Imperial Chemical Industries Limited

Zeneca Limited

Robin Wood

David R Brittain

George R Brown

David Waterson

Robert J Pearce

Keith H Gibson

Arnold H Ratcliffe

Brian B Masek

Nicholas John Newcombe

Elaine Sophie Elizabeth Stokes

David J Brown

John Graham Cumming

William J Watkins

Elaine Sophie Stokes

Heterocyclic compounds useful as pharmaceutical agents

Use of oxido-squalene cyclase inhibitors to lower blood cholesterol

The invention concerns pharmaceutically useful compounds of the formula I, in which R.sup.1, R.sup.2, R.sup.3, R.sup.4, Ra, Rb, A, X and Z have the various meanings defined herein, and their non-toxic salts, and pharmaceutical compositions containing them. The novel compounds are of value in treating conditions such as hypertension and congestive heart failure. The invention further concerns processes for the manufacture of the novel compounds and the use of the compounds in medical treatment.

1,6-naphthyridinone derivatives having angiotension II antagonist

1,6-naphthyridone derivatives having angiotensin II antagonist activity

The invention concerns 1'-(4-bromo-2-fluorobenzyl)-7'-chloro-spiro[imidazolidine-4,3'-indoline]-2 ,2',5-trione in racemic or dextrorotatory form; pharmaceutical compositions thereof for use in the treatment or prophylaxis of certain complications of diabetes; and processes for its manufacture.

Aldose reductase inhibition by spiro indoline derivatives

The invention provides novel spiro[oxazolidine-5,3'-indoline]-2,2',4-triones of formula I bearing substituted benzyl or cinnamyl on the indoline nitrogen, together with salts and non-toxic, biodegradable precursors thereof. The compounds are potent inhibitors of the enzyme aldose reductase and are useful in treating or preventing certain diabetic complications. The invention also provides pharmaceutical compositions containing, and processes for the manufacture of, the compounds of formula I and their salts and derivatives.

1'-Substituted-spiro[oxazolidine-5-3'-indoline]-2,2', 4-trione

The invention concerns novel trifluoromethyl derivatives of 1'-halogenobenzyl-spiro[imidazolidine-4,3'-indoline]-2,2',5-trione (I), their pharmaceutically acceptable salts, and non-toxic, biodegradable precursors thereof. The derivatives are potent inhibitors of the enzyme aldose reductase and are useful in treating or preventing certain complications of diabetes. The invention also provides pharmaceutical compositions and processes for the manufacture of the derivatives.

7'-Trifluoromethyl-spiro[imidazolidine-4,3'-indoline]-2,2',5-triones as

The invention provides a pharmaceutical composition comprising an aldose reductase inhibitory 1'substituted-spiro[pyrrolidine-3,3'-indoline]-2,2',5-trione of the formula: ##STR1## wherein Ra is (2-7C)alkyl or (3-7C)alkenyl, naphthylmethyl or cinnamyl optionally bearing one or two halogeno nuclear substituents, or Ra is benzyl optionally bearing one or two substituents and benzene ring A optionally bears one or two substituents, trifluoromethyl and nitro; or a salt thereof with a base affording a pharmaceutically acceptable cation; or a non-toxic, biodegradable precursor thereof; together with a pharmaceutically acceptable diluent or carrier. The invention also provides novel compounds of formula I and processes for their manufacture. The compositions are of application in the treatment or prophylaxis of the side effects of diabetes or galactosemia.

1'-Substituted-spiro[pyrrolidine-3,3'-indoline]-2,2',5-triones

The invention provides various medical compositions for use in treating or preventing certain of the side effects of diabetes or galactosemia. The active ingredients are selected from a series of novel aldose reductase inhibitory spiro-linked pyrrolidine-2,5-diones of the general formula: ##STR1## or a pharmaceutically acceptable salt, or a non-toxic, biodegradable precursor thereof. Processes for the production of these compounds are also provided. A particular compound suitable for use as an active ingredient is spiro[pyrrolidine-3,9'-xanthene]-2,5-dione.

Spiro-linked pyrrolidine-2,5-diones active as enzyme aldose reductase

The invention concerns novel 1'-substituted spiro[imidazolidine-4,3'-indoline]-2,2',5-triones of the formula: ##STR1## in which R.sup.1 is (1-12C)alkyl; phenyl, naphthylmethyl or cinnamyl optionally bearing 1-2 halogeno substituents; or benzyl optionally bearing 1-3 substituents independently selected from halogeno, trifluoromethyl, (1-4C)-alkyl, (1-4C)alkoxy, nitro, cyano and hydroxy; and ring A optionally bears one substituent selected from halogeno, (1-4C)alkyl, (1-4C)alkoxy, nitro and hydroxy, or two substituents independently selected from halogeno (1-4C)alkyl and nitro; or a pharmaceutically acceptable salt thereof; but excluding those compounds wherein R.sup.1 is methyl, ethyl, n-propyl or unsubstituted benzyl and benzene ring A is unsubstituted. The compounds of the invention are potent inhibitors of the enzyme aldose reductase and are of use in the treatment or prophylaxis of certain complications of diabetes or galactosemia. The invention also embraces processes for the manufacture of the novel compounds of formula I, as well as pharmaceutical compositions of such compounds. A representative compound is 1'-(2-fluoro-4-bromobenzyl)-spiro]imidazolidine-4,3'-indoline]-2,2',5-trio ne.

1'-Substituted spiro[imidazolidine-4,3'-indoline]2,2',5-triones

The invention provides a pharmaceutical composition comprising an aldose reductase inhibitory 1'-substituted-spiro[pyrrolidine-3,3'-indoline]-2,2',5-trione of the formula: ##STR1## wherein Ra is (2-7C)alkyl or (3-7C)alkenyl, naphthylmethyl or cinnamyl optionally bearing one or two halogeno nuclear substituents, or Ra is benzyl optionally bearing one or two substituents and benzene ring A optionally bears one or two substituents, trifluoromethyl and nitro; or a salt thereof with a base affording a pharmaceutically acceptable cation; or a non-toxic, biodegradable precursor thereof; together with a pharmaceutically acceptable diluent or carrier. The invention also provides novel compounds of formula I and processes for their manufacture. The compositions are of application in the treatment or prophylaxis of the side effects of diabetes or galactosemia.

The invention provides an aldose reductase inhibitory pyrrole derivative of the formula: ##STR1## in which Ra is an optionally substituted benzyl or cinnamyl radical, and ring A is the benzene ring of an optionally substituted benzo[b]thiophene, benzo[b]furan, quinoline or N-alkylquinolone, together with pharmaceutically acceptable salts and non-toxic biodegradable precursors thereof. The compounds of formula I are useful in the treatment of prophylaxis of the side-effects of diabetes or galactosemia.

Aldose reductase inhibitory pyrrole derivatives

This invention relates to enzyme inhibitory, novel phthalazin-4-ylacetic acid derivatives of the general formula I: ##STR1## and pharmaceutically acceptable salts as appropriate, to pharmaceutical compositions thereof, and to analogy processes for their manufacture. The compounds of formula I are inhibitors of the enzyme aldose reductase in vivo and as such may be useful in the reduction or prevention of the development of the peripheral effects such as macular oedema, cataract, retinopathy or impaired neural conduction. A preferred compound is 2-(2-fluoro-4-bromobenzyl)-1,2-dihydro-1-oxophthalazin-4-ylacetic acid.

Pharmaceutical compositions and method for the production of an

The invention provides novel non-toxic biodegradable derivatives of the formula: ##STR1## wherein Ra is (1-12C)alkyl, phenyl, naphthylmethyl or cinnamyl, the aromatic rings of which optionally bear one or two halogeno substituents, or Ra is benzyl optionally bearing up to 3 substituents independently selected from halogeno, trifluoromethyl, (1-4C)alkyl, (1-4C)alkoxy, nitro, cyano and hydroxy; Rb and Rc are independently selected from hydrogen and non-toxic biodegradable protecting radicals, but are not both hydrogen; and benzene ring A optionally bears one substituent selected from halogeno, (1-4C)alkyl, (1-4C)alkoxy, nitro and hydroxy, or bears two substituents independently selected from halogeno, (1-4C)alkyl and nitro; pharmaceutical compositions thereof; and processes for their manufacture. The amides of formula I in which Rb.dbd.Rc.dbd.H are potent inhibitors of the enzyme aldose reductase. The derivatives of formula I provided by the invention are of use in vivo in the treatment or prophylaxis of certain complications of diabetes or galactosemia.

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Stockport, United Kingdom

Robin Wood