Sulfonated amino acid derivatives and metalloproteinase inhibitors containing the same

A pharmaceutical composition comprising a compound of formula I:

• wherein R1 is optionally substituted lower alkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, or optionally substituted heteroarylalkyl;
• R2 is hydrogen, optionally substituted lower alkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, or optionally substituted heteroarylalkyl;
• R3 is optionally substituted heteroarylene;
• R4 is a bond, —(CH2)m—, —CH═CH—, —C≡C—, —CO—, —CO—NH—, —N═N—, —N(RA)—, —NH—CO—NH—, —NH—CO—, —S—, —SO2NH—, —SO2—NH—N═CH—, or tetrazol-diyl;
• R5 is optionally substituted lower alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, or an optionally substituted non-aromatic heterocyclic group;
• RA is hydrogen or lower alkyl;
• Y is —NHOH or —OH;
• and
• m is 1 or 2;
• provided R2 is hydrogen when Y is —NHOH,
• R5 is optionally substituted aryl or optionally substituted heteroaryl when R4 is —CO—NH—, —NH—CO—, or —NH—CO—NH—;
• and
• R5 is optionally substituted aryl or optionally substituted heteroaryl when R4 is tetrazol-diyl;
• and
• its optically active substance, pharmaceutically acceptable salt, or hydrate thereof and a pharmaceutically acceptable carrier.

A compound of formula I:

• wherein R1 is optionally substituted lower alkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, or optionally substituted heteroarylalkyl;
• R2 is hydrogen, optionally substituted lower alkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, or optionally substituted heteroarylalkyl;
• R3 is optionally substituted heteroarylene;
• R4 is a bond, —(CH2)m—, —CH═CH—, —C≡C—, —CO—, —CO—NH—, —N═N—, —N(RA)—, —NH—CO—NH—, —NH—CO—, —S—, —SO2NH—, —SO2—NH—N═CH—, or tetrazol-diyl;
• R5 is optionally substituted lower alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, or an optionally substituted non-aromatic heterocyclic group;
• RA is hydrogen or lower alkyl;
• Y is —NHOH or —OH;
• and
• m is 1 or 2;
• provided R2 is hydrogen when Y is —NHOH,
• R5 is optionally substituted aryl or optionally substituted heteroaryl when R4 is —CO—NH—, —NH—CO—, or —NH—CO—NH—,
• R5 is lower alkyl, optionally substituted aryl, or optionally substituted heteroaryl when R4 is tetrazol-diyl;
• and
• its optically active substance, pharmaceutically acceptable salt, or hydrate thereof.

A compound of the formula IV:

• wherein R1 is optionally substituted lower alkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, or optionally substituted heteroarylalkyl;
• R2 is hydrogen, optionally substituted lower alkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, or optionally substituted heteroarylalkyl;
• R7 is optionally substituted aryl or optionally substituted heteroaryl;
• R11 is a bond, —CH═CH—, or —C≡C—;
• X is oxygen atom or sulfur;
• and
• Y is —NHOH or —OH,
• its optically active substance, pharmaceutically acceptable salt, or hydrate thereof.

A compound of the formula VIII:

• wherein R1 is optionally substituted lower alkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, or optionally substituted heteroarylalkyl;
• R2 is hydrogen, optionally substituted lower alkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, or optionally substituted heteroarylalkyl;
• R7 is optionally substituted aryl or optionally substituted heteroaryl;
• and
• R11 is a bond —CH═CH— or —C≡C—,
• its optically active substance, pharmaceutically acceptable salt, or hydrate thereof.

A compound of the formula XIII:

• wherein R1 is optionally substituted lower alkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, or optionally substituted heteroarylalkyl;
• R7 is optionally substituted aryl or optionally substituted heteroaryl;
• and
• R11 is a bond —CH═CH— or —C≡C—, its optically active substance, pharmaceutically acceptable salt, or hydrate thereof.

A method of inhibiting the activity of a metalloproteinase, comprising administering to a subject in need thereof an effective amount of a compound of the formula I:

• wherein R1 is optionally substituted lower alkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, or optionally substituted heteroarylalkyl;
• R2 is hydrogen, optionally substituted lower alkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, or optionally substituted heteroarylalkyl;
• R3 is optionally substituted heteroarylene;
• R4is a bond, —(CH2)m—, —CH═CH—, —C≡C—, —CO—, —CO—NH—, —N═N—, —N(RA)—, —NH—CO—NH—, —NH—CO—, —S—, —SO2NH—, —SO2—NH—N═CH—, or tetrazol-diyl;
• R5 is optionally substituted lower alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, or an optionally substituted non-aromatic heterocyclic group;
• RA is hydrogen or lower alkyl;
• Y is —NHOH or —OH;
• and
• m is 1 or 2;
• provided R2 is hydrogen when Y is —NHOH,
• R5 is not lower alkyl when R4 is —CO—NH— or —NH—CO—NH—,
• its optically active substance, pharmaceutically acceptable salt, or hydrate thereof.

A method of inhibiting the activity of a type-IV collagenase, comprising administering to a subject in need thereof an effective amount of a compound of the formula I:

• wherein R1 is optionally substituted lower alkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, or optionally substituted heteroarylalkyl;
• R2 is hydrogen, optionally substituted lower alkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, or optionally substituted heteroarylalkyl;
• R3 is optionally substituted heteroarylene;
• R4 is a bond, —(CH2)m—, —CH═CH—, —C≡C—, —CO—, —CO—NH—, —N═N—, —N(RA)—, —NH—CO—NH—, —NH—CO—, —S—, —SO2NH—, —SO2—NH—N═CH—, or tetrazol-diyl;
• R5 is optionally substituted lower alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, or an optionally substituted non-aromatic heterocyclic group;
• RA is hydrogen or lower alkyl;
• Y is —NHOH or —OH;
• and
• m is 1 or 2;
• provided R2 is hydrogen when Y is —NHOH—,
• R5 is not lower alkyl when R4 is —CO—NH— or —NH—CO—NH—,
• its optically active substance, pharmaceutically acceptable salt, or hydrate thereof.