Femtogenix Limited

Medimmune Limited

King's College London

Secretary of State for Health and Social Care

Khondaker Mirazur Rahman

David Edwin Thurston

Paul Joseph Mark Jackson

Philip Wilson Howard

John Mark Sutton

Peter William Taylor

Pietro Picconi

Shirin Jamshidi

Mark Benjamin Laws

Kazi Nahar

Charlotte Hind

The invention relates to antibiotic compounds of formula (A1) and pharmaceutically acceptable salts, solvates, tautomers and combinations thereof, wherein X and L are optional linkers and one of Ror Rcomprises Ar, wherein Aris an antibiotic resistance breaker moiety which comprises an optionally substituted Caryl, Caralkyl, Cheteroaryl, Cheteroaralkyl, Cheterocyclyl, Cheterocyclalkyl, Ccarbocyclyl, Ccarbocyclalkyl, &#x2014;C(&#x2550;NR')&#x2014;NR&#x2032;R&#x2033; or &#x2014;CH&#x2014;CH&#x2550;CHgroup; wherein after administration of the compound to a bacterial infection this moiety reduces or prevents efflux. The invention also discloses pharmaceutical compositions comprising compounds of formula (A1) and the use of such compounds as medicaments, in particular, to treat bacterial infections, such as drug-resistant bacterial infections.

Antibiotic resistance breakers

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 pyrrolobenzodiazepines compounds (PBDs) and to pharmaceutically acceptable salts thereof, which are useful as medicaments, in particular, to treat bacterial infections. The PBDs are compounds of formula (I): and salts and solvates thereof; wherein: dotted lines indicates the optional presence of a double bond; X, X, X, Xand Xare connecting functional groups; L is Calkylene; R, Rand Rare independently selected from phenylene, cyclopentanylene, cyclohexanylene, 5- to 9-membered heteroarylene and 5- to 6-membered hetereocyclylene groups, and these groups are optionally substituted with up to three optional substituent groups; Ris selected from N(Calkyl)(Calkyl), 5- to 6-membered nitrogen-containing hetereocyclyl groups, a monosaccharide moiety and an amino monosaccharide moiety wherein these groups are optionally substituted; and Rand Reither together form a double bond, or are selected from H and OR, or Ris a prodrug moiety and Ris OR; m is 0 or 1; with the proviso that when Xis C(O)NH then the up to three optional substituents of Rare not selected from (CH2)-COR; with the proviso that when Xis (CH)O then Ris not phenylene, m is 1 and Ris not a 5- to 9-membered heteroarylene; and with the proviso that when Xis C(O)NH or NHC(O) that Rand/or Ris not 5- to 9-membered heteroarylene. 

PBD antibacterial 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. 

Growing community of inventors

London, United Kingdom

Khondaker Mirazur Rahman