Newcastle University Ventures Limited

Cancer Research Campaign Technology Limited

Alan H Calvert

Bernard Thomas Golding

David Richard Newell

Roger J Griffin

Nicola J Curtin

Francis Thomas Boyle

Martin E M Noble

Philip J Jewsbury

Jane A Endicott

Jane Nicola Curtin

Jane Nicola Curtain

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##

Benzoxazole carboxamides 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. Representative of the compounds are 2-methyl, 2-t-butyl, 2-phenyl or 2-(4-methoxyphenyl) benzoxazole-4-carboxamide.

Benzoxazole-4-carboxamides and their use in inhibiting poly (adp-ribose)

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 compounds 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 --X--Y-- that represents the grouping (a), (b) or (c )wherein R.sup.5 is H, alkyl, aryl or aralkyl.

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Tyne and Wear, United Kingdom

Alan H Calvert