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(12) United States Patent (10) Patent No.: US 7,038,054 B1 Baldwin Et Al

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(12) United States Patent (10) Patent No.: US 7,038,054 B1 Baldwin Et Al US007038054B1 (12) United States Patent (10) Patent No.: US 7,038,054 B1 Baldwin et al. (45) Date of Patent: May 2, 2006 (54) DAZABICYCLONONANE SCAFFOLD FOR FOREIGN PATENT DOCUMENTS COMBINATORAL SYNTHESIS WO WO9931.100 A1 * 6, 1999 (75) Inventors: John J. Baldwin, Gwynedd Valley, PA OTHER PUBLICATIONS (US); Vinh D. Tran, North Brunswick, Fernandez et al. Journal of Molecular Structure (1995), NJ (US) 355(3): 229-238.* (73) Assignee: Pharmacopeia Drug Discovery, Inc., Miyazawa, CA 123:169517, abstract of CA 2128493, 1995.* Cranbury, NJ (US) Farina, CA 128:140612, abstract of WO 9801443, 1998.* Fernandez, CA 124:164269, abstract of J of Molecular (*) Notice: Subject to any disclaimer, the term of this Structure, vol. 372(2-3), pp. 203-213, 1995.* patent is extended or adjusted under 35 Fernandez, CA 124:29044, abstract of J of Molecular U.S.C. 154(b) by 454 days. Streructure, vol. 355(3), pp. 229-238, 1995.* Fernandez et al. “Structural conformational, biochemical, (21) Appl. No.: 10/166,833 and pharmacological . J. Molecular Structure 372, 203-213 (1995). (22) Filed: Jun. 11, 2002 Fernandez et al. “Synthesis and structural and conformational study of Some amides . J. Molecular Related U.S. Application Data Structure 355, 229-238 (1995). (62) Division of application No. 09/652,178, filed on Aug. * cited by examiner 31, 2000, now abandoned. Primary Examiner D. Margaret Seaman (74) Attorney, Agent, or Firm Heslin Rothenberg Farley & (60) Provisional application No. 60/152.252, filed on Sep. Mesiti, P.C.: Philip E. Hansen 3, 1999. (57) ABSTRACT (51) Int. C. C07D 471/02 (2006.01) Diazabicyclononanes of formula I and their synthesis (52) U.S. Cl. ....................................... 54.6/122; 514/300 (58) Field of Classification Search ................ 54.6/122; 514/3OO See application file for complete search history. (56) References Cited U.S. PATENT DOCUMENTS 3.962,449 A * 6, 1976 Binnig et al. ............... 514,300 are disclosed. The compounds are useful as scaffolds for 4,556,662 A 12/1985 Binnig et al. ............... 514,300 4.959,373 A * 9/1990 Lubisch et al. ............. 514,300 constructing combinatorial libraries. 5,677,311 A 10/1997 Miyazawa et al. .......... 514,299 6,291,475 B1* 9/2001 Alstermark et al. ........ 514,300 8 Claims, No Drawings US 7,038,054 B1 1. 2 DAZABICYCLONONANE SCAFFOLD FOR ments the template may be directly attached to the identifier. COMBINATORIAL SYNTHESIS (See PCT application WO95/19567.) CROSS REFERENCE TO RELATED Throughout this application, various references are APPLICATIONS referred to within parentheses or square brackets. The dis closures of these publications in their entireties are hereby This application is a divisional of U.S. application Ser. incorporated by reference into this application. Variables are No. 09/652,178, filed Aug. 31, 2000, now abandoned, which defined when introduced and retain that definition through claims the benefit of Provisional Application No. 60/152, out. The term “combinatorial library” refers to a collection 252, filed Sep. 3, 1999, the entire disclosure of which is 10 of molecules based on logical design and involving the incorporated herein by reference. selective combination of building blocks by means of simul taneous chemical reactions. Each species of molecule in the FIELD OF THE INVENTION library is referred to as a member of the library. The invention relates to diazabicyclononanes, to their 15 SUMMARY OF THE INVENTION synthesis and to their use as templates for the construction of combinatorial libraries. In one aspect, the invention relates to diazabicy BACKGROUND OF THE INVENTION clononanes (also known as bispidines) of formula I Combinatorial organic synthesis is becoming an impor tant tool in drug discovery. Methods for the synthesis of large numbers of diverse compounds have been described Ellman, et. al. Chem. Rev. 96: 555-600 (1996), as have methods for tagging systems Ohlmeyer et al., Proc. Natl. 25 Acad. Sci. USA, 90, 10922–10926, (1993). The growing importance of combinatorial synthesis has created a need for molecules which can be readily elaborated into libraries by simple and readily variable chemistry. Because the literature abounds with methods for fashioning amide bonds and with 30 methods for protecting nonreacting groups from the chemi wherein A is C=O or CH-NHR'. cal transformations induced by reagents for fashioning R" is hydrogen or the residue of a solid substrate; amide bonds, molecules that offer differentiable amines are R is hydrogen or a first amino-protecting group; of great utility as so-called scaffolds for combinatorial R is hydrogen or a second amino-protecting group, synthesis. 35 Receptors are molecules which selectively interact with with the proviso that no more than one of R, R and R is other molecules. Antibodies, which represent one class of hydrogen. A single amino-protecting group cannot function naturally occurring receptor molecules, bind to other mol as both the first amino-protecting group and the second ecules (antigens) with very high selectivity; they are also 40 amino-protecting group, i.e. R and R cannot be the same. known to catalyze chemical reactions by selectively binding The compounds are useful as scaffolds or templates for the transition states. Monoclonal antibodies are used as constructing combinatorial libraries, for constructing Syn medicinal and diagnostic agents. Although antibodies are thetic receptors and for constructing combinatorial libraries proteins, all receptor molecules need not be proteins. Recep of these receptors. tor molecules perform a variety of tasks from selective 45 binding of Substrates to catalyzing chemical reactions, and In another aspect the invention relates to preparing a their effectiveness is dependent upon their ability to bind combinatorial library, said method comprising the steps of molecular species (Substrates or acceptors) with high selec (a) coupling a compound of formula tivity. For example, the free energy for an antibody binding its antigen is normally from 6–15 kcal/mol. 50 There is considerable interest in synthetic receptors and R2 libraries thereof. For example, Still et al. (U.S. Pat. No. N 5,804,563 and PCT US95/00572) have described synthetic receptors which comprise a polyfunctional organic template N covalently linked to two or more oligomers. In Stills case, 55 n1, YR3 as well as in the present invention, the oligomers may be oligoamides, oligoesters, oligoureas, oligourethanes, oli goamines, oligoethers, oligosulfonamides, oligonucleotides, oligosaccharides, peptides, etc. In the construction of a library, a template or scaffold (the 60 , wherein A is CH-NH, to a solid substrate to provide a two will be used interchangeably herein) may be linked to a Substrate-linked template having two protected active sites. solid substrate and to an identifier which uniquely defines In these compounds, R is a first amino-protecting group, R the synthetic receptor. The identifier is a stable chemical is a second amino-protecting group and R and R are molecule or a plurality of stable chemical molecules distin orthogonally removable. The substrate-linked template is guishable and detectable to picomolar levels. Usually the 65 then (b) reacted with an activator to remove a first protecting template is covalently linked to a solid Support which is in group therefrom to expose a first active site, followed by (c) turn covalently linked to the identifier, but in some embodi coupling an amine-reactive moiety to the exposed first active US 7,038,054 B1 3 site; (d) reacting the Substrate-linked template with an activator to remove a second protecting group therefrom to expose a second active site; and (e) coupling an amine reactive moiety to the exposed second active site. The amine-reactive moieties may include the oligomers of Still, noted above. The method may include the additional step of coupling an identifier to the solid Substrate between steps (c) and (d). In another aspect, the invention relates to a process for 10 synthesizing a diazabicyclononane of formula R4 and o1 15 (f) reductively aminating the keto-diurethane. Preferably, R 1s. is t-butyl and R is allyl. DETAILED DESCRIPTION OF THE fyN's 2O INVENTION HN O The invention relates to compounds of formula I wherein R is t-butyl or allyl, R is t-butyl or allyl and 25 RzR; comprising (a) reacting 1-benzyl-4-piperidone with O-methylbenzy lamine, paraformadehyde and acetic acid to provide a dif ferentially protected diazabicyclononanone of formula O A preferred Subset of the genus includes compounds wherein 35 A is CH NH, particularly those in which R and R are chosen from t-butoxycarbonyl, allyloxycarbonyl, benzy loxycarbonyl, fluorenylmethoxycarbonyl, benzyl and C-phenylethyl. Preferred embodiments of the subgenus are N N those in which one of RandR is t-butoxycarbonyl and the other is chosen from allyloxycarbonyl, benzyloxycarbonyl, Ph - ls Ph 40 and fluorenylmethoxycarbonyl. This subgenus is useful for attaching to a solid Substrate as a scaffold for preparing libraries. (b) selectively cleaving the C.-methylbenzyl group from one 45 Another preferred Subset of the genus includes com pounds that are intermediates in the synthesis of the fore amine to provide an aminoketone; going subgenus. In these compounds A is C=O, one of R (c) reacting the aminoketone with a precursor to a urethane and R is hydrogen and the other is chosen from t-butoxy to provide a keto-urethane of formula carbonyl, allyloxycarbonyl, benzyloxycarbonyl, fluorenyl 50 methoxycarbonyl, benzyl and C.-methylbenzyl. In another subgenus, A is CH-NHR'. R' is the residue of R4 a solid substrate, one of R and R is hydrogen and the other o1 is chosen from t-butoxycarbonyl, allyloxycarbonyl, benzy loxycarbonyl, fluorenylmethoxycarbonyl, benzyl and 1s. 55 C-phenylethyl. Compounds in which one of R and R is t-butoxycarbonyl and the other is chosen from allyloxycar bonyl, benzyloxycarbonyl, and fluorenylmethoxycarbonyl n1/N-1N Ph ; are particularly preferred.
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