Pharma Mar, S.a.

Pharmamar

Maria Zarzuelo

Ignacio Manzanares

Pilar Gallego

Carmen Cuevas

Marta Perez

Jose Luis Chicharro

Carolina Fernandez

Andrés Francesch

Maria Flores

Carolina Fernández

José Luis Chicharro

Simon Munt

Andres Francesh

Fernando De La Calle

Fernando De Calle

María Jesus Martin

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

Processes are provided for preparing compounds with a fused ring structure of formula (XIV). Such products include ecteinascidins and have a spiroamine-1,4-bridge. The process involving forming a 1,4 bridge using a 1-labile, 10-hydroxy, 18-protected hydroxyl, di-6,8-en-5-one fused ring compound. After formation of the 1,4 brige, C-18 protection is removed before spiroamine introduction. 

Synthetic process for the manufacture of an ecteinaschidin compound

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.

This invention relates to compounds of the formula: 

Antitumoral ecteinascidin derivatives

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Madrid, Spain

Maria Zarzuelo