Imperial Chemical Industries Limited

Zeneca Limited

Ici Americas, Inc.

Astrazeneca Ab

Other

National Research Development Corporation

British Technology Group Limited

James Michael Wardleworth

Francis Thomas Boyle

Tobias O Yellin

David J Gilman

David Huw Davies

Zbigniew Stanley Matusiak

Zbigniew S Matusiak

Peter Beverley Scholes

Zbigniew Stanely Matusiak

Peter Wedderburn Kenny

Gareth Morse Davies

Andrew John Barker

Jean-Claude Arnould

Stephen John Pegg

Robert G Andrew

This invention relates to compounds of formula (I) that inhibit farnesylation of gene products through inhibition of the enzyme farnesyl-protein transferase (FPTase). The invention also relates to methods of manufacturing the compounds, pharmaceutical compositions and methods of treating diseases, especially cancer, which are mediated through farnesylation.

Farnesyl transferase inhibitors

The present invention relates to inhibitors of ras farnesylation of the Formula Iwherein:

3-mercaptopyrrolidines as farnesyl protein transferase inhibitors

Inhibitors of farnesyl protein transferase

Pharmaceutical compositions comprising an inhibitor of ras farnesylation of formula (I) wherein, R is for example H and further values as defined in the specification; R is for example H and further values as defined in the specification; R is for example H or a substituent having values as defined in the specification; p is 0-3 in which R values can be the same or different; L is a linking moiety for example &mdash;CO&mdash;NH &mdash; and further values as defined in the specification; A is selected from phenyl; naphthyl; a 5-10 membered monocyclic or bicyclic heteroaryl ring containing up to 5 heteroatoms where the heteroatoms are independently selected from O, N and S; or a &mdash;S&mdash;S-dimer thereof when R &equals;H; or an enantiomer, diastereoisomer, pharmaceutically acceptable salt, prodrug or solvate thereof together with a pharmaceutically acceptable diluent or carrier. A particular use is cancer therapy.

4-mercaptopyrrolidine derivatives as farnesyl transferase inhibitors

Imidazolyl compounds as inhibitors of farnesyl-protein tranferase

Pharmaceutical compositions comprising an inhibitor of ras farnesylation of formula (I) wherein, R,is for example H and further values as defined in the specification; R,is for example H and further values as defined in the specification; R,is for example H or a substituent having values as defined in the specification; p is 0-3 in which R,values can be the same or different; L is a linking moiety for example &mdash;CO&mdash;NH,&mdash; and further values as defined in the specification; A is selected from phenyl; naphthyl; a 5-10 membered monocyclic or bicyclic heteroaryl ring containing up to 5 heteroatoms where the heteroatoms are independently selected from O, N and S; or a &mdash;S&mdash;S&mdash; dimer thereof when R,&equals;H; or an enantiomer, diastereoisomer, pharmaceutically acceptable salt, prodrug or solvate thereof together with a pharmaceutically acceptable diluent or carrier. A particular use is cancer therapy.

4-Mercaptopyrrolidine derivatives as farnesyl transferase inhibitors

The invention relates to quinazoline derivatives or pharceutically-acceptable salts thereof, which possess anti-tumor activity; to processes for their manufacture; and to pharmaceutical compositions containing them. The invention provides a quinazoline of the formula: ##STR1## wherein R.sup.1 is (1-4C)alkyl; the quinazoline ring may optionally bear one or two further substituents selected from halogeno, (1-4C)alkyl and (1-4C)alkoxy;

Quinazoline thymidylate synthase inhibitors

The invention relates to quinazoline derivatives, or pharmaceutically-acceptable salts thereof, which possess anti-tumour activity; to processes for their manufacture; and to pharmaceutical compositions containing them. The invention provides a quinazoline of the formula: ##STR1## wherein R.sup.1 includes hydrogen, amino and alkyl or alkoxy each of up to 4 carbon atoms;

Anti-tumor compounds

The use of an olefinic compound of the formula

Use of olefinic compounds

Heterocyclic compounds of the formula: ##STR1## wherein X and Y, which may be the same or different, are each a .dbd.N-- or .dbd.CH-- group and R is a phenyl radical which optionally bears one or more substituents selected from halogen atoms, amino, cyano, carbamoyl, hydroxy and nitro radicals, 1-6C alkyl, halogenoalkyl, alkoxy, halogenoalkoxy and alkylamino radicals, di(1-6C alkyl)amino and 2-6C alkoxycarbonyl radicals, and n is 1 to 6, but excluding the compound wherein X and Y are each .dbd.N--, R is 2,4-dichlorophenyl and n is 1; and the pharmaceutically or veterinarily acceptable acid addition salts thereof; processes for their manufacture; and pharmaceutical and veterinary compositions containing them.

1,3-diazolyl-2-phenylalkyl-2-propanol derivatives

The invention relates to guanidine derivatives of imidazoles and thiazoles which are histamine H-2 antogonists and which inhibit the secretion of gastric acid, to methods for their manufacture, to pharmaceutical compositions containing them and to methods of using such guanidine derivatives and compositions. The guanidine derivatives are of the general formula I: ##STR1## in which X is S or NH, Y is O, S, or SO, m is 1 to 4 and n is suitably 1 to 4, R.sup.1 is hydrogen, halogen or alkyl, R.sup.2 is hydrogen, alkyl, alkanoyl or aroyl, A is a 3,4-dioxocyclobuten-1,2-diyl radical or C.dbd.Z in which Z is O, S, NCN, NNO.sub.2, CHNO.sub.2, NCONH.sub.2, C(CN).sub.2, NCOR.sup.3, NCO.sub.2 R.sup.3, NSO.sub.2 R.sup.3 or NR.sup.4 in which R.sup.3 is alkyl or aryl and R.sup.4 is hydrogen or alkyl, B is alkoxy or alkylthio or NR.sup.5 R.sup.6 in which R.sup.5 and R.sup.6 are independently hydrogen, alkyl, alkenyl, cycloalkyl, hydroxyalkyl, alkoxyalkyl, alkylaminoalkyl or dialkylaminoalkyl; and the salts thereof.

Guanidine derivatives of imidazoles and thiazoles

The invention relates to guanidine derivatives of imidazoles and thiazoles which are histamine H-2 antagonists and which inhibit the secretion of gastric acid, to methods for their manufacture, to pharmaceutical compositions containing them and to methods of using such guanidine derivatives and compositions. The guanidine derivatives are of the general formula I: ##STR1## in which X is S or NH, Y is O, S, or SO, m is 1 to 4 and n is suitably 1 to 4, R.sup.1 is hydrogen, halogen or alkyl, R.sup.2 is hydrogen, alkyl, alkanoyl or aroyl, A is a 3,4-dioxocyclobuten-1,2-diyl radical or C.dbd.Z in which Z is O, S, NCN, NNO.sub.2, CHNO.sub.2, NCONH.sub.2, C(CN).sub.2, NCOR.sup.3, NCO.sub.2 R.sup.3, NSO.sub.2 R.sup.3 or NR.sup.4 in which R.sup.3 is alkyl or aryl and R.sup.4 is hydrogen or alkyl, B is alkoxy or alkylthio or NR.sup.5 R.sup.6 in which R.sup.5 and R.sup.6 are independently hydrogen, alkyl, alkenyl, cycloalkyl, hydroxyalkyl, alkoxyalkyl, alkylaminoalkyl or dialkylaminoalkyl; and the salts thereof.

The invention relates to guanidine derivatives of imidazoles and thiazoles which are histamine H-2 antagonists and which inhibit the secretion of gastric acid, to methods for their manufacture, to pharmaceutical compositions containing them and to methods of using such guanidine derivatives and compositions. The guanidine derivatives are of the general formula I: ##STR1## in which X is S or NH, Y is O, S, or SO, m is 1 to 4 and n is suitably 1 to 4, R.sup.1 is hydrogen, halogen or alkyl, R.sup.2 is hydrogen, alkyl, alkanoyl or aroyl, A is a 3,4-dioxocyclobuten-1,2-diyl radical or C=Z in which Z is O, S, NCN, NNO.sub.2, CHNO.sub.2, NCONH.sub.2, C(CN).sub.2, NCOR.sup.3, NCO.sub.2 R.sup.3, NSO.sub.2 R.sup.3 or NR.sup.4 in which R.sup.3 is alkyl or aryl and R.sup.4 is hydrogen or alkyl, B is alkoxy or alkylthio or NR.sup.5 R.sup.6 in which R.sup.5 and R.sup.6 are independently hydrogen, alkyl, alkenyl, cycloalkyl, hydroxyalkyl, alkoxyalkyl, alkylaminoalkyl or dialkylaminoalkyl; and the salts thereof.

Growing community of inventors

Macclesfield, United Kingdom

James Michael Wardleworth