion or ointment. Cream or ointment formulations that may be used for the drug are conventional formulations well known in the art, for example, as described in standard text books of pharmaceutics and cosmetics, such as Harry's Cosmeticology published by Leonard Hill Books, and the British Pharmacopoeia.

Suppositories will contain conventional suppository bases, e.g. cocoa-butters or other glyceride. For parenteral administration, fluid unit dosage forms are prepared utilizing the drug and a sterile vehicle. The drug, depending on the vehicle and concentration used, can be suspended in the vehicle.

Advantageously, adjuvants such as a local anaesthetic, preservative and buffering agents can be dissolved in the vehicle. To enhance the stability the composition can be frozen after filling into the vial and water removed under vacuum. The dry lypophilized powder is then sealed in the vial.

The drug can be sterilised by exposure to ethylene oxide before suspending in the sterile vehicle. Advantageously, a surfactant or wetting agent is included in the composition to facilitate uniform distribution of the drug.

For topical application to the ear, the drug may be made up into a suspension in a suitable liquid carrier, such as water, glycerol, diluted ethanol, propylene glycol, polyethylene glycol or fixed oils. For topical application to the eye, the drug is formulated as a suspension in a suitable, sterile aqueous or non-aqueous vehicle. Additives, for instance buffers such as sodium metabisulphite or disodium edetate; preservatives including bactericidal and fungicidal agents, such as phenylmercuric acetate or nitrate, benzalkonium chloride or chlorhexidine, and thickening agents such as hypromellose may also be included.

The dosage employed for compositions administered topically will, of course, depend on the size of the area being treated. For the ears and eyes each dose will typically be in the range from 10 to 100 mg of the drug.

The compositions may contain from 0.1% to 99% by weight, preferably from 10-60% by weight, of the drug.depending on the method of administration. Where the compositions are in unit dose form, each dosage unit will preferably contain from 50-500 mg, of the drug. The dosage as employed for adult human treatment will preferably range from 100 mg to 3 g, per day, for instance 250 mg to 2 g of the drug per day, depending on the route and frequency of administration.

Biological Data - Compounds of formula (I) selected from those in which R° denotes an 5-substituted oxazol-2-yl or an aryl ketone were found to have geometric mean values in the range of <0.02 to 0.07μg ιrιl^~l when tested against a selection of strains of M. fermentans, where determined after 6 days incubation of the organism on modified Hayflick Agar medium at 37°C.

Claims

The use of a compound of formula (I):

OH

in which R° denotes:

(a) a group R^* which is a 5-membered heterocyclic group having a 6π-electron system with up to four heteroatoms which may be selected from oxygen, sulphur and nitrogen, and optionally substituted with two substituents R^ and ^ which may be the same or different and each is selected from (Cι_2())alkyl, (C2-8)alkenyl, (C3_7)cycloalkyl, aryl(Cι_ g)alkyl, aryl or heterocyclyl, each of which may be optionally substituted; or

(b) a group -COR^ in which R⁴- denotes an optionally substituted phenyl group; in the manufacture of a medicament for treating M. fermentans - induced infection in humans.

2. A use as claimed in claim 1 in which the human subject is also infected with HIV.

3. A use as claimed in claim 1 or 2 in which R^ denotes a group:

in which R^ and R^ are as hereinbefore defined,

Xis a divalent group -Y-C=C-, and Y is oxygen or sulphur; for instance an oxazolyl, thiazolyl, isoxazolyl or isothiazolyl, preferably oxazolyl and especially oxazol-2-yl; or a group which is a trivalent, 5-membered heterocyclic group having a 6-π electron system, bonded via carbon, the five ring atoms being either one carbon atom and four atoms selected from carbon and nitrogen, two carbon atoms, two nitrogen atoms and one atom selected from oxygen and sulphur, or four carbon atoms and one atom selected from oxygen and sulphur, and R^ and R^ are as defined in claim 1 and are each substituents on a carbon or nitrogen.

4. A use as claimed in claim 1 or 2 in which the group R* denotes a group of the formula:

in which R > denotes an optionally substituted isoxazol-5-yl, a fur-2-yl, a fur-3-yl or a pyridyl group bonded by a carbon atom thereof to the oxazolyl moiety.