Histogranin peptides and their analgesic use

A compound of Formula I:

• wherein
• R1 represents hydrogen, alkyl, alkenyl, alkynyl, —(CH2)n—NH2, —(CH2)n—NH—C(═NH)NH2, or
• wherein “n” is an integer from 0 to 10;
• R2 represents —(CH2)nCONH2, wherein “n” represents an integer from 0 to 10;
• R3 represents hydrogen, alkyl, alkenyl, alkynyl, the radical of formula:
• or the radical of formula:
• wherein “n” represents an integer from 0 to 10;
• and
• R11, R12 and R13 may be the same or different and represent hydrogen, alkyl, alkenyl, alkynyl, —I, —F, —Br, —Cl, or —OH;
• and
• R4 represents —(CH2)nNH2, —(CH2)nNHC(═NH)NH2, or
• wherein “n” represents an integer from 0 to 10;
• R5 and R9 may be the same or different and represent hydrogen, alkyl, alkenyl, alkynyl, alkylcarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, dialkylamino, or —(CH2)naryl, wherein “n” is an integer from 1 to 10;
• R6, R7, and R8 may be the same or different and represent hydrogen, alkyl, alkenyl, or alkynyl;
• R10 represents hydroxy, alkoxy, alkenyloxy, alkynyloxy, amino, alkylamino, dialkylamino, alkylaryl, arylalkoxy, aryloxy, alkoxyaryl, A1, A1-A2, A1-A2-A3, A1-A2-A3-A4, or, A1-A2-A3-A4-A5,
• wherein
• A1 represents threonine or serine;
• A2 represents leucine, glycine, alanine, valine, or isoleucine;
• A3 represents tyrosine, phenylalanine, or tryptophan;
• A4 represents glycine, alanine, leucine, isoleucine, or valine;
• and
• A5 represents phenylalanine, tyrosine, or tryptophan;
• or pseudopeptide analogues thereof wherein one or more of the carbonyl groups of the peptide linkage is replaced by —C(═S)— or by —CH2—, and/or wherein one or more of the amide bonds, —C(O)—NH—, is replaced by the retro-inverso form, —NH—C(O)—, thereof;
• and
• pharmaceutically acceptable salts and esters thereof;
• wherein said compound is selected from the group consisting of compounds A, B, C, D and E, and pharmaceutically acceptable salts and esters thereof;
• wherein compounds A, B, C, D and E are defined as set forth below:
• A A compound of Formula I,
• wherein
• R1 is hydrogen;
• R2 is —CH2)nCONH2, wherein “n” is 2;
• R3 is alkyl;
• R4 is —(CH2)nNHC(═NH)NH2, wherein “n” is 3
• R5 and R9 are hydrogen;
• R6, R7, and R8 are hydrogen;
• R10 is hydroxy,
• B A compound of Formula I,
• wherein
• R1 is —(CH2)n—NH—C(═NH)NH2, wherein “n” is 3;
• R2 is —(CH2)nCONH2, wherein “n” is 2;
• R3 is alkyl;
• R4 is —(CH2)nNHC(═NH)NH2, wherein “n” is 3;
• R5 and R9 are hydrogen;
• R6, R7, and R8 are hydrogen;
• R10 is hydroxy,
• C A compound of Formula I,
• wherein
• R1 is —(CH2)n—NH—C(═NH)NH2, wherein “n” is 3;
• R2 is —(CH2)nCONH2, wherein “n” is 2;
• R3 is hydrogen;
• R4 is —(CH2)nNHC(═NH)NH2, wherein “n” is 3;
• R5 and R9 are hydrogen;
• R6, R7, and R8 are hydrogen;
• R10 is hydroxy,
• D A compound of Formula I,
• wherein
• R1 is hydrogen;
• R2 is —(CH2)nCONH2, wherein “n” is 2;
• R3 is hydrogen;
• R4 is —(CH2)nNHC(═NH)NH2, wherein “n” is 3;
• R5 and R9 are hydrogen;
• R6, R7, and R8 are hydrogen;
• R10 is hydroxy,
• E A compound of Formula I,
• wherein
• R1 is —(CH2)n—NH—C(═NH)NH2, wherein “n” is 3;
• R2 is —(CH2)nCONH2, wherein “n” is 2;
• R3 is hydrogen;
• R4 is —(CH2)nNHC(═NH)NH2, wherein “n” is 3;
• R5 and R9 are hydrogen;
• R6, R7, and R8 are hydrogen;
• R10 is A1-A2-A3-A4-A5,
• wherein
• A1 is threonine;
• A2 is leucine;
• A3 is tyrosine;
• A4 is glycine;
• and
• A5 is phenylalanine.