Spirogen Limited

Femtogenix Limited

National Institutes of Health, a Component of the US Dept. of Health & Human Services

Medimmune Limited

Midwest Research Institute

Starks Associates Inc.

Spirogen Sarl

David Edwin Thurston

Philip Wilson Howard

Khondaker Mirazur Rahman

Paul Joseph Mark Jackson

Paul S Liu

B Rao Vishnuvajjala

Kenneth M Snader

Stephen John Gregson

Luke Y Hsiao

Peter William Taylor

Gregory Turner

Geoffrey Wells

Tsveta Stefanova Hadjivassileva

Christopher John Pepper

B Rao Vishnuvaijala

Peter William School Of Pharmacy Taylor

Tsveta Stepanova Hadjivassileva

The invention relates to a compound of formula (I) or formula (II) or pharmaceutically acceptable salts, solvates, tautomers, stereoisomers or mixtures thereof; which are useful as medicaments, in particular as anti-proliferative agents and for use as a drug in an antibody-drug conjugate and in the treatment of proliferative diseases. 

Cytotoxic agents

The invention relates to compounds comprising a substituted pyrrolo-, indolino- or tetrahydroisoquinoline-benzodiazepines alkylating moiety linked via the A-ring to aromatic groups of formula (Ia), and to pharmaceutically acceptable salts thereof, which are useful as medicaments, in particular as anti-proliferative agents. 

Anti-liferative agents comprising substituted benzo[e]pyrido[1,2-a][1,4]diazepines

The invention relates to pyrridinobenzodiazepines (PDDs) comprising three fused 6-7-6-membered rings linked to aromatic groups, and pharmaceutically acceptable salts thereof, which are useful as medicaments, in particular as anti-proliferative agents. PDDs may be represented by formula (I) and pharmaceutically acceptable salts thereof. 

Substituted 6a,7,8,9,10,12-hexahydrobenzo[e]pyrido[1,2-a][1,4]diazepines as anti-proliferative agents

The invention relates to pyrridinobenzodiazepines (PDDs) comprising three fused 6-7- 6-membered rings and to benzopyrridodiazecines (BPDs) comprising three fused 6-8- 6-membered rings and, in particular, to PDD or BPD dimers linked together or PDD and BPD monomers linked to aromatic groups, and pharmaceutically acceptable salts thereof, which are useful as medicaments, such as anti-proliferative agents. PDDs and BPDs may be represented by formula (I): and salts or solvates thereof, wherein R, R-Rand Rare independently selected substituent groups; and either: (i) Rand Rtogether form a double bond; (ii) Ris H and Ris OH; or (iii) Ris H and Ris ORand Ris Calkyl; wherein each of m, n, u and w may be 0 or 1; where (a) the compound is a dimer with each monomer being the same or different and being of formula (I) where one of R, R, Rand Rof the first monomer and one of R', R&#x2032;, Rand R&#x2032;of the second monomer form together a bridge having the formula &#x2014;X-L-X&#x2032;&#x2014; linking the monomers and m+n+u+w=1; or (b) a dimer and one of R, Rand Rof the first monomer and one of R&#x2032;, R&#x2032;and Rof the second monomer form together a bridge having the formula &#x2014;X-L-X&#x2032;&#x2014; linking the monomers and m=n=u=w=o; or (c) one of R, R, Rand Rhas the formula: &#x2014;X-L-X&#x2032;-D or &#x2014;(CH)f-O&#x2014;Rand m+n+u+w=o or 1; or (d) Rhas the formula: &#x2014;X-L-X&#x2032;&#x2014; D or &#x2014;(CH)&#x2014;O&#x2014;and m+n+u+w=1; and X-L-X&#x2032;&#x2014; is a linker group and D has the formula (II) or (III). 

Pyrridinobenzodiazepine and benzopyrridodiazecine compounds

The invention relates to pyrrolo[2,1-c][1,4]benzodiazepines (PBDs) of formula (I) and in particular to PBD dimers linked through the C1 position, and PBD monomers linked through the C1 position to aromatic groups, and pharmaceutically acceptable salts thereof, which are useful as medicaments, in particular as anti-proliferative agents. (I) and salts or solvates thereof, wherein: the dotted lines indicates the optional presence of a double bond between C1 and C2 or C2 and C3; R-Rare independently selected substituent groups; and either: (i) Rand Rtogether form a double bond; (ii) Ris H and Ris OH; or (iii) Ris H and Ris ORand Ris Calkyl; where Rhas the formula: -X-L-X'-D-X-L-X&#x2032;- is a linker group and D has the formula (II) or (III): or where the compound is a dimer with each monomer being the same or different and being of formula (I) where the Rof the first monomer and R&#x2032;or R&#x2032;of the second monomer, or Rof the first monomer and R&#x2032;of the second monomer, form together a bridge having the formula -X-L-X&#x2032;- linking the monomers. 

Pyrrolobenzodiazepine compounds

Novel pyrrolobenzodiazepines (PBDs) having a (1-methyl-1H-pyrrol-3-yl)phenyl based amino acid residue and use thereof as antiproliferative agents are disclosed herein. 

Pyrrolobenzodiazepines as antiproliferative agents

A compound of formula (I) or a salt or solvate thereof, wherein the dotted double bond indicates the presence of a single or double bond between C2 and C3; Ris selected from &#x2014;H, &#x2014;OH, &#x2550;O, &#x2550;CH, &#x2014;CN, &#x2014;R, OR, halo, dihalo, &#x2550;CHR, &#x2550;CHRR', &#x2014;O&#x2014;SO&#x2014;R, COR and COR; Ris selected from H, R, OH, OR, SH, SR, NH, NHR, NRR&#x2032;, nitro, MeSn and halo; where R and R&#x2032; are independently selected from optionally substituted Calkyl, Cheterocyclyl and Caryl groups; Rand Reither together form a double bond, or are selected from H and QRrespectively, where Q is selected from O, S and NH and Ris H or Calkyl or H and SOM, where x is 2 or 3, and M is a monovalent pharmaceutically acceptable cation; A is selected from (A1), (A2), (A3), (A4) or (A5) where Xand Yare selected from: CH and NH; CH and NMe; N and NMe; CH and S; N and S; N and O; and CH and O, respectively; Xand Yare selected from: CH and NH; CH and NMe; N and NMe; CH and S; N and S; N and O; and CH and O, respectively; Zis selected from O and S; Zis selected from CH and N; F is selected from a single bond and -(E-F)&#x2014;; each E is independently selected from a single bond, and &#x2014;C(&#x2550;O)&#x2014;NH&#x2014;; each Fis independently a Cheteroarylene group; m is 1, 2 or 3; G is selected from hydrogen, Calkyl, &#x2014;C(&#x2550;O)&#x2014;O&#x2014;Calkyl, &#x2014;(CH)&#x2014;Cheterocycloalkyl, and &#x2014;O&#x2014;(CH)&#x2014;Cheterocycloalkyl group; each n is 0-4; provided that A2 is not A2&#x2032;, where Xand Yof A2&#x2032; are selected from: CH and NMe; COH and NMe; CH and S; N and NMe; N and S, respectively; and provided that A3 is not A3&#x2032;, where Xand Yof A3&#x2032; are selected from: CH and NMe; COH and NMe; CH and S; N and NMe; N and S, respectively; B is either a single bond or (B1), where X and Y of B1 are selected from: CH and NMe; COH and NMe; CH and S; N and NMe; N and S, respectively; and Ris Calkyl. 

Pyrrolobenzodiazepines

A compound of formula (I); or a salt or solvate thereof, wherein: the dotted line indicates the optional presence of a double bond between C2 and C3; Ris selected from &#x2014;H, &#x2014;OH, =0, &#x2550;CH, &#x2014;CN, &#x2014;R, OR, halo, &#x2550;CH&#x2014;R, O&#x2014;SO&#x2014;R, COR and COR; Ris selected from H, R, OH, OR, SH, SR, NH, NHR, NRR', nitro, MeSn and halo, where R and R&#x2032; are independently selected from optionally substituted Calkyl, Cheterocyclyl and Caryl groups; Rand Reither together form a double bond, or are selected from H and YR, where Y is selected from O, S and NH and R is H or Calkyl or H and SOM, where x is 2 or 3 and M is a monovalent pharmaceutically acceptable cation; each X is independently a heteroarylene group; n is from 1 to 6; and Ris Calkyl. The compound is useful for the treatment of proliferative diseases. 

Alkyl 4- [4- (5-oxo-2,3,5, 11a-tetrahydo-5H-pyrrolo [2, 1-c] [1,4] benzodiazepine-8-yloxy)-butyrylamino]-1H-pyrrole-2-carboxylate derivatives and related compounds for the treatment of a proliferative disease

Disclosed are compounds of Formula I wherein X, Y, R-R, T, T, Z, and p are as described herein; a pharmaceutical composition comprising a compound of Formula I and a carrier; a method of inhibiting growth of a cell, which method comprises administering in an amount effective to inhibit growth a compound of Formula I; a method of treating cancer in a mammal, which method comprises administering in an amount effective to treat cancer a compound of Formula I; a method of treating a viral, parasitic, or bacterial infection of a cell, which method comprises administering in an amount effective to treat a viral, parasitic, or bacterial infection a compound of Formula I; and a method of preparing a compound of Formula I as described herein.

Pyrrolobenzodiazepine derivatives, compositions comprising the same and methods related thereto

A compound of formula (IV): O is a solid support; L is a linking group or a single bond; X' is selected from CO, NH, S, or O; A is O, S, NH, or a single bond; Rand Rare independently selected from: H, R, OH, OR, &#x2550;O, &#x2550;CH&#x2014;R, &#x2550;CH, CH&#x2014;COR, CH&#x2014;COH, CH&#x2014;SOR, O&#x2014;SOR, COR, COR, CN and there is optionally a double bond between C1 and C2 or C2 and C3; R, R, and Rare independently selected from H, R, OH, OR, halo, nitro, amino, MeSn; Ris either H or R; Q is S, O or NH; Ris a nitrogen protecting group; and Y is a divalent group such that HY&#x2550;R, and other related compounds and collections of compounds. 

Library of compounds comprising pyrrolobenzodiazepine moieties

A compound of formula (I) and salts and solvates thereof, wherein: Ris a nitrogen protecting group and Ris either OH or O&#x2014;R, wherein Ris an oxygen protecting group, or Rand Rtogether form a double bond between N10 and C11; and Rand Rare selected from the same options as Rand Rrespectively. 

Disclosed are compounds of Formula (I) wherein X, Y, Ri-R, T, T, Z, and p are as described herein; a pharmaceutical composition comprising a compound of Formula (I) and a carrier; a method of inhibiting growth of a cell, which method comprises administering in an amount effective to inhibit growth a compound of Formula (I); a method of treating cancer in a mammal, which method comprises administering in an amount effective to treat cancer a compound of Formula (I); a method of treating a viral, parasitic, or bacterial infection of a cell, which method comprises administering in an amount effective to treat a viral, parasitic, or bacterial infection a compound of Formula (I); and a method of preparing a compound of Formula (I) as described herein. 

Compounds of formula (I): formula (I) and salts, solvates, chemically protected forms, and prodrugs thereof, are disclosed wherein Ris selected from: an optionally substituted napthyl group; an optionally substituted thiophenyl or furanyl group; and a phenyl group substituted by: one or more chloro or fluoro groups; an ethyl or propyl group; a 4-t-butyl group; a 2-methyl group; or two methyl groups in the 2- and 6-positions. 

A compound of formula I: or solvate thereof, wherein n is 1 to 10, and M and M' are independently selected from monovalent pharmaceutically acceptable cations, or together represent a divalent pharmaceutically acceptable cation.

Growing community of inventors

London, United Kingdom

David Edwin Thurston