Amino acid derivatives

Details Amino acid derivatives Amino acid derivatives

1998-06-30

2001-06-12

Barts, Samuel (Department: 1621)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Ester doai

C514S563000, C562S575000, C560S170000

Reexamination Certificate

active

06245810

ABSTRACT:

TECHNICAL FIELD
This invention relates to novel amino acid derivatives which have immunomodulating activity, antitumor activity and/or hematopoietic stem cell-amplifying activity and are represented by the general formula (I) shown hereinafter, and also it relates to salts of salt-formable ones of said amino acid derivatives. Further, this invention relates to an immunomodulator comprising as active ingredient a novel amino acid derivative represented by the general formula (I) or a salt thereof, and an antitumor agent comprising as active ingredient a novel amino acid derivative represented by the general formula (I) or a salt thereof, as well as a hematopoietic stem cell amplifier comprising as active ingredient a novel amino acid derivative represented by the general formula (I) or a salt thereof.
BACKGROUND ART
Because many of antitumor agents which have heretofore been clinically used are inherently cytotoxic substances, they are accompanied by the drawbacks that they generally have strong toxicity, can give damages to normal cells along with their ability to prevent growth of cancer cells, and hence can induce strong side-effects. There is accordingly an outstanding demand for novel antitumor agents which have such a mechanism of the activity as different from that of the conventional antitumor agents, show low toxicity and weaker side-effects and are effective for therapeutic treatment of human tumors.
DISCLOSURE OF THE INVENTION
As a result of an extensive investigation, we, the present inventors, have succeeded in synthesizing novel amino acid derivatives which can be represented by the general formula (I) shown hereinafter, and we have also found that these amino acid derivatives stimulate activation of T cell of mammals and hence have one or more of the immunomodulating activity and the antitumor and/or carcinostatic activities against various tumors and/or cancers, as well as the hematopoietic stem cell-amplifying activity. Based on these findings, the present invention has been completed.
According to a first aspect of the present invention, therefore, there is provided a novel amino acid derivative of the hereinafter described formula (I) or a salt thereof, as a novel substance. This novel amino acid derivative according to the present invention is a compound which is represented by the following general formula (I), namely an amino acid derivative having the general formula (I):
wherein
y stands for an integer of 0 or 1;
R
1
represents an unsubstituted C
1
-C
8
alkyl group; or R
1
represents a C
1
-C
8
alkyl group substituted by one to four substituents which may be the same or different and are each (i) a group represented by the formula —OR
6
in which R
6
denotes a hydrogen atom, a C
1
-C
3
alkyl group or an acyl group represented by —COR
7
(where R
7
is a hydrogen atom, methyl group or ethyl group), or a group represented by
 (where a is an integer of 0 to 3), (ii) a group represented by the formula
 in which R
8
denotes a hydrogen atom, a C
1
-C
3
alkyl group or an acyl group represented by —COR
10
(where R
10
is a hydrogen atom, methyl group or ethyl group), and R
9
denotes a hydrogen atom or a C
1
-C
3
alkyl group, (iii) a group represented by the formula —SR
11
in which R
11
denotes a hydrogen atom or C
1
-C
3
alkyl group, (iv) a group represented by the formula —COR
12
in which R
12
denotes a hydroxyl group or a group represented by —OR
13
(where R
13
is a C
1
-C
3
alkyl group), or (v) a phenyl group;
or R
1
represents a C
1
-C
8
alkyl group substituted by hydroxyl group(s) and amino group(s);
R
2
represents a hydrogen atom, a C
1
-C
5
alkyl group, or a group represented by the formula
 (where b is an integer of 0 to 3);
R
3
represents (i) a hydrogen atom, (ii) a C
1
-C
8
alkyl group, (iii) a C
1
-C
4
alkenyl group, or (iv) a group represented by the formula —(CH
2
)
c
—R
14
in which R
14
denotes a group represented by —OR
15
(where R
15
is a hydrogen atom, a C
1
-C
3
alkyl group or a group represented by
 d being an integer of 0 to 3, or R
15
is a group represented by —COR
16
, R
16
being a hydrogen atom, methyl group or ethyl group); or R
14
denotes a group represented by —SR
17
(where R
17
is a hydrogen atom, a C
1
-C
3
alkyl group or a group represented by
 e being an integer of 0 to 2); or R
14
denotes a group represented by —SO
2
R
18
(where R
18
is a group represented by —OR
19
, R
19
being a hydrogen atom or a C
1
-C
3
alkyl group, or R
18
is a group represented by
 R
20
and R
21
independently being a hydrogen atom or a C
1
-C
3
alkyl group); or R
14
denotes a group represented by —COR
22
(where R
22
is a group represented by —OR
23
, R
23
being a hydrogen atom or a C
1
-C
3
alkyl group, or R
22
is a group represented by
 and R
25
independently being a hydrogen atom or a C
1
-C
3
alkyl group); or R
14
denotes a group represented by
 R
26
and R
27
independently being a hydrogen atom or a C
1
-C
3
alkyl group; or R
14
denotes a group
 (where R
28
is a hydrogen atom or a C
1
-C
3
alkyl group); or R
14
denotes a group represented by a group
 where R
29
is a hydrogen atom or a C
1
-C
3
alkyl group); or R
14
denotes a thiazolyl group, and c stands for an integer of 1 to 3, or (v) a group represented by the formula
 in which R
30
and R
31
denote a hydrogen atom, a hydroxyl group, a C
1
-C
3
alkoxyl group or a halogen atom and f stands for an integer of 0 to 3, or (vi) a group represented by the formula
 in which R
32
denotes a hydrogen atom, a C
1
-C
3
alkyl group, a group represented by
 (where i is an integer of 0 to 3) or a group represented by —COR
34
(where R
34
is a hydrogen atom, methyl group or ethyl group); and R
33
denotes a hydrogen atom, a phenyl group or a group represented by
 (where R
35
and R
36
independently are a hydrogen atom or a C
1
-C
3
alkyl group); g stands for an integer of 0 to 3, and h stands for an integer of 0 to 2, or (vii) a group represented by the formula
 in which R
37
denotes a hydrogen atom or a C
1
-C
3
alkyl group;
or R
3
represents (viii) a C
1
-C
8
alkyl group having one to three hydroxyl group(s) as substituents on the non-terminal carbon atom(s) present in the chain of said C
1
-C
8
alkyl group; or
R
2
and R
3
may be coupled to each other as taken with the nitrogen atom to which R
2
is attached and also with the carbon atom to which R
3
is attached, to form a ring of the formula
 said ring
 being selected from the group consisting of a cyclic radical having a cyclic structure
 [in which R
38
is a hydrogen atom, a group represented by
 (k: an integer of 0 to 3) or a group represented by —COR
40
(where R
40
is a hydrogen atom, methyl or ethyl group), and j stands for an integer of 2 to 4] and a cyclic radical having a cyclic structure
 [in which X is an oxygen atom, a sulfur atom or a group —NR
41
(where R
41
is a hydrogen atom or a C
1
-C
3
alkyl group), l stands for an integer of 1 to 3, and m stands for an integer of 0 to 2];
R
4
represents a hydrogen atom, a C
1
-C
3
alkyl group or a group represented by
 where n stands for an integer of 0 to 2; or
R
3
and R
4
may be coupled to each other to form a chain of methylene group(s), so that R
3
and R
4
, as taken together with the carbon atom to which R
3
and R
4
are attached, may form a cyclic group
 (where p is an integer of 2 to 5); and
R
5
represents a group represented by the formula —OR
42
in which R
42
denotes a hydrogen atom, a C
1
-C
3
alkyl group or a group
 (q: an integer of 0-2), or R
5
represents a group represented by the formula
 in which R
43
and R
44
denote a hydrogen atom or a C
1
-C
3
alkyl group;
with the proviso that R
1
is not such a C
5
alkyl group as substituted by two of a group of the formula —OR
6
, when y is zero and when R
3
is represented by a group —(CH
2
)
c
—R
14
where R
14
is —OR
15
and c is 1 and when R
4
is a methyl group;
or a salt of said amino acid d

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