Macrolide compounds for inducing chondrogenic differentiation

Details Macrolide compounds for inducing chondrogenic differentiation Macrolide compounds for inducing chondrogenic differentiation

2001-12-04

2002-12-03

Spivack, Phyllis G. (Department: 1614)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

C514S410000, C514S411000, C514S183000

Reexamination Certificate

active

06489340

ABSTRACT:

TECHNICAL FIELD
This invention relates to a new use of macrolide compounds for inducing chondrogenic differentiation.
DISCLOSURE OF INVENTION
The inventors of this invention have surprisingly found that the macrolide compounds mentioned here-in-below has an inducing activity of chondrogenic differentiation.
Accordingly, this invention provides a new use of the macrolide compounds for inducing chondrogenic differentiation.
Further, this invention provides an agent for inducing chondrogenic differentiation, which comprises the macrolide compounds.
Still further, this invention provides a method for inducing chondrogenic differentiation, which comprises administering said macrolide compounds to mammals.
Still further, this invention provides a method for preventing or treating damages of cartilage, which comprises administering said macrolide compounds to mammals.
The term “macrolide compound” for use in accordance with the invention is the generic name of compounds with 12 members or more, which belong to macrocyclic lactones.
As a particular example of the macrolide compound, 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) are two adjacent hydrogen atoms, and R
2
may optionally be an alkyl group, or
(b) forms 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.
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, trimethylsilylpropoxycarbonylbutylcarbamoyl, etc.) and so on.
Examples of the aromatic acyl groups include an aroyl group optionally having one or more suitable substituents such as nitro, e.g., benzoyl, toluoyl, xyloyl, naphthoyl, nitrobenzoyl, dinitrobenzoyl, nitronaphthoyl, etc.; and an arenesulfonyl group optionally having one or more suitable substituents such as halogen, e.g., benzenesulfonyl, toluenesulfonyl, xylenesulfonyl, naphthalenesulfonyl, fluorobenzenesulfonyl, chlorobenzenesulfonyl, bromobenzenesulfonyl, iodobenzenesulfonyl, etc.
Examples of the aliphatic acyl groups substituted by an aromatic group include or(lower)alkanoyl group optionally having one or more suitable substituents such as lower alkoxy or trihalo(lower)alkyl, e.g., phenylacetyl, phenylpropionyl, phenylbutyryl, 2-trifluoromethyl-2-methoxy-2-phenylacetyl, 2-ethyl-2-trifluoromethyl-2-phenylacetyl, 2trifluoromethyl-2-propoxy-2-phenylacetyl, etc.
More preferable acyl groups among the aforesaid acyl groups are C
1
-C
4
alkanoyl group optionally having carboxy, cyclo (C
5
-C
6
)alkoxy(C
1
-C
4
)alkanoyl group having two (C
1
-C
4
) alkyls at the cycloalkyl moiety, camphorsulfonyl group, carboxy-(C
1
-C
4
)alkylcarbamoyl group, tri(C
1
-C
4
)alkylsilyl(C
1
-C
4
)alkoxycarbonyl(C
1
-C
4
)alkylcarbamoyl group, benzoyl group optionally having one or two nitro groups, benzenesulfonyl group having halogen, or phenyl(C
1-C
4
)alkanoyl group having C
1
-C
4
alkoxy and trihalo(C
1
-C
4
)alkyl group. Among these, the most preferable ones are acetyl, carboxypropionyl, menthyloxyacetyl, camphorsulfonyl, benzoyl, nitrobenzoyl, dinitrobenzoyl, iodobenzenesulfonyl and 2-trifluoromethyl-2-methoxy-2-phenylacetyl.
Preferable examples of the “5- or 6-membered nitrogen, sulfur and/or oxygen containing heterocyclic ring” include a pyrrolyl group and a tetrahydrofuryl group.
R
24
is an optionally substituted ring system which may contain one or more heteroatoms. Preferably R
24
may be cyclo(C
5-7
)alkyl group optionally having suitable substituents, and the f

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