Analogs of parathyroid hormone

1. A peptide of the formula (V):

wherein

A 1 is Ala, Ser, or Dap;

A 3 is Ser or Aib;

A 5 is His, Ile, or Cha;

A 7 is Leu, Cha, Nle, β-Nal, Trp, Pal, Phe, or p-X-Phe in which X is OH, a halogen, or CH 3 ;

A 8 is Leu, Met, or Cha;

A 10 is Asp or Asn;

A 11 is Lys, Leu, Cha, Phe, or β-Nal;

A 12 is Gly or Aib;

A 14 is Ser or His;

A 15 is Ile, or Cha;

A 16 is Gln or Aib;

A 17 is Asp or Aib;

A 18 is Leu, Aib, or Cha;

A 19 is Arg or Aib;

A 22 is Phe, Glu, Aib, Acc, or Cha;

A 23 is Phe, Leu, Lys, Acc, or Cha;

A 24 is Leu, Lys, Acc, or Cha;

A 25 is His, Aib, or Glu;

A 26 is His, Aib, or Lys;

A 27 is Leu, Lys, Acc, or Cha;

A 28 is Ile, Leu, Lys, Acc, or Cha;

A 29 is Ala, Glu, or Aib;

A 30 is Glu, Cha, Aib, Acc, or Lys;

A 31 is Ile, Leu, Cha, Lys, Acc, or deleted;

A 32 is His or deleted;

A 33 is Thr or deleted;

A 34 is Ala or deleted;

each of R 1 and R 2 is, independently, H, C 1-12 alkanyl, C 7-20 phenylalkyl, C 11-20 naphthylalkyl, C 1-12 hydroxyalkyl, C 2-12 hydroxyalkenyl, C 7-20 hydroxyphenylalkyl, or C 11-20 hydroxynaphthylalkyl; or one and only one of R 1 and R 2 is COE 1 in which E 1 is C 1-12 alkyl, C 2-12 alkenyl, C 7-20 phenylalkyl, C 11-20 naphthylalkyl, C 1-12 hydroxyalkyl, C 2-12 hydroxyalkenyl, C 7-20 hydroxyphenylalkyl, or C 11-20 hydroxynaphthylalkyl; and

R 3 is OH, NH 2 , C 1-12 alkoxy, or NH—Y—CH 2 -Z in which Y is a C 1-12 hydrocarbon moiety and Z is H, OH, CO 2 H or CONH 2 ;

provided that at least one of A 23 , A 24 , A 27 , A 28 , or A 31 is Lys; or a pharmaceutically acceptable salt thereof.

2. A peptide of claim 1 , wherein A 22 is Glu, Aib, Acc, or Cha; A 23 is Leu, Lys, Acc, or Cha; A 25 is Aib or Glu; A 26 is Aib or Lys; A 28 is Leu, Lys, Acc, or Cha; A 29 is Glu or Aib; A 30 is Cha, Aib, Acc, or Lys; A 31 is Leu, Cha, Acc, or Lys; A 32 is His; A 33 is Thr; and A 34 is Ala; or a pharmaceutically acceptable salt thereof.

3. A peptide of claim 2 , wherein at least one of A 7 and A 11 is Cha; or a pharmaceutically acceptable salt thereof.

4. A peptide of claim 2 , wherein at least one of A 16 or A 19 is Aib; or a pharmaceutically acceptable salt thereof.

5. A pharmaceutical composition comprising the peptide of claim 1 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or diluent.

6. A pharmaceutical composition comprising the peptide of claim 1 or a pharmaceutically acceptable salt thereof, a bisphosphonate or calcitonin, and a pharmaceutically acceptable carrier or diluent.

7. A pharmaceutical composition comprising a pharmaceutically acceptable carrier or diluent and a peptide of the following formula (VI):

wherein

A 1 is Ala, Ser, or Dap;

A 3 is Ser or Aib;

A 5 is His, Ile, Acc, or Cha;

A 7 is Leu, Cha, Nle, β-Nal, Trp, Pal, Acc, Phe, or p-X-Phe in which X is OH, a halogen, or CH 3 ;

A 8 is Leu, Met, Acc, or Cha;

A 10 is Asp or Asn;

A 11 is Lys, Leu, Cha, Acc, Phe, or β-Nal;

A 12 is Gly, Acc, or Aib;

A 14 is Ser or His;

A 15 is Ile, Acc, or Cha;

A 16 is Gln or Aib;

A 17 is Asp or Aib;

A 18 is Leu, Aib, Acc, or Cha;

A 19 is Arg or Aib;

A 22 is Phe, Glu, Aib, Acc, or Cha;

A 23 is Phe, Leu, Lys, Acc, or Cha;

A 24 is Leu, Lys, Acc, or Cha;

A 25 is His, Lys, Aib, Acc, or Glu;

A 26 is His, Aib, Acc, or Lys;

A 27 is Leu, Lys, Acc, or Cha;

A 28 is Ile, Leu, Lys, Acc, or Cha;

A 29 is Ala, Glu, Acc, or Aib;

A 30 is Glu, Leu, Nle, Cha, Aib, Acc, or Lys;

A 31 is Ile, Leu, Cha, Lys, Acc, or deleted;

A 32 is His or deleted;

A 33 is Thr or deleted;

A 34 is Ala or deleted;

each of R 1 and R 2 is, independently, H, C 1-12 alkanyl, C 7-20 phenylalkyl, C 11-20 naphthylalkyl, C 1-12 hydroxyalkyl, C 2-12 hydroxyalkenyl, C 7-20 hydroxyphenylalkyl, or C 11-20 hydroxynaphthylalkyl; or one and only one of R 1 and R 2 is COE 1 in which E 1 is C 1-12 alkyl, C 2-12 alkenyl, C 7-20 phenylalkyl, C 11-20 naphthylalkyl, C 1-12 hydroxyalkyl, C 2-12 hydroxyalkenyl, C 7-20 hydroxyphenylalkyl, or C 11-20 hydroxynaphthylalkyl; and

R 3 is OH, NH 2 , C 1-12 alkoxy, or NH—Y—CH 2 -Z in which Y is a C 1-12 hydrocarbon moiety and Z is H, OH, CO 2 H or CONH 2 ;

provided that at least one of A 5 , A 7 , A 8 , A 11 , A 12 , A 15 , A 18 , A 22 , A 23 , A 24 , A 25 , A 26 , A 27 , A 28 , A 29 , A 30 , or A 31 is Acc; or a pharmaceutically acceptable salt thereof.

8. A peptide of formula (III):

wherein

A 1 is Ser, Ala, or Dap;

A 3 is Ser, Thr, or Aib;

A 5 is Leu, Nle, Ile, Cha, β-Nal, Trp, Pal, Phe or p-X-Phe, in which X is OH, a halogen, or CH 3 ;

A 7 is Leu, Ile, Nle, Cha, β-Nal, Trp, Pal, Phe, or p-X-Phe in which X is OH, a halogen, or CH 3 ;

A 8 is Met, Nva, Leu, Val, Ile, Cha, or Nle;

A 11 is Leu, Nle, Ile, Cha, β-Nal, Trp, Pal, Phe or p-X-Phe in which X is OH, a halogen, or CH 3 ;

A 12 is Gly or Aib;

A 15 is Leu, Nle, Ile, Cha, β-Nal, Trp, Pal, Phe, or p-X-Phe in which X is OH, a halogen, or CH 3 ;

A 16 is Ser, Asn, Ala, or Aib;

A 17 is Ser, Thr, or Aib;

A 18 is Met, Nva, Leu, Val, Ile, Nle, Cha, or Aib;

A 19 is Glu or Aib;

A 21 is Val, Cha, or Met;

A 23 is Trp or Cha;

A 24 is Leu or Cha;

A 27 is Lys, Aib, Leu, hArg, Gln, or Cha;

A 28 is Leu or Cha;

A 30 is Asp or Lys;

A 31 is Val, Nle, Cha, or deleted;

A 32 is His or deleted;

A 33 is Asn or deleted;

A 34 is Phe, Tyr, Amp, Aib, or deleted;

each of R 1 and R 2 is, independently, H, C 1-12 alkyl, C 2-12 alkenyl, C 7-20 phenylalkyl, C 11-20 naphthylalkyl, C 1-12 hydroxyalkyl, C 2-12 hydroxyalkenyl, C 7-20 hydroxyphenylalkyl, or C 11-20 hydroxynaphthylalkyl; or one and only one of R 1 and R 2 is COE 1 in which E 1 is C 1-12 alkyl, C 2-12 alkenyl, C 7-20 phenylalkyl, C 11-20 naphthylalkyl, C 1-12 hydroxyalkyl, C 2-12 hydroxyalkenyl, C 7-20 hydroxy-phenylalkyl, or C 11-20 hydroxynaphthylalkyl; and

R 3 is OH, NH 2 , C 1-12 alkoxy, or NH—Y—CH 2 -Z in which Y is a C 1-12 hydrocarbon moiety and Z is H, OH, CO 2 H, or CONH 2 ; or a pharmaceutically acceptable salt thereof;

provided that at least A 7 is β-Nal, Trp, Pal, Phe, or p-X-Phe; A 15 is β-Nal, Trp, Pal, Phe, or p-X-Phe; A 27 is hArg; or A 31 is Nle.

9. A peptide of claim 8 , wherein

A 3 is Ser or Aib;

A 8 is Met, Nva, Leu, Val, Ile, or Nle;

A 16 is Asn or Aib;

A 18 is Met, Aib, or Nle;

A 21 is Val;

A 27 is Lys, Aib, Leu, hArg, or Cha;

A 31 is Val, Nle, or Cha;

A 32 is His;

A 33 is Asn;

A 34 is Phe, Tyr, Amp, or Aib;

R 1 is H; R 2 is H; and R 3 is NH 2 ;

or a pharmaceutically acceptable salt thereof.

10. A method of treating osteoporosis in a patient, which comprises administering to said patient a peptide of claim 8 or a pharmaceutically acceptable salt thereof.

11. A method of treating osteoporosis in a patient, which comprises administering to said patient a combination of a bisphosphonate or calcitonin and a peptide of claim 8 or a pharmaceutically acceptable salt thereof.

12. A pharmaceutical composition comprising a peptide of claim 8 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or diluent.

13. A pharmaceutical composition comprising a peptide of claim 8 or a pharmaceutically acceptable salt thereof, a bisphosphonate or calcitonin and a pharmaceutically acceptable salt thereof.

14. A method of treating osteoporosis in a patient, which comprises administering to said patient a peptide of claim 9 or a pharmaceutically acceptable salt thereof.

15. A method of treating osteoporosis in a patient, which comprises administering to said patient a combination of a bisphosphonate or calcitonin and a peptide of claim 9 or a pharmaceutically acceptable salt thereof.

16. A pharmaceutical composition comprising a peptide of claim 9 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or diluent.