Smithkline Beecham Corporation

Burroughs Wellcome Co.

Glaxo Wellcome Inc.

Robert Ferone

William Pendergast

Julius Vass Johnson

Scott Howard Dickerson

Gary Keith Smith

David Stanley Duch

Arthur Koch

Stanley Robert Bushby

James J Burchall

Michael J Dunkley

Robert Cullen

Scott H Dickerson

The use of a protecting agent, for example a folate derivative such as folic acid or leucovorin, in combination with a non-competitive folic acid analogue, for example benzoquinazoline derivatives, for use in reducing the side effects associated with the administration of such non-competitive folic acid analogues, and pharmaceutical formulations comprising such combinations are disclosed.

Combination of benzoquinazoline antifolates and protecting agents

Compounds of formula (I) or salts thereof, wherein the dotted Line represents a single or double bond, R is alkyl or amino optionally substituted by alkyl, alkanoyl or benzyl group; R , R , R and R are the same or different and each is selected from hydrogen, phenyl, halo, nitro, a group S(O) R wherein n is the integer 0, 1 or 2 and R is halo or alkyl or a group NR R wherein R and R are both hydrogen, a group NR R wherein R and R are the same or different and each is hydrogen or alkyl, a group OR wherein R is hydrogen or C of alkyl optionally substituted by halo; a C aliphatic group optionally substituted by a group OR or NR R wherein R and R are the same or different and each is hydrogen or alkyl; or two of R to R are linked together to form a benzo group, or one of R to R is a group X&mdash;Y&mdash;R wherein X is CH , NR , CO or S(O) and Y is CH , NR , O or S(O) , or X&mdash;Y is O, NR , &mdash;CH&boxH;CH&mdash; or N&boxH;N&mdash;, are disclosed as pharmacological agents useful in the treatment of tumours. Pharmaceutical compositions and methods for the preparation of compounds of formula (I) are also described.

Pharmaceutically active benzoquinazoline compounds

The use of a protecting agent, for example a folate derivative such as folic acid or leucovorin, in combination with a non-competitive folic acid analogue, for example benzoquinazoline derivatives, for use in reducing the side effects associated with the administration of such non-competitive folic acid analogues, and pharmeceutical formulations comprising such combinations are disclosed.

Compounds of formula (I) or salts thereof, wherein the dotted line represents a single or double bond, R,is alkyl or amino optionally substituted by alkyl, alkanoyl or benzyl group; R,, R,, R,and R,are the same or different and each is selected from hydrogen, phenyl, halo, nitro, a group S(O),R,wherein n is the integer 0, 1 or 2 and R,is halo or alkyl or a group NR,R,wherein R,and R,are both hydrogen, a group NR,R,wherein R,and R,are the same or different and each is hydrogen or alkyl, a group OR,wherein R,is hydrogen or C,of alkyl optionally substituted by halo; a C,aliphatic group optionally substituted by a group OR,or NR,R,wherein R,and R,are the same or different and each is hydrogen or alkyl; or two of R,to R,are linked together to form a benzo group, or one of R,to R,is a group X&mdash;Y&mdash;R,wherein X is CH,, NR,, CO or S(O),and Y is CH,, NR,, O or S(O),, or X&mdash;Y is O, NR,, &mdash;CH&boxH;CH&mdash; or N&boxH;N&mdash;, are disclosed as pharmacological agents useful in the treatment of tumours. Pharmaceutical compositions and methods for the preparation of compounds of formula (I) are also described.

Compounds of the formula (I) or salts thereof, ##STR1## wherein the dotted line represents a single or double bond, R.sup.1 is alkyl or amino optionally substituted by alkyl, alkanoyl or benzyl group: R.sup.2, R.sup.3, R.sup.4 and R.sup.5 are the same or different and each is selected from hydrogen, phenyl, halo, nitro, a group S(O).sub.n R.sup.8 wherein n is the integer 0, 1 or 2 and R.sup.8 is halo or alkyl or a group NR.sup.9 R.sup.10 are both hydrogen, a group NR.sup.11 R.sup.12 wherein R.sup.11 and R.sup.12 are the same or different and each is hydrogen or alkyl, a group OR.sup.13 wherein R.sup.13 is hydrogen or C.sub.1-4 alkyl substituted by halo; a C.sub.1-4 aliphatic group optionally substituted by a group OR.sup.14 or NR.sup.14 R.sup.15 wherein R.sup.14 and R.sup.15 are the same or different and each is hydrogen or alkyl; ot two of R.sup.2 to R.sup.5 are linked together to form a benzp group, one of R.sup.2 to R.sup.3 is a group X--Y--R.sup.16 wherein X is CH.sub.2, NR.sup.17, CO, or S(O).sub.m and Y is CH.sub.2, NR.sup.17, O or S(O).sub.m, or X--Y is CH.sub.2,NR.sup.17, --CH.dbd.CH-- or --N.dbd.N--, are disclosed as pharmacological agents useful in the treatment of tumors. Pharmaceutical compositions and methods for the preparation of compounds of formula (I) are also disclosed.

The present invention relates to novel benzoquinazoline thymidylate synthase inhibitors, to pharmaceutical formulations containing them and to their use in medicine.

Pharmaceutical compounds

A composition for testing or treating microbial systems or infections, comprising an effective potentiating amount of a microbial dihydropteridine antagonist, which itself inhibits hydroxymethyldihydropteridine pyrophospokinase and has a sufficiently low toxicity, in combination with an effective amount of a competitor of para-aminobenzoic acid or an inhibitor of dihydrofolate reductase or both, its method of preparation, and its use in the inhibition of the production of dihydrofolic acid by microorganisms under in vivo or in vitro conditions.

Growing community of inventors

Raleigh, NC, United States of America

Robert Ferone