Cancer Research Technology Limited

Newcastle University Ventures Limited

Kudos Pharmaceuticals Limited

Cancer Research Campaign Technology Limited

Astex Therapeutics Limited

David Richard Newell

Bernard Thomas Golding

Roger J Griffin

Alan H Calvert

Roger John Griffin

Ian Robert Hardcastle

Nicola J Curtin

Niall Morrison Barr Martin

Graeme Cameron Murray Smith

Nicola Curtin

Hilary Alan Calvert

Laurent Jean Martin Rigoreau

Keith Allan Menear

Marc Geoffrey Hummersone

Paul Workman

Florence Irene Raynaud

Bernard Paul Nutley

Xiao-ling Fan Cockcroft

Martin E M Noble

Kappusamy Saravanan

Francis Thomas Boyle

Vincent Junior Ming-lai Loh

Jane A Endicott

Philip J Jewsbury

Miles Stuart Congreve

Andrew Madin

Christopher William Murray

Valerio Berdini

Gordon Saxty

Maria Grazia Carr

Adrian Liam Gill

Owen Callaghan

Mark Frigerio

Hendrika Maria Gerarda Willems

Per Kallblad

Jane Nicola Curtin

John Lunec

Jane Nicola Curtain

Marine Desage-El Murr

A compound of formula or a prodrug and/or a pharmaceutically acceptable salt thereof, wherein X is O, N or S; Ris hydrogen, halo, hydroxy, substituted or unsubstituted alkyl, substituted or unsubstituted hydroxyalkyl, substituted or unsubstituted alkylamine, alkoxy, substituted or unsubstituted aryl or heteroaryl, and substituted or unsubstituted aralkyl or heteroaralkyl; Ris hydrogen, halo, hydroxy, substituted or unsubstituted alkyl, substituted or unsubstituted hydroxyalkyl substituted or unsubstituted alkylamine, alkoxy, substituted or unsubstituted aryl or heteroaryl, and substituted or unsubstituted aralkyl or heteroalkyl; Ris hydrogen, halo, hydroxy, substituted or unsubstituted alloy substituted or unsubstituted hydroxyalkyl, substituted or unsubstituted alkylamine alkoxy, substituted or unsubstituted aryl or heteroaryl, and substituted or unsubstituted aralkyl or heteroalkyl; and R-R, is used to represent groups R, R, Rand Rwhich are H, OH, alkyl, alkoxy, alkylamine, hydroxyalkyl, halo, CF, NH, NO, COOH, C&#x2550;O.

Isoindolin-1-one derivatives

The present invention relates to FGFR pharmacophores, and in particular to compounds which are capable of binding to FGFR with greater affinity than their binding to VEGFR and methods of identifying such compounds using the pharmacophore. The present invention further relates to compositions, methods and uses of the compounds and the pharmacophores disclosed herein.

FGFR pharmacophore compounds

A compound of formula I: and isomers, salts, solvates, chemically protected forms, and prodrugs thereof, wherein: Rand Rare independently selected from hydrogen, an optionally substituted Calkyl group, Cheterocyclyl group, or Caryl group, or may together form, along with the nitrogen atom to which they are attached, an optionally substituted heterocyclic ring having from 4 to 8 ring atoms; Q is &#x2014;NH&#x2014;C(&#x2550;O)&#x2014; or &#x2014;O&#x2014;; Y is an optionally substituted Calkylene group; X is selected from SRor NRR, wherein, R, or Rand Rare independently selected from hydrogen, optionally substituted Calkyl, Caryl, or Cheterocyclyl groups, or Rand Rmay together form, along with the nitrogen atom to which they are attached, an optionally substituted heterocyclic ring having from 4 to 8 ring atoms; if Q is &#x2014;O&#x2014;, X is additionally selected from &#x2014;C(&#x2550;O)&#x2014;NRR, wherein Rand Rare independently selected from hydrogen, optionally substituted Calkyl, Caryl, or Cheterocyclyl groups, or Rand Rmay together form, along with the nitrogen atom to which they are attached, an optionally substituted heterocyclic ring having from 4 to 8 ring atoms; and if Q is &#x2014;NH&#x2014;C(&#x2550;O)&#x2014;, &#x2014;Y&#x2014;X may additionally be selected from Calkyl.

DNA-PK inhibitors

Compounds of formula I: wherein A, B and D are respectively selected from the group consisting of:

The invention relates to the use of compounds of formula (I) and isomers, salts, solvates, chemically protected forms, and prodrugs thereof, in the preparation of a medicament for inhibiting the activity of DNA-PK, wherein Rand Rare independently hydrogen, an optionally substituted Calkyl group, Cheterocyclyl group, or Caryl group, or may together form, along with the nitrogen atom to which they are attached, an optionally substituted heterocyclic ring having from 4 to 8 ring atoms; X and Y are selected from CRand O, O and CR'and NR&#x2033;and N, where the unsaturation is in the appropriate place in the ring, and where one of Rand Ror R&#x2032;is an optionally substituted Cheteroaryl or Caryl group, and the other of Rand Ror R&#x2032;is H, or Rand Ror R&#x2033;together are &#x2014;A&#x2014;B&#x2014;, which collectively represent a fused optionally substituted aromatic ring. The compounds also selectively inhibit the activity of DNA-PK compared to PI 3-kinase and/or ATM.

A compound of formula I: and isomers, salts, solvates, chemically protected forms, and prodrugs thereof, wherein:

The invention relates to the use of compounds of formula (I) and isomers, salts, solvates, chemically protected forms, and prodrugs thereof, in the preparation of a medicament for inhibiting the activity of DNA-PK, wherein Rand Rare independently hydrogen, an optionally substituted Calkyl group, Cheterocyclyl group, or Caryl group, or may together form, along with the nitrogen atom to which they are attached, an optionally substituted heterocyclic ring having from 4 to 8 ring atoms; X and Y are selected from CRand O, O and CR'and NR&#x2033;and N, where the unsaturation is in the appropriate place in the ring, and where one of Rand Ror R&#x2032;is an optionally substituted Cheteroaryl or Caryl group, and the other of Rand Ror R&#x2032;is H, or Rand Ror R&#x2033;together are -A-B&#x2014;, which collectively represent a fused optionally substituted aromatic ring. The compounds also selectively inhibit the activity of DNA-PK compared to PI 3-kinase and/or ATM.

The present invention provides compounds of formula (I) and isomers, salts, solvates, chemically protected forms, and prodrugs thereof, wherein Rand Rare independently hydrogen, an option ally substituted Calkyl group, Cheterocyclyl group, or Caryl group, or may together form, along with the nitrogen atom to which they are attached, an optionally substituted heterocyclic ring having from 4 to 8 ring atoms; and Ris an optionally substituted Cheterocyclyl or Caryl group, and their use as pharmaceuticals, particularly in treating diseases which are retroviral mediated or ameliorated by the inhibition of DNA-PK, 

Thiopyrane-4-ones as DNA protein kinase inhibitors

A range is disclosed of pyrimidine derivatives (I) which can act as inhibitors of cyclin dependent kinases (CDK's) and which thereby can provide useful therapeutic compounds for use in treatment of tumours or other cell proliferation disorders. The compounds of this invention bind to CDK molecules in a manner that appears to differ from that of known CDK inhibitors such as olomoucine and roscovitine. In formula (I), X is O, S or CHR where R is H or C alkyl; D is H or NZ Z where Z and Z are each independently H, C alkyl, C hydroxyalkyl, optionally substituted aryl or optionally substituted aralkyl; A is selected from H, C alkyl, C alkoxy, hydroxy, CH (CH ) OH (n&equals;1-4), and NR R where R and R are each independently H or C alkyl; Y is or includes an optionally substituted 4- to 8-membered carbocyclic or heterocyclic ring; D&prime; is H or NZ Z where Z and Z are each independently H, C alkyl, C hydroxyalkyl, optionally substituted aryl or optionally-substituted aralkyl; E is selected from NO, NO , N&boxH;N&mdash;Ar where Ar is an optionally substituted aryl or optionally substituted aralkyl, NR R or Nr Nr R (R , R and R each being independently H, C alkyl, C hydroxyalkyl, an optionally substituted aryl or an optionally substituted aralkyl), C(R )&boxH;U (R being hydrogen, C alkyl or substituted alkyl, e.g. hydroxyalkyl, or an unsubstituted or substituted aryl or aralkyl, e.g. benzyl, and U being selected from O, Nr &prime;, NOR &prime; and N&mdash;NR &prime;R &Prime; where R &prime; and R &Prime; are each independently H, C alkyl or CONH ), T, CH T, CHT and CT , where T is a halide I, Br, Cl or F.

Cyclin dependent kinase inhibitors

A range of 3-oxybenzamide compounds and related quinazolinone compounds are disclosed which can act as potent inhibitors of the DNA repair enzyme poly(ADP-ribose) polymerase or PARP enzyme (EC 2.4.2.30), and which thereby can provide useful therapeutic compounds for use in conjunction with DNA-damaging cytotoxic drugs or radiotherapy to potentiate the effects of the latter. The coumpounds disclosed include 3-benzyloxybenzamides, 3-oxybenzamides in which a chain of 5 or more methylene groups terminate in a halogen atom or in a purin-9-yl moiety, certain benzoxazole-4-carboxamide compounds and certain quinazolinone compounds. In formula X and Y together may form a bride &mdash;X&mdash;Y&mdash; that represents the grouping (a), (b) or (c) wherein R,is H, alkyl, aryl or aralkyl.

Method of improving the effectiveness of a cytotoxic drug or radiotherapy using a quinazolinone compound

Benzimidazole-4-carboxamide compounds (I) which can act as potent inhibitors of the DNA repair enzyme poly(ADP-ribose) polymerase or PARP enzyme (EC 2.4.2.30), and which thereby can provide useful therapeutic compounds for use in conjunction with DNA-damaging cytotoxic drugs or radiotherapy to potentiate the effects of the latter. In formula (I), R and R&prime; may each be selected independently from hydrogen, alkyl, hydroxyalkyl (e.g. CH,CH,OH), acyl (e.g. acetyl or benzoyl) or an optionally substituted aryl (e.g. phenyl) or aralkyl (e.g. benzyl or carboxybenzyl) group. R is generally a substituted phenyl group in the most preferred compounds. The compounds may also be used in the form of pharmaceutically acceptable salts or pro-drugs.

Benzimidazole compounds

Method of treating a tumour or other cell proliferation disorder which comprises administering an effective amount of a purine compound which inhibits cyclic dependent kinase activity. Novel purine compounds and pharmaceutical compositions are also disclosed.

Cyclin dependent kinase inhibiting purine derivatives

A range of dipyridamole analogues useful for inhibiting transport of nucleosides or purines across cell membranes, thereby to potentiate the activity of various cytotoxic antitumor drugs, is disclosed. These analogues comprise compounds having general structural formula (I) or pharmaceutically acceptable salts thereof; wherein R,is chloro and R,is diethanolamino, or R,and R,are identical and are selected from allyl, halo, diethanolamino, solketalo and a group having the formula: &mdash;O&mdash;R,or &mdash;NHR,, R,being selected from alkyl, hydroxyalkyl, alkoxyalkyl, dialkoxyalkyl and 2-oxo-alkyl wherein the or each alkyl and/or alkoxy moiety has less than six carbon atoms, and R,and R,are identical and are selected from piperidino, N-tetrahydroisoquinolyl, and a benzylamino group having structural formula (II) wherein R,is H, or an optionally substituted alkyl or benzyl group, and R,and R,represent H or optional substituents in the aromatic nucleus selected from halo, alkyl, alkoxy, hydroxy, trifluoromethyl, azido, cyano, nitro, carboxyl, carboxylic ester, amino or a substituted amino NR,R,where R,and R,each represent hydrogen or alkyl, subject to the provisos that (a) if R,and R,are both chloro or diethanolamino, R,and R,are not both benzylamino, i.e. R,and R,do not correspond to structure II with R,, R,and R,each being hydrogen, and (b) if R,and R,are both piperidino, R,and R,are not both chloro, diethanolamino, solketalo or (2,3-dimethoxy)propoxy

Pyrimidopyrimidine compounds

Phosphate derivatives are disclosed of quinazolinone compounds having structural formula (I) or a pharmaceutically acceptable salt thereof, wherein X' represent hydroxyl, alkyl, alkoxy, or O--Z where Z is a phosphate or phosphate derivative; Y' represents hydrogen, alkyl or an optionally substituted aryl group or optionally substituted aralkyl group; and R' is hydrogen, alkyl, or CH.sub.2 --O--Z where Z is again a phosphate or phosphate derivative; subject to the proviso that if neither X' nor R' contains Z, Y' is an aryl or aralkyl group having an O--Z substituent therein with Z once again being a phosphate or phosphate derivative as hereinabove defined. These compounds are useful as prodrugs for providing active PARP inhibiting substances for medical use in conjunction with a cytotoxic drug or radiotherapy in order to increase the effectiveness of the latter, especially in connection with antitumor treatment. ##STR1##

Quinazolinone compounds

Benzimidazole-4-carboxamide compounds (I) which can act as potent inhibitors of the DNA repair enzyme poly(ADP-ribose) polymerase or PARP enzyme (EC 2.4.2.30), and which thereby can provide useful therapeutic compounds for use in conjunction with DNA-damaging cytotoxic drugs or radiotherapy to potentiate the effects of the latter. In formula (I), R and R' may each be selected independently from hydrogen, alkyl, hydroxyalkyl (e.g. CH.sub.2 CH.sub.2 OH), acyl (e.g. acetyl or benzoyl) or an optionally substituted aryl (e.g. phenyl) or aralkyl (e.g. benzyl or carboxybenzyl) group. R is generally a substituted phenyl group in the most preferred compounds. The compounds may also be used in the form of pharmaceutically acceptable salts or pro-drugs. ##STR1##

Growing community of inventors

Newcastle upon Tyne, United Kingdom

David Richard Newell