Process for preparing combinatorial amide alcohol libraries

Details Process for preparing combinatorial amide alcohol libraries Process for preparing combinatorial amide alcohol libraries

1999-06-18

2001-07-24

Venkat, Jyothsna (Department: 1618)

Chemistry: analytical and immunological testing

Involving an insoluble carrier for immobilizing immunochemicals

C435S007100, C435S007200, C435S091500, C436S501000, C544S058400, C544S162000, C544S363000, C544S295000, C544S377000, C546S086000, C546S087000, C546S168000, C546S245000, C548S530000

Reexamination Certificate

active

06265228

ABSTRACT:

TECHNICAL FIELD
This invention relates generally to the synthesis of chemical compounds, and more particularly, to the synthesis of combinatorial libraries of amide alcohols.
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)). 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. 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 oligopeptides; the oligonucleotides function as genetic tags and are chemically linked to the oligopeptides, which are the compounds of interest. WO 93/06121 teaches methods for 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, 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 also relates to seven libraries of compounds containing hydroxy amides amides and the use of the libraries to identify biologically active members by screening bioassays.
In one aspect, the invention relates to a combinatorial chemical library comprising a plurality of members of the Formula I:
(T′—L)
q
—[S]—C(O)—L′—Z  I
or
[S]—C(O)—L′—Z  I′
wherein:
[S] is a solid support;
T′—L— is an identifier residue;
—L′—Z is a linker/compound residue;
q is zero (formula I′) or 1-30;
Z is
R
1
is C
1
to C
20
hydrocarbon, substituted aryl, substituted aralkyl or (CH
2
)
n
NHC(O)R
3
;
R
2
is C
1
to C
20
hydrocarbon, substituted alkyl, substituted aryl, heteroaryl, aryloxyalkyl, alkoxyalkyl, or —CH(R
4
)OC(O)NHR
3
;
R
3
is C
1
to C
20
hydrocarbon or substituted aryl;
R
4
and R
5
are independently lower alkyl or aryl;
n is 1-4;
Y is chosen from —P(O)(OR
6
)(OR
7
), —CH(OH)—COR
8
, —CH
2
CH═CH
2
, —CH
2
CH(OH)CH
2
OH, —CH
2
CHO, —CH
2
CH
2
OH, —CH
2
CH
2
OC(O)NHR
26
, —CH
2
CH
2
NR
27
R
28
, and
R
6
and R
7
are independently C
1
to C
20
hydrocarbon or —(CH
2
)
n
R
9
, or, when R
6
and R
7
are methylene radicals, they may fuse to form a ring;
R
8
is chosen from —NHR
10
, —N(lower alkyl)R
10
—NH(CH
2
), R
11
, —NHCH(R
12
)C(OH)(R
13
)(R
14
), —NHCH(R
15
)C(O)R
16
,
X is chosen from CH
2
, O, S, NC(O)O-alkyl, NC(O)-aralkyl, NC(O)-aryl, NC(O)-heteroaryl,
R
9
is chosen from halogen, perfluoroalkyl, and aryl;
R
10
is chosen from C
1
to C
20
hydrocarbon,
R
11
is chosen from substituted alkyl, heteroaryl, heterocycloalkyl, —O(CH
2
)
n
OH, —NR
5
alkyl, aryl-SO
2
NH
2
, —CH
2
NHSO
2
-aryl, and
R
12
is chosen from hydrogen, C
1
to C
20
hydrocarbon, substituted alkyl, —C(C)OH
2
, —C(O)NH-alkyl, —C(O)NH-aryl, and —C(O)NH-aralkyl;
R
13
and R
14
are independently H, alkyl, or aryl;
R
15
is chosen from hydrogen and C
1
to C
20
hydrocarbon;
R
16
is chosen from —NHalkyl and —NHCHR
24
CONHR
25
;
R
17
, R
18
, R
20
, R
21
are independently H, alkyl, halo, or alkoxy;
R
19
is chosen from H, —(CH
2
)
n
OH, —(CH
2
)
n
OMe, and CONHR
23
;
R
22
is chosen from H and OH;
R
23
is chosen from H, C
1
to C
20
hydrocarbon and substituted aryl;
R
24
and R
25
are H or C
1
to C
20
hydrocarbon;
R
26
is chosen from H, lower alkyl, aralkyl and aryl;
R
27
is chosen from H, alkyl, CH
2
(CH
2
)
n
-alkoxy, arylalkyl, heteroarylalkyl
R
28
is chosen from H, —C(O)R
29
, —SO
2
R
30
, —C(O)NH
30
alkyl, arlalkyl, and heteroarylalkyl;
or together —NR
27
R
28
form a nitrogenous heterocycle chosen from: piperidine, 3 substituted-piperidine, 4-substituted-piperidine, 4-substituted-piperazine, morpholine, pyrrolidine, 2-substituted-pyrrolidine, tetrahydroisoquinoline and substituted tetrahydroisoquinoline;
R
29
is chosen from alkyl, arylalkyl, heteroarylalkyl, aryl, heteroaryl and —CH
2
O-aryl; and
R
30
is chosen from alkyl, arylakyl and aryl.
Preferred libraries of Formula I are those wherein T′—L— is of the Formula
wherein:
n=3-12;
Ar is halophenyl; and
q=1-12.
More preferred libraries of Formula I are those wherein T′—L— is of the Formula II and n is 3-12 and Ar is a pentachlorophenyl.
Other preferred libraries of Formula I are those wherein —L′— is
such that the left-hand bond as shown is the point of attachment to —C(O)— the 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 a residue of formula (a), photolytic cleavage may be represented by:
wherein L″ is the residue from L′ and the genus H—Z may be represented by Formula III:
A preferred embodiment of the invention is a library comprising members of Formula I wherein R
1
is selected from the 15 residues of the amines of Table 2-1; R
2
is selected from the 31 residues of the acids of Table 2-2; and Y is P(O)(OR
6
)(OR
7
), as selected from the 7 phosphinate residues of Table 2-3.
Another preferred embodiment of the invention is a library comprising members of Formula I wherein R
1
and R
2
are selected as above from Tables 2-1 and 2-2; Y is —CH(OH)—COR
8
; and R
8
is selected from the residues of the amines in Table 2-4.
Other preferred embodiments of the invention are libraries comprising members of Formula I wherein R
1
and R
2
are selected as above from Tables 2-1 and 2-2 and Y is one of —CH—CH═CH
2
, —CH
2
CH(OH)CH
2
OH, —CH
2
CHO, and —CH
2
CH
2
OH.
Another preferred embodiment of the invention is a library comprising members of Formula I wherein R
1
and R
2
are selected as above from Tables 2-1 and 2-2, Y is —CH
2
CH
2
OC(O)NHR
26
and R
26
is lower alkyl or phenyl.
Another preferred embodiment of the invention is a library comprising members of Formula I wherein R
1
and R
2
are selected as above from Tables 2-1 and 2-2; Y is —CH
2
CH
2
NR
27
R
28
; R
27
is chosen from the residues of Table 2-7; an R
28
is chosen from the residues of Tables 2-9 to 2-11.
Another preferred embodiment of the invention is a library comprising members of Formula I wherein R
1
and R
2
are selected as above from Tables 2-1 and 2-2,Y is —CH
2
CH
2
NR
27
R
28
and together —NR
27
R
28
form a nitrogenous heterocycle chosen from the residues of Table 2-8.
Another aspect of the invention is the use of the combinatorial library described above in assays to discovery 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 library of Formula I and testing the library 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. 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 chemical structures of compounds identified as having a desired characteristic can be determined by either decoding the tags (T, T′—L— of Formula I) or by deconvolution of the library (Smith et al.,
Bio Med. Chem. Lett.,
4, 2821 (1994); Kurth et al.,
J. Org. Ch

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