Peptide parathyroid hormone analogs

A cyclic peptide compound of formula

• X-A10-A11-A12-A13-A14-A15-A16-A17-A18-A19-A20-A21-A22-A23-A24-A25-A26-A27-Y
• or a pharmaceutically acceptable salt or prodrug thereof wherein
• X is selected from the group consisting of
• (a) R1a-A0-A1-A2-A3-A4-A5-A6-A7-A8-A9-,
• (b) R1a-A2-A3-A4-A5-A6-A7-A8-A9-,
• (c) R1b-A3-A4-A5-A6-A7-A8-A9-,
• (d) R1a-A4-A5-A6-A7-A8-A9-,
• (e) R1a-A5-A6-A7-A8-A9-,
• (f) R1a-A6-A7-A8-A9-,
• (g) R1a-A7-A8-A9-,
• (h) R1a-A8-A9-,
• (i) R1a-A9-, and
• (j) R1a-;
• Y is selected from the group consisting of
• (a) -R3,
• (b) -A28-R3,
• (c) -A28-A29-R3,
• (d) -A28-A29-A30-R3,
• (e) -A28-A29-A30-A31-R3,
• (f) -A28-A29-A30-A31-A32-R3,
• (g) -A28-A29-A30-A31-A32-A33-R3, and
• (h) -A28-A29-A30-A31-A32-A33-A34-R3;
• R1a is H, alkyl, aralkyl or —COR2;
• R1b is R1a or a group of formula
• R2 is alkyl, alkenyl, alkynyl, aryl or aralkyl;
• R3 is a group of formula A35—OR4 or A35—NR4R5;
• R4 and R5 are independently H or lower alkyl;
• R6 and R9 are independently H or alkyl:
• R7 is alkyl;
• R8 is H, alkyl or COR2;
• R10 is H or halogen;
• R11 is alkyl or aralkyl;
• m is 1, 2 or 3;
• n is 3 or 4;
• A0 is absent or a peptide of from one to six amino acid residues;
• A1 is Ser, Ala, Gly or D-Pro, or an equivalent amino acid thereof;
• A2 is Ala, Val or Gly, or an equivalent amino acid thereof;
• A3 is Ala, Ser, Gly or D-Pro, or an equivalent amino acid thereof;
• A4 is Glu, Ala or Gly, or an equivalent amino acid thereof;
• A5 is Ile, His, Ala or Gly, or an equivalent amino acid thereof;
• A6 is Ala, Gln, Gly or D-Pro, or an equivalent amino acid thereof;
• A7 is Ala, Leu, Gly, or an equivalent amino acid thereof;
• A8 is Leu, Nle, Gly or D-Pro, or an equivalent amino acid thereof;
• A9 is His, Ala, D-Pro or Gly, or an equivalent amino acid thereof;
• A10 is Ala, Asn, Asp, Cys, homo-Cys, Glu, Gly, Lys, Orn, Ser, Thr, D-Pro, —NHCH(CH2)mNH2)CO— or —NHCH[(CH2)nCO2H]CO—;
• A11 is Ala, Gly, Leu or Lys, or an equivalent amino acid thereof;
• A12 is Ala or Gly, or an equivalent amino acid thereof;
• A13 is Ala, Asn, Asp, Cys, homo-Cys, Glu, Gly, Lys, Orn, Ser, Thr, —NHCH(CH2)mNH2)CO— or —NHCH[(CH2)nCO2H]CO—;
• A14 is Ala, Asn, Asp, Cys, homo-Cys, Glu, Gly, His, Lys, Orn, Ser, Thr, D-Pro, —NHCH(CH2)mNH2)CO— or —NHCH[(CH2)nCO2H]CO—;
• A15 is Ala, Gly, Ile, D-Pro or Leu, or an equivalent amino acid thereof;
• A16 is Asn, Ala, Gly, D-Pro or Gln, or an equivalent amino acid thereof;
• A17 is Ala, Asn, Asp, Cys, homo-Cys, Glu, Gly, Lys, Orn, Ser, Thr, D-Pro, —NHCH(CH2)mNH2)CO— or —NHCH[(CH2)nCO2H]CO—;
• A18 is Asp, Cys, homo-Cys, Glu, His, Leu, Lys, Orn, Nle, Ser, Thr, —NHCH(CH2)mNH2)CO— or —NHCH[(CH2)nCO2H]CO—;
• A19 is Arg or Glu, or an equivalent amino acid thereof;
• A20 is Arg or an equivalent amino acid thereof;
• A21 is Arg, Asp, Cys, homo-Cys, Glu, Lys, Orn, Ser, Thr, Val, —NHCH(CH2)mNH2)CO— or —NHCH[(CH2)nCO2H]CO—;
• A22 is Asp, Cys, homo-Cys, Glu, His, Lys, Orn, Phe, Ser, Thr, —NHCH(CH2)mNH2)CO— or —NHCH[(CH2)nCO2H]CO—;
• A23 is Leu, Phe or Trp, or an equivalent amino acid thereof;
• A24 is Leu or an equivalent amino acid thereof;
• A25 is Arg, Asp, Cys, homo-Cys, Glu, His, Lys, Orn, D-Pro, Ser, Thr, —NHCH(CH2)mNH2)CO— or —NHCH[(CH2)nCO2H]CO—;
• A26 is Asp, Cys, homo-Cys, Glu, His, Lys, Orn, Ser, Thr, —NHCH(CH2)mNH2)CO— or —NHCH[(CH2)nCO2H]CO—;
• A27 is Leu or Lys, or an equivalent amino acid thereof;
• A28 is Ile or Leu, or an equivalent amino acid thereof;
• A29 is Ala, Asp, Cys, homo-Cys, Glu, Gln, Lys, Orn, Ser, Thr, —NHCH(CH2)mNH2)CO— or —NHCH[(CH2)nCO2H]CO—;
• A30 is Asp, Cys, homo-Cys, Glu, Gly, Lys, Orn, Ser, Thr, —NHCH(CH2)mNH2)CO— or —NHCH[(CH2)nCO2H]CO—;
• A31 is Ile, Leu or Val, or an equivalent amino acid thereof;
• A32 is His, or an equivalent amino acid thereof;
• A33 is Asn or Thr, or an equivalent amino acid thereof;
• A34 is Ala or Phe, or an equivalent amino acid thereof;
• A35 is absent or a peptide of from 1 to 4 amino acids;
• and
• the side chains of at least one of the following pairs of amino acid residues, A10 and A14, A13 and A17, A14 and A18, A17 and A21, A18 and A22, A21 and A25, A25 and A29 and A26 and A30 are linked through an amide, ester, disulfide or lanthionine bond to form a bridge, and the side chain of each of A10, A13, A14, A17, A18, A21, A22, A25, A26, A29, and A30, contributes, at most, to the formation of a single bridge;
• provided that when the side chains of A13 and A17 or A26 and A30 are linked through an amide, disulfide or lanthionine bond to form a bridge, then the side chains of at least one of the following pairs of amino acid residues, A10 and A14, A14 and A18, A17 and A21, A18 and A22, A21 and A25 and A25 and A29 are also linked through an amide, ester, disulfide or lanthionine bond.