Iomet Pharma Ltd.

Other

University of Dundee

Cyclacel Limited

Susan Davis

Phillip Martin Cowley

Alan Wise

Michael Kiczun

Christopher Walpole

Simon Richard Green

Judy H Chiao

Ian Gilbert

Neil Norcross

Daniella I Zheleva

Laura Cleghorn

Margaret Huggett

Geoffrey I Shapiro

David Blake

Barbara Forte

Chimed Jansen

Beatriz Baragana

Phillip Cowley

The present invention relates to a novel class of chromene-2-carboxamide compounds inhibitors of general formula I wherein R, R, R, R, R, R, R, Rand X are as defined herein, to their use in medicine, and their use as anti-infective agents in particular, to compositions containing them, to processes for their preparation and to intermediates used in such processes.

Anti-infective agents

Provided is a tryptophan-2,3-dioxygenase (TDO) and/or indoleamine-2,3-dioxygenase (IDO) inhibitor compound for use in medicine, which compound comprises formula (I) wherein X, and Xmay be the same or different and each is independently selected from C, N, O and S; X, X, X, and Xmay be the same or different and each is independently selected from C and N; each bond represented by a dotted line may be present or absent, provided that at least one such bond is present; R, R, R, R, Rand Rmay be present or absent and may be the same or different and each is independently selected from H and a substituted or unsubstituted organic group, provided that the number of R, R, R, R, Rand Rgroups present is such that the respective valencies of X, X, X, X, X, and Xare maintained; and wherein at least one of Rand Rcomprises a group Y, wherein Y is a group having a formula selected from (II), (III), (IV), (V), (VI), (VII) wherein L may be present or absent, and may be a substituted or unsubstituted organic linking group; Rand Rmay be the same or different and are selected from H and a substituted or unsubstituted organic group; each Rmay be the same or different and is selected from H and a substituted or unsubstituted organic group; Ris selected from a substituted or unsubstituted alcohol group or ether group; each Rmay be the same or different and is selected from H and a substituted or unsubstituted organic group; Xmay be selected from C and N; X, X, X, X, X, X, X, Xand Xmay be the same or different and each is independently selected from C, N, O and S; each bond represented by a dotted line may be present or absent; and each Rmay be the same or different and is selected from H and a substituted or unsubstituted organic group. 

Pharmaceutical compound

Provided is a tryptophan-2,3-dioxygenase (TDO) and/or indoleamine-2,3-dioxygenase (IDO) inhibitor compound for use in medicine, which compound comprises the following formula: wherein X, X, X, X, and Xmay be the same or different and each is independently selected from C, N and O; each atom having a dotted line may independently have a double bond or a single bond, provided that valencies at each atom are maintained; each R, R, R, R, and Rmay be present or absent and may be the same or different and is selected from H and a substituted or unsubstituted organic group, provided that the number of such R groups present is such that the valencies of X, X, X, X, and Xare maintained; one or two Rgroups may be present and are selected from H and a substituted or unsubstituted organic group, provided that the number of Rgroups present is such that the valency of the carbon atom to which they are attached is maintained, and provided that at least one Ris an organic group comprising an atom double-bonded to an oxygen atom (preferably a carbonyl group or a sulphonyl group) at an &#x3b1;-, &#x3b2;-, or &#x3b3;-position to the carbon atom to which the Ris attached and in which the atom double-bonded to an oxygen atom is also bonded to a hetero-atom. 

Indole derivatives for use in medicine

Provided is a compound for use in medicine for inhibiting tryptophan-2,3-dioxygenase (TDO) and/or indoleamine-2,3-dioxygenase (IDO), which compound comprises formula (I) wherein X, X, and X, may be the same or different and each is independently selected from C and N; X, X, X, and Xmay be the same or different and each is independently selected from C, N, O and S wherein when Xis N it has a double bond and wherein when Xis N it has a double bond; the dotted line is a bond which may be present or absent; R, R, R, R, R, R, and Rmay be present or absent and may be the same or different and each is independently selected from H and a substituted or unsubstituted organic group, provided that at least one of R, R, Rand Rcomprises a group Y; and provided that the number of R, R, R, R, R, R, and Rgroups present is such that the respective valencies of X, X, X, X, X, X, and Xare maintained; and wherein Y is a group having a formula selected from (II), (III), (IV), (V) wherein L may be present or absent, and may be a substituted or unsubstituted organic linking group, and Rand Rmay be the same or different and are selected from H and a substituted or unsubstituted organic group, Xis selected from C and N, and each Rmay be the same or different and is selected from H and a substituted or unsubstituted organic group. 

Inhibitors of tryptophan-2,3-dioxygenase or indoleamine-2,3-dioxygenase

Provided is a tryptophan-2,3-dioxygenase (TDO) and/or indoleamine-2,3-dioxygenase (IDO) inhibitor compound for use in medicine, which compound comprises the following formula: wherein X, X, X, X, and Xmay be the same or different and each is independently selected from C, N and O; each atom having a dotted line may independently have a double bond or a single bond, provided that valencies at each atom are maintained; each R, R, R, R, R, and Rmay be present or absent and may be the same or different and is selected from H and a substituted or unsubstituted organic group, provided that the number of such R groups present is such that the valencies of X, X, X, X, and Xare maintained; one or two Rgroups may be present and are selected from H and a substituted or unsubstituted organic group, provided that the number of Rgroups present is such that the valency of the carbon atom to which they are attached is maintained, and provided that at least one Ris an organic group comprising an atom double-bonded to an oxygen atom (preferably a carbonyl group or a sulphonyl group) at an &#x3b1;-, &#x3b2;-, or &#x3b3;-position to the carbon atom to which the Ris attached and in which the atom double-bonded to an oxygen atom is also bonded to a hetero-atom. 

A first aspect of the invention relates to a method of treating a proliferative disorder in a subject, said method comprising administering to the subject a therapeutically effective amount of (i) sapacitabine, or a metabolite thereof; and (ii) seliciclib; in accordance with a dosing regimen comprising at least one first treatment cycle and at least one second treatment cycle, wherein said first treatment cycle comprises: (a) administering a therapeutically effective amount of sapacitabine, or a metabolite thereof, for 3 to 5 consecutive days for 2 weeks, starting on day d, where d is the first day of treatment with sapacitabine, or the metabolite thereof, in said first treatment cycle; and (b) optionally administering a therapeutically effective amount of seliciclib for 3 to 5 consecutive days for 2 weeks, starting on day (d&#x2212;1) relative to the administration of sapacitabine or the metabolite thereof, in said first treatment cycle; followed by a rest period of at least 2 weeks, or until treatment-related toxicities are resolved, whichever is longer; and wherein said second treatment cycle comprises: (a) administering a therapeutically effective amount of sapacitabine, or a metabolite thereof, for 3 to 5 consecutive days for 2 weeks, starting on day d, where d is the first day of treatment with sapacitabine, or the metabolite thereof, in said second treatment cycle; and (b) administering a therapeutically effective amount of seliciclib for 3 to 5 consecutive days for 2 weeks, starting on day (d&#x2212;1) relative to the administration of sapacitabine or the metabolite thereof, in said second treatment cycle; followed by a rest period of at least 2 weeks, or until treatment-related toxicities are resolved, whichever is longer. Further aspects of the invention relate to a kit of parts, and corresponding uses.

Dosage regimen for sapacitabine and seliciclib

Growing community of inventors

Dundee, United Kingdom

Susan Davis