Bristol-myers Squibb Compnay

Douglas D McLeod

T G Murali Dhar

Jack Z Gougoutas

Chenkou Wei

Mary F Malley

Yu Fan

Joerg Deerberg

Albert J DelMonte

Robert E Waltermire

Tai-Yuen Yue

A process is provided for preparing spiro-hydantoin compounds of the formula II wherein Z is N or CR; K and L are independently O or S; Ar is an optionally substituted aryl or heteroaryl; Ais a linker, G' is a linker; Q is a linker; and R, R, R, and Rare defined in the specification. The process optionally includes the enantiomeric separation of intermediates to allow preparation of enantiomers of the spiro-hydantoin compounds of formula II. Substituted spiro-hydantoin compounds may be prepared from the spiro-hydantoin compounds of formula II. The spiro-hydantoin compound of formula II and the substituted spiro-hydantoin compounds are useful in the treatment of immune or inflammatory diseases. Also, provided are products made by the instant inventive process and crystalline forms (prepared by any process) of the substituted spiro-hydantoin compound, 5-[(5S,9R)-9-(4-Cyanophenyl)-3-(3,5-dichlorophenyl)-1-methyl-2,4-dioxo-1,3,7-triazaspiro[4.4]non-7-ylmethyl]-thiophene-3-carboxylic acid, including solvates and salts thereof, as well as methods of use thereof. Crystalline forms of certain intermediates are provided.

Crystalline forms and process for preparing spiro-hydantoin compounds

A novel process for the asymmetric synthesis of substituted cyclic &bgr;-amino-carboxylates of the type shown in the specification from appropriate &bgr;-enamino-ester starting materials is described. These compounds are useful as intermediates for MMP and TACE inhibitors.

Asymmetric catalytic hydrogenation process for preparation of chiral cyclic &bgr;-aminoesters

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Kingston, NJ, United States of America

Douglas D McLeod