WO2009081366A1

WO2009081366A1 - Palladium and platinum phosphine complexes and their use as anti-tumour agents

Info

Publication number: WO2009081366A1
Application number: PCT/IB2008/055457
Authority: WO
Inventors: Richard John Bowen
Original assignee: Richard John Bowen
Priority date: 2007-12-20
Filing date: 2008-12-19
Publication date: 2009-07-02

Abstract

This invention relates to novel palladium (Pd) and platinum (Pt) phosphine complexes. The invention further relates to their use, more particularly, but not exclusively, as anti tumour agents. According to a first aspect of the invention there is provided a complex having the general Formula (I); wherein: (i) M is a Pt or Pd metal; (ii) Formula (II) and Formula (II) are ligands wherein P is bound to M and wherein (a) A may be a (CH2)n group wherein n is 2, 3, cis CH=CH or CΞC, (b) R1, R2, R3, R4, R5, R6, R7 and R8 are the same or different and may be selected from the group consisting of phenyl, substituted phenyl, 4-pyridyl, substituted 4-pyridyl, 3-pyridyl, substituted 3-pyridyl, 2-pyridyl and substituted 2-pyridyl, (iii) X may be a monovalent anion or 2X may be a divalent anion, and (iv) M's metal centre is co-ordinatingly saturated such that X is unable to bind with M The present invention also relates to the use of a complex of Formula (I) in the manufacture of a medicament for the inhibition of tumours

Description

PALLADIUM AND PLATINUM PHOSPHINE COMPLEXES AND THEIR USE AS

ANTI-TUMOUR AGENTS

Field of the Invention

This invention relates to novel palladium (Pd) and platinum (Pt) phosphme complexes The invention further relates to their use, more particularly, but not exclusively, as anti tumour agents

Background to the Invention

Bis-chelated V2 M(I) diphosphine complexes of the type [M(R₂P(CHz)_nPRs)_Z]⁺, where M = Au(I), Ag(I) or Cu(I) and R = aryl, n = 2 or 3 and analogous complexes with cis- R₂PCH=CHPR₂, exhibit antitumour activity against a range of tumour models (Berners-Price et al 1988) In particular, the Au(I) complex [Au(dppe)₂]CI (where dppe is 1 , 2 bιs(dιphenylphosphino)ethane) (Figure 1 ) showed potent activity against a range of tumour models in mice and was active in a ctsplatin-resistant subline of P 388 leukaemia (Berners-Price et aϊ 1986) indicating that this class of compound may have potential for the treatment of cisplatin resistant tumours

Fig 1 [Au(dppe)₂]Ci

While evidence suggests that mitochondria are implicated in the mechanism of cytotoxicity for this class of compound (Berners-Price et al 1996, Dong et al 1997), the clinical development of [Au(dppe)₂JCI was precluded as a result of toxic side effects associated with altered mitochondrial function (Hoke et al 1988, Smith et al 1989)

Since the lipophilic cationic properties of [Au(dppe)₂]CI promote its non-selective uptake in mitochondria of all cells, with heart and liver tissue being particularly sensitive owing to the higher numbers of mitochondria, the strategy of developing more hydrophiJic analogues that may retain the antitumour activity, while being less toxic to mitochondπa was adopted in recent work (Bowen 1999, Berπers-Pπce et al 1999) In order to retain aromatic substituents that appear to be important for antitumour activity, all the phenyl groups in dppe were replaced with hydrophthc pyπdyl groups These varieties were designed to encompass a range of water solubilities by being representative of symmetric, unsymmetric and asymmetric bidentate phosphine ligands In doing so, by replacing the phenyl groups with pyπdyl substituents (R = 2-pyrιdyl, 3-pyrιdyl or 4- pyπdyl) in order to vary the hydrophilic character (Berners-Pπce et al 1998, Berners-Pπce et al 1999, 1337), complexes which exhibited differences in cellular uptake and hence differences in antitumour selectivity, potency and hepatoxicity were achieved (Berners-Price et al 1997, Berners-Price et al 1999, McKeage et al 2000)

In undertaking these investigations, ft became apparent that the position of the N atom in the pyndyl ring finely modulated the hpophilic-hydrophilic balance by influencing the structural types that exist for Au(I), Ag(I) and Cu(I) complexes (Bowen 1999) The different solubility profile of these complexes influences their cellular uptake and hence differences in antitumour activity and selectivity (Bowen 1999).

Complexes of other metals and implications for mode of action

It has been suggested that the phosphine itself is the cytotoxic agent and the role of the metal may be largely to protect the phosphine and deliver it to cellular targets (Berners-Pπce et al 1988) The biological profile of the Group 11 diphosphine complexes may result from their high lipophihcity which allows them to penetrate cells and their high kinetic and thermodynamic stability which prevents unwanted side reactions in vivo (Berners-Pπce et al 1988). In addition, the requirement of sufficient lability in the metal-P bond has been proposed, so that the phosphine itself is released at the target site (Berners-Price et al 1987) The Rh(I) complex RhCi(PPh₃)dppe turned out to be inactive against P388 leukaemia (Johnson et al 1985, MirabeSli et al 1987) Substituting Pt(II), Pd(II) and Ni(II) in complexes having the general formula [MCl₂(dppe)] unexpectedly turned out to be inactive against leukaemia as well, even though the skilled person would have expected them to have similar activity to [Au(dppe)₂]CI complexes Some say that the lack of effectiveness can be attributed to the kinetic stability of the M-P bonds, thus circumventing release of the phosphine at the target site or the non-cationsc nature of these complexes Other dppe complexes of for example Pt(II) and Pd(II) were found to be less active than the phosphine alone as shown in Khohkar et al , 1990. while the Pd analogues of [Au(dppe)₂]CI, {[Pd(dppe)₂]CI₂ and [Pd{dppen);]Ci₂} (where dppen is 1 , 2- bis (diphenylphosphino) ethylene) showed iow potency against a tumour cell hne composed of murine and human tumour cell lines (Schuπg et al 1989)

Again, while these complexes are lipophilic, it is plausible that the cationic nature of these complexes is diminished in solution with equilibria involving the binding of halide to the metal centre possible The iow ants-tumour activity of palladium complexes has been attributed to rapid hydrolysis processes leading to easy dissociation in solution of leaving groups and to the formation of very reactive species unable to reach their pharmacological targets (Akdi et al 2002)

In considering this data and the work relating to the 1 2 adducts of Ag(I), Au(I) and Cu(I) with 1 ,2-bιs(dι-π-pyπdylphosphιno)ethane (dnpype) for n=2, 3 and 4, it has been suggested that rather than the metal simply acting as a carrier for the cytotoxic ligand, it may be the overall lipophilic cationic character of the complexes that is important for antitumour activity (Berners-Price et al 1999)

The introduction of cispfatm and other platinum-based drugs into the clinical treatment of cancer has resulted in dramatic improvements in the response rates for some tumour types, in particular, testicular, ovaπan and bladder cancers A major clinical limitation to their efficacy is the occurrence of tumours that are resistant to these drugs

The Applicant now hypothesises that a critical reason for the low potency or inactivity of previously prepared and tested phosphine complexes of Pt and Pd is, that with respect to this class of compounds, the scientific community was not taking into account the requirement of preserving the cationic nature of the complex in solution, in addition to the requirements of stability and lipophiticity

It is believed by the Applicant that the cationic nature of the complex will be retained by having M co-ordinatingly saturated with phosphorus donor atoms and optionally including a non co-ordinating anion in the complex The selectivity of such drugs may be enhanced by adjusting the lipophiliαty of the drug by replacing one or more of the phenyl substituents of the complex with 2-, 3-, or 4-pyπdyl groups The potential significance of the Applicant's invention is that complexes of the invention appear to have a different mechanism of action to other drugs in clinical use by selectively targeting the mitochondria of transformed cells. Furthermore, the complexes of the present invention offer great potential value for combination chemotherapy or for treatment of cancers that are resistant to other anti-cancer drugs and, in particular, cispiatin owing to a potentially different mode of action

Object of the Invention

It is an object of the invention to provide novel palladium and platinum phosphine complexes It is a further object of the invention to provide novel palladium and platinum phosphine complexes whtch exhibit anti tumour characteristics that overcome or at least minimise the disadvantages set out above

It is also a further object of the invention to provide novel palladium and platinum phosphine complexes for use in the treatment and inhibition of tumours

Yet a further object of the invention is to provide cationic palladium and platinum phosphine complexes in which selectivity towards tumour cells can be achieved by finely modulating the hydrophiliolipophiiic balance of the complex

Summary and Description of the Invention

According to a first aspect of the invention there is provided a complex having the general formula I,

wherein

(i) M is a Pt or Pd metal,

(if) R₁ R,

and

π y

H A r

are ligands wherein P is bound to M and wherein

(a) A may be a (CH₂)_n group wherein n is 2, 3, cis CH=CH or C=C

(b) R₁, R₂, R₃, R4, R5. Re. R? and R₈ are the same or different and may be selected from the group consisting of phenyl, substituted phenyl, 4-pyrιdyl, substituted 4-pyπdyl, 3-pyπdyi, substituted 3-pyπdyl, 2-pyπdyl and substituted 2-pyπdyl,

(HI) X may be a monovalent anion or 2X may be a divalent anion, and

<ιv) M's metal centre is co-ordinatingly saturated such that X is unable to bind with M

in one embodiment of the invention at least one of R₁, R₂, R₃, R₄, R₅, R₆, R₇ and R₈ is selected from the group consisting of phenyi, substituted phenyl, 4-pyπdyl, substituted 4-pyrιdyl, 3-pyrιdyl, substituted 3-pyrιdyl, 2-pyπdyl and substituted 2- pyπdyl. It is envisaged by the Applicant that preparing the 2-, 3- and 4-pyπdyi analogue complexes of formula I will reveat that the position of the N atom wilt modulate the hydrophilic-lipohihc balance of the complexes and modify selectivity and cytotoxic properties of anti-neoplastic drugs containing Platinum Group Metals

Appropriate substituents on the phenyl and/or 4-pyrιdyl, 3-pyrιdyl, 2-pyrιdyl ring include nitro, sulphonate, halogen, Ci_-4 alkyl, haloalkyl, alkoxy inclusive of methoxy and ethoxy, oxygen, hydrogen, acyl (e g acetyl), ammo, acylamino, alkylamino, aldehyde, hydroxy, hydroxylalkyl and derivatives thereof, thiol, thiol substituted with CM alkyl, amide, keto, carboxylate including dι- and trt-carboxylate, sulphoxy, sulphoxyalkyl, sulphoxide, sulphone, amide derivatives with the C₁₄ alkyl substituent, sulphate esters, hydroxyesters, phosphate esters, carboxylic acid esters inclusive of acetate, sulphonic acid and phosphinic acid It will be appreciated that where R₁, R₂, R₃, R₄, R₅, R₆, R₇ and R₈ are selected from the group consisting of substituted 4-pyπdyl, substituted 3-pyrιdyl and substituted 2- pyπdyl, the abovementioned substituents may either be substitυents on one or more C atom of the pyridyl ring or substituents on the nitrogen atom of the pyπdy! ring

The Applicant strongly believes that the abovementsoned substituents on the phenyl and/or pyπdy! ring are unlikely to adversely affect the anti-tumour activity of the complex of formula I provided that (i) the metal complexes of these substituted phosphines are stable, (n) the complexes retain cationic properties in solution, and (in) the complexes are lipophilic.

It is envisaged by the Applicant that unlike previous studies of phosphine complexes of Platinum Group Metals, the complex of the present invention defined by formula I will exhibit enhanced antitumour activity provided that some lipophilic cationic nature of the complex is retained in solution Accordingly, the Applicant believes that the retention of some lipophilic catsonic nature requires the metal M to have a centre which is co-ordinatmgly saturated by phosphorus donor atoms and optionally that a non-coordinating anion is incorporated in the complex to ensure that the anion is excluded from the coordination sphere

In one embodiment of the invention, X may be nitrate, bromide, chloride, iodide, hexafluorophosphate or any other non-toxic anion Preferably X is a non coordinating anion

For the purposes of this specification, the term "non-toxic anion" is meant to refer to any anion that has minimal or benign toxicity as discussed in U S Pat No 5,037,812

In an embodiment of the invention, preferred anions are those available in pharmaceutical or food grade The pharmaceutical acceptability of a particular anion can be determined by conventional techniques for determining toxicology.

Suitable pharmaceutically acceptable anions include monocarboxylates (e g formate, acetate, lactate, hippurate, ammo acids), di and tri-carboxylates (e g malonate, citrate), phosphates and phosphate esters, phospholipids, sulphates, carbonates, bicarbonates, halides, nitrates, PF₆, methanesuifonate, 2- hydroxypropanoate, glucuronate, cyanate, citrate, trifluoromethane-sulfonate, 2- oxopropanoate, 4-hydroxyibutaπoate, hydroxy-acetate, 2-hydroxybutanoate, 2,3- dihydroxypropanoate, 2-hydroxyethy[ sulfonate {isethionate), 2-hydroxypropanoate (lactate), 2-oxopropanoate, hydroxy acetate and 2,3-dihydroxypropanoate

According to a second aspect of the invention there is provided a complex of formula i as hereinbefore described for use in the treatment or inhibition of tumours

According to a third aspect of the invention there is provided the use of a complex of formula I as hereinbefore described in the manufacture of a medicament for the inhibition of tumours

According to a fourth aspect of the invention there is provided a pharmaceutical composition comprising a pharmaceutically acceptable earner and a complex of formula I as hereinbefore described for treating or inhibiting tumours

The invention will now be described with reference to the following non-limiting example

Example of performing the invention

In the example that follows, the preparation procedure was carried out under inert conditions The solvent (either diethyl ether or tetrahydrofυran) was dried, distilled and degassed according to standard procedures prior to use

Preparation of complexes of d3pyrpe [i.e 1,2-bιs(di-3-pyndylphosphmo)θthane]

[Pd(d3pyrpe)₂].2 PF₆

Two stoichiometric equivalents of R¹R²P - Y - PR¹R² where R¹ and R² are both 3- pyπdyl and Y is CH₂CH₂ was reacted with Na₂PdCI₄ to produce an analogue of formula I in which X is chloride, R¹ and R² are both 3-pyπdyl and Y is CH₂CH₂

Said analogue was reacted with two stoichiometric equivalents of NH₄PF₆ in a metathesis reaction wherein the potentially coordinating chloride anion is exchanged by the weakly coordinating anion, PF₆ ^" The resulting product, namely an analogue of formula I in which R¹ and R^z are both 3-pyndyl, Y is CH₂CH₂ and X is PF₆ , was then collected by filtration and recrystallised to a constant melting point. References

Berners-Price S. J. and Sadler P. J., Struct. Bonding (Berlin), 1988, 70, 27.

Berners-Price S. J., Mirabelli C. K., Johnson R. K., Mattern M. R., McCabe F. L., Faucette L. F., Sung C. -M., Mong S. -M., Sadler P. J. and Crooke S. T., Cancer Res., 1986, 46, 5486.

Berners-Price S. J. and Sadler P. J., Coord. Chem. Rev., 1996, 151 , 1.

Dong Y., Bemers-Price S. J., Thorburn D. R., Antalis T,, Dickinson J., Hurst

T., Qui L., Khoo S. K. and Parsons P. G., Biochem. Pharmacol., 1997, 53,

1673.

Hoke, G. D., Rush G. F., Bossard G. E., McArdie J. V., Jensen B. D. and Mirabelli C. K., J. Biol. Chem., 1988, 263, 11203.

Smith P. F., Hoke G. D., Alberts D. W., Bugelski P. J., Lupo S., Mirabelli C. K. and Rush G. F., J. Pharmacol. Exp. Therap., 1989, 249, 944.

Bowen R. J., PhD Thesis, 1999

Berners-Price SJ, Bowen RJ, Galettis P, Healy PC, McKeage, Structural and solution chemistry of gold(l) and silver(l) complexes of bidentate pyridyl phosphines: selective antitumour agents, Coord. Chem. Revs., 1999, 185-186: 823-836

Berners-Price S. J., Bowen R. J., Harvey P. J., Healy P. C. and Koutsantoπis G. A., J. Chem. Soc, Dalton Trans., 1998, 1743.

Berners-Price S. J., Bowen R. J., Hambley T. W. and Healy P. C, J. Chem. Soc, Dalton Trans., 1999, 1337.

Berners-Price S. J. and Sadler P. J., Chem. Brit, 1987, 23, 541. Johnson R K , Mirabeili C K , Faucette L F McCabe F L , Sutton B M , Bryan D L , Girard G R and Hill D T , Proc Amer Assoc Cancer Res , 1985, 26, 254

Mirabelii C K , Hill D T , Faucette L F , McCabe F L , Girard G R., Bryan D L , Sutton B M , Bartus J O , Crooke S T and Johnson R K ₁ J Med Chβm , 1987, 30, 2181

Khohkar A R , Xu Q and Siddik Z H, J lnorg Biochem , 1990, 39, 117

Schυπg J, Meinema H, Timmer K, Long B, Casazza A, Antitumor activity of bιs[bιs(dιphenylphosphιno)alkane and alkene] group VII metal complexes, Prog.Clin Biochem Med , 1989, 10 205-216

Akdi K, Vilaplana R, Kamah S, Navarro J, Salas J, Gonzalez-Vilchez F , Study of the biological effects and DNA damage exerted by a new dipalladium- Hmtpo complex on human cancer cells, J lnorg Biochem , 2002, 90 51-60

Claims

1 A complex having the general formula I

2 +

2 X (D

Re

wherein

(ι) M is a Pt or Pd metal,

<«>

and

R, *7

X

are ligands wherein P is bound to M and wherein (a) A is a (CH₂)_n group wherein n is 2, 3, cis CH=CH or CΞC

(b) Ri, R₂, R₃, R₄, R₅, R₆ R₇ and R₅ are the same or different and are selected from the group consisting of phenyl, substituted phenyl, 4-pyπdyl, substituted 4-pyπdyi, 3-pyrιdyl, substituted 3-pyrιdy!, 2-pyrιdyl and substituted 2-pyπdyl,

(in) X may be a monovalent anion or 2X may be a divalent anion, and

(ιv) M¹S metai centre is co-ordinatingly saturated such that X is unable to bind with M

The complex according to claim 1 , wherein at least one of Ri, R₂, Re, R₄, R₅, R₆, R₇ and R₈ is selected from the group consisting of phenyl, substituted phenyl, 4-pyndyl, substituted 4-pyrιdyl, 3-pyπdyl, substituted 3-pyndyl, 2- pyπdyl and substituted 2-pyrιdyl

The complex according to claim 1 , wherein substituents on the phenyl and/or 4-pyrιdyl, 3-pyπdyl, 2-pyrιdyl ring include nitro, sulphonate, halogen, C_w aikyl, haloalkyl, alkoxy inclusive of methoxy and ethoxy, oxygen, hydrogen, acyl (e g acetyl), amino, acyiamino, alkylamino, aldehyde, hydroxy, hydroxylalkyl and derivatives thereof, thiol, thiol substituted with C_1-4 alkyl, amide, keto, carboxylate including di- and tπ-carboxylate, sulphoxy, sulphoxyalkyl, sulphoxide, sulphone, amide derivatives with the C_H alkyl substituent, sulphate esters, hydroxyesters, phosphate esters, carboxylic acid esters inclusive of acetate, sulphonic acid and phosphinic acid

The complex according to claim 1, wherein X is nitrate, bromide, chloride, iodide, hexafluorophosphate or any other non-toxic anion

The complex according to claim 1 or claim 4, wherein X is a non co-ordinating anion

The complex according to any one of claims 1 , 4 or 5, wherein X is a pharmaceutically acceptable anion The complex according to claim 6, wherein the pharmaceutically acceptable anion is selected from the group consisting of monocarboxyiates (e g formate, acetate, lactate, hippurate, amino acids), di and tπ-carboxylates {e g malonate, citrate), phosphates and phosphate esters, phospholipids, sulphates, carbonates, bicarbonates, haltdes, nitrates, PF₆, methanesulfonate, 2-hydroxypropanoate, giucuronate, cyanate, citrate, tπfluoromethane-sulfoπate, 2-oxopropanoate, 4-hydroxylbutanoate, hydroxy- acetate, 2-hydroxybutanoate, 2,3-dιhydroxypropaπoate, 2-hydroxyethyl sulfonate (isethionate), 2-hydroxypropanoate {lactate), 2-oxopropanoate, hydroxyacetate and 2,3-dιhydroxypropanoate

A complex according to claim 1 for use in the treatment or inhibition of tumours

The use of a complex according to claim 1 in the manufacture of a medicament for the inhibition of tumours

A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a complex according to claim 1 for treating or inhibiting tumours