Combinatorial hydroxy-amino acid amide libraries

Details Combinatorial hydroxy-amino acid amide libraries Combinatorial hydroxy-amino acid amide libraries

1999-06-21

2001-04-17

Ambrose, Michael G. (Department: 1626)

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

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

Reexamination Certificate

active

06218551

ABSTRACT:

TECHNICAL FIELD
This invention relates generally to the synthesis of chemical compounds, and more particularly, to the synthesis of a combinatorial chemical library of hydroxy-amino acid amide compounds.
BACKGROUND OF THE INVENTION
Methods for the synthesis of large numbers of diverse compounds which can be screened for various possible physiological or other activities are of interest (Ellman, et. al.,
Chem. Rev.,
96, 555-600 (1996)). Synthesis techniques have been developed in which individual units are sequentially added to produce all or a substantial number of the possible compounds which can result from all the different choices possible at each sequential stage of the synthesis. For these techniques to be successful, it is necessary for the compounds to be amenable to methods by which one can determine the structure of the compounds so made. Examples of such techniques include, the technique of Brenner and Lerner [
PNAS USA,
81, 5381-83 (1992) and WO 93/20242], according to which oligonucleotides are produced in parallel with, and are chemically linked as genetic tags, to oligopeptides as the compounds of interest. WO 93/06121 teaches methods for the particles-based synthesis of random oligomers wherein identification tags on the particles are used to facilitate identification of the oligomer sequence synthesized. Ohlmeyer, et al.,
Proc. Natl. Acad. Sci. USA,
90, 10922-10926 (December 1993), discloses a detachable tagging system.
SUMMARY OF THE INVENTION
The present invention relates to combinatorial libraries of compounds optionally encoded with tags, and to the use of these libraries in assays to discover biologically active compounds. The present invention further relates to two libraries of compounds containing amino- and carboxy-derivatized, 4-substitued-4-amino-3-hydroxybutyric acid (statine) residues and to the use of these two libraries to identify biologically active members of the libraries by screening bioassays.
I. Preferred Embodiments
The combinatorial chemical library of the present invention is represented by Formula I:
(T′—L&Parenclosest;
8
Ŝ—C(O)—L′—Z  I
wherein:
Ŝ is a solid support;
T′—L— is an identifier residue;
—L′—Z is a linker/compound residue;
q is 0-30; and
—Z is
wherein:
R
1
is chosen from the group consisting of H, alkyl, cycloalkyl, and substituted alkyl; and
R
2
is —C(O)CH
2
CH(OH)CH(R
3
)NH—
wherein:
R
3
is chosen from the group consisting of H, alkyl, aryl, arylalkyl and heteroarylalkyl; and
Y is —C(O)R
4
, -Aa-C(O)R
4
, or —C(O)R
5
;
wherein:
R
4
is chosen from the group consisting of alkyl, aryl, heteroaryl, substituted alkyl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl and substituted heterocycloalkyl;
Aa is an amino acid;
R
5
is
wherein:
x is 0 or 1;
R
6
and R
7
are each independently chosen from the group consisting of H, akyl, substituted alkyl, alkylcarbonyl, substituted alkylcarbonyl and C(O)R
4
; and
R
8
is alkyl or arylalkyl.
Preferred libraries of Formula I are those wherein T′—L— is of Formula II
wherein:
n is 3-12;
Ar is halophenyl; and
q is 3-12.
More-preferred libraries of Formula I are those wherein T′—L— is of Formula II and n is 3-12 and Ar is a pentachlorophenyl or, n is 3-6 and Ar is 2,4,6-trichlorophenyl.
Other preferred libraries of Formula I are those wherein —L′— is of Formula (a)
wherein the left-hand bond is the point of attachment to —C(O)— and the right-hand bond is the point of attachment to —Z.
Depending on the choice of —L′— (see Table 1), the compounds or ligands —Z of Formula I may be detached by photolytic, oxidative, acidic, basic, or other cleavage techniques. For example, when —L′— is of Formula (a), photolytic cleavage of compounds of Formula I may be represented by:
wherein —L″ is the residue from —L′— and H—Z is of Formula III:
HN(R
1
)C(O)CH
2
CH(OH)CH(R
3
)NH—Y  III
A preferred embodiment of the invention is a library of Formula I wherein:
R
1
is chosen from the 7 residues of the amines of Table 2-1;
R
2
is chosen from the 3 residues of the hydroxy amino acids of Table 2-2;
Y is -Aa-C(O)R
4
;
Aa is chosen from the 31 residues of the amino acids of Table 2-3; and
R
4
is chosen from the 20 residues of the carboxylic acids of Table 2-4.
Another preferred embodiment of the invention is a library of Formula I wherein:
R
1
is chosen from the 7 residues of the amines of Table 2-1;
R
2
is chosen from the 3 residues of the hydroxy amino acids of Table 2-2;
Y is —C(O)R
5
;
R
5
is chosen from the 3 residues of the diamino acids in Table 3-1;
R
6
is chosen from the 15 residues of the aldehydes and carboxylic acids of Table 3-2; and
R
7
is chosen from the 20 residues of the carboxylic acids of Table 3-3.
One aspect of the invention is the use of the combinatorial chemical library of Formula I in assays to discover biologically active compounds or ligands of Formula III. Thus, another aspect of the invention is a method of identifying a compound having a desired characteristic which comprises synthesizing a combinatorial chemical library of Formula I and testing the library compounds of Formula I, either attached to or detached from, the solid supports, in an assay which identifies compounds of Formula III having the desired characteristic. Thus, another aspect of the invention is a method of identifying a compound having a desired characteristic which comprises testing a library of compounds of Formula I, either attached to, or detached from, the solid support, in an assay which identifies compounds of Formula III having the desired characteristic. A further aspect of the invention is determining the structure of any compound so identified.
It is within the scope of the present invention that the chemical structures of compounds identified as having a desired characteristic can be determined by either decoding the tags (T, or T′—L— of Formula 1) or by deconvolution of the library. [See Smith et al.,
BioMed. Chem. Lett.,
4, 2821 (1994); Kurth et al.,
J. Org. Chem.,
59, 5862 (1994); Murphy et al.,
J. Am. Chem. Soc.,
117, 7029 (1995); Campell et al.,
J. Am. Chem. Soc.,
118, 5381 (1995); and Erb et al.,
Proc. Natl. Acad. Sci. USA,
91, 11422 (1994), the disclosures of which are incorporated herein by reference.].
When q is 0, the resultant untagged libraries are of Formula I′:
Ŝ—C(O)—L′—Z  I′
wherein each of the symbols is defined as in Formula I.
Another embodiment of the invention is a method of synthesizing a combinatorial chemical library of Formula Ia
Ŝ—C(O)—L′—N(R
1
)C(O)CH
2
CH(OH)CH(R
3
)NH—Y  Ia
which comprises reacting a compound of Formula IV
Ŝ—(O)—L′—N(R
1
)C(O)CH
2
CH(OH)CH(R
3
)NH
2
  IV
with a carboxylic acid, dissolved in a suitable solvent such as dimethylformamide, at a concentration of 0.05M to 0.01M (high dilution), at 25° C., in the presence of DIEA and a suitable coupling reagent, such as HATU.
Another embodiment of the invention is a combinatorial chemical library of Formula IV, IVa, IVb, IVc, IVd or IVe.
 Ŝ—C(O)—L′—N(R
1
)C(O)CH
2
CH(OH)CH(R
3
)NH
2
  IV
(S)—C(O)L′N(R
1
)C(O)CH
2
CH(OH)CH(R
3
)NH-Aa-H  IVa
wherein x is 0 or 1. This library of compounds is additionally useful as chemical intermediates in the preparation of sub-libraries within the combinatorial libraries of Formula I and I′.
Thus, another embodiment of the present invention is a combinatorial chemical library of Formula IVX
Ŝ—C(O)—L′—N(R
1
)C(O)CH
2
CH(OH)CH(R
3
)NH-R
15
  IVX
wherein
R
15
is
Another aspect of the invention is a method of synthesizing a combinatorial chemical library of Formula IVd or IVe which comprises reacting a compound of Formula V or VI
with a catalytic amount of palladium tetrakistriphenylphosphine or other palladium zero (Pd
0
) catalysts in the presence of tributyltin hydride in acetic acid and methylene chloride at room temperature for about 1 hour.
Another embodiment of the inventi

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