WO2008090327A1 - Nouvelle association destinée à être utilisée dans le traitement du cancer - Google Patents

Nouvelle association destinée à être utilisée dans le traitement du cancer Download PDF

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WO2008090327A1
WO2008090327A1 PCT/GB2008/000213 GB2008000213W WO2008090327A1 WO 2008090327 A1 WO2008090327 A1 WO 2008090327A1 GB 2008000213 W GB2008000213 W GB 2008000213W WO 2008090327 A1 WO2008090327 A1 WO 2008090327A1
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compound
combination product
formula
alkyl
benzyl
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PCT/GB2008/000213
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English (en)
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Christian Hedberg
Jacob Westman
Björn Eriksson
Guido Kurz
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Betagenon Ab
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    • 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
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • A61K31/138—Aryloxyalkylamines, e.g. propranolol, tamoxifen, phenoxybenzamine
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
    • A61K39/39533—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals
    • A61K39/39558—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals against tumor tissues, cells, antigens
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • This invention relates to a novel pharmaceutical combination.
  • Elevated plasma free fatty acids stimulate pancreatic ⁇ -cells and is one cause of hyperinsulinemia.
  • Excess adiposity is associated to different degrees with an increased risk of developing cancers, such as colorectal adenomas, breast cancer (postmenopausal), endometrial cancer, kidney cancer, oesophageal adenocarcinoma, ovarian cancer, prostate cancer, pancreatic cancer, gallbladder cancer, liver cancer and cervical cancer (CaIIe and Kaaks (2004), Nature Reviews Cancer, 4, 579-591 ).
  • cancers such as colorectal adenomas, breast cancer (postmenopausal), endometrial cancer, kidney cancer, oesophageal adenocarcinoma, ovarian cancer, prostate cancer, pancreatic cancer, gallbladder cancer, liver cancer and cervical cancer (CaIIe and Kaaks (2004), Nature Reviews Cancer, 4, 579-591 ).
  • hyperinsulinemia has been shown to be prospective risk factor for death and data support that the insulin level could be used as a marker of prostate cancer prognosis (Hammarsten and H ⁇ gstedt (2005) European Journal of Cancer, 41 , 2887).
  • hyperinsulinemia Several mechanisms may link hyperinsulinemia to the incidence and outcome of breast cancer. Firstly, chronic hyperinsulinemia results in increased production of ovarian testosterone and oestrogen and inhibition of hepatic production of sex hormone binding globulin, a sex-hormonal profile that is associated with breast cancer. Secondly, hyperinsulinemia suppresses hepatic production of insulin-like growth factor binding protein-1 (IGFBP-1 ), and thus increases circulating levels of IGF-1 , which has potent mitogenic effect on breast tissue. Thirdly, insulin itself may have a direct mitogenic effect on breast cancer cells. The study by Hardy et al ((2005), J. Biol. Chem.
  • Neoplastic cells synthesise lipids to a much larger extent than their normal counterparts and metabolise glucose differently. It has been suggested that this aberrant metabolism constitutes a therapeutic target.
  • pathways/targets include glycolysis interfering agents, lipid synthesis pathway, AMPK activating agents and agents affecting mitochondrial function.
  • WO 2005/051890 discloses inter alia thiazolidinones (which are ultimately substituted with a cyclopropyl group) that may be useful in the treatment of diabetes.
  • thiazolidinones which are ultimately substituted with a cyclopropyl group
  • WO 2005/051890 discloses inter alia thiazolidinones (which are ultimately substituted with a cyclopropyl group) that may be useful in the treatment of diabetes.
  • thiazolidinones that are substituted in the 5-position with heterocyclyl, heteroaryl or, particularly, aryl group, either directly or via an alkylene linker group.
  • EP 1 535 915 discloses various furan and thiophene-based compounds. Cancer is mentioned as one of numerous indications.
  • EP 1 559 422 discloses a huge range of compounds for use in the treatment of inter alia cancer. However, this document does not appear to relate to thiazolidinones.
  • US patent application US 2006/0089351 discloses various benzothiazole derivatives as neuropeptide Y receptor antagonists, and therefore of use in the treatment of eating disorders.
  • International patent application WO 2006/020680 discloses a vast range of heterocyclic compounds as modulators of nuclear receptors.
  • US 6,353,006 discloses various heterocycles for use in modulating progesterone receptor mediated processes, and therefore of use in the treatment of e.g. diseases relating to deficiencies in bone mineral density, such as osteopenia or osteoporosis.
  • HER2-positive breast cancer is a more aggressive disease with a greater likelihood of recurrence, a poorer prognosis, and a decreased chance of survival compared with HER2 -negative breast cancer.
  • Herceptin is the first humanized monoclonal antibody approved for the treatment of HER2-positive metastatic breast cancer. It is designed to target and block the function of HER2 protein overexpression, and acts by attaching itself to the HER2 protein, thereby blocking the latter's interaction between human epidermal growth factor.
  • Herceptin also works by attracting the body's own immune cells to help destroy the cancer cells.
  • the drug which is typically administered by infusion, is only effective in patients with high levels of the HER2 protein.
  • HER2 protein presently, only about one in five women with breast cancer (and fewer men) have tumours that are sensitive.
  • Herceptin may increase effectiveness of certain chemotherapy drugs, particularly paclitaxel (Taxol®) and docetaxel (Taxotere®) and may improve survival.
  • chemotherapy drugs particularly paclitaxel (Taxol®) and docetaxel (Taxotere®) and may improve survival.
  • Herceptin is licensed in many countries as a treatment for patients with early stage breast cancer. In the UK, clinical guidance states that Herceptin should be considered as a possible treatment for women with HER2 positive breast cancer following surgery and adjuvant chemotherapy (and radiotherapy if appropriate).
  • the drug may also be used to treat patients with advanced breast cancer in combination with or without the chemotherapy drugs mentioned above. It may also be given on its own to patients with advanced breast cancer who have already received at least two courses of chemotherapy.
  • Tyrosine kinases are enzymes that catalyse the phosphorylation of tyrosine residues. TKs are involved in cellular signalling pathways and regulate key cell functions such as proliferation, differentiation, anti-apoptotic signalling and neurite outgrowth.
  • Unregulated activation of TKs through mechanisms such as point mutations or over-expression, can lead to various forms of cancer as well as benign proliferative conditions.
  • TK inhibitors such as lapatanib (Tykerb®) have been developed to block the ATP-binding site and prohibit the autophosphorylation of tyrosine residues, thereby preventing activation of the intracellular signalling pathways in tumor cells.
  • TKIs may stabilize tumor progression, creating in many instances a disease state this is no longer life threatening. Furthermore, side effects are considerably reduced when compared to conventional chemotherapeutic agents, such as those mentioned hereinbefore, and clear synergistic effects have been observed when TKIs are combined with such agents and/or radiotherapy.
  • a combination product comprising: (a) a compound of formula I,
  • X represents -[C(R 8 )(R 8 )],,-; n represents 0, 1 , 2 or 3;
  • T represents -S- or -O-;
  • W represents -NR 7 -, -CR 7 R 7 -, -NR 7 C(O)-, -NR 7 S(O) 2 -, -NR 7 C(O)NR 7 -, -NR 7 C(O)O- or a bond; one of A 1 or A 2 represents a double bond and the other represents a single bond; when A 1 represents a single bond, A 2 is a double bond and R 6 is absent; when A 2 represents a single bond, A 1 is a double bond and, if present, one R 7
  • R 1 represents -C(O)NR 3 R 2 , -NR 3 R 2 , -C(O)OR 2 , -NR 4 C(O)NR 3 R 2 , -NR 4 C(O)OR 2 ,
  • R 2 and R 5 independently represent, on each occasion when used herein, hydrogen, alkyl, cycloalkyl, heterocyclyl, benzyl, aryl or heteroaryl (which latter six groups are optionally substituted by one or more groups selected from B 7 , B 8 , B 9 ,
  • R 3 , R 4 , R 6 and R 7 independently represent, on each occasion when used herein, hydrogen, alkyl, cycloalkyl, aryl or benzyl (which latter four groups are optionally substituted by one or more groups selected from B 13 , B 14 , B 15 and B 16 , respectively), or heterocyclyl or heteroaryl (which latter two groups are optionally substituted by one or more groups selected from B 14 and B 15 , respectively);
  • Rs and Rg are independently selected from hydrogen, alkyl and aryl (which latter two groups are optionally substituted by B 16a and B 16b , respectively);
  • Rio represents hydrogen, alkyl or aryl (which latter two groups are optionally substituted by one or more groups selected from B 17 and B 18 , respectively);
  • B 1 to B 18 independently represent cyano, -NO 2 , halo, -OR 11 , -NR 12 Ri 3 , -SR 14 ,
  • Rii Ri2, Ri3, Ri 4 .
  • Ri 6 > Ri6a, Ri6b, Rise and Ried independently represent H or Ri 7 ;
  • Ri 5 and Ri 7 independently represent, on each occasion when used herein, C 1-6 alkyl optionally substituted by one or more halo atoms, or a pharmaceutically-acceptable salt or solvate, or a pharmaceutically functional derivative thereof, provided that, when n represents O and R 1 represents an optionally substituted alkyl group, then that alkyl group is saturated; and
  • TKI tyrosine kinase inhibitor
  • EGFR Human Epidermal Growth Factor
  • erbB1 HER-1 /Human Epidermal Growth Factor
  • HER3 HER3
  • HER4 erbB4
  • HER2 erbB2
  • Preferred TKIs thus include imatinib, gefitinib, erlotinib, canertinib, sunitinib, zactima, vatalanib, sorafenib, leflunomide and, particularly, lapatinib.
  • Combination products of the invention include those that comprise trastuzumab.
  • Pharmaceutically-acceptable salts of compounds of formula I, or TKIs, that may be mentioned include acid addition salts and base addition salts.
  • Such salts may be formed by conventional means, for example by reaction of a free acid or a free base form of e.g. a compound of formula I with one or more equivalents of an appropriate acid or base, optionally in a solvent, or in a medium in which the salt is insoluble, followed by removal of said solvent, or said medium, using standard techniques (e.g. in vacuo, by freeze-drying or by filtration).
  • Salts may also be prepared by exchanging a counter-ion of e.g. a compound of formula I in the form of a salt with another counter-ion, for example using a suitable ion exchange resin.
  • Examples of pharmaceutically acceptable addition salts include those derived from mineral acids, such as hydrochloric, hydrobromic, phosphoric, metaphosphoric, nitric and sulphuric acids, and organic acids, such as tartaric, acetic, citric, malic, lactic, fumaric, benzoic, glycolic, gluconic, succinic, alkylsulphonic and arylsulphonic acids.
  • Preferred salts of e.g. imatinib include mesylate salts.
  • “Pharmaceutically functional derivatives” of compounds of formula I as defined herein, and TKIs includes ester derivatives and/or derivatives that have, or provide for, the same biological function and/or activity as any relevant compound. Thus, for the purposes of this invention, the term also includes prodrugs of compounds of formula I and TKIs.
  • prodrug of a relevant compound includes any compound that, following oral or parenteral administration, is metabolised in vivo to form that compound in an experimentally-detectable amount, and within a predetermined time (e.g. within a dosing interval of between 6 and 24 hours (i.e. once to four times daily)).
  • parenteral administration includes all forms of administration other than oral administration.
  • Prodrugs of compounds of formula I may be prepared by modifying functional groups present on the compound in such a way that the modifications are cleaved, in vivo when such prodrug is administered to a mammalian subject. The modifications typically are achieved by synthesizing the parent compound with a prodrug substituent.
  • Prodrugs include compounds of formula I wherein a hydroxyl, amino, sulfhydryl, carboxy or carbonyl group in a compound of formula I is bonded to any group that may be cleaved in vivo to regenerate the free hydroxy!, amino, sulfhydryl, carboxy, or carbonyl, group, respectively.
  • prodrugs include, but are not limited to, esters and carbamates of hydroxy functional groups, esters groups of carboxyl functional groups, N-acyl derivatives and N-Mannich bases. General information on prodrugs may be found e.g. in Bundegaard, H. "Design of Prodrugs” p. 1-92, Elesevier, New York-Oxford (1985).
  • Compounds of formula I may contain double bonds and may thus exist as E (entadel) and Z ⁇ zusammen) geometric isomers about each individual double bond. All such isomers and mixtures thereof are included within the scope of the invention.
  • Compounds of formula I may also contain one or more asymmetric carbon atoms and may therefore exhibit optica! and/or diastereoisomerism.
  • Diastereoisomers may be separated using conventional techniques, e.g. chromatography or fractional crystallisation. The various stereoisomers may be isolated by separation of a racemic or other mixture of the compounds using conventional, e.g. fractional crystallisation or HPLC, techniques.
  • the desired optical isomers may be made by reaction of the appropriate optically active starting materials under conditions which will not cause racemisation or epimerisation (i.e.
  • a 'chiral pool' method by reaction of the appropriate starting material with a 'chiral auxiliary' which can subsequently be removed at a suitable stage, by derivatisation (i.e. a resolution, including a dynamic resolution), for example with a homochiral acid followed by separation of the diastereomeric derivatives by conventional means such as chromatography, or by reaction with an appropriate chiral reagent or chiral catalyst all under conditions known to the skilled person. All stereoisomers and mixtures thereof are included within the scope of the invention.
  • alkyl refers to an unbranched or branched, cyclic, saturated or unsaturated (so forming, for example, an alkenyl or alkynyl) hydrocarbyl radical, which may be substituted or unsubstituted (with, for example,
  • alkyl refers to an acyclic group, it is preferably C 1-I0 alkyl and, more preferably, C 1 ⁇ alkyl (such as ethyl, propyl, (e.g. n-propyl or isopropyl), butyl (e.g. branched or unbranched butyl), pentyl or, more preferably, methyl).
  • alkyl is a cyclic group
  • cycloalkyl (which may be where the group "cycloalkyl” is specified), it is preferably C 3- -I 2 cycloalkyl and, more preferably, C 5 . 10 (e.g. C 5 .7) cycloalkyl.
  • alkylene refers to C 1-10 (e.g. C 1-6 ) alkylene and, preferably C 1-3 alkylene, such as pentylene, butylene (branched or unbranched), preferably, propylene ( ⁇ -propylene or isopropylene), ethylene or, more preferably, methylene (i.e. -CH 2 -).
  • halogen when used herein, includes fluorine, chlorine, bromine and iodine.
  • Heterocyclyl groups that may be mentioned include non-aromatic monocyclic heterocyclyl groups in which one or more (e.g. one to four) of the atoms in the ring system is other than carbon (i.e. a heteroatom, which heteroatom is preferably selected from N, O and S), and in which the total number of atoms in the ring system is between three and twelve (e.g. between five and ten). Further, such heterocycloalkyl groups may be saturated or unsaturated containing one or more double and/or triple bonds, forming for example a C 2-q heterocycloalkenyl (where q is the upper limit of the range) or a C 3 . q heterocycloalkynyl group.
  • C 2-q heterocycloalkyl groups that may be mentioned include 7- azabicyclo[2.2.1]heptanyl, 6-azabicyclo[3.1.1]heptanyl, 6-azabicyclo[3.2.1]- octanyl, ⁇ -azabicyclo[3.2.1]octanyl, aziridinyl, azetidinyl, dihydropyranyl, dihydropyridyl, dihydropyrrotyl (including 2,5-dihydropyrrolyl), dioxolanyl (including 1 ,3-dioxolanyl), dioxanyl (including 1 ,3-dioxanyl and 1 ,4-dioxanyl), dithianyl (including 1 ,4-dithianyl), dithiolanyl (including 1 ,3-dithiolanyl), imidazolidinyl, imidazolinyl, morpholinyl, 7-oxabicyclo[2.
  • heterocycloalkyl groups may, where appropriate, be located on any atom in the ring system including a heteroatom.
  • the point of attachment of heterocycloalkyl groups may be via any atom in the ring system including (where appropriate) a heteroatom (such as a nitrogen atom), or an atom on any fused carbocyclic ring that may be present as part of the ring system.
  • Heterocycloalkyl groups may also be in the N- or S- oxidised form.
  • Preferred heterocycly! groups include cyclic amino groups such as pyrrolidinyl, piperidyl, piperazinyl, morpholinyl or a cyclic ether such as tetrahydrofuranyl, monosaccharide.
  • aryl when used herein includes C 6- i 4 (such as C 6- i3 (e.g. C 6-10 )) aryl groups. Such groups may be monocyclic, bicyclic or tricyclic and have between 6 and 14 ring carbon atoms, in which at least one ring is aromatic. The point of attachment of aryl groups may be via any atom of the ring system. However, when aryl groups are bicyclic or tricyclic, they are linked to the rest of the molecule via an aromatic ring.
  • C ⁇ -u aryl groups include phenyl, naphthyl and the like, such as 1 ,2,3,4-tetrahydronaphthyl, indanyl, indenyl and fluorenyl. Most preferred aryl groups include phenyl.
  • heteroaryl when used herein refers to an aromatic group containing one or more heteroatom(s) (e.g. one to four heteroatoms) preferably selected from N, O and S (so forming, for example, a mono-, bi-, or tricyclic heteroaromatic group).
  • Heteroaryl groups include those which have between 5 and 14 (e.g. 10) members and may be monocyclic, bicyclic or tricyclic, provided that at least one of the rings is aromatic. However, when heteroaryl groups are bicyclic or tricyclic, they are linked to the rest of the molecule via an aromatic ring.
  • Heterocyclic groups that may be mentioned include benzothiadiazolyl (including 2,1 ,3- benzothiadiazolyl), isothiochromanyl and, more preferably, acridinyl, benzimidazolyl, benzodioxanyl, benzodioxepinyl, benzodioxolyl (including 1 ,3- benzodioxolyl), benzofuranyl, benzofurazanyl, benzothiazolyl, benzoxadiazolyl (including 2,1 ,3-benzoxadiazolyl), benzoxazinyl (including 3,4-dihydro-2H-1 ,4- benzoxazinyl), benzoxazolyl, benzomorpholinyl, benzoselenadiazolyl (including 2,1 ,3-benzoselenadiazolyl), benzothienyl, carbazolyl, chromanyl, cinnolinyl, furanyl
  • heteroaryl groups may, where appropriate, be located on any atom in the ring system including a heteroatom.
  • the point of attachment of heteroaryl groups may be via any atom in the ring system including (where appropriate) a heteroatom (such as a nitrogen atom), or an atom on any fused carbocyclic ring that may be present as part of the ring system.
  • Heteroaryl groups may also be in the N- or S- oxidised form.
  • heteroaryl groups include pyridyl, pyrrolyl, quinolinyl, furanyl, thienyl, oxadiazolyl, thiadiazolyl, thiazolyl, oxazolyl, pyrazolyl, triazolyl, tetrazolyl, isoxazolyl, isothiazolyl, imidazolyl, pyrimidinyl, indolyl, pyrazinyl, indazolyl, pyrimidinyl, thiophenetyl, pyranyl, carbazolyl, acridinyl, quinolinyl, benzoimidazolyl, benzthiazolyl, purinyl, cinnolinyl and pterdinyl.
  • the substituents are preferably on the phenyl ring of the benzyl group, rather than on the methylene (-CH 2 -) group.
  • Y preferably represents -C(O)-;
  • R 1 represents -C(O)NR 3 R 2 , -NR 3 R 2 , -C(O)OR 2 , -NR 4 C(O)NR 3 R 2 , -NR 4 C(O)OR 2 ,
  • R 2 and R 5 independently represent, on each occasion when used herein, hydrogen, alkyl, haloalkyl, cycloalkyl, heterocyclyl, benzyl, aryl or heteroaryl;
  • R 3 , R 4 , R 6 and R 7 independently represent, on each occasion when used herein, aryl or, more particularly, hydrogen, alkyl, haloalkyl, cycloalkyl or benzyl;
  • R 8 and Rg are independently selected from hydrogen, alkyl and aryl
  • R 10 represents hydrogen, alkyl, haloalkyl or aryl.
  • B 1 to B 18 independently represent halo, -ORn, -NR 12 R13, -SR 14 , -Si(Ri 5 ) 3l -C(O)OR 16 or aryl (which aryl group is itself optionally substituted by one or more groups selected from halo or R 17 , or is preferably unsubstituted); Rn, R 12 , R 1 S 1 Ru and R 16 independently represent R 17 or, more preferably, H.
  • B 1 to B 18 may alternatively independently represent functional groups such as hydroxyl, amine, sulfide, silyl, carboxylic acid, halogen, aryl, etc.
  • W represents -N-
  • a 2 represents a single bond and A-i is a double bond; and/or RQ represents H; Ri and R 5 independently represent aryl or heteroaryl.
  • X is alkylene or a bond (i.e. when n represents O);
  • T represents -S-;
  • W represents -NR 7 -;
  • a 1 , A 2 , Ri, R 2 and R 5 are as hereinbefore defined; and/or
  • R 3 , R 4 and R 6 independently represent hydrogen, alkyl (e.g. optionally substituted by one or more groups selected from B 13 ), haloalkyl, cycloalky! (e.g. optionally substituted by one or more groups selected from B 14 ) or benzyl (e.g. optionally substituted by one or more groups selected from B 16 ).
  • More preferred compounds of formula I include those in which:
  • R 1 and R 2 independently represent aryl (e.g. phenyl) as hereinbefore defined (i.e.
  • R 1 represents aryl optionally substituted by one or more B 5 groups and R 2 represents aryl optionally substituted by one or more B 11 groups); when Ri and/or R 2 represent phenyl, it/they is/are substituted para relative to the point of attachment of the Ri or R 2 group to X; B 5 and B 11 independently represent halo; and/or R 5 represents heteroaryl (e.g. pyridyl).
  • More preferred compounds of formula I include those in which: R 1 represents -C(O)NHR 2 ; R 2 represents aryl (e.g. phenyl); when R 2 represents phenyl, it is substituted (i.e. with a B 11 substituent) at the para position (relative to the point of attachment of the R 2 group to the remainder of the compound of formula I); and/or B 11 represents d-C 6 alkyl.
  • R 1 is -NHR 2 ;
  • R 2 is aryl (e.g. phenyl); when R 2 represents phenyl, it is substituted (i.e. with a B 11 substituent) at the para position;
  • B 11 represents C 1 -C 6 alkyl
  • Y C(H)-
  • R 5 represents aryl (e.g. phenyl); and/or when R 5 represents phenyl, it is either unsubstituted or substituted with a halogen
  • R 6 represents aryl (e.g. phenyl); when R 5 represents phenyl, it is substituted (i.e. with a B 11 substituent) at the para position;
  • B 11 represents R 1 7; and/or
  • Ri 7 represents C 1 ⁇ alkyl preferably substituted by one or more halo atoms (so forming a haloalkyl group).
  • R 5 represents aryl (e.g. phenyl); when R 5 represents phenyl, it is substituted (i.e. with a B 11 substituent) at the para position; B 11 represents halo or R 1 7; and/or
  • Rn represents d. 6 alkyl preferably substituted by one or more halo atoms (so forming a haloalkyl group).
  • X represents a single bond (i.e. n represents 0); R 1 is -C(O)NHR 2 ; R 2 is aryl (e.g. phenyl); when R 2 represents phenyl, it is substituted with B 11 ; B 11 represents R 1 7; and/or Ru represents C r C 6 alkyl.
  • Preferred compounds of formula I include those in which:
  • T represents -S-;
  • Y C(R 10 )-, preferably, -S(O) 2 - or, more preferably,
  • R 1 0 represents H or, more preferably, alkyl (e.g. methyl or trifluoromethyl);
  • W represents -CR 7 R 7 -, a bond, or, more preferably,
  • R 5 represents optionally substituted (i.e. by B 7 ) alkyl (such as Ci -3 alkyl, e.g. propylene or, preferably, isopropyl or methyl; so forming, for example, a benzyl group), cycloalkyl (e.g. cyclohexyl) or, more preferably represents optionally substituted (i.e. by B 11 ) aryl (e.g. phenyl) or optionally substituted (i.e. by B 12 ) heteroaryl (e.g. 2-pyridyl); n represents 3 or O or, more preferably, 1 or 2;
  • R 8 and R 9 independently represent C 1-3 (e.g. Ci -2 ) alkyl (e.g. methyl) or, more preferably, H;
  • R 1 represents (e.g. when n represents 1 ) alkyl or, more preferably -NR 3 R 2 , -OR 2 ,
  • -SR 2 -NR 4 C(O)R 2 , -NR 4 C(O)NR 3 R 2 , -NR 4 C(O)OR 2 , particularly -C(O)NR 3 R 2 , -C(O)OR 2 , more particularly, optionally substituted (i.e. by B 6 ) heteroaryl (e.g. furanyl, such as furan-2-yl or thienyl, such as thien-2-yl) or, especially, optionally substituted (i.e. by B 5 ) aryl (e.g. phenyl);
  • heteroaryl e.g. furanyl, such as furan-2-yl or thienyl, such as thien-2-yl
  • aryl e.g. phenyl
  • R 4 represents C 1 .3 (e.g. C 1-2 ) alkyl (e.g. methyl) or H;
  • R 3 represents Ci -3 (e.g. C 1-2 ) alkyl (e.g. methyl) or, preferably, H;
  • R 2 represents optionally substituted (i.e. by B 7 ) alky! (such as C 1-3 alkyl, e.g. ethyl or, preferably, methyl; so forming, for example, a benzyl group) or, preferably, optionally substituted (i.e. by B 11 ) aryl (e.g. phenyl) or (e.g. when Ri represents
  • R 6 represents alkyl such as
  • C 1-6 e.g. C 1-3 alkyl (e.g. methyl) or aryl (e.g. phenyl), both of which may be substituted by one or more of B 13 or B 15 , respectively, or are more preferably unsubstituted, or, more preferably R 6 represents H; when W represents -NR 7 - and R 6 is absent, then R 7 represents C 1-3 (e.g. C 1-2 ) alkyl (e.g. methyl), aryl (e.g.
  • phenyl or benzyl, all of which may be substituted by one or more B 13 , B 15 and B 16 , respectively, or, are more preferably unsubstituted; when W represents -CR 7 R 7 -, then A 2 represents a double bond; when W represents -CR 7 R 7 -, then each R 7 independently represents, at each occurrence, C 1-3 (e.g. Ci -2 ) alkyl or H; B 1 to B 18 (and, in particular, B 5 , B 6 , B 11 and B 12 ) independently represent cyano,
  • halo e.g. chloro, fluoro or bromo
  • -OR 11 e.g. chloro, fluoro or bromo
  • -C(O)OR 16 e.g. -C(O)NR 16a Ri 6 b or
  • B 4 to B 6 , B 10 to B 12 , B 15 , B 16 and B 18 (and, in particular, B 5 , B 11 and B 12 ) represents
  • R 17 ; and/or B 1 to B 18 (and, in particular, B 1 and B 7 ) independently represent heteroaryl (e.g. fura ⁇ yl, such as furan-2-yl or thienyl, such as thien-2-yl) or, preferably, aryl (e.g. phenyl), both of which may be substituted by one or more groups selected from halo (e.g. fluoro) or Ri 7 ;
  • heteroaryl e.g. fura ⁇ yl, such as furan-2-yl or thienyl, such as thien-2-yl
  • aryl e.g. phenyl
  • Rn represents Ci -3 (e.g. Ci- 2 ) alkyl (e.g. methyl or ethyl) or H;
  • R 16 represents H or C 1 . 3 (e.g. Ci -2 ) alkyl (e.g. ethyl);
  • Ri6 a , Ri6 b , Rise and R 16d independently represent C 1-2 alkyl or, more preferably, H;
  • Ri 7 represents Ci -4 (e.g. C 1 . 3 ) alkyl (e.g. methyl or isopropyl) optionally substituted by one or more halo (e.g. fluoro) atoms (so forming, for example, a trifluoromethyl group).
  • Ci -4 e.g. C 1 . 3 alkyl (e.g. methyl or isopropyl) optionally substituted by one or more halo (e.g. fluoro) atoms (so forming, for example, a trifluoromethyl group).
  • W represents -NR 7 -, -NR 7 C(O)- or -NR 7 S(O) 2 -;
  • Ri represents phenyl optionally substituted by B 5 ;
  • R 5 represents phenyl optionally substituted by B 11 ;
  • R 6 and R 7 (if present) independently represent hydrogen;
  • B 5 represents halo or, preferably, Ri 7 ;
  • B 11 represents R 17 or, preferably, halo (e.g. chloro);
  • Ri 7 represents C 1 . 3 alkyl (e.g. methyl) optionally substituted by one or more halo (e.g. fluoro) atoms (so forming, for example, a trifluoromethyl group); when R 1 represent an optionally substituted phenyl group, then it is preferably a trifluoromethylphenyl group (e.g. 3-trifluoromethylphenyl); when R 5 represents an optionally substituted phenyl group, then it is preferably a halophenyl group (i.e. one in which the phenyl group is substituted with one or more halo substituents), such as monochlorophenyl (e.g. 2-chlorophenyl, 3- chlorophenyl or, preferably, 4-chlorophenyl) or dichlorophenyl (e.g. 3,4- dichlorophenyl).
  • halo e.g. fluoro
  • Rio does not represent H; when Y represents W does not represent -N(R 7 )C(O)-; n represents 2, 3 or, more preferably, 1;
  • R 3 , R 4 , Re and R 7 independently represent, on each occasion when used herein, hydrogen, alkyl, cycloalkyl, aryl or benzyl (which latter four groups are optionally substituted by one or more groups selected from B 13 , B 14 , B 15 and B 16 , respectively);
  • R 1 does not represent H or alkyl as hereinbefore defined
  • R 5 does not represent H.
  • Preferred compounds of formula I include those in which: when X does not represent a single bond (i.e. n does not represent 0), then R 1 does not represent -NR 3 R 2 , -OR 2 , -SR 3 , -NR 4 C(O)R 2 , -NR 4 C(O)NR 3 R 2 or
  • R 5 does not represent alkyl or cycloalkyl
  • R 5 does not represent hydrogen; when X represents a single bond (i.e. n represents O) and R 5 represents optionally substituted aryl, then Ri does not represent an optionally substituted alkyl group or hydrogen; when X represents -CH 2 - and R 5 represents optionally substituted aryl, then R 1 does not represent -C(O)NR3R2,' when X represents -CH 2 - and R 5 represents optionally substituted alkyl or aryl, then R 1 does not represent -C(O)NR 3 R 2 .
  • R 6 and Rg both represent H; R 6 represents H.
  • Particularly preferred compounds of formula I include; 5-(4-fluorobenzyl)-2-(pyridin-2-ylimino)thiazolidin-4-one;
  • Compounds of formula I may be known and/or may be commercially available. Other compounds of formula I (e.g. that are not commercially available) may be prepared in accordance with techniques that are well known to those skilled in the art, for example as described hereinafter.
  • R a represents Ci -6 alkyl (e.g. ethyl; so forming an ester group)
  • L 1 represents a suitable leaving group, such as a sulfonate group (e.g. mesylate or, preferably, tosylate) or, for example preferably, halo (e.g. bromo or chloro); or
  • T a represents O or, more preferably, S and R5 and R 6 are as hereinbefore defined, under reaction conditions known to those skilled in the art, for example for reaction (A) above conditions such as those described in Blanchet et al, Tetrahedron Letters, 2004, 45, 4449-4452; for reaction (B) above, conditions such as those described in St. Laurent ef al, Tetrahedron Letters, 2004, 45, 1907-1910; K. Arakawa et al., Chem. Pharm. Bull. 1997, 45, 1984- 1993; A. Mustafa, W. Musker, A.F.A.M. Shalaby, A.H. Harhash, R.
  • L 2 represents a suitable leaving group, such as halo (e.g. chloro), with a compound of formula VII,
  • T a is as hereinbefore defined but is preferably S and R 5 is as hereinbefore defined under conditions known to those skilled in the art, for example such as those described in Zbirovsky and Seifert, Coll. Czech. Chem. Commun. 1977, 42, 2672-2679 or Von Zaki El-Heweri, Franz Runge, Journal furdorfe Chemie, 4, Band 16, 1962, e.g. in the presence of base (e.g. an aqueous solution of NaOH) in an appropriate solvent (e.g. acetone), for example at elevated temperature (e.g. 50°);
  • base e.g. an aqueous solution of NaOH
  • an appropriate solvent e.g. acetone
  • X a represents -[RsRg] n - in which n represents 1 , 2 or 3 and Ri 3 represents R 1 as hereinbefore defined, or n represent 0 and R-i a represents R 1 as hereinbefore defined provided that it does not represent hydrogen, aryl or heteroaryl
  • L 3 represents a suitable leaving group (e.g. a halo, such as chloro, iodo or, preferably, bromo, or a sulfonate group), under reaction conditions known to those skilled in the art, for example, in the presence of a suitable base (e.g. an organometallic base (e.g. an organolithium), an alkali metal base (e.g.
  • reaction conditions include those described in the journal article mentioned in respect of process step (ii) above;
  • W represents -NR 7 C(O)-, -NR 7 S(O) 2 -, -NR 7 C(O)NR 7 -, -NR 7 C(O)O- or -NR 7 -, -CR 7 R 7 - or a bond, reaction of a corresponding compound of formula I in which n represents O and R 1 represents H with a compound of formula IX,
  • R ⁇ represents alkyl optionally substituted by B 1 as hereinbefore defined, under standard reactions conditions known to those skilled in the art.
  • a suitable base such as NaOAc or an appropriate base described hereinafter in respect of process step (vii)
  • a suitable solvent e.g. glacial acetic acid
  • reaction in the presence of a suitable base (e.g. lithium diisopropylamide or another suitable base described in process step (vii) below) in the presence of an appropriate solvent (e.g. anhydrous THF) at room temperature or below (e.g. about O 0 C) under an inert atmosphere.
  • a suitable base e.g. lithium diisopropylamide or another suitable base described in process step (vii) below
  • an appropriate solvent e.g. anhydrous THF
  • R 1 represents optionally substituted alkenyl as described above
  • this may involve an intermediate which is the above- mentioned compound of formula I in which R 1 represents alkyl substituted by -OH as defined above (which intermediate may be isolable), which intermediate may need to be transformed to the alkenyl group separately, for example by converting the -OH group to a better leaving group, for example by reaction with trifluoroacetic anhydride or the like optionally in the presence of a suitable base (e.g. triethylamine) and a catalyst (e.g. DMAP) in an appropriate solvent (e.g. dichloromethane) at below room temperature (such as at about O 0 C) e.g. employing conditions described in Zbirovsky and Seifert, Coll. Czech. Chem. Commun. 1977, 42, 2672-2679;
  • a suitable base e.g. triethylamine
  • a catalyst e.g. DMAP
  • an appropriate solvent e.g. dichlor
  • R 6a represents alkyl, cycloalkyl or benzyl (e.g. which are optionally substituted by one or more groups selected from B 13 , B 14 or B 16 , respectively) and L 4 represents a suitable leaving group such as halo (e.g. iodo or bromo) or a sulfonate group, under standard reaction conditions, for example at around room temperature, in the presence of a suitable base (e.g.
  • R 16a and Ri 6 b are as hereinbefore defined, for example under standard coupling reaction conditions.
  • R ⁇ represents H
  • a suitable coupling reagent e.g.
  • the reaction may be performed in the presence of an appropriate reagent (e.g. trimethylaluminium) in the presence of a suitable solvent (e.g. benzene), for example at elevated temperature (e.g. about 60 0 C), e.g. as described in Hwang, K.-J.; O'Neil, J.-P.; Katzenellenbogen, J. A. J. Org. Chem. 1992, 57, 1262;
  • an appropriate reagent e.g. trimethylaluminium
  • a suitable solvent e.g. benzene
  • elevated temperature e.g. about 60 0 C
  • W x represents -C(O)-, -S(O) 2 , -C(O)NR 7 - or -C(O)O-
  • L 5 represents a suitable leaving group such as halo (e.g. chloro) and R 5 is as hereinbefore defined, under reaction conditions known to those skilled in the art, for example in the presence of a suitable base (e.g. NaH, NaOH, triethylamine, pyridine, another suitable base mentioned at process step (vii) above or mixtures thereof) and solvent (e.g. pyridine (which may serve as the base and solvent) DMF or dichloromethane (e.g.
  • a suitable base e.g. NaH, NaOH, triethylamine, pyridine, another suitable base mentioned at process step (vii) above or mixtures thereof
  • solvent e.g. pyridine (which may serve as the base and solvent) DMF or dichloromethane (e.g.
  • R 5 is as hereinbefore defined, under standard conditions, for example, in the presence of a suitable solvent (e.g. a polar aprotic solvent such as toluene) and at elevated temperature (e.g. reflux), for example as described in the journal article mentioned in respect of process (viii) above.
  • a suitable solvent e.g. a polar aprotic solvent such as toluene
  • elevated temperature e.g. reflux
  • R 1 c represents aryl or heteroaryl (e.g. optionally substituted by B 5 and B 6 ) to form the corresponding diazonium salt (for example by reaction with sodium nitrite at low temperatures such as at about 0 0 C) followed by reaction with a compound of formula XVI,
  • R a is as defined above, in the presence of a suitable solvent (e.g. acetone) and a hydrohalic acid which is preferably concentrated (e.g. in the case where L 1 represents chloro, concentrated hydrochloric acid) optionally in the presence of an agent that aids the Michael addition of the halide onto the acrylate/enone such as cuprous oxide.
  • a suitable solvent e.g. acetone
  • a hydrohalic acid which is preferably concentrated (e.g. in the case where L 1 represents chloro, concentrated hydrochloric acid) optionally in the presence of an agent that aids the Michael addition of the halide onto the acrylate/enone such as cuprous oxide.
  • L 1 represents a sulfonate group (e.g. a toslyate or mesylate) may be prepared by reaction of a compound corresponding to a compound of formula III but in which L 1 represents -OH with an appropriate sulfonyl chloride (e.g. tosyl chloride or mesyl chloride) under standard conditions known to those skilled in the art, such as those described in respect of preparation of compounds of formula I above (process step (vi) above).
  • Compounds of formula Vl may be prepared by reaction of a compound of formula XVII,
  • L 6 represents a suitable leaving group such as halo (e.g. chloro) and L 2 is as hereinbefore defined, with ammonia (e.g. in gaseous or other form) for example under standard conditions known to those skilled in the art, such as those described in respect of preparation of compounds of formula I above (process step (vi) above) or, preferably, in the presence of diethyl ether at low temperature (e.g. about O 0 C) in which case the skilled person will appreciate that the ammonia additionally serves as a base.
  • ammonia e.g. in gaseous or other form
  • Substituents such as R-i, R 5 , Re, X, W and Y in final compounds of formula I or relevant intermediates may be modified one or more times, after or during the processes described above by way of methods that are well known to those skilled in the art. Examples of such methods include substitutions, reductions, oxidations, alkylations, acylations, hydrolyses, esterifications, and etherifications.
  • the precursor groups can be changed to a different such group, or to the groups defined in formula I, at any time during the reaction sequence.
  • the protection and deprotection of functional groups may take place before or after a reaction in the above-mentioned schemes.
  • Protecting groups may be removed in accordance with techniques that are well known to those skilled in the art and as described hereinafter. For example, protected compounds/intermediates described herein may be converted chemically to unprotected compounds using standard deprotection techniques.
  • the term "functional groups” means, in the case of unprotected functional groups, hydroxy-, thiolo-, aminofunction, carboxylic acid and, in the case of protected functional groups, lower alkoxy, N-, O-, S- acetyl, carboxylic acid ester.
  • Combination products according to the invention provide for the administration of compounds of formula I in conjunction with trastuzumab or TKI (or salt or other derivative thereof), and may thus be presented either as separate formulations, wherein at least one of those formulations comprises compound of formula I 1 and at least one comprises trastuzumab or TKI, or may be presented (i.e. formulated) as a combined preparation (i.e. presented as a single formulation including a compound of formula I and trastuzumab or TKI).
  • a pharmaceutical formulation including a compound of formula I, or a pharmaceutically-acceptable salt or solvate, or a pharmaceutically functional derivative thereof; trastuzumab or a TKI, or a pharmaceutically-acceptable salt or solvate, or a pharmaceutically functional derivative thereof; and a pharmaceutically-acceptable adjuvant, diluent or carrier (which formulation is hereinafter referred to as a "combined preparation"); and
  • a pharmaceutical formulation including trastuzumab, or a TKI, or a pharmaceutically-acceptable salt or solvate, or a pharmaceutically functional derivative thereof, in admixture with a pharmaceutically- acceptable adjuvant, diluent or carrier, which components (a) and (b) are each provided in a form that is suitable for administration in conjunction with the other.
  • a method of making a kit of parts as defined above comprises bringing component (a), as defined above, into association with a component (b), as defined above, thus rendering the two components suitable for administration in conjunction with each other.
  • components (a) and (b) of the kit of parts may be:
  • kit of parts comprising: (I) one of components (a) and (b) as defined herein; together with (II) instructions to use that component in conjunction with the other of the two components.
  • kits of parts described herein may comprise more than one formulation including an appropriate quantity/dose of compound of formula I, and/or more than one formulation including an appropriate quantity/dose of trastuzumab or
  • formulations may be the same, or may be different in terms of the dose of either compound, chemical composition(s) and/or physical form(s).
  • the combination products according to the invention find utility in the treatment of cancer.
  • cancer will be understood by those skilled in the art to include one or more diseases in the class of disorders that is characterized by uncontrolled division of cells and the ability of these cells to invade other tissues, either by direct growth into adjacent tissue through invasion, proliferation or by implantation into distant sites by metastasis.
  • combination products according to the invention are capable of inhibiting the proliferation of cancer cells.
  • proliferation we include an increase in the number and/or size of cancer cells.
  • combination products according to the invention are capable of inhibiting metastasis of cancer cells.
  • metastasis we mean the movement or migration (e.g. invasiveness) of cancer cells from a primary tumour site in the body of a subject to one or more other areas within the subject's body (where the cells can then form secondary tumours).
  • the invention provides combinations and methods for inhibiting, in whole or in part, the formation of secondary tumours in a subject with cancer. It will be appreciated by skilled persons that the effect of a combination product according to the invention as described herein on “metastasis” is distinct from any effect such a combination product may or may not have on cancer cell proliferation.
  • combination products according to the invention may be capable of inhibiting the proliferation and/or metastasis of cancer cells selectively.
  • the combination product inhibits the proliferation and/or metastasis of cancer cells to a greater extent than it modulates the function (e.g. proliferation) of non-cancer cells.
  • the combination product inhibits the proliferation and/or metastasis of cancer cells only.
  • the cancer cells may be selected from the group consisting of cancer cells of the breast, bile duct, brain, colon, stomach, reproductive organs, thyroid, hematopoetic system, lung and airways, skin, gallbladder, liver, nasopharynx, nerve cells, kidney, prostate, lymph glands and gastrointestinal tract.
  • the cancer is selected from the group of colon cancer (including colorectal adenomas), breast cancer (e.g. postmenopausal breast cancer), endometrial cancer, cancers of the hematopoetic system (e.g.
  • the cancer is selected from the group of colon, prostate and, particularly, breast cancer.
  • the cancer cells are breast cancer cells.
  • Combination products according to the invention are particularly useful in the treatment of HER2- positive cancers.
  • Combination products according to the invention may also find utility for example in adjuvant therapy (i.e. reducing the risk of the cancer coming back after surgery), in neo-adjuvant therapy (before surgery, to shrink a large breast cancer so that a lumpectomy is possible), in the control of breast cancers that have come back after initial treatment, or in the control of breast cancers that cannot be removed when first diagnosed.
  • adjuvant therapy i.e. reducing the risk of the cancer coming back after surgery
  • neo-adjuvant therapy before surgery, to shrink a large breast cancer so that a lumpectomy is possible
  • a method of treatment of cancer which method comprises the administration of a combination product according to the invention to a patient in need of such treatment.
  • treatment include the therapeutic, or palliative, treatment of patients in need of, as well as the prophylactic treatment and/or diagnosis of patients which are susceptible to, cancer.
  • kits of parts as described herein by “administration in conjunction with”, we include that respective formulations comprising compound of formula I and trastuzumab or TKI (or salt/solvate/derivative thereof) are administered, sequentially, separately and/or simultaneously, over the course of treatment of the relevant condition.
  • the term "administration in conjunction with” includes that the two components of the combination product (compound of formula I and trastuzumab or TKI) are administered (optionally repeatedly), either together, or sufficiently closely in time, to enable a beneficial effect for the patient, that is greater, over the course of the treatment of the relevant condition, than if either a formulation comprising compound of formula I 1 or a formulation comprising trastuzumab or TKI, are administered (optionally repeatedly) alone, in the absence of the other component, over the same course of treatment. Determination of whether a combination provides a greater beneficial effect in respect of, and over the course of treatment of, a particular condition will depend upon the condition to be treated or prevented, but may be achieved routinely by the skilled person.
  • the term "in conjunction with” includes that one or other of the two formulations may be administered (optionally repeatedly) prior to, after, and/or at the same time as, administration with the other component.
  • the terms “administered simultaneously” and “administered at the same time as” include that individual doses of compound of formula I and trastuzumab or TKI are administered within 48 hours (e.g. 24 hours) of each other.
  • Patients include mammalian (including human) patients.
  • the term "effective amount” refers to an amount of a compound, which confers a therapeutic effect on the treated patient (e.g. sufficient to treat or prevent the disease).
  • the effect may be objective (i.e. measurable by some test or marker) or subjective (i.e. the subject gives an indication of or feels an effect).
  • compounds of formula I may be administered alone, but are preferably administered orally, intravenously, intramuscularly, cutaneously, subcutaneously, transmucosally (e.g. sublinguaily or buccally), rectally, transdermal ⁇ , nasally, pulmonarily (e.g. tracheally or bronchially), topically, by any other parenteral route, in the form of a pharmaceutical preparation comprising the compound in a pharmaceutically acceptable dosage form.
  • Preferred modes of delivery include oral, intravenous, cutaneous or subcutaneous, nasal, intramuscular, or intraperitoneal delivery.
  • Compounds of formula I will generally be administered as a pharmaceutical formulation in admixture with a pharmaceutically acceptable adjuvant, diluent or carrier, which may be selected with due regard to the intended route of administration and standard pharmaceutical practice.
  • a pharmaceutically acceptable adjuvant diluent or carrier
  • Such pharmaceutically acceptable carriers may be chemically inert to the active compounds and may have no detrimental side effects or toxicity under the conditions of use.
  • Suitable pharmaceutical formulations may be found in, for example, Remington The Science and Practice of Pharmacy, 19th ed., Mack Printing Company, Easton, Pennsylvania (1995).
  • a parenterally acceptable aqueous solution may be employed, which is pyrogen free and has requisite pH, isotonicity, and stability. Suitable solutions will be well known to the skilled person, with numerous methods being described in the literature.
  • Suitable formulations for use in administering trastuzumab and TKIs are described in the literature (see for example Martindale - The Complete Drug Reference (34 th Edition) (e.g. at pages 589 to 590, 557 to 558 and 562), and the documents referred to therein, the relevant disclosures in all of which documents are hereby incorporated by reference). Otherwise, the preparation of suitable formulations, and in particular combined preparations including both compound of formula I and trastuzumab or TKI may be achieved non-inventively by the skilled person using routine techniques and/or in accordance with standard and/or accepted pharmaceutical practice.
  • suitable formulations of trastuzumab for infusion include solutions and/or suspensions of the active ingredient in an appropriate isotonic solution (e.g. NaCI 0.9%).
  • the amount of active ingredients in the formulation(s) will depend on the severity of the condition, and on the patient, to be treated, as well as the compound(s) which is/are employed, but may be determined non-inventively by the skilled person.
  • active ingredients may be administered at varying therapeutically effective doses to a patient in need thereof.
  • the dose administered to a mammal, particularly a human, in the context of the present invention should be sufficient to effect a therapeutic response in the mammal over a reasonable timeframe.
  • the selection of the exact dose and composition and the most appropriate delivery regimen will also be influenced by inter alia the pharmacological properties of the formulation, the nature and severity of the condition being treated, and the physical condition and mental acuity of the recipient, as well as the potency of the specific compound, the age, condition, body weight, sex and response of the patient to be treated, and the stage/severity of the disease.
  • Administration of active ingredients may be continuous or intermittent (e.g. by bolus injection).
  • the dosage may also be determined by the timing and frequency of administration.
  • the dosage can vary from about 0.01 mg to about 1000 mg per day of the relevant compound of formula I (or, if employed, a corresponding amount of a pharmaceutically acceptable salt or prodrug thereof).
  • trastuzumab Suitable doses of trastuzumab are known to those skilled in the art (e.g. infusion doses of about 4 mg/kg body weight followed by about 2 mg/kg doses as weekly intervals).
  • the medical practitioner or other skilled person, will be able to determine routinely the actual dosage, which will be most suitable for an individual patient.
  • the above-mentioned dosages are exemplary of the average case; there can, of course, be individual instances where higher or lower dosage ranges are merited, and such are within the scope of this invention.
  • Combination products according to the invention may be further combined in combination therapy with other chemotherapeutic agents known in the art to be of use in combination with e.g. trastuzumab, such as paclitaxel and docetaxel.
  • chemotherapeutic agents known in the art to be of use in combination with e.g. trastuzumab, such as paclitaxel and docetaxel.
  • Combination products according to the invention may also comprise, in place of a compound selected from trastuzumab, or a tyrosine kinase inhibitor, or a pharmaceuticalfy-acceptable salt, solvate or pharmaceutically functional derivative of a tyrosine kinase inhibitor, a compound selected from the following: (i) a glitazone (such as rosiglitazone); (ii) metformin;
  • statin such as fluvastatin, simvastatin, rosuvastatin, pravastatin, atorvastatin and, particularly, lovastatin
  • an antibody other than trastuzumab that is useful in the treatment of cancer, such as bevacizumab, cetuximab or panitumumab; and/or
  • mTOR mammalian target of rapamycin
  • a combination product comprising (a) a compound of formula I as hereinbefore defined, or a pharmaceutically-acceptable salt or solvate, or a pharmaceutically functional derivative thereof; and (b) a compound selected from a glitazone, metformin, a statin, an antibody (other than trastuzumab) that is useful in the treatment of cancer, or an inhibitor of activity of the mammalian target of rapamycin, or a pharmaceutically-acceptable salt, solvate or pharmaceutically functional derivative (as hereinbefore defined) of a glitazone, metformin, a statin or an inhibitor of activity of the mammalian target of rapamycin.
  • the combination products/methods described herein may have the advantage that, in the treatment of cancer, they may be more convenient for the physician and/or patient than, be more efficacious than, be less toxic than, have a broader range of activity than, be more potent than, produce fewer side effects than, or that they may have other useful pharmacological properties over, similar methods (treatments) known in the prior art for use in the treatment of cancer or otherwise.
  • Figures 1a to 1e are representative examples of cell cycle analysis using Flow Cytometer. Cells were incubated with or without linolenic acid and the compound of Example 95 below (Compound X) for 24 hours. Histograms represent accumulated events and their distribution in the cell cycle by intensity of Pl staining (FL3).
  • Figure 2A is a histogram summarizing 4 experiments where one compound is identified and verified as an FFA antagonist. Cells were incubated with or without linolenic acid and the Compound X for 24 hours at indicated concentrations. Cells in S-phase from untreated sample were set to 100% in each experiment.
  • Figures 2B and 2C are histograms where compounds are identified and verified as FFA antagonists.
  • Cells were incubated with or without linolenic acid and the compound of Examples 4 and 6 below (Compound 2 and Compound Y, respectively) for 24 hours at indicated concentrations.
  • Figures 3A to 3F show hematoxylin stained sections from tumors dissected from vehicle or test compound treated mice.
  • Example 36 5-(4-Fluorobenzvn-2-(A/-phenyl-A/-(pyridin-2-yl)amino')thiazol-4(5H)-one
  • Example 37 2-(2-(A/-pheny[-A/-p-tolylannino ' )-4,5-dihvdro-4-oxothiazol-5-yl)-A/-p-tolylacetamicle
  • Example 59 5-f1-(4-Fluorophenyl)-1-methylethyl1-2-(pyridin-2-ylimino)thiazolidin-4-one
  • Example 60 5-(4-MethoxyphenethyO-2-(p-tolylimino)thiazolidin-4-one
  • Example 70 5-
  • Example 71 5- ⁇ fMethyl-(3-trifluoromethylphenyl)anriinolrnethyl ⁇ -2-p-tolylirnino-thiazolidin-4-one
  • Example 102 5-(3-(Trifluoromethyl)benzyl)-2-(benzylimino)thiazolidin-4-one
  • Example 103 2-((Pyridin-2-v ⁇ methylamino)-5-(4-fluorobenzyl)thiazol-4(5H)-one
  • Example 113 1-(5-(4-Fluorobenzyl)-4,5-dihvdro-4-oxothiazol-2-yl)-3-(pyridin-2-yl)urea
  • Example 114 5-(3-(Trifluoromethyl)be ⁇ zyl)-2-tosyliminothiazolidin-4-one
  • Example 135 N-(2,4-DimethylphenylV2-(4-oxo-2-(phenylimino)thiazolidin-5-yl)acetamide
  • Example 136 ⁇ /-(2,4-Dimethoxyphenyl)-2-(4-oxo-2-(phenylimino)thiazolidin-5-yl)acetamide
  • Example 155 5-(3-(Trifluoromethyl)benzyl)-4-methyl-/V-p-tolylthiazol-2-amine
  • Example 156 ⁇ /-(5-(4-Fluorobenzyl)-4-methylthiazol-2-yQpyridin-2 -amine
  • D-MEM Dulbecco's modified Eagle's medium
  • Glucose glutamate
  • GlutaMAXTM1 Pyruvate
  • VA/ Foetal Bovine Serum Gibco 10500-064
  • PEST 100 U/ml penicillin, 100ug/ml streptomycin, Gibco 15140-122
  • CyStain Pl absolute T Kit (Partec # 05-5023) Linolenic acid 99%, L2376 from Sigma Aldrich Dimethyl sulfoxide (DMSO)
  • MDA-MB-231 cells were cultured in the propagation media D-MEM +1000mg/L Glucose +GlutaMAXTM1 ⁇ Pyruvate supplemented with 10% VA/ Foetal Bovine Serum and PEST (100 U/mL penicillin, 100 ⁇ g/mL streptomycin). Cells were seeded in 6 well plates to a density of 300 000 cells/well in propagation media. After 24 hours, media was replaced with serum free D-MEM media.
  • Linolenic acid was diluted in DMSO to a concentration of 100 mM and added to the culture media to a final concentration of 100 ⁇ M.
  • Compounds were as dissolved in DMSO to a concentrations of 10 mM (Compounds of Examples 95 and 6 (Compound X and Compound Y, respectively)) and 40 mM (Compound of Example 4 (Compound Z)) and added to the culture media to a final concentration of 10 ⁇ M (X and Y) and 40 ⁇ M (Z) respectively.
  • the described method was shown to exhibit the sensitivity required to detect an antagonist to free fatty acid stimulation.
  • the measurement of DNA synthesis for quantification of cell proliferation minimizes errors inherent in several other assays.
  • the relevant compounds attenuate the FFA induced cell proliferation in a human breast cancer cell line.
  • the ability of Compounds X, Y and Z to inhibit such proliferation may be expressed as percentage antagonist activity as follows: Compound X - 70% at a concentration of 10 ⁇ M Compound Y - 100% at a concentration of 10 ⁇ M Compound Z - 50% at a concentration of 10 ⁇ M. Similar experiments were conducted in respect of compounds of the examples above, which were also found to exhibit percentage antagonist activities at least 20% at a concentration of 10 ⁇ M.
  • mice 5 week old Athymic BALB/cA nude mice were delivered from Taconic (Denmark) and kept under barrier conditions for 1 week acclimatisation. At 6 weeks, 17 mice were injected subcutaneously on the flank with 1.8 x 10 6 MDA-MB-231 human breast cancer cells (LGC Promochem-ATCC) in a 50/50 v/v solution of phosphate buffered saline (PBS) (Gibco 10010-015, Invitrogen) Matrigel HC (BD Biosciences).
  • PBS phosphate buffered saline
  • mice After 11 days, palpable tumors were observed in 16 mice. 2 mice were sacrificed and the tumors dissected and examined. 2 groups of 7 mice each were treated once daily by intraperitoneal injections of 1 mg/kg bodyweight of the compund of Example 6 (Compound Y) in PBS/1 %v/v dimethylsufoxide or vehicle control respectively for 9 days. The mice were sacrificed by cervical dislocation and tumors were dissected.
  • the tumor tissue were fixated overnight in PBS (containing 4% w/v paraformaldehyde (Scharlau PA0095, Sharlau Chemie SA, Spain) at +4 0 C.
  • the tumor tissue were then cryopreserved by 24 hour incubation in PBS containing 30% w/v sucrose (BDH #102745C (www.vwr.com)) at +4 0 C and embedded in Tissue-Tek embedding media (Sakura Finetek Europa BV, Netherlands).
  • 10 ⁇ m cryosections were generated an stained with Mayers Hematoxylin (Dako) for 5 min and destained for 3 x 10 minutes in tap water. Slides were mounted using Dako faramount aqueous mounting medium and examined using a Nikon Eclipse TS 100 microscope documented using a Nikon coolpix 4500. Results
  • mice treated with test compound and vehicle were analyzed for morphology by microscopic examination of hematoxylin stained cryosections. The results are shown in Figures 3A to 3F.
  • Figure 3A shows a hematoxylin stained section from a tumor dissected from a vehicle treated mouse at 1Ox magnification. It is to be noted that there is a relative abundance of cells in the interior of the section as well as the relative thickness of the uninterrupted zone of cell in the periphery of the section.
  • Figure 3B shows a hematoxylin stained section from a tumor dissected from a vehicle treated mouse at 2Ox magnification. It is to be noted that the cells in the interior of the section display morphology consistent with adenocarcinoma.
  • Figure 3C shows a hematoxylin stained section from a tumor dissected from a vehicle treated mouse at 4Ox magnification. It is to be noted that no cell displaying morphology indicative of macrophage/monocyte could be found.
  • Figure 3D shows a hematoxylin stained section from a tumor dissected from a mouse treated with the Compound Y at 10x magnification.
  • the low cell density in the interior of the section and the thin layer of cells displaying morphology is to be noted, which is consistent with poorly differentiated adenocarcinoma.
  • Figure 3E shows a hematoxylin stained section from a tumor dissected from mouse treated with the Compound Y at 2Ox magnification. The lack of cells displaying fibroblast morphology in the interior of the section is to be noted.
  • Figure 3F shows a hematoxylin stained section from a tumor dissected from a mouse treated with the compound of Compound Y at 4Ox magnification.
  • the accumulation of cells displaying morphology indicative of macrophage/monocyte in the interior of the section (black arrows) is to be noted.
  • the main finding was that the cell-density in the interior of the tumors was markedly reduced in tumors dissected from test compound treated mice as compared to tumors from vehicle treated mice. Moreover, the majority of the cells found in the interior of the sections from the treated group displayed a morphology inconsistent with adenocarcinoma while cells displaying macrophage/monocyte morphology was a frequent finding. In contrast, only one of seven tumors from the vehicle treated group showed indication of macrophage/monocyte infiltration.
  • 5,000 SK-BR-3 human breast cancer cells/well are plated in 96-well plates containing complete culture media (DMEM 10% Fetal Calf Serum, Gibco).
  • trastuzumab Herceptin
  • Compound Y are added to a final concentration of 10 ⁇ g/mL and 10 ⁇ M, respectively.
  • bromodeoxyuridine (5-bromo-2-deoxyuridine; BrdU) is added according to the manufacturer's recommendation (Cell proliferation ELISA, BrdU, Roche).
  • trastuzumab treated cells and the Compound Y treated cells show a significant reduction in proliferation.
  • the combination of 10 ⁇ g/mL trastuzumab and 10 ⁇ M Compound Y displays a synergistic effect on cell proliferation.

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Abstract

L'invention concerne une association médicamenteuse comprenant : (a) un composé de formule (I), dans laquelle X, Y, T, W, A1, A2, R1, R5 et R6 ont les significations données dans la description, et (b) du trastuzumab ou un inhibiteur de tyrosine kinase. L'association médicamenteuse selon l'invention trouve une utilité particulière dans le traitement du cancer.
PCT/GB2008/000213 2007-01-22 2008-01-22 Nouvelle association destinée à être utilisée dans le traitement du cancer WO2008090327A1 (fr)

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US10710986B2 (en) 2018-02-13 2020-07-14 Gilead Sciences, Inc. PD-1/PD-L1 inhibitors
US10774071B2 (en) 2018-07-13 2020-09-15 Gilead Sciences, Inc. PD-1/PD-L1 inhibitors
US10899735B2 (en) 2018-04-19 2021-01-26 Gilead Sciences, Inc. PD-1/PD-L1 inhibitors
US11236085B2 (en) 2018-10-24 2022-02-01 Gilead Sciences, Inc. PD-1/PD-L1 inhibitors
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Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8865754B2 (en) 2011-03-03 2014-10-21 Proteotech Inc. Compounds for the treatment of neurodegenerative diseases
EP4275759A3 (fr) * 2016-09-26 2024-01-17 Dana-Farber Cancer Institute, Inc. Dérivés de quinoline en tant qi'inhibiteurs de la protéine chromobox (cbx) pour le traitement du cancer
US10710986B2 (en) 2018-02-13 2020-07-14 Gilead Sciences, Inc. PD-1/PD-L1 inhibitors
US11555029B2 (en) 2018-02-13 2023-01-17 Gilead Sciences, Inc. PD-1/PD-L1 inhibitors
US10899735B2 (en) 2018-04-19 2021-01-26 Gilead Sciences, Inc. PD-1/PD-L1 inhibitors
US10774071B2 (en) 2018-07-13 2020-09-15 Gilead Sciences, Inc. PD-1/PD-L1 inhibitors
US11236085B2 (en) 2018-10-24 2022-02-01 Gilead Sciences, Inc. PD-1/PD-L1 inhibitors

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