Astex Therapeutics Limited

Cancer Research Technology Limited

The Institute of Cancer Research: Royal Cancer Hospital

John Francis Lyons

Neil Thomas Thompson

Neil Gallagher

Christopher William Murray

Stephen Murray Yule

Jayne Elizabeth Curry

Andrew James Woodhead

Martyn Frederickson

Kyla Merriom Thompson

Miles Stuart Congreve

Brian John Williams

Valerio Berdini

Ian James Collins

Gianni Chessari

Alison Jo-Anne Woolford

Paul Graham Wyatt

Robert George Boyle

Michael Alistair O'Brien

Adrian Liam Gill

Michelle Dawn Garrett

Mladen Vinkovic

Lynsey Helen Fazal

Matthew Simon Squires

Neil James Gallagher

The invention provides a combination comprising:   Also provided are pharmaceutical compositions containing the combinations and medical uses of the combinations.

Combination of isoindolinone derivatives with SGI-110

The invention provides an acid addition salt of a compound of the formula (1). Also provided by the invention are processes for preparing the compound of formula (1) and alkyl analogs thereof, novel intermediates for use in the process and methods for preparing the intermediates. The invention also provides new medical uses of compounds of the formula (1) and its ethyl analog.

Hydrobenzamide derivatives as inhibitors of Hsp90

The invention provides combinations comprising (or consisting essentially of) one or more ancillary compound(s) and a compound of the formula (I): or salts, tautomers, solvates and N-oxides thereof; wherein Ris hydroxy or hydrogen; Ris hydroxy; methoxy or hydrogen; provided that at least one of Rand Ris hydroxy; Ris selected from hydrogen; halogen; cyano; optionally substituted Chydrocarbyl and optionally substituted Chydrocarbyloxy; Ris selected from hydrogen; a group &#x2014;(O)&#x2014;Rwhere n is 0 or 1 and Ris an optionally substituted acyclic Chydrocarbyl group or a monocyclic carbocyclic or heterocyclic group having 3 to 7 ring members; halogen; cyano; hydroxy; amino; and optionally substituted mono- or di-Chydrocarbyl-amino; or Rand Rtogether form a monocyclic carbocyclic or heterocyclic ring of 5 to 7 ring members; and NRRforms an optionally substituted bicyclic heterocyclic group having 8 to 12 ring members of which up to 5 ring members are heteroatoms selected from oxygen, nitrogen and sulphur. The combinations have activity as Hsp90 and/or glycogen synthase kinase-3 and/or cyclin dependent kinase inhibitors.

Pharmaceutical combinations

The invention provides combinations comprising (or consisting essentially of) one or more ancillary compound(s) and a compound of the formula (I): or salts, tautomers, solvates and N-oxides thereof; wherein Ris hydroxy or hydrogen; Ris hydroxy; methoxy or hydrogen; provided that at least one of Rand Ris hydroxy; Ris selected from hydrogen; halogen; cyano; optionally substituted Chydrocarbyl and optionally substituted Chydrocarbyloxy; Ris selected from hydrogen; a group &#x2014;(O)&#x2014;Rwhere n is 0 or 1 and Ris an optionally substituted acyclic Chydrocarbyl group or a monocyclic carbocyclic or heterocyclic group having 3 to 7 ring members; halogen; cyano; hydroxy; amino; and optionally substituted mono- or di-Chydrocarbyl-amino; or Rand Rtogether form a monocyclic carbocyclic or heterocyclic ring of 5 to 7 ring members; and NRRforms an optionally substituted bicyclic heterocyclic group having 8 to 12 ring members of which up to 5 ring members are heteroatoms selected from oxygen, nitrogen and sulphur. The combinations have activity as Hsp90 and/or glycogen synthase kinase-3 and/or cyclin dependent kinase and/or aurora kinase inhibitors.

The invention provides a compound for use in medicine, the compound being a compound of the formula (VI) or a salt, solvate, tautomer or N-oxide thereof: wherein the bicyclic group: is selected from the structures C1, C5 and C6: wherein n is 0, 1, 2 or 3; Ris hydrogen, hydroxy, or O&#x2014;R; Ris hydroxy, methoxy or O&#x2014;R; provided that at least one of Rand Ris O&#x2014;R; Ris L-R; SOH; a glucuronide residue; a mono-, di- or tripeptide residue; or Lis a bond, C&#x2550;O, (C&#x2550;O)O, (C&#x2550;O)NRor S(O)NR; x is 1 or 2; Ris hydrogen or a an optionally substituted Chydrocarbyl group containing 0, 1 or 2 carbocyclic rings and 0, 1, 2, 3, 4, 5 or 6 carbon-carbon multiple bonds, provided that Ris not hydrogen when Lis a bond, C&#x2550;O or (C&#x2550;O)O; and provided also that O&#x2014;Rdoes not contain an O&#x2014;O moiety; and excluding compounds wherein Ris hydroxy and Ris methoxy; Rand Rare the same or different and each is a group R; and R, R, Rand Rare defined in the claims. The compounds of formula (VI) are pro-drugs of parent compounds wherein Rand/or Rare hydroxy, wherein the parent compounds have Hsp90 inhibiting activity.

Pharmaceutical compounds

The invention provides a combination comprising an ancillary compound (e.g. one, two or more ancillary compounds) and a compound of the formula (I) having protein kinase B inhibiting activity: wherein A is a saturated hydrocarbon linker group containing from 1 to 7 carbon atoms, the linker group having a maximum chain length of 5 atoms extending between Rand NRRand a maximum chain length of 4 atoms extending between E and NRR, wherein one of the carbon atoms in the linker group may optionally be replaced by an oxygen or nitrogen atom; and wherein the carbon atoms of the linker group A may optionally bear one or more substituents selected from oxo, fluorine and hydroxy, provided that the hydroxy group when present is not located at a carbon atom &#x3b1; with respect to the NRRgroup and provided that the oxo group when present is located at a carbon atom &#x3b1; with respect to the NRRgroup; E is a monocyclic or bicyclic carbocyclic or heterocyclic group; Ris an aryl or heteroaryl group; and R, R, Rand Rare as defined in the claims. Also provided are patient packs, pharmaceutical kits and packs and compositions containing the combinations, methods for preparing the combinations and their use in combination therapy as anticancer agents. 

Pharmaceutical combinations comprising pyrazole derivatives as protein kinase modulators

The invention provides combinations of an ancillary compound and a compound which is a salt of 1-cyclopropyl-3-[3-(5-morpholin-4-ylmethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-urea selected from the lactate and citrate salts and mixtures thereof. Also provided are crystalline forms of the salts, methods for making the salts and their uses in treating cancers. The invention further provides combinations of an ancillary compound and a compound of the formula (I) as defined in PCT/GB2004/002824 (WO 2005/002552) or a compound of the formula (I') or a salt, solvate, tautomer or N-oxide thereof, wherein R, E, A and M are as defined in the claims.

Pharmaceutical combinations of 1-cyclopropyl-3-[3-(5-morpholin-4-ylmethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-urea

The invention provides a combination comprising a cytotoxic compound, a signalling inhibitor, an ancillary agent, or two or more further anti-cancer agents, and a compound having the formula (Ib): or salts or tautomers or N-oxides or solvates thereof;wherein

Combinations of pyrazole kinase inhibitors

A method for the treatment of: A. a disease state or condition mediated by a kinase wh ich is BCR-abl, VEGFR, PDGFR, EGFR, FLT3, JAK, C-abl, PDK1, Chk, FGFR, Ret, Eph, or Src; or B. a cancer in which the cancer cells thereof contain a drug resistant kinase mutation which is: (a) a threonine gatekeeper mutation; or (b) a drug-resistant gatekeeper mutation; or (c) an imatinib resistant mutation; or (d) a nilotinib resistant mutation; or (e) a dasatinib resistant mutation; or (f) a T670l mutation in KIT; or (g) a T674l mutation in PDGFR; or (h) T790M mutation in EGFR; or (i) a T315l mutation in abl; or C. a cancer which expresses a mutated molecular target which is a mutated form of BCRabl, c-kit, PDGF, EGF receptor or ErbB2; which method comprises administering to a patient in need thereof a therapeutically effective amount of a compound of the formula (l or l'): or a salt, solvate, tautomer or N-oxide thereof. 

The invention provides combinations comprising (or consisting essentially of) one or more ancillary compound(s) and a compound of the formula (I): or salts, tautomers, solvates and N-oxides thereof; wherein Ris hydroxy or hydrogen; Ris hydroxy; methoxy or hydrogen; provided that at least one of Rand Ris hydroxy; Ris selected from hydrogen; halogen; cyano; optionally substituted Chydrocarbyl and optionally substituted Chydrocarbyloxy; Ris selected from hydrogen; a group &#x2014;(O)&#x2014;Rwhere n is 0 or 1 and Ris an optionally substituted acyclic Chydrocarbyl group or a monocyclic carbocyclic or heterocyclic group having 3 to 7 ring members; halogen; cyano; hydroxy; amino; and optionally substituted mono- or di-Chydrocarbyl-amino; or Rand Rtogether form a monocyclic carbocyclic or heterocyclic ring of 5 to 7 ring members; and NRRforms an optionally substituted bicyclic heterocyclic group having 8 to 12 ring members of which up to 5 ring members are heteroatoms selected from oxygen, nitrogen and sulphur. The combinations have activity as Hsp90 inhibitors.

Growing community of inventors

Cambridge, United Kingdom

John Francis Lyons