Ethylenediamine compound libraries

Details Ethylenediamine compound libraries Ethylenediamine compound libraries

1998-08-21

2001-11-13

Venkat, Jyothsna (Department: 1627)

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

Organic compounds

Nitrogen attached directly or indirectly to the purine ring...

C544S242000, C544S372000, C544S384000, C544S406000, C546S245000, C546S246000, C548S531000, C435S007100, C435S091500, C435S091500, C435S091500, C435S091500, C435S091500, C435S091500, C435S091500, C435S091500, C435S091500, C435S091500, C435S091500, C436S518000, C436S536000

Reexamination Certificate

active

06316623

ABSTRACT:

FIELD OF THE INVENTION
The present invention relates to diverse combinatorial libraries, processes and apparatus, in particular to diverse libraries of compounds incorporating ethylenediamine scaffolds.
BACKGROUND OF THE INVENTION
Discovery of new therapeutic compounds for treating diseases has typically involved screening individual compounds against targets representative of a particular disease of interest. The iterative process relies upon finding a compound having at least a minimal level of activity in an assay and then synthesizing as many derivatives of the lead compound as possible. The derivatives tested would form the basis of a “structure-activity relationship” (SAR) which would hopefully provide insight for designing a lead compound. Often the process is repeated time and again before any lead is uncovered. The obvious and major drawback in this drug discovery process is the generation of compounds on a one-at-a-time basis requiring much labor, time and expense.
Advances in robotics and solid-phase chemical synthesis has spawned the combinatorial approach for preparing libraries of compounds which makes synthesizing thousands of diverse compounds feasible. What once took months or even years by the traditional approach has become possible in a matter of weeks and even days through combinatorial chemistry, thereby drastically reducing the time, labor and expense involved in drug discovery.
The combinatorial approach has been adapted for preparing vast libraries of oligomeric compounds such as peptides and non-oligomeric small organic molecules on the order of 10
2
to 10
6
discreet compounds. Theoretically the total number of compounds in a library is limited only by the number of available reagents for forming substituents on a central scaffold.
SUMMARY OF THE INVENTION
In accordance with an aspect of the present invention there is provided a combinatorial library comprising a plurality of ethylenediamine compounds of formula (I):
wherein:
m is 0 or 1;
n is 0 or 1;
o is 1, 2 or 3 provided that m+n+o is 2 or 3;
p is 0, 1, 2 or 3;
R
1
and R
2
are independently H or a hydrocarbyl group selected from C
1
-C
10
alkyl, C
2
-C
10
alkenyl, C
2
-C
20
alkynyl, C
6
-C
14
aryl, C
6
-C
14
aralkyl, C
3
-C
14
cycloalkyl, C
5
-C
14
fused cycloalkyl, C
4
-C
14
heterocyclyl, C
4
-C
14
heterocycloalkyl, C
4
-C
14
heteroaryl, C
4
-C
14
heteroarylalkyl, and CH(R
2
)—NH—R
2
; wherein said hydrocarbyl group is optionally substituted with acyl, alkoxy, alkoxycarbonyl, alkyl, alkenyl, alkynyl, amino, amido, azido, aryl, heteroaryl, carboxylic acid, cyano, guanidino, halo, haloalkyl, haloalkoxy, hydrazino, hydroxyl, alkylsulfonyl, nitro, sulfide, sulfone, sulfonate, sulfonamide, thiol or thioalkoxy;
R
3
, R
4
and R
5
are independently H; an amino protecting group; or CH
2
, CH(R
2
), C═O, C═S, S(═O)
2
, C(═O)NH, C(═S)NH or C(═O)O substituted with H or a hydrocarbyl group selected from C
1
-C
10
alkyl, C
2
-C
10
alkenyl, C
2
-C
20
alkynyl, C
6
-C
14
aryl, C
6
-C
14
aralkyl, C
3
-C
14
cycloalkyl, C
5
-C
14
fused cycloalkyl, C
4
-C
14
heterocycle, C
4
-C
14
heterocyclylalkyl, C
4
-C
14
heteroaryl, C
4
-C
14
heteroarylalkyl or CH(R
2
)—NH—R
2
; wherein said hydrocarbyl group is optionally substituted with oxo, acyl, alkoxy, alkoxycarbonyl, alkyl, alkenyl, alkynyl, amino, amido, azido, aryl, heteroaryl, carboxylic acid, cyano, guanidino, halo, haloalkyl, haloalkoxy, hydrazino, hydroxyl, alkylsulfonyl, nitro, sulfide, sulfone, sulfonate, sulfonamide, thiol, and thioalkoxy; and
R
6
is H or —R
x
—R
y
wherein R
x
is a linker and R
y
is a solid support.
Another aspect of the present invention, there is provided a process for preparing support bound-compounds of formula (X):
wherein R
6
is a solid support, comprising:
attaching an ethylenediamine scaffold of the formula (II)
wherein Pg is an amino protecting group to a solid support via a free amino group to form a support-bound scaffold of formula (III)
reacting the amino group of formula (III) bound to support R
6
with an R
3
-building block to give a support-bound scaffold of formula (IV):
reacting the scaffold of formula (IV) with a heterocyclic alcohol of formula (V):
wherein Pg′ is an amino protecting group to give a support-bound scaffold of formula (VI):
and
removing one or both amino protecting groups Pg and Pg′ from the scaffold of formula (VI) and reacting the deprotected amine or amines with an R
4
- or R
5
-building block to give a support-bound compound of formula (X).
In another aspect of the invention, there is provided a process for preparing support bound-compounds of formula (X):
comprising:
attaching an ethylenediamine scaffold of the formula (II)
to a solid support via a free amino group to form a support-bound scaffold of formula (III):
reacting the scaffold of formula (III) with a heterocyclic alcohol of formula (V):
to give a support-bound scaffold of formula (XII):
reacting the amino group of formula (XII) bound to support R
6
with an R
3
-building block to give a support-bound scaffold of formula (VI):
and
removing one or both amino protecting groups Pg and Pg′ from the scaffold of formula (VI) and reacting the deprotected amine or amines with an R
4
- or R
5
-building block to give a support-bound compound of formula (X).
In yet another aspect, there is provided novel compounds of formula (I) and pharmaceutical compositions thereof.
DETAILED DESCRIPTION OF THE INVENTION
The present invention provides combinatorial libraries of ethylenediamine compounds of formula (I):
The term“library”, as used herein, refers to a collection of compounds created by a combinatorial process having a common chemical structure or scaffold with one or more variable substituents, the scaffold in the present invention being an ethylenediamine. Libraries include mixtures of compounds of the invention as well as individual compounds substantially free of other related compounds arranged in arrays. In a preferred embodiment, libraries of the invention comprise at least two, three, four or five compounds of formula (I). In another preferred embodiment, libraries of the invention comprises at least ten, fifteen, twenty, fifty or one hundred compounds of formula (I).
In a preferred embodiment, substituents R
1
and R
2
are selected independently from H or a hydrocarbon chain such as C
1-10
alkyl, C
2-10
alkenyl or alkynyl, the chain being optionally substituted with a cyclic group such as a C
3-7
cycloalkyl, C
5-14
aryl, or 5-14 membered heterocycle or heteroaryl group. Included by the term“hydrocarbon chain” are straight and branched alkyl, alkenyl and alkynyl groups. By “hetero” is meant a group incorporating one or more heteroatom selected N, O and S as well as SO and SO
2
. Said cyclic groups may be mono-, bi- or tricyclic and may themselves be substituted with substituents selected from halogen, hydroxyl, amino, carboxyl and alkyl. In a particularly preferred embodiment, both R
1
and R
2
are independently H or C
1-4
alkyl and most preferably both are H.
Substituents R
3
, R
4
and R
5
in preferred embodiments are each independently H, an amino protecting group or a divalent group such as CH
2
, CH(R
2
), C═O, C═S, S(═O)
2
, C(═O)NH, C(═S)NH or C(═O)O substituted with H or a hydrocarbon chain as described previously for R
3
. Again the hydrocarbon chain is optionally substituted with a cyclic group as described previously which in turn is optionally substituted with halogen, hydroxyl, amino, carboxyl and alkyl.
Preferably R
3
is selected from H, 2-pyrazine-carboxyl, carboxamidino, 3-(trifluoromethyl)benzoyl, carbamoyl, 2-aminopropionyl, imidizolyl-4-carboxyl, isonipecotyl, 3,5-diaminobenzoyl, isovaleryl, nalidixyl, hydroxyacetyl and thymine-1-acetyl. More preferably, R
3
is selected from H, 2-pyrazinyl-carbonyl, aminocarbonyl, p-tolylsulfonyl, p-nitrophenyl-carbonyl, and p-tolylaminocarbonyl.
Preferably, R
4
is selected from H, 2-pyrazine-carboxyl, 3,5-bis(trifluoromethyl)phenylcarbamoyl, 3-(trifluorome

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