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1. (WO1998051324) PEPTIDE PARATHYROID HORMONE ANALOGS
Note: Text based on automatic Optical Character Recognition processes. Please use the PDF version for legal matters

What is Claimed is:
1. A cyclic peptide compound of formula
2


or a pharmaceutically acceptable salt or prodrug thereof wherein



Y is selected from the group consisting of



R1a is H, alkyl, aralkyl or -COR2;

R1b is R1a or a group of formula


or
;

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;

A13 is Asn or Thr, or an equivalent amino acid thereof r; and

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, A2, and A25 and A25 and A29 are also linked through an amide, ester, disulfide or lanthionine bond.

2. A peptide compound according to claim 1. or a pharmaceutically acceptable salt or prodrug therof wherein the bridge formed from the side chains of one pair of amino acid residues is non-overlapping with a bridge formed between the side chains of another pair of amino acid residues.

3. A peptide compound according to claim 2, or a pharmaceutically acceptable salt or prodrug thereof wherein

A10 is Ala, Asn, Asp, Gly or Lys;

A13 is Ala, Gly or Lys;

A14 is Ala, Asp, Gly, His, Lys or Ser;

A17 is Ala, Asp, Gly, Lys or Ser;

A18 is Asp, Leu, Lys, Orn or Nle;

A21 is Arg, Asp, Lys or Val;

A22 is Asp, Glu. Lys, Orn or Phe;

A25 is Arg, Asp, Glu, His or Lys;

A26 is His or Lys;

A29 is Ala, Asp, Glu or Gln;

A30 is Asp, Glu or Lys, 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, A2, and A25, A25 and A29 and A26 and A30 are linked through an amide 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

(a) that when the side chains of A13 and A17 are linked through an amide bond to form a bridge, then the side chains of at least one of A18 and A22, A21 and A25, and A25 and A29 are also linked through an amide bond;

(b) that when the side chains of A26 and A30 are linked through an amide bond to form a bridge, then the side chains of at least one of A10 and A14, A14 and A18, A17 and A21, A18 and A22 and A21 and A25 are also linked through an amide bond; and

(c) that when the side chains of A13 and A17 and A26 and A30 are linked through an amide bond to form a bridge, then the side chains of A18 and A22 or A21 and A25 are also linked through an amide bond.

4. A peptide compound according to claim 3, or a pharmaceutically acceptable salt or prodrug thereof wherein R1a is H and Y is NH2.

5. A peptide compound according to claim 4, or a pharmaceutically acceptable salt or prodrug thereof wherein X is


6. A peptide compound according to claim 5, or a pharmaceutically acceptable salt or prodrug thereof wherein A1 is Ala, Gly or D-Pro; A8 is Nle and A27 is Leu.

7. A peptide compound according to claim 6, or a pharmaceutically acceptable salt or prodrug thereof wherein (i) the side chains of A10 and A14 are linked through an amide bond to form a bridge;

(ii) the side chains of A14 and A18 are linked through an amide bond to form a bridge;
(iii) the side chains of A17 and A21 are linked through an amide bond to form a bridge;
(iv) the side chains of A18 and A22 are linked through an amid bond to form a bridge;
(v) the side chains of A21 and A25 are linked through an amide bond to form a bridge; or
(vi) the side chains of A25 and A29 are linked through an amide bond to form a bridge.

8. A peptide compound according to claim 7, or a pharmaceutically acceptable salt or prodrug thereof wherein A10 is Asp or Lys; A13 is Lys; A14 is Asp or Lys; A17 is Asp or Ser; A18 is Nle; A21 is Arg or Val; A22 is Glu or Phe; A25 is Arg or His; A26 is Lys or His, A29 is Ala or Gln; and A30 is Asp or Glu; and the side-chains of A10 and A14 are linked through an amide bond to form a bridge.

9. A peptide compound according to claim 7, or a pharmaceutically acceptable salt or prodrug thereof wherein A10 is Asn or Asp; A13 is Lys; A14 is Asp or Lys; A17 is Asp or Ser; A18 is Nle; A2, is Arg or Val; A22 is Glu or Phe; A25 is Arg or His; A26 is His or Lys; A29 is Ala or Gln; and A30 is Asp or Glu; and the side chains of A14 and A18 are linked through an amide bond to form a bridge.

10. A peptide compound according to claim 7, or a pharmaceutically acceptable salt or prodrug thereof wherein A10 is Asn or Asp; A13 is Lys; A14 is His or Ser; A17 is Asp or Lys; A18 is Nle; A2, is Asp or Lys; A22 is Glu or Phe; A25 is Arg or His; A26 is His or Lys; A29 is Ala or Gln; and A30 is Asp or Glu; and the side chains of A17 and A2, are linked through an amide bond to form a bridge.

1 1. A peptide compound according to claim 7, or a pharmaceutically acceptable salt or prodrug thereof wherein A10 is Asn or Asp; A13 is Lys; A14 is His or Ser; A17 is Asp or Ser; A18 is Asp, Lys or Orn;

A21 is Arg or Val; A22 is Asp, Glu, Lys or Orn; A25 is Arg or His; A26 is His or Lys; A29 is Ala or Gln; and A30 is Asp or Glu; and the side chains of A18 and A22 are linked through an amide bond to form a bridge.

12. A peptide compound according to claim 7, or a pharmaceutically acceptable salt or prodrug thereof wherein A10 is Asn or Asp; A13 is Lys; A14 is His or Ser; A17 is Asp or Ser; A18 is Nle; A2, is Asp or Lys; A22 is Glu or Phe; A25 is Asp or Lys; A26 is His or Lys; A29 is Ala or Gln; and A30 is Asp or Glu; and the side chains of A21 and A25 are linked through an amide bond to form a bridge.

13. A peptide compound according to claim 7, or a pharmaceutically acceptable salt or prodrug thereof wherein A10 is Asn or Asp; A13 is Lys; A14 is His or Ser; A17 is Asp or Ser; A18 is Nle; A2, is Arg or Val; A22 is Glu or Phe; A25 is Asp or Lys; A26 is His or Lys; A29 is Asp or Lys; and A30 is Asp or Glu; and the side chains of A25 and A29 are linked through an amide bond to form a bridge.

14. A peptide compound according to claim 6, or a pharmaceutically acceptable salt or prodrug thereof wherein
(i) the side-chains of A13 and A17 are linked through an amide bond and the side-chains of A18 and

A22 are linked through an amide bond to form a bridge; and
(ii) the side-chains of A18 and A22 are linked through an amide bond and the side-chains of A26 and A30 are linked through an amide bond to form a bridge.

15. A peptide compound according to claim 14, or a pharmaceutically acceptable salt or prodrug thereof wherein A10 is Asn or Asp; A13 is Lys or Asp; A14 is His or Ser; A17 is Lys or Asp; A18 is Lys or Asp; A2, is Val or Arg; A22 is Glu, Lys or Asp; A25 is Arg or His; A25 is His or Lys; A29 is Ala or Gln; and A30 is Asp or Glu; and the side-chains of A13 and A17 are linked through an amide bond and the side-chains of A18 and A22 are linked through an amide bond to form a bridge.

16. A peptide compound according to claim 14, or a pharmaceutically acceptable salt or prodrug thereof wherein A10 is Asn or Asp; A13 is Lys; A14 is His or Ser; A17 is Ser or Asp; A18 is Lys or Asp; A2, is Val or Arg; A22 is Glu, Lys or Asp; A25 is Arg or His; A26 is Lys or Asp; A29 is Ala or Gln; and A30 is Lys or Asp; and the side-chains of A18 and A22 are linked through an amide bond and the side-chains of A26 and A30 are linked through an amide bond to form a bridge.

17. A peptide compound according to claim 6, or a pharmaceutically acceptable salt or prodrug thereof wherein the side-chains of A13 and A17 are linked through an amide bond and the side-chains of A18 and A22 are linked through an amide bond and the side chains of A26 and A30 are linked through an amide bond to form a bridge.

18. A peptide compound according to claim 17, or a pharmaceutically acceptable salt or prodrug thereof, wherein A10 is Asn or Asp; A13 is Lys or Asp; A14 is His or Ser; A17 is Lys or Asp; A18 is Lys or Asp; A21 is Val or Arg; A22 is Glu, Lys or Asp, A25 is Arg or His; A26 is Lys or Asp; A29 is Ala or Gln; and A30 is Lys or Asp.

19. A peptide compound according to claim 1 selected from




or a pharmaceutically acceptable salt or prodrug thereof.
20. A peptide compound according to claim 1 selected from

;




or a pharmaceutically acceptable salt or prodrug thereof. 21. A peptide compound according to claim 1 selected from




or a pharmaceutically acceptable salt or prodrug thereof.

22. Bicyclo(K13-D17,K26-D30)[A1,Nle8,18,D17,L27]hPTH(1-31)NH2 (SEQ ID NO: 79)
or a pharmaceutically acceptable salt or prodrug thereof.

23. A peptide compound according to claim 4, or a pharmaceutically acceptable salt or prodrug thereof wherein X is


24. A peptide compound according to claim 23, or a pharmaceutically acceptable salt or prodrug thereof wherein A8 is Nle and A27 is Leu.

25. A peptide compound according to claim 24, or a pharmaceutically acceptable salt or prodrug thereof wherein the side chains of A18 and A22 are linked through an amide bond to form a bridge.

26. A peptide compound according to claim 25, or a pharmaceutically acceptable salt or prodrug thereof wherein A10 is Asn or Asp; A13 is Lys; A14 is His or Ser; A17 is Asp or Ser; A18 is Asp, Lys or Orn; A2] is Arg or Val; A22 is Asp, Glu, Lys or Orn; A25 is Arg or His; A26 is His or Lys; A29 is Ala or Gln; and A30 is Asp or Glu.

27. A peptide compound according to claim 1 selected from




or a pharmaceutically acceptable salt or prodrug thereof.

28. A pharmaceutical composition comprising a peptide compound of claim 1, or a pharmaceutically acceptable salt or prodrug thereof and a pharmaceutically acceptable carrier.

29. A method of treating diseases associated with calcium regulation in a patient in need of such treatment comprising administering to the patient a therapeutically effective amount of the peptide compound of claim 1, or a pharmaceutically acceptable salt or prodrug thereof.

30. A method of treating diseases associated with calcium regulation in a patient in need of such treatment comprising administering to the patient a therapeutically effective amount of the peptide compound of claim 5, or a pharmaceutically acceptable salt or prodrug thereof.

31. The method of claim 30 wherein said diseases associated with calcium regulation in the body are selected from hypocalcemia; osteopaenia, osteoporosis; hyperparathyroidism; hypoparathyroidism; glucocorticoid- and immunosuppresant-induced osteopaenia: and bone fracture and refracture.

32. A method of treating osteopaenia or osteoporosis in a host mammal in need of such treatment comprising administering to a mammal in need of such treatment a therapeutically effective amount of the peptide compound of claim 5, or a pharmaceutically acceptable salt or prodrug thereof.

33. The method of claim 30 comprising the pulsatile subcutaneous or intrapulmonary administration of a therapeutically effective amount of the peptide compound of claim 1 , or a pharmaceutically acceptable salt or prodrug thereof.

34. The method of claim 32 comprising the pulsatile subcutaneous or intrapulmonary administration of a therapeutically effective amount of the peptide compound of claim 4, or a pharmaceutically acceptable salt or prodrug thereof.

35. A method of treating diseases associated with calcium regulation in a patient in need of such treatment comprising administering to the patient a therapeutically effective amount of the peptide compound of claim 23, or a pharmaceutically acceptable salt or prodrug thereof.

36. The method of claim 35 wherein said diseases associated with calcium regulation in the body are selected from hyperparathyrodism and hyperparathyrodism-related hypercalcemia crisis, hypercalcemia of malignancy, renal failure and hypertension.

37. The method of claim 35 comprising the pulsatile subcutaneous or intrapulmonary administration of a therapeutically effective amount of the peptide compound of claim 23, or a pharmaceutically acceptable salt or prodrug thereof.

38. The method of claim 36 comprising the pulsatile subcutaneous or intrapulmonary administration of a therapeutically effective amount of the peptide compound of claim 23, or a pharmaceutically acceptable salt or prodrug thereof.

39. A peptide compound of formula


or a pharmaceutically acceptable salt or prodrug thereof wherein

X is selected from the group consisting of


Y is selected from the group consisting of



R1a is H, alkyl, aralkyl or -COR2;
R1b is R1a or a group of formula


or
;

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;
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, 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 or Gly or D-Pro or an equivalent amino acid thereof;
A, is His, Ala, Gly or D-Pro or an equivalent amino acid thereof;
A10 is Ala, Asn, Gly Lys, Asp or D-Pro or an equivalent amino acid thereof; 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, Gly or Lys or an equivalent amino acid thereof;
A14 is Ala, Gly, His, Ser, Asp, Lys or D-Pro or an equivalent amino acid thereof; 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, Asp, Gly, Ser, Lys or D-Pro or an equivalent amino acid thereof;

A18 is Lys or an equivalent amino acid thereof;
A19 is Arg or Glu or an equivalent amino acid thereof;
A20 is Arg or an equivalent amino acid thereof;
A21 is Arg, Lys, Asp or Val or an equivalent amino acid thereof;
A22 is Asp, Lys, Orn or Glu or an equivalent amino acid thereof;
A23 is Leu, Phe or Trp or an equivalent amino acid thereof;
A24 is Leu or an equivalent amino acid thereof;
A25 is Arg, His, Asp, Lys or Glu or an equivalent amino acid thereof;

A26 is Lys or His or an equivalent amino acid thereof;
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, Glu or Gln or an equivalent amino acid thereof;
A30 is Asp, Lys or Glu or an equivalent amino acid thereof;
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; and

A34 is Ala or Phe or an equivalent amino acid thereof; and

A35 is absent or a peptide of from 1 to 4 amino acids.

40. A peptide compound according to claim 39, or a pharmaceutically acceptable salt or prodrug thereof wherein R1a is H and Y is NH2.

41. A peptide compound according to claim 40, or a pharmaceutically acceptable salt or prodrug thereof wherein X is


42. A peptide compound according to claim 41 , or a pharmaceutically acceptable salt or prodrugh thereof wherein
A1 is Ser, Ala, Gly or D-Pro;

A2 is Ala, Val or Gly;

A3 is Ala, Ser, Gly or D-Pro;

A4 is Glu, Ala or Gly;

A5 is Ile, His, Ala or Gly;

A6 is Ala, Gln, Gly or D-Pro;

A7 is Ala, Leu, Gly;

A8 is Leu, Nle, Gly or D-Pro;

A9 is His, Ala. Gly or D-Pro;

A10 is Ala, Asn, Gly, Asp or D-Pro; A11 is Ala, Gly, Leu or Lys;
A12 is Ala or Gly;
A13 is Ala, Gly or Lys;
A14 is Ala, Gly, His, Ser or D-Pro; A1s is Ala, Gly, Ile or D-Pro; A16 is Asn, Ala, Gly, D-Pro or Gln; A17 is Ala, Asp, Gly, Ser or D-Pro; A18 is Lys;
A19 is Arg or Glu;
A20 is Arg;
A21 is Arg or Val;
A22 is Asp, Lys, Orn or Glu;
A23 is Leu, Phe or Trp;
A24 is Leu;
A25 is Arg or His;
A26 is Lys or His;

A27 is Leu or Lys;

A28 is Ile or Leu or an equivalent amino acid thereof;

A29 is Ala or Gln;

A30 is Asp or Glu;

A31 is Ile, Leu or Val;

A32 is His;

A33 is Asn or Thr; and

A14 is Ala or Phe.

43. A peptide compound according to claim 42, or a pharmaceutically acceptable salt or prodrug thereof wherein A1 is Ala, Gly or D-Pro; A8 is Nle, A22 is Asp and A27 is Leu.

44. A peptide compound according to claim 43, or a pharmaceutically acceptable salt or prodrug thereof wherein X is R1a-A1-A2-A3-A4-A5-A6-A7-A8-A9-.

45. A peptide compound according to claim 1 which is [A1,Nle8,K18,D22,L27]hPTH(1-31)NH2 (SEQ ID NO: 4)
or a pharmaceutically acceptable salt or prodrug thereof.

46. A pharmaceutical composition comprising a peptide compound of claim 39, or a
pharmaceutically acceptable salt or prodrug thereof, and a pharmaceutically acceptable carrier.

47. A method of treating diseases associated with calcium regulation in a patient in need of such treatment comprising administering to the patient a therapeutically effective amount of the peptide compound of claim 39, or a pharmaceutically acceptable salt or prodrug thereof.

48. The method of claim 47 wherein said diseases associated with calcium regulation in the body are selected from hypocalcemia; osteopaenia, osteoporosis; hyperparathyroidism; hypoparathyroidism; glucocorticoid- and immunosuppresant-induced osteopaenia; and bone fracture and refracture.

49. A method of treating osteopaenia or osteoporosis in a host mammal in need of such treatment comprising administering to a mammal in need of such treatment a therapeutically effective amount of the peptide compound of claim 39, or a pharmaceutically acceptable salt or prodrug thereof.

50. The method of claim 47 comprising the pulsatile subcutaneous or intrapulmonary administration of a therapeutically effective amount of the peptide compound of claim 40, or a pharmaceutically acceptable salt or prodrug thereof.

51. The method of claim 49 comprising the pulsatile subcutaneous or intrapulmonary administration of a therapeutically effective amount of the peptide compound of claim 40, or a pharmaceutically acceptable salt or prodrug thereof.

52. A peptide compound according to claim 1 which is
Cyclo(K18-D22)[A1,Nle8,K18,D22,L27]hPTH(1-31)NH2 (SEQ ID NO: 3) or a pharmaceutically
acceptable salt or prodrug thereof.

53. A peptide compound according to claim 1 which is
Cyclo(K18-D22)[A1,Nle8,K18,D22,L27]hPTH(1-34)NH2 (SEQ ID NO: 46) or a pharmaceutically acceptable salt or prodrug thereof.

54. A peptide compound according to claim 1 which is
Cyclo(K18-D22)[A1,10,Nle8,K18,D22,L27]hPTH(1-31)NH2 (SEQ ID NO: 12) or a pharmaceutically acceptable salt or prodrug thereof.

55. A peptide compound according to claim 1 which is
Cyclo(K18-D22)[A1,12,Nle8,K18,D22,L27]hPTH(1-31 )NH2 (SEQ ID NO: 14) or a pharmaceutically acceptable salt or prodrug thereof.

56. A peptide compound according to claim 1 which is
Cyclo(K18-D22)[A1, 13,Nle8,K18,D22,L27]hPTH(1-31)NH2 (SEQ ID NO: 15) or a pharmaceutically acceptable salt or prodrug thereof.

57. A peptide compound according to claim 1 which is
Cyclo(K18-D22)[A1,14,Nle8,K18,D22,L27]hPTH(1-31)NH2 (SEQ ID NO: 16) or a pharmaceutically acceptable salt or prodrug thereof.

58. A peptide compound according to claim 1 which is
Cyclo(K18-D22)[A1,16,Nle8,K18,D22,L27]hPTH(1-31)NH2 (SEQ ID NO: 18) or a pharmaceutically acceptable salt or prodrug thereof.

59. A peptide compound according to claim 1 which is
Cyclo(K18-D22)[A1,17,Nle8,K18,D22,L27]hPTH(1-31)NH2 (SEQ ID NO: 19) or a pharmaceutically acceptable salt or prodrug thereof.

60. A peptide compound according to claim 1 which is
Cyclo(K18-D22)[A1,G3,Nle8,K18,D22,L27]hPTH(1-31)NH2 (SEQ ID NO: 22) or a pharmaceutically acceptable salt or prodrug thereof.

61. A peptide compound according to claim 1 which is
Cyclo(K18-D22)[A1,G13,Nle8,K18,D22,L27]hPTH(1-31)NH2 (SEQ ID NO: 31) or a pharmaceutically acceptable salt or prodrug thereof.

62. A peptide compound according to claim 1 which is
Cyclo(K18-D22)[A1,G16,Nle8,K18,D22,L27]hPTH(1-31)NH2 (SEQ ID NO: 34) or a pharmaceutically acceptable salt or prodrug thereof.

63. A peptide compound according to claim 1 which is
Cyclo(K18-D22)[A1,G17,Nle8,K18,D22,L27]hPTH(1-31)NH2 (SEQ ID NO: 35) or a pharmaceutically acceptable salt or prodrug thereof.

64. A peptide compound according to claim 1 which is
Cyclo(K18-D22)[D-P1,Nle8,K18,D22,L27]hPTH(1-31)NH2 (SEQ ID NO: 36) or a pharmaceutically acceptable salt or prodrug thereof.

65. A peptide compound according to claim 1 which is
Cyclo(D18-K22)[A1,Nle8,D18,K22,L27]hPTH(1-31)NH2 (SEQ ID NO: 47) or a pharmaceutically acceptable salt or prodrug thereof.

66. A peptide compound according to claim 1 which is
Cyclo(K18-E22)[A1,Nle8,K18,E22,L27]hPTH(1-31)NH2 (SEQ ID NO: 50) or a pharmaceutically acceptable salt or prodrug thereof.

67. A peptide compound according to claim 1 which is
Cyclo(O18-E22)[A1,Nle8,O18,E22,L27]hPTH(1-31)NH2 (SEQ ID NO: 51 ) or a pharmaceutically acceptable salt or prodrug thereof.

68. A peptide compound according to claim 1 which is
Cyclo(K18-D22)[A1,Nle8,K18,D22,L27]hPTH(1-30)NH2 (SEQ ID NO: 52) or a pharmaceutically acceptable salt or prodrug thereof.

69. A peptide compound according to claim 1 which is
Cyclo(K14-D18)[A1,Nle8,K14,D18,L27]hPTH(1-31)NH2 (SEQ ID NO: 67) or a pharmaceutically acceptable salt or prodrug thereof.

70. A peptide compound according to claim 1 which is
Cyclo(K18-D22)[K18,D22]hPTHrP(1-34)NH2 (SEQ ID NO: 71) or a pharmaceutically acceptable salt or prodrug thereof.

71. A peptide compound according to claim 1 which is
Bicyclo(K13-D17,K18-D22)[A1,Nle8,D17,22,K18,L27]hPTH(1-31)NH2 (SEQ ID NO: 73) or a pharmaceutically acceptable salt or prodrug thereof.

72. A peptide compound according to claim 1 which is
Bicyclo(K18-D22,K26-D30)[A1,Nle8,K18,D22,L27]hPTH(1-31)NH2 (SEQ ID NO: 74) or a pharmaceutically acceptable salt or prodrug thereof.

73. A peptide compound according to claim 1 which is
Tricyclo(K13-D17,K18-D22,K26-D30)[A1,Nle8,K18,D17,22,L27]hPTH(1-31)NH2 (SEQ ID NO: 80) or a pharmaceutically acceptable salt or prodrug thereof.