Organic compounds -- part of the class 532-570 series – Organic compounds – Unsubstituted hydrocarbyl chain between the ring and the -c-...
Reexamination Certificate
2001-03-28
2003-12-09
Raymond, Richard L. (Department: 1624)
Organic compounds -- part of the class 532-570 series
Organic compounds
Unsubstituted hydrocarbyl chain between the ring and the -c-...
C544S121000, C544S368000, C546S187000, C546S198000, C548S217000, C548S222000
Reexamination Certificate
active
06660858
ABSTRACT:
BACKGROUND OF THE INVENTION
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-aminobenzoxazole 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 synthesizing more complex compounds, such as 2 -aminobenzoxazole derivatives.
Benzoxazoles and related derivative compounds have been the subject of investigation in a number of different biological areas. For example, such compounds have been proposed or used as 5-HT
3
antagonists, 5-HT
3
agonists or 5-HT
4
(5-hydroxytryptamine, or seortonin) agonists (Monge et al.,
J. Med. Chem.,
37:1320 (1994) and Yasao et al.,
J. Med. Chem.,
41:3015 (1998); as antihistamines (Hong et al.,
Tetr. Lett.,
38:5607 (1997); and as immunological agents (St. Gorgiev et al.,
Eur. J. Med. Chem.,
24:639-41 (1989).
Benzoxazole derivatives have long been the subject of serial chemical synthesis. See, for example, Iwamatsu et al., U.S. Pat. No. 5,631,257; Bowles et al., U.S. Pat. No. 5,206,366; De Nanteuil et al., 6,040,327; Griffin et al., 6,015,827; De Nanteuil et al., 5,972,968; Bradbury et al., U.S. Pat. No. 5,387,592; Poss et al., U.S. Pat. No. 5,190,942; Arrowsmith et al., U.S. Pat. No. 5,158,964; Iijima et al., U.S. Pat. No. 4,948,900; Iijima et al., U.S. Pat. No. 4,897,393; Saitoh et al., U.S. Pat. No. 4,728,612; Saitoh et al., 4,690,926; Dawson et al., U.S. Pat. No. 4,416,892; Chu-Moyer et al.,
J. Org. Chem.,
60:5721 (1995); Lok et al.,
J. Org. Chem.,
61:3289 (1996); and Kover et al.,
Synthesis,
1124 (1994).
Benzoxazole derivative synthesis has even been extended to combinatorial chemical methods. Wang et al.,
Tetr. Lett.,
38:6529 (1997). However, the libraries to date contain compounds of limited diversity and complexity. Indeed, more complex benzoxazole derivatives, especially those amino substituted at the 2 -position, have been difficult to attain.
A need therefore exists to develop more complex libraries based on heterocyclic medicinal compounds that 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-aminobenzoxazole derivatives, are desired.
This invention satisfies this need and provides related advantages as well. The present invention overcomes the known limitations of classical serial organic synthesis of 2-aminobenzoxazole derivatives, for example, as well as the shortcomings of combinatorial chemistry related to 2-aminobenzoxazole derivatives. The present invention allows for rapid generation of large diverse libraries of complex 2-aminobenzoxazole 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-aminobenzoxazole derivatives and the general techniques of synthesis of combinatorial libraries to prepare highly diverse new 2-aminobenzoxazole derivative compounds.
SUMMARY OF THE INVENTION
The present invention relates to novel 2-aminobenzoxazole derivative compounds of the following formula:
wherein R
1
to R
4
and Z 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-aminobenzoxazole derivative compounds.
REFERENCES:
patent: 4416892 (1983-11-01), Dawson
patent: 4728612 (1988-03-01), Saitoh et al.
patent: 4948900 (1990-08-01), Iijima et al.
patent: 5158964 (1992-10-01), Arrowsmith et al.
patent: 5190942 (1993-03-01), Poss
patent: 5206366 (1993-04-01), Bowles
patent: 5387592 (1995-02-01), Bradbury et al.
patent: 5631257 (1997-05-01), Iwamatsu et al.
patent: 5972968 (1999-10-01), De Nanteuil et al.
patent: 6015827 (2000-01-01), Griffin et al.
patent: 6040327 (2000-03-01), De Nanteuil et al.
Shiokawa et al., Chemical Abstracts, vol. 133:4649, 2000.*
Annoura et al., Chemical Abstracts, vol. 125:114483, 1996.*
Meanwell et al., Chemical Abstracts, vol. 119:271117, 1993.*
Malen et al., Chemical Abstracts, vol. 115:256155, 1991.*
Herrin et al., Chemical Abstracts, vol. 83:201749, 1975.*
Chu-Moyer and Berger, “Preparation of the Four Regioisomeric 2-(Methylthio)oxazolopyridines: Useful Synthons for Elaboration to 2-(Amino substituted)oxazolopyridines,”J. Org. Chem.,60:5721-25 (1995).
Hong et al., “Palladium Catalyzed Amination of 2-Chloro-1,3-Azole Derivatives: Mild Entry to Portent H1-Antihistaminic Norastemizole,”Tetr. Lett.,38:5607-10 (1997).
Lok et al., “Facile Rearrangements of Alkylamino Heterocycles with Noble Metal Cations,”J. Org. Chem.,61:3289-97 (1996).
Kover et al., “Novel and Efficient Synthesis of 6-Chloro-2-(Substituted amino)benzoxazoles,” Synthesis, 1124-26 (1994).
Monge et al., “Synthesis of 2-Piperazinylbenzothiazole and 2-Piperazinylbenzoxazole Derivatives with 5-HT3Antagonist and 5-HT4Agonist Properties,” J. Med. Chem., 37:1320-25 (1994).
St. Gorgiev et al., “Drug-induced modifications of the immune response17.2-Benzoxazolecarboxamide derivatives,”Eur. J. Med. Chem.,24:639-41 (1989).
Sato et al., “Benzoxazole Derivatives as Novel 5-HT3Receptor Partial Agonists in the Gut,”J. Med. Chem.,41:3015-21 (1988).
Wang and Hauske, “Solid-Phase Synthesis of Benzoxazoles via Mitsunobu Reaction,”Tetr. Lett.,38:6529-32 (1997).
Chen Yuewu
Hannah Amy L.
Sutton Scott C.
Zhu Shirong
Law Office of David Spotter
Lion Bioscience AG
Raymond Richard L.
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