`
`Monheim, 17 November 2000
`
`To
`L. Hakes PCD
`
`D. Schacht PAT
`
`It is known since several years that the major metabolite DD 01 of'-Iolterodine is equipotent
`to the parent drug:
`‘
`.
`'
`PC.'I‘ W0 94!1 1337 (26.05.1994); US 5,559,269 (243.1996); H. Postlind,‘A. Lindéren, S. H.
`G. Anclerssen: Xlth Symp. In Microsomes and Drug Oxidation, July 21 -24, 1996, Los
`Angeles (USA); P.—G. Gillberg, B. Sparf, L. Nilvebrant: Neurourol. Urodyn, 15 (1996) 303-
`9; L. Palmer, L. Andcrsson, T. Andersson, U. Stenberg: J’. Phartnac. Biomed. final“ 16 (1997)
`155-165.
`
`During a meeting, helt at Monheim on August 28”‘ (1997), the options were discussed
`between Bengt Sparf, Peter Ncy, and Claus O. Meese that the scaffold ofthe active hydroxy
`metabolite DD 01 could be chemically convened into a different active derivative.
`From the knowledge of the patent literature (PCT W0 89f06644, 27.07.1989 and
`EP 325 571, 07.08.1991‘) it appeared obvious to Bengt Sparf that the phenolic hydroxy group
`of the active derivative of DD 01 should be free in order to elicit optimum anti-muscarinic
`receptor binding:
`
`Proposals of B. Sparf
`
`Benzylic: hydroxy +3» R43
`group derivatlzed
`-
`
`(e.g. ester}
`
`However, subsequent laboratory work disclosed that this objective cannot be achieved. In
`contrast, the following discoveries led to SCHWARZ Pharmt-.’s proposals for novel (inactive)
`\
`jprodrugsl
`
`I RESTRICTED CONFIDENTIAL - SUBJECT TO PROTECTIVE ORDER
`
`UCBOOT1 9290
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2093 - 0001
`
`
`
`RESTRICTED CONFIDENTIAL - SUBJECT TO PROTECTIVE ORDER
`
`UCBO0T19291
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2093 - 0002
`
`
`
`Prodrug Preposais,__of SCHWAR2 Pharma
`
`Phenolic hydmxy
`O-R e-<—— greupderivatized
`
`(e.g. ester)
`
`-
`
`-
`
`Benzylic rnonoestexrs of DD 01 cannot be prepared chemically. A new enzymatic
`process was then developed which regioselectively led to benzylic rnonoesters. Studies
`on these derivatives showed that these are chemically unstable.
`
`i
`
`- ‘
`
`«'
`
`Both phenolic monoesters and diesfer dcrivativeg ofDD 01 are chemically_ stable and
`bi_oiogienlly inactive, but release the active parent hydroxy metabolite under in-vitro or
`in-vivo conditions {prodrug principle).
`'
`
`,
`
`-
`
`—
`
`-
`
`The novel prodrugs exhibit improved oral hioavailability and transdennal penetration
`rate.
`.
`-
`
`New synthetic routes were developed that reduce the number of steps and allow for at
`enantiorner resolution on ém earlgqstage.
`-
`
`Stable, non-hygroscopic, and crystalline salts were developed, among those the
`fismaratc salt SPM 8272, SP’s drug candidate of the SPM 007 series.
`
`:0 N9’
`
`Peter Ney
`NPTA
`
`‘
`
`Claus O. Meese
`SIL
`
`<‘00‘/his1ary.doe>
`
`RESTRICTED CONFIDENTIAL — SUBJECT To PROTECTIVE ORDER
`
`ucEoo7192éé ”
`
`A
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2093 - 0003
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