Spirogen Limited

Spirogen Sarl

Medimmune Limited

Other

The United States of America, as Represented by the Secretary, Department of Health and Human Services

Spirogen Developments Sàrl

Stephen John Gregson

Philip Wilson Howard

Luke Masterson

Zhizhi Chen

David Edwin Thurston

Arnaud Charles Tiberghien

Paul S Liu

B Rao Vishnuvajjala

Kenneth M Snader

Peter William Taylor

Jean-Noel Levy

Tsveta Stefanova Hadjivassileva

Peter William School Of Pharmacy Taylor

Tsveta Stepanova Hadjivassileva

A compound of formula I and salts and solvates thereof, wherein: Rand Rare independently 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; Ris selected from H, R, OH, OR, SH, SR, NH, NHR, NRR&#x2032;, nitro, MeSn and halo; R&#x2033; is a Calkylene group, which chain may be interrupted by one or more heteroatoms, e.g. O, S, NR(where Ris H or Calkyl), and/or aromatic rings, e.g. benzene or pyridine; Y and Y&#x2032; are selected from O, S, or NH; R, R, Rare selected from the same groups as R, Rand Rrespectively; Ris selected from OH, OR, where Ris Calkyl; and Ris a linker for connection to a cell binding agent. 

Pyrrolobenzodiazepine conjugates

A compound of formula (I): (I) and its conjugates. 

A conjugate comprising a PBD dimer linked from the tether joining the two PBD units, wherein the linker is of formula (A1):(Formula (A1)) wherein Ris selected from H and Calkyl; L is a linker connected to a cell binding agent; CBA is the cell binding agent; n is an integer selected in the range of 0 to 48; Q is: (Formula (Q)), where Qis such that Q is an amino-acid residue, a dipeptide residue or a tripeptide residue. 

Pyrrolobenzodiazepines and conjugates thereof

Unsymmetrical pyrrolobenzodiazepine-dimers for treatment of proliferative diseases

The present invention is directed to novel pyrrolobenzodiazepine dimers and methods of using the dimers in the treatment of proliferative diseases.

Compounds of the formula I: or solvate thereof, wherein:

Pyrrolobenzodiazepines

Claimed are unsymmetrical Pyrrolobenzodiazepine-dimers (PBD-dimers) of formula (I), that are unsymmetrical due at least to the values that the variables Rand Rrepresent. Formula (I), wherein: Ris of formula (II), where A is a Caryl group, X is selected from the group comprising: OH, SH, COH, COH, N&#x2550;C&#x2550;O, NHR, wherein Ris selected from the group comprising H and Calkyl, and (OCH)OCH, where m is 1 to 3, and either: (i) Qis a single bond, and Qis selected from a single bond and &#x2014;Z&#x2014;(CH)&#x2014;, where Z is selected from a single bond, O, S and NH and n is from 1 to 3; or (ii) Qis &#x2014;CH&#x2550;CH&#x2014;, and Qis a single bond; Ris a Caryl group, optionally substituted by one or more substituents selected from the group comprising: halo, nitro, cyano, ether, Calkyl, Cheterocyclyl and bis-oxy-Calkylene. The other variables are as defined in the claims. The compounds are useful for the treatment of proliferative diseases. 

Methods of preparing ZC-423 (I) which result in varying enantiomeric ratios. 

The invention relates to certain pyrrolobenzodiazepines (PBDs), and in particular pyrrolobenzodiazepine dimers bearing C2 substitutions, including compounds of formula (T): wherein: Ris CHR, and Ris independently selected from H, R, COR, COR, CHO, COH, and halo; Rand Rare independently selected from H, R, OH, OR, SH, SR, NH, NHR, NRR', NO, MeSn and halo; Ris independently selected from H, R, OH, OR, SH, SR, NH, NHR, NRR&#x2032;, NO, MeSn and halo; Ris independently selected from H, R, OH, OR, SH, SR, NH, NHR, NRR&#x2032;, NO, MeSn and halo; R is independently selected from optionally substituted Calkyl, Cheterocyclyl and Caryl groups; or the compound is a dimer with each monomer being of formula (M), where the Rgroups or Rgroups of each monomer form together a dimer bridge having the formula &#x2014;X&#x2014;R&#x2033;&#x2014;X&#x2014; linking the monomers; wherein R&#x2033; is a Calkylene group, which chain may be interrupted by one or more heteroatoms, e.g. O, S, N(H), and/or aromatic rings, e.g. benzene or pyridine; and each X is independently selected from O, S, or N(H); or any pair of adjacent groups from Rto Rtogether form a group &#x2014;O&#x2014;(CH)&#x2014;O&#x2014;, where p is 1 or 2, and salts and solvates thereof, and their use as intermediates for the preparation of other PBD compounds. 

The present inventors have developed a key intermediate for the production of C2 substituted PBDs, which has a leaving group at the C2 position, a carbamate protecting group at the N10 position and a protected hydroxy group at the C11 position. In a first aspect, the present invention comprises a compound with a the formula (I), wherein: Ris a carbamate-based nitrogen protecting group; Ris an oxygen protecting group; and Ris a labile leaving group. In a further aspect, the present invention comprises a method of synthesising a compound of formula (III), or a solvate thereof, from a compound of formula (I) as defined in the first aspect, Ris either O&#x2014;R11, wherein Ris as defined in the first aspect, or OH, or Rand Rtogether form a double bond between N10 and C11; and Ris R. The other substituents are defined in the claims. Further aspects of the present invention relate to compounds of formula (III) (including solvates thereof when Rand Rform a double bond between N10 and C11, and pharmaceutical salts thereof), pharmaceutical compositions comprising these, and their use in the manufacture of a medicament for the treatment of a proliferative disease. 

11-hydroxy-5h-pyrrolo[2,1-c][1,4] benzodiazepin-5-one derivatives as key intermediates for the preparation of c2 substituted pyrrolobenzodiazepines

Compounds of the formula: (I) or solvate thereof, wherein: Ris an optionally substituted Caryl group; Rand Rare independently 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; Ris selected from H, R, OH, OR, SH, SR, NH, NHR, NHRR&#x2032;, nitro, MeSn and halo; R&#x2033; is a Calkylene group, which chain may be interrupted by one or more heteroatoms and/or aromatic rings; X is selected from O, S, or NH; z is 2 or 3; M is a monovalent pharmaceutically acceptable cation; R&#x2032;, R&#x2032;, R&#x2032;, R&#x2032;, X&#x2032; and M&#x2032; are selected from the same groups as R, R, R, R, X and M respectively, or M and M&#x2032; may together represent a divalent pharmaceutically acceptable cation. 

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. 

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.

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London, United Kingdom

Stephen John Gregson