WO2016059198A1

WO2016059198A1 - Compounds

Info

Publication number: WO2016059198A1
Application number: PCT/EP2015/073974
Authority: WO
Inventors: Parvez Iqbal HARIS; Richard Owen JENKINS
Original assignee: De Montfort University
Priority date: 2014-10-17
Filing date: 2015-10-16
Publication date: 2016-04-21
Also published as: GB201707536D0; GB2546703A; GB201418491D0

Abstract

The present invention relates to arsenic compounds, particularly arsenobetaine and arsenosugar analogues and derivatives and their use in therapy, particularly for the prevention and/or treatment of cancer.

Description

Compounds

Field of the Invention The present invention relates to arsenic compounds, particularly arsenobetaine and arsenosugar analogues and derivatives and their use in therapy, particularly for the prevention and/or treatment of cancer.

Background of the Invention

There are a number of naturally occurring arsenic compounds that are commonly found in various types of food. Arsenobetaine or 2-trimethylarsoniumylacetate, for example, is the most abundant organoarsenic compound found in marine mammals. Arsenosugars are also found to be abundant in seaweed and in some marine foods. Most arsenic compounds are considered to be highly toxic to humans. However, compounds such as arsenobetaine and arsenosugars have been classed as relatively inert and nontoxic.

Whilst various studies have been carried out on arsenic compounds such as arsenobetaine and arsenosugars, these have mainly focussed on determining their toxicity profiles. Some studies have also been carried out to determine their metabolic pathways in mammals, but no conclusive mechanisms have yet been identified. Furthermore, studies of arsenic compounds such as arsenobetaine or arsenosugar analogues and derivatives for any therapeutic indications have so far been limited.

Accordingly, the present invention provides arsenic compounds, particularly arsenobetaine and arsenosugar analogues and derivatives and their use in therapy, more particularly for the prevention and/or treatment of cancer, and even more particularly for the prevention and/or treatment of breast, ovarian, uterine, endometrial, cervical, womb, testis, thyroid, osteosarcoma and/or prostate cancer, preferably breast cancer.

Summary of the Invention

A first aspect of the invention provides a compound of Formula (I) or a pharmaceutically acceptable salt thereof

R¹

R²— As— R⁴

R³ Formula (I)

for use in therapy, wherein

R¹, R² and R³ are independently alkyl;

R⁴ is selected from the group consisting of optionally substituted alkyl, optionally substituted heteroalkyi, optionally substituted alkenyl, optionally substituted cycloalkyi, optionally substituted heterocycloalkyi, optionally substituted heteroaryl, optionally substituted aryl, optionally substituted carboxyalkyi, optionally substituted hydroxyalkyi, halo, -OR⁵, =0, -COOR⁶, -CN, -NR⁷R⁸, -SR⁹, L-X-SR⁹, -L'-R¹⁰ and -L'-R¹¹-R¹²;

R⁵, R⁶, R⁷, R⁸ and R⁹ are independently selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted heteroalkyi, optionally substituted alkenyl, optionally substituted cycloalkyi, optionally substituted heterocycloalkyi, optionally substituted heteroaryl, optionally substituted aryl, optionally substituted carboxyalkyi and optionally substituted hydroxyalkyi;

L is optionally substituted aryl;

X is absent, alkylene or -NHC(0)(CH₂)_n-;

n is 0 or an integer between 1 and 20;

L' is alkyl;

R¹⁰ and R¹¹ are independently optionally substituted heterocycloalkyi;

R¹² is -OR¹³;

R¹³ is optionally substituted alkyl; and

= is a single bond or a double bond, and wherein when it is a single bond, the As ion has a positive charge.

The compound of Formula (I) may be a compound of Formula (la):

R

2 ' ⁺ 4

R²— As R⁴ R³

Formula (la)

wherein R⁴ is selected from the group consisting of optionally substituted alkyl, optionally substituted heteroalkyi, optionally substituted alkenyl, optionally substituted cycloalkyi, optionally substituted heterocycloalkyi, optionally substituted heteroaryl, optionally substituted aryl, optionally substituted carboxyalkyi, optionally substituted hydroxyalkyi, halo, -OR⁵, -COOR⁶, -CN, -NR⁷R⁸, -SR⁹, L-X-SR⁹, -L'-R¹⁰ and -L'-R¹¹-R¹²; and

R¹, R², R³, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹ , R¹², R¹³, X, L, L' and n are as defined above for Formula (I). The compound of Formula (I) may be a compound of Formula (lb):

R

R²-As=R⁴ R³

Formula (lb)

wherein R⁴ is =0; and

R¹, R² and R³ are as defined above for Formula (I).

R¹, R² and R³ may independently be Ci_-2o alkyl, preferably C-_\.-_\2 alkyl, more preferably Ci_-6 alkyl, and more preferably methyl, ethyl or propyl. Methyl is particularly preferred.

R⁴ may be selected from the group consisting of optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted carboxyalkyl, optionally substituted hydroxyalkyl, =0, -SR⁹, L-X-SR⁹, -L'-R¹⁰ and -L'-R¹¹-R¹², preferably R⁴ is selected from the group consisting of optionally substituted Ci_-6 alkyl, optionally substituted C_2-6 carboxyalkyl, optionally substituted Ci_-2o hydroxyalkyl, -L'-R¹⁰ and -L'-R¹¹- R¹² and more preferably R⁴ is optionally substituted C_2-4 carboxyalkyl.

In certain embodiments, the compound of Formula (I) may be a compound of Formula (lc):

Formula (lc)

wherein R¹³, R¹⁴, R¹⁵, R¹⁶, R¹⁷ and R¹⁸ may independently be selected from the group consisting of H, =0, -OH, -COOH, -S0₃H, and -OS0₃H.

In other certain embodiments, the compound of Formula (I) may be a compound of Formula (Id):

Formula (Id)

wherein R¹⁹, R²⁰ and R²¹ may independently be selected from the group consisting of H, -OH, -OR¹³, -COOH, -S0₃H, and -OS0₃H; and

R¹³ is as defined above for Formula (I).

In a further embodiment, the compound of Formula (I) may be a compound Formula (le):

Formula (le)

wherein R²² may be selected from the group consisting of H, -OH and -OR¹³; and R¹³ is as defined above for Formula (I).

In an embodiment, R⁴ may be -SR⁹, wherein R⁹ is optionally substituted alkyl. R may be -SR , wherein -SR is glutathionyl.

In a further embodiment, R may be L-X-SR , wherein L is aryl, X is - NHC(0)(CH₂)_n-, n is an integer between 1 and 6, and R⁹ is optionally substituted heteroalkyl. R⁴ may be N-(S-glutathionylacetyl)amino)aryl. R⁴ may be 4-N-(S- glutathionylacetyl)amino)phenyl.

L may be optionally substituted phenyl, preferably phenyl.

X may be -NHC(0)(CH₂)_n-, wherein n is an integer between 1 and 6, preferably between 1 and 3.

L' may be C_1-6 alkyl, preferably C_1-3 alkyl and more preferably a methylene group.

In an embodiment, R¹, R² and R³ may each be C_1-6 alkyl, and R⁴ may be selected from the group consisting of optionally substituted C_1-6 alkyl, optionally substituted C_2-6 carboxyalkyl, optionally substituted C_1-20 hydroxyalkyl, =0, -L'-R¹⁰ and -L'-R¹¹-R¹².

In a further embodiment, R¹, R² and R³ may each be methyl, and R⁴ may be optionally substituted alkyl or optionally substituted C_2-6 carboxyalkyl. In a further embodiment, R¹, R² and R³ may each be methyl, and R⁴ may be optionally substituted alkyl having a terminal substituent selected from the group consisting of -COOH, -OH and -OSO₃H. In such embodiments, the compounds may be optionally substituted with one or more hydroxy (-OH) groups in addition to the terminal substituent.

In any of the above embodiments, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹ and R¹³ may optionally be substituted by one or more substituents independently selected from the group consisting of halo, aliphatic, heteroaliphatic, alkoxy, oxo (=0), alkylamino (monoalkylamino or dialkylamino), -NH₂, -N0₂, -OH, -COOH, -S0₃H, -CN, -OSO₃H, hydroxyalkyl, alkylcarbonyloxy, alkoxycarbonyl, alkylcarbonyl, carboxyalkyl and alkylsulfonylamino. Preferred substituents include halo, alkoxy, oxo, -COOH, -NH₂, N0₂, - OH, -SO₃H, -OSO₃H and -CN, and more preferably -OH, -COOH, halo and -OSO₃H.

The compound of Formula (I) may be selected from:

The compound of Formula (I) may be

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

A third aspect of the invention provides a compound or a pharmaceutically acceptable salt thereof of any of the first aspect of the invention or a pharmaceutical composition of the second aspect of the invention for use in therapy.

A fourth aspect of the invention provides a compound or a pharmaceutically acceptable salt thereof of any of the first aspect of the invention or a pharmaceutical composition of the second aspect of the invention for use in preventing and/or treating cancer, particularly a hormone-induced cancer. The cancer is particularly selected from the group consisting of ovarian, uterine, endometrial, cervical, womb, testis, thyroid, osteosarcoma and prostate cancer, preferably breast cancer. A fifth aspect of the invention provides a method for preventing and/or treating cancer, particularly a hormone-induced cancer 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. The cancer is particularly selected from the group consisting of breast, ovarian, uterine, endometrial, cervical, womb, testis, thyroid, osteosarcoma and prostate cancer, preferably breast cancer.

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 cancer. In particular, the compounds are provided for the prevention and/or treatment of hormone-induced cancers. The cancer is particularly selected from the group consisting of breast, ovarian, uterine, endometrial, cervical, womb, testis, thyroid, osteosarcoma and prostate cancer).

In particular the compounds of the present invention are provided for the prevention and/or treatment of breast cancer.

Throughout this text, the prevention and/or treatment of cancer means any effect which mitigates damage, to any extent. The term "treatment" means any amelioration of a disorder, disease, syndrome, condition, pain or a combination of two or more thereof. The term "prevention" means to prevent the condition from occurring, lessening the severity of the condition or to prevent the patient from deteriorating or getting worse, for example by halting the progress of the disease without necessarily ameliorating the condition.

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 treating or reducing the severity of symptoms of cancer, particularly a hormone induced cancer. The compounds are particularly useful for treating or reducing the severity of symptoms of breast, ovarian, uterine, endometrial, cervical, womb, testis, thyroid, osteosarcoma and prostate cancer, more particularly breast cancer. Compounds of the invention are also useful for administration to patients susceptible to, at risk of or suffering from cancer as set out above. Compounds useful for the prevention of cancer as set out above 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 compounds of the present invention are provided for the prevention and/or treatment of cancer in a subject in need thereof. The subject can be a human or an animal, particularly aquatic animals such as fish or domestic or farm animals such as dogs, cats, mice, rats, cattle, sheep, pigs and fowl. The subject is preferably a human. The term "halogen" or "halo" as used herein means fluorine, chlorine, bromine, iodine and the like.

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 C_1-2o 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 (d. ₆) 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 "heteroalkyl" as used herein refers to an alkyl group as defined above, having one or more heteroatoms selected from O, N and S.

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 "Ci_-8 alkoxy group" and even more preferably a "C_1-6 alkoxy group".

The term "cycloalkyl" as used herein refers to a fully saturated hydrocarbon cyclic group. Preferably, a cycloalkyl group is a C_3-6 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 O, N and S. A heterocycle preferably has 3 to 7 ring atoms, and more preferably has 5 or 6 ring atoms.

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 aryl 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 O, 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 O, 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 O, 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. The term "optionally substituted" as used herein refers to a group that may be unsubstituted or substituted by one or more substituents.

An aryl, heteroaryl 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, heteroaliphatic, alkoxy, oxo, alkylamino (monoalkylamino or dialkylamino), -NH₂, -N0₂, -OH, -COOH, -SO₃H, -CN, -OSO₃H, hydroxyalkyl, alkylcarbonyloxy, alkoxycarbonyl, alkylcarbonyl, carboxyalkyl and alkylsulfonylamino. An aliphatic (including alkyl, alkenyl and cycloalkyl), heteroalkyl, carboxyalkyl, or hydroxyalkyl group as referred to herein may be unsubstituted or may independently be substituted with aryl, heteroaryl, heterocycle or with any one or more of the substituents listed above for aryl, heteroaryl or heterocycle groups.

The terms "aralkyl" and "heteroaralkyl" 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 "aralkyl" or "heteroaralkyl" group may be substituted with any one or more of the substituents listed above for an aliphatic group and the aryl or heteroaryl component of an "aralkyl" or "heteroaralkyl" group may be substituted with any one or more of the substituents listed above for aryl, heteroaryl or heterocycle groups. Preferably, aralkyl is benzyl. The term "oxo", as used herein, refers to a double bonded oxygen (=0) radical wherein the bond partner is a carbon atom. Such a radical can also be thought as a carbonyl group

The invention extends to prodrugs of the aforementioned compounds. A prodrug is any compound that may be converted under physiological conditions or by solvolysis to any of the compounds of the invention or to a pharmaceutically acceptable salt of the compounds of the invention. A prodrug may be inactive when administered to a subject but is converted in vivo to an active compound of the invention. 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 groups -OH, -COOH, -S0₃H, -OSO₃H and -NH₂ as referred to herein may be in the protonated or deprotonated form. For example -COOH as used herein also includes the deprotonated form, -COO^". This also applies to any other substituent mentioned herein which may exist in the protonated or deprotonated form.

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 conditions.

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, Vinca 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. Brief description of the drawings

Figure 1 : MDA-MB-231 primary tumor growth. Arsenobetaine (Compound 2), administered at 1300 mg/kg (Group 3) versus the corresponding Vehicle Control Aqua ad injectabile (Group 1 ). Data are displayed as means ± SEM.

Figure 2: MDA-MB-231 primary tumor volumes, measured in vivo on day 64. Arsenobetaine (Compound 2), administered at 1300 mg/kg (Group 3) versus the corresponding Vehicle Control Aqua ad injectabile (Group 1 ). Data are displayed both as means + SEM (A) and as individual data points together with their corresponding median values (B).

Figure 3: MDA-MB-231 primary tumor volumes (mm³). Compound 2 (arsenobetaine), administered at 1300 mg/kg (Group 3) versus the corresponding Vehicle Control Aqua ad injectabile (Group 1 ). Data are displayed both as means + SEM (A) and as individual data points together with their corresponding median values (B).

Figure 4: MDA-MB-231 primary tumor weight (g). Compound 2 (arsenobetaine), administered at 1300 mg/kg (Group 3) versus the corresponding Vehicle Control Aqua ad injectabile (Group 1 ). Data are displayed both as means + SEM (A) and as individual data points together with their corresponding median values (B).

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.

Efficacy of arsenobetaine in subcutaneous xenograft tumor models using the MDA- MB-231 cell line

Through in vivo studies with mice, arsenobetaine has been shown to display antitumoral activity against breast cancer. For this investigation MDA-MB 231 breast cancer cell line which is a model of ER-negative breast cancers was used. For pre-clinical studies, MDA-MB 231 cell line is particularly useful as it is highly aggressive both in vivo and in vitro.

This study part consisted of experimental groups each containing 12 female BALB/c nude mice after randomization. On day O, 5x10⁶ MDA-MB-231 tumor cells in 10ΟμΙ PBS were implanted subcutaneously (s.c.) into the left flank of all female BALB/c nude mice. On day 41 , after a mean tumor volume of approx. 200mm³ was reached, the tumor-bearing animals were randomized into groups according to tumor sizes. On the same day, treatment with Vehicle and arsenobetaine was initiated. Vehicle (8ml/kg=200μl/25g Aqua ad injectabile; Group 1 ), compound 2 (arsenobetaine, 1300mg/kg) was administered 1x daily orally (p.o.) (see Table 1 ).

Table 1 : study design (MDA-MB-231)

1 ) All animals listed here share the common suffix /13; 2) which equals to 200μΙ per 25g mouse Tumor implantation

On day O, 5x10⁶ MDA-MB-231 tumor cells in 100μΙ PBS was implanted subcutaneously (s.c.) into the left flank of female BALB/c nude mice (MDA-MB-231 ), using a 29G needle syringe. In the following, animal weights were measured (balance: Mettler Toledo PB602-L). Primary tumors were measured by calipering (manual caliper, OMC Fontana). Tumor sizes were calculated according to the formula W²xL/2 (L= length and W= the perpendicular width of the tumor, L>W). On day 41 , after a mean tumor volume of approx. 200mm³ was reached, tumor-bearing animals were randomized into according to tumor sizes. On the same day, treatment with Vehicle and arsenobetaine (compound 2) was initiated (see Table 1 ). Treatment of the animals was made by oral gavage (p.o.). The frequency of administration MDA-MB-231 : on days 41-45, 48-52 and 55-59. The dose volume of 8ml/kg (equals to 20C^I/25g mouse) was used. Volumes were adjusted according to individual animal weights.

Animal weights increased continuously until start of treatment on day 41 . After start of each of the three treatment cycles (days 41 -45, 48-52 and 55-59, respectively) animal weights of both groups started to decrease but recovered always after completion of each treatment cycle.

In vivo findings

Tumor growth was homogeneous within both groups until start of treatment on day 41 (Figure 1 ). In the following, regular tumor growth could be observed in case of the Vehicle Control (Group 1 ). In the case, where animals were treated with 1300 mg/kg arsenobetaine (Compound 2), a noticeable and comparable inhibition of tumor growth could be observed as measured on day 64 (Figure 2).

Necropsy findings

Primary tumor volumes and wet weights were determined during necropsy on day 64 (Figures 3 and 4). The obtained results correspond to the in vivo findings, presented above. A noticeable and comparable, antitumoral efficacy could be addressed to arsenobetaine in the MDA-MB-231 tumor model.

Antitumoral efficacy of arsenobetaine against human breast cancer MDA-MB-231 tumors, growing as subcutaneous xenografts in BALB/c nude mice

This study was performed using female BALB/c nude mice after randomization. Beside the Vehicle Control Aqua ad injectabile (Group 1 ), the effect of arsenobetaine (Group 2) was evaluated in this study part.

At day 64, this study part was terminated due to ethical reasons (tumor burden, tumor ulceration), all animals sacrificed and a necropsy performed. After start of each of the three treatment cycles animal weights of both groups started to decrease but recovered always after completion of each treatment cycle. Based on both the in vivo monitoring of tumor growth as well as the necropsy findings, a noticeable antitumoral efficacy could be addressed to arsenobetaine in the MDA-MB-231 tumor model.

Claims

1. A compound of Formula (I) or a pharmaceutically acceptable salt thereof

R¹

R²— As— R⁴

R³

Formula (I)

for use in therapy, wherein

R¹, R² and R³ are independently alkyl;

L is optionally substituted aryl;

X is absent, alkylene or -NHC(0)(CH₂)_n-;

n is 0 or an integer between 1 and 20;

L' is alkyl;

R¹⁰ and R¹¹ are independently optionally substituted heterocycloalkyi;

R¹² is -OR¹³;

R¹³ is optionally substituted alkyl; and

= is a single bond or a double bond, and wherein when it is a single bond, the

As ion has a positive charge.

2. The compound of claim 1 , wherein said compound is a compound of Formula (la):

R

7 ' ⁺ 4

R²-As R⁴

R³

Formula (la) wherein R⁴ is selected from the group consisting of optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted alkenyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted heteroaryl, optionally substituted aryl, optionally substituted carboxyalkyl, optionally substituted hydroxyalkyl, halo, -OR⁵, -COOR⁶, -CN, -NR⁷R⁸, -SR⁹, L-X-SR⁹, -L'-R¹⁰ and -L'-R¹¹-R¹²; and

R¹, R², R³, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹ , R¹², R¹³, X, L, L' and n are as defined above for Formula (I) of claim 1.

3. The compound of claim 1 , wherein said compound is a compound of Formula (lb):

R

R²-As=R⁴

I

R³

Formula (lb)

wherein R⁴ is =0; and

R¹, R² and R³ are as defined above for Formula (I) of claim 1 .

4. The compound according to any preceding claim, wherein R¹, R² and R³ are independently C_1-2o alkyl, preferably C_1-12 alkyl, more preferably C_1-6 alkyl, and more preferably methyl.

5. The compound according to any of claims 1 , 2 or 4 wherein R⁴ is selected from the group consisting of optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted carboxyalkyl, optionally substituted hydroxyalkyl, =0, -SR⁹, L-X-SR⁹, -L'-R¹⁰ and -L'-R¹¹-R¹².

6. The compound according to claim 5, wherein R⁴ is selected from the group consisting of optionally substituted Ci_-6 alkyl, optionally substituted C_2-6 carboxyalkyl, optionally substituted Ci_-20 hydroxyalkyl, -L'-R¹⁰ and -L'-R¹¹-R¹².

7. The compound according to claim 6, wherein R⁴ is optionally substituted C_2-4 carboxyalkyl.

8. The compound according to claim 1 or claim 2, wherein said compound is a compound of Formula (lc):

Formula (lc)

wherein R¹³, R ⁴, R ⁵, R¹⁶, R¹⁷ and R ⁸ are independently selected from the group consisting of H, =0, -OH, -COOH, -S0₃H, and -OS0₃H.

9. The compound according to claim 1 or claim 2, wherein said compound is a compound of Formula (Id):

Formula (Id)

wherein R¹⁹, R²⁰ and R²¹ are independently selected from the group consisting of H, -OH, -OR¹², -SO₃H, and -OSO₃H; and

R¹³ is as defined above for Formula (I) of claim 1.

10. The compound according to claim 9, wherein said compound is a compound of Formula (le):

Formula (le)

wherein R²² is selected from the group consisting of H, -OH and -OR¹³; and R¹³ is as defined above for Formula (I) of claim 1.

1 1 . The compound according to claim 1 , wherein R⁴ is glutathionyl or N-(S- glutathionylacetyl)amino)aryl.

12. The compound according to any of claims 1-2 and 4-1 1 , wherein L' is Ci_-6 alkyl, preferably Ci_-3 alkyl and more preferably a methylene group.

13. The compound according to claim 1 , wherein R¹, R² and R³ are each Ci_-6 alkyl, and R⁴ is selected from the group consisting of optionally substituted Ci_-6 alkyl, optionally substituted C₂-₆ carboxyalkyl, optionally substituted Ci_-2o hydroxyalkyl, =0, -L'-R¹⁰ and -L'- R¹¹-R¹².

14. The compound according to claim 13, wherein R¹, R² and R³ are each methyl, and R⁴ is optionally substituted alkyl or optionally substituted C_2-6 carboxyalkyl.

15. The compound according to any of claims 1 -2 and 4-14, wherein R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹ and R¹³ are optionally substituted by one or more substituents independently selected from the group consisting of halo, aliphatic, heteroaliphatic, alkoxy, oxo, alkylamino (monoalkylamino or dialkylamino), -NH₂, -N0₂, -OH, -COOH, - S0₃H, -CN, -OSO₃H, hydroxyalkyl, alkylcarbonyloxy, alkoxycarbonyl, alkylcarbonyl, carboxyalkyl and alkylsulfonylamino.

16. The compound of claim 15, wherein said one or more substituents are selected from the group consisting of halo, alkoxy, oxo, -COOH, -NH₂, N0₂, -OH, -SO₃H, -OSO₃H and -CN.

17. The compound of claim 16, wherein said one or more substituents are selected from the group consisting of -OH, -COOH, halo and -OSO₃H.

18. The compound according to claim 1 , wherein the compound of Formula (I) is selected from:

d according to claim 18, wherein said compound of Formula (I)

20. A compound as claimed in any one of claims 1 to 19 for use in the prevention and/or treatment of cancer.

21 The compound as claimed in any one of claims 1 to 20 for use in the prevention and/or treatment of breast, ovarian, uterine, endometrial, cervical, womb, testis, thyroid, osteosarcoma and/or prostate cancer.

22. 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.

23. The pharmaceutical composition of claim 22, for use in preventing and/or treating cancer.

24. The pharmaceutical composition of claim 22 or claim 23, for use in preventing and/or treating breast, ovarian, uterine, endometrial, cervical, womb, testis, thyroid, osteosarcoma and/or prostate cancer.

25. A method for preventing and/or treating cancer 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 1 to 19 or a pharmaceutical composition as defined in claim 22.

26. The method of claim 25 for preventing and/or treating breast, ovarian, uterine, endometrial, cervical, womb, testis, thyroid, osteosarcoma and/or prostate cancer.