Process for the preparation of macrocyclic metalloprotease inhibitors

US6562963B2 · kind B2 · utility

Inventors

• Roberta L. Dorow · Portage, US
• Silvio Campagna · Candia, US
• Pasquale N. Confalone · Wilmington, US
• Fuqiang Jin · Wilmington, US
• Zhe Wang · Xiangtan City, CN

Key dates

• Filing date: Jul 31, 2001
• Grant date: May 13, 2003
• Expiry date: Jul 31, 2021

Classification

• Technology area (CPC C): Chemistry; Metallurgy
• CPC primary: C07D273/02
• WIPO field: Organic fine chemistry
• WIPO sector: Chemistry

Abstract

The present invention is directed to a process for the preparation of a compound of formula (X-a) or a pharmaceutically acceptable salt form thereof,wherein:R1 is selected from the group consisting of:C1-5 alkyl substituted with 0-5 R1a,—(CH2)r—C3-10 cycloalkyl substituted with 0-5 R1a, and—(CH2)r-aryl substituted with 0-5 R1a.Compounds of Formula (X-a) are macrocyclic molecules containing anti-succinate residues which inhibit metalloproteinases such as aggrecanase, and the production of tumor necrosis factor (TNF). The anti-succinates are formed by an Ireland Claisen rearrangement of a silyl ketene acetal which proceeds with high stereoselectivity.