Synthetic resins or natural rubbers -- part of the class 520 ser – Synthetic resins – Mixing of two or more solid polymers; mixing of solid...
Reexamination Certificate
2002-10-31
2003-09-16
Lipman, Bernard (Department: 1713)
Synthetic resins or natural rubbers -- part of the class 520 ser
Synthetic resins
Mixing of two or more solid polymers; mixing of solid...
C525S054110, C525S332200, C525S374000
Reexamination Certificate
active
06620882
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to a novel solid support template of Formula 1 and methods for producing novel highly functionalized imidazoles, pyrazinones and benzodiazepinones through a plurality of chemical reactions utilizing the solid support template.
BACKGROUND OF INVENTION
Heterocyclic compounds occupy a very important position in the arsenal of clinically useful therapeutic agents. Because of the beneficial medicinal effects of members of this vast class of compounds, interest remains strong for the synthesis of novel heterocyclic compounds and known heterocyclic ring systems where there is ample novel chemistry left to explore.
Advances in molecular biology and application of automated techniques in biological screening allow the testing of a large number of compounds to be carried out rapidly and efficiently. The field of combinatorial chemistry has arisen largely out of the need to synthesize larger numbers of diverse compounds more rapidly than conventional organic synthesis techniques permit, to keep pace with high throughput biological screening capabilities. The present invention introduces a novel method based a solid support template for the efficient preparation of a wide range of novel and highly substituted heterocycles in large numbers.
Chemical synthesis of heterocyclic organic molecules on solid phase support has received considerable attention in recent years (Corbett, J. W., Org. Prep. Proc. Int., 1998, 30, 489; Nefzi, A., Ostresh, J. M., Houghten, R. A., 1997, 97, 449; Hermkens, P. H. H., Ottenheijm, H. C. J. and Rees, D. C.,
Tetrahedron
1997, 53, 5643-5678; Balkenhohl, F., von dem Bussche-Hunnefeld, C., Lansky, A. and Zechel, C.,
Angew. Chem. Int. Ed. Engl.
1996, 35, 2288-2337; Hermkens, P. H. H., Ottenheijm, H. C. J. and Rees, D. C.,
Tetrahedron
1996, 52, 4527-4554).
In most solid phase syntheses of heterocyclic compounds a single heterocyclic scaffold is produced where substitution from appropriate positions on the heterocycle permits numerous analogues to be made that all possess is the same heterocyclic scaffold. In order to prepare a different heterocyclic scaffold, as well as the substituents on the scaffold, requires that a new synthetic approach must be used. This oftentimes requires significant effort and time to optimize the synthetic procedure by which novel heterocyclic compounds can be prepared.
Recently published work (by Keating, T. A. and Armstrong, R. W.,
J. AM. Chem. Soc.
1996, 118, 2574-2583) has demonstrated the synthesis of several heterocyclic & acyclic compounds from a common cyclohexenamide Ugi reaction product in solution phase (see scheme A). Chemical modification of the cyclohexenamide under acidic conditions leads to a munchnone intermediate (see scheme A) which reacts with a number of nucleophiles (alcohols and mercaptans), inter- or intramolecularly, and also dipolarophiles (disubstituted acetylenes) to form the products shown in scheme A.
The synthetic strategy using the Ugi cyclohexenamide allows not only the generation of analogues of the same scaffold but also the synthesis of novel scaffolds, eg. 1,4-benzodiazepinone, pyrrole, 2-acetamido-2-deoxy-D-manno-&dgr;-lactone and several acyclic modified Ugi products.
There is a need in the field of combinatorial chemistry for highly efficient synthetic methods like the example in scheme A for accessing a wide range of compounds that possess structural diversity in the scaffold, as well as, large numbers of analogues of single scaffolds. The synthetic method in the present invention allows the synthesis of large numbers of heterocyclic compounds on solid support where not only the side chains can be easily varied but also many unique heterocyclic scaffolds are synthesized from the same building block.
The present invention relates to a novel solid support template and its use for preparing many novel heterocyclic scaffolds and analogues thereof.
SUMMARY OF INVENTION
The present invention relates to a solid support template of Formula 1, wherein
P is the solid support, and include the following:
a.) beads, pellets, disks, fibers, gels, or particles such as cellulose beads, pre-glass beads, silica gels, polypropylene beads, polyacrylamide beads, polystyrene beads that are lightly cross-linked with 1-2% divinylbenzene and optionally grafted with polyethylene glycol and optionally functionalized with amino, hydroxy, carboxy or halo groups; and
b.) soluble supports such as low molecular weight non-cross-linked polystyrene and polyethylene glycol.
The term solid support is used interchangeably with the term resin or bead in this invention and is intended to mean the same thing.
L is a suitable linker, a multifunctional chemical monomer in which one functional group reacts with the polymer to form a covalent bond and the other functional group reacts with R
1
through a plurality of chemical reactions to provide the desired templates for further chemistry. Commercially available resins, like Rink resin, Wang resin and Hydroxymethyl polystyrene are useful in this method. The linkers present in these resins allow the cleavage of final products by a variety of mild chemical conditions that allow isolation of compounds of this invention. The hydroxymethyl polystyrene resin, the Wang resin and the Rink resin are examples of solid phase supports used in the preparation of compounds of this invention. Other known or commercially available solid phase supports work in this method and are considered to lie within the scope of this invention.
R
1
is selected from a group consisting of a covalent bond or a multifunctional chemical monomer possessing at least two attachment points which link nitrogen in the template backbone and the linker L. An example of such a monomer is derived from an amino acid, such Phenylalanine or &bgr;-alanine.
A is selected from the group consisting of
Pg is a protecting group which includes but not limited to Fmoc, Boc, Alloc;
R
2
, R
3
, R
4
, R
5
, R
6
and R
7
are independently selected from a group consisting of hydrogen, substituted alkyl, substituted alkenyl, substituted alkenylaxyl, substituted alkynyl, substituted aryl, substituted heteroaryl, substituted alkylaryl, substituted cycloalkyl and substituted cycloalkenyl, substituted heterocyclyl; or
R
4
and R
5
taken in combination, are substituted saturated heterocyles; or
R
6
and R
7
taken in combination, are substituted cycloalkyl and substituted saturated heterocyles;
R
8
and R
9
taken in combination are substituted aromatic or heteroaromatic rings;
REFERENCES:
patent: 5856506 (1999-01-01), Lazo et al.
patent: 5872262 (1999-02-01), Dolle, III et al.
patent: 5932695 (1999-08-01), Floyd et al.
patent: 6117940 (2000-09-01), Mjalli
Campian Eugene
Lou Boliang
Yang Kexin
Zhang Jinfang
Advanced Syntech LLC
Stites & Harbison
Vanderburgh John E.
LandOfFree
Solid support template for preparation of highly... does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Solid support template for preparation of highly..., we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Solid support template for preparation of highly... will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-3101180