Glaxo Group Limited

Glaxo Laboratories Limited

Gordon H Phillipps

David C Humber

George B Ewan

Christopher Earle Newall

Barry A Coomber

Brian M Bain

Robin Lawrence

Christopher Williamson

Barry E Ayres

Stuart B Laing

Ian P Steeples

Michael G Lester

Stanley F Dyke

Esme J Bailey

Martin Christopher Cook

Paul Spencer Jones

David I Scopes

Niall Galbraith Weir

Peter D Howes

John Colin Clark

Leslie Stephenson

Peter John May

Michael Wright

Anne Christine Hunter

Brian R Cowley

Alan Frederick English

Gillian Helen Stribley

David Robert Marshall

David B Ewan

Anthony J Pateman

Raymond A Borella

Martin E Cooper

There are provided compounds of general formula ##STR1## (wherein R.sup.1 is a hydrogen atom or a methyl group;

Isoquinoline derivatives with anti-tumor activity

A process is described for the preparation of compounds of formula (1) ##STR1## [where OR is hydroxyl, protected hydroxyl or OP(O)(OCH.sub.2 Ph)(OR.sup.1) (where Ph is phenyl and OR.sup.1 is hydroxyl or protected hydroxyl)] and salts thereof, which comprises reacting a compound of formula (2) ##STR2## with a compound of formula (3) ##STR3## (where OR is as defined above and one of X.sup.1 and X.sup.2 is a leaving group and the other is a hydrogen atom) or a salt thereof, followed, if desired, by removal of the hydroxyl protecting group when present and/or by salt formation. The compounds of formula (1) are either anticancer agents or intermediates useful in the synthesis of anticancer agents.

Preparation of

Compounds of formula (I) ##STR1## (wherein R.sup.1 is a hydrogen atom or a methyl group;

Isoquinoline derivatives

There are provided compounds of the general formula (1) ##STR1## (wherein R.sup.1 and R.sup.2, which may be the same or different, each represents a hydrogen atom, a hydroxyl group or a group --OP(O) (OH) (OR.sup.4) [where R.sup.4 represents a hydrogen atom or an alkyl (optionally substituted by a hydroxyl, alkoxy, cyclic ether or cycloalkyl group), alkenyl cycloalkyl, aryl, aralkyl or aroylalkyl group], with the proviso that at least one of R.sup.1 and R.sup.2 represents a group --OP(O) (OH) (OR.sup.4); and R.sup.3 represents a hydrogen or halogen atom or a methyl group), and salts thereof. The novel compounds exhibit interesting anti-cancer activity.

Isoquinoline derivatives and their use as anti-cancer agents

Pharmaceutical compositions for combatting cancer comprising a compound of formula (I) ##STR1## (wherein R.sup.1 represents a hydrogen atom or a C.sub.1-4 alkyl, C.sub.2-4 alkenyl or C.sub.2-4 alkynyl group;

5,14-Dihydrobenz[5,6]isoindolo[2,1-b]isoquinoline-8,13-dione ##STR1## exhibits anticancer activity. The compound can be prepared by reaction of 2-formyl-3-carboxyl-1,2,3,4-tetrahydroisoquinoline with 1,4-naphthoquinone and is particularly suitably administered parenterally in microcrystalline suspension form.

Isoquinoline compound

Androstane carbothioic acids of the formula: ##STR1## wherein R.sup.1 represents a hydrogen atom, a hydroxy group in the .alpha.-configuration, a methyl group which may be in either the .alpha.- or .beta.-configuration, or a methylene group;

Androstane carbothioic acids

Compounds of the general formula: ##STR1## wherein X represents a halogen atom or a trifluoromethyl group; R.sup.1 represents a hydrogen atom or a lower alkyl group and Het represents an optionally substituted C-attached 5-7 membered aromatic heterocyclic ring which ring contains one or more heteroatoms selected from O, N and S and optionally carries a fused ring and where an acidic or basic group is present, the salts thereof have been found to possess excellent metaphase arresting ability and are of use in combating abnormal cell proliferation. Thus a knowledge of the cell division cycles of the normal and abnormal cells enables a cytotoxic drug to be administered while the abnormal cells are in a phase susceptible to attack and while the normal cells are in a non-susceptible phase. The compounds of the invention are prepared by alkylation, deprotection of a protected keto group, oxidation or electrophilic halogenation.

Substituted pyrimidin-2-ones, the salts thereof, pharmaceutical

Compounds of the general formula: ##STR1## (wherein X represents a halogen atom or a trifluoromethyl group; R.sup.1 represents an optionally substituted C.sub.6-10 carbocyclic aromatic group; and R.sup.2 represents a hydrogen atom or a lower alkyl, C.sub.7-16 aralkyl or C.sub.6-10 aryl group or the group COR.sup.1a, in which R.sup.1a is as defined for R.sup.1, R.sup.1 and R.sup.1a being the same or different) and where an acidic or basic group is present, the salts thereof have been found to possess excellent metaphase arresting ability and are of use in combating abnormal cell proliferation. Thus a knowledge of the cell division cycles of the normal and abnormal cells enables a cytotoxic drug to be administered while the abnormal cells are in a phase susceptible to attack and while the normal cells are in a non-susceptible phase. The compounds of the invention are prepared by alkylation, deprotection of a protected keto group, oxidation or electrophilic halogenation. Pharmaceutical compositions containing the compounds of formula I, and where appropriate, the physiologically compatible salts thereof; and methods for the use of the compounds are described and claimed.

Substituted pyrimidin-2-ones, the salts thereof, processes for their

##STR1## wherein R.sup.1 is a C.sub.1-8 alkyl group or a C.sub.3-7 cycloalkyl group; R.sup.2 is a hydrogen atom, a C.sub.1-6 alkoxy group or a C.sub.2-5 alkanoyloxy group;

11.alpha.-Amino-androstanes

Compounds of the formula ##STR1## wherein R.sup.1 is a C.sub.1-8 alkyl group or a C.sub.3-7 cycloalkyl group;

11.alpha.-amino-androstanes

Compounds of the formula ##STR1## wherein R.sup.1 is a C.sub.1-8 alkyl group or a C.sub.3-7 cycloalkyl group, and R.sup.2 is a C.sub.1-6 alkyl group or a C.sub.3-6 cycloalkyl group and the D-homo analogues thereof having the group --CO.sub.2 R.sup.2 (wherein R.sup.2 is as defined above) at the 17.alpha..beta.-position, and acid addition salts thereof have activity as antidysthythmic agents and may be applicable for the treatment of dysrthymias in humans or animals. The compounds may be provided in the form of compositions in admixture with pharmaceutical carriers and excipients and may be prepared by a variety of processes known for producing steroids of this type. The invention also provides intermediates for the preparation of the compounds of formula (I) wherein R.sup.2 and/or R.sup.1 are replaced with hydrogen atoms, and processes for the preparation of such intermediates.

11.alpha.-Amino-3.beta.-hydroxy-androstanes

Compounds of formula ##STR1## wherein: R.sup.1 is a C.sub.1-8 alkyl group or a C.sub.3-7 cycloalkyl group;

Compounds of formula ##STR1## (wherein): R.sup.1 is a hydrogen atom, a C.sub.1-8 alkyl group or a C.sub.3-7 cycloalkyl group; and

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Wembley, United Kingdom

Gordon H Phillipps