Hydroxamic acid and its derivatives as inhibitors of melanocyte tyrosinase for topical skin lighteners

2) A method of inhibiting or preventing pigment production in a mammal comprising administering to the mammal an effective amount of a compound defined by structure (II), or a pharmaceutically acceptable salt thereof:

• 45
• wherein:
• M is a pharmaceutically acceptable cation;
• R1 is hydrogen, or C1-C6 alkyl or cycloalkyl;
• W2 is CR2R2′, NR2, O or S;
• W3 is CR3R3′, NR3, O or S;
• W4 is CR4R4′, NR4, O or S;
• W5 is CR5R5′, NR5, O or S;
• and W6 is C6NR6′, O or S;
• R2, R3, R4, R5, and R6 are independently selected from (i) hydrogen, (ii) halogen, (iii) NO2, (iv) —CN, (v) —OR10 or phenoxy, (vi) —NHSO2—C1-3alkyl, (vii) —NHCO—C1-5 alkyl, (viii) oxime, (ix) hydrazine, (x) —NR9R10, (xi) SO2, (xii) SO3, (xiii) SR10, (xiv) C1-5 acyloxy, (xv) PO3, (xvi) PO4, (xvii) thiol, (xviii) —COOR9, (xix) C2-5 alkynyl, (xx) C(O)C1-3 alkyl, and (xxi) —C1-8 alkyl, —C2-8 alkenyl, aryl, heteroaryl, or heterocycle, optionally substituted with one or more of —OH, —SH, C(O)H, COOR9, C1-5 acyloxy, halogen, NR9R10, C1-5 thioether, or C1-5 alkoxy;
• R2′, R3′, R4′, R5′, and R6′ are independently H or a valence for bonding;
• R2, R3, R4, R5, and R6 are independently selected from (i) substituted or unsubstituted alkyl, alkenyl, aryl, or heterocycle, (ii) —C1-5 alkoxy, (iii) —OH, (iv) hydrogen, (v) C(O)—C1-3 alkyl, (vi) —(CH2)1-5C(O)NR9R10, or (vii) a valence for bonding;
• alternatively, R3 and R4, or R4 and R5, combine to form a fused ring-structure which is cycloalkyl, aryl, heterocyclyl or heteroaryl selected from phenyl, cyclopentyl, cyclohexyl, pyrrole, furan, thiophene, pyrazole, pyridine, —X—(CH2)—X—, or —(CH2)2X— wherein X is independently NH, S, or O;
• R9 is hydrogen or C1-3 alkyl;
• R10 is hydrogen, C1-8 alkyl, —C2-8 alkenyl, —(CH2)nOm(CH2)n′-aryl, —(CH2)nOm(CH2)n′-heteroaryl, or —(CH2)nOm(CH2)n′-heterocycle, optionally substituted with one or more of —OH, —SH, C(O)H, COOR9, C1-8 acyloxy, halogen, NR9R9, C1-5 thioether, or C1-5 alkoxy;
• m is 0 or 1;
• and
• n and n′ are independently 0, 1, 2, or 3.

3) A method of inhibiting or preventing pigment production in a mammal comprising administering to the mammal an effective amount of a compound defined by structure (III), or a pharmaceutically acceptable salt thereof:

• 46
• wherein:
• M is a pharmaceutically acceptable cation;
• R1 is hydrogen, or C1-C6 alkyl or cycloalkyl;
• W4 is CR4 or N;
• R2, R3, R4, R5, and R6 are independently selected from (i) hydrogen, (ii) halogen, (iii) NO2, (iv) —CN, (v) —OR10 or phenoxy, (vi) —NHSO2-C1-3alkyl, (vii) —NHCO—C1-5 alkyl, (viii) oxime, (ix) hydrazine, (x) —NR9R10, (xi) SO2, (xii) SO3, (xiii) SR10, (xiv) C1-5 acyloxy, (xv) PO3, (xvi) PO4, (xvii) thiol, (xviii) —COOR9, (xix) C2-5 alkynyl, (xx) C(O)C1-3 alkyl, and (xxi) —C1-8 alkyl, —C2-8 alkenyl, aryl, heteroaryl, or heterocycle, optionally substituted with one or more of —OH, —SH, C(O)H, COOR9, C1-5 acyloxy, halogen, NR9R10, C1-5 thioether, or C1-5 alkoxy;
• alternatively, R3 and R4, or R4 and R5, combine to form a fused ring-structure which is cycloalkyl, aryl, heterocyclyl or heteroaryl selected from phenyl, cyclopentyl, cyclohexyl, pyrrole, furan, thiophene, pyrazole, pyridine, —X—(CH2)—X—, or —(CH2)2X— wherein X is independently NH, S, or O;
• R9 is hydrogen or C1-3 alkyl;
• R10 is hydrogen, C1-8 alkyl, —C2-8 alkenyl, —(CH2)nOm(CH2)n′-aryl, —(CH2)nOm(CH2)n′-heteroaryl, or —(CH2)nOm(CH2)n′-heterocycle, optionally substituted with one or more of —OH, —SH, C(O)H, COOR9, C1-8 acyloxy, halogen, NR9R9, C1-5 thioether, or C1-5 alkoxy;
• m is 0 or 1;
• and
• n and n′ are independently 0, 1, 2, or 3.

4) A method of inhibiting or preventing pigment production in a mammal comprising administering to the mammal an effective amount of a compound defined by one of structures (IV)-(XXIV):

• 47 48 49 50 51
• or a pharmaceutically acceptable salt, wherein:
• R1 is H or C1-C6 alkyl or cycloalkyl;
• R2, R3, R4, R5, and R6 are independently selected from (i) hydrogen, (ii) halogen, (iii) NO2, (iv) —CN, (v) —OR10 or phenoxy, (vi) —NHSO2—C1-3alkyl, (vii) —NHCO—C1-5 alkyl, (viii) oxime, (ix) hydrazine, (x) —NR9R10, (xi) SO2, (xii) SO3, (xiii) SR10, (xiv) C1-5 acyloxy, (xv) PO3, (xvi) PO4, (xvii) thiol, (xviii) —COOR9, (xix) C2-5 alkynyl, (xx) C(O)C1-3 alkyl, and (xxi) —C1-8 alkyl, —C2-8 alkenyl, aryl, heteroaryl, or heterocycle, optionally substituted with one or more of —OH, —SH, C(O)H, COOR9, C1-5 acyloxy, halogen, NR9R10, C1-5 thioether, or C1-5 alkoxy;
• alternatively, R3 and R4, or R4 and R5, combine to form a fused ring-structure which is cycloalkyl, aryl, heterocyclyl or heteroaryl selected from phenyl, cyclopentyl, cyclohexyl, pyrrole, furan, thiophene, pyrazole, pyridine, —X—(CH2)—X—, or —(CH2)2X— wherein X is independently NH, S, or O;
• R9 is hydrogen or C1-3 alkyl;
• R10 is hydrogen, C1-8 alkyl, —C2-8 alkenyl, —(CH2)nOm(CH2)n′-aryl, —(CH2)nOm(CH2)n′-heteroaryl, or —(CH2)nOm(CH2)n′-heterocycle, optionally substituted with one or more of —OH, —SH, C(O)H, COOR9, C1-8 acyloxy, halogen, NR9R9, C1-5 thioether, or C1-5 alkoxy;
• m is 0 or 1;
• and
• n and n′ are independently 0, 1, 2, or 3.

57) A topical skin treatment pharmaceutical composition comprising a compound defined by one of structures (IV)-(XXIX):

• 52 53 54 55 56
• or a pharmaceutically acceptable salt thereof, wherein:
• R1 is hydrogen, or C1-C6 alkyl or cycloalkyl;
• R2, R3, R4, R5, and R6 are independently selected from (i) hydrogen, (ii) halogen, (iii) NO2, (iv) —CN, (v) —OR10 or phenoxy, (vi) —NHSO2-C1-3alkyl, (vii) —NHCO—C1-5 alkyl, (viii) oxime, (ix) hydrazine, (x) —NR9R10, (xi) SO2, (xii) SO3, (xiii) SR10, (xiv) C1-5 acyloxy, (xv) PO3, (xvi) PO4, (xvii) thiol, (xviii) —COOR9, (xix) C2-5 alkynyl, (xx) C(O)C1-3 alkyl, and (xxi) —C1-5 alkyl, —C2-8 alkenyl, aryl, heteroaryl, or heterocycle, optionally substituted with one or more of —OH, —SH, C(O)H, COOR9, C1-5 acyloxy, halogen, NR9R10, C1-5 thioether, or C1-5alkoxy;
• alternatively, R3 and R4, or R4 and R5, combine to form a fused ring-structure which is cycloalkyl, aryl, heterocyclyl or heteroaryl selected from phenyl, cyclopentyl, cyclohexyl, pyrrole, furan, thiophene, pyrazole, pyridine, —X—(CH2)—X—, or —(CH2)2X— wherein X is independently NH, S, or O;
• R9 is hydrogen or C1-3 alkyl;
• R10 is hydrogen, C1-8 alkyl, —C2-8 alkenyl, —(CH2)nOm(CH2)n′-aryl, —(CH2)nOm(CH2)n′-heteroaryl, or —(CH2)nOm(CH2)n′-heterocycle, optionally substituted with one or more of —OH, —SH, C(O)H, COOR9, C1-8 acyloxy, halogen, NR9R9, C1-5 thioether, or C1-5alkoxy;
• m is 0 or 1;
• and
• n and n′ are independently 0, 1, 2, or 3.

59) A compound selected from the following, or a pharmaceutically acceptable salt thereof:

• 2-methoxybenzohydroxamic acid;
• 3-methoxybenzohydroxamic acid;
• 3-phenoxybenzohydroxamic acid;
• 3-methylbenzohydroxamic acid;
• 3,N-dimethylbenzohydroxamic acid;
• 3-acetamidobenzohydroxamic acid;
• 3-amino-4-methylbenzohydroxamic acid;
• 2-aminobenzohydroxamic acid;
• 2-acetamidobenzohydroxamic acid;
• 2-hydroxy-4-methoxybenzohydroxamic acid;
• and
• potassium salt of 2-hydroxy-5-acetylbenzohydroxamic acid.