GB2522029A

GB2522029A - Compounds

Info

Publication number: GB2522029A
Application number: GB1400366.9A
Authority: GB
Inventors: Dr Avninder S Bhambra; Dr Randolph R J Arroo; Dr Ketan C Ruparelia; Dr Kenneth J M Beresford
Original assignee: De Montfort University
Current assignee: De Montfort University
Priority date: 2014-01-09
Filing date: 2014-01-09
Publication date: 2015-07-15
Also published as: GB201400366D0

Abstract

Chalcone analogues and derivatives for use in the prevention and/or treatment of sleeping sickness, also known as Human African trypanosomiasis (HAT), African lethargy or Congo trypanosomiasis. The chalcone compounds disclosed therein have activity against the pathogens responsible for sleeping sickness but also have very low levels of toxicity unlike prior art compounds.

Description

Compounds

Field of the Invention

The present invention relates to chalcone analogues and derivatives and their use in the prevention and/or treatment of sleeping sickness, also known as Human African trypanosomiasis (HAT), African lethargy or Congo trypanosomiasis.

Background of the Invention

The burden of neglected tropical diseases (NTD's), termed due to an unprofitable market for most major pharmaceutical companies represent multiple parasitic, bacterial and viral pathogens affecting over one billion people worldwide. Leading public bodies such as the World Health Organization (WHO) have continuously strategised efforts to reduce the negative impact of NTD's imposed on world health, social and economic areas, by investing in scientific research and development in attempts to generate novel, safe and economically favourable chemotherapeutics, currently severely lacking due to reasons including emerging resistance, high toxicity and unfavourable administration regimens.

Sleeping sickness, also known as Human African trypanosomiasis (HAT), is a fatal parasitic disease caused by trypanosomes. The pathogens responsible for sleeping sickness on the African continent include Ttypanosoma bruce! rhodesiense (Tbr) and Tiypanosoma bruce! gambiense (T.b.g). Infection occurs in a bi-stage process encompassing (1) the haemolymphatic phase and (2) the advanced neurological phase from which patient recovery is unlikely. At present, seventy million people are at risk, with an estimated infection population of seventy thousand.

Treatment options for sleeping sickness are scarce, highly toxic, no longer effective or very difficult to administer, particularly for the advanced fatal second stage of the disease.

Pentamidine is currently used in the treatment of the first stage of T.b.g sleeping sickness and Suramin is used in the treatment of the first stage of T.b.r sleeping sickness. The treatment of the second stage of the disease includes melarsoprol, which is highly toxic due to its arsenic-based structure, and can lead to reactive encephalopathy which proves fatal in up to 10% of patients. Furthermore, the pathogens responsible for sleeping sickness have shown increasing resistance against melarsoprol, making them less effective. Eflornithine is the most recent clinically registered antiprotozoal drugs (1990) for the treatment of the second stage of sleeping sickness. However, this drug is only effective against T.b.g., and the regimen for administration can be strict and difficult to apply.

Accordingly, there is a need for safer, more effective compounds for the treatment and/or prevention of sleeping sickness that address the above disadvantages. The present invention therefore provides novel chalcone analogues and derivatives that are not only active against the pathogens responsible for sleeping sickness, but more importantly, show very low toxicity levels.

Summary of the Invention

A first aspect of the invention provides a compound of Formula (I) or a pharmaceutically acceptable salt thereof Formula (I) for use in the prevention and/or treatment of sleeping sickness, wherein rings A and B are independently an optionally substituted aryl or an optionally provided that at least one of rings A and B is an optionally substituted monocyclic heteroaryl.

In certain embodiments, ring A is an optionally substituted monocyclic heteroaryl and ring B is an optionally substituted aryl. In another embodiment, ring A is an optionally substituted aryl and ring B is an optionally substituted monocyclic heteroaryl. In a further embodiment, ring A is an optionally substituted monocyclic heteroaryl and ring B is an optionally substituted heteroaryl. In yet another embodiment, ring A is an optionally substituted heteroaryl and ring B is an optionally substituted monocyclic heteroaryl.

In a preferred embodiment, ring A is an optionally substituted monocyclic heteroaryl having 5 or 6 ring atoms, at least one ring atom being a heteroatom selected from 0, N or Sand ring B is an optionally substituted aryl having 6 to 10 carbon atoms.

In certain embodiments, ring A and/or ring B may optionally be substituted by one or more substituents independently selected from the group consisting of halo, aliphatic, alkoxy, carbonyl, alkylamino (monoalkylamino or dialkylamino), -NH2, -NO2, -OH, -000H, -ON, hydroxyalkyl, alkylcarbonyloxy, alkoxycarbonyl, alkylcarbonyl, alkylsulfonylamino or two adjacent substituents on the ring, taken together with the intervening ring atoms, form an optionally substituted fused 3 to 8 membered non-aromatic ring having 0 to 3 ring heteroatoms selected from the group consisting of 0, N and S. Preferred substituents include halo, alkoxy, carbonyl, -NH2, NO2, -OH or -ON, preferably halo or alkoxy, and most preferably halo.

In certain embodiments, at least one of rings A and B is an optionally substituted monocyclic heteroaryl, wherein at least one ring atom is N. Preferably at least one of rings A and B is an optionally substituted pyridine, more preferably ring A is an optionally In some embodiments, ring A is an optionally substituted monocyclic heteroaryl, wherein at least one ring atom is N, and ring B is an optionally substituted aryl. In other embodiments, ring A is an optionally substituted aryl, and ring B is an optionally substituted monocyclic heteroaryl wherein at least one ring atom is N. In certain embodiments, ring A is an optionally substituted monocyclic heteroaryl, wherein at least one ring atom is N, and ring B is a substituted aryl. In other embodiments, ring A is a substituted aryl, and ring B is an optionally substituted monocyclic heteroaryl wherein at least one ring atom is N. In yet fuither embodiments, ring A is an optionally substituted pyridine and ring B is an In a fuither embodiment, ring A is an optionally substituted pyridine and ring B is a In a further embodiment, ring A is an optionally substituted pyridine and ring B is an aryl substituted by one or more substituents independently selected from the group consisting of halo, aliphatic, alkoxy, carbonyl, alkylamino (monoalkylamino or dialkylamino), -NH2, -NO2, -OH, -COOH, -ON, hydroxyalkyl, alkylcarbonyloxy, alkoxycarbonyl, alkylcarbonyl, alkylsulfonylamino or two adjacent substituents on the ring, taken together with the intervening ring atoms, form an optionally substituted fused 3 to 8 membered non-aromatic ring having 0 to 3 ring heteroatoms selected from the group consisting of 0, N and S. Preferred substituents include halo, alkoxy, carbonyl, -NH2, NO2, -OH or -CN, preferably halo, alkoxy or-OH, and most preferably halo.

In certain particular embodiments, the compound of Formula (I) is selected from: cTro Compound 1 Compound 2 H3 Br Compound 3 Compound 4 00CH3 Compound 5 Compound 6 0 r#voI1:r: Compound 7 Compound 8 NIIII'iIIIII Br Br Compound 9 Compound 10 Compound 11 Compound 12 Compound 13 Compound 14 Q0o:r Q0c: Compound 15 Compound 16

O CYO

Compound 17 Compound 18 In a preferred embodiment, the compound of Formula (I) is selected from:

O

Compound 2 Compound 4 Compound 7 Compound 8 N1IIJ''1uI1J Br B Compound 9 Compound 11 QOocI Compound 12 Compound 13 oOcc> Compound 14 Compound 16 O QOo Compound 17 Compound 18 A second aspect of the invention provides a compound of Formula (II) or a pharmaceutically acceptable salt thereof R2 Formula (II) for use in the prevention and/or treatment of sleeping sickness, wherein R1 and R2 together with the intervening atoms form a five or six membered optionally substituted heteroaryl or optionally substituted heterocycle; and rings A and B are independently an optionally substituted aryl or an optionally provided that at least one of rings A and B is an optionally substituted monocyclic heteroaryl.

In a preferred embodiment, ring A is an optionally substituted monocyclic heteroaryl having 5 or 6 ring atoms, at least one ring atom being a heteroatom selected from 0, N or Sand ring B is an optionally substituted awl having 6 to 10 carbon atoms.

In certain embodiments, ring A and/or ring B may optionally be substituted by one or more substituents independently selected from the group consisting of halo, aliphatic, alkoxy, carbonyl, alkylamino (monoalkylamino or dialkylamino), -NH2, -NO2, -OH, -COOH, -CN, hydroxyalkyl, alkylcarbonyloxy, alkoxycarbonyl, alkylcarbonyl, alkylsulfonylamino or two adjacent substituents on the ring, taken together with the intervening ring atoms, form an optionally substituted fused 3 to 8 membered non-aromatic ring having 0 to 3 ring heteroatoms selected from the group consisting of 0, N and S. Preferred substituents include halo, alkoxy, carbonyl, -NH2, NO2, -OH or -CN, preferably halo or alkoxy, and most preferably halo.

In certain embodiments, at least one of rings A and B is an optionally substituted monocyclic heteroaryl, wherein at least one ring atom is N. Preferably at least one of rings A and B is an optionally substituted pyridine, more preferably ring A is an optionally In some embodiments, ring A is an optionally substituted monocyclic heteroaryl, wherein at least one ring atom is N, and ring B is an optionally substituted aryl. In other embodiments, ring A is an optionally substituted aryl, and ring B is an optionally substituted monocyclic heteroaryl wherein at least one ring atom is N. In certain embodiments, ring A is an optionally substituted monocyclic heteroaryl, wherein at least one ring atom is N, and ring B is a substituted aryl. In other embodiments, ring A is a substituted aryl, and ring B is an optionally substituted monocyclic heteroaryl wherein at least one ring atom is N. In yet further embodiments, ring A is an optionally substituted pyridine and ring B is an In a further embodiment, ring A is an optionally substituted pyridine and ring B is a In a further embodiment, ring A is an optionally substituted pyridine and ring B is an aryl substituted by one or more substituents independently selected from the group consisting of halo, aliphatic, alkoxy, carbonyl, alkylamino (monoalkylamino or dialkylamino), -NH2, -NO2, -OH, -COOH, -ON, hydroxyalkyl, alkylcarbonyloxy, alkoxycarbonyl, alkylcarbonyl, alkylsulfonylamino or two adjacent substituents on the ring, taken together with the intervening ring atoms, form an optionally substituted fused 3 to 8 membered non-aromatic ring having 0 to 3 ring heteroatoms selected from the group consisting of 0, N and S. Preferred substituents include halo, alkoxy, carbonyl, -NH2, NO2, -OH or -ON, preferably halo, alkoxy or-OH, and most preferably halo.

In certain embodiments, R1 and R2 together with the intervening atoms form a five or six membered optionally substituted heteroaryl. In a preferred embodiment, R1 and R2 together with the intervening atoms form a five or six membered optionally substituted heteroaryl, wherein at least one ring atom is N. In a particularly preferred embodiment, R1 and R2 together with the intervening atoms form a pyrimidine, pyrimidine, pyridine, pyridone or pyrazole.

In certain particular embodiments, the compound of Formula (II) has the structures:

NN

Formula (hA)

H N N

Formula (IIB) Formula (IIC) 0 Formula (lID) Formula (lIE) wherein rings A and B are as defined above and R3 is selected from the group consisting of halo, optionally substituted aliphatic, alkoxy, optionally substituted aryl, optionally substituted heteroaryl, alkylamino (monoalkylamino or dialkylamino), -NH2, -NO2, -OH, - 000H, -CN, hydroxyalkyl, alkylcarbonyloxy, alkoxycarbonyl, alkylcarbonyl or alkylsulfonylamino.

In preferred embodiments, R3 is selected from halo, optionally substituted aliphatic, alkoxy, optionally substituted aryl, optionally substituted heteroaryl, preferably halo, aliphatic or phenyl.

The compounds of Formula (II) may be obtained by modification of the o,13-unsaturated moiety of the compounds according to Formula (I), and can therefore be considered as derivatives of the compounds of Formula (I). In particular, a compound of Formula (II) may be obtained by addition and/or cyclisation across the o,-unsaturated moiety of the compound of Formula (I).

A third aspect of the invention provides a pharmaceutical composition comprising a compound or a pharmaceutically acceptable salt thereof of any of the first or second aspects of the invention, optionally together with a pharmaceutically acceptable excipient.

A fourth aspect of the invention provides a compound or a pharmaceutically acceptable salt thereof of any of the first or second aspects of the invention or a pharmaceutical composition of the third aspect of the invention for use in preventing and/or treating sleeping sickness.

A fifth aspect of the invention provides a compound or a pharmaceutically acceptable salt thereof of any of the first or second aspects of the invention or a pharmaceutical composition of the third aspect of the invention for use as an active agent against Tiypanosoma brucei rhode.siense (T.b.r) and Trypanosoma brucei gambiense (T.b.g), preferably against Tnjpanosoma brucei gambiense (T.b.g).

A sixth aspect of the invention provides a method for preventing and/or treating sleeping sickness which comprises administering to a subject in need thereof an effective amount of a compound or a pharmaceutically acceptable salt thereof or a pharmaceutical composition as defined herein.

Detailed Description of the Invention

The meanings of terms used in the specification of the present application will be explained below, and the present invention will be described in detail.

The compounds of the present invention are provided for the prevention and/or treatment of sleeping sickness. In particular the compounds of the present invention are active against Tiypanosoma brucei rhodesiense (Tb.,) and Te'ypanosoma brucei gambiense (T.b.g), which are known pathogens which cause sleeping sickness. In a preferred embodiment, the compounds of the present invention are active against Ttypanosoma brucei rhodesiense (T.b.r).

Compounds of the invention, when used for preventing or treating a disease, may be administered in an "effective amount". By an "effective amount" it is meant a "therapeutically effective amount", namely an amount of compound sufficient, upon single dose or multiple dose administration, to cause a detectable decrease in disease severity, to prevent advancement of a disease or alleviate disease symptoms beyond that expected in the absence of treatment.

Compounds of the invention are useful for reducing the severity of symptoms of sleeping sickness. Compounds of the invention are also useful for administration to patients susceptible to, at risk of or suffering from sleeping sickness. Compounds useful for the prevention of sleeping sickness are not required to absolutely prevent occurrence of the disorder in all cases, but may prevent or delay onset of the disorder when administered to a patient susceptible to or at risk of the disorder.

The term "halogen" or "halo" as used herein means fluorine, chlorine, bromine, iodine and the like, preferably bromine, fluorine or chlorine, and more preferably bromine.

The term "aliphatic" as used herein refers to a straight or branched chain hydrocarbon which is completely saturated or contains one or more units of unsaturation. Thus, aliphatic may be alkyl, alkenyl or alkynyl, preferably having 1 to 12 carbon atoms, up to 6 carbon atoms or up to 4 carbon atoms.

The term "alkyl" as used herein refers to a straight or branched chain alkyl group.

Preferably, an alkyl group as referred to herein is a C112 alkyl group. More preferably, an alkyl group as referred to herein is a lower alkyl having 1 to 6 carbon atoms. The alkyl group therefore has 1, 2, 3, 4, 5 or 6 carbon atoms. Specifically, examples of "a lower (C1 ) alkyl" include methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, n-pentyl, 1, 1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1 -ethylpropyl, n- hexyl, 1 -ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1 -ethylbutyl, 1-methylbutyl, 2- methylbutyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl and the like.

The term "alkoxy" as used herein refers to an oxy group that is bonded to an alkyl group as defined herein. An alkoxy is preferably a "C1.12 alkoxy group", more preferably a "C1.10 alkoxy group", even more preferably a "01.8 alkoxy group" and even more preferably a "O.

6 alkoxy group".

The term "carbocycle" as used herein refers to a saturated or partially unsaturated cyclic group having 3 to 8 ring carbon atoms. A carbocycle is preferably a "cycloalkyl", which as used herein refers to a fully saturated hydrocarbon cyclic group. Preferably, a cycloalkyl group is a C3-C6 cycloalkyl group.

The term "heterocycle" as used herein refers to a saturated or partially unsaturated cyclic group having, in addition to carbon atoms, one or more heteroatoms selected from 0, N and S. A heterocycle preferably has 3 to 7 ring atoms, and more preferably has 5 or 6 ring atoms.

The term "haloalkyl" as used herein refers to an alkyl group as described above, substituted with one or more halogen atom(s), preferably 1, 2 or 3 halogen atom(s).

Preferably, a haloalkyl is a 01.6 haloalkyl. Specifically, examples of a "01.6 haloalkyl" include fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, difluroethyl, trifluoroethyl, chloromethyl, bromomethyl, iodomethyl and the like, preferably trifluoromethyl.

The term "aryl" as used herein refers to a monocyclic or bicyclic aromatic ring having 6 to 14 carbon atoms, preferably 6 to 10 carbon atoms. Preferably, an awl is phenyl.

The term "heteroaryl" as used herein refers to a monocyclic or bicyclic aromatic ring system having 5 to 14 ring atoms, at least one ring atom being a heteroatom selected from 0, N or S. Preferably a heteroaryl is a monocyclic or bicyclic aromatic ring system having 5 to 10 ring atoms, at least one ring atom being a heteroatom selected from 0, N or S. Preferably a monocyclic heteroaryl is an aromatic ring system having 5 to 7 ring atoms, at least one ring atom being a heteroatom selected from 0, N or S. Preferably, a monocyclic heteroaryl is an aromatic ring system having 5 or 6 ring atoms, at least one ring atom being N. An aryl, heteroaryl, carbocycle or heterocycle group as referred to herein may be unsubstituted or may be substituted by one or more substituents independently selected from the group consisting of halo, aliphatic, alkoxy, carbonyl, alkylamino (monoalkylamino or dialkylamino), -NH2, -NO2, -OH, -000H, -ON, hydroxyalkyl, alkylcarbonyloxy, alkoxycarbonyl, alkylcarbonyl or alkylsulfonylamino. Preferred substituents include halo, lower alkyl, -NH2, NO2, -OH or -CN, preferably halo. In some embodiments, two adjacent substituents on the aryl, heteroaryl, carbocycle or heterocycle group, taken together with the intervening ring atoms, form an optionally substituted fused 3 to 8 membered non-aromatic ring having 0 to 3 ring heteroatoms selected from the group consisting of 0, N and S. In preferred embodiments, two adjacent substituents on the aryl, heteroaryl, carbocycle or heterocycle group, taken together with the intervening ring atoms, form an optionally substituted fused 5 or 6 mernbered non-aromatic ring having 1 to 3 ring heteroatoms selected from the group consisting of 0, N and S. In particularly preferred embodiments, two adjacent substituents on the aryl, heteroaryl, carbocycle or heterocycle group, taken together with the intervening ring atoms, form an optionally substituted fused orS membered non-aromatic ring having 1 to 3 N atoms.

An aliphatic group or a haloalkyl group as referred to herein may be unsubstituted or may independently be substituted with aryl, heteroaryl, carbocycle, heterocycle or with any one or more of the substituents listed above for aryl, heteroaryl, carbocycle or heterocycle groups.

The terms "alkylaryl" and "alkylheteroaryl" as used herein refers to an alkyl group as defined above substituted with an aryl or heteroaryl group as defined above. The alkyl component of an "alkylaryl" or "alkylheteroaryl" group may be substituted with any one or more of the substituents listed above for an aliphatic group and the awl or heteroaryl component of an "alkylaryl" or "alkylheteroaryl" group may be substituted with any one or more of the substituents listed above for aryl, heteroaryl, carbocycle or heterocycle groups. Preferably, alkylaryl is benzyl.

In compounds of the invention, one or more asymmetric carbon atoms may be present. For such compounds, the invention is understood to include all isomeric forms (e.g. enantiomers and diastereoisomers) of the compounds as well as mixtures thereof, for example racemic mixtures.

The compounds of the invention may be provided as the free compound or as a suitable salt or hydrate thereof. Salts should be those that are pharmaceutically acceptable and salts and hydrates can be prepared by conventional methods, such as contacting a compound of the invention with an acid or base whose counterpart ion does not interfere with the intended use of the compound. Examples of pharmaceutically acceptable salts include hydrohalogenates, inorganic acid salts, organic carboxylic acid salts, organic sulfonic acid salts, amino acid salt, quaternary ammonium salts, alkaline metal salts, alkaline earth metal salts and the like.

The compounds of the invention can be provided as a pharmaceutical composition. The pharmaceutical composition may additionally comprise a pharmaceutically acceptable excipient for example a pharmaceutically acceptable carrier and/or a pharmaceutically acceptable diluent. Suitable carriers and/or diluents are well known in the art and include pharmaceutical grade starch, mannitol, lactose, magnesium stearate, sodium saccharin, talcum, cellulose, glucose, sucrose (or other sugar), magnesium carbonate, gelatin oil, alcohol, detergents, emulsifiers or water (preferably sterile).

A pharmaceutical composition may be provided in unit dosage form, will generally be provided in a sealed container and may be provided as part of a kit. Such a kit would normally (although not necessarily) include instructions for use. It may include a plurality of said unit dosage forms.

A pharmaceutical composition may be adapted for administration by any appropriate route, for example by the oral (including buccal or sublingual), rectal, nasal, topical (including buccal, sublingual or transdermal), vaginal or parenteral (including subcutaneous, intramuscular, intravenous or intradermal) route. Such compositions may be prepared by any method known in the art of pharmacy, for example by admixing the active ingredient with a carrier(s) or excipient(s) under sterile condiflons.

Pharmaceutical compositions adapted for oral administration may be presented as discrete units such as capsules or tablets; as powders or granules; as solutions, syrups or suspensions (in aqueous or non-aqueous liquids; or as edible foams or whips; or as emulsions). Suitable excipients for tablets or hard gelatine capsules include lactose, maize starch or derivatives thereof, stearic acid or salts thereof. Suitable excipients for use with soft gelatine capsules include for example vegetable oils, waxes, fats, semi-solid, or liquid polyols etc. For the preparation of solutions and syrups, excipients which may be used include for example water, polyols and sugars. For the preparation of suspensions oils (e.g. vegetable oils) may be used to provide oil-in-water or water in oil suspensions.

Pharmaceutical compositions adapted for topical administration may be formulated as ointments, creams, suspensions, lotions, powders, solutions, pastes, gels, sprays, aerosols or oils. For infections of the eye or other external tissues, for example mouth and skin, the compositions are preferably applied as a topical ointment or cream. When formulated in an ointment, the active ingredient may be employed with either a paraffinic or a water-miscible ointment base. Alternatively, the active ingredient may be formulated in a cream with an oil-in-water cream base or a water-in-oil base. Pharmaceutical compositions adapted for topical administration to the eye include eye drops wherein the active ingredient is dissolved or suspended in a suitable carrier, especially an aqueous solvent. Pharmaceutical compositions adapted for topical administration in the mouth include lozenges, pastilles and mouth washes. Pharmaceutical compositions adapted for rectal administration may be presented as suppositories or enemas.

Pharmaceutical compositions adapted for nasal administration wherein the carrier is a solid include a coarse powder having a particle size for example in the range 20 to 500 microns which is administered in the manner in which snuff is taken, i.e. by rapid inhalation through the nasal passage from a container of the powder held close up to the nose. Suitable compositions wherein the carrier is a liquid, for administration as a nasal spray or as nasal drops, include aqueous or oil solutions of the active ingredient.

Pharmaceutical compositions adapted for administration by inhalation include fine particle dusts or mists which may be generated by means of various types of metered dose pressurised aerosols, nebulizers or insufflators. Pharmaceutical compositions adapted for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams or spray formulations.

Pharmaceutical compositions adapted for parenteral administration include aqueous and non-aqueous sterile injection solution which may contain anti-oxidants, buffers, bacteriostats and solutes which render the formulation substantially isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents. Excipients which may be used for injectable solutions include water, alcohols, polyols, glycerine and vegetable oils, for example. The compositions may be presented in unit-dose or multi-dose containers, for example sealed ampoules and vials, and may be stored in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carried, for example water for injections, immediately prior to use. Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and

tablets.

The pharmaceutical compositions may contain preserving agents, solubilising agents, stabilising agents, wetting agents, emulsifiers, sweeteners, colourants, odourants, salts, buffers, coating agents or antioxidants. They may also contain an adjuvant and/or therapeutically active agents in addition to the substance of the present invention.

Dosages of the substance of the present invention can vary between wide limits, depending upon a variety of factors including the disease or disorder to be treated, the age, weight and condition of the individual to be treated, the route of administration etc. and a physician will ultimately determine appropriate dosages to be used. Typically, however, the dosage adopted for each route of administration when a compound of the invention is administered to adult humans is 0.001 to 500 mg/kg. Such a dosage may be given, for example, from 1 to 5 times daily by bolus infusion, infusion over several hours and/or repeated administration. The compositions may be administered in conjunction with one or more other therapeutically active agents, especially those effective for treating cancers (i.e. a chemotherapeutic agent). Another chemotherapeutic agent may be, for example, mitoxantrone, V/twa alkaloids, such as vincristine and vinblastine, anthracycline antibiotics such as daunorubicin and doxorubicin, alkylating agents such as chlorambucil and melphalan, taxanes such as paclitaxel, anti-folates such as methotrexate and tomudex, epipodophyllotoxins such as etoposide, camptothecins such as irinotecan and its active metabolite SN-38 and DNA methylation inhibitors. The other active compound(s) may be incorporated in the same composition as the compounds of the present invention or they may be administered alongside the compounds of the present invention, e.g. simultaneously or sequentially. Thus, the invention provides a kit of parts comprising a compound of the invention and another chemotherapeutic agent, optionally with instructions for use.

Examples

The following examples of the invention are provided to aid understanding of the invention but should not be taken to limit the scope of the invention.

Reagents were used as received from Sigma-Aldrich Chemical Company (Dorset, UK).

1H-NMR and 13C-NMR spectra were recorded on a Bruker 400MHz Super-conducting Spectrometer at 30°C. Tetramethylsilane was used as an internal standard for 1H-NMR spectra. Infrared spectra (IR) were recorded on a Perkin-Elmer 298 Spectrophotometer.

Mass spectra were recorded on a Micromass Quattro II Low Resolution Triple Quadruple Mass Spectrometer by the EPSRC National Mass Spectrometry Service Centre (Swansea, UK). Melting points were determined using a Gallenkarnp melting point apparatus and are uncorrected. Thin layer chromatography (TLC) was carried out using Merck aluminium sheet -silica Gel 60F254 coated plates which were visualised under UV light and stained with either iodine, 2,4-dinitrophenyihydrazine, or phosphomolybdic acid.

Elemental analyses (CHN) were carried out by Warwick Analytical Services (Coventry, UK) using a CE440 elemental analyser.

General procedure for the preparation of Compounds of Formula (l' Formula (I) To a stirred solution of the relevant carboxaldehyde (1.0 eq, 9.35 mmols) in 1, 4-dioxane (2.5 ml), lithium hydroxide monohydrate (1.6 eq, 14.95 mmols) was added. This was followed by the addition of the relevant substituted acetophenone (1.0 eq, 9.35mmols).

The mixture was stirred at room temperature and sequentially monitored by TLC (Hexane: Ethyl acetate, 4:6), until the reaction was complete (24h). The resulting cream precipitate was quenched with water (30m1) and extracted with ethyl acetate (3 x 30m1). The combined organic extracts were washed with brine (50 ml), dried with anhydrous magnesium sulfate and the solvent removed in vacuo. The crude product was recrystallised from ethanol.

Chemical Structure and Physical Properties of Compounds of Formula (I) (F)-1 -(3'-Bromopheny-3-(3-pyridinyl)prop-2-en-1 -one (Compound 1) 3H (DMSO-d5) 7.50-7.60 (2H, m, ArH), 7.79 (1H, d, J=16.l2Hz), 7.83 (1H, m, ArH), 8.09 (1H, d, J=16.l2Hz), 8.13(1H, m, ArH), 8.36(1H, m, ArH), 8.40 (1H, m, ArH), 8.65 (1H, dd, ArH), 9.05 (1H, d, ArH); 13C-60 (DMSO-d5), 118.02, 122.13, 123.40, 123.87, 127.57, 130.55, 135.30, 139.26, 146.63, 151.16, 187.63; Mass Spectrum (MALDI) mlz 288.0 (M+, 100%); HRMS found [M] 288.0025, C14H10BrNO requires [M] 288.0019; Anal. Calcd C14H10BrNO: C, 58.36; H, 3.50, Found C, 58.26; H, 3.44.

(E)-1 -(phenyl)-3-(3-pyridinyl)prop-2-en-1-one (Compound 2) ooc 8H (DMSO-d5) 7.40-7.50(1H, m, AIH), 7.58 (2H, t, ArH), 7.68(1H, t, AIH), 7.77 (1H, d, J=16.67Hz), 8.08 (1H, d, J16.67Hz), 8.18 (2H, d, AIH), 8.36 (1H,d,ArH), 8.62 (1H, m, ArH), 9.04(1H,s,ArH); 13C-60 (DMSO-d6), 123.90, 128.89, 130.48, 133.35, 1235.13, 137.26, 140.357, 149.34, 150.37, 188.97; Mass Spectrum (MALDI) mlz 210.0 (M+1, 100%); HRMS found [M+1] 210.0913, C14H12N0 requires [M+1] 210.0913; Anal. Calcd C14H11N0: C, 80.36; H, 5.30, Found C, 80.36; H, 5.26.

(F)-1 -(3'-methoxyphenyl)-3-(3-pyridinyl)prop-2-en-1-one (Compound 3) H3 3H (CDCI3) 7.13-7.16(1H, m, ArH), 7.30 (1H, m, ArH), 7.44(1H, t, ArH), 7.54-7.62 (2H, m, ArH), 7.56 (1H, d, J14.9OHz), 7.76 (1H, d, J=14.9OHz),7.94 (H, m, AIH), 8.62 (1H, dd, ArH), 8.8 (1H, d, ArH); l3C-öc (CDCI3), 55.48, 112.90, 119.61, 120.77, 121.309, 123.84, 129.69, 130.65, 139.08, 140.90, 150.3, 151.11, 159.96, 189.49; Mass Spectrum (MALDI) m/z 240.0 (M+1, 100%); HRMS found [M+1]t 240.1019, C15H14N02 requires [M+1]t 240.1019; Anal. Calcd C15H13N02: C, 75.30; H, 5.48, Found C, 875.53; H, 5.42.

(E)-1 -(4'-BromophenyD-3-(pyridinyl)prop-2-en-1-one (Compound 4) 3H (CDCI3) 7.29-7.39(2H, m, ArH), 7.53 (1H, d, J=l6Hz), 7.64 (2H, d, ArH), 7.76 (1H, d, J=l6Hz), 7.88 (2H, d, ArH), 7.94 (1H,m,ArH), 8.64 (1H, d, ArH), 8.86(1H, d, ArH); 13C-6 (CDCI3), 123.20, 123.82, 128.33, 130.06, 130.47, 131.81, 134.63, 141.50, 150.06, 151.32, 188.66; Mass Spectrum (MALDI) m/z 289.0 (M+, 100%); HRMS found [M+1] 289.9997, C14H11BrNO requires [M+1]t 289.9998; Anal. Calcd C14H10BrNO: C, 58.36; H, 3.50, Found C, 58.34; H, 3.46.

(F)-1 -(2'-Bromophenyfl-3-(pyridinyl)prop-2-en-1-one (Compound 5) fl 8H (CDCI3) 7.38-7.42(2H, m, ArH), 7.52 (1H, d, J=15.6Hz), 7.67(1H, dd, ArH), 7.79 (1H, d, J=15.6Hz), 7.93-8.14 (2H, m, AIH), 8.15 (1H, t, AIH), 8.65 (1H, d, ArH), 8.87(1H, s, ArH); 13C-öc (CDCI3), 123.11, 127.04, 130.34, 131.56, 134.63, 135.96, 139.53, 141.81, 150.15, 151.41, 186.12; Mass Spectrum (MALDI) m/z 289.0 (M+, 100%); HRMS found [M+1]t 289.9999, C14H11BrNO requires [M+1] 289.9998; Anal. Calcd C14H10BrNO: C, 58.36; H, 3.50, Found C, 58.30; H, 3.42 (E)-1 -(2'-methoxyphenyl)-3-(3-pyridinyF)prop-2-en-1-one (Compound 6) 0 OCH3 3H (DMSO-d5) 7.09-7.13(2H, m, ArH), 7.48-7.51 (1H, m, ArH), 7.72-7.76 (1H, d, J=14.l4Hz), 8.08-8.12 (1H, d, J=14.l4Hz), 8.19-8.22 (2H, m, ArH), 8.35-8.37 (1H, tt, ArH), 8.61-8.63 (1H, dd, ArH), 9.03(1H, d, ArH); 13C-o (CDCI3), 55.48, 112.90, 119.61, 120.77, 121.309, 123.84, 129.69, 130.65, 139.08, 140.90, 150.3, 151.11, 159.96, 189.49; Mass Spectrum (MALDI) m/z 240.0 (M+1, 100%); HRMS found [M+1]t 240.1017, C15H14N02.0.5H20 requires [M+1]t 240.1019; Anal. Calcd C15H13N02: C, 75.30; H, 5.48, Found C, 74.03; H, 5.57.

(E)-1 -(4'-methoxyphenyl)-3-(3-pyridinyl)prop-2-en-1-one (Compound 7) 0C H3 8H (DMSO-d8) 7.10-7.13(2H, m, ArH), 7.48-7.52 (1H, m, ArH), 7.72-7.76 (1H, d, J=l6Hz), 8.08-8.12 (1H, d, J=l6Hz),8.19-8.23 (2H, m, ArH), 8.35-8.37 (1H, U, ArH), 8.61-8.62 (1H, dd, ArH), 9.03(1H, d, ArH); 13C-o (CDCI3), 55.59, 114.07, 123.22, 129.31, 130.16, 131.05, 134.71, 139.68, 150.25, 163.38, 187.10; Mass Spectrum (MALDI) m/z 240.0 (M+1, 100%); HRMS found [M+1] 240.1017, C15H14N02 requires [M÷1] 240.1019; Anal.

Calcd C15H13N02.0.15H20: C, 75.30; H, 5.48, Found C, 74.41; H, 5.77.

(E)-1 -(3', 4'-dimethoxyphenyl)-3-(3-pyridinyl)prop-2-en-1 -one (Compound 8) 6H (DMSO-d6) 3.87(6H, d, (OMe)2), 7.12-7.14(2H, m, ArH), 7.50-7.52 (1H, m, ArH), 7.72 (1H, d, J=l4Hz), 7.93-7.96 (1H, d, J=l4Hz), 8.08-8.12 (1H, m, ArH), 8.62-8.61 (1H, s, ArH), 9.04-9.05 (1H, dd, ArH); l3C-8 (CDCI3), 55.55, 55.80, 110.91, 123.60, 123.86, 130.20, 130.63, 134.82, 139.61, 146.63, 148.82, 150.80, 187.07; Mass Spectrum (MALDI) m/z 270.0 (M+1, 100%); HRMS found [M-'-1] 270.1125, C16H15N03 requires [Mi-i] 270.1125; Anal. Calcd C15H15N03.0.1H20: C, 71.36; H, 5.61, Found C, 70.97; H, 5.65.

(E)-1 -(3'-Bromophenvfl-3-(4-pvridinvl)prop-2-en-1 -one (Compound 9)

NOG

3H (CDCI3) 7.36-7.39 (1H, m, ArH), 7.53-7.59 (1H, d, J=15.84Hz), 7.65-7.68 (2H, d, ArH), 7.76-7.82 (1H, d, J=15.84Hz), 7.88-7.91 (2H, d, ArH), 7.91-7.97 (1H,m,ArH), 8.64-8.66 (1H, dd, ArH), 8.86-8.87 (1H, d, ArH); 13C-o (CDCI3), 123.25, 123.82, 130.06, 132.09, 134.64, 141.52, 150.06, 151.34,185.00; Mass Spectrum (MALDI) m/z 289.0 (M+, 100%); HRMS found [M+1]t 289.9998, C14H11BrNO requires [M+1]t 289.9998; Anal. Calcd C14H10BrNO: C, 58.36; H, 3.50, Found C, 58.20; H, 3.46.

(E)-1 -(3'-Bromophenvfl-3-(2-pvridinvl)prop-2-en-1 -one (Compound 10) 8H (DMSO-d5) 7.40-7.50(2H, m, ArH), 7.50-7.55 (1H, d, J=l2Hz), 7.70-7.75 (1H, d, J=l2Hz), 7.88-8.00(2H, m, ArH), 8.10 (2H, m, ArH), 8.20 (1H, d, ArH), 8.70 (1H, d, ArH); 13C-8 (CDCI3), 124.96, 126.87, 127.54, 130.91, 135.70, 137.17, 143.82, 150.05, 152.63, 188.31; Mass Spectrum (MALDI) mlz 288.0 (M+, 100%); HRMS found [Mi-i]t 289.0056, C14H11BrNO requires [Mi-i]t 289.0052; Anal. Calcd C14H10BrNO: C, 58.36; H, 3.50, Found C, 58.18; H, 3.42.

(F)-1 -(3-pyridinyl)-3-(3'-Bromophenyl)prop-2-en-1-one (Compound 11) Br 3H (CDCI3) 7.41-7.43 (2H, m, ArH), 7.52-7.56 (1H, d, J=16.5lHz), 7.70-7.73 (1H, m, ArH) 7.79-7.83 (1H, d, J=16.5lHz), 7.93-7.98 (2H, m, ArH), 8.14-8.15 (1H,t,ArH), 8.65-8.66 S (1H, d, ArH), 8.87 (1H, s, AIH); 13C-80 (CDCI3), 123.11, 123.20, 126.58, 130.43, 131.57, 134.64, 135.97, 142.26, 150.15, 151.41, 188.38; Mass Spectrum (MALDI) mlz 288.0 (M+, 100%); HRMS found [M÷1] 289.0055, C14H11BrNO requires [M+1]t 289.0052; Anal. Calcd C14H10BrNO: C, 58.36; H, 3.50, Found C, 58.30; H, 3.45.

(E)-1 -(3'-Fluorophenvfl-3-(3-pyridinvl)prop-2-en-1 -one (Compound 12) 6H (DMSO-d6) 7.52-7.50 (2H, m, ArH), 7.63-7.67 (1H, m, ArH), 7.81-7.84 (1H, d, J=l6Hz), 7.98-7.99 (1H, dd, ArH), 8.01 (1H, dd, ArH), 8.12-8.38 (1H, d, J=l6Hz),8.40 (1H, tt, ArH), 8.63 (1H, dd, ArH), 9.05-9.06 (1H, d, ArH); 13C-o (DMSO-d5), 115.04, 120.05, 123.28, 124.13, 124.79, 135.03, 135.26, 139.70, 150.49, 160.94, 161.12, 187.75; Mass Spectrum (MALDI) m/z 228.0 (M+1), 100%); HRMS found [M] 228.0820, C14H11N0F requires [M] 228.081 9; Anal. Calcd C14H10FN0.0.05H20: C, 73.71; H, 4.46, Found C, 73.78; H, 4.50.

(E)-1 -(3'-Chlorophenyl)-3-(3-pyridinyl)prop-2-en-1 -one (Compound 13) oH (DMSO-d5) 7.50-7.53 (1H, m, ArH), 7.62-7.66 (1H, t, ArH), 7.76-7.77 (1H, m, ArH), 7.80-7.84 (1H, d, J=15.65Hz), 8.10-8.13 (1H, d, J15.65Hz),8.15 (1H, tt, ArH), 8.24 (1H, t, ArH), 8.39-8.42 (1H, tt, ArH), 8.63-8.65 (1H, dd, ArH), 9.06-9.07 (1H, d, ArH); 13C-o (DMSO-d6), 123.43, 128.28, 130.36, 133.06, 135.30, 141.36, 150.52. 151.17, 187.72; Mass Spectrum (MALDI) mlz 244.0 (M+1), 100%); HRMS found [M] 244.0524, C14H11N0C1 requires [M] 244.0524; Anal. Calcd C14H10N0C1.0.05H20: C, 68.75; H, 4.16, Found C, 68.86; H, 4.12.

(E)-1 -(3',4'Methylenedioxyphenyl)-3-(3-pyridinyl)prop-2-en-1 -one (Compound 14) 3H (DMSO-d6) 6.07 (2H, s, OCH2O), 6.93 (1H, m, ArH),7.00 (1H, m, ArH), 7.10 (1H, m, ArH), 7.20 (1H, m, ArH), 7.50 (1H, d), 7.60 (1H, d), 7.70 (1H, m, ArH), 8.63 (1H, dd, ArH), 9.06 (1H, d, ArH); 13C-80 (DMSO-d5), 46.22, 102.12, 108.19, 125.32, 130.09, 135.08, 139.95, 147.46, 195.05; Mass Spectrum (MALDI) mlz 254.0 (M+1), 100%); HRMS found [M]t 254.0811, C15H12N03 requires [M] 254.0812; Anal. Calcd C15H11N03: C, 71.14; H, 4.38, Found C, 70.91; H, 4.36.

(E)-1 -(3'-Bromo-4'-Fluorophenyl)-3-(3-pyridinyl)prop-2-en-1-one (Compound 15) ox1 6H (CDCI3) 7.18-7.26 (2H, m, ArH), 7.65-7.67 (1H, d, ArH), 7.88-7.92 (2H, m, ArH), 8.15- 8.17 (2H, dd, ArH), 8.48 (1H, s, ArH), 8.57 (1H, d, ArH), ; 13C-o (CDCI3), 116.71, 116.93, 129.25, 134.06, 161.76, 195.07; Mass Spectrum (MALDI) m/z 307.0 (M+1), 100%).

(F)-1 -(3',4'-Difluorophenyl)-3-(3-pyridinyl)prop-2-en-1 -one (Compound 16) 3H (DMSO-d5) 7.50-7.53 (1H, m, ArH), 7.63-7.70 (1H, m, ArH), 7.79-7.83 (1H, d, J=l5Hz), 7.08-8.12 (2H, d, J15Hz, ArH), 8.24-8.29 (1H, m, ArH), 8.37-8.39 (1H, tt, ArH),8.63- 8.65(1H, dd, ArH), 9.05-9.06 (1H, d, ArH); 13C-Sc (DMSO-d5), 117.89, 118.07, 123.12, 126.48, 130.33, 134.70, 141.36, 150.48, 150.88, 186.53; Mass Spectrum (MALDI) mlz 246.0 (M+1), 100%); HRMS found [M] 246.0724, C14H9N0F2 requires [M] 246.0725; Anal. Calcd C14H9F2N0: C, 68.57; H, 3.70, Found C, 68.48; H, 3.70.

(E)-1 -(3'-Hvdroxyphenvl)-3-(3-pyridinvl)prop-2-en-1 -one (Compound 17) 8H (DMSO-d6) 7.07-7.10 (1H, dd, ArH), 7.37-7.41 (1H, t, ArH), 7.48-7.51 (2H, m, ArH), 7.65-7.66 (1H, d, AIH), 7.73-7.77 (1H, d, J12.9Hz), 7.99-8.03 (1H, d, J12.9Hz), 8.31- 8.37 (1H, d, ArH), 8.62 (1H, s, ArH), 9.02(1H, s, ArH), 9.85(1H, s, OH); l3C-öc (DMSO S d6), 114.67, 119.71, 120.50, 123.90, 124.05, 129.87, 135.05, 138.70, 140.34, 150.34, 157.75, 188.88; Mass Spectrum (MALDI) mlz 226.0 (M+1), 100%); Anal. Calcd C14H11N02: C, 74.65; H, 4.92, Found C, 74.51; H, 4.92.

(F)-1 -(3-pyridinyl)-3-(3-pyridinyl)prop-2-en-1-one (Compound 18) 3H (DMSO-d6) 7.50-7.52 (1H, dd, ArH), 7.53-7.66 (2H, m, ArH), 7.81-7.85 (1H, d, J=l4Hz), 8.10-8.14 (1H, d, J12.9Hz), 8.38-8.40 (1H, d, ArH), 8.48-8.50 (1H, d, ArH), 8.63- 8.64(1H, d, ArH), 8.84-8.86(1H, 5, ArH), 9.06(1H, 5, ArH), 9.37(1H, 5, ArH); 13C-8 (DMSO-d6), 123.61, 123.93, 130.30, 132.54, 135.29, 141.29, 149.79, 151.23, 153.50, 188.27; Mass Spectrum (MALDI) mlz 211.0 (M+1), 100%); HRMS found [M] 211.0864, C13H11N20 requires [Mlt 211.0866;Anal. Calcd C13H10N2O.0.05H20: C, 73.95; H, 4.82, Found C, 73.90; H, 4.79.

General Synthetic Method for the Preparation of Compounds of Formula (IIA)

NN

Formula (IIA) A solution of chalcone (9 mmol), guanidine hydrochloride (1.29 g, 13.5 mmol) and aqueous potassium hydroxide (4.94 cm3, 50% w/v, 36 mmol) in ethanol (30 cm3) was heated at reflux for 6 h. Hydrogen peroxide solution (1.84 cm3, 50% wlv, 27 mmol) was added drop-wise to the solution and allowed to continue for 1 h. The reaction was quenched with water (40 cm3) and the resulting mixture extracted with dichloromethane (3 x 50 cm3). The combined organic extracts were dried (MgSO4) and the solvent removed in vacuo. The pyrimidine was purified by either recrystallisation from methanol or ethanol, or by flash chromatography on silica gel using ethyl acetate -hexane (6:4) as eluent.

General Synthetic Method for the Preparation of Compounds of Formula (IIB)

H N N

Formula (IIB) Sodium nitrite solution (1.08 cm3, 50% wlv, 7.8 mmol) was added to a refluxing solution of the amino-pyrimidine (1.31 mmol) in glacial acetic acid (50 cm3). After 3 h at reflux the solution was allowed to cool and the solvent removed in vacuo. The crude product was recrystallised from ethanol.

General Synthetic Method for the Preparation of Compounds of Formula (IIC) Formula (IIC) A mixture of the chloropyridine (3.7 mmol), ammonium formate (1.39 g, 22 mmol) and 10% palladium on carbon (1 g, 3.7 mmol) in ethanol (20 ml) was refluxed under nitrogen for 30 minutes. The mixture was allowed to cool to room temperature and filtered through Celite pad. The filtrate was concentrated in vacuo. Recrystallisation from methanol or by flash column chromatography, if necessary, on silica gel using dichloromethane/ethanol (9.8:0.2) as eluent afforded the 2,4-diarylpyridine.

General Synthetic Method for the Preparation of Compounds of Formula (lID) Formula (lID) A mixture of chalcone (3.2 mmol), 2-acetamidoacetamide (N-ci-acetylglycinamide, 0.46 g, 4.0 mmol) and cesium carbonate (1.3 g, 4.0 mmol) in DMF (10 ml) was heated to 150°C for 1 hour. TLC analysis (DCM/ethanol 9.5:0.5) under a UV light showed a fluorescent blue polar spot for the pyridone. The reaction mixture was allowed to cool to room temperature and quenched with hydrochloric acid (10%, 70 ml). The mixture was stirred at room temperature for 15 minutes and the precipitate formed was collected by filtration and washed with water (20 ml). The pyridone was purified by triturating in minimal volume of ethyl acetate (5-15 ml) overnight to afford a brown powder.

General Synthetic Method for the Preparation of Compounds of Formula (lIE) Formula (lIE) Hydrazine hydrate (0.18 cm3, 5.7 mmol) was added drop-wise to a refluxing solution of epoxy-chalcone (3.8 mmol) in ethanol (40 cm3). After 6 h at reflux the solution was allowed to cool to room temperature and the solvent removed in vacuo. The residue was dissolved in glacial acetic acid (30 cm3). Concentrated sulphuric acid (0.25 cm3) was added and the solution heated at reflux for 0.5 h. After cooling (ice bath) the solution was neutralised with concentrated ammonia solution and poured onto ice. The resulting brown precipitate was isolated by vacuum filtration. The pyrazole was purified by either recrystalisation from ethanol, or flash chromatography on silica gel using ethyl acetate -hexane (7:3) as eluent.

Table 1 below sets out exemplary compounds of the invention which were tested for anti-trypanosomal activity.

Table 1 -Anti-trypanosomal Activity Control Cells T. b. rho clesiense STIB900 Structure MWt ______________________ ________ MCF1OA KB Cells IC50 (pgiml) lCao (UM) 288.15 6 13.48 0.50 0.144 209.25 6 7.73 0.09 0.019 239.28 4 2.26 0.12 0.029 288.15 -7.91 0.01 0.003 239.28 4 22.47 0.43 0.104 239.28 5 20.75 0.17 0.040 269.30 4 22.84 0.08 0.022 288.15 -22.70 0.03 0.010 288.15 -43.68 0.01 0.003 227.24 -19.53 0.03 0.006 243.69 5 12.74 0.02 0.006 253.26 7 59.39 0.19 0.047 245.23 6 20.72 0.05 0.012 224.28 5 21.69 0.06 0.013 210.24 14 17.02 0.02 0.005 Feritamidirie 340.42 --0.01 _____________ Melarsoprol 398.341 --0.01 ______________ Podophyllotoxin _________ -0.05 _______________ _____________ KB cells -a cell line derived from a human carcinoma of the nasopharynx, typically used as an assay for antineoplastic agents

Claims

CLAIMS1. A compound of Formula (I) or a pharmaceutically acceptable salt thereof Formula (I) for use in the prevention and/or treatment of sleeping sickness, wherein rings A and B are independently an optionally substituted aryl or an optionally provided that at least one of rings A and B is an optionally substituted monocyclic heteroaryl.
2. A compound of Formula (II) or a pharmaceutically acceptable salt thereof R2 Formula (II) for use in the prevention and/or treatment of sleeping sickness, wherein R1 and R2 together with the intervening atoms form a five or six membered optionally substituted heteroaryl or optionally substituted heterocycle; and rings A and B are independently an optionally substituted aryl or an optionally provided that at least one of rings A and B is an optionally substituted monocyclic heteroaryl.
3. The compound of claim 2 wherein said compounds of Formula (II) has the one of the following structures:NNFormula (IIA)H N NFormula (IIB) Formula (IIC) Formula (lID) Formula (lIE) wherein rings A and B are as defined in claim 2 and R3 is selected from the group consisting of halo, optionally substituted aliphatic, alkoxy, optionally substituted aryl, optionally substituted heteroaryl, alkylamino (monoalkylamino or dialkylamino), -NH2, -NO2, -OH, -COOH, -CN, hydroxyalkyl, alkylcarbonyloxy, alkoxycarbonyl, alkylcarbonyl or alkylsulfonylamino.
4. A compound of claim 3, wherein R3 is selected from halo, optionally substituted aliphatic, alkoxy, optionally substituted aryl, optionally substituted heteroaryl, preferably selected from halo, aliphatic or phenyl.
5. A compound according to any preceding claim, wherein ring A is an optionally substituted monocyclic heteroaryl having 5 or 6 ring atoms, at least one ring atom being a heteroatom selected from 0, N or S and ring B is an optionally substituted aryl having 6 to carbon atoms.
6. A compound according to any preceding claim, wherein ring A and/or ring B are optionally substituted by one or more substituents independently selected from the group consisting of halo, aliphatic, alkoxy, carbonyl, alkylamino (monoalkylamino or dialkylamino), -NH2, -NO2, -OH, -000H, -CN, hydroxyalkyl, alkylcarbonyloxy, alkoxycarbonyl, alkylcarbonyl, alkylsulfonylamino or two adjacent substituents on the ring, taken together with the intervening ring atoms, form an optionally substituted fused 3 to 8 membered non-aromatic ring having 0 to 3 ring heteroatoms selected from the group consisting of 0, N and S.
7. A compound of any one of claims 1 to 4, wherein at least one of rings A and B is an optionally substituted monocyclic heteroaryl, wherein at least one ring atom is N, preferably wherein at least one of rings A and B is an optionally substituted pyridine, and more preferably wherein ring A is an optionally substituted pyridine.
8. A compound of any one of claims ito 4, wherein ring A is an optionally substituted monocyclic heteroaryl, wherein at least one ring atom is N, and ring B is an optionally
9. A compound of claim 8, wherein ring A is an optionally substituted monocyclic heteroaryl, wherein at least one ring atom is N, and ring B is a substituted aryl.
10. A compound of claim 8, wherein ring A is an optionally substituted pyridine and ring B is an optionally substituted aryl.
11. A compound of claim 10, wherein ring A is an optionally substituted pyridine and
12. A compound according to claim 1, wherein the compound of Formula (I) is selected from: QOQBr Compound I Compound 2 H3 Br Compound 3 Compound 4 000H3 Compound 5 Compound 6 Compound 7 Compound 8 Br Br Compound 9 Compound 10 Br Compound 11 Compound 12 QoocI Compound 13 Compound 14 Qoo:r (XX Compound 15 Compound 16O CYOCompound 17 Compound 18
13. A pharmaceutical composition comprising a compound as defined in any preceding claim or a pharmaceutically acceptable salt thereof, optionally together with a pharmaceutically acceptable excipient and/or adjuvant and/or another therapeutically active agent.
14. A pharmaceutical composition of claim 13, for use in preventing and/or treating sleeping sickness.
15. A compound or a pharmaceutically acceptable salt thereof as defined in any of claims 1 to 12 or a pharmaceutical composition of claim 13 or 14 for use as an active agent against Ttypanosoma brucel rhodesiense (T.b.O and Trypanosoma brucei gambiense (T.b.g), preferably against Trypanosoma bruceigambiense (T.b.g).
16. A method for preventing and/or treating sleeping sickness which comprises administering to a subject in need thereof an effective amount of a compound or a pharmaceutically acceptable salt thereof as defined in any of claims ito 12 or a pharmaceutical composition as defined in claim 13 or 14.