Sulphonyl compounds for use as linkers in solid phase and...

Details Sulphonyl compounds for use as linkers in solid phase and... Sulphonyl compounds for use as linkers in solid phase and...

1999-06-30

2001-05-01

Venkat, Jyothsna (Department: 1627)

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

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

C435S007100, C435S007200, C436S501000, C436S518000, C530S331000, C530S332000, C530S333000, C530S334000, C530S335000, C530S336000

Reexamination Certificate

active

06225480

ABSTRACT:

BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to the field of the solid phase chemistry. More particularly, the present invention provides a linker for solid phase and combinatorial synthesis of an organic compound containing —NH— group in its molecule (e.g. amidino group).
2. Description of the Background
Chemical methods have been developed recently for the synthesis of combinatorial libraries of various organic compounds such as peptides, benzodiazepines, oligosaccharides, etc. Solid phase methods are often employed to synthesize the combinatorial libraries because it offers advantages over traditional solution-based methods, for examples, a) excess reagents and soluble by-products can be simply removed by resin washing; b) the technique is readily amenable to automation, enabling many compounds to be prepared simultaneously; c) resin bound toxic or hazardous compounds can be handled safely without risk to users or the environment. In combinatorial synthesis using the solid phase synthesis, it is very important to choose a “suitable linker” in accordance with the object compound to be synthesized.
Up to now, however, a linker efficiently available for amidino group in the solid phase synthesis has not been known. Therefore, such linker is desired.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
The linker of the present invention can be shown by the following formula (I):
 X—SO
2
—R
1
—(A)
m
—R
2
  (I)
wherein
R
1
is a group of the formula (A), (B), (C), (D) and (E):
[wherein R
3
, R
4
, R
5
, R
6
, R
7
, R
8
, R
9
, R
10
, R
11
, R
12
, R
13
, R
14
, R
15
, R
16
, R
17
and R
18
are the same or different hydrogen, lower alkyl or lower alkoxy, and n is an integer of 1 to 3],
R
2
is a group which can form a chemical bond to a resin which may be protected by a conventional protective group,
A is lower alkylene or a group of the formula:
—A
1
—O—A
2
—
(wherein A
1
and A
2
are each lower alkylene),
X is a leaving group, and
m is an integer of 0 or 1,
with proviso that A is (C
2
-C
6
)alkylene, and
m is an integer of 1,
when R
1
is a group of the formula (A).
The linker of the present invention can be prepared by the following reaction scheme.
wherein R
1
, R
2
, A, X and m are each as defined above.
The sulfonation reaction can be carried out, for example, in accordance with the methods described in Examples in this specification, but not limited thereto, the reaction can be carried out according to the methods known in this field of the art.
The starting compound (II) or a salt thereof can be prepared according to Preparations in this specification or similar manners thereto, for instance. Further, one can prepare the compound (II) or a salt thereof from a known compound in accordance with the known methods in this field of the art.
In the above and following description of the present specification, suitable examples and illustrations of the various definitions which the present invention includes within the scope thereof are explained in detail as follows.
Suitable “salt” may be the conventional ones and include a metal salt such as an alkali metal salt (e.g. sodium salt, potassium salt, etc) and an alkaline earth metal salt (e.g. calcium salt, magnesium salt, etc), an ammonium salt, an organic base salt (e.g. trimethylamine salt, triethylamine salt, pyridine salt, picoline salt, dicyclohexylamine salt, N,N′-dibenzylethylenediamine salt, etc), an organic acid salt (e.g. acetate, trifluoroacetate, maleate, tartrate, fumarate, methanesulfonate, benzenesulfonate, formate, toluenesulfonate, etc), an inorganic acid salt (e.g. hydrochloride, hydrobromide, hydriodide, sulfate, phosphate, etc), a salt with an amino acid (e.g. arginine, aspartic acid, glutamic acid, etc), and the like.
Suitable “lower alkyl” may include straight or branched ones having 1 to 6 carbon atom(s) such as methyl, ethyl, propyl, isopropyl, butyl, t-butyl, pentyl, hexyl, or the like.
Suitable “lower alkylene” may include straight or branched ones having 1 to 6 carbon atom(s) such as methylene, ethylene, trimethylene, 1-methylethylene, tetramethylene, pentamethylene, hexamethylene, or the like.
Suitable “lower alkoxy” may include straight or branched ones having 1 to 6 carbon atom(s) such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, t-butoxy, pentyloxy, hexyloxy, or the like.
Suitable “a group which can form a chemical bond to a resin” may be selected in accordance with the kind of resin (e.g. amino-resin, etc) and the concrete examples thereof can be exemplified as follows (the corresponding resin type is also indicated; <P> means “resin”).
 1)
—COOH
(H
2
N-<P>)
 2)
—NH
2
(HOOC-<P>)(Z-SO
2
-<P>; Z means a leaving group)
 3)
a leaving group (H
2
N-<P>)
 4)
—C═P&phgr;
3
; &phgr; means “phenyl” (OHC-<P>)
 5)
—C═CH
2
(Z-&phgr;-<P>)
 6)
—C═CH—X
((HO)
2
B-&phgr;-<P>)
 7)
—CHO
(&phgr;
3
P—CH-<P>)(H
2
N-<P>)
(HO—CH
2
CH(OH)CH
2
-<P>)
 8)
—OH
(Z-CH
2
-<P>)
 9)
—SH
(Z-CH
2
-<P>)
10)
—Si(CH
3
)
2
H
(H
2
C═CH-<P>)
11)
—SO
2
Z
(H
2
N-<P>)
Suitable “protected carboxy” may be the conventionally protected carboxy and may include esterified carboxy such as lower alkoxycarbonyl (e.g. methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, t-butoxycarbonyl, pentyloxycarbonyl, hexyloxycarbonyl, etc), halo(lower)alkoxycarbonyl (e.g. trichloroethoxycarbonyl, etc) and the like.
Suitable “a leaving group” may include halogen (e.g. fluoro, chloro, bromo, iodo), lower alkoxy as mentioned above, aryloxy (e.g. phenoxy, etc), and the like.
Preferred embodiment of the linker (I) may be as follows.
1. the linker (I) wherein
R
1
is a group of the formula (A) wherein R
3
, R
4
and R
5
are each lower alkyl,
R
2
is a group which can form a chemical bond to a resin which may be protected by a conventional protective group,
A is (C
2
-C
4
)alkylene or a group of the formula:
 —A
1
—O—A
2
—
[wherein A
1
and A
2
are each (C
1
-C
4
)alkylene],
X is halogen,
m is an integer of 1,
in which the more preferred one may be the linker (I) wherein
R
1
is a group of the formula:
R
2
is carboxy or protected carboxy,
A is trimethylene,
X is chloro, and
m is an integer of 1.
2. the linker (I) wherein
R
1
is a group of the formula (B) wherein R
6
, R
7
, R
8
and R
9
are each lower alkyl, R
10
is hydrogen, and n is an integer of 3,
R
2
is a group which can form a chemical bond to a resin which may be protected by a conventional protective group,
A is (C
1
-C
4
)alkylene or a group of the formula:
—A
1
—O—A
2
—
[wherein A
1
and A
2
are each (C
1
-C
4
)alkylene],
X is halogen, and
m is an integer of 0 or 1,
in which the more preferred one may be the linker (I) wherein
R
1
is a group of the formula:
R
2
is carboxy or protected carboxy,
A is methylene or —(CH
2
)
2
—O—CH
2
—,
X is chloro, and
m is an integer of 1.
3. the linker (I) wherein
R
1
is a group of the formula (B) wherein R
6
, R
7
, R
8
, R
9
and R
10
are each lower alkyl, and n is an integer of 3,
R
2
is a group which can form a chemical bond to a resin which may be protected by a conventional protective group,
A is (C
1
-C
4
)alkylene or a group of the formula:
—A
1
—O—A
2
—
[wherein A
1
and A
2
are each (C
1
-C
4
)alkylene],
X is halogen, and
m is an integer of 0 or 1,
in which the more preferred one may be the linker (I) wherein
R
1
is a group of the formula:
R
2
is carboxy or protected carboxy,
X is chloro, and
m is an integer of 0, or
R
1
is a group of the formula:
R
2
is carboxy or protected carboxy,
A is methylene,
X is chloro, and
m is an integer of 1.
4. the linker (I) wherein
R
1
is a group of the formula (C) wherein R
11
, R
12
, R
13
, R
14
are each lower alkyl, and R
15
is hydrogen,
R
2
is a group which can form a chemical bond to a resin which may be protected by a conventional protective group,
A is (C
1
-C
4
)alkylene or a group of the formula:
—A
1
—O—A
2
—
[wherein A
1

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