Organic compounds -- part of the class 532-570 series – Organic compounds – Unsubstituted hydrocarbyl chain between the ring and the -c-...
Patent
1997-09-19
2000-08-22
Raymond, Richard L.
Organic compounds -- part of the class 532-570 series
Organic compounds
Unsubstituted hydrocarbyl chain between the ring and the -c-...
540455, 540469, C07D47108
Patent
active
061074829
DESCRIPTION:
BRIEF SUMMARY
FIELD OF THE INVENTION
This invention relates to macrocyclic compounds and libraries of these compounds. The macrocyclic compounds of the invention have a plurality of nitrogenous sites that are derivatized by reaction with active forms of reactant compounds. The reactant compounds, upon covalently binding to the macrocyclic nitrogenous substrates, introduce diversity into the macrocyclic compounds. The reactant compounds are selected to be compounds that have, aside from a group capable of reacting with a nitrogenous species, a further functional group thereon that gives each individual compound at least one property that renders it diverse as compared to the other reactant compounds. Hence the incoming reactant compound bearing a chemical functional moiety imparts diversity to the macrocyclic compound and, upon bonding with the macrocycle, its residue can be referred to as a pendant chemical functional group.
The addition of the chemical functional groups at the several nitrogenous sites on the macrocyclic compound yields a macrocyclic compound having a unique set of properties. These properties include the overall global shape, the conformational space, electron density, dipole moment and ability of the compound to interact with enzyme pockets and other binding sites and other similar properties. Combinatorialized libraries of the macrocycles are synthesized having various permutations and combinations of the several chemical functional groups at the nitrogenous sites. Such synthesis is effected at each of the nitrogenous sites by presenting each nitrogenous site with several of the reactant compounds such that combinatorial mixtures are obtained. The libraries are deconvoluted to yield unique macrocyclic compounds. Preferred macrocycles of the invention have cyclophane-like structures.
The chemical functional groups on the macrocyclic compounds of the invention provide for binding of the compounds to proteins, including enzymes, nucleic acids, lipids and other biological targets. In preferred embodiments, the compounds of the invention act as inhibitors of pathogens such as virus, mycobacterium, bacteria (gram negative and gram positive), protozoa and parasites; as inhibitors of ligand-receptor interactions such as PDGF (platelet derived growth factor), LTB.sub.4 (leukotriene B.sub.4), IL-6 and complement C5.sub.A ; as inhibitors of protein/protein interactions including transcription factors such as p50 (NF.kappa.B protein) and fos/jun; as inhibitors of enzymes such as phospholipase A.sub.2 ; and for the inhibition of cell-based interactions including ICAM induction (using inducers such as IL1-.beta., TNF and LPS). In other preferred embodiments, the compounds of the invention are used as diagnostic reagents, including diagnostic reagents in the tests for each of the above noted systems, and as reagents in assays and as probes. In even further preferred embodiments, the compounds of the invention are used as metal chelators and contrast agent carriers. In even further preferred embodiments, the compounds of the invention are used as herbicides and insecticides.
BACKGROUND OF THE INVENTION
Traditional processes of drug discovery involve the screening of complex fermentation broths and plant extracts for a desired biological activity or the chemical synthesis of many new compounds for evaluation as potential drugs. The advantage of screening mixtures from biological sources is that a large number of compounds are screened simultaneously, in some cases leading to the discovery of novel and complex natural products with activity that could not have been predicted otherwise. The disadvantages are that many different samples must be screened and numerous purifications must be carried out to identify the active component, often present only in trace amounts. On the other hand, laboratory syntheses give unambiguous products, but the preparation of each new structure requires significant amounts of resources. Generally, the de novo design of active compounds based on the high resolution structures of enzym
REFERENCES:
patent: 3687808 (1972-08-01), Merigan et al.
patent: 4987227 (1991-01-01), Burrow et al.
patent: 5276131 (1994-01-01), Akkapeddi et al.
patent: 5288514 (1994-02-01), Ellman
patent: 5324483 (1994-06-01), Cody et al.
patent: 5385893 (1995-01-01), Kiefer
patent: 5403572 (1995-04-01), Gries et al.
patent: 5410045 (1995-04-01), Sessler et al.
patent: 5565562 (1996-10-01), Parker et al.
Karaman et al., J. Org. Chem., vol. 57, pp. 1555-1559, 1992.
Alul, R. et al., "Oxalyl-CPG: A Liable Support for Synthesis of Sensitive Oligonucleotide Derivatives", Nucleic Acids Research, 1991, 19, 1527-1532.
Beaucage, S. and Iyer, "Advances in the Synthesis of Oligonucleotides by the Phosphoramidite Approach", Tetrahedron Letters, 1992, 48, 2223-2311.
Bomalaski, J. et al., "Human Extracellular Recombinant Phospholipase A.sub.2 Induces an Inflammatory response in Rebbit Joint", J. Immunol., 1991, 146, 3904-3910.
Bradshaw, J. et al., "Aza-Crown Macrocycles", John Wiley & Sons, New York, NY 1993.
Carell, T. et al., "A Novel Procedure for the Syntehsis of Libraries Containing Small Organic Molecules", Angew. Chem. Int. Ed. Engel., 1994, 33, 2061-2064.
Chem. abstr., vol. 124(7), issued 1996 (Columbus, Ohio, USA), p. 1319, col. 2, the abstract No. 87049y, Irie et al., "Method for Producing Carbamoyloxa-crosslinked Metacyclophane Compounds," JP 07-233,173 (Sep. 5, 1995), see entire abstract.
Dennis, E., "Phospholipases", The Enzymes, 16, Chapter 9, pp. 307-353, Boyer, P.D., ed., Academic Press, New York, 1983.
DeWitt, S.H. et al., "Diversomers : An approach to Nonpeptide, Nonoligomeric Chemical Diversity", Proc. Natl. Acad. Sci, USA, 1993, 90, 6909-6913.
Dietrich, B. et al. (eds.), "Aspects of Organic and Inorganic Supramolecular Chemistry", Macrocyclic Chemistry, VCH, New York, NY, 1993.
Ecker, D. et al., "Rational Screening of Oligonucleotide Combinatorial Libraries for Drug Discovery", Nucleic Acides Res., 1993, 21, 1853-1856.
Englisch, U. and Gauss, "Chemically Modified Oligonucleotides as Probes and Inhibitors", Angew. Chem. Int. Ed. Engl., 1991, 30, 613-722.
Geysen, H. et al., "Strategies for Epitope Analysis Using Peptide Synthesis", J. Immun. Meth., 1987, 102, 259-274.
Glaser, K., et al., "Phospholipase A.sub.2 Enzymes: Regulation and Inhibition", TiPs Reviews, 1992, 14, 92-98.
Green and Wuts, Protective Groups in Organic Synthesis, 2d Edition, John Wiley & Sons, New York, 1991.
Hata, T. et al., "One-step Synthesis of 5'-Azido-nucleosides", J. Chem. Soc. Perkin I, 1980, 306-310.
Hiroshige et al., "Palladium-mediated Macrocyclization on Solid Support and Its Applications to Combinatorial Synthesis", J. Am. Chem. Soc., 1995, 117, 11590-11591.
Houghten, R. et al., "Generation and Use of Synthetic Peptide Combinatorial Libraries for Basic Research and Drug Discovery", Nature, 1991, 354, 84-86.
Iwata et al., Bull. Chem. Soc. Jpn., 1986, 59, 1031-1036.
Kikuchi et al., "Molecular Recognition by Macrocyclic Receptors Having Miltiple Hydrophobic Branches in a Synthetic Bilayer Membrane", J. Phys. Org. Chem., 1992, 5, 633-643.
Koraman et al., J. Org. Chem., 1992, 57, 1555-1559.
Kroschwitz, J.I. (ed.), "Concise Encyclopedia of Polymer Science and Engineering", 858-859, John Wiley & Sons, 1990.
McMurry, et al., "Convenient Synthesis of Bifunctional Tetraaza Macrocycles", Bioconjugate Chem., 1992, 3, 108-117.
Mellor, D.P., Chemistry of Chelation and Chelating Agents in International Encyclopedia of Pharmacolaogy and Therapeutics, Section 70, The Chelation of Heavy Metals, Levine, W.G. Ed., Pergamon Press, Elmford, N.Y., 1979.
Ohlmeyer, M. et al., "Complex Synthetic Chemical Libraries Indexed with Molecular Tags", Proc. Natl. Acad. Sci. USA, 1993, 90, 10922-10926.
Owens, R. et al., "The Rapid Identification of HIV Protease Inhibitors Through the Synthesis and Screening of Defined Peptide Mixtures", Biochem & Biophys. Res. Comm., 1991, 181, 402-408.
Pruzanski, W. et al., "Enzymatic Activity and Immunoreactivity of Extracellular Phospholipase A.sub.2 in Inflammatory Synovial Fluid
An Haoyun
Cook Phillip Dan
Fraser Allister S.
Guinosso Charles J.
Kung Pei-Pei
ISIS Pharmaceuticals Inc.
Raymond Richard L.
LandOfFree
Nitrogenous macrocyclic compounds does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Nitrogenous macrocyclic compounds, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Nitrogenous macrocyclic compounds will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-582661