Epoxysuccinamide derivatives

An epoxysuccinamide derivative having the following formula (1) and its physiologically acceptable salt:

• wherein
• R1 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, or an aralkyl group consisting of an aryl group having 6 to 20 carbon atoms and an alkyl group having 1 to 6 carbon atoms;
• R2 represents an isobutyl group or an isopropyl group;
• R3represents a hydrogen atom or an aryl group having 6 to 20 carbon atoms;
• X represents —O— or —NR4— in which R4 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 consisting of 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 consisting of a heterocyclic group having 3 to 12 carbon atoms and an alkyl group having 1 to 6 carbon atoms;
• Y1 represents OR5 in which R5 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 consisting of an aryl group having 6 to 20 carbon atoms and an alkyl group having 1 to 6 carbon atoms, an acetoxy group, a benzoyloxy group, a heterocyclic group having 3 to 12 carbon atoms, or a heterocyclic-alkyl group consisting of a heterocyclic group having 3 to 12 carbon atoms and an alkyl group having 1 to 6 carbon atoms;
• and
• Y2 represents a hydrogen atom;
• provided that the alkyl group for R5 may have one or more substituents selected from the group consisting of hydroxyl, amino, alkylamino having 1-6 carbon atoms, dialkylamino having 2-12 carbon atoms in total, alkoxy having 1-6 carbon atoms, carboxyl, alkoxycarbonyl having 2-7 carbon atoms, —CONH2, alkylaminocarbonyl having 2-7 carbon atoms, dialkylaminocarbonyl having 3-13 carbon atoms in total, and guanidino;
• provided that the aryl group for R1, R3 and R5 may have one or more substituents selected from the group consisting of alkyl having 1-6 carbon atoms, hydroxyl, amino, alkylamino having 1-6 carbon atoms, dialkylamino having 2-12 carbon atoms in total, alkoxy having 1-6 carbon atoms, halogen, haloalkyl having 1-6 carbon atoms, cyano, nitro, carboxyl, alkoxycarbonyl having 2-7 carbon atoms, —CONH2, alkylaminocarbonyl having 2-7 carbon atoms, dialkylaminocarbonyl having 3-13 carbon atoms in total, amidino, and guanidino;
• provided that the heterocyclic group for R5 may have one or more substituents selected from the group consisting of alkyl having 1-6 carbon atoms, hydroxyl, amino, alkylamino having 1-6 carbon atoms, dialkylamino having 2-12 carbon atoms in total, alkoxy having 1-6 carbon atoms, halogen, haloalkyl having 1-6 carbon atoms, cyano, nitro, carboxyl, alkoxycarbonyl having 2-7 carbon atoms, —CONH2, alkylaminocarbonyl having 2-7 carbon atoms, dialkylaminocarbonyl having 3-13 carbon atoms in total, amidino, and guanidino;
• and
• provided that the heterocyclic group for R3, R4 and R5 is selected from the group consisting of pyridyl, pyrrolidinyl, piperidinyl, furyl, thienyl, piperazinyl, indolyl and benzimidazolyl.

An epoxysuccinamide derivative selected from the group consisting of the following compounds and its physiologically acceptable salt:

• ethyl (2S,3S)-3-[[1-(S)-benzoyl-3-methylbutyl]carbamoyl]oxirane-2-carboxylate;
• ethyl (2S,3s)-3-[[1-(S)-benzoyl-2-methylpropyl]carbamoyl]oxirane-2-carboxylate;
• and
• ethyl (2S,3S)-3-[[1-(S)-(2-methyl-2-propenyloxy)methyl-3-methylbutyl]carbamoyl]oxirane-2-carboxylate.

A method for treating a bone disease selected from the group consisting of osteoporosis, malignant hypercalcemia and Paget's disease, the method comprising injecting or orally administering into a patient an epoxysuccinamide derivative having the following formula (1) and its physiologically acceptable salt in an amount of 0.01 to 100 mg/day in the case of injection or in an amount of 0.1 mg/day to 1 g/day in the case of oral administration:

• wherein
• R1 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, or an aralkyl group consisting of an aryl group having 6 to 20 carbon atoms and an alkyl group having 1 to 6 carbon atoms;
• R2 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, or an aralkyl group consisting of an aryl group having 6 to 20 carbon atoms and an alkyl group having 1 to 6 carbon atoms;
• R3 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 consisting of 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 consisting of a heterocyclic group having 3 to 12 carbon atoms and an alkyl group having 1 to 6 carbon atoms;
• X represents —O— or —NR4— in which R4 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 consisting of 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 consisting of a heterocyclic group having 3 to 12 carbon atoms and an alkyl group having 1 to 6 carbon atoms;
• Y1 represents a hydroxyl group, an alkoxy group having 1 to 6 carbon atoms, an acetoxy group, or an aralkyloxy group consisting of an aryl group having 6 to 20 carbon atoms and an alkyl group having 1 to 6 carbon atoms;
• and
• Y2 represents a hydrogen atom or an alkyl group having 1 to 10 carbon atoms;
• provided that the aryl group for R1 to R4 may have one or more substituents selected from the group consisting of alkyl having 1-6 carbon atoms, hydroxyl, amino, alkylamino having 1-6 carbon atoms, dialkylamino having 2-12 carbon atoms in total, alkoxy having 1-6 carbon atoms, halogen, haloalkyl having 1-6 carbon atoms, cyano, nitro, carboxyl, alkoxycarbonyl having 2-7 carbon atoms, —CONH2, alkylaminocarbonyl having 2-7 carbon atoms, dialkylaminocarbonyl having 3-13 carbon atoms in total, amidino, and guanidino;
• and
• provided that the heterocyclic group for R3 and R4 is selected from the group consisting of pyridyl, pyrrolidinyl, piperidinyl, furyl, thienyl, piperazinyl, indolyl and benzimidazolyl.

A method for treating arthritis which comprises injecting or orally administering into a patient an epoxysuccinamide derivative having the following formula (1) and its physiologically acceptable salt in an amount of 0.01 to 100 mg/day in the case of injection or in an amount of 0.1 mg/day to 1 g/day in the case of oral administration:

• wherein
• R1 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, or an aralkyl group consisting of an aryl group having 6 to 20 carbon atoms and an alkyl group having 1 to 6 carbon atoms;
• R2 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, or an aralkyl group consisting of an aryl group having 6 to 20 carbon atoms and an alkyl group having 1 to 6 carbon atoms;
• R3 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 consisting of 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 consisting of a heterocyclic group having 3 to 12 carbon atoms and an alkyl group having 1 to 6 carbon atoms;
• X represents —O— or —NR4— in which R4 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 consisting of 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 consisting of a heterocyclic group having 3 to 12 carbon atoms and an alkyl group having 1 to 6 carbon atoms;
• Y1 represents a hydroxyl group, an alkoxy group having 1 to 6 carbon atoms, an acetoxy group, or an aralkyloxy group consisting of an aryl group having 6 to 20 carbon atoms and an alkyl group having 1 to 6 carbon atoms;
• and
• Y2 represents a hydrogen atom or an alkyl group having 1 to 10 carbon atoms;
• provided that the aryl group for R1 to R4 may have one or more substituents selected from the group consisting of alkyl having 1-6 carbon atoms, hydroxyl, amino, alkylamino having 1-6 carbon atoms, dialkylamino having 2-12 carbon atoms in total, alkoxy having 1-6 carbon atoms, halogen, haloalkyl having 1-6 carbon atoms, cyano, nitro, carboxyl, alkoxy-carbonyl having 2-7 carbon atoms, —CONH2, alkylamino-carbonyl having 2-7 carbon atoms, dialkylaminocarbonyl having 3-13 carbon atoms in total, amidino, and guanidino;
• and
• provided that the heterocyclic group for R3 and R4 is selected from the group consisting of pyridyl, pyrrolidinyl, piperidinyl, furyl, thienyl, piperazinyl, indolyl and benzimidazolyl.

A method for treating a bone disease selected from the group consisting of osteoporosis, malignant hypercalcemia and Paget's disease, the method comprising injecting or orally administering into a patient an epoxysuccinamide derivative having the following formula (1) and its physiologically acceptable salt in an amount of 0.01 to 100 mg/day in the case of injection or in an amount of 0.1 mg/day to 1 g/day in the case of oral administration:

• wherein
• R1 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, or an aralkyl group consisting of an aryl group having 6 to 20 carbon atoms and an alkyl group having 1 to 6 carbon atoms;
• R2 represents an isobutyl group or an isopropyl group;
• R3 represents a hydrogen atom or an aryl group having 6 to 20 carbon atoms;
• X represents —O— or —NR4— in which R4 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 consisting of 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 consisting of a heterocyclic group having 3 to 12 carbon atoms and an alkyl group having 1 to 6 carbon atoms;
• Y1 represents OR5 in which R5 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 consisting of an aryl group having 6 to 20 carbon atoms and an alkyl group having 1 to 6 carbon atoms, an acetoxy group, a benzoyloxy group, a heterocyclic group having 3 to 12 carbon atoms, or a heterocyclic-alkyl group consisting of a heterocyclic group having 3 to 12 carbon atoms and an alkyl group having 1 to 6 carbon atoms;
• and
• Y2 represents a hydrogen atom;
• provided that the alkyl group for R5 may have one or more substituents selected from the group consisting of hydroxyl, amino, alkylamino having 1-6 carbon atoms, dialkylamino having 2-12 carbon atoms in total, alkoxy having 1-6 carbon atoms, carboxyl, alkoxycarbonyl having 2-7 carbon atoms, —CONH2, alkylaminocarbonyl having 2-7 carbon atoms, dialkylaminocarbonyl having 3-13 carbon atoms in total, and guanidino;
• provided that the aryl group for R1, R3 and R5 may have one or more substituents selected from the group consisting of alkyl having 1-6 carbon atoms, hydroxyl, amino, alkylamino having 1-6 carbon atoms, dialkylamino having 2-12 carbon atoms in total, alkoxy having 1-6 carbon atoms, halogen, haloalkyl having 1-6 carbon atoms, cyano, nitro, carboxyl, alkoxycarbonyl having 2-7 carbon atoms, —CONH2, alkylaminocarbonyl having 2-7 carbon atoms, dialkylaminocarbonyl having 3-13 carbon atoms in total, amidino, and guanidino;
• provided that the heterocyclic group for R5 may have one or more substituents selected from the group consisting of alkyl having 1-6 carbon atoms, hydroxyl, amino, alkylamino having 1-6 carbon atoms, dialkylamino having 2-12 carbon atoms in total, alkoxy having 1-6 carbon atoms, halogen, haloalkyl having 1-6 carbon atoms, cyano, nitro, carboxyl, alkoxycarbonyl having 2-7 carbon atoms, —CONH2, alkylaminocarbonyl having 2-7 carbon atoms, dialkylaminocarbonyl having 3-13 carbon atoms in total, amidino, and guanidino;
• and
• provided that the heterocyclic group for R1 and R5 is selected from the group consisting of pyridyl, pyrrolidinyl, piperidinyl, furyl, thienyl, piperazinyl, indolyl and benzimidazolyl.

A method for treating arthritis which comprises injecting or orally administering into a patient an epoxysuccinamide derivative having the following formula (1) and its physiologically acceptable salt in an amount of 0.01 to 100 mg/day in the case of injection or in an amount of 0.1 mg/day to 1 g/day in the case of oral administration:

• wherein
• R1 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, or an aralkyl group consisting of an aryl group having 6 to 20 carbon atoms and an alkyl group having 1 to 6 carbon atoms;
• R2 represents an isobutyl group or an isopropyl group;
• R3 represents a hydrogen atom or an aryl group having 6 to 20 carbon atoms;
• X represents —O— or —NR4— in which R4 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 consisting of 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 consisting of a heterocyclic group having 3 to 12 carbon atoms and an alkyl group having 1 to 6 carbon atoms;
• Y1 represents OR5 in which R5 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 consisting of an aryl group having 6 to 20 carbon atoms and an alkyl group having 1 to 6 carbon atoms, an acetoxy group, a benzoyloxy group, a heterocyclic group having 3 to 12 carbon atoms, or a heterocyclic-alkyl group consisting of a heterocyclic group having 3 to 12 carbon atoms and an alkyl group having 1 to 6 carbon atoms;
• and
• Y2 represents a hydrogen atom;
• provided that the alkyl group for R5 may have one or more substituents selected from the group consisting of hydroxyl, amino, alkylamino having 1-6 carbon atoms, dialkylamino having 2-12 carbon atoms in total, alkoxy having 1-6 carbon atoms, carboxyl, alkoxycarbonyl having 2-7 carbon atoms, —CONH2, alkylaminocarbonyl having 2-7 carbon atoms, dialkylaminocarbonyl having 3-13 carbon atoms in total, and guanidino;
• provided that the aryl group for R1, R3 and R5 may have one or more substituents selected from the group consisting of alkyl having 1-6 carbon atoms, hydroxyl, amino, alkylamino having 1-6 carbon atoms, dialkylamino having 2-12 carbon atoms in total, alkoxy having 1-6 carbon atoms, halogen, haloalkyl having 1-6 carbon atoms, cyano, nitro, carboxyl, alkoxycarbonyl having 2-7 carbon atoms, —CONH2, alkylaminocarbonyl having 2-7 carbon atoms, dialkylaminocarbonyl having 3-13 carbon atoms in total, amidino, and guanidino;
• provided that the heterocyclic group for R5 may have one or more substituents selected from the group consisting of alkyl having 1-6 carbon atoms, hydroxyl, amino, alkylamino having 1-6 carbon atoms, dialkylamino having 2-12 carbon atoms in total, alkoxy having 1-6 carbon atoms, halogen, haloalkyl having 1-6 carbon atoms, cyano, nitro, carboxyl, alkoxycarbonyl having 2-7 carbon atoms, —CONH2, alkylaminocarbonyl having 2-7 carbon atoms, dialkylaminocarbonyl having 3-13 carbon atoms in total, amidino, and guanidino;
• and
• provided that the heterocyclic group for R4 and R5 is selected from the group consisting of pyridyl, pyrrolidinyl, piperidinyl, furyl, thienyl, piperazinyl, indolyl and benzimidazolyl.