WO2018170553A1 - Complexes et leurs utilisations - Google Patents

Complexes et leurs utilisations Download PDF

Info

Publication number
WO2018170553A1
WO2018170553A1 PCT/AU2018/050267 AU2018050267W WO2018170553A1 WO 2018170553 A1 WO2018170553 A1 WO 2018170553A1 AU 2018050267 W AU2018050267 W AU 2018050267W WO 2018170553 A1 WO2018170553 A1 WO 2018170553A1
Authority
WO
WIPO (PCT)
Prior art keywords
aryl
heteroaryl
cycloalkyl
alkyl
cycloalkenyl
Prior art date
Application number
PCT/AU2018/050267
Other languages
English (en)
Inventor
Massimiliano MASSI
Peter Vernon SIMPSON
Marco Falasca
Original Assignee
Curtin University Of Technology
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from AU2017901034A external-priority patent/AU2017901034A0/en
Application filed by Curtin University Of Technology filed Critical Curtin University Of Technology
Publication of WO2018170553A1 publication Critical patent/WO2018170553A1/fr

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4196—1,2,4-Triazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/42—Oxazoles
    • A61K31/421—1,3-Oxazoles, e.g. pemoline, trimethadione
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/426—1,3-Thiazoles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F13/00—Compounds containing elements of Groups 7 or 17 of the Periodic System

Definitions

  • the present invention generally relates to rhenium complexes that are useful in the treatment of cancer.
  • the present invention also relates to processes for preparing the rhenium complexes .
  • Cancer is one of the leading causes of death and, as such, the drive to discover new anti-cancer drugs is an expanding area of research.
  • One class of frontline anti-cancer agents are the platinum-based drugs cisplatin, carboplatin, and
  • oxaliplatin oxaliplatin. These agents are extremely effective at eradicating cancer cells (either alone or in combination with other treatments, but suffer from severe side-effects and poor activity against platinum-resistant cancers.
  • organometallic and inorganic complexes have been studied extensively as anti-cancer agents as an alternative to organic-based drugs.
  • gold, platinum, and ruthenium have attracted considerable attention and have been shown to be particularly
  • Organometallic complexes of rhenium that contain the robust Re (CO) 3 fragment have recently shown potential as cytotoxic agents, but they have been far less studied. All the reported cytotoxic rhenium complexes contain bidentate or tridentate ligands of nitrogen, oxygen, and phosphorous donors, a chemical design that seems to be predominantly inspired by the use of these species as luminescent cellular markers . Other rare examples include rhenium complexes bearing cyclopentadienyl ligands. However, the mechanism of action of these rhenium complexes has not been established in detail yet, which hinders the
  • the present invention relates to rhenium complexes, more specifically rhenium complexes bound to C-donor N- heterocyclic carbene (NHC) ligands and their use in treating of cancer and inhibiting Aurora kinase
  • a method for treatment or prophylaxis of a cancer comprising administering an effective amount of a rhenium complex of formula (I) to a subject in need thereof:
  • ring A is selected from one of the following
  • Y is CR 6 or N
  • Z is CR 7 or N
  • Ri is selected from halo, thiocyanate, isothiocyanate , alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl , aryl, heterocyclyl , heteroaryl, -Ci-6alkylaryl , -Ci- 6 alkylheteroaryl, -C 2 - 6 alkenylaryl, C 2 - 6 alkenylheteroaryl, -C2-6alkynylaryl and -C2-6alkynylheteroaryl ;
  • R 2 and R 3 are independently selected from H, halo, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heterocyclyl, heteroaryl, alkoxy and acyl;
  • cycloalkyl cycloalkenyl, aryl, heterocyclyl or heteroaryl ring
  • R4 is selected from alkyl, alkenyl, alkynyl,
  • cycloalkyl cycloalkenyl, aryl, heteroaryl, -Ci-6alkylNRsR9 , -Ci- 6 alkylORio and -Ci- 6 alkylP (R13) m ;
  • each of Rs a , Rsb, Rsc and Rsd is independently selected from H, halo, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heterocyclyl, heteroaryl, alkoxy or acyl;
  • R6 and R7 are independently selected from H, halo, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heterocyclyl, heteroaryl, alkoxy and acyl;
  • R2 and R7 together with the carbon atoms to which they are attached form an optionally substituted cycloalkyl, cycloalkenyl , aryl, heterocyclyl or heteroaryl ring;
  • R.8 and Rg is H and the other is selected from the group consisting of H, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heterocyclyl, heteroaryl and -C (O) Rn;
  • Rio is selected from alkyl, alkenyl, alkynyl,
  • cycloalkyl cycloalkenyl, aryl, heterocyclyl, heteroaryl and -C (O) Rn;
  • Rn is selected from alkyl, alkenyl, alkynyl,
  • each Ri3 is independently selected from alkyl, cycloalkyl, aryl, heterocyclyl and heteroaryl;
  • alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heterocyclyl and heteroaryl group may be optionally substituted.
  • the present invention provides use of a rhenium complex of formula (I) as defined above in the manufacture of a medicament for treatment or
  • a further aspect of the present invention provides a method for treatment or prophylaxis of a disease
  • a rhenium complex of formula (I) as defined above in the manufacture of a medicament for treatment or prophylaxis a disease associated with Aurora kinase activity.
  • a further aspect of the present invention provides an Aurora kinase phosphorylation inhibitor comprising a rhenium complex of formula (I) as defined above.
  • Another further aspect of the present invention provides a method of inhibiting Aurora kinase
  • phosphorylation comprising exposing a cell comprising an Aurora kinase to a rhenium complex of formula (I) as defined above.
  • Another yet further aspect of the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a rhenium complex of formula (I) as defined above and a
  • Another still further aspect of the present invention provides a rhenium complex of formula (la) :
  • ring A is selected from one of the following
  • Y is CR 6 or N;
  • Z is CR 7 or N;
  • Ri is selected from halo, thiocyanate, isothiocyanate , alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl , aryl, heterocyclyl , heteroaryl, -Ci-6alkylaryl ,
  • R 2 and R 3 are independently selected from H, halo, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heterocyclyl, heteroaryl, alkoxy and acyl;
  • cycloalkyl cycloalkenyl, aryl, heterocyclyl or heteroaryl ring
  • R4 is selected from alkyl, alkenyl, alkynyl,
  • cycloalkyl cycloalkenyl, aryl, heteroaryl, -Ci-ealkylNRsRg,
  • R5b, R5c and Rsd are each independently selected from H, halo, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heterocyclyl, heteroaryl, alkoxy or acyl;
  • R6 and R7 are independently selected from H, halo, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heterocyclyl, heteroaryl, alkoxy and acyl;
  • cycloalkyl cycloalkenyl, aryl, heterocyclyl or heteroaryl ring
  • Re and Rg is H and the other is selected from the group consisting of H, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heterocyclyl, heteroaryl and -C (O) Rn;
  • Rio is selected from alkyl, alkenyl, alkynyl,
  • cycloalkyl cycloalkenyl, aryl, heterocyclyl, heteroaryl and -C (O) Rn;
  • Rn is selected from alkyl, alkenyl, alkynyl,
  • each Ri3 is independently selected from alkyl, cycloalkyl, aryl, heterocyclyl and heteroaryl;
  • cycloalkenyl , aryl, heterocyclyl and heteroaryl group may be optionally substituted
  • R 4 is n-butyl or mesityl, Ri is not CI o
  • R4 is mesityl, Ri is not CI or Br;
  • R5b, R5c, R5d are each hydrogen and R 4 is butyl, Ri is not CI or Br, Detailed description
  • an element means one element or more than one element.
  • alkyl refers to a straight chain or branched saturated hydrocarbon group having 1 to 15 carbon atoms. Where appropriate, the alkyl group may have a specified number of carbon atoms. For example,
  • Ci-6alkyl which includes alkyl groups having 1, 2, 3, 4, 5 or 6 carbon atoms in a linear or branched arrangement.
  • suitable alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, n-pentyl, 2-methylbutyl, 3-methylbutyl , 4-methylbutyl, n-hexyl, 2-methylpentyl, 3-methylpentyl , 4-methylpentyl , 5-methylpentyl, 2-ethylbutyl ,
  • alkenyl refers to a straight chain or branched hydrocarbon group having one or more double bonds between carbon atoms and having 2 to 15 carbon atoms. Where appropriate, the alkenyl group may have a specified number of carbon atoms. For example, C 2 -C6 as in "C 2 -C 6 alkenyl” includes groups having 2, 3, 4, 5 or 6 carbon atoms in a linear or branched arrangement.
  • alkenyl groups include, but are not limited to, ethenyl, propenyl, isopropenyl, butenyl, butadienyl, pentenyl, pentadienyl, hexenyl, hexadienyl, heptenyl, octenyl, nonenyl, decenyl, undecenyl and dodecenyl.
  • alkynyl refers to a straight chain or branched hydrocarbon group having one or more triple bonds and having 2 to 15 carbon atoms . Where appropriate, the alkynyl group may have a specified number of carbon atoms.
  • C 2 -C6 as in "C 2 -C 6 alkynyl” includes groups having 2, 3, 4, 5 or 6 carbon atoms in a linear or branched arrangement.
  • suitable alkynyl groups include, but are not limited to ethynyl, propynyl, butynyl, pentynyl and hexynyl .
  • cycloalkyl refers to a saturated cyclic hydrocarbon.
  • the cycloalkyl ring may include a specified number of carbon atoms.
  • a 3- to 8-membered cycloalkyl group includes a ring having 3, 4, 5, 6, 7 or 8 carbon atoms.
  • suitable cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,
  • cycloalkenyl refers to an unsaturated cyclic hydrocarbon.
  • the cycloalkenyl ring may include a specified number of carbon atoms.
  • a 5- to 8-membered cycloalkenyl group includes 5, 6, 7 or 8 carbon atoms.
  • the cycloalkenyl group has one or more double bonds and when more than one double bond is present, the double bonds may be unconjugated or
  • Suitable cycloalkenyl groups include, but are not limited to, cyclopentenyl ,
  • cycloheptadienyl cycloheptatrienyl, cyclooctenyl , cyclooctadienyl and cyclooctatrienyl.
  • aryl is intended to mean any stable, substituted or unsubstituted monocyclic, bicyclic or tricyclic carbon ring system of up to 7 atoms in each ring, wherein at least one ring is aromatic.
  • aryl groups include, but are not limited to, phenyl, mesityl, naphthyl, tetrahydronaphthyl , indanyl, fluorenyl, phenanthrenyl, biphenyl and
  • alkoxy refers to an alkyl group with an oxygen atom bonded anywhere along the hydrocarbon chain, especially where the oxygen atom is bonded at the beginning of the hydrocarbon chain. Examples include methoxy, ethoxy, propoxy, i-propoxy, n-butoxy, t- butoxy and pentoxy.
  • acyl refers to the group -C(0)R, where R is hydrogen or an optionally substituted alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl or aryl.
  • R is hydrogen or an optionally substituted alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl or aryl.
  • suitable acyl groups include formyl, acetyl, propionyl, benzoyl and acryloyl .
  • halogen refers to bromine (bromo) , chlorine (chloro), iodine (iodo) and fluorine (fluoro).
  • heterocyclic or “heterocyclyl” as used herein, refers to a cyclic hydrocarbon in which 1 to 4 carbon atoms have been replaced by heteroatoms
  • a heterocyclic ring may be saturated or unsaturated but not aromatic.
  • suitable heterocyclyl groups include, but are not limited to, azetidine, tetrahydrofuranyl, tetrahydrothiophenyl, pyrrolidinyl , 2-oxopyrrolidinyl , pyrrolinyl, pyranyl, dioxolanyl, piperidinyl, 2-oxopiperidinyl, pyrazolinyl, imidazolinyl , thiazolinyl, dithiolyl, oxathiolyl,
  • heteroaryl represents a stable monocyclic, bicyclic or tricyclic ring of up to 7 atoms in each ring, wherein at least one ring is aromatic and at least one ring contains from 1 to 4 heteroatoms selected from the group consisting of 0, N and S .
  • Heteroaryl groups within the scope of this definition include, but are not limited to, acridinyl, carbazolyl, cinnolinyl, quinoxalinyl , quinazolinyl, pyrazolyl, indolyl, isoindolyl, 1H, 3H-l-oxoisoindolyl,
  • benzothienyl benzofuranyl , benzodioxane, benzodioxin, quinolinyl, isoquinolinyl, oxazolyl, isoxazolyl,
  • heteroaryl groups have 5- or 6-membered rings, such as pyrazolyl, furanyl, thienyl, oxazolyl, indolyl, isoindolyl, 1H, 3H-l-oxoisoindolyl, isoxazolyl, imidazolyl, pyrazinyl, pyridazinyl, pyridyl, pyridinyl, pyrimidinyl, pyrrolyl, thiazolyl, isothiazolyl, 1 , 2 , 3-triazolyl,
  • phosphonium refers to a positively charged phosphorous atom.
  • organophosphorous refers to a compound having a substituent for a substituent for a substituent for a substituent for a substituent for a substituent for a substituent for a substituent for a substituent for a substituent for a substituent for a substituent for a substituent for a substituent for a substituent for a substituent for a substituent for a substituent for a substituent for a substituent for phosphine
  • -Ci- 6 alkyl -C 2 - 6 alkenyl, -C 2 - 6 alkynyl, -aryl, -aldehyde, oxo, halo, nitro, cyano, haloCi- 6 alkyl-, haloC 2 - 6 alkenyl- , haloC 2 - 6 alkynyl-, haloaryl-, -hydroxy, -Ci- 6 alkylhydroxy, Ci- 6 alkoxy-, -OCi- 6 alkylhydroxy, -OCi- 6 alkylCi- 6 alkoxy,
  • Preferred substituents of groups include, but are not limited to, Ci-6alkyl, especially methyl, Ci-6alkoxy, especially methoxy, aryl, especially phenyl, and acyl, especially phenylC( O ) - , optionally further substituted with halo .
  • the complexes of the invention may be in the form of pharmaceutically acceptable salts. It will be appreciated however that non-pharmaceutically acceptable salts also fall within the scope of the invention since these may be useful as intermediates in the preparation of
  • Suitable pharmaceutically acceptable salts include, but are not limited to, salts of pharmaceutically
  • sulphuric phosphoric, nitric, carbonic, boric, sulfamic and hydrobromic acids, or salts of pharmaceutically acceptable organic acids such as acetic, propionic, butyric, tartaric, maleic, hydroxymaleic, fumaric, citric, lactic, mucic, gluconic, benzoic, succinic, oxalic, phenylacetic, methanesulphonic, toluenesulphonic,
  • Base salts include, but are not limited to, those formed with pharmaceutically acceptable cations, such as sodium, potassium, lithium, calcium, magnesium, ammonium and alkylammonium.
  • Basic nitrogen-containing groups may be quaternized with such agents as lower alkyl halide, such as methyl, ethyl, propyl, and butyl chlorides, bromides and iodides; dialkyl sulfates like dimethyl and diethyl sulfate; and others .
  • lower alkyl halide such as methyl, ethyl, propyl, and butyl chlorides, bromides and iodides
  • dialkyl sulfates like dimethyl and diethyl sulfate; and others .
  • the salts may also include a non-coordinating anion such as hexafluorophosphate, tetrafluoroborate ,
  • Triflate salts are also included. Such salts may not be suitable as pharmaceutically acceptable salts, however may be useful for synthesis and/or purification processes.
  • Phosphorous-containing groups may be present in a number of different stable oxidation states in the
  • Phosphorous-containing groups may comprise an
  • Organophosphine e.g. a complex of formula (I) wherein R 4 is -Ci- 6 alkylP ( Ri3 ) and m is 2 .
  • Organophosphines may be prone to oxidation under mild conditions, and therefore the present compounds may also include corresponding phosphine oxides (e.g. a compound of formula (I) wherein R 4 is -Ci- 6 alkylP(0) (Ris ) .
  • Phosphorous-containing compounds of the invention may comprise a phosphonium atom. Due to the positive charge on the phosphonium atom, phosphonium-containing complexes are typically provided in the form of a salt. Phosphonium compounds of the invention may be provided as any suitable salt form, for example, selected from any of the above salts, and preferably in the form of a salt comprising a non-coordinating anion.
  • organophosphonium compounds such as an organic compound
  • alkylphosphonium compound may form a phosphorous ylid upon exposure to a base.
  • phosphorous ylid refers to a neutral dipolar molecule
  • rhenium complexes of the invention may possess asymmetric centres and are therefore capable of existing in more than one
  • the invention thus also relates to rhenium complexes in substantially pure isomeric form at one or more asymmetric centres, e.g., greater than about 90% ee, such as about 95% or 97% ee, or greater than 99% ee, as well as mixtures, including racemic mixtures, thereof.
  • asymmetric centres e.g., greater than about 90% ee, such as about 95% or 97% ee, or greater than 99% ee, as well as mixtures, including racemic mixtures, thereof.
  • Such isomers may be prepared by asymmetric synthesis, for example using chiral intermediates, or by chiral resolution.
  • the rhenium complexes of the present invention are inhibitors of Aurora kinase phosphorylation, and therefore useful as therapeutic agents for the treatment of a variety of cancers.
  • Aurora kinase There are three subtypes of Aurora kinase, namely Aurora A, Aurora B and Aurora C. Therefore, in some embodiments, Aurora kinase is Aurora A, Aurora B or Aurora C.
  • Aurora A plays a crucial role in mitotic entry and G2 checkpoint control. Dysregulation of Aurora A induces abnormal G2-M transition in mammalian cells leading to chromosome instability and eventually in the development and progression of malignant tumors.
  • AURKA Aurora kinase A gene
  • a rhenium complex of formula (I) acts as a cytostatic drug by inducing a cell cycle arrest at the G 2 /M phase associated with inhibition of the phosphorylation of Aurora A kinase.
  • a method for treatment or prophylaxis of a cancer comprising administering an effective amount of a rhenium complex of formula (I) to a subject in need thereof:
  • ring A is selected from one of the following
  • Y is CR 6 or N
  • Z is CR 7 or N
  • Ri is selected from halo, thiocyanate, isothiocyanate , alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl , aryl, heterocyclyl , heteroaryl, -Ci-6alkylaryl,
  • R 2 and R 3 are independently selected from H, halo, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heterocyclyl, heteroaryl, alkoxy and acyl;
  • cycloalkyl cycloalkenyl, aryl, heterocyclyl or heteroaryl ring
  • R4 is selected from alkyl, alkenyl, alkynyl,
  • cycloalkyl cycloalkenyl, aryl, heteroaryl, -Ci- 6al kylNRsR9 , -Ci- 6 alkylORio and -Ci- 6 alkylP (R13 ) m ;
  • each of Rs a , Rsb, Rsc and Rsd is independently selected from H, halo, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heterocyclyl, heteroaryl, alkoxy or acyl;
  • R6 and R7 are independently selected from H, halo, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heterocyclyl, heteroaryl, alkoxy and acyl;
  • cycloalkyl cycloalkenyl, aryl, heterocyclyl or heteroaryl ring
  • Re and Rg is H and the other is selected from the group consisting of H, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl , aryl, heterocyclyl, heteroaryl and -C (O) Rn;
  • Rio is selected from alkyl, alkenyl, alkynyl,
  • cycloalkyl cycloalkenyl, aryl, heterocyclyl, heteroaryl and -C (O) Rn;
  • Rn is selected from alkyl, alkenyl, alkynyl,
  • each Ri3 is independently selected from alkyl, cycloalkyl, aryl, heterocyclyl and heteroaryl;
  • each alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heterocyclyl and heteroaryl group may be optionally substituted.
  • the carbene ligand is normal, abnormal or a mixture thereof. In a particular embodiment, the carbene ligand is normal.
  • ring A is selected from one of the following structures :
  • ring A has the following structure :
  • R 2 and R 3 are each H; or R 2 and R 3 together with the carbon atoms to which they are attached form an optionally substituted cycloalkyl, cycloalkenyl , aryl, heterocyclyl or heteroaryl ring. In a particular embodiment, R 2 and R 3 together with the carbon atoms to which they are attached form an optionally substituted aryl, especially a phenyl group.
  • the ring B is selected from one of the following structures:
  • the rhenium complex of formula (I) is a rhenium complex of formula (II) :
  • Y is CR 6 or N
  • Z is CR 7 or N
  • Ri is selected from halo, thiocyanate, isothiocyanate , alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heterocyclyl, heteroaryl, -Ci-6alkylaryl ,
  • R 2 and R3 are each H, halo, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl , aryl, heterocyclyl, heteroaryl, alkoxy or acyl;
  • cycloalkyl cycloalkenyl, aryl, heterocyclyl or heteroaryl ring
  • R4 is selected from alkyl, alkenyl, alkynyl,
  • cycloalkyl cycloalkenyl, aryl, heteroaryl, -Ci-ealkylNRsRg , -Ci- 6 alkylORio and -Ci- 6 alkylP (R13 ) m ;
  • R6 and R7 are independently selected from H, halo, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heterocyclyl, heteroaryl, alkoxy and acyl;
  • cycloalkyl cycloalkenyl, aryl, heterocyclyl or heteroaryl ring
  • Re and Rg is H and the other is selected from the group consisting of H, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heterocyclyl, heteroaryl and -C (O) Rn;
  • Rio is selected from alkyl, alkenyl, alkynyl,
  • cycloalkyl cycloalkenyl, aryl, heterocyclyl, heteroaryl and -C (O) Rn;
  • Rn is selected from alkyl, alkenyl, alkynyl,
  • each Ri3 is independently selected from alkyl, cycloalkyl, aryl, heterocyclyl and heteroaryl;
  • alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heterocyclyl and heteroaryl group may be optionally substituted.
  • the rhenium complex of formula (I) is a rhenium complex of formula (III) :
  • one of Wi and W2 is N and the other is CR12 , wherein
  • R12 is H, halo, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl , aryl, heterocyclyl, heteroaryl, alkoxy or acyl;
  • Y is CR 6 or N
  • Z is CR 7 or N
  • Ri is selected from halo, thiocyanate, isothiocyanate , alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heterocyclyl, heteroaryl, -Ci- 6 alkylaryl ,
  • R2 and R 3 are each H, halo, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heterocyclyl, heteroaryl, alkoxy or acyl;
  • cycloalkyl cycloalkenyl, aryl, heterocyclyl or heteroaryl ring
  • R4 is selected from alkyl, alkenyl, alkynyl,
  • cycloalkyl cycloalkenyl, aryl, heteroaryl, -Ci-ealkylNRsRg, -Ci- 6 alkylORio and -Ci- 6 alkylP (R13 ) m ;
  • R6 and R 7 are independently selected from H, halo, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heterocyclyl, heteroaryl, alkoxy and acyl;
  • cycloalkyl cycloalkenyl, aryl, heterocyclyl or heteroaryl ring
  • R.8 and Rg is H and the other is selected from the group consisting of H, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl , aryl, heterocyclyl, heteroaryl and -C (O) Rn;
  • Rio is selected from alkyl, alkenyl, alkynyl,
  • cycloalkyl cycloalkenyl, aryl, heterocyclyl, heteroaryl and -C (O) Rn;
  • Rn is selected from alkyl, alkenyl, alkynyl,
  • each Ri3 is independently selected from alkyl, cycloalkyl, aryl, heterocyclyl and heteroaryl;
  • alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heterocyclyl and heteroaryl group may be optionally substituted.
  • Ri is selected from halo
  • Ri is optionally substituted and selected from C 2 - 6 alkynylaryl and
  • the C 2 - 6 alkynylaryl may be -ethynylphenyl .
  • the heteroaryl may be 5- or 6-membered ring, such as pyridyl, tetrazolyl and imidazolyl, each of which may be optionally substituted with alkyl or aryl.
  • Ri may be pyridyl, phenyltetrazolyl or 3-methyl-l-imidazolyl .
  • R4 is selected from alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, -Ci- ealkylNRsRg and -Ci- 6 alkylORio .
  • R4 is optionally substituted and selected from alkyl, aryl, -Ci-6alkylNRsRg, -Ci-6alkylORio or -Ci-6alkylP (R13)
  • the alkyl may be Ci-isalkyl, especially ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl and dodecyl .
  • the aryl may be phenyl or substituted phenyl such as mesityl.
  • Rg and Rio may be -C(0)Rn, where Rn may be a substituted Co- 4 alkylheteroaryl .
  • R 4 is propyl indomethacin, propyl indomethacinamide or propyl acetamide .
  • ring A is ; Y is CR.6 ; Z is CR7; Ri is halo; R2 and R3 are each H, or R2 and R3 together with the carbon atoms to which they are attached form an aryl ring; R 4 is selected from alkyl, aryl, propyl
  • R6 and R7 are each H; each Ri3 is independently selected from alkyl, cycloalkyl, aryl, heterocyclyl and heteroaryl; and m is 2 or 3.
  • the rhenium complex of formula (I) is:
  • Rhenium Complexes of formula (II) include Rhenium Complexes 5, 6, 9, 10, 12, 14, 15, 16, 17, 18, 19,
  • the complex is selected from Rhenium Complexes 9, 21, 26,
  • rhenium complexes of formula (III) include Rhenium Complexes 1, 2, 3, 4, 7 and 8, especially Rhenium Complexes 1, 2, 3 and 4.
  • the present invention provides use of a rhenium complex of formula (I) as defined above in the manufacture of a medicament for treatment or prophylaxis of a cancer.
  • a further aspect of the present invention provides a method for treatment or prophylaxis of a disease
  • a rhenium complex of formula (I) as defined above in the manufacture of a medicament for treatment or prophylaxis a disease associated with Aurora kinase activity.
  • a further aspect of the present invention provides an Aurora kinase phosphorylation inhibitor comprising a rhenium complex of formula (I) as defined above.
  • Another further aspect of the present invention provides a method of inhibiting Aurora kinase
  • phosphorylation comprising exposing a cell comprising an Aurora kinase to a rhenium complex of formula (I) as defined above.
  • the cell is in vivo. In other embodiments, the cell is in vitro.
  • the cancer may be a blood cancer or bone marrow cancer. In other embodiments, the cancer is a solid tumour cancer.
  • the cancer is leukemia such as acute lymphocytic leukemia, acute myelogenous leukemia, chronic lymphocytic leukemia or chronic myelogenous leukemia.
  • the cancer is a lymphoma such as Hodgkin' s disease, non-Hodgkin' s lymphoma or AIDs- associated lymphoma.
  • the cancer is a myeloma such as multiple myeloma.
  • the cancer is a solid tumour cancer, for example, bladder cancer, brain tumour, spinal tumour, breast cancer, cervical cancer, colon cancer, rectal cancer, esophageal cancer, Ewing' s sarcoma, head or neck cancer, oral cancer, ovarian cancer, endometrial cancer, uterine cancer, kidney cancer, adrenal cancer, liver cancer, skin cancer such as melanoma, osteosarcoma, bone cancer, pancreatic cancer, prostate cancer,
  • a solid tumour cancer for example, bladder cancer, brain tumour, spinal tumour, breast cancer, cervical cancer, colon cancer, rectal cancer, esophageal cancer, Ewing' s sarcoma, head or neck cancer, oral cancer, ovarian cancer, endometrial cancer, uterine cancer, kidney cancer, adrenal cancer, liver cancer, skin cancer such as melanoma, osteosarcoma, bone cancer, pancreatic cancer, prostate cancer,
  • testicular cancer thyroid cancer
  • biliary tract cancer a malignant neoplasm originating from a malignant neoplasm originating from a malignant neoplasm originating from a malignant neoplasm originating from a malignant neoplasm originating from a malignant neoplasm originating from a malignant neoplasm originating from a malignant neoplasm originating from a malignant nasis, othelial cancer and nerve cancer.
  • the cancer is a cancer associated with Aurora kinase activity such as a blood cancer, breast cancer, uterine cancer, cervical cancer, pancreatic cancer, prostate cancer, bladder cancer, kidney cancer, stomach cancer, esophageal cancer, liver cancer, colon cancer, rectal cancer, biliary tract cancer, lung cancer, cancer of the oral cavity, bone cancer such as osteosarcoma, pharyngeal cancer, melanoma, a brain tumour such as a brain neoplasm or a nerve cancer such as neuroblastoma .
  • Aurora kinase activity such as a blood cancer, breast cancer, uterine cancer, cervical cancer, pancreatic cancer, prostate cancer, bladder cancer, kidney cancer, stomach cancer, esophageal cancer, liver cancer, colon cancer, rectal cancer, biliary tract cancer, lung cancer, cancer of the oral cavity, bone cancer such as osteosarcoma, pharyngeal cancer, melanoma, a brain tumour such as a brain neoplasm or
  • the cancer is pancreatic cancer. In another embodiment, the cancer is neuroblastoma.
  • the cancer is associated with a KRAS mutation.
  • KRAS is a protooncogene .
  • the presence of KRAS-mut in cancerous tissue may be detected by any means known in the art, for example therascreen KRAS test (QUIAGEN) .
  • the rhenium complexes are cytostatic agents, while in other embodiments, the rhenium complexes are cytotoxic agents.
  • the subjects (or individuals or patients) to be treated are vertebrate subjects, such as a mammalian subject or a fish subject.
  • Mammalian subjects include but are not limited to humans, primates, livestock animals such as sheep, cattle, pigs, horses, donkeys and goats; laboratory test animals such as mice, rats, rabbits and guinea pigs; companion animals such as cats and dogs or captive wild animals such as those kept in zoos.
  • the subject is a human.
  • Fish subjects include but are not limited to zebrafish.
  • an "effective amount” means an amount necessary to at least partly attain the desired response, or to delay the onset or inhibit progression or halt altogether, the onset or progression of a particular disease being treated.
  • the amount varies depending upon the health and physical condition of the subject to be treated, the taxonomic group of subject to be treated, the degree of protection desired, the formulation of the rhenium complex, the assessment of the medical situation, and other relevant factors . It is expected that the amount will fall in a relatively broad range that can be determined through routine trials .
  • An effective amount in relation to a human subject may lie in the range of about 0.1 ng per kg of body weight to 1 g per kg of body weight per dosage.
  • the dosage is preferably in the range of 1 pq to 1 g per kg of body weight per dosage, such as in the range of 1 mg to 1 g per kg of body weight per dosage. In one embodiment, the dosage is in the range of 1 mg to 500 mg per kg of body weight per dosage. In another embodiment, the dosage is in the range of 1 mg to 250 mg per kg of body weight per dosage. In yet another embodiment, the dosage is in the range of 1 mg to 100 mg per kg of body weight per dosage, such as up to 50 mg per kg of body weight per dosage. In yet another embodiment, the dosage is in the range of 1 pq to 1 mg per kg of body weight per dosage .
  • Dosage regimes may be adjusted to provide the optimum therapeutic response. For example, several divided doses may be administered daily, weekly, monthly or other suitable time intervals, or the dose may be proportionally reduced as indicated by the exigencies of the situation.
  • treatment does not necessarily imply that a subject is treated until total recovery. “Treatment” may reduce the severity of an existing condition.
  • prophylaxis does not necessarily mean that the subject will not eventually contract a disease condition.
  • prophylaxis may be considered to include delaying the onset of a particular condition. Accordingly, treatment and prophylaxis include amelioration of the symptoms of a particular condition or preventing or otherwise reducing the risk of developing a particular condition.
  • the rhenium complex of formula (I) may be administered together with another therapy. Administration may be in a single composition or in separate compositions simultaneously or sequentially such that both are active at the same time in the body.
  • the rhenium complex of formula (I) is administered together with another therapy, especially another therapy to treat cancer, for example radiotherapy or in combination with a second anti-cancer drug.
  • the amount of the second anticancer drug may be reduced when administration is together with a rhenium complex of formula (I) .
  • the second anti-cancer drug may be a known anticancer drug.
  • known anti-cancer agents include the following: oestrogen receptor modulators, androgen receptor modulators, retinoid receptor modulators, cytotoxic agents, anti-proliferative agents, and further angiogenesis inhibitors.
  • Oxestrogen receptor modulators refers to compounds which interfere with or inhibit the binding of oestrogen to the receptor, regardless of mechanism.
  • oestrogen receptor modulators include, but are not limited to, tamoxifen, raloxifene, idoxifene, LY353381, LY 117081, toremifene, fulvestrant, 4- [7- ( 2 , 2-dimethyl-l-oxopropoxy- -methyl-2- [4- [2- (1- piperidinyl ) ethoxy] phenyl ] -2H-1- benzopyran-3-yl] phenyl 2 , 2-dimethylpropanoate, 4,4'- dihydroxybenzophenone-2 , 4-dinitrophenylhydrazone and SH646.
  • Androgen receptor modulators refers to compounds which interfere with or inhibit the binding of androgens to the receptor, regardless of mechanism.
  • Examples of androgen receptor modulators include finasteride and other 5ot-reductase inhibitors, nilutamide, flutamide,
  • Retinoid receptor modulators refers to compounds which interfere with or inhibit the binding of retinoids to the receptor, regardless of mechanism. Examples of such retinoid receptor modulators include bexarotene, tretinoin, 13-cis-retinoic acid, 9-cis-retinoic acid,
  • Cytotoxic agents refers to compounds which result in cell death primarily through direct action on the cellular function or inhibit or interfere with cell myosis, including alkylating agents, tumour necrosis factors, intercalators , microtubulin inhibitors and topoisomerase inhibitors .
  • cytotoxic agents include, but are not limited to, tirapazimine, sertenef, cachectin, ifosfamide, tasonermin, lonidamine, carboplatin, altretamine, prednimustine , dibromodulcitol, ranimustine, fotemustine, nedaplatin, oxaliplatin, temozolomide , heptaplatin, estramustine , improsulfan tosylate, trofosfamide, nimustine, dibrospidium chloride, pumitepa, lobaplatin, satraplatin, profiromycin,
  • microtubulin inhibitors examples include
  • paclitaxel vindesine sulfate, 3 ' , 4 ' -didehydro-4 ' -deoxy- 8 ' -norvincaleukoblastine , docetaxol, rhizoxin, dolastatin, mivobulin isethionate, auristatin, cemadotin, RPR109881, BMS184476, vinflunine, cryptophycin, 2,3,4,5,6- pentafluoro-N- ( 3-fluoro-4-methoxyphenyl )
  • benzenesulfonamide anhydrovinblastine, N, -dimethyl-L- valyl-L-valyl-N-methyl-L-valyl-L-prolyl-L-proline-t- butylamide, TDX258 and BMS188797.
  • Topoisomerase inhibitors are, for example, topotecan, hycaptamine, irinotecan, rubitecan, 6-ethoxypropionyl- 3 ' , 4 ' -O-exobenzylidenechartreusin, 9-methoxy-N, -dimethyl- 5-nitropyrazolo [3,4,5-kl]acridine-2-(6H) -propanamine, l-amino-9-ethyl-5-fluoro-2 , 3-dihydro-9-hydroxy-4-methyl- 1H, 12H-benzo [de] pyrano [3 ' , 4 ' :b, 7] indolizino [1, 2b]
  • Anti-proliferative agents include antisense RNA and
  • DNA oligonucleotides such as G3139, ODN698, RVASKRAS, GEM231 and INX3001 and antimetabolites such as
  • galocitabine cytarabine ocfosfate, fosteabine sodium hydrate, raltitrexed, paltitrexid, emitefur, tiazofurin, decitabine, nolatrexed, pemetrexed, nelzarabine, 2 ' -deoxy- 2 ' -methylidenecytidine, 2 ' -fluoromethylene-2 ' - deoxycytidine, N- [5- (2, 3-dihydrobenzofuryl ) sulfonyl] -N' - (3, 4-dichlorophenyl) urea, N6- [4-deoxy-4- [N2- [2 (E) , 4 (E) - tetradecadienoyl ] glycylamino] -L-glycero-B-L-mannohepto- pyranosyl] adenine, aplidine,
  • Antiproliferative agents also include monoclonal antibodies to growth factors other than those listed under “angiogenesis inhibitors”, such as
  • trastuzumab and tumour suppressor genes, such as p53, which can be delivered via recombinant virus-mediated gene transfer (see US Patent No. 6,069,134, for example) .
  • the rhenium complexes of the present invention may also be suitable for administration at the same time as radiotherapy, alone or in combination with one or more anti-cancer drugs.
  • a rhenium complex may be administered as a neat chemical, it is generally preferable that it is formulated in a pharmaceutical composition.
  • a pharmaceutical composition comprising a rhenium complex of formula (I) as defined above and a pharmaceutically acceptable carrier.
  • composition may be in any suitable form suitable for oral, rectal, nasal, topical (including buccal and sub-lingual), vaginal or parenteral (including intramuscular, sub-cutaneous and intravenous) administration.
  • the pharmaceutical composition is in a form suitable for oral administration. In another embodiment, the pharmaceutical composition is in a form suitable for parenteral administration. In this
  • the pharmaceutical composition may be in a form suitable for intravenous administration, for example, an injectable composition.
  • administration may be in the form of capsule or tablet.
  • the oral composition may also comprise conventional excipients such as starch, lactose, talc, magnesium stearate and so on.
  • the oral composition may also comprise other excipients known in the art for oral compositions, including for example, a diluent, a binder, a lubricant, a fluidizing agent, and an adhesion inhibitor.
  • the pharmaceutical composition for parenteral administration, more specifically, for intravenous administration may be in form of an injectable
  • the injectable composition may comprise conventional excipients such as a solvent (such as an alcohol including ethanol or benzylalcohol,
  • the injectable composition may also comprise other excipients known in the art for such kinds of compositions.
  • the injectable composition can also be freeze-dried to be in the form of a powder.
  • the powder would then be dissolved in a suitable solvent such as an alcohol, and diluted with a phosphate buffer saline (PBS) or saline, before administration to a subject.
  • PBS phosphate buffer saline
  • ring A is selected from one of the following
  • Y is CR 6 or N
  • Z is CR 7 or N
  • Ri is selected from halo, thiocyanate, isothiocyanate , alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl , aryl, heterocyclyl , heteroaryl, -Ci-6alkylaryl ,
  • R2 and R 3 are independently selected from H, halo, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heterocyclyl, heteroaryl, alkoxy and acyl;
  • cycloalkyl cycloalkenyl, aryl, heterocyclyl or heteroaryl ring
  • R4 is selected from alkyl, alkenyl, alkynyl,
  • cycloalkyl cycloalkenyl, aryl, heteroaryl, -Ci-6alkylNRsR9 , -Ci- 6 alkylORio and -Ci- 6 alkylP (R13 ) m ;
  • R5b, R5c and Rsd are each independently selected from H, halo, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heterocyclyl, heteroaryl, alkoxy or acyl;
  • R6 and R7 are independently selected from H, halo, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heterocyclyl, heteroaryl, alkoxy and acyl; or R.2 and R7 together with the carbon atoms to which they are attached form an optionally substituted
  • cycloalkyl cycloalkenyl , aryl, heterocyclyl or heteroaryl ring;
  • R.8 and Rg is H and the other is selected from the group consisting of H, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heterocyclyl, heteroaryl and -C (O) Rn;
  • Rio is selected from alkyl, alkenyl, alkynyl,
  • cycloalkyl cycloalkenyl, aryl, heterocyclyl, heteroaryl and -C (O) Rn;
  • Rn is selected from alkyl, alkenyl, alkynyl,
  • each Ri3 is independently selected from alkyl, cycloalkyl, aryl, heterocyclyl and heteroaryl;
  • alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heterocyclyl and heteroaryl group may be optionally substituted;
  • R.4 is mesityl, Ri is not CI or Br;
  • Ri is mesityl
  • B is pyridyl, ring
  • R4 is n-butyl, Ri is not CI or Br.
  • the rhenium complex of formula (la) is:
  • the rhenium complexes may be synthesised by reaction of a pyridyl, pyrimidyl, quinoxyl, quinolinyl or isoquinolinyl derivative of an imidazolium salt, thiazolium salt, oxazolium salt, benzimidazolium salt, benzothiazolium salt or benzoxazolium salt with Re(CO)5X complexes in the presence of a solvent, such as toluene or dichloromethane, at reflux and in the presence of a base, such as triethylamine as shown in Scheme 1.
  • a solvent such as toluene or dichloromethane
  • This method is particularly useful in preparing rhenium complexes in which the group X is a halide such as a chloride or bromide.
  • the group X when it is a halide such as chloride or bromide, may be readily replaced by reaction with a sodium salt in the presence of silver triflate to produce a rhenium complex where X is other than chloride or bromide, as shown in Scheme 2.
  • the resulting product when the reaction of Scheme 1 is undertaken, the resulting product may be a functionalised normal carbene or an abnormal carbene as shown in Scheme 3.
  • Figure 1 is a graphical representation showing the activity of rhenium complexes 9 (yellow diamond) , 10 (blue square) and 21 (red triangle) against pancreatic cancer cells AsPCl (a), CFPAC (b) and HPAF (c) . The results are shown as cell counts as a percent of control.
  • Figure 2 provides a graphical representation of a cell cycle analysis of AsPCl cells exposed to rhenium complexes 9, 10 and 21 and controls gemcitabine,
  • Nocodazole (a positive G2/M blocker) and DMSO vehicle control.
  • the left hand blue panel shows the G0/G1 gated population, the central red panel shows the S gated population and the right hand green panel shows the G2/M gated population together with the relative abundances in percent .
  • Figure 3 provides graphical representations of the apoptotic index and cytotoxicity index for Rhenium Complex 9 (a and b) , Rhenium Complex 21 (c and d) and Rhenium Complex 10 (e and f ) .
  • Figure 4 is a Western blot analysis of activated phosphor-Aurora A (Threonine 288) in AsPCl cells treated for 24 hours with Rhenium Complexes 9, 10 and 21. Samples were analysed for Aurora A phosphorylation (Th-288), Total Aurora A protein (Aurora-A) and ⁇ -Actinin. The same blot used for phosphor-Aurora A was stripped and then reprobed with Anti-Aurora A antibody. Results are representative of three independent experiments .
  • Figure 5 is a graphical representation showing the activity of Rhenium Complex 9 against neuroblastoma cancer cell line SHSY5. The results are shown as cell counts as a percent of control.
  • Figure 6 is a graphical representation showing the activity of Rhenium Complexes 10, 21, 26 and 27 against neuroblastoma cancer cell line SHSY5. The results are shown as cell counts as a percent of control.
  • Figure 7 is a series of images showing the activity of Rhenium Complex 21 compared to a dimethylsulphoxide (DMSO) control in primary cells derived from KPC mice primary pancreatic tumour.
  • DMSO dimethylsulphoxide
  • Figure 8 is a dose response curve for the activity of Rhenium Complex 21 against primary cells derived from KPC mice primary pancreatic tumour (p ⁇ 0.0001; one-way ANOVA) .
  • Figure 9 is a series of graphical representations of zebrafish hatching counts at various time points after treatment with DMSO (negative control) , Rhenium Complex 21, Rhenium Complex 37 or cisplatin (positive control).
  • Figure 10 is a series of graphical representations of zebrafish mortality rates at various time points after treatment with DMSO (negative control) , Rhenium Complex 21, Rhenium Complex 37 or cisplatin (positive control).
  • Figure 11 is a graphical representation of zebrafish heartbeats following treatment with various doses of Rhenium Complex 21 compared to a DMSO control.
  • CiiHi 5 BrN 4 .1.25 (H 2 0) : C 43.22, H 5.77, N 18.33; found: C 42.82, H 5.32, N 18.19.
  • FT-IR (ATR) Vmax/cm "1 : 3372 br w, 2958 w, 1570 m, 1469 m, 1195 m, 972 m. ! H-NMR ⁇ /ppm
  • Triethylamine (1.03 mL, 7.40 mmol) was added to a mixture of 1- (2-pyridyl) -4-butyl-l, 2, 4-triazolium bromide (210 mg, 0.74 mmol) and Re(CO) 5 Br (301 mg, 0.74 mmol) in toluene (10 mL) and then heated at reflux for 2 days. The yellow solution was decanted off and the remaining residue washed with toluene (2 x 5 mL) , and the combined organic
  • Triethylamine (0.80 mL, 5.74 mmol) was added to a mixture of 1- ( 2 , 6-pyrimidyl ) -3-butyl-imidazolium
  • Triethylamine (0.98 mL, 7.04 mmol) was added to a mixture of l-butyl-4- (2, 6-pyrimidyl) -1, 2, 4-triazolium bromide (200 mg, 0.70 mmol) and Re(CO)5Br (286 mg, 0.70 mmol) in toluene (10 mL) and then heated at reflux for 3 days. The yellow solution was decanted off and the remaining residue washed with toluene (2 x 5 mL) , and the combined organic
  • hexafluorophosphate was added to an aqueous solution of the complex prepared in Example 3 until precipitation ceased. The resulting solid was collected, dried, and used in the following reaction without further purification. Triethylamine (0.52 mL, 3.72 mmol) was added to a mixture of l-butyl-4- (2, 6-pyrimidyl) -1, 2, 4-triazolium
  • Rhenium Complex 14 was obtained by dichloromethane (2 mL) and precipitated with diethyl ether/petroleum spirits (50/50) . The resulting solids was collected, washed with diethyl ether/petroleum spirits (50/50, x 3 mL) , and dried to afford Rhenium Complex 14 as a yellow solid. Yield: 17 mg, 56%.
  • Anal. calc. for C 2 iHi3l 30 3 Re C 37.73, H 1.96, N 6.29; found: C 37.40, H 1.63, N 6.20.
  • Rhenium Complex 15 was collected, washed with diethyl ether/petroleum spirits (50/50, x 3 mL) , and dried to afford Rhenium Complex 15 as a yellow solid. Yield: 12.4 mg, 61%.
  • Triethylamine (0.50 mL, 3.55 mmol) was added to a mixture of l-propylacetamide-4- (2-pyridyl) -imidazolium
  • Rhenium Complex 12 12.7 mg, 6%; Rhenium Complex 13: 7.1 mg, 3%.
  • Rhenium Complex 12 Anal. calc. for
  • Rhenium Complex 13 FT-IR (ATR) Vmax/cm "1 : 2004 s (CO), 1861 br s (2 x CO) , 1647 w, 1611 w, 1473 m.
  • acetonitrile (4 mL) was heated at 130 °C in a sealed tube for 2 d. The solution was concentrated to ca 2 mL and dropped into diethyl ether (10 mL) . The resulting gum slowly solidified with stirring (30 min) and was
  • Rhenium complex 9 Triethylamine (0.45 mL, 3.19 mmol) was added to a mixture of azolium salt from b) (199 mg, 0.32 mmol) and Re(CO)5Br (130 mg, 0.32 mmol) in toluene (10 mL) and then heated at reflux for 2 d. The yellow solution was decanted off and the remaining residue washed with toluene (2 ⁇ 5 mL) , and the combined organic
  • Triethylamine (0.18 mL, 1.80 mmol) was added to a mixture of azolium salt from b) (154 mg, 0.18 mmol) and Re(CO) 5 Br (74 mg, 0.18 mmol) in toluene (8 mL) and then heated at reflux for 2 d. The mixture was concentrated in vacuo and the resulting residue was subjected to column chromatography on acidic alumina (Brockmann grade II, gradient elution using dichloromethane/methanol). Two main fractions were obtained, the first being 10 and the second being 11.
  • deionised water ca. 10 mL was added to the orange solution and extracted with dichloromethane (3 ⁇ 10 mL) . The organic extracts were combined, dried (MgSO and concentrated under reduced pressure to afford fluffy yellow solid (45 mg, 94%); m.p. 208°C (dec) .
  • v max (ATR- FTIR, acetone solution) /cm "1 : 2021 s (CO, A'(l)), 1906 s (CO, A") cm-1.
  • Pentacarbonylrhenium bromide 55 mg, 0.135 mmol was added to a mixture of [QuImPhOMe] [PF 6 ] salt (50 mg, 0.112 mmol) and triethylamine (85 L, 0.615 mmol) in toluene (ca. 10 mL) .
  • the reaction mixture was heated to reflux under nitrogen for 2 days. Over time, yellow precipitate formed. After heating was stopped and reaction left to cool down at room temperature, the mixture was washed with water and extracted with DCM. The dark yellow organic extracts were dried (MgS04) and concentrated under reduced pressure to afford orange-grey solid (101 mg, 90%). M.p. 258°C (dec).
  • Triethylamine (0.26 mL, 1.87 mmol) was added to a mixture of the azolium salt of Example 5 (138.5 mg, 0.19 mmol) and Re(CO)5Br (76 mg, 0.19 mmol) in toluene (7 mL) and the resulting mixture was heated at reflux for 3 d.
  • the yellow toluene solution of the crude product was decanted, and the residue rinsed with toluene (3 mL) .
  • the combined toluene fractions were concentrated in vacuo.
  • Triethylamine (0.38 mL, 2.70 mmol) was added to a mixture of the azolium salt of Example 5 (200.0 mg, 0.27 mmol) and
  • Rhenium Complexes 9, 10 and 21 were tested against a panel of human pancreatic cell lines comprising HPAF-11, AsPCl and CFPAC.
  • Control cells used were healthy human embryonic kidney 293T cells (HEK293T) .
  • Table 1 IC 50 ( ⁇ ) values for Rhenium Complexes 9, 10 and 21 against pancreatic cancer cell lines
  • Figure 1 shows the cell number as a percent of control where AsPCl, HPAFII and CFPAC cells were treated with Rhenium Complexes 9, 10 and 21 at concentrations of 0.5 ⁇ , 1 ⁇ , 2.5 ⁇ , 5 ⁇ and 10 ⁇ . The results show that
  • Rhenium Complexes 9, 10 and 21 significantly decreased the percentage of viable pancreatic cancer cells .
  • Exponentially growing AsPCl cells were cultured in a T75 flask at a seeding density of 20,000 cells per cm 2 in complete media. After an overnight incubation media was changed and cells were treated with Gemcitabine, Rhenium Complexes 9, 10 and 21 at 10 ⁇ . Vehicle-control was treated with DMSO 0.1% and the G 2 /M cell cycle arrest positive control with Nocodazole 200 ng/mL. After 24 hours of treatment cell were washed in PBS and trypsinized, resuspended again in PBS and counted. An equal amount of cells per each condition was then pelleted and fixed in cold Ethanol 70% on ice for at least 30 minutes.
  • AsPCl cells were cultured in a 96 wells plate, 2,000 were seeded per well in triplicate for each condition. After an overnight incubation, cells were exposed to new complete media additioned with 5 ⁇ IncuCyte Caspase 3/7 probe
  • Cytotoxicity Index is defined as the ratio between red fluorescent cells and cellular
  • Example 30 Inhibition of Aurora A in pancreatic cells
  • Protein content was evaluated via IR spectrometry [Direct Detect® Assay-free Cards - Millipore] , and 30 g resuspended in Laemmli Buffer lx and loaded in each lane. Proteins were separated with a 10 % polyacrylamide gel following a classic SDS-PAGE protocol. Lysates were resolved at 130V for 75 minutes ca. and blotted onto a nitrocellulose membrane with a Trans-Blot Turbo Transfer System, following proprietary
  • Rhenium Complexes 10, 21, 26, 27 and 9 were tested against neuroblastoma cells (SHSY5) at concentrations of 0.5 ⁇ , 1 ⁇ , 2.5 ⁇ , 5 ⁇ and 10 ⁇ .
  • Control cells used were healthy human embryonic kidney 293T cells (HEK293T) .
  • Table 2 IC 50 ( ⁇ ) values for Rhenium Complexes 9, 21, 26 and 27 against neuroblastoma cancer cell line SHSY5
  • Figures 5 and 6 show the cell counts as a percentage of control cells at concentrations of 0.1%, 0.5 ⁇ , 1 ⁇ , 2.5 ⁇ , 5 ⁇ and 10 ⁇ of Rhenium Complex 9 ( Figure 5) and 10, 21, 26 and 27 ( Figure 6) .
  • the results show that the rhenium complexes significantly decreased the percentage of viable neuroblastoma cells, especially Rhenium Complex 9.
  • Example 32 Activity of Rhenium Complexes 37 and 38 against various cell lines (cancerous and non-cancerous) and comparison of efficacy with carboplatin.
  • Rhenium Complexes 37 and 38 were tested against HPAF and AsPCl pancreatic cancer cell lines. These results are compared with published results for
  • SI refers to the selectivity index derived from dividing the corresponding IC50 against healthy RC-124 by the IC50 against the corresponding cancer cell line.
  • Rhenium Complexes 37 and 38 have some efficacy against HPAF and AsPCl pancreatic cancer cell lines.
  • the KPC mouse model ( KrasLSL . G12D/+; p53R172H/+;
  • PdxCretg/+ is a well validated genetically engineered mouse model (GEMM) for human pancreatic ductal
  • KPC mice have mutated KRAS and p53 in the pancreas, and develop an array of premalignant lesions that progress to PDAC with 100% penetrance with characteristics very similar to human PDAC.
  • Cells were isolated from primary tumours in KPC mice and cultured. In culture, KPC primary cells show some "islet" of epithelioid-like cells interconnected by a matrix of fibroblast-like cells .
  • Figure 7 shows that treatment with Rhenium Complex 21 significantly reduces the growth of KPC primary cells .
  • Figure 7 also shows that both the epithelioid-like cells and the fibroblast-like cells are affected by Rhenium Complex 21 treatment.
  • Figure 8 shows that this growth reduction proceeds in a dose dependent manner.
  • Toxicity has been tested using a zebrafish model. Embryos were treated 24 hours post fertilization (hpf ) , hatching and mortality rate were scored as indexes of toxicity. Dimethylsulphoxide (DMSO) and Cisplatin (drug of reference as standard of therapy) were used as controls.
  • DMSO dimethylsulphoxide
  • Cisplatin drug of reference as standard of therapy
  • Figure 9 shows that Rhenium Complex 21 has lower toxicity compared to cisplatin and that Rhenium Complex 37 has similar toxicity to the cisplatin control.
  • Rhenium Complex 37 has similar toxicity to cisplatin, for
  • Figure 11 shows that Rhenium Complex 21 surprisingly did not have an effect on the heart rate of the zebrafish compared to the DMSO control.

Abstract

La présente invention concerne des complexes du rhénium tricarbonyle et leur utilisation dans le traitement du cancer et l'inhibition de la kinase Aurora. Les complexes du rhénium tricarbonyle comprennent un ligand carbène N-hétérocyclique C-donneur (NHC). L'invention concerne également des procédés de préparation des complexes de rhénium.
PCT/AU2018/050267 2017-03-23 2018-03-23 Complexes et leurs utilisations WO2018170553A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
AU2017901034 2017-03-23
AU2017901034A AU2017901034A0 (en) 2017-03-23 Complexes and uses thereof

Publications (1)

Publication Number Publication Date
WO2018170553A1 true WO2018170553A1 (fr) 2018-09-27

Family

ID=63583878

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/AU2018/050267 WO2018170553A1 (fr) 2017-03-23 2018-03-23 Complexes et leurs utilisations

Country Status (1)

Country Link
WO (1) WO2018170553A1 (fr)

Non-Patent Citations (12)

* Cited by examiner, † Cited by third party
Title
CASSON ET AL.: "N-Heterocyclic carbenes as pi*-acceptors in luminescent Re(I) triscarbonyl complexes", DALTON TRANSACTIONS, vol. 40, no. 44, 2011, pages 11960 - 11967, XP055552063 *
CHAN ET AL.: "Rhenium and Technetium Tricarbonyl Complexes of N-Heterocyclic Carbene Ligands", INORGANIC CHEMISTRY, vol. 53, no. 20, 2014, pages 10862 - 10873, XP055552029 *
HUCKABA ET AL.: "Photocatalytic Reduction of CO2 with Re-Pyridyl-NHCs", INORGANIC CHEMISTRY, vol. 55, no. 2, 2016, pages 682 - 690, XP055552034 *
JIN ET AL.: "C02 reduction with Re(I)-NHC compounds: driving selective catalysis with a silicon nanowire photoelectrode", CHEMICAL COMMUNICATIONS, vol. 52, no. 99, 2016, pages 14258 - 14261, XP055552059 *
LI ET AL.: "Blue-Green Luminescent Rhenium(I) Tricarbonyl Complexes with Pyridine- Functionalized N-Heterocyclic Carbene Ligands", ORGANOMETALLICS, vol. 31, no. 10, 2012, pages 3829 - 3835, XP055552026 *
LIYANAGE ET AL.: "Electrocatalytic Reduction of CO2 to CO With Re-Pyridyl-NHCs: Proton Source Influence on Rates and Product Selectivities", INORGANIC CHEMISTRY, vol. 55, no. 12, 2016, pages 6085 - 6094, XP055552042 *
MUKUTA ET AL.: "Photochemical Processes in a Rhenium(I) Tricarbonyl N-Heterocyclic Carbene Complex Studied by Time-Resolved Measurements", INORGANIC CHEMISTRY, vol. 56, no. 6, 27 February 2017 (2017-02-27), pages 3404 - 3413, XP055552050 *
SIMPSON ET AL.: "Defining the Anti-Cancer Activity of Tricarbonyl Rhenium Complexes: Induction of G2/M Cell Cycle Arrest and Blockade of Aurora-A Kinase Phosphorylation", CHEMISTRY - A EUROPEAN JOURNAL, vol. 23, no. 27, 23 March 2017 (2017-03-23), pages 6518 - 6521, XP055552072 *
SIMPSON ET AL.: "Photophysical and photochemical studies of tricarbonyl rhenium(I) N- heterocyclic carbene complexes containing azide and triazolate ligands", NEW JOURNAL OF CHEMISTRY, vol. 40, no. 7, 2016, pages 5797 - 5807, XP055552057 *
STANTON ET AL.: "Re(I) NHC Complexes for Electrocatalytic Conversion of CO2", INORGANIC CHEMISTRY, vol. 55, no. 6, 2016, pages 3136 - 3144, XP055552038 *
VAUGHAN ET AL.: "The photochemistry of rhenium(I) tricarbonyl N-heterocyclic carbene complexes", DALTON TRANSACTIONS, vol. 42, no. 39, 2013, pages 14100 - 14114, XP055552065 *
WANG ET AL.: "Synthesis, structure and luminescent properties of rhenium(I) carbonyl complexes containing pyrimidine-functionalized N-heterocyclic carbenes", INORGANICA CHIMICA ACTA, vol. 394, 2013, pages 488 - 493, XP055552068 *

Similar Documents

Publication Publication Date Title
CN102822171B (zh) 作为自分泌运动因子抑制剂的苯并萘啶胺类
US8252800B2 (en) Protein tyrosine kinase inhibitors
DE102009019962A1 (de) 3-([1,2,3]Triazol-4-yl)-pyrrolo[2,3-b]pyridinderivate
WO2007107221A1 (fr) Derive de 4-(pyrrolopyridinyl)-pyrimidinyl-2-amine
WO2006114180A1 (fr) Nouveaux aza-heterocycles constituant des inhibiteurs de kinases
DE102007028515A1 (de) 6-(Pyrrolopyridinyl)-pyrimidinyl-2-amin-derivate
EP2121681B1 (fr) Composés et méthode de traitement un cancer
DE102010049877A1 (de) 7-((1,2,3)Triazol-4-yl)-pyrrolo(2,3) pyrazinderivate
DE102008005493A1 (de) 4-(Pyrrolo[2,3-c] pyridine-3-yl)-pyrimidin-2-yl-amin-derivate
DE102010050558A1 (de) 1H-Pyrrolo[2,3-b]pyridinderivate
DE102011008352A1 (de) 5-([1,2,3]Triazol-4-yl)-7H-pyrrolo-[2,3-d]pyrimidinderivate
JP6001072B2 (ja) ピリド−ピリミジン誘導体
EP1551824B1 (fr) Inhibiteurs de proteine tyrosine kinase
WO2018170553A1 (fr) Complexes et leurs utilisations
WO2017059401A2 (fr) Ligands du récepteur des androgènes
DE102007008419A1 (de) 4-(Pyrrolopyridinyl)-pyrimidinyl-2-amin-derivate
WO2014194975A1 (fr) Inhibiteur quinoléique du récepteur d'origine nantaise mst1r
WO2022198325A1 (fr) Dérivé(s) de camptothécine (cpt) ainsi que procédés et utilisations s'y rapportant

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 18770171

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 18770171

Country of ref document: EP

Kind code of ref document: A1