Epoxysuccinamide derivatives

Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...

Reexamination Certificate

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Reexamination Certificate

active

06689785

ABSTRACT:

FIELD OF THE INVENTION
This invention relates to a novel epoxysuccinamide derivative and remedies for treating bone diseases and arthritis using the same.
BACKGROUND OF THE INVENTION
In the bone tissue, bone resorption and bone formation are continuously and simultaneously performed by osteoclasts and osteoblasts, respectively. The structure and amount of the bone is kept on their balance. However, if the excessive bone resorption continues for a long time, bone diseases such as osteoporosis develop. In addition, malignant hypercalcemia and Paget's disease are accompanied by abnormal enhancement of excessive bone resorption.
The process of bone resorption by osteoclasts can be divided into two steps, namely, dissolution of minerals (i.e., decalcification) and degradation of bone matrix. The degradation of bone matricx is considered to occur by the action of lysosomal enzymes According to recent studies, it is recognized that among the lysosomal enzymes, cathepsin L and its analogous enzyme, namely, cathepsin K, which are cysteine proteases, play a key role [Kakegawa and Katsunuma, Molecular Medicine, 30(10), 1310-1318 (1993), Tezuka et al., J. Biol. Chem., 269, 1106-1109(1994), Inui et al., J. Biol. Chem., 272, 8109(1997)]. Further, it has been reported that a cysteine protease inhibitor blocks the bone resorption [J. M. Delaisse et al., Biochem. Biophys., Res. Commun., 125, 441-447(1984)]. Therefore, compounds which inhibit action of cysteine protease such as cathepsin L are considered to be of value for treating bone diseases such as osteoporosis.
Japanese Patent Publication No. 61-55509 describes epoxysuccinic acid derivatives (i.e., epoxysuccinamic acid compounds) as compounds for inhibiting the action of a protease which have a thiol group participating in their action.
Further, it has been already proposed that certain epoxysuccinic acid derivatives be employed for treating bone diseases [Japanese Patent Provisional Publications No. 63-284127 and No. H2-2186101].
Each of Japanese Patent Provisional Publications No. H8-41043 and H8-104684 describes that epoxysuccinamide derivatives having a specific chemical structure are effective for treating bone diseases.
WO 96/30354 describes the use of new epoxysuccinamides as remedies for treating bone diseases.
SUMMARY OF THE INVENTION
It is an object of the present invention to provide a compound and a pharmaceutical composition which are useful for prevention and treatment of bone diseases such as osteoporosis, malignant hypercalcemia and Paget's disease.
It is another object of the invention to provide a compound and a pharmaceutical composition which are useful for treating osteoarthritis and rheumatoid arthritis which are accompanied by abnormal enhancement of activities of cysteine proteases such as cathepsin B and cathepsin L.
It is a further object of the invention to provide a compound which is useful as a medicine for treating diseases in which cathepsin B and cathepsin L participate, such as muscular dystrophy and muscular atrophy.
The present inventors have earnestly studied to accomplish the abovementioned objects and have found that new epoxysuccinamide derivatives having the below-mentioned formula (1) or their physiologically acceptable salts show a potent inhibitory action against cathepsin L and cathepsin L, and further show high effectiveness in inhibiting bone resorption and in treating a postmenopausal osteoporosis model, and furthermore show effectiveness in treating a rheumatoid arthritis model: salt:
wherein
R
1
represents a hydrogen atom, an alkyl group having 1 to 10 carbon atoms, an alkenyl group having 2 to 10 carbon atoms, an alkynyl group having 2 to 10 carbon atoms, an aryl group having 6 to 20 carbon atoms, an aralkyl group comprising an aryl group having 6 to 20 carbon atoms and an alkyl group having 1 to 6 carbon atoms, a heterocyclic group having 3 to 12 carbon atoms, or a heterocyclic-alkyl group comprising a heterocyclic group having 3 to 12 carbon atoms and an alkyl group having 1 to 6 carbon atoms;
R
2
represents an alkyl group having 1 to 10 carbon atoms, an alkenyl group having 2 to 10 carbon atoms, an alkynyl group having 2 to 10 carbon atoms, an aryl group having 6 to 20 carbon atoms, an aralkyl group comprising an aryl group having 6 to 20 carbon atoms and an alkyl group having 1 to 6 carbon atoms, a heterocyclic group having 3 to 12 carbon atoms, or a heterocyclic-alkyl group comprising a heterocyclic group having 3 to 12 carbon atoms and an alkyl group having 1 to 6 carbon atoms;
R
3
represents a hydrogen atom, an alkyl group having 1 to 10 carbon atoms, an alkenyl group having 2 to 10 carbon atoms, an alkynyl group having 2 to 10 carbon atoms, an aryl group having 6 to 20 carbon atoms, an aralkyl group comprising an aryl group having 6 to 20 carbon atoms and an alkyl group having 1 to 6 carbon atoms, a heterocyclic group having 3 to 12 carbon atoms, or a heterocyclic-alkyl group comprising a heterocyclic group having 3 to 12 carbon atoms and an alkyl group having 1 to 6 carbon atoms;
X represents —O— or —NR
4
— in which R
4
is a hydrogen atom, an alkyl group having 1 to 10 carbon atoms, an aryl group having 6 to 20 carbon atoms, an aralkyl group comprising an aryl group having 6 to 20 carbon atoms and an alkyl group having 1 to 6 carbon atoms, a heterocyclic group having 3 to 12 carbon atoms, or a heterocyclic-alkyl group comprising a heterocyclic group having 3 to 12 carbon atoms and an alkyl group having 1 to 6 carbon atoms;
Y
1
represents OR
5
in which R
5
is a hydrogen atom, an alkyl group having 1 to 10 carbon atoms, an aryl group having 6 to 20 carbon atoms, an aralkyl group comprising an aryl group having 6 to 20 carbon atoms and an alkyl group having 1 to 6 carbon atoms, an acyl group having 2 to 20 carbon atoms, a heterocyclic group having 3 to 12 carbon atoms, or a heterocyclic-alkyl group comprising a heterocyclic group having 3 to 12 carbon atoms and an alkyl group having 1 to 6 carbon atoms, SR
6
in which R
6
is a hydrogen atom, an alkyl group having 1 to 10 carbon atoms, an aryl group having 6 to 20 carbon atoms, an aralkyl group comprising an aryl group having 6 to 20 carbon atoms and an alkyl group having 1 to 6 carbon atoms, an acyl group having 2 to 20 carbon atoms, a heterocyclic group having 3 to 12 carbon atoms, or a heterocyclic-alkyl group comprising a heterocyclic group having 3 to 12 carbon atoms and an alkyl group having 1 to 6 carbon atoms, or NR
7
R
8
in which R
7
is a hydrogen atom, an alkyl group having 1 to 10 carbon atoms, an aryl group having 6 to 20 carbon atoms, an aralkyl group comprising an aryl group having 6 to 20 carbon atoms and an alkyl group having 1 to 6 carbon atoms, an acyl group having 2 to 20 carbon atoms, a heterocyclic group having 3 to 12 carbon atoms, a heterocyclic-alkyl group comprising a heterocyclic group having 3 to 12 carbon atoms and an alkyl group having 1 to 6 carbon atoms, and R
8
is a hydrogen atom, an alkyl group having 1 to 10 carbon atoms, an aryl group having 6 to 20 carbon atoms, an aralkyl group comprising an aryl group having 6 to 20 carbon atoms and an alkyl group having 1 to 6 carbon atoms, a heterocyclic group having 3 to 12 carbon atoms, or a heterocyclic-alkyl group comprising a heterocyclic group having 3 to 12 carbon atoms and an alkyl group having 1 to 6 carbon atoms;
Y
2
represents a hydrogen atom or an alkyl group having 1 to 10 carbon atoms; or
Y
1
and Y
2
in combination with each other can form ═O, ═S, ═N—R
9
in which R
9
is a hydrogen atom, an alkyl group having 1 to 10 carbon atoms, an aryl group having 6 to 20 carbon atoms, an aralkyl group comprising an aryl group having 6 to 20 carbon atoms and an alkyl group having 1 to 6 carbon atoms, a heterocyclic group having 3 to 12 carbon atoms, or a heterocyclic-alkyl group comprising a heterocyclic group having 3 to 12 carbon atoms and an alkyl group having 1 to 6 carbon atoms, or ═N—OR
10
in which R
10
is a hydrogen atom, an alkyl group having 1 to 10 carbon atoms, an aryl gro

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