WO2010086613A1 - Composés utiles en tant qu'inhibiteurs tel que ampk - Google Patents

Composés utiles en tant qu'inhibiteurs tel que ampk Download PDF

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Publication number
WO2010086613A1
WO2010086613A1 PCT/GB2010/000144 GB2010000144W WO2010086613A1 WO 2010086613 A1 WO2010086613 A1 WO 2010086613A1 GB 2010000144 W GB2010000144 W GB 2010000144W WO 2010086613 A1 WO2010086613 A1 WO 2010086613A1
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formula
compound
pharmaceutically
methyl
thiazol
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PCT/GB2010/000144
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English (en)
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Jacob Westman
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Betagenon Ab
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D277/38—Nitrogen atoms
    • C07D277/42—Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D285/00—Heterocyclic compounds containing rings having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by groups C07D275/00 - C07D283/00
    • C07D285/01—Five-membered rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a carbon chain containing aromatic rings

Definitions

  • This invention relates to pharmaceutically-useful compounds.
  • the invention also relates to the use of such compounds in the treatment of cancer.
  • AMPK represents a new target for the treatment of several diseases, including cancer.
  • 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.
  • AMPK activators also suppress lipid synthesis in tumour cells. It has also been shown that it is a link between AMPK and other anti-cancer targets such as LKB1 and caspase-3 activation.
  • Elevated plasma free fatty acids stimulate pancreatic ⁇ -cells and is one cause of hyperinsulinemia.
  • 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 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.
  • 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.
  • insulin itself may have a direct mitogenic effect on breast cancer cells.
  • 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.
  • AMP-activated protein kinase is a protein kinase enzyme that consists of three protein sub-units and is activated by hormones, cytokines, exercise, and stresses that diminish cellular energy state (e.g. glucose deprivation). Activation of AMPK increases processes that generate adenosine 5'-triphosphate (ATP) (e.g., fatty-acid oxidation) and restrains others such as fatty acid-, glycerolipid- and protein-synthesis that consume
  • ATP adenosine 5'-triphosphate
  • AMPK is a protein kinase enzyme that piays an important role in cellular energy homeostasis. Therefore, the activation of AMPK is coupled to glucose lowering effects and triggers several other biological effects, including the inhibition of cholesterol synthesis, lipogenesis, triglyceride synthesis, and the reduction of hyperinsulinemia.
  • AMPK is a preferred target for the treatment of the metabolic syndrome and especially type 2 diabetes.
  • AMPK is also involved in a number of pathways that are important for many different diseases (e.g. AMPK is also involved in a number of pathways that are important in CNS disorders, fibrosis, osteoporosis, heart failure and sexual dysfunction).
  • AMPK is also involved in a number of pathways that are important in cancer. Several tumour suppressors are part of the AMP pathway. AMPK acts as a negative regulator of the mammalian TOR (mTOR) and EF2 pathway, which are key regulators of cell growth and proliferation. The deregulation may therefore be linked to diseases such as cancer (as well as diabetes). AMPK activators may therefore be of utility as anti-cancer drugs.
  • mTOR mammalian TOR
  • EF2 EF2 pathway
  • AMPK activators e.g. metformin, glitazones
  • compounds that are AMPK activators, and preferably direct activators of AMPK may find utility as anti-cancer drugs, as well as for the treatment of many other diseases.
  • 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.
  • X represents Q-[CR x R y ] n -Z;
  • Q and Z independently represent a bond, S or O;
  • R x and R y are independently selected from H, halo, C 1-6 alkyl (optionally substituted by one or more halo atoms), or R x and R y are linked to form, along with the carbon atom to which they are attached, a non-aromatic 3- to 8-membered ring, optionally containing 1 to 3 heteroatoms selected from O, S and N, which ring is itself optionally substituted by one or more substituents selected from halo or C 1-6 alkyl (optionally substituted by one or more halo atoms);
  • T S or O
  • M represents -C(O)- or -S(O) 2 -;
  • Y represents -NR a -[CR x R y ] m - or -NR a C(O)-[CR x R y ] m -;
  • R a represents H or C 1 .6 alkyl (optionally substituted by one or more halo atoms);
  • E represents halo or C 1-6 alkyl (optionally substituted by one or more groups selected from, -0R b , aryl or heteroaryl (which latter two groups may be optionally substituted by one or more -R c groups), or, preferably, halo);
  • a 1 to A 5 respectively represent C(R 1 ), C(R 2 ), C(R 3 ), C(R 4 ) and C(R 5 ), or, alternatively, up to two of A 1 to A 5 may independently represent N;
  • D 1 to D 5 each independently represent C(R 6 ), or, alternatively, up to two of D 1 to D 5 may independently represent N;
  • R 6 independently represents, on each occasion when used herein, H, cyano, -NO 2 , halo, -R 8 , -OR 8 , -N(R 8 )C(O)R 8 , -NR 9 R 10 , -SR 11 , -Si(R 12 ) 3 , -OC(O)R 13 , -C(O)OR 13 , -C(O)R 14 , -C(O)NR 15a R 15b , -S(O) 2 NR 15c R 15d , aryl or heteroaryl (which aryl and heteroaryl groups are themselves optionally and independently substituted by one or more groups selected from halo and R 16 ), or any two R 6 groups which are adjacent to each other are optionally linked to form, along with two atoms of the essential benzene ring in the compound of formula I 1 an aromatic or non-aromatic 3- to 8-membered ring, optionally containing 1 to 3 heteroatoms selected from
  • R b and, more preferably, R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15a , R 15b , R 15c and R 15d independently represent H or R 16 ;
  • R 16 represents, on each occasion when used herein, C 1-6 alkyl optionally substituted by one or more halo atoms; n represents 3, or preferably, 1 or 2; m represents 1 , 2, or preferably O; or a pharmaceutically-acceptable salt or solvate, or a pharmaceutically functional derivative thereof.
  • N takes it normal designation (nitrogen) in compounds of formula I.
  • Pharmaceutically-acceptable salts 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 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 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; from organic acids, such as tartaric, acetic, citric, malic, lactic, fumaric, benzoic, glycolic, gluconic, succinic, arylsulphonic acids; and from metals such as sodium, magnesium, or preferably, potassium and calcium.
  • mineral acids such as hydrochloric, hydrobromic, phosphoric, metaphosphoric, nitric and sulphuric acids
  • organic acids such as tartaric, acetic, citric, malic, lactic, fumaric, benzoic, glycolic, gluconic, succinic, arylsulphonic acids
  • metals such as sodium, magnesium, or preferably, potassium and calcium.
  • “Pharmaceutically functional derivatives” of compounds of formula I as defined herein 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.
  • prodrug of a relevant compound of formula I 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 hydroxyl, 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.
  • M is as hereinbefore defined.
  • the relevant proton may be attached to either of the two different nitrogen atoms, and the 'proton shift' may be accompanied by one or more double bond shift.
  • Compounds of formula I contain one or more asymmetric carbon atoms and may therefore exhibit optical 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 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.
  • alky 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, one or more halo atoms).
  • alkyl refers to an acyclic group, it is preferably C 1- - I0 alkyl and, more preferably, Ci. 6 alkyl (such as ethyl, propyl, (e.g. n-propyl or isopropyl), butyl (e.g.
  • alkyl is a cyclic group (which may be where the group “cycloalkyl” is specified), it is preferably C 3 - I2 cycloalkyl and, more preferably, C 5- I 0 (e.g. C 5-7 ) cycloalkyl.
  • alkylene refers to C MO (e.g. C 1-6 ) alkylene and, preferably Ci -3 alkylene, such as pentylene, butylene (branched or unbranched), preferably, propylene (/7-propylene or isopropylene), ethylene or, more preferably, methylene (i.e. -CH 2 -).
  • C MO e.g. C 1-6
  • Ci -3 alkylene such as pentylene, butylene (branched or unbranched), preferably, propylene (/7-propylene or isopropylene), ethylene or, more preferably, methylene (i.e. -CH 2 -).
  • halogen when used herein, includes fluorine, chlorine, bromine and iodine.
  • aryl when used herein includes C 6-M (such as C 6- i 3 (e.g. C 6-I0 )) 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 6- - I4 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
  • 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.
  • 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, be ⁇ zodioxanyl, 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, benzomo ⁇ holinyl, benzoselenadiazolyl (including 2,1 ,3-benzo
  • 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.
  • Particularly preferred heteroaryl groups include monocylic heteroaryl groups.
  • R 6 and R 7 are both aryl groups substituted by one or more C 1-6 alkyl groups
  • the alkyl groups in question may be the same or different.
  • R b or, more preferably, R 8 , R 9 , R 10 , R 11 , R 12 , R 13 ,
  • R 14 , R 15a , R 15b , R 15c and R 15d independently represent R 16 then those R 16 groups may be the same or different.
  • E represents halo or C 1-3 alkyl (optionally substituted by one or more groups selected from, -OR b , phenyl or pyridyl (which latter two groups may be optionally substituted by one or more -R c groups), or, preferably, halo).
  • E represents halo or Ci -3 alkyl (optionally substituted by one or more groups selected from, -OR b , phenyl (which latter group may be optionally substituted by one or more -R c groups), or, preferably, halo).
  • E represents halo or Cv ⁇ alkyl optionally substituted by one or more halo atoms.
  • Compounds of formula I that may be mentioned include those in which: at least one of R 1 to R 5 is not H.
  • R 1 to R 5 when present, represents halo, -R 7 , -CF 3 , -CN, -NO 2 , -C(O)R 7 , -C(O)OR 7 , -N(R 7a )R 7b , -N(RV, -SR 7 , -OR 7 , -NH(O)R 7 or -SO 3 R 7 .
  • R 1 to R 5 when present, represents -C(O)R 7 , -N(R 7 V. or, more preferably, halo, -R 7 , -CF 3 , -CN, -NO 2 , -SR 7 , -OR 7 (e.g. -OCH 3 , or more preferably, -OCHF 2 or -OCF 3 ), -C(O)OR 7 , -N(R 7a )R 7b or a triazolyl group.
  • R 1 to R 5 when present, represents -C(O)R 7 , -N(R 7 V. or, more preferably, halo, -R 7 , -CF 3 , -CN, -NO 2 , -SR 7 , -OR 7 (e.g. -OCH 3 , or more preferably, -OCHF 2 or -OCF 3 ), -C(O)OR 7 , -N(R 7a )R 7b or
  • R 1 to R 5 when present, represents halo, -R 7 , -CF 3 , -CN 1 -C(O)OR 7 , -N(R 7a )R 7b , -OR 7 or a triazolyl group.
  • R 1 to R 5 represents -CH 3 , -OCH 3 , -CN, -Cl, -Br, -F, -C(O)OCH 3 , -C(O)OCH 3 , -CF 3 , -OH, -OCF 3 , -OCF 2 or a triazolyl group.
  • R 1 to R 5 represents -CH 3 , -OCH 3 , -Cl, -Br, -F, -CF 3 , -OH, -OCF 3 , -OCF 2 or a triazolyl group.
  • R c group when present, represents halo, -R 7 , -CF 3 , -CN, -C(O)OR 7 ,
  • R c group is present and represents -CH 3 , -OCH 3 , -CN, -Cl, -Br, -F,
  • R c group is present and represents -CH 3 , -OCH 3 , -Cl, -Br, -F, -CF 3 , -OH, -OCF 3 , -OCF 2 or a triazolyl group.
  • R 6 independently represents -NO 2 , or more preferably, H, -CN, -Br, -Cl, -F, -R 8 , -OR 8 , -NR 9 R 10 , -SR 11 , -C(O)OR 13 , -C(O)R 14 , -C(O)NR 15a R 15b , -S(O) 2 NR 15c R 15d , aryl or heteroaryl (which aryl and heteroaryl groups are themselves optionally and independently substituted by one or more groups selected from halo and R 16 ).
  • R 6 independently represents -NO 2 , or more preferably, H, -CN, -Br, -Cl, -F 1 -R 8 , -OR 8 , -NR 9 R 10 , -C(O)R 14 , -C(O)NR 15a R 15b or -SR 11 .
  • R 6 independently represents, -CN, -Br, -R 8 , -C(O)R 14 , -C(O)NR 15a R 15b or, most preferably, H, -F or -Cl.
  • R a represents H or Ci -3 alkyl (optionally substituted by one or more halo atoms);
  • R a represents -CH 3 , -CH 2 CH 3 , -CF 3 , -CF 2 H, or particularly H;
  • each -[CR x R y ]- unit may be independently selected from:
  • R x and R y are independently selected from H, halo, C 1-6 alkyl (optionally substituted by one or more halo atoms); and (b) a unit wherein R x and R y are linked to form, along with the carbon atom to which they are attached, a non-aromatic 3- to 8-membered ring, optionally containing 1 to 3 heteroatoms selected from O, S and N, which ring is itself optionally substituted by one or more substituents selected from halo or Ci- 6 alkyl (optionally substituted by one or more halo atoms), provided that no more than one unit is selected from (b)
  • each -[CR x R y ]- unit may be independently selected from:
  • R x and R y are independently selected from H, halo, Ci -3 alkyl (optionally substituted by one or more halo atoms);
  • Y represents -NR a -[CR x R y ] m -, or preferably -NH-.
  • Y represents -NR a C(O)-[CR x R y ] m -, or preferably -NHR 3 C(O)-.
  • X represents Q-[CR x R y ] n -Z, or more preferably -[CH] 2 -.
  • R x and R y are independently selected from H, halo, Ci -6 alkyl (optionally substituted by one or more halo atoms).
  • n 2 or, more preferably, 1.
  • More preferred compounds of formula I include those of the examples described hereinafter.
  • Preferred compounds of formula I include: i) 2-(3,4-dichlorophenylamino)-5-methyl-5-(3-trifluoromethylbenzyl)-thiazol-4-one; ii) 2-(3,4-dichlorophenylamino)-5-methyl-5-(3-bromobenzyl)-thiazol-4-one; iii) 2-(3,4-dichlorophenylamino)-5-methyl-5-(3-fluorobenzyl)-thiazol-4-one; iv) 2-(3,4-dichlorophenylamino)-5-methyl-5-(3-methoxybenzyl)-thiazol-4-one; v) 2-(3,4-dichlorophenylamino)-5-methyl-5-(benzyl)-thiazol-4-one; vi) 2-(3,4-dichlorophenylamino)-5-methyl-5-(3-chlorobenzyl)-thiazol-4-one;
  • More preferred compounds of formula I are compounds (i) to (xxxvi) above.
  • L 2 represents a suitable leaving group such as iodo, bromo, chloro or a sulfonate group (e.g. -OS(O) 2 CF 3 , -OS(O) 2 CH 3 Or -OS(O) 2 PhMe) and m, R x , R y and D 1 to D 5 are as hereinbefore defined, for example optionally in the presence of an appropriate metal catalyst (or a salt or complex thereof) such as Cu, Cu(OAc) 2 , CuI (or Cul/diamine complex), copper tris(triphenylphosphine)bromide, Pd(OAc) 2 , Pd 2 (dba) 3 or NiCI 2 and an optional additive such as Ph 3 P, 2,2'-bis(diphenylphosphino)-1 ,1'-binaphthyl, xantphos, NaI or an appropriate crown ether such as 18-crown-6-benzene, in the presence of an appropriate base such
  • This reaction may be carried out at room temperature or above (e.g. at a high temperature, such as the reflux temperature of the solvent system that is employed);
  • J is -OH, -Br or -Cl and m, R", R y and Di to D 5 are as hereinbefore defined, for example under standard coupling reaction conditions.
  • a suitable solvent e.g. tetrahydrofuran, pyridine, toluene, dichioromethane, chloroform, acetonitrile or dimethylformamide
  • a suitable base e.g. triethylamine, Hunig's base, pyridine
  • an appropriate temperature e.g. -20°C to 10CTC.
  • a suitable coupling reagent e.g. 1 ,1 '-carbonyldiimidazole, /V./V-dicyclohexylcarbodiimide, 1-(3-dimethylamino-propyl)-3-ethylcarbodiimide (or hydrochloride thereof), N 1 N 1 - disuccinimidyl carbonate, benzotriazol-1 -yloxytris(dimethylamino)-phosphonium hexafluorophosphate, 2-(1 /-/-benzotriazol-1 -yl)-1 ,1 ,3,3-tetramethyluronium hexafluoro- phosphate, benzotriazol-1 -yloxytris-pyrrolidinophosphonium hexafluorophosphate, bromo-tris-pyrrolidinophosponium hexafluoro-phosphate,
  • a suitable coupling reagent e.
  • a 1 to A 5 , Q, R x , R y and n are as hereinbefore defined and L 3 represents a suitable leaving group such as halo (e.g. chloro, bromo), under reaction conditions known to those skilled in the art, for example in the presence of a suitable base (e.g. NaH, NaOAc, nBuLi), in the presence of a suitable solvent (e.g. THF, diethyl ether, hexanes, toluene) and from reduced to elevated temperature (e.g. from -70 0 C to 150 0 C);
  • a suitable base e.g. NaH, NaOAc, nBuLi
  • a suitable solvent e.g. THF, diethyl ether, hexanes, toluene
  • E, M, T 1 Y and Di to D 5 are as hereinbefore defined and DD represents halo (e.g. chloro, bromo, iodo), with a compound of formula VIII,
  • a 1 to A 5 , Q, R x , R y and n are as hereinbefore defined and Z a represents O or S, under reaction conditions known to those skilled in the art, for example in the presence of a suitable base (e.g. NaH, NaOAc 1 NaOH, NaOMe, NaOEt), in a suitable solvent (e.g. THF 1 diethylether, methanol, ethanol) and from reduced to elevated temperature (e.g. from -70 0 C to 150 0 C);
  • a suitable base e.g. NaH, NaOAc 1 NaOH, NaOMe, NaOEt
  • a suitable solvent e.g. THF 1 diethylether, methanol, ethanol
  • a 1 to A 5 , M, X, T, Y and D 1 to D 5 are as hereinbefore defined, with a compound of formula X, E a -L 4 X
  • E a represents Ci -6 alkyl optionally substituted by one or more halo atoms and L 4 represents a suitable leaving group such as halo (e.g. iodo), under reaction conditions known to those skilled in the art, e.g. such as those described in process (iv) above;
  • halo e.g. iodo
  • a 1 to A 5 , Q, R x , R y , n, and E are as hereinbefore defined, EE represents halo (e.g. chloro, bromo, iodo) and R 22 represents C M alkyl, with a compound of formula XII,
  • T, Y and Di to D 5 are as hereinbefore defined, under reaction conditions known to those skilled in the art, e.g. in an appropriate solvent (e.g. toluene, xylenes, DCM, chloroform), optionally in the presence of an base (e.g. pyridine, Hunig's base, triethylamine) and at reduced to elevated temperatures (e.g. from 0 0 C to 14O 0 C);
  • an appropriate solvent e.g. toluene, xylenes, DCM, chloroform
  • an base e.g. pyridine, Hunig's base, triethylamine
  • elevated temperatures e.g. from 0 0 C to 14O 0 C
  • a 1 to A 5 , Q, n, R x , R y , and E are as hereinbefore defined and EA represents halo (e.g. chloro, bromo, iodo), with a compound of formula XIV,
  • T, Y and Di to D 5 are as hereinbefore defined, under reaction conditions known to those skilled in the art, e.g. in an appropriate solvent (e.g. toluene, xylenes, DCM, chloroform, acetonitrile), optionally in the presence of a base (e.g. pyridine, Hunig's base, triethylamine, potassium carbonate) and at reduced to elevated temperatures (e.g. from 0 0 C to 14O 0 C); or
  • an appropriate solvent e.g. toluene, xylenes, DCM, chloroform, acetonitrile
  • a base e.g. pyridine, Hunig's base, triethylamine, potassium carbonate
  • elevated temperatures e.g. from 0 0 C to 14O 0 C
  • E represents a C 1 .3 alkyl group substituted by an aryl or a six-membered heteroaryl group (containing one or two nitrogen atoms), which two groups may be optionally substituted by one or more -R c groups that correspond to R 1 to R 5 ), reaction of a compound of formula XIVa,
  • L 3 ' represents a suitable leaving group such as halo (e.g. chloro, bromo) and A 1 . to A 5 - respectively represent C(R 1' ), C(R 2' ), C(R 3' ), C(R 4' ) and C(R 5' ), or, alternatively, up to two Of A 1 to A 5 may independently represent N, wherein R 1' to R 5' independently represent H, halo, -R 7 , -CF 3 , -CN, -NO 2 , -C(O)R 7 , -C(O)OR 7 , -N(R 7a )R 7b , -N(RV, -SR 7 , -OR 7 , -NH(O)R 7 or -SO 3 R 7 , or any two of R 1' to R 5' which are adjacent to each other are optionally linked to form, along with two atoms of the essential benzene ring in the compound of formula I
  • E, EE and R s are as hereinbefore defined, with a compound of formula Vl as hereinbefore defined, under reaction conditions known to those skilled in the art, for example in the presence of a suitable base (e.g. lithium diisopropylamide, sodium methoxide, sodium exthoxide), in a suitable solvent (e.g. methanol, ethanol, THF) and from reduced to elevated temperature (e.g. from -70 0 C to 10O 0 C); and
  • a suitable base e.g. lithium diisopropylamide, sodium methoxide, sodium exthoxide
  • a suitable solvent e.g. methanol, ethanol, THF
  • elevated temperature e.g. from -70 0 C to 10O 0 C
  • a 1 to A 5 are as hereinbefore defined, with sodium nitrite, under reaction conditions known to those skilled in the art, for example, in the presence of a suitable acid (e.g. hydrochloric acid, hydrobromic acid, hydroiodic acid), a suitable solvent (e.g. acetone) and from reduced to elevated temperature (e.g. from -20 0 C to 50 0 C), followed by reaction of the resulting diazonium salt intermediate with a compound of formula XVII,
  • a suitable acid e.g. hydrochloric acid, hydrobromic acid, hydroiodic acid
  • a suitable solvent e.g. acetone
  • E and R 22 are as hereinbefore defined, under reaction conditions known to those skilled in the art, for example in a suitable solvent (e.g. acetone) and in the presence of a suitable metal salt (e.g. CuCI, CuBr, CuI) and from reduced to elevated temperature (e.g. from -70 0 C to 50 0 C).
  • a suitable solvent e.g. acetone
  • a suitable metal salt e.g. CuCI, CuBr, CuI
  • elevated temperature e.g. from -70 0 C to 50 0 C.
  • Ai to A 5 , Q, R", R y , n, and EA are as hereinbefore defined, with a compound of formula X as hereinbefore defined, under reaction conditions known to those skilled in the art, e.g. such as those described in process (a) above.
  • Substituents such as R 1 , R 2 , R 3 and R 4 in final compounds of formula I (or precursors thereto and other 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 (e.g. carbonyl bond reductions in the presence of suitable and, if necessary, chemoselective, reducing agents such as LiBH 4 or NaBH 4 ), 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.
  • 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.
  • compounds of formula I may be AMPK agonists, i.e. they may activate AMPK.
  • AMPK' we mean that the steady state level of phosphorylation of the Thr-172 moiety of the AMPK- ⁇ subunit is increased compared to the steady state level of phosphorylation in the absence of the agonist.
  • ACC acetyl-CoA carboxylase
  • the compounds of formula I may be AMPK activators, they may therefore be useful in the treatment of diseases such as those described herein, especially cancer.
  • Compounds of formula I may reduce the rate of cell proliferation when tested in an assay using a human breast cancer cell line (e.g. MDA-MB-231). The compounds may thus possess a beneficial inhibitory effect on the ability of tumors of this type, and of cancers generally, to survive.
  • Compounds of formula I may also reduce the rate of cell proliferation when tested in other cancer cells lines such as MCF-7, PC-3, Jurkat, Skov- 3, HL60, MV4-11 , HT-29, K562, MDA-MB231 , HCT116wt, HCT116P53-/-, A-549, DU- 145, LOVO, HCT-116 and PANC-1.
  • cancer cells lines such as MCF-7, PC-3, Jurkat, Skov- 3, HL60, MV4-11 , HT-29, K562, MDA-MB231 , HCT116wt, HCT116P53-/-, A-549, DU- 145, LOVO, HCT-116 and PANC-1.
  • a compound of formula I or a pharmaceutically-acceptable salt or solvate, or a pharmaceutically functional derivative thereof, for the manufacture of a medicament for the treatment of cancer.
  • the compounds of formula I may be useful in the treatment of both primary and metastatic cancers.
  • 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.
  • compounds of formula I are capable of inhibiting the proliferation of cancer cells.
  • proliferation we include an increase in the number and/or size of cancer cells.
  • compounds of formula I are capable of inhibiting metastasis of cancer cells.
  • metastasis we mean the movement or migration (e.g. invasiveness) of cancer cells from a primary tumor 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 tumors).
  • the invention provides compounds and methods for inhibiting, in whole or in part, the formation of secondary tumors in a subject with cancer. It will be appreciated by skilled persons that the effect of a compound of formula I on "metastasis" is distinct from any effect such a compound may or may not have on cancer cell proliferation.
  • compounds of formula I 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 compound inhibits the proliferation • and/or metastasis of cancer cells only.
  • cancer cells may be selected from the group consisting of cancer cells of the breast, bile duct, brain, colon, stomach, reproductive organs, thyroid, hematopoietic 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 hematopoietic system (e.g.
  • the cancer is selected from the group of colon, prostate and, particularly, breast cancer.
  • the cancer is a non-solid tumor, it is preferably a hematopoietic tumor such as a leukemia (e.g. Acute Myelogenous Leukemia (AML), Chronic Myelogenous Leukemia (CML), Acute Lymphocytic Leukemia (ALL), Chronic Lymphocytic Leukemia (CLL).
  • AML Acute Myelogenous Leukemia
  • CML Chronic Myelogenous Leukemia
  • ALL Chronic Lymphocytic Leukemia
  • CLL Chronic Lymphocytic Leukemia
  • the cancer cells are breast cancer cells.
  • a method of treatment of cancer comprises the administration of an effective amount of a compound of formula I, or a pharmaceutically-acceptable salt or solvate, or a pharmaceutically functional derivative thereof, to a patient in need of such treatment.
  • Compounds of formula I may also be of use in the treatment of a disorder or condition ameliorated by the activation of AMPK. According to a further aspect of the invention, there is provided the use of a compound of formula I, or a pharmaceutically-acceptable salt or solvate, or a pharmaceutically functional derivative thereof, for the manufacture of a medicament for the treatment of a disorder or condition ameliorated by the activation of AMPK.
  • disorder or condition ameliorated by the activation of AMPK will be understood by those skilled in the art to include, in addition to cancer, diabetes, hyperinsuiinemia and associated conditions, a condition/disorder where fibrosis plays a role, sexual dysfunction, osteoporosis and neurodegenerative diseases.
  • Compounds of formula I may thus also be indicated for use in the treatment of a disorder or a condition caused by, linked to, or contributed to by, hyperinsuiinemia.
  • hyperinsuiinemia disorder or condition caused by, linked to, or contributed to by, hyperinsuiinemia
  • treatment of hyperinsuiinemia or an associated condition will be understood by those skilled in the art to include hyperinsuiinemia and associated conditions, such as type 2 diabetes, glucose intolerance, insulin resistance, metabolic syndrome, dyslipidemia, hyperinsulinism in childhood, hypercholesterolemia, high blood pressure, obesity, fatty liver conditions, diabetic nephropathy, diabetic neuropathy, diabetic retinopathy, cardiovascular disease, atherosclerosis, cerebrovascular conditions such as stroke, systemic lupus erythematosus, neurodegenerative diseases such as Alzheimer's disease, and polycystic ovary syndrome.
  • Other disease states include progressive renal disease such as chronic renal failure.
  • Preferred disorders include hyperinsuiinemia and, particularly, type 2 diabetes.
  • Certain compounds of formula I may also have the additional advantage that they exhibit partial agonist activity and may therefore be useful in conditions, such as late type 2 diabetes, in which stimulation of the production of insulin is required.
  • agonist activity we include direct and indirect-acting agonists.
  • a method of treatment of a disorder or condition ameliorated by the activation of AMPK comprises the administration of an effective amount of a compound of formula I, or a pharmaceutically-acceptable salt or solvate, or a pharmaceutically functional derivative thereof, to a patient in need of such treatment.
  • Compounds of formula I may thus also be of use in the treatment of a condition/disorder where fibrosis plays a role.
  • Compounds of formula I may also be useful in the treatment of sexual dysfunction (e.g. the treatment of erectile dysfunction).
  • a condition/disorder where fibrosis plays a role includes (but is not limited to) scar healing, keloids, scleroderma, pulmonary fibrosis (including idiopathic pulmonary fibrosis), nephrogenic systemic fibrosis, and cardiovascular fibrosis (including endomyocardial fibrosis), systemic sclerosis, liver cirrhosis, eye macular degeneration, retinal and vitreal retinopathy, Crohn's/inflammatory bowel disease, post surgical scar tissue formation, radiation and chemotherapeutic-drug induced fibrosis, and cardiovascular fibrosis.
  • Compounds of formula I may thus also be of use in the treatment of osteoporosis.
  • Compounds of formula I may thus also be of use in the treatment of inflammation.
  • Compounds of formula I may thus also be of use in the treatment of sexual dysfunction.
  • Compounds of formula I may thus also be of use in the treatment of heart failure.
  • Compounds of formula I may also be of use in the treatment of lung disease.
  • Compounds of formula I may also be of use in the treatment of obesity.
  • Compounds of formula I may also be of use in the treatment of dry-type age-related macular degeneration.
  • Compounds of formula I may also be of use as an agent for cardioprotection.
  • Compounds of formula I may thus also be of use in the treatment of neurodegenerative diseases (e.g. Alzheimer ' s disease, Parkinson's disease and Huntington ' s disease, amyotrophic lateral sclerosis, polyglutamine disorders, such as spinal and bulbar muscular atrophy (SBMA), dentatorubral and pallidoluysian atrophy (DRPLA), and a number of spinocerebellar ataxias (SCA)).
  • neurodegenerative diseases e.g. Alzheimer ' s disease, Parkinson's disease and Huntington ' s disease, amyotrophic lateral sclerosis, polyglutamine disorders, such as spinal and bulbar muscular atrophy (SBMA), dentatorubral and pallidoluysian atrophy (DRPLA), and a number of spinocerebellar ataxias (SCA)).
  • 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, the relevant disease states.
  • 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. sublingually 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. A brief review of methods of drug delivery may also be found in e.g. Langer, Science 249, 1527 (1990).
  • Another aspect of the present invention includes a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula I 1 or a pharmaceutically-acceptable salt or solvate, or a pharmaceutically functional derivative thereof, in combination with a pharmaceutically acceptable excipient, such as an adjuvant, diluent or carrier.
  • the amount of compound of formula I in the formulation 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.
  • compounds of formula I 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 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 a compound of formula I (or, if employed, a corresponding amount of a pharmaceutically acceptable salt or prodrug thereof).
  • 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.
  • the compounds of formula I may be used or administered in combination with one or more additional drugs useful in the treatment of cancer, in combination therapy.
  • a combination product comprising:
  • each of components (A) and (B) is formulated in admixture with a pharmaceutically-acceptable adjuvant, diluent or carrier.
  • cancer therapies such as cytostatica, irradiation and photodynamic therapy, among others known to the physician.
  • the other therapeutic agent is a cytostatic (such as a taxane (e.g. docetaxel and, particularly, paclitaxe! or preferably, a platin (e.g. cisplatin and carboplatin) or an anthracycline (e.g. doxorubicin)) or an angiogenesis inhibitor, or a pharmaceutically-acceptable salt, solvate or pharmaceutically functional derivative of either of these.
  • the other therapeutic agent may also be selected from:
  • an aromatase inhibitor i.e. a compound that blocks the production of estrogen from adrenal androgens via the aromatase pathway in peripheral tissues
  • a pharmaceutically-acceptable salt, solvate or pharmaceutically functional derivative thereof i.e. anastrozole, letrozole and exemastane
  • trastuzumab Herceptin
  • another antibody that is useful in the treatment of cancer such as bevacizumab, cetuximab or panitumumab;
  • a tyrosine kinase inhibitor i.e. a compound that blocks (or is capable of blocking), to a measurable degree, the autophosphorylation of tyrosine residues, thereby preventing activation of the intracellular signalling pathways in tumor cells
  • a pharmaceutically-acceptable salt, solvate or pharmaceutically functional derivative thereof include inhibitors of the vascular endothelial growth factor (VEGF) family, and/or the HER-family of TKs, such as HER- 1 /Human Epidermal Growth Factor (EGFR; erbB1), HER3 (erbB3), HER4 (erbB4) and, more particularly, HER2 (e ⁇ t»B2).
  • VEGF vascular endothelial growth factor
  • HER-family of TKs such as HER- 1 /Human Epidermal Growth Factor (EGFR; erbB1), HER3 (erbB3), HER4 (erbB4) and, more particularly, HER2 (
  • Preferred TKIs thus include imatinib, gefitinib, erlotinib, canertinib, sunitinib, zactima, vatalanib, sorafenib, leflunomide and, particularly, lapatinib; (v) a glitazone, such as troglitazone, pioglitazone and rosiglitazone, or a pharmaceutically-acceptable salt, solvate or pharmaceutically functional derivative thereof;
  • a biguanide such as phenformin, buformin, or, most preferably, metformin, or a pharmaceutically-acceptable salt, solvate or pharmaceutically functional derivative thereof;
  • statin such as fluvastatin, simvastatin, rosuvastatin, pravastatin, atorvastatin and, particularly, lovastatin, or a pharmaceutically-acceptable salt, solvate or pharmaceutically functional derivative thereof
  • mTOR mammalian target of rapamycin
  • oligomycin such as oligomycin A, oligomycin B, oligomycin C, oligomycin D
  • rutamycin A oligomycin E, oligomycin F, rutamycin B, 44-homooligomycin A and 44-homooligomycin B, or a pharmaceutically-acceptable salt, solvate or pharmaceutically functional derivative thereof;
  • AICAR aminoimidazole carboxamide ribonucleotide
  • PPAR peroxisome proliferator-activated receptor
  • a SIRT1 activator such as resveratrol and SRT-1720 (N-[2-[3-(piperazin-1- ylmethyl)imidazo[2, 1 -b][1 ,3]thiazol-6-yl]phenyl]quinoxal-ine-2-carboxamide), or a pharmaceutically-acceptable salt, solvate or pharmaceutically functional derivative thereof; and/or (xvi) salidroside, or a pharmaceutically-acceptable salt, solvate or pharmaceutically functional derivative thereof.
  • agonist we include direct and indirect-acting agonists.
  • Such combination products according to the invention are also particularly useful in the treatment of patients at a high risk of breast cancer.
  • combination products according to the invention are particularly useful in the treatment of HER2-positive cancers.
  • compositions solvates or pharmaceutically functional derivatives of any of the compounds listed in categories (i), (ii) and (iv) to (xvi) above are as described hereinbefore.
  • preferred pharmaceutically-acceptable salts include those of citric acid
  • preferred pharmaceutically-acceptable salts include mesylate salts
  • preferred pharmaceutically-acceptable salts include maleate salts.
  • Combination products as described herein provide for the administration of compound of formula I in conjunction with the other therapeutic agent, and may thus be presented either as separate formulations, wherein at least one of those formulations comprises compound of formula I, and at least one comprises the other therapeutic agent, or may be presented (i.e. formulated) as a combined preparation (i.e. presented as a single formulation including compound of formula I and the other therapeutic agent).
  • compositions including a compound of formula I; another therapeutic agent useful in the treatment of cancer; and a pharmaceutically-acceptable adjuvant, diluent or carrier; and
  • kits of parts comprising components:
  • a pharmaceutical formulation including another therapeutic agent useful in the treatment of cancer, 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.
  • Components (a) and (b) of the kits of parts described herein may be administered simultaneously or sequentially.
  • 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 the other therapeutic agent, in order to provide for repeat dosing. If more than one formulation (comprising either active compound) is present, such 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).
  • kits of parts as described herein by “administration in conjunction with”, we include that respective formulations comprising compound of formula I and the other therapeutic agent 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 the other therapeutic agent) 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, or a formulation comprising the other therapeutic agent, 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 the other therapeutic agent are administered within 48 hours (e.g. 24 hours) of each other.
  • the compounds/combinations/methods/uses described herein may have the advantage that, in the treatment of the conditions described herein, they may be more convenient for the physician and/or patient than, be more efficacious than, be less toxic than, have better selectivity, have a broader range of activity than, be more potent than, produce fewer side effects than, or may have other useful pharmacological properties over, similar compounds, combinations, methods (treatments) or uses known in the prior art for use in the treatment of those conditions or otherwise, for example over the compounds disclosed in international patent applications WO 2007/010273 and WO 2007/010281.
  • Figure 1 which shows the effect of the compound of Example 1 on AMPK phosphorylation. After starvation of PC3 cells in serum-free medium for 5 h, and 2.5, 5 and 10 ⁇ M of the compound of Example 1 was added and incubated for an additional 24 h.
  • the Figure provides representative immunoblots of AMPK phosphorylation by the compound of Example 1.
  • Figure 2 which shows the effect of the compound of Example 1 on eEF2 phosphorylation. After starvation of PC3 cells in serum-free medium for 5 h, 10 ⁇ M of the compound of Example 1 was added and incubated for an additional 24 h. The Figure provides representative immunoblots of eEF2 phosphorylation by the compound of Example 1. The compound of Example 1 stimulates eEF2 phosphorylation in PC3 cells
  • the relevant intermediate is commercially available (e.g. from Chemical Diversity, San Diego, CA 1 USA or other available commercial sources).
  • LC-MS was performed on a Sciex API 150 LC/ES-MS equipped with an ACE 3 C8 column (30 x 3.0 mm) using a flow of 1 mL/min.
  • Two gradient systems of acetonitrile in water (with 0.1 % TFA) are used for elution: A) 5-100% under 10 min, then 2 min 100% isocratic or B) 90-100% under 2 min, then 2 min 100% isocratic.
  • Direct inlet ES-MS was also performed on a Bruker Esquire LC/ES-MS. 1 H nuclear magnetic resonance was recorded on a Bruker Avance DRX 400 spectrometer at 400.01 MHz using residual solvent as internal standard.
  • EtOH 50 mL was added to a slurry of NaOAc (2.4 g) and 1-(3,4-dichloro-phenyl)-3-(4- methoxybenzyl)-thiourea (5 g; from step (a)(i) above) in EtOH (150 mL). The mixture was heated at 60 C C and stirred for one week. The solvent was then removed under reduced pressure and the solid was triturated twice with Et 2 O to give 2-[(E)-3,4-dichloro- phenylimino]-3-(4-methoxy-benzyl)-5-methylthiazolidin-4-one as a yellow solid with >90% purity.
  • the phases were separated and the aq. phase was extracted using 3x EtOAc (100 mL).
  • the combined organic phases were washed using 1x H 2 O followed by 1x Brine (300 mL), dried (MgSO 4 ) and the solvent removed under reduced pressure to afford the crude product as a yellow oil (1.9 g).
  • the crude product was purified by flash column chromatography on silica using a gradient of 90:10 to 80:20 petrolium ether/EtOAc.
  • the title compound may be prepared using procedures described in the specification above (e.g. by using bromofluoro acetic acid methyl ester instead of 2-bromopropionic acid ethyl ester in step (b) of Route A above).
  • 2-(3,4-Dichlorophenyl)imino-3-[(2,4-dimethoxyphenyl)methyl]thiazolidin-4-one was formed from 1-(3,4-dichlorophenyl)-3-[(2,4 dimethoxyphenyl)methyl]-thiourea and methyl 2-bromoacetate following the procedure set out in Example 1 , step (b) above.
  • a solution of 20 mg 2-(3,4-dichlorophenyl)imino-3-[(2,4-dimethoxyphenyl)methyl]thiazolidin-4-one in 300 ⁇ l_ dry 2-MeTHF was added to 5 mg solid NaH in a vial.
  • cancer cell lines including source, tumor type, and morphology may be obtained from the American Type Culture Collection (ATCC) or its website (www.atcc.org).
  • ATCC American Type Culture Collection
  • the cell lines are both from primary tumors and metastatic sites (for example, MCF-7, MDA-MB231 , HT-29, SKOV-3 and PC-3 among others tested).
  • D-MEM Dulbecco's modified Eagle's medium
  • Glucose GlutaMAXTM1 + Pyruvate (Gibco #21885-025)
  • VA/ Foetal Bovine Serum Gibco 10500-064
  • 5-bromo-2-deoxyuridine BrdU
  • Dimethyl sulfoxide DMSO
  • PC-3 and MCF-7 cancer cell lines were propagated in D-MEM (Gibco 21885) supplemented with 10% Foetal calf serum. 15000 cells per well were seeded in 96 well plates and incubated overnight. The culture media was changed to serum-free D-MEM for 24 h. The culture media was then changed to serum free D-MEM containing either 0.2 % DMSO as vehicle control or 10, 5, or 2.5 ⁇ M (as indicated below) of the compound of Example 1 , Example 2(a), Examples 2(c) to 2(h), Example 2(ii) or Example 3 in 0.2% DMSO in quadruplicate. After 18 h incubation, BrdU was added according to manufacturer's recommendations. After 6 h incubation in the presence of BrdU, the culture media was removed and BrdU incorporation was measured using "Cell Proliferation ELISA, BrdU colorimetric" Roche (11647229001) according to manufacturer's recommendations. Results
  • Proliferation rate of PC-3 and MCF-7 cells are reduced by relevant concentrations of the test compounds as measured by BrdU incorporation.
  • Example 1 the compounds of Example 1 , Example 2(A), Examples 2(C) to 2(H), Example 2(FF) and Example 3 relative to the vehicle control (which displayed a BrdU incorporation of 1 unit) displayed the following (approximate) units of BrdU incorporations at the indicated concentrations in Table 1 below.
  • the preparation of the above assay is repeated using different cancer cell lines.
  • the cell lines MDA-MB-231 , Jurkat and Skov-3 may be used.
  • mice 5 week old Athymic BALB/cA nude mice are delivered from Taconic (Denmark) and kept under barrier conditions for 1 week acclimatisation. At 6 weeks, 17 mice are 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 are observed in 16 mice. 2 mice are sacrificed and the tumors dissected and examined. 2 groups of 7 mice each are treated once daily by intraperitoneal injections of 1-10 mg/kg bodyweight of test compound in 79% PBS/20% Solutol HS 15(BASF)/1 % DMSO or vehicle control respectively for 5-30 days. The mice are sacrificed by cervical dislocation and tumors are dissected.
  • the tumor tissue are fixated overnight in PBS (containing 4% w/v paraformaldehyde (Scharlau PA0095, Sharlau Chemie SA, Spain) at +4 0 C.
  • the tumor tissue is cryopreserved by 24 hour incubation in PBS containing 30% w/v sucrose (BDH #102745C (www.vwr.com) at +4°C and is embedded in Tissue-Tek embedding media (Sakura Finetek Europa BV, Netherlands).
  • 10 ⁇ m cryosections are generated and stained with Mayers Hematoxylin (Dako) for 5 minutes and destained for 3 x 10 minutes in tap water. Slides are mounted using Dako faramount aqueous mounting medium and are examined using a Nikon Eclipse TS 100 microscope documented using a Nikon coolpix 4500.
  • mice treated with test compound and vehicle are analyzed for morphology by microscopic examination of hematoxylin stained cryosections.
  • mice are injected subcutaneously. After 6 days, palpable tumors were observed in the 16 mice. 2 groups of 8 mice each were treated once daily by intraperitoneal injections of 7.5 mg/kg bodyweight of test compound in 79% PBS/20% Solutol HS 15(BASF)/1 % DMSO or vehicle control respectively for 27 days. Tumor size is measured by calliper every third day.
  • the results of the tumor area in the first group of mice (treated with test compound) were compared against the second ('untreated') group of mice after a certain number of days.
  • Example 1 The compound of Example 1 was synthesized by iNovacia AB, Sweden. A stock solution of 10 ⁇ M was prepared by dissolving the compound in 100% DMSO.
  • PC3 cells were purchased from LGC Promochem-ATCC (ATCC catalog no CRL- 1435). PC3 cells were maintained in Dulbecco's modified Eagle's medium (Gibco 21885) containing 5% fetal bovine serum (Gibco 10500-064), 25 ⁇ g/ml Gentamicin (Gibco 15750) and 1x non essential amino acids (Gibco 1 1140). The cells were incubated in a humidified atmosphere of 5% CO2 at 37°C and passaged every 3 days by trypsinization.
  • Dulbecco's modified Eagle's medium Gibco 21885
  • fetal bovine serum Gibco 10500-064
  • 25 ⁇ g/ml Gentamicin Gibco 15750
  • 1x non essential amino acids Gabco 1 1140
  • PC3 cells were cultured in complete medium with 10% fetal bovine serum in 60-mm-diameter dishes, grown to 70-80% confluence and cultured in serum- free Dulbecco's modified Eagle's medium for 5 h. Cells were then treated with 2.5, 5 or 10 ⁇ M of the compound of Example 1 for 24 h. The final concentration of DMSO did not exceed 0.1%, which did not affect AMPK or eEF2 phosphorylation. 0.1 % DMSO was used as control.
  • Filters were washed in 2OmM TRIS pH 7.5, 137mM NaCI, 25%v/v Tween20 for 3x5min. Filters were incubated in blocking solution with secondary antibody, peroxidase conjugated Goat anti-rabbit IgG (Jackson immunoResearch #111-035-003) at room temperature for 1 h. Filters were washed as above for 3x10 min. Signal was developed with SuperSignal West Dura ECL kit (Pierce #1859024) and exposed to Hyperfilm ECL (Amersham #28906837).
  • Compound Example 1 stimulates AMPK phosphorylation
  • the phosphorylation of AMPK and its downstream target, eEF2 were used as indicators of AMPK activation.
  • the Western blot result showed that the compound of Example 1 stimulated the phosphorylation of Thr-172 of the AMPK ⁇ -subunit.
  • AMPK activation by the compound of Example 1 in PC3 cells was further confirmed by enhanced phosphorylation of eEF2.
  • Test D In vitro cytotoxicity data with several cell lines in a 96 well plate
  • Cells are seeded and grown in the presence of varying concentrations of test compound(s) for a period of 3 days (72 hours). The cells are then fixed to the plate and exposed to the dye sulphorhodamine B (SRB). The varying amounts of inhibition of proliferation produces a standard curve from which the IC 50 value is determined.
  • SRB dye sulphorhodamine B
  • Section A Seeding the cells into the plate
  • Assay uses a sterile 96 well plate cell culture plate (Microtest flat bottom tissue culture plate, Falcon 3072).
  • Section B Adding Test Compound(s) to cells
  • test articles Dilute the test articles to 250 ⁇ M in the cell culture medium in a separate tube, which will make start concentration of 50 ⁇ M.
  • Stock concentration of test compound(s) is 1OmM, therefore dilute 1 :40 to obtain 250 ⁇ M concentration.
  • Blank control Pipette 100 ⁇ l_ blank medium to row 1 and 12, 25 ⁇ l_ form this will be added to assay plate containing cells.
  • Section C Fixing and staining the cells
  • Adherent cell lines Fix cells to the plate by carefully adding 30 ⁇ L of cold 50% v/v Trichloroacetic acid (TCA BDH 102863H) to the cell culture medium already in the welis so the final concentration of TCA is 10% v/v.
  • TCA BDH 102863H 50% v/v Trichloroacetic acid
  • Suspension cell lines Fix cells to the plate by carefully adding 30 ⁇ l_ of cold 80% v/v Trichloroacetic acid (TCA BDH 102863H) to the cell culture medium already in the wells so the final concentration of TCA is 16% v/v. 1. Incubate at 4 0 C for 1 hour. 2. Submerge plate in a plastic container containing distilled water such that each well fills with water. Leave to soak for 1 minute. Flick off wash solution into the sink and repeat this washing step a further four times. Finally, flick off wash solution and leave to air dry.
  • TCA BDH 102863H Trichloroacetic acid
  • Section A Seeding the assay plates
  • test compound(s) Dilute the test compound(s) to 120 ⁇ M in the cell culture medium in a separate tube, which will make start concentration of 40 ⁇ M.
  • Blank control Pipette 200 ⁇ l_ blank medium per well to Column 1 by quadruplicate.
  • Section C Staining and counting the cell colonies
  • each colony must have 50 cells.

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Abstract

La présente invention concerne un composé de formule (I), dans laquelle X, T, Y, E, M, A1 à A5 et D1 à D5 ont les significations données dans la description. Les composés selon l'invention sont utiles dans le traitement du cancer.
PCT/GB2010/000144 2009-01-30 2010-01-29 Composés utiles en tant qu'inhibiteurs tel que ampk WO2010086613A1 (fr)

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KR100971446B1 (ko) * 2001-12-31 2010-07-21 알디피에이 엘엘씨 위성 포지셔닝 시스템에 의해 이네이블링되는 미디어 측정시스템 및 방법
US8367863B2 (en) 2007-12-20 2013-02-05 Envivo Pharmaceuticals, Inc. Tetrasubstituted benzenes
US8889730B2 (en) 2012-04-10 2014-11-18 Pfizer Inc. Indole and indazole compounds that activate AMPK
US9156831B2 (en) 2013-01-23 2015-10-13 Astrazeneca Ab Chemical compounds
US9394285B2 (en) 2013-03-15 2016-07-19 Pfizer Inc. Indole and indazole compounds that activate AMPK
CN109045049A (zh) * 2018-06-15 2018-12-21 上海交通大学医学院附属第九人民医院 红景天苷及其衍生物在制备眼科纤维化细胞外基质蛋白异常疾病的抑制剂药物中的应用
US10858359B2 (en) 2016-06-07 2020-12-08 Jacobio Pharmaceuticals Co., Ltd. Heterocyclic ring derivatives useful as SHP2 inhibitors
US10988466B2 (en) 2017-03-23 2021-04-27 Jacobio Pharmaceuticals Co., Ltd. Heterocyclic derivatives useful as SHP2 inhibitors

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Cited By (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR100971446B1 (ko) * 2001-12-31 2010-07-21 알디피에이 엘엘씨 위성 포지셔닝 시스템에 의해 이네이블링되는 미디어 측정시스템 및 방법
US8367863B2 (en) 2007-12-20 2013-02-05 Envivo Pharmaceuticals, Inc. Tetrasubstituted benzenes
US8664249B2 (en) 2007-12-20 2014-03-04 Envivo Pharmaceuticals, Inc. Tetrasubstituted benzenes
US8889730B2 (en) 2012-04-10 2014-11-18 Pfizer Inc. Indole and indazole compounds that activate AMPK
US9156831B2 (en) 2013-01-23 2015-10-13 Astrazeneca Ab Chemical compounds
US9657008B2 (en) 2013-01-23 2017-05-23 Astrazeneca Ab Chemical compounds
US9394285B2 (en) 2013-03-15 2016-07-19 Pfizer Inc. Indole and indazole compounds that activate AMPK
US10858359B2 (en) 2016-06-07 2020-12-08 Jacobio Pharmaceuticals Co., Ltd. Heterocyclic ring derivatives useful as SHP2 inhibitors
US10988466B2 (en) 2017-03-23 2021-04-27 Jacobio Pharmaceuticals Co., Ltd. Heterocyclic derivatives useful as SHP2 inhibitors
CN109045049A (zh) * 2018-06-15 2018-12-21 上海交通大学医学院附属第九人民医院 红景天苷及其衍生物在制备眼科纤维化细胞外基质蛋白异常疾病的抑制剂药物中的应用
CN109045049B (zh) * 2018-06-15 2022-04-29 上海交通大学医学院附属第九人民医院 红景天苷及其衍生物在制备眼科纤维化细胞外基质蛋白异常疾病的抑制剂药物中的应用

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