Imperial Chemical Industries Limited

Zeneca Limited

Astrazeneca Ab

Astra Zeneca U.k. Limited

Michael J Smithers

Andrew G Brewster

George R Brown

Alan Wellington Faull

John Wall Rayner

Reginald Jessup

John Preston

Robert J Pearce

Andrew Stocker

Peter W Caulkett

Richard E Shute

Michael Garth Wayne

Stuart D Mills

Paul Turner

David Huw Davies

Victor G Matassa

David Bryan Haydock

Nowak Thorsten

Sturat D Mills

Compounds of formula (I), wherein Gis CH or N; Gis CH or N; Ris a variety of optional substituents; Lis (1-4C)alkylene; Tis CH or N; Rand Rare independently hydrogen or (1-4C)alkyl or are joined to form a ring; Xand Xrepresent various linking groups; Ar is phenylene or certain heteroaryl rings and Q represents a variety of aromatic or heterocyclic rings systems, and pharmaceutically acceptable salts thereof are described as useful antithrombotic and anticoagulant agents, and are selective Factor Xa inhibitors. Processes for their preparation and pharmaceutical compositions containing them are also described.

Aminoheterocyclic derivatives as antithrombotic or anticoagulant agents

The invention relates to heterocyclic derivatives of formula (I)A&#x2014;B&#x2014;X&#x2014;T(R)&#x2014;L&#x2014;T(R)&#x2014;X&#x2014;Q&#x2003;&#x2003;(I)or pharmaceutically-acceptable salts thereof, which possess antithrombotic and anticoagulant properties and are accordingly useful in methods of treatment of humans or animals. The invention also relates to processes for the preparation of the heterocyclic derivatives, to pharmaceutical compositions containing them and to their use in the manufacture of medicaments for use in the production of an antithrombotic or anticoagulant effect.

Heterocyclic derivatives

The invention relates to heterocyclic derivatives of formula (I) and (Ia), or pharmaceutically-acceptable salts thereof, which possess antithrombotic and anticoagulant properties and are accordingly useful in methods of treatment of humans or animals. The invention also relates to processes for the preparation of the heterocyclic derivatives, to pharmaceutical compositions containing them and to their use in the manufacture of medicaments for use in the production of an antithrombotic or anticoagulant effect.

Heterocyclic derivatives which inhibit Factor Xa

The invention relates to heterocyclic derivatives of the formula (I): A&mdash;B&mdash;X,&mdash;T,(R,)&mdash;L,&mdash;T,(R,)&mdash;X,&mdash;Q or pharmaceutically acceptable salts thereof, which possess antithrombotic and anticoagulant properties due to their inhibition of Factor Xa and are accordingly useful in methods of treatment of humans or animals. The invention also relates to processes for the preparation of the heterocyclic derivatives, to pharmaceutical compositions containing them and to their use in the manufacture of medicaments for use in the production of an antithrombotic or anticoagulant effect.

Heterocycle derivatives which inhibit factor Xa

Compounds of formula I ##STR1## and metabolically labile esters and amides thereof, and pharmaceutically acceptable salts thereof, in which R.sup.13, M.sup.2, X.sup.1, Z.sup.1, Z.sup.1a, X.sup.2 and A.sup.1 have the meanings given in the specification. The compounds are useful as inhibitors of the binding of fibrinogen to glycoprotein IIb/IIIa. Novel intermediates are also disclosed.

Heterocyclic compounds

Compounds of formula I ##STR1## and metabolically labile esters and amides thereof, and pharmaceutically acceptable salts thereof, in which R.sup.13, M.sup.2, X.sup.1, Z.sup.1, Z.sup.1a, X.sup.2 and A.sup.1 have the meanings given in the specification. The compounds are useful as inhibitors of the binding of fibrinogen to glycoprotein IIb/IIIa. Intermediates are also disclosed.

The invention concerns pharmaceutically useful 1,3-dioxane alkenoic acid derivatives of formula VII and formula XI containing a pyridyl moiety at position 4 of the dioxane ring and in which the groups at positions 2, 4 and 5 have cis-relative stereochemistry, wherein X is hydrogen, alkoxy or hydroxy, Y is vinylene, n is 1 or 2, A.sup.1 is alkylene, R.sup.1 is a variety of substituents defined hereinafter, Ra and Rb are independently methyl or ethyl, R.sup.2 is hydroxy, a physiologically acceptable alcohol residue or alkanesulphonamido, and the pharmaceutically acceptable salts thereof.

4-pyridyl-1,3-dioxane derivatives

The invention concerns novel, pharmaceutically useful 1,3-dioxane alkenoic acid derivatives of the formula I containing a pyridyl moiety at position 4 of the dioxane ring and in which the groups at positions 2, 4 and 5 have cis-relative stereochemistry, X is hydrogen, alkoxy or hydroxy, Y is vinylene, n is 1 or 2, A.sup.1 is alkylene, R.sup.1 is a variety of substituents defined hereinafter, and R.sup.2 is hydroxy, a physiologically acceptable alcohol residue or alkanesulphonamido, and the pharmaceutically acceptable salts thereof. The invention also includes processes for the manufacture and use of the acid derivatives as well as pharmaceutical compositions for therapeutic use in one or more of a variety of diseases such as ischaemic heart disease, cerebrovascular disease, asthmatic disease and/or inflammatory disease.

Pyridyl substituted alkenoic acid derivatives

4-pyridyl substituted-1,3-dioxane compounds

The invention describes the novel compound 6(Z)-8-([2,4,5-cis]-4-o-hydroxyphenyl-2-trifluoromethyl-1,3-dioxan-5-yl)oc tenoic acid of formula I and its pharmaceutically acceptable salts and pharmaceutical compositions, which are of value in treating certain pulmonary and/or vascular disorders. Also described are various processes for the manufacture of the novel compound and intermediates for use therein.

Octenoic acid derivatives useful as thromboxane A.sub.2 inhibitors

The invention concerns novel, pharmaceutically useful 1,3-dioxane alkenoic acid derivatives of the formula I containing a pyridyl moiety at position 4 of the dioxane ring and in which the groups at positions 2, 4 and 5 have cis-relative stereochemistry, X is hydrogen, alkoxy or hydroxy, Y is vinylene, n is 1 or 2, A.sup.1 is alkylene, the substituents R.sup.1 and R.sup.2 at position 2 of the dioxane ring have a variety of values defined hereinafter, and R.sup.4 is hydroxy, a physiologically acceptable alcohol residue or alkanesulphonamido, and the pharmaceutically acceptable salts thereof. The invention also includes processes for the manufacture and use of the acid derivatives as well as pharmaceutical compositions for therapeutic use in one or more of a variety of diseases such as ischaemic heart disease, cerebrovascular disease, asthmatic disease and/or inflammatory disease.

Pyridine derivatives

The invention describes novel (2-styryl-, 2-naphthyl- and 2-phenethyl-4-o-hydroxyphenyl-1,3-dioxan-5-yl)alkenoic acids and related tetrazoles and sulphonamides, of the formula I wherein Q completes a benzene or pyridine ring, Y is vinylene, Z is carboxy, 1(H)-tetrazol-5-yl or a group of the formula --CO.NHSO.sub.2 R.sup.6, and R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6, A.sup.1, A.sup.2, n and m have the meanings defined in the specification, and pharmaceutically acceptable salts thereof, for use in conjunction with their pharmaceutical compositions in treating certain pulmonary and/or vascular disorders. The invention also describes various processes and intermediates for the manufacture of the novel compounds.

Alkene derivatives

The invention concerns novel therapeutic agents containing a (Z)-(2-alkoxyalkyl- or 2-aryloxyalkyl-4-phenyl-1,3-dioxan-5-yl)alkenoic acid, or a related tetrazole derivative, which antagonizes one or more of the actions of thromboxane A.sub.2, together with a compound which inhibits the synthesis of thromboxane A.sub.2. The compositions are useful as medicines in treating a variety of diseases or medical conditions in which thromboxane A.sub.2 and/or other prostanoid contractile substances are involved.

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Macclesfield, United Kingdom

Michael J Smithers