Triazole compounds and methods of making same

Details Triazole compounds and methods of making same Triazole compounds and methods of making same

1999-06-29

2002-03-26

Higel, Floyd D. (Department: 1626)

Organic compounds -- part of the class 532-570 series

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

C514S383000, C540S229000, C540S229000

Reexamination Certificate

active

06362342

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 specific embodiment, the invention provides novel triazoles 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 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 what 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 triazoles.
Combinatorial approaches have recently been extended to “organic,” or non-peptide, libraries. Zambias et al. (U.S. Pat. No. 5,712,171) describe a method of generating libraries that contain aminimides, oxazolones, sulfonylaminides and phosphonylaminides as the core structure in spatially arranged arrays. Combinatorial chemical methods have been applied to a limited number of heterocyclic compounds, as described, for example, in Wilson et al.,
Molecular Diversity,
3:95-112 (1998); U.S. Pat. Nos. 5,288,514; 5,324,483; and Goff et al.,
J. Org. Chem.,
60:5748-5749 (1995). See also U.S. Pat. Nos. 5,549,974 and 5,506,337. However, the heterocyclic libraries to date contain compounds of limited diversity and complexity.
Substituent limitations have been overcome for mixtures of peptides and peptidomimetics through the use of solid phase techniques versus solution-phase. An important step in the development of solid-phase techniques was the discovery of methods to prepare large numbers of individual compounds simultaneously, as described, for example, by Houghten in U.S. Pat. No. 4,631,211. These solid phase methods, however, have rarely been applied to the syntheses of complex heterocyclic structures. Therefore a need exists to develop more complex “organic” libraries based on heterocyclic medicinal compounds which would need less time and effort in the synthesis and testing required to bring an organic pharmacetical product to fruition. In short, improved methods for generating therapeutically useful heterocyclic compounds, such as triazole derivatives, are desired.
Triazole compounds have been the subject of investigation in a number of different biological areas. For example, triazole derivatives have been proposed as useful: (a) as benzodiazepine receptor agonists (Francis et al.,
J. Med. Chem.,
34:281-290 (1991); (b) in treating cardiovascular disorders (U.S. Pat. No. 5,098,920); (c) as fungicides and plant-growth regulators (U.S. Pat. No. 4,598,085); (d) as insecticides (U.S. Pat. No. 5,756,522) (e) in treating allergies; (f) in treating hypertension (U.S. Pat. No. 4,338,453); and (g) as angiotensin antagonists (U.S. Pat. No. 5,281,614). However, more complex triazole derivatives, especially with substitutions at the 1 and 2 nitrogen positions, 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 triazole derivatives, for example, as well as the shortcomings of combinatorial chemistry related to triazole compounds. The present invention allows for rapid generation of large diverse libraries of complex triazoles as discrete molecules or molecules bound to solid support, such as a resin. 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. Therefore, building blocks, such as those described above, can provide libraries that consist of large numbers as well as 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 triazoles and the general techniques of synthesis of combinatorial libraries to prepare highly diverse new triazole compounds.
SUMMARY OF THE INVENTION
The present invention relates to novel triazole compounds of the following formula:
wherein R
1
to R
5
have the meanings provided below (with R
4
—R
5
attached to either the one-position or two-position nitrogen on the triazole ring).
The invention further relates to combinatorial libraries containing two or more such compounds, and to methods of generating triazole compounds.


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