Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
1999-09-29
2002-10-01
Northington Davis, Zinna (Department: 1627)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C514S318000, C514S332000, C514S336000, C514S341000, C514S343000, C514S314000, C544S124000, C546S193000, C546S167000, C546S257000, C546S276400, C546S275100, C546S280100, C546S283400
Reexamination Certificate
active
06458789
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates generally to the synthesis of compounds comprising heterocyclic rings. In one embodiment, the invention provides novel 2-aminopyridine derivative compounds as well as novel combinatorial libraries comprised of such compounds.
2. Background Information
The process of discovering new therapeutically active compounds for a given indication involves the screening of all compounds from available compound collections. From the compounds tested, one or more structures is selected as a promising lead. A large number of related analogs are then synthesized in order to develop a structure-activity relationship and select one or more optimal compounds. With traditional “one-at-a-time” synthesis and biological testing of analogs, this optimization process is long and labor intensive. Adding significant numbers of new structures to the compound collections used in the initial screening step of the discovery and optimization process cannot be accomplished with traditional “one-at-a-time” synthesis methods, except over a time frame of years or even decades. Faster methods are needed that allow for the preparation of up to thousands of related compounds in a matter of days or a few weeks. This need is particularly evident when it comes to synthesizing more complex compounds, such as 2-aminopyridine derivative compounds.
Combinatorial approaches have been extended to “organic,” or non-peptide, libraries. Combinatorial chemical methods have even been extended to pyridine derivative compounds, as described, for example, in Mohan et al,
Bioorg.
&
Med. Chem. Lett.,
8:1877-1882 (1998); Tadesse et al,
J. Comb. Chem.,
1:184-187 (1999); Gordeev et al,
Tetr. Lett.,
37:4643-4646 (1996); Chen et al,
Tetr. Lett.,
39:3401-3404 (1998); Coterill et al.,
Tetr. Lett.,
39:1117-1120 (1998); Lago et al.,
Tetr. Lett.,
39:3885-3888 (1998); and Powers et al.,
Tetrahedron,
54:4085-4096 (1998). However, the libraries to date contain compounds of limited diversity and complexity.
A need therefore exists to develop more complex libraries based on heterocyclic medicinal compounds which would need less time and effort in the synthesis and testing required to bring an organic pharmaceutical product to fruition. In short, improved methods for generating therapeutically useful heterocyclic compounds, such as 2-aminopyridine derivatives, are desired.
Pyridine derivative compounds have been the subject of investigation in a number of different biological areas. For example, pyridine derivatives have been proposed or used as anticoagulents (see Mohan et al., supra), antihistamines, antiseptics, antiarrhythmics and antirheumatics (see, Gordeev et al, supra).
Pyridine derivatives have also been the subject of serial chemical synthesis. See, for example, Katritzky et al.,
J. Org. Chem.,
62:6210-6214 (1997); Nitta et al.,
Bull. Chem. Soc. Jpn.,
64:1325-1331 (1991); and Pabst et al.,
Tetr. Lett.,
39:6691-6694 (1998). However, more complex pyridine derivatives, especially those amino substituted at the 2 position, have been difficult to attain.
This invention satisfies this need and provides related advantages as well. The present invention overcomes the known limitations to classical serial organic synthesis of 2-aminopyridine derivatives, for example, as well as the shortcomings of combinatorial chemistry related to 2-aminopyridine derivatives. The present invention allows for rapid generation of large diverse libraries of complex 2-aminopyridine derivatives as discrete molecules. The present invention can utilize a readily available pool of building blocks that can be incorporated into the various regions of the molecule. Furthermore, the method of making the present invention allows for the use of building blocks that contain a wide range of diverse functionality. Such building blocks can provide combinatorial libraries that consist of large numbers as well as combinatorial libraries that are extremely diverse with respect to the functionality contained within those libraries. The present invention combines the techniques of solid-phase synthesis of 2-aminopyridine derivatives and the general techniques of synthesis of combinatorial libraries to prepare highly diverse new 2-aminopyridine derivative compounds.
SUMMARY OF THE INVENTION
The present invention relates to novel 2-aminopyridine derivative compounds of the following formula:
wherein R
1
to R
5
have the meanings provided herein.
The invention further relates to combinatorial libraries containing two or more such compounds, as well as methods of preparing 2-aminopyridine derivative compounds.
REFERENCES:
patent: 5021421 (1991-06-01), Hino et al.
patent: 1420987 (1976-01-01), None
patent: WO 98/16508 (1998-04-01), None
patent: WO 98/40356 (1998-09-01), None
Han et al., “Liquid-phase combinatorial synthesis,”Proc. Natl. Acad. Sci. USA, 92 : 6419-6423 (1995).
Chen et al., “Solid Phase Synthesis of 2, 4-Disubstituted Pyridine and Tetrahydropyridine Derivatives: Resin Activation/Capture Approach/Reacap Technology,”Tetr. Lett., 39:3401-3404 (1998) .n et al.Tetr. Lett. 39:3401-3404 (1998).
Cotterill et al., “Microwave Assisted Combinatorial Chemistry Synthesis of Substituted Pyridines,”Tetr. Lett., 39:1117-1120 (1998).
Gordeev et al., “Approaches to Combinatorial Synthesis of Heterocycles: Solid Phase Synthesis of Pyridines and Pyrido [2,3-d]pyrimidines,”Tetr. Lett., 37:4643-4646 (1996).
Katritzky et al., “Benzotriazole-Assisted Preparations of 2-(Substituted amino) pyridines and Pyrid-2-ones,”J. Org. Chem., 62:6210-6214 (1997).
Lago et al., “Solid Phase Synthesis of a 1,3,5-Trisubstituted Pyridinium Salt Library,”Tetr. Lett., 39:3885-3888 (1998).
Mohan et al., “Solid-Phase Synthesis of N-Substituted Amidinophenoxy Pyridines As Factor XA Inhibitors,”Bioorg.&Med. Chem. Lett., 8:1877-1882 (1998).
Nitta et al., “On the Reaction of (Vinylimino) phosphoranes. Part 17.) Preparation of N-Vinylcarbodiimides and Their [4+2]Cycloaddition with Several Dienophiles to Give Pyridine Ring System,”Bull. Chem. Soc. Jpn., 64:1325-1331 (1991).
Pabst et al., “A New and Simple ′Lego′System for the Synthesis of Branched Oligopyridines,”Tetr. Lett., 39:6691-6694 (1998).
Powers et al., “Automated Parallel Synthesis of Chalcone-Based Screening Libraries,”Tetrahedron, 54:4085-4096 (1998).
Tadesse et al., Solid-Phase Synthesis of Highly Functionalized 2,2′-Bipyridines,J. Comb. Chem., 1:184-187 (1999).
Chassaing Christophe
Flatt Brenton T.
Forood Behrouz
Katritzky Alan K.
Davis Zinna Northington
Law Office of David Spolter
Lion Bioscience AG
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