Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2000-09-12
2003-04-08
Chang, Ceila (Department: 1627)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C548S303100
Reexamination Certificate
active
06545032
ABSTRACT:
DESCRIPTION
1. Technical Field
The present invention relates generally to the combinatorial synthesis of [3,5,7]-1H-imidazo[1,5-a]imidazol-2(3H)-one derivatives. More specifically, the invention provides novel [3,5,7]-1H-imidazo[1,5-a]imidazol-2(3H)-one compounds as well as novel combinatorial libraries comprised of many such compounds, and methods of synthesizing the libraries.
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 structure(s) is selected as a promising lead. A large number of related analogs are then synthesized to develop a structure-activity relation-ship 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 months or even years. Faster methods are needed that permit 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 the [3,5,7]-1H-imidazo[1,5-a]imidazol-2(3H)-one compounds of the present invention.
Solid-phase techniques for the synthesis of peptides have been extensively developed and combinatorial libraries of peptides have been prepared with great success. During the past four years there has been substantial development of chemically synthesized combinatorial libraries (SCLs) made up of peptides.
The preparation and use of synthetic peptide combinatorial libraries has been described for example by Dooley in U.S. Pat. No. 5367.053; Huebner in U.S. Pat. No. 5,182,366; Appel et al in WO Pct 92/09300; Geysen in published European Patent Application 0 138 855 and Pimmg in U.S. Pat. No. 5,143,854. Such SCLs provide the efficient synthesis of an extraordinary number of various peptides in such libraries and the rapid screening of the library that identifies lead pharmaceutical peptides.
Peptides have been, and remain, attractive targets for drug discovery. Their high affinities and specificities toward biological receptors as well as the ease with which large peptide libraries can be combinatorially synthesized make them attractive drug targets. The screening of peptide libraries has led to the identification of many biologically-active lead compounds. However, the therapeutic application of peptides is limited by their poor stability and bioavailability in vivo. Therefore, there is a need to synthesize and screen compounds that can maintain high affinity and specificity toward biological receptors, while exhibiting improved pharmacological properties relative to peptides.
Combinatorial approaches have recently been extended to “organic” or non-peptide libraries.
Significantly, many biologically active compounds contain the imidazole moiety. Such compounds are conformationally constrained scaffolds, are quite common in nature and many imidazole-containing natural products have been isolated encompassing a wide range of biological activities. The imidazole ring system is of particular importance because it is present in the essential amino acid histidine. The histidine residues are found at the active site of ribonuclease and several other enzymes. Drugs such as cimetidine were designed with histamine itself as the starting point [C. R. Ganellin, in
Medicinal Chemistry
, ed. S. M. Roberts and B. J. Price, Academic Press, London, 1985, p.93; G. J. Durant,
Chem Soc. Rev
., 1985, 84, 375].
Several other classes of drugs are based on the imidazole ring. 2-Nitroimidazole (azomycin) is a naturally occurring antibiotic and some synthetic nitroimidazoles are active against intestinal infections (Reviews:
Nitroimidazoles; Chemistry; Pharmacology and Clinical Applications
, eds. A. Breccia, B. Cavalleri, and G. E. Adams, Plenum Press, New York, 1982; J. H. Boyer,
Nitrazoles
, VCH, Deerfield Beach, Fla., 1986).
Imidazole-containing moieties are found in many biologically active compounds and are known to have useful therapeutic implications. There is a need to further study and develop large numbers of [3,5,7]-1H-imidazo[1,5-a]imidazol-2(3H)-one compounds and their binding to biological receptors. These compounds of the present invention are principally derived from the synthesis of dipeptides, but the dipeptides are substantially modified. In short, they are chemically modified through, acylation and cyclization via Bischler-Naprielski reaction into the subject [3,5,7]-1H-imidazo[1,5-a]imidazol-2(3H)-one, thus providing mixtures and individual compounds of substantial diversity.
BRIEF SUMMARY OF THE INVENTION
The invention provides a rapid approach for combinatorial synthesis and screening of individual compounds and libraries of [3,5,7]-1H-imidazo[1,5-a]imidazol-2(3H)-one compounds. The present invention further provides libraries and individual compounds and their pharmaceutically-acceptable salts of Formula I. The present invention also relates to the preparation of synthetic combinatorial libraries of organic compounds and their pharmaceutically-acceptable salts of Formula I, wherein R
1
, R
2
and R
3
have the meanings provided below.
The present invention has several benefits and advantages. One benefit is the provision of a new synthesis for bicyclic [3,5,7]-1H-imidazo[1,5-a]imidazol-2(3H)-one compounds. The present invention provides a large array of diverse [3,5,7]-1H-imidazo[1,5-a]imidazol-2(3H)-one compounds that can be screened for biological activity, and as described below, are biologically active.
An advantage of the invention is that individual compounds can be prepared or libraries containing a plurality of compounds can be prepared.
Another benefit of the invention is that the yield of bicyclic compound produced is relatively great compared to that obtained in prior syntheses of the parental compound.
Still further benefits and advantages of the invention will be apparent to the skilled worker from the discussion that follows.
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patent: 5541061 (1996-07-01), Fodor et al.
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Rubini, et al, Tetrahedron, 1986, 42(21), 6039-6045.*
S.H. Baek, et al., “Identification of the Peptides that Stimulate the Phosphoinositide Hydrolysis in Lymphocyte Cell Lines from Peptide Libraries,”J. of Biol. Chem., 271(14):8170-8175 (1996).
E. Bianchi, et al., “A Conformationally Homogeneous Combinatorial Peptide Library,” 1995Academic Press Limited, pp. 154-160, Accepted Dec. 23, 1994.
Birkett, et al., “Synthesis and Intramolecular Cyclisation of 5-Aminoimidazolealkanoates and Their Conversion to Purine Derivatives,”Synthesis,157-59 (1991).
B. Dëprez, et al., “Orthogonal Combinatorial Chemical Libraries,”J. Am. Chem. Soc.117:5405-5406 (1995).
B. Fleckenstein, et al., “New Ligands Binding to the Human Leukocyte Antigen Class II Molecule DRBI*0101 Based on the Activity Pattern of an Undecapeptide Library,”Eur. J. Biochem., 240:71-77 (1996).
S.P.A. Fodor, et al., “Light-Directed, Spatially Addressable Parallel Chemical Synthesis,”Science,251:767-778 (1991).
B.R. Gundlach, et al., “Specificity and Degeneracy of Minor Histocompatablity Antigen-Specific MHC-Restricted CTL,”J. Immunol.156:3645-3651 (1996).
B.R. Gundlach, et al., “Determination of T Cell Epitopes with Random Peptide Libraries,”J. Immunol. Methods192:149-155 (1996
ElAbdellaoui Hassan M.
Houghten Richard A.
Ostresh John M.
Chang Ceila
Small Andrea D.
Torrey Pines Institute for Molecular Studies
Welsh & Katz Ltd.
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