Organic compounds -- part of the class 532-570 series – Organic compounds – Nitrogen attached directly or indirectly to the purine ring...
Reexamination Certificate
1999-09-30
2004-01-13
Aulakh, Charanjit S. (Department: 1627)
Organic compounds -- part of the class 532-570 series
Organic compounds
Nitrogen attached directly or indirectly to the purine ring...
C546S276400, C546S275700, C546S268100, C546S262000, C546S256000, C546S193000, C546S309000, C546S297000, C544S360000
Reexamination Certificate
active
06677452
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates generally to the synthesis of compounds comprising heterocyclic rings. In one specific embodiment, the invention provides novel pyridine carboxamide or sulfonamide derivative compounds as well as novel combinatorial libraries comprised of such compounds.
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 pyridine carboxamide or sulfonamide derivative compounds.
Combinatorial chemical methods have 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 pyridine derivative 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 pyridine carboxamide or sulfonamide 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). And pyridine carboxamide derivatives have fibirnogen receptor antagonists (see Duggan et al., WO 9800134 A1 (1998)).
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). Pyridine carboxamide derivatives have also been the subject of serial chemical synthesis. See Lago et al., supra. However, more complex pyridine carboxamide or sulfonamide 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 pyridine carboxamide or sulfonamide derivatives, for example, as well as the shortcomings of combinatorial chemistry related to pyridine carboxamide or sulfonamide derivatives. The present invention allows for rapid generation of large diverse libraries of complex pyridine carboxamide or sulfonamide 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 pyridine carboxamide or sulfonamide derivatives and the general techniques of synthesis of combinatorial libraries to prepare highly diverse new pyridine carboxamide or sulfonamide derivative compounds.
SUMMARY OF THE INVENTION
The present invention relates to novel pyridine carboxamide or sulfonamide derivative compounds of the following formula:
wherein R
1
to R
6
have the meanings provided herein.
The invention further relates to combinatorial libraries containing two or more such compounds, as well as methods of preparing pyridine carboxamide or sulfonamide derivative compounds.
REFERENCES:
patent: 3615504 (1971-10-01), Monbaliu et al.
patent: 0 429 372 (1991-05-01), None
patent: WO 97/28128 (1997-08-01), None
patent: WO 98/00134 (1998-08-01), None
Gordon et al., “Applications of Combinatorial Technologies to Drug Discovery,”J. Med. Chem.,37(10) : 1385-1401 (1994).
Romero et al., “Discovery, Synthesis, and Bioactivity of Bis(heteroaryl) piperazines,”J. Med. Chem.,37:999-1014 (1994).
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).
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).
Ngu and Patel, Preparation of Acid-labile Resins with Halide Linkers and their Utility in Solid Phase Organic Synthesis,Tetr. Lett.,38:973-976 (1997).
Pabst et al., “A New and Simple ‘LEGO’ System for the Synthesis of Branched Oligopyridines,”Tetr. Lett.,39:6691-6694 (1998).
Power 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).
Chen Yuewu
Lang Hengyuan
Pei Yazhong
Aulakh Charanjit S.
Law Office of David Spolter
Lion Bioscience AG
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