Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2001-03-20
2002-07-16
Berch, Mark L. (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C548S543000, C548S544000, C548S546000, C548S547000, C548S550000, C548S551000, C546S194000, C546S196000, C546S197000, C546S198000, C546S199000, C546S200000, C546S201000, C546S202000, C546S205000, C546S206000, C546S219000, C540S524000, C540S526000, C540S531000, C514S424000, C514S425000
Reexamination Certificate
active
06420415
ABSTRACT:
This application is the National Stage of International Application No. PCT/JP99/05103, filed on Sep. 20, 1999.
TECHNICAL FIELD
The present invention relates to a novel thiol derivative which has an excellent matrix metalloprotease inhibiting activity, and is useful as a therapeutic agent or a prophylactic agent against osteoarthritis and rheumatoid arthritis, and also as an agent for inhibiting the metastasis, the infiltration and the proliferation of various cancers.
BACKGROUND ART
A matrix metalloprotease (MMP) is an endopeptidase playing a physiologically important role in tissue reconstruction, and its protease activity is under strict control. However, such control is disturbed in pathological conditions to induce an excessive degradation of the extracellular matrix, thus being involved pathogenically in articular diseases such as osteoarthritis and rheumatoid arthritis, bone diseases such as osteoporosis, periodontosis, tumor infiltration or metastasis, corneal ulceration and the like.
At least 15 types of MMPs are now known, and are classified based on their primary structure and substrate specificity into 5 groups consisting of the collagenase group (MMP-1, 8, 13), the gelatinase group (MMP-2, 9), the stromelysin group (MMP-3, 10), the membrane-type MMP group (MT1, 2, 3, 4-MMP) and the miscellaneous group(MMP-7, 11, 12, 18). Among these groups, MMP-13 in the collagenase group is reported to be expressed exclusively in cartilage and bone tissues and produced at a higher level in articular diseases.
In addition, MMP-13 is assumed to be deeply involved in bone or articular diseases due to its higher collagen degrading activity when compared with other collagenases.
A large number of MMP inhibitors have been reported (Current Pharmaceutical Design, 2, 624-661 (1996)), Expert Opinion on Therapeutic Patents, 6, 1305-1315 (1996), and a large number of thiol derivatives were also reported recently (WO97-3783, WO97-38007, WO97-48685, EP818443, WO98-3164, WO98-3166, WO98-6696, WO98-8814, WO98-12211, WO98-23588, Bioorganic & Medicinal Chemistry Letters, 8, 1157-1162 (1998), Bioorganic & Medicinal Chemistry Letters, 8, 1163-1168 (1998)).
Those also reported in a large number are the compounds exhibiting inhibitory effects on MMP-13, which are classified broadly into hydroxamic acid derivatives (British Journal of Pharmacology, 121, 540-546 (1997), WO97-31892, WO98-15525, WO98-16506, WO98-16520), carboxylic acid derivatives (Journal of Clinical Investigation, 99, 1534-1545 (1997), WO98-6711, WO98-9934, WO98-17643) and thiol derivatives (WO98-3164, WO98-3166).
A novel compound which is more satisfactory when compared with conventional MMP inhibitors in terms of efficacy, duration and safety is desired.
DISCLOSURE OF INVENTION
In the course of research under the circumstances described above, we finally discovered that, due to the chemical structure characterized substantially by the substitution of the nitrogen atom on a ring represented by Formula:
wherein each Y may be same or different and is a hydrogen atom, an optionally substituted hydrocarbon group, a halogen atom, a carboxyl group, an acyl group, an optionally substituted hydroxy group, an optionally substituted amino group, SR
5
(wherein R
5
is a hydrogen atom, an optionally substituted hydrocarbon group, an acyl group or an optionally substituted heterocyclic group), an oxo group, a thioxo group, an optionally substituted imino group, a nitro group or a cyano group, n is an integer of 1 to 3 and q
2
is an integer of 0 to 2n+3 with a group represented by Formula:
wherein ring A and ring B may be same or different and each is an optionally substituted homocyclic or heterocyclic ring, wherein the substituents on ring A (or ring B) are bound to the position capable of being substituted on ring B (or ring A) and taken together with ring A, ring B and X
2
to form a condensed ring, X
1
is a bond, an optionally substituted divalent C
1-3
aliphatic hydrocarbon group or —NR
3
— (wherein R
3
is a hydrogen atom, an optionally substituted hydrocarbon group or an acyl group), X
2
is a bond, an optionally substituted divalent C
1-3
aliphatic hydrocarbon group, —NR
4
— (wherein R
4
is a hydrogen atom, an optionally substituted hydrocarbon group or an acyl group), —O— or —S(O)
p
— (wherein p is 0, 1 or 2); and also by the substitution on the carbon atom capable of being substituted on a ring represented by Formula:
wherein each symbol has a meaning described above with a group represented by Formula:
wherein each R
1
may be same or different and is a hydrogen atom, an optionally substituted hydrocarbon group, an acyl group, an optionally substituted heterocyclic group or SR
2
(wherein R
2
is a hydrogen atom, an optionally substituted hydrocarbon group, an acyl group or an optionally substituted heterocyclic group), each m may be same or different and is 0 or 1, q
1
is an integer of 1 to 2n+4, a compound represented by Formula:
wherein ring A and ring B may be same or different and each is an optionally substituted homocyclic or heterocyclic ring, wherein the substituents on ring A (or ring B) is bound to the position capable of being substituted on ring B (or ring A) and taken together with ring A, ring B and x
2
to form a condensed ring, each R
1
may be same or different and is a hydrogen atom, an optionally substituted hydrocarbon group, an acyl group, an optionally substituted heterocyclic group or SR
2
(wherein R
2
is a hydrogen atom, an optionally substituted hydrocarbon group, an acyl group or an optionally substituted heterocyclic group), X
1
is a bond, an optionally substituted divalent C
13
aliphatic hydrocarbon group or —NR
3
— (wherein R
3
is a hydrogen atom, an optionally substituted hydrocarbon group or an acyl group), x
2
is a bond, an optionally substituted divalent C
1-3
aliphatic hydrocarbon group, —NR
4
— (wherein R
4
is a hydrogen atom, an optionally substituted hydrocarbon group or an acyl group), —O— or —S(O)
p
— (wherein p is 0, 1 or 2), each Y may be same or different and is a hydrogen atom, an optionally substituted hydrocarbon group, a halogen atom, a carboxyl group, an acyl group, an optionally substituted hydroxy group, an optionally substituted amino group, SR
5
(wherein R
5
is a hydrogen atom, an optionally substituted hydrocarbon group, an acyl group or an optionally substituted heterocyclic group), an oxo group, a thioxo group, an optionally substituted imino group, a nitro group or a cyano group, each m may be same or different and is 0 or 1, n is an integer of 1 to 3, q
1
is an integer of 1 to 2n+4, q
2
is an integer of 0 to 2n+3, and the sum of q
1
and q
2
is 2n+4 or a salt thereof unexpectedly exhibits an excellent MMP inhibiting effect (especially an MMP13 inhibiting effect) resulting from its specific chemical structure in combination with excellent duration and safety, and such pharmacological effect is useful in a prophylactic and therapeutic agent against osteoarthritis, rheumatoid arthritis, osteoporosis, cancer, periodontosis or corneal ulcer, whereby establishing the invention.
Thus, the present invention is:
(1) a compound represented by Formula (I) shown above or a salt thereof (provided that when ring B is a nitrogen-containing heterocyclic ring then X
2
binds to a position capable of being substituted except for a nitrogen atom on ring B);
(2) a compound of the above (1) wherein each of ring A and ring B is an optionally substituted benzene ring;
(3) a compound of the above (1) wherein each R
1
may be same or different and is a hydrogen atom, an optionally substituted lower alkyl group, —(C═O)—R
6
(wherein R
6
is a hydrogen atom, an optionally substituted hydrocarbon group, an optionally substituted amino group or an optionally substituted hydroxy group) or SR
2
(wherein R
2
has a meaning defined in claim
1
);
(4) a compound of the above (1) wherein each R
1
may be same or different and is represented by Formula:
wherein each symbol has a meaning defined in the above (1), or by formula:
wherein each symbol has a meaning
Nara Hiroshi
Takizawa Masayuki
Yamashita Toshiro
Yoshimura Koji
Berch Mark L.
Chao Mark
Habte Kahsay
Ramesh Elaine M.
Takeda Chemical Industries Ltd.
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