Pharma Mar, S.a.

Jose Luis Chicharro

Ignacio Manzanares

Pilar Gallego

Maria Zarzuelo

Carolina Fernandez

Carmen Cuevas

Marta Perez

Simon Munt

Maria Flores

Andres Francesh

Fernando De La Calle

Fernando De Calle

This invention relates to antitumoral ecteinascidin derivatives that contain a fused ecteinascidin five ring system with a 1,4-bridge having the structure of formula (VIa) or (VIb) as described herein and compounds in which the &#x2014;NHor &#x2014;OH of the 1,4-bridge is derivatized, and related pharmaceutical compositions and methods. Such ecteinascidin derivatives include, but are not limited to, those compounds having formula (XVIIb): in which Rand Rtogether form a group of formula (VIa) or (VIb) as described herein, and R, R, R, R, R, R, and Rare as defined herein.

Anititumoral ecteinascidin derivatives

Methods are provided for preparing a compound with a fused ring structure of formula (XIV) which comprises one or more reactions starting from a 21-cyano compound of formula (XVI) where typically; Ris an amidomethylene group or an acyloxymethylene group; Rand Rare independently chosen from &#x2014;H, &#x2014;OH or &#x2014;OCOCHOH, or Rand Rare both keto and the ring A is a p-benzoquinone ring; Rand Rare both &#x2014;H ozone is &#x2014;H and the other is &#x2014;OH, &#x2014;OCHor &#x2014;OCHCH, or Rand Rtogether form a keto group; and Rand Rare independently chosen from &#x2014;H or &#x2014;OH, or Rand Rare both keto and the ring A is a p-benzoquinone ring. In modified starting materials, the 21-cyano group can be replaced by other groups introduced using nucleophilic reagents. 

Hemisynthetic method and new compounds

Methods are provided for preparing a compound with a fused ring structure of formula (XIV) which comprises one or more reactions starting from a 21-cyano compound of formula (XVI) where typically: Ris an amidomethylene group or an acyloxymethylene group; Rand Rare independently chosen from &#x2014;H, &#x2014;OH or &#x2014;OCOCHOH, or Rand Rare both keto and the ring A is a p-benzoquinone ring; Rand Rare both &#x2014;H ozone is &#x2014;H and the other is &#x2014;OH, &#x2014;OCHor &#x2014;OCHCH, or Rand Rtogether form a keto group; and Rand Rare independently chosen from &#x2014;H or &#x2014;OH, or Rand Rare both keto and the ring A is a p-benzoquinone ring. In modified starting materials, the 21-cyano group can be replaced by other groups introduced using nucleophilic reagents.

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Madrid, Spain

Jose Luis Chicharro