Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2000-10-02
2004-01-06
Shah, Mukund J. (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C544S054000, C544S088000, C544S242000, C546S290000
Reexamination Certificate
active
06673804
ABSTRACT:
TECHNICAL FIELD
The present invention relates to novel sulfonamide derivatives having excellent matrix metalloproteinase 13 inhibitory action and aglycanase inhibitory action, and to pharmaceutical compositions containing the same.
BACKGROUND ART
A nonsteroidal anti-inflammatory drug (NSAID) is conventionally used for the treatment of osteoarthritis and chronic rheumatoid arthritis. However, such therapeutic methods are only symptomatic therapies, and there are still no medicaments for etiotropic therapy that inhibits the progress of these diseases.
In addition, in the field of antitumor drugs, since drugs currently used in the clinical setting are generally associated with strong adverse side effects, there is a need for drugs that are effective for not only the treatment of cancer, but also for both the prevention of the disease and the prevention of relapse and that cause only mild adverse side effects, if any.
Matrix metalloproteinase (hereinafter referred to as “MMP”) is known to be an enzyme that decomposes protein components of connective tissue. MMP-13 (collagenase-3), which is one of several subtypes of MMP, has strong decomposition activity against type II collagen, one of the main components of joint cartilage. MMP-13 is an enzyme that is found locally in joints, and its expression has been reported to be elevated in the joints of patients with osteoarthritis and chronic rheumatoid arthritis as compared with that in the joints of healthy people (P. G. Mitchell et al., Journal of Clinical Investigation, vol. 97, 761-768, 1996; P. Reboul et al., Journal of Clinical Investigation, vol. 97, 2011-2019, 1996; D. Wemicke et al., Journal of Rheumatology, vol. 23, 590-595, 1996). Based on these reports, MMP-13 is considered to play an important role in the destruction of joint cartilage matrix in the course of development of arthritis.
In addition, aglycan, another main component of joint cartilage, is reported to be decomposed by an enzyme referred to as aglycanase in osteoarthritis. Although the actual form of aglycanase has not been identified, this enzyme is known to cleave aglycan at an extremely characteristic sequence of Glu373-Ala374 (J. D. Sandy et al., Journal of Biological Chemistry, vol. 266, 8683-8685, 1990; J. D. Sandy et al., Journal of Biological Chemistry, vol. 270, 2550-2556, 1995).
Thus, on the basis of the above findings, compounds that strongly inhibit both MMP, particularly MMP-13, and aglycanase are considered to be useful as therapeutic and preventive agents against osteoarthritis and other forms of arthritis.
On the other hand, MMP-13 is known to be expressed at a high level in breast carcinoma and several other cancerous tissues, and it has been indicated that it has a strong possibility of playing an important role in the growth and metastasis of these cancers (J. M. P. Freije et al., Journal of Biological Chemistry, vol. 269, 16766-16773, 1994). Thus, compounds that have inhibitory action against this enzyme are considered to be useful inhibitors of metastasis, invasion and growth of various cancer cells.
Compounds having MMP inhibitory activity, for example, those shown below, are disclosed in WO 97/27174. However, the inhibitory action of these compounds against MMP-13 is not disclosed, and there is no disclosure or suggestion of aglycanase inhibitory action.
As a result of earnest research on the synthesis and pharmacological action of compounds that strongly inhibit both MMP-13 and aglycanase, the inventors of the present invention found that novel sulfonamide derivatives have potent MMP-13 inhibitory activity and aglycanase inhibitory activity, thereby leading to completion of the present invention.
Disclosure of the Invention
The present invention relates to
(1) a compound of the following formula (I) or a pharmacologically acceptable salt, ester or other derivative thereof:
{wherein
R
1
represents a hydroxyl group or a hydroxyamino group;
R
2
represents a hydrogen atom, a lower alkyl group, a lower alkyl group substituted with at least one group selected from Substituent group &agr;, a cycloalkyl group having from 3 to 7 carbon atoms or a group of the formula: —A—R
6
[wherein
A represents a lower alkylene group or a lower alkylene group interrupted by an oxygen atom, —S(O)
m
— or —N(R
9
)—;
R
6
represents a group of the following formula (II), (III) or (IV):
(wherein
X represents an oxygen atom, a sulfur atom, —N(R
10
)— or —C(R
11
)(R
12
);
Y represents an oxygen atom, a carbonyl group, —S(O)
n
—, —N(R
10
)— or —C(R
11
)(R
12
);
R
7
and R
8
may be the same or different from each other and each represents a hydrogen atom, a lower alkyl group, a carboxyl group, one group selected from Substituent group &agr;, a lower alkyl group substituted with at least one group selected from Substituent group &agr;, a lower alkoxy group substituted with at least one group selected from Substituent group &agr;, a lower alkylthio group substituted with at least one group selected from Substituent group &agr;, a lower alkylsulfinyl group substituted with at least one group selected from Substituent group &agr; or a lower alkylsulfonyl group substituted with at least one group selected from Substituent group &agr;, or R
7
and
R
8
may form, together with the carbon atom(s) to which they are attached, a non-aromatic hydrocarbon ring, a non-aromatic heterocycle, a non-aromatic hydrocarbon ring substituted with at least one group selected from Substituent group &agr; and Substituent group &bgr;, a non-aromatic heterocycle substituted with at least one group selected from Substituent group &agr; and Substituent group &bgr;, an aryl ring, a heteroaryl ring, an aryl ring substituted with at least one group selected from Substituent group &agr; and Substituent group &bgr; or a heteroaryl ring substituted with at least one group selected from Substituent group &agr; and Substituent group &bgr;; and
R
9
, R
10
, R
11
and R
12
may be the same or different from one another and each represents a hydrogen atom or a lower alkyl group, and further R
11
and R
12
may form, together with the carbon atom(s) to which they are attached, a non-aromatic hydrocarbon ring, a non-aromatic heterocycle, a non-aromatic hydrocarbon ring substituted with at least one group selected from Substituent group &agr; and Substituent group &bgr; or a non-aromatic heterocycle substituted with at least one group selected from Substituent group &agr; and Substituent group &bgr;,
with the proviso that when R
7
and R
8
are attached to the same carbon atom, R
7
and R
8
do not form, together with the carbon atom to which they are attached, an aryl ring, a heteroaryl ring, an aryl ring substituted with at least one group selected from Substituent group &agr; and Substituent group &bgr; or a heteroaryl ring substituted with at least one group selected from Substituent group &agr; and Substituent group &bgr;), and
m and n may be the same or different from each other and each represents 0, 1 or 2],
R
3
represents a hydrogen atom, a lower alkyl group, a cycloalkyl group having from 3 to 7 carbon atoms, an alkenyl group, an alkynyl group, a lower alkyl group substituted with at least one group selected from Substituent group &agr;, a cycloalkyl group having from 3 to 7 carbon atoms substituted with at least one group selected from Substituent group &agr; and Substituent group &bgr;, an alkenyl group substituted with at least one group selected from Substituent group &agr; or an alkynyl group substituted with at least one group selected from Substituent group &agr;;
R
4
represents an arylene group, a heteroarylene group, an arylene group substituted with at least one group selected from Substituent group &agr; and Substituent group &bgr; or a heteroarylene group substituted with at least one group selected from Substituent group &agr; and Substituent group &bgr;; and
R
5
represents a lower alkyl group, a lower alkyl group substituted with at least one group selected from Substituent group &agr;, an aryl group, a heteroaryl group, an aryl group substituted with at least one g
Kimura Tomio
Miyazaki Shoujiro
Takasaki Wataru
Tanzawa Kazuhiko
Ueda Keiji
Liu Hong
Sankyo Company Limited
Shah Mukund J.
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