Azatide peptidomimetics

Details Azatide peptidomimetics Azatide peptidomimetics

1998-09-01

2003-12-16

Baker, Maurie Garcia (Department: 1639)

Chemistry: natural resins or derivatives; peptides or proteins;

Peptides of 3 to 100 amino acid residues

Containing at least one abnormal peptide link, e.g., gamma...

C435S007100, C435S007200, C435S091500, C436S501000, C436S518000, C436S528000, C530S323000, C530S330000, C530S334000, C530S335000, C530S338000

Reexamination Certificate

active

06664372

ABSTRACT:

TECHNICAL FIELD
The present invention relates to compounds that mimic peptides. More particularly, the present invention relates to the synthesis of peptides in which &agr;-carbons of the peptide backbone have been replaced by trivalent nitrogen atoms using either solution phase or liquid phase synthetic methodologies.
BACKGROUND
Peptidomimetics have become immensely important for both organic and medicinal chemists (Spatola et al.
Chemistry and Biochemistry of Amino Acids, Peptides, and Proteins
; Weinstein, B., Ed.; Marcel Dekker: New York, 1983; pp. 267-357; Sherman et al.
J. Am. Chem. Soc
. 1990, 112, 433; Hirschmann et al.
Angew. Chem. Int. Ed. Engl
. 1990, 29, 1278; Gante et al.
Angew. Chem. Int. Ed. Engl
. 1994, 33, 1699). Synthetic interest in these surrogate peptide structures has been driven by the pharmaceutical industry's needs for molecules with improved pharmacokinetic properties (Hodgson et al.
Bio/Technology
1993, 11, 683). Biophysical studies on these pseudopeptides has allowed elucidation of the functional role of the peptide backbone (Marshall et al.
Chemical Recognition in Biological Systems
; Creighton et al. The Chemical Society: London, 1982; p 278; Farmer et al.
Drug Design
; Ariens, E. J., Ed.; Academic Press, New York, 1980, p. 121) and with an ever-increasing level of synthetic sophistication the degree of peptide mimicry within a peptidomimetric can be tailored to chemist's needs. Indeed, the alteration of peptides to peptidomimetics has included peptide side chain manipulations, amino acid extensions (Freidinger et al.
Science
1980, 210, 656; Paruszewski et al.
Rocz. Chem
. 1973, 47, 735; Stachowiak et al.
J. Med. Chem
. 1979, 22, 1128), deletions (Rivier et al. Chemia 1972, 26, 303; Sarantakis et al. Clin. Endocrinol. 1976, 5, 2755), substitutions, and most recently backbone modifications (Hagihara et al.
J. Am. Chem. Soc
. 1992, 114, 6568; Simon et al.
Proc. Natl. Acad. Sci. USA
1992, 89, 9367; Smith et al.
J. Am. Chem. Soc
. 1992, 10 114, 10672; Cho et al.
Science
1993, 261, 1303; Liskamp et al.
Angew. Chem. Int. Ed. Engl
. 1994, 33, 633; Burgess et al.
Angew. Chem. Int. Ed. Engl
. 1995, 34, 907). It is this latter development that has been exploited for the synthesis of biomimetic polymeric structures. Such progress has been fueled by the suggestion that peptidomimetics may provide novel scaffolds for the generation of macromolecules with new properties of both biological and chemical interest.
The most common manipulation involving the &agr;-carbon atom of peptides is the inversion of stereochemistry to yield D-amino acids (Spatola et al.
Chemistry and Biochemistry of Amino Acids, Peptides, and Proteins
; Weinstein, B., Ed.; Marcel Dekker: New York, 1983; pp. 267-357). The importance of this substitution in affording compounds with improved biological potencies, altered conformational properties (Mosberg et al.
Proc. Natl. Acad. Sci. USA
1983, 80, 5871), and increased resistance to enzymatic degradation has been widely recognized and exploited (Dooley et al.
Science
1994, 266, 2019). Replacement of the &agr;-hydrogen of the common amino acids by a methyl group, or by any other substituents (NH
2
CRR′CO
2
H) are both further examples of &agr;-alkyl modification. Azapeptides, however, are peptides in which one (or more) of the &agr;-carbon(s) has been replaced by a trivalent nitrogen atom (
FIG. 5
) (Gante et al.
Synthesis
1989, 405). This transformation results in a loss of asymmetry associated with the &agr;-carbon and yields a structure that can be considered intermediate in configuration between D- and L- amino acids (Aubry et al.
Biopolymers
1989, 28, 109). Interest in this &agr;-carbon replacement unit stems from its ability to provide resistance to enzymatic cleavage and its capacity to act as a selective inhibitor of cysteine (Magrath et al.
J. Med. Chem
. 1992, 35, 4279) and serine proteases (Elmore et al.
Biochem. J
. 1968, 107, 103; Barker et al.
Biochem. J
. 1974, 139, 555; Gray et al. Tetrahedron 1977, 33, 837; Gupton et al.
J. Biol. Chem
. 1984, 259, 4279; Powers et al.
J. Biol. Chem
. 1984, 259, 4288). While the synthesis of azapeptides has been reported (Bentley et al.
J. Chem. Soc
. (C) 1966, 60; Dutta et al. J. Chem. Soc. Perkin Trans 1 1975, 1712; Furr et al.
J. Chem. Soc. Perkin Trans
1 1979, 379; Quibell et al.
J. Chem. Soc. Perkin Trans
1 1993, 2843), the synthesis of a “pure azapeptide”, or what we will term an “azatide” has yet to be accomplished. The earliest attempts to make pure azatides can be dated to Gante and co-workers. (Gante et al.
Chem. Ber
. 1965, 98, 3340; Gante et al.
Proc. Am. Pept. Symp
. 13th. 1993, 1994, 299) However, the methodology that was reported does not allow azatide stepwise chain lengthening in a repetitive manner of anything but hydrazine units.
The utility of azatide compounds has been demonstrated in the treatment of various disorders including cancers, viral infections and cataracts. For example, Moretti et al,
J. Clin. Endocrino. Metab
., 81(11), 3930-3937, 1996, show that azatide compounds are used as LH-releasing hormone agonists to interfere with stimulatory actions of epidermal growth factor in human prostatic cancer cell lines. Jeyarajah et al,
Gynecol. Oncol
., 63(1), 47-52, 1996, use an azatide gonadotropin-releasing hormone analog for treatment of recurrent endometrial cancers. Brower et al,
J. Surg. Res
., 52(1), 6-14, 1992, show differential effects of azatide containing LHRH and somatostatin analogs on human breast cancers. Hellberg et al., PCT Int. Appl. WO 9640107 A1 961219, demonstrate the use of (N,N′-bis(mercaptoacetyl) hydrazine derivatives as anticataract agents. Nakashima et al., EP 672678 A1 950920, show the preparation and use of azapeptide compounds as neurokinin A antagonists. Azatide type compounds have been used as retroviral protease inhibitors, Kempf et al., PCT Int. Appl. WO 9414436 A1 940707, lipoxygenase inhibitors (Atkinson et al Eur. Pat. Appl. EP 146243 A1 850626) and immunosuppressant rapamycin carbamate analogs, Kao et al. U.S. application Ser. No. 5,411,967A 950502.
What is needed is either a solution phase or liquid phase synthetic methodology for synthesizing azatides using monomeric “&agr;-aza-amino acids” which can be coupled in a linear and stepwise chain-lengthening fashion. What are needed are azatides as mimetics for peptides which are are easy to synthesize, more stable and more active than the parent peptides. Moreover, azatide mimetics are needed for stability as compared to various natural peptide products and compounds which possess better bioavailability and exhibit greater activity as compared to known peptides.
SUMMARY OF THE INVENTION
The invention is directed to the azatides and a method for the synthesis of azatide mimetics. In particular, an efficient method has been developed for the solution and liquid phase syntheses of biopolymer mimetics consisting of “&agr;-aza-amino acids” linked in a repetitive manner to form an azatide oligomer. A general synthetic procedure is claimed which provides the use and synthesis of a wide variety of Boc-protected aza-amino acid monomers with optimization of solution phase procedures for the coupling of aza-amino acids in a repetitive manner. In addition, the design and synthesis of a linker is employed that supports azatide synthesis using a liquid phase synthetic format. Oligoazatides can now be rapidly assembled on a homogeneous polymeric support. Using the methodology provides a potential source of new peptidomimetic libraries.
One aspect of the invention is directed to a process for synthesizing an oligoazatide. The process employs a support material with a linker unit attached thereto. The preferred support material is a soluble homopolymer support, e.g., polyethylene glycol monomethyl ether (MeO-PEG). Polyethylene glycol monomethyl ether is soluble in aqueous media but precipitates in ether. Precipitation of the support material with ether can be employed for purifying coupled molecules. Alternative soluble supports having this

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