Combinatorial library of substituted statine esters and...

Details Combinatorial library of substituted statine esters and... Combinatorial library of substituted statine esters and...

1998-05-15

2001-07-03

Celsa, Bennett (Department: 1627)

Chemistry: analytical and immunological testing

Involving an insoluble carrier for immobilizing immunochemicals

C436S523000, C436S524000, C435S007100, C435S091500, C435S091500, C435S091500, C435S091500, C544S390000, C544S400000, C564S193000, C546S343000, C546S348000

Reexamination Certificate

active

06255120

ABSTRACT:

FIELD OF THE INVENTION
This invention relates generally to the synthesis of chemical compounds, and more particularly, to the synthesis of a combinatorial library of hydroxyamides.
BACKGROUND OF THE INVENTION
Methods for the synthesis of large numbers of diverse compounds that can be screened for various possible physiological or other activities are advantageous (Ellman, et al.
Chem. Rev.
96, 555-600 (1996)). Techniques have been developed in which individual units are added sequentially as part of the chemical synthesis 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. Many diverse compounds are produced by a series of reactions of a multiplicity of synthons in various combinations. Each compound in a combinatorial library results from the reaction of a subset of synthons. For these techniques to be successful, the compounds should be amenable to methods by which one can determine the structure of the compounds so made. A premier example of such techniques is the production of oligonucleotide “tags” in parallel with oligopeptide compounds of interest (Brenner and Lerner
Proc. Natl. Acad. Sci. USA
81, 5381-83 (1992) and WO 93/20242). Methods for particle-based synthesis of random oligomers wherein identification tags on the particles are used to facilitate identification of the synthesized oligomer sequence are known (WO 93/06121). A detachable tagging system that is useful in sequential synthesis of large numbers of compounds has been disclosed (Ohlmeyer et al.,
Proc. Natl. Acad. Sci. USA,
90, 10922-10926 (1993)).
SUMMARY OF THE INVENTION
The present invention relates to a combinatorial library of hydroxyamides optionally encoded with tags. The present invention also relates to the use of this library in assays to discover biologically active compounds.
In one aspect, the invention relates to a combinatorial chemical library for biological assay comprising a plurality of members of Formula I:
(T′-L)
q
—[S]—C(O)—L′-Z   I
wherein:
T′ is a tag;
L is a first linker;
T′-L- together form an identifier residue;
q is 0-30;
[S] is a solid support;
-L′ is a second linker;
-Z is a compound of formula:
wherein:
R
1
is chosen from the group consisting of alkyl, aralkyl, aryl, —(CH
2
)
n
—NHC(O)R
5
and —(CH
2
)
n
-cycloalkyl; where n=1-4;
R
2
is chosen from the group consisting of alkyl, aralkyl, aryl, aryloxyalkyl, cycloalkyl, —(CH
2
)
n
-cycloalkyl, heteroaryl, —CH(R
6
)OC(O)NHR
5
,
wherein m=0-3; or R
2
is the descarboxy residue of an N-capped-&agr;-amino acid;
Y is —NR
3
R
4
or —OR
9
;
R
3
and R
4
are independently selected from the group consisting of H, alkyl, aralkyl, heteroarylalkyl, heterocycloalkyl, —CH(R
5
)CH(R
6
)OH, —CH(R
5
)C(O)NHR
6
and —CH(R
5
)C(O)NHCH(R
6
)C(O)NHR
7
; or
R
3
and R
4
together are
wherein X=O or NR
8
;
R
5
are independently selected from the group consisting of alkyl, aralkyl and aryl;
R
6
is H, lower alkyl, aryl or aralkyl;
R
7
is H or alkyl;
R
8
is chosen from the group consisting of H, R
5
, C(O)R
5
, C(O)OR
5
and —SO
2
R
5
; and
R
9
is alkyl, aryl, aralkyl or R
7
CH═CH(CH
2
)
{overscore (n)}
.
The invention further relates to methods of synthesizing a library comprising a plurality of members of Formula I.
Another aspect of the invention is the use of the herein described combinatorial library in assays to discover biologically active compounds of Formula III:
Thus, another aspect of the invention is a method for identifying a compound having a desired characteristic, which comprises testing a combinatorial library comprising a plurality of members of Formula I, either attached to or detached from the solid supports, in a biological assay which identifies compounds of Formula III having the desired characteristics.
DETAILED DESCRIPTION OF THE INVENTION
Abbreviations and Definitions
The following abbreviations and terms have the indicated meanings throughout:
Ac=acetyl
AFC=7-aminotrifluoromethyl coumarin
allyl=—CH
2
CH═CH
2
AMC=7-amino-4-methyl coumarin
ANP=atrial natriuretic peptide
BNB=4-bromomethyl-3-nitrobenzoic acid
BSA=bovine serum albumin
BOC=t-butyloxy carbonyl
Bu=butyl
c—=cyclo
CCD=charge-coupled device
Cdk-4=Cyclin-dependent kinase-4
DABCYL=4-(4-dimethylaminophenylazo)benzoic acid
Dansyl=5-(dimethylamino)-1-naphthalenesulfonyl
DBU=Diazabicyclo[5,4,0]undec-7-ene
DCM=Dichloromethane=methylene chloride=CH
2
Cl
2
DIC=diisopropylcarbodiimide
DIEA=diisopropylethyl amine
DMAP=4-N,N-dimethylaminopyridine
DMF=N,N-dimethylformamide
DMSO=Dimethyl sulfoxide
DNA=deoxyribonucleic acid
DVB=1,4-divinylbenzene
EDANS=5-[(2-aminoethyl)amino]naphthalene-1-sulfonic acid
EtOAc=Ethyl acetate
FACS=fluorescence activated cell sorting
Fmoc=9-fluorenylmethoxycarbonyl
GC=gas chromatography
HFC=4-trifluoromethylumbelliferyl
HIV=Human immunodeficiency virus
HOAc=acetic acid
HOBt=hydroxybenzotriazole
hr=hour(s)
IBX=iodoxybenzoic acid
IL=interleukin
in vacuo=under vacuum
m—=meta
MAP=microtubule-associated proteins
Me=methyl
MeOH=methanol
MNA=4-methoxy-2-naphthylamine
NAD=nicotinamide adenine dinucleotide
NADH=nicotinamide adenine dinucleotide, reduced form
NADP=nicotinamide adenine dinucleotide phosphate
NADPH=nicotinamide adenine dinucleotide phosphate, reduced form
NBD=7-nitrobenz-2-oxa-1,3-diazol-4-yl
PEG=polyethylene glycol
PfP=pentafluorophenyl
Ph=phenyl
PhOH=phenol
PKA=Protein kinase A
pyr=pyridine
RNA=Ribonucleic acid
r.t.=room temperature
SAR=structure activity relationship
sat'd=saturated
s—=secondary
SPA™=scintillation proximity assay
t—=tertiary
TBS=tert-butyldimethylsilyl
TEA=triethylamine
TFA=trifluoroacetic acid
THF=tetrahydrofuran
TMS=trimethylsilyl
Tris=tris(hydroxymethyl)aminomethane
Tween 20=polyoxyethylenesorbitan monolaurate
U=unit
UV=ultraviolet light
v=volume
wt=weight
“Acylamino” means acylamino groups of from 1 to 8 carbon atoms of a straight, branched or cyclic configuration and combinations thereof. Examples of acylamino groups include: acetylamino, butyrylamino, cyclohexylcarbonylamino, and the like.
“Alkenyl” is C
2
-C
8
alkenyl group of a linear, branched, or cyclic (C
5
-C
6
) configuration and combinations thereof. Examples of alkenyl groups include: vinyl, allyl, isopropenyl, pentenyl, hexenyl, c-hexenyl, 1-propenyl, 2-butenyl, 2-methyl-2-butenyl, and the like.
“Alkoxy” means alkoxy groups of from 1 to 8 carbon atoms of a straight, branched, cyclic configuration and combinations thereof. Examples of alkoxy groups include: methoxy, ethoxy, propoxy, isopropoxy, cyclopropyloxy, cyclohexyloxy and the like.
“Alkyl” is intended to include linear or branched hydrocarbon structures and combinations thereof.
“Aralkyl” means an alkyl containing an aryl ring. For example: benzyl, phenethyl, 4-chlorobenzyl, 2,2-diphenylethyl and the like.
“Aryl” is a 6-membered or 10-membered aromatic ring system where each of the rings is optionally substituted with 1-3 substituents selected from alkyl, halogen, hydroxy, alkoxy, aryloxy, haloalkyl, phenyl and heteroaryl; and wherein the phenyl ring is optionally substituted with 1-3 substituents selected from alkyl, halogen or alkoxy. Examples of aryl groups are phenyl, 3,4-dichlorophenyl, biphenyl and naphthyl.
“Aryloxy” means a phenoxy or naphthyloxy group where the phenyl or naphthyl ring is optionally substituted with 1 to 2 groups selected from halo, alkoxy or alkyl.
“Aryloxyalkyl” means an alkyl containing a phenoxy or naphthyloxy group.
“Carboxyalkyl” means —C

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