Organic compounds -- part of the class 532-570 series – Organic compounds – Nitrogen attached directly or indirectly to the purine ring...
Reexamination Certificate
1999-05-12
2002-08-27
Celsa, Bennett (Department: 1627)
Organic compounds -- part of the class 532-570 series
Organic compounds
Nitrogen attached directly or indirectly to the purine ring...
C544S384000, C544S386000, C544S387000, C544S389000, C544S404000
Reexamination Certificate
active
06441172
ABSTRACT:
TECHNICAL FIELD
The invention relates to the synthesis of individual di- and tri-substituted-1,4-diazacyclic compounds having 6- to 8-atoms in the cyclic ring, their corresponding 1,6-diketo-2,5-diazacyclic compounds and similar 1,4-diazacyclic ring compounds having one ring carbonyl group and 6-8 atoms in the ring, and libraries of such compounds. The present invention further relates to methods of preparing and using the libraries of compounds as well as individual compounds of the libraries.
BACKGROUND ART
Heterocyclic compounds having a high degree of structural diversity have proven to be broadly and economically useful as therapeutic agents. [For reviews on solid phase organic synthesis, see: (a) Gallop, M. A. et al.,
J. Med. Chem
., 1994, 37, 1233. (b) Gordon, E. M. et al.,
J. Med. Chem
., 1994, 37, 1385. (c) Thompson, L. A. et al.,
Angew. Chem. Int. Ed. Engl
., 1996, 35, 17.(e) Hermkens, P. H. H. et al.,
Tetrahedron
, 1996, 52, 4527. (f) Nefzi, A. et al.,
Chem. Rev
. 1997, 97, 449.] A number of approaches have been reported for the solid phase synthesis of diketopiperazine derivatives: Gordon and Steele developed a strategy for the solid phase synthesis of diketopiperazines based on reductive amination on the solid support [Gordon, D. et al.,
BioMed. Chem. Lett
., 1995, 5, 47]. A similar approach has been published by Krchnàk and co-workers for the synthesis of persubstituted 2,5-diketopiperazines [Krchnàk, V. et al., In
Molecular Diversity and Combinatorial Chemistry: Libraries and Drug Discovery
; Chaiken, I. M., Janda, K. D. Eds., American Chemical Society: Washington, DC. 1996, pp 99-117], and Scott and co-workers developed an alternative strategy for the synthesis of a similar diketopiperazine library using bromocarboxylic acids and a range of amines [Scott, B. O. et al.,
Mol. Diversity
, 1995, 1, 125].
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 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 months or even years. Faster methods are needed that allow 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 4,5-disubstituted-2,3-diketopiperazine and 1,4,5-trisubstituted-2,3-diketopiperazine compounds of the present invention.
Solid-phase techniques for the synthesis of peptides have been extensively developed and combinatorial libraries of peptides have been generated 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. 5,367,053; 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 which 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 which can maintain high affinity and specificity toward biological receptors but which have improved pharmacological properties relative to peptides.
Combinatorial approaches have recently been extended to “organic” or non-peptide libraries. The organic libraries to the present, however, are of limited diversity and generally relate to peptidomimetic compounds; in other words, organic molecules that retain peptide chain pharmacophore groups similar to those present in the corresponding peptide. Although the present invention is principally derived from the synthesis of dipeptides, the dipeptides are substantially modified. In short, they are chemically modified through alkylation, acylation, reduction, and cyclization into the subject diketopiperazines, thus providing mixtures and individual compounds of substantial diversity.
Significantly, many biologically active compounds contain diketopiperazines.
Diketopiperazines are conformationally constrained scaffolds that are quite common in nature, and many natural products containing a diketopiperazine structure have been isolated that encompass a wide range of biological activities. Included in such compounds are inhibitors of the mammalian cell cycle reported by Cui et al.,
J. Antibiot
., 47:1202 (1996), inhibitors of plasminogen activator-1, and topoisomerase reported by Charlton et al.,
P. Thromb. Haeomast
., 75:808 (1996) and Funabashi et al.,
J. Antibiot
., 47:1202 (1994). Diketopiperazines have been reported by Terret et al.,
Tetrahedron
, 51:8135 (1995) to be useful as ligands to the neurokinin-2 receptor. Barrow et al.,
Bioorg. Med. Chem. Lett
., 5:377 (1996) found diketopiperazines to be competitive antagonists to Substance P at the neurokinin-1 receptor. Because, diketopiperazine 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 2,3-diketopiperazine compounds and their analogues of larger ring size.
This invention satisfies these needs and provides related advantages as well. The present invention overcomes the known limitations to classical organic synthesis of cyclic 2,3-diketopiperazines. Existing reported approaches for the synthesis of diketopiperazines describe only the synthesis of 2,5-diketopiperazines, the present invention provides a large array of diverse 1,4,5-trisubstituted- and 4,5-disubstituted-2,3-diketopiperazine compounds that can be screened for biological activity, related piperazine and larger ringed compounds, as described below, that exhibit biological activity.
BRIEF SUMMARY OF THE INVENTION
The invention provides a rapid synthesis of (1-substituted or 1,2-disubstituted)-(4-aminoalkyl)-1,4-diazacyclic compounds having 6- to 8-atoms in the cyclic ring and the corresponding 1,6-diketo-(2-substituted or 2,3-disubstituted)-(5-aminoalkyl)-2,5-diazacyclic compounds and related cyclic amino amides and cyclic keto diamines of Formula I, hereinafter, and further provides combinatorial libraries that contain those compounds. The naming system used herein is understood to not be in conformance with naming systems usually used in organic chemistry, and relies upon the structural features common to all of the contemplated compounds as is discussed below.
It is first to be noted that the contemplated compounds can have one of two structure types that each contain a cyclic compound in which two nitrogen atoms are present in the ring at what can be considered positions 1 and 4. The first compound type contains one or two carbonyl groups that can be bonded to a ring amine, in which the first amine contains another amine at the 2- through 7-position of an alkyl group bon
Houghten Richard A.
Nefzi Adel
Ostresh John M.
Celsa Bennett
Torrey Pines Institute for Molecular Studies
LandOfFree
Diketodiazacyclic compounds, diazacyclic compounds and... does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Diketodiazacyclic compounds, diazacyclic compounds and..., we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Diketodiazacyclic compounds, diazacyclic compounds and... will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-2951434