Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2000-08-22
2002-05-07
Fay, Zohreh (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S912000, C514S913000
Reexamination Certificate
active
06384073
ABSTRACT:
TECHNICAL FIELD
This invention relates to a new use of macrolide compounds for eye diseases. More specifically, this invention relates to a new use of macrolide compounds for preventing or treating glaucoma.
BACKGROUND ART
Glaucoma is a group of eye diseases characterized by an increase in intraocular pressure that causes pathological changes in the optic disk and typical defects in the field of vision. Normally, primary glaucoma (e.g., primary angle-closure glaucoma, primary open-angle glaucoma, etc.,), secondary glaucoma (e.g., secondary angle-closure glaucoma, secondary open-angle glaucoma, etc.,) and congenital glaucoma are exemplified as the particular ones thereof.
The progressive optic neuropathy that is accompanied by normal intraocular pressure, open iridocorneal angles and no evidence of other systemic disease is commonly termed normal-pressure glaucoma. 25% of patients suffering from glaucoma are regarded as the ones suffering normal-pressure glaucoma. Patients suffering from normal-pressure glaucoma also have neuronal damage, which results in loss of vision. However, the mechanism by which the damage occurs is not clearly understood.
Many macrolide compounds having immunosuppressive activity are already known. For example, the tricyclic macrolide compound and its pharmaceutically acceptable salt for use in accordance with this invention is known to have excellent immunosuppressive activity, antimicrobial activity and other pharmacological activities and, as such, be of value for the treatment or prevention of rejection reactions by transplantation of organs or tissues, graft-vs.-host diseases, autoimmune diseases, and infectious diseases [EP-A-0184162, EP-A-0323042, etc.].
DISCLOSURE OF INVENTION
The inventors of this invention have surprisingly found that the macrolide compounds mentioned here-in-below are useful for preventing or treating eye diseases, such as, glaucoma, more particularly, normal-pressure glaucoma.
Accordingly, this invention provides a new use of the macrolide compounds for preventing or treating glaucoma.
Further, this invention provides a prophylactic or therapeutic agent for glaucoma, which comprises the macrolide compounds.
Still further, this invention provides a method for preventing or treating glaucoma, which comprises administering said macrolide compounds to mammals.
As a particular example of the macrolide compounds, the tricyclic compound of the following formula (I) can be exemplified.
(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, 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, carboxypropylcarba
Fay Zohreh
Fujisawa Pharmaceutical Co. Ltd.
Oblon & Spivak, McClelland, Maier & Neustadt P.C.
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