Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Peptide containing doai
Reexamination Certificate
2001-03-14
2004-12-21
Tate, Christopher (Department: 1654)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Peptide containing doai
C514S002600, C514S011400, C514S886000, C424S078050
Reexamination Certificate
active
06833353
ABSTRACT:
FIELD OF THE INVENTION
This invention relates to a new use of an immunosuppressant. More specifically, this invention relates to a new use of immunosuppressant as matrix metallproteinases production inhibitor (hereinafter, referred to as MMP-production inhibitor).
BACKGROUND ART
Matrix metalloproteinases (hereinafter, referred to as MMPs) are a large family of Zn
2+
endopeptidases that include 72 and 92 kDa gelatinase, collagenase, stromelysin and membrane-bound MMPs. They are expressed in inflammatory coditions and collectively capable of degrading most connective tissues. MMPs, such as gelatinase (MMP-2, MMP-9), stromelysin (MMP-3) and collagenase (MMP-1, MMP-8, MMP-13), are involved in tissue matrix degradation and have been implicated in many pathological conditions involving abnormal connective tissue and basement membrane matrix metabolism.
DISCLOSURE OF THE INVENTION
This invention provides a new use of an immunosuppressant as MMP-production inhibitor.
Further, this invention provide a new MMP-production inhibitor comprising an immunosuppressant as an active ingredient.
Still further, this invention provide a new use of an immunosuppressant for manufacturing a medicament for preventing or treating MMP-mediated diseases, and a new method by using its medicament and a medicament therefor.
Various immunosuppressants have already been known. For example, it is well known that cyclosporins and tacrolimus (FK506), and their derivatives, possess a strong immunosuppressive activity, which were shown in, for example, J. Antibiotics 40(1987), 1256-1265, U.S. Pat. No. 4,929,611, and so on.
The inventors of this invention have surprisingly found that the immunosuppressant mentioned herein below has a new activity, i.e., MMP-production inhibitory activity.
The “immunosuppressant” used in the present invention should not be limited.
One example of the immunosuppressant is macrolides of the following formula (I).
(wherein each of adjacent pairs of R
1
and R
2
, R
3
and R
4
, and R
5
and R
6
independently
(a) is two adjacent hydrogen atoms, but R
2
may also be an alkyl group or
(b) may form another bond formed between the carbon atoms to which they are attached;
R
7
is a hydrogen atom, a hydroxy group, a protected hydroxy group, or an alkoxy group, or an oxo group together with R
1
;
R
8
and R
9
are independently a hydrogen atom or a hydroxy group;
R
10
is a hydrogen atom, an alkyl group, an alkyl group substituted by one or more hydroxy groups, an alkenyl group, an alkenyl group substituted by one or more hydroxy groups, or an alkyl group substituted by an oxo group;
X is an oxo group, (a hydrogen atom and a hydroxy group), (a hydrogen atom and a hydrogen atom), or a group represented by the formula —CH
2
O—;
Y is an oxo group, (a hydrogen atom and a hydroxy group), (a hydrogen atom and a hydrogen atom), or a group represented by the formula N—NR
11
R
12
or N—OR
13
;
R
11
and R
12
are independently a hydrogen atom, an alkyl group, an aryl group or a tosyl group;
R
13
, R
14
, R
15
, R
16
, R
17
, R
18
, R
19
, R
22
and R
23
are independently a hydrogen atom or an alkyl group;
R
24
is an optionally substituted ring system which may contain one or more heteroatoms;
n is an integer of 1 or 2; and
in addition to the above definitions, Y, R
10
and R
23
, together with the carbon atoms to which they are attached, may represent a saturated or unsaturated 5- or 6-membered nitrogen, sulfur and/or oxygen containing heterocyclic ring optionally substituted by one or more groups selected from the group consisting of an alkyl, a hydroxy, an alkoxy, a benzyl, a group of the formula —CH
2
Se(C
6
H
5
), and an alkyl substituted by one or more hydroxy groups.
Preferable R
24
may be cyclo(C
5-7
)alkyl group, and the following ones can be exemplified.
(a) a 3,4-di-oxo-cyclohexyl group;
(b) a 3-R
20
-4-R
21
-cyclohexyl group,
in which R
20
is hydroxy, an alkoxy group, an oxo group, or a —OCH
2
OCH
2
CH
2
OCH
3
group, and
R
21
is hydroxy, —OCN, an alkoxy group, a heteroaryloxy which may be substituted by suitable substituents, a —OCH
2
OCH
2
CH
2
OCH
3
group, a protected hydroxy group, chloro, bromo, iodo, aminooxalyloxy, an azido group, p-tolyloxythiocarbonyloxy, or R
25
R
26
CHCOO—,
in which R
25
is optionally protected hydroxy or protected amino, and
R
26
is hydrogen or methyl, or
R
20
and R
21
together form an oxygen atom in an epoxide ring; or
(c) cyclopentyl group substituted by methoxymethyl, optionally protected hydroxymethyl, acyloxymethyl
(in which the acyl moiety optionally contains either a dimethylamino group which may be quaternized, or a carboxy group which may be esterified), one or more amino and/or hydroxy groups which may be protected, or aminooxalyloxymethyl. A preferred example is a 2-formyl-cyclopentyl group.
The definitions used in the above general formula (I) and the specific and preferred examples thereof are now explained and set forth in detail.
The term “lower” means, unless otherwise indicated, a group having 1 to 6 carbon atoms.
Preferable examples of the “alkyl groups” and an alkyl moiety of the “alkoxy group” include a straight or branched chain aliphatic hydrocarbon residue, for example, a lower alkyl group such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, neopentyl and hexyl.
Preferable examples of the “alkenyl groups” include a straight or branched chain aliphatic hydrocarbon residue having one double-bond, for example, a lower alkenyl group such as vinyl, propenyl (e.g., allyl group), butenyl, methylpropenyl, pentenyl and hexenyl.
Preferable examples of the “aryl groups” include phenyl, tolyl, xylyl, cumenyl, mesityl and naphthyl.
Preferable protective groups in the “protected hydroxy groups” and the “protected amino” are 1-(lower alkylthio)-(lower) alkyl group such as a lower alkylthiomethyl group (e.g., methylthiomethyl, ethylthiomethyl, propylthiomethyl, isopropylthiomethyl, butylthiomethyl, isobutylthiomethyl, hexylthiomethyl, etc.), more preferably C
1
-C
4
alkylthiomethyl group, most preferably methylthiomethyl group;
trisubstituted silyl group such as a tri(lower)alkylsilyl (e.g., trimethylsilyl, triethylsilyl, tributylsilyl, tert-butyldimethylsilyl, tri-tert-butylsilyl, etc.) or lower alkyl-diarylsilyl (e.g., methyldiphenylsilyl, ethyldiphenylsilyl, propyldiphenylsilyl, tert-butyldiphenyl-silyl, etc.), more preferably tri(C
1
-C
4
)alkylsilyl group and C
1
-C
4
alkyldiphenylsilyl group, most preferably tert-butyldimethylsilyl group and tert-butyldiphenylsilyl group; and an acyl group such as an aliphatic, aromatic acyl group or an aliphatic acyl group substituted by an aromatic group, which are derived from a carboxylic acid, sulfonic acid or carbamic acid.
Examples of the aliphatic acyl groups include a lower alkanoyl group optionally having one or more suitable substituents such as carboxy, e.g., formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, hexanoyl, carboxyacetyl, carboxypropionyl, carboxybutyryl, carboxyhexanoyl, etc.;
a cyclo(lower)alkoxy(lower)alkanoyl group optionally having one or more suitable substituents such as lower alkyl, e.g., cyclopropyloxyacetyl, cyclobutyloxypropionyl, cycloheptyloxybutyryl, menthyloxyacetyl, menthyloxypropionyl, menthyloxybutyryl, menthyloxypentanoyl, menthyloxyhexanoyl, etc.; a camphorsulfonyl group; or a lower alkylcarbamoyl group having one or more suitable substituents such as carboxy or protected carboxy, for example, carboxy(lower)alkylcarbamoyl group (e.g., carboxymethylcarbamoyl, carboxyethylcarbamoyl, carboxypropylcarbamoyl, carboxybutylcarbamoyl, carboxypentylcarbamoyl, carboxyhexylcarbamoyl, etc.), tri-(lower)alkylsilyl (lower) alkoxycarbonyl (lower) alkylcarbamoyl group (e.g., trimethylsilylmethoxycarbonylethylcarbamoyl, trimethylsilylethoxycarbonylpropylcarbamoyl, triethylsilylethoxycarbonylpropylcarbamoyl, tert-butyldimethylsilylethoxycarbonylpropylcarbamoyl, tri-methylsilylpropoxycarbonylbutylcarbamoyl, etc.) and so on.
Examples of the aromatic acyl groups include an aroyl group optionally having one or more suitab
Ishikawa Takeshi
Johki Shigeru
Sakai Fumihiko
Yamamoto Nobuchika
Yamazaki Harumi
Chism B. Dell
Fujisawa Pharmaceutical Co. Ltd.
Leydig , Voit & Mayer, Ltd.
Tate Christopher
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