Melanocortin-1 Receptor-Specific Cyclic Peptides

A cyclic peptide of formula (I):

• including all enantiomers, stereoisomers or diastereoisomers thereof, or a pharmaceutically acceptable salt of any of the foregoing,
• wherein:
• R1 is —H, —NH—R10, —NH—R10—R11 or —NH—R11;
• R2 is —CH— or —N—;
• R3 is —H, —CH3 or —CH2—, and if it is —CH2— forms with R4 a ring of the general structure
• R4 is —H, —(CH2)z— if R3 is —CH2—, and if it is —(CH2)z— forms the ring with R3, wherein any H in —(CH2)z— is optionally substituted with R12, or R4 is —(CH2)w—R13—(CH2)w—R14, wherein any H in either (CH2)w is optionally substituted with —(CH2)w—CH3;
• R5 is —(CH2)w—R15;
• R6 is —H, —CH3 or —CH2—, and if it is —CH2— forms with R7 a ring of the general structure
• R7 is —(CH2)z— if R6 is —CH2—, and if it is —(CH2)z— forms the ring with R6, or R7 is —(CH2)w—R16;
• R8 is —R17—R18 or —R18;
• R9 is
• —(CH2)x—C(═O)—NH—(CH2)y—,
• —(CH2)x—NH—C(═O)—(CH2)y—,
• —(CH2)x—C(═O)—(CH2)z—C(═O)—(CH2)y—,
• —(CH2)x—C(═O)—NH—C(═O)—(CH2)y—,
• —(CH2)x—NH—C(═O)—NH—(CH2)y—,
• —(CH2)x—NH—C(═O)—(CH2)z—C(═O)—NH—(CH2)y—, or
• —(CH2)x—S—S—(CH2)y—;
• R10 is from one to three amino acid residues;
• R11 is H or a C1 to C17 acyl group, wherein the C1 to C17 comprises a linear or branched alkyl, cycloalkyl, alkylcycloalkyl, aryl or alkylaryl;
• R12 is optionally present, and if present is independently in each instance —R13—(CH2)w—R14;
• R13 is optionally present, and if present is independently in each instance
• —O—,
• —S—,
• —NH—,
• —S(═O)2—,
• —S(═O)—,
• —S(═O)2—NH—,
• —NH—S(═O)2—,
• —C(═O)—,
• —C(═O)—O—,
• —O—C(═O)—,
• —NH—C(═O)—O—,
• —O—C(═O)—NH—,
• —NH—C(═O)—, or
• —C(═O)—NH—;
• R14 is independently in each instance —H, —CH3, —N(R19a)(R19b), —NH—(CH2)z—N(R19a)(R19b), —NH—C(═NH)—N(R19a)(R19b), —NH—C(═O)—N(R19a)(R19b), —O(R19a), —(R19a)(R19b), —S(═O)2(R19a), —C(═O)—O(R19a),
• wherein any ring in R14 is optionally substituted with one or more ring substituents, and when one or more substituents are present, are the same or different and independently hydroxyl, halogen, sulfonamide, alkyl, —O-alkyl, aryl, —O-aryl, C(═O)—OH, or C(═O)—N(R19a)(R19b);
• R15 is phenyl, naphthyl or pyridyl, optionally substituted with one or more substituents independently selected from halo, (C1-C10)alkyl-halo, (C1-C10)alkyl, (C1-C10)alkoxy, (C1-C10)alkylthio, aryl, aryloxy, nitro, nitrile, sulfonamide, amino, monosubstituted amino, disubstituted amino, hydroxy, carboxy, and alkoxy-carbonyl;
• R16 is —H, —N(R19a)(R19b), —NH—(CH2)—N(R19a)(R19b), —NH—C(═NH)—N(R19a)(R19b), —NH—C(═O)—N(R19a)(R19b), —O(R19a), a linear or branched C1 to C17 alkyl chain, —C(═O)—N(R19a)(R19b), —S(═O)2(R19a),
• wherein any ring is optionally substituted with one or more optional ring substituents, and when one or more substituents are present, are the same or different and independently hydroxyl, halogen, sulfonamide, alkyl, —O-alkyl, aryl, aralkyl, O-aralkyl, or —O-aryl;
• R17 is from one to three amino acid residues;
• R18 is —OH, —N(R19a)(R19b), —N(R19a)(CH2)w—(C1-C7)cycloalkyl, or —O—(CH2)w—(C1-C7)cycloalkyl;
• R19a and R19b are each independently H or a C1 to C4 linear or branched alkyl chain;
• w is in each instance independently 0 to 5;
• x is 1 to 5;
• y is 1 to 5;
• and
• z is in each instance independently 1 to 5.