Chemistry: natural resins or derivatives; peptides or proteins; – Peptides of 3 to 100 amino acid residues – Cyclic peptides
Reexamination Certificate
1999-04-07
2001-05-08
Venkat, Jyothsna (Department: 1627)
Chemistry: natural resins or derivatives; peptides or proteins;
Peptides of 3 to 100 amino acid residues
Cyclic peptides
C424S177100, C435S007100, C435S007200, C436S501000, C436S518000, C514S009100, C514S011400, C530S333000, C530S334000
Reexamination Certificate
active
06228986
ABSTRACT:
BACKGROUND OF THE INVENTION
The application of solid-phase combinatorial chemistry and parallel synthesis techniques for the preparation of non-peptide drug-like molecules has greatly expanded the diversity of agents available for biological screening in the pharmaceutical industry. There has been considerable effort to increase the size and diversity of corporate sample collections to feed HTS (high throughput screening) programs. HTS can potentially deliver a plethora of lead structures, active in novel therapeutic targets, for the medicinal chemist to explore. While there have been many reports in the literature describing methods to prepare acyclic and cyclic (5-, 6- and 7-membered cycles and fused-cycles) compound libraries for HTS; as well as for lead optimization programs, there has been few reports describing the solid-phase synthesis of macrocylic compound libraries.
1
To achieve a truly diverse sample collection for screening, it is desirable that the sample collection contain molecules of varying degrees of conformational flexibility as listed in table I.
TABLE I
Conformational
Molecules
Flexibility
Examples
Acyclic
High
oligonucleotides
1a
, peptides
1b
, peptoids
1c
,
b-peptoids
1d
, oligocarbamates
1e
Macrocyclic
Medium
cyclic peptides
1f
, macrocycles
1g
Cyclic
Low
benzodiazepines
1h
, hydantoins
1i
,
diketopiperazines
1j
, 2-
alkylthiobenzimidazoles
1k
Acyclic molecules, because they can adopt multiple low energy conformations, would be expected to be fairly promiscuous and provide a higher hit rate relative to the more restricted molecules. Acyclics; however, provide little information about the required spatial arrangement of pharmacophoric groups. On the other hand, cyclic conformationally restricted molecules would be expected to provide valuable structural information concerning the binding requirements. Macrocylic compounds, neither completely rigid nor flexible, would be unique in their coverage of 3-d space and would be a valuable addition to our sample collection. The fact that cyclic peptides have long been of interest due to their attractive biological profile provides further incentive for synthetic investigation. It has been well documented that cyclic peptides often display increased selectivity, better bioavailability, and less susceptibility to proteolytic degradation than corresponding polypeptides. The preparation of cyclic peptides on a solid support has been established as an efficient method of synthesis that avoids undesired cross coupling reactions common to macrocyclization by providing a “pseudo-diluted” environment.
2
SUMMARY OF THE INVENTION
The invention relates to an efficient solid-phase synthesis of novel 14-membered ring dipeptide derived macrocycles from readily available building blocks.
3
Thus, the invention relates to a process for preparing a macrocyclic compound selected from those of the formula:
wherein:
R
1
is selected from naphthyl, diphenyl, and phenoxyphenyl;
R
2
is selected from C
1
-C
6
alkyl, benzyl, C
1
-C
6
alkylamino, CH
2
SCH
2
Ph, and CH
2
(4-MeO)Ph;
R
3
is selected from hydrogen and C
1
-C
6
alkyl; and
R
4
is selected from hydrogen, phenyl, C
1
-C
6
alkyl;
or R
3
and R
4
taken together form a 5-6 membered carbocyclic ring; which comprises:
preparing a resin-bound protected dipeptide precursor of the formula:
from a resin-bound orthogonally protected lysine residue by reductive alkylation of the &agr;-nitrogen followed by acylation with an Fmoc-aminoacid to provide the protected dipeptide precursor; and
removing the Fmoc-group, acylating with a succinic anhydride, removing the methyltrityl-group followed by macrocyclization to provide the desired macrocycle of formula I.
This approach uses the side-chain functionality of lysine in the final ring closure.
4
In addition, this route proved well suited for sort and mix combinatorial chemistry.
5
With the IRORI microkans and our visual tagging method, a diverse three dimensional library of 500 single pure compounds was generated.
6,7
REFERENCES:
patent: 5849691 (1998-12-01), Majer et al.
Hermkens et al. Tetrahedron, vol. 52, No. 13, pp. 4527-4534, Mar. 1996.*
Richter, L. S.; Tom, J. Y. K.; Burnier, J. P. Tet. lett. 1994, 35, pp. 5547-5550 Peptide-Cyclizations on Solid Support: A Fast and Efficient Route to Small Cyclopeptides.
Dutta, A. S. ; Gormley, J. J. ; McLachlan, P. F.; Major, J. S., J. Med. Chem 1990, 33, pp. 2560-2568 Ihnibitors of Human Renin. Cyclic Peptide Analogues Containing a D-PHE-LYS-D-TRP Sequence.
Guiles Joseph W.
Lanter Carolina L.
Rivero Ralph A.
Dow Kenneth J.
Garcia Maurie E.
Ortho-McNeil Pharmaceutical , Inc.
Venkat Jyothsna
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