Oligomers and polymers of cyclic imino carboxylic acids

Details Oligomers and polymers of cyclic imino carboxylic acids Oligomers and polymers of cyclic imino carboxylic acids

2000-06-13

2004-04-27

Baker, Maurie Garcia (Department: 1639)

Organic compounds -- part of the class 532-570 series

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

C548S518000, C548S530000, C548S537000, C548S539000

Reexamination Certificate

active

06727368

ABSTRACT:

FIELD OF THE INVENTION
The present invention is directed to unnatural polypeptide-like molecules which are oligomers or polymers of constrained imino carboxylic acids, methods of generating combinatorial libraries using these residues, and combinatorial libraries formed thereby.
DESCRIPTION OF THE PRIOR ART
Chemists have long sought to extrapolate the power of biological catalysis and recognition to synthetic systems. These efforts have focused largely on low molecular weight catalysts and receptors. Most biological systems, however, rely almost exclusively on large polymers such as proteins and RNA to perform complex chemical functions.
Proteins and RNA are unique in their ability to adopt compact, well-ordered conformations. These two biopolymers are unique also because they can perform complex chemical operations (e.g., catalysis, highly selective recognition, etc.). Folding is linked to function in both proteins and RNA because the creation of an “active site” requires proper positioning of reactive groups. Consequently, there has been a long-felt need to identify synthetic polymer backbones which display discrete and predictable folding propensities (hereinafter referred to as “foldamers”) to mimic natural biological systems. Such backbones will provide molecular “tools” to probe the functionality of large-molecule interactions (e.g. protein-protein and protein-RNA interactions).
Much work on &bgr;-amino acids and peptides synthesized therefrom has been performed by a group led by Dieter Seebach in Zurich, Switzerland. See, for example, Seebach et al. (1996)
Helv. Chim. Acta
. 79:913-941; and Seebach et al. (1996)
Helv. Chim. Acta
. 79:2043-2066. In the first of these two papers Seebach et al. describe the synthesis and characterization of a &bgr;-hexapeptide, namely (H-&bgr;-HVal-&bgr;-HAla-&bgr;-HLeu)
2
—OH. Interestingly, this paper specifically notes that prior art reports on the structure of &bgr;-peptides have been contradictory and “partially controversial.” In the second paper, Seebach et al. explore the secondary structure of the above-noted &bgr;-hexapeptide and the effects of residue variation on the secondary structure.
Dado and Gellman (1994)
J. Am. Chem. Soc
. 116:1054-1062 describe intramolecular hydrogen bonding in derivatives of &bgr;-alanine and &ggr;-amino butyric acid. This paper postulates that &bgr;-peptides will fold in manners similar to &agr;-amino acid polymers if intramolecular hydrogen bonding between nearest neighbor amide groups on the polymer backbone is not favored.
Suhara et al. (1996)
Tetrahedron Lett
. 37(10): 1575-1578 report a polysaccharide analog of a &bgr;-peptide in which D-glycocylamine derivatives are linked to each other via a C-1 &bgr;-carboxylate and a C-2 &agr;-amino group. This class of compounds has been given the trivial name “carbopeptoids.”
Regarding methods to generate combinatorial libraries, several recent reviews are available. See, for instance, Ellman (1996)
Acc. Chem. Res
. 29:132-143 and Lam et al. (1997)
Chem. Rev
. 97:411-448.
SUMMARY OF THE INVENTION
The present invention is drawn to a genus of oligomers and polymers of conformationally-restricted imino carboxylic acids. The preferred oligomers and polymers of the invention strongly favor a discrete secondary structure (although this is not a requirement of the invention). These stable secondary structures include helices analogous to the well-known poly(proline) II helical structure seen in &agr;-amino acids.
More specifically, the invention is directed to compounds of the formula: comprising formula:
X—{A}
n
—Y
wherein n is an integer greater than 1; and
each A, independent of every other A, is selected from the group consisting of:
wherein R
1
, R
2
, and R
5
are independently selected from the group consisting of hydrogen, linear or branched C
1
-C
6
-alkyl, alkenyl, or alkynyl; mono-or di-C
1
-C
6
alkylamino, mono- or bicyclic aryl, mono- or bicyclic heteroaryl having up to 5 heteroatoms selected from N, O, and S; mono- or bicyclic aryl-C
1
-C
6
-alkyl, mono- or bicyclic heteroaryl-C
1
-C
6
-alkyl, —(CH
2
)
1-6
—OR
3
, —(CH
2
)
1-6
—SR
3
, —(CH
2
)
1-6
—S(═O)—CH
2
—R
3
, —(CH
2
)
1-6
—S(═O)
2
—CH
2
—R
3
, —(CH
2
)
1-6
—NR
3
R
3
, —(CH
2
)
1-6
—NHC(═O)R
3
, —(CH
2
)
1-6
—NHS(═O)
2
—CH
2
—R
3
, —(CH
2
)
1-6
—O—(CH
2
)
2-6
—R
4
, —(CH
2
)
1-6
—S—(CH
2
)
2-6
—R
4
, —(CH
2
)
1-6
—S(═O)—(CH
2
)
2-6
—R
4
, —(CH
2
)
1-6
—S(═O)
2
—(CH
2
)
2-6
—R
4
, —(CH
2
)
1-6
—S(═O)
2
—(CH
2
)
2-6
—R
4
, —(CH
2
)
1-6
—NH—(CH
2
)
2-6
—R
4
, —(CH
2
)
1-6
—N—{(CH
2
)
2-6
—R
4
}
2
, —(CH
2
)
1-6
—NHC(═O)—(CH
2
)
2-6
—R
4
, and —(CH
2
)
1-6
—NHS(═O)
2
—(CH
2
)
2-6
—R
4
; wherein
R
3
is independently selected from the group consisting of hydrogen, C
1
-C
6
-alkyl, alkenyl, or alkynyl; mono- or bicyclic aryl, mono- or bicyclic heteraryl having up to 5 heteroatoms selected from N, O, and S; mono- or bicyclic aryl-C
1
-C
6
-alkyl, mono- or bicyclic heteroaryl-C
1
-C
6
-alkyl; and
R
4
is selected from the group consisting of hydroxy, C
1
-C
6
-alkyloxy, aryloxy, heteroaryloxy, thio, C
1
-C
6
-alkylthio, C
1
-C
6
-alkylsulfinyl, C
1
-C
6
-alkylsulfonyl, arylthio, arylsulfinyl, arylsulfonyl, heteroarylthio, heteroarylsulfinyl, heteroarylsulfonyl, amino, mono- or di-C
1
-C
6
-alkylamino, mono- or diarylamino, mono- or diheteroarylamino, N-alkyl-N-arylamino, N-alkyl-N-heteroarylamino, N-aryl-N-heteroarylamino, aryl-C
1
-C
6
-alkylamino, carboxylic acid, carboxamide, mono- or di-C
1
-C
6
-alkylcarboxamide, mono- or diarylcarboxamide, mono- or diheteroarylcarboxamide, N-alkyl-N-arylcarboxamide, N-alkyl-N-heteroarylcarboxamide, N-aryl-N-heteroarylcarboxamide, sulfonic acid, sulfonamide, mono- or di-C
1
-C
6
-alkylsulfonamide, mono- or diarylsulfonamide, mono- or diheteroarylsulfonamide, N-alkyl-N-arylsulfonamide, N-alkyl-N-heteroarylsulfonamide, N-aryl-N-heteroarylsulfonamide, urea; mono- di- or tri-substituted urea, wherein the subsitutent(s) is selected from the group consisting of C
1
-C
6
-alkyl, aryl, heteroaryl; O-alkylurethane, O-arylurethane, and O-heteroarylurethane;
R
6
is selected from the group consisting of hydrogen, linear or branched C
1
-C
6
-alkyl, alkenyl, or alkynyl; mono-or di-C
1
-C
6
alkylamino, mono- or bicyclic aryl, mono- or bicyclic heteroaryl having up to 5 heteroatoms selected from N, O, and S; mono- or bicyclic aryl-C
1
-C
6
-alkyl, mono- or bicyclic heteroaryl-C
1
-C
6
-alkyl, —S(═O)
2
—(CH
2
)
1-6
—R
3
, —C(═O)R
3
, —S(═O)
2
—(CH
2
)
2-6
R
4
, and —C(═O)—(CH
2)
1-6
—R
4
;
wherein R
3
and R
4
are as defined above;
R
7
and R
8
are selected from the group listed above for R
1
, R
2
and R
5
, and are further selected from the group consisting of hydroxy, C
1
-C
6
-alkyloxy, aryloxy, heteroaryloxy, thio, C
1
-C
6
-alkylthio, C
1
-C
6
-alkylsulfinyl, C
1
-C
6
-alkylsulfonyl, arylthio, arylsulfinyl, arylsulfonyl, heteroarylthio, heteroarylsulfinyl, heteroarylsulfonyl, amino, mono- or di-C
1
-C
6
-alkylamino, mono- or diarylamino, mono- or diheteroarylamino, N-alkyl-N-arylamino, N-alkyl-N-heteroarylamino, N-aryl-N-heteroarylamino, aryl-C
1
-C
6
-alkylamino, carboxylic acid, carboxamide, mono- or di-C
1
-C
6
-alkylcarboxamide, mono- or diarylcarboxamide, mono- or diheteroarylcarboxamide, N-alkyl-N-arylcarboxamide, N-alkyl-N-heteroarylcarboxamide, N-aryl-N-heteroarylcarboxamide, sulfonic acid, sulfonamide, mono- or di-C
1
-C
6
-alkylsulfonamide, mono- or diarylsulfonamide, mono- or diheteroarylsulfonamide, N-alkyl-N-arylsulfonamide, N-alkyl-N-heteroarylsulfonamide, N-aryl-N-heteroarylsulfonamide, urea; mono- di- or tri-substituted urea, wherein the subsitutent(s) is selected from the group consisting of C
1
-C
6
-alkyl, aryl, heteroaryl; O-alkylurethane, O-arylurethane, and O-heteroarylurethane
one of X or Y is hydrogen or an amino-terminal capping group (such as formyl, acetyl, tBoc, Fmoc, etc.);
the other of X or Y is hydroxy or a carboxy-terminal capping group (such as NH2, NH(alkyl), N(alkyl)
2
, etc.);
and salts thereof.
As noted above, each “A” substituent is select

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