Pth2 receptor selective compounds

Abstract

This invention relates to a series of PTH and PTHrP analogues that selectively bind to PTH2 receptors and as such may be useful in treating abnormal CNS functions; abnormal pancreatic functions; divergence from normal mineral metabolism and homeostasis; male infertility; regulation of abnormal blood pressure; and hypothalmic disease.

1 . A PTH analogue or a truncated PTH analogue or a pharmaceutically acceptable salt thereof that selectively binds to the PTH2 receptor. 
   
   
       2 . A PTH analogue or a truncated PTH analogue or a pharmaceutically acceptable salt thereof according to  claim 1  where said analogue is a selective PTH2 receptor agonist. 
   
   
       3 . A PTH analogue or a truncated PTH analogue or a pharmaceutically acceptable salt thereof according to  claim 1  where said analogue is a selective PTH2 receptor antagonist. 
   
   
       4 . A method of selectively binding a PTH2 receptor which comprises administering to a patient in need thereof an effective amount of an analogue according to  claim 1  or a pharmaceutically-acceptable salt thereof. 
   
   
       5 . A method of selectively eliciting an agonist response from the PTH2 receptor which comprises administering to a patient in need thereof an effective amount of an analogue according to  claim 2  or a pharmaceutically acceptable salt thereof. 
   
   
       6 . A method of selectively eliciting an antagonist response from the PTH2 receptor which comprises administering to a patient in need thereof an effective amount of an analogue according to  claim 3  or a pharmaceutically acceptable salt thereof. 
   
   
       7 . An analogue according to  claim 1  wherein said analogue is of formula (I),
   (R 1 R 2 )-A 1 -A 2 -A 3 -A 4 -A 5 -A 6 -A 7 -A 8 -A 9 -A 10 -A 11 -A 12 -A 13 -A 14 -A 15 -A 16 -A 17 -A 18 -A 19 -A 20 -A 21 -A 22 -A 23 -A 24 -A 25 -A 26 -A 27 -A 28 -A 29 -A 30 -A 31 -A 32 -A 33 -A 34 -A 35 -A 36 -A 37 -A 38 -R 3 ,  (I)   or a pharmaceutically-acceptable salt thereof wherein   A 1  is a hydrophilic or a lipophilic amino acid;   A 2  is a lipophilic amino acid;   A 3  is a hydrophilic or a lipophilic amino acid;   A 4  is a hydrophilic amino acid;   A 5  is a hydrophilic or a lipophilic amino acid;   A 6  is a hydrophilic amino acid or is deleted;   A 7  is a hydrophilic or a lipophilic amino acid or is deleted;   A 8  is a lipophilic amino acid or is deleted;   A 9  is a hydrophilic amino acid or is deleted;   A 10  is a hydrophilic amino acid or is deleted;   A 11  is a hydrophilic or a lipophilic amino acid or is deleted;   A 12  is a hydrophilic or a lipophilic amino acid or is deleted;   A 13  is a hydrophilic amino acid;   A 14  is a hydrophilic amino acid or is deleted;   A 15  is a lipophilic amino acid or is deleted;   A 16  is a hydrophilic or a lipophilic amino acid or is deleted;   A 17  is a hydrophilic or a lipophilic amino acid or is deleted;   A 18  is a lipophilic amino acid or is deleted;   A 19  is a hydrophilic or a lipophilic amino acid or is deleted;   A 20  is a hydrophilic amino acid or is deleted;   A 21  is a hydrophilic or a lipophilic amino acid or is deleted;   A 22  is a lipophilic or a hydrophilic amino acid or is deleted;   A 23  is a hydrophilic or a lipophilic amino acid;   A 24  is a hydrophilic or a lipophilic amino acid;   A 25  is a hydrophilic amino acid;   A 26  is a hydrophilic amino acid;   A 27  is a lipophilic or a hydrophilic amino acid;   A 28  is a lipophilic amino acid;   A 29  is a lipophilic or a hydrophilic amino acid;   A 30  is a hydrophilic or a lipophilic amino acid;   A 31  is a lipophilic or a hydrophilic amino acid or is deleted;   A 32  is a hydrophilic amino acid or is deleted;   A 33  is a hydrophilic amino acid or is deleted;   A 34  is a lipophilic amino acid or is deleted;   A 35  is a lipophilic amino acid or is deleted;   A 36  is a lipophilic or a hydrophilic amino acid or is deleted;   A 37  is a lipophilic amino acid or is deleted;   A 38  is a lipophilic or a hydrophilic amino acid or is deleted;
 R 1  and R 2  are each independently selected from the group consisting of H, (C 1-30 )alkyl, (C 2-30 )alkenyl, phenyl-(C 1-30 )alkyl, naphthyl(C 1-30 )alkyl, hydroxy(C 1-30 )alkyl, hydroxy(C 2-30 )alkenyl, hydroxy-phenyl(C 1-30 )alkyl or hydroxy-naphthyl(C 1-30 )alkyl; 
 or one of R 1  or R 2  is COE 1  where E 1  is (C 1-30 )alkyl, (C 2-30 )alkenyl, phenyl(C 1-30 )alkyl, naphthyl(C 1-30 )alkyl, hydroxy(C 1-30 )alkyl, hydroxy(C 2-30 )alkenyl, hydroxy-phenyl(C 1-30 )alkyl or hydroxy-naphthyl(C 1-30 )alkyl; and 
 R 3  is OH, NH 2 , (C 1-30 )alkoxy or NH—Y—CH 2 -Z, where Y is a (C 1-30 ) hydrocarbon moiety and Z is CO 2 H or CONH 2 ; 
   provided that the compound is not PTH(1-34)R 3 , PTH(1-35)R 3 , PTH(1-36)R 3 , PTH(1-37)R 3 , or PTH(1-38)R 3 .   
   
   
       8 . A method of selectively binding a PTH2 receptor which comprises administering to a patient in need thereof an effective amount of an analogue according to  claim 7  or a pharmaceutically-acceptable salt thereof. 
   
   
       9 . An analogue according to  claim 1  of formula (II),
   (R 1 R 2 )-A 1 -A 2 -A 3 -A 4 -A 5 -A 6 -A 7 -A 8 -A 9 -A 10 -A 11 -A 12 -A 13 -A 14 -A 15 -A 16 -A 17 -A 18 -A 19 -A 20 -A 21 -A 22 -A 23 -A 24 -A 25 -A 26 -A 27 -A 28 -A 29 -A 30 -A 31 -A 32 -A 33 -A 34 -A 35 -A 36 -A 37 -A 38 -R 3 ,  (III)   or a pharmaceutically-acceptable salt thereof wherein   A 1  is Ser, Ala, Dap, Thr, Aib or is deleted;   A 2  is Val, Leu, Ile, Phe, Nle, β-Nal, Aib, p-X-Phe, Acc, Cha, Met or is deleted;   A 3  is Ser, Thr, Aib or is deleted;   A 4  is Glu, Asp or is deleted;   A 5  is Leu, Val, Nle, Ile, Cha, β-Nal, Trp, Pal, Acc, Phe, p-X-Phe or is deleted;   A 6  is Gln, a hydrophilic amino acid or is deleted;   A 7  is Leu, Val, Nle, Ile, Cha, β-Nal, Trp, Pal, Acc, Phe, p-X-Phe, a lipophilic amino acid, or is deleted;   A 8  is Met, Nva, Leu, Val, Ile, Cha, Acc, Nle, p-X-Phe, Phe, β-Nal, Bpa, a lipophilic amino acid or is deleted;   A 9  is His, a hydrophilic amino acid or is deleted;   A 10  is Asn, a hydrophilic amino acid or is deleted;   A 11  is Leu, Val, Nle, Ile, Cha, β-Nal, Trp, Pal, Acc, Phe, p-X-Phe, a hydrophilic amino acid or is deleted;   A 12  is Gly, Acc, Aib, or is deleted;   A 13  is Lys, Arg or HN—CH((CH 2 ) n NH—R 4 )—C(O);   A 14  is His or is deleted;   A 15  is Leu, Val, Nle, Ile, Cha, β-Nal, Trp, Pal, Acc, Phe, p-X-Phe or is deleted;   A 16  is Ser, Asn, Ala, Aib or is deleted;   A 17  is Ser, Thr, Aib or is deleted;   A 18  is Met, Nva, Leu, Val, Ile, Nle, p-X-Phe, Phe, ,-Nal, Acc, Cha, Aib or is deleted;   A 19  is Glu, Aib or is deleted;   A 20  is Arg, Lys, HN—CH((CH 2 ) n NH—R 4 )—C(O) or is deleted;   A 21  is Val, Leu, Ile, Phe, Nle, β-Nal, Aib, p-X-Phe, Acc, Cha, Met or is deleted;   A 22  is Acc, Aib, Glu or is deleted;   A 23  is Trp, Acc, Phe, p-X-Phe, Aib, β-Nal or Cha;   A 24  is Leu, Acc, Ile, Val, Phe, β-Nal, Nle, Aib, p-X-Phe or Cha;   A 25  is Arg, Lys or HN—CH((CH 2 ) n NH—R 4 )—C(O);   A 26  is Arg, Lys or HN—CH((CH 2 ) n NH—R 4 )—C(O);   A 27  is Lys, Aib, Leu, hArg, Gln, Acc, Arg, Cha, Nle, Ile, Val, Phe, β-Nal, or p-X-Phe,   where the Lys is optionally substituted on the e-amino group by an acyl group;   A 23  is Leu, Acc, Cha, Ile, Val, Phe, Nle, β-Nal, Aib or p-X-Phe;   A 29  is Gln, Acc or Aib;   A 30  is Asp, Lys, Arg or is deleted;   A 31  is Val, Leu, Nle, Acc, Cha, Phe, Ile, β-Nal Aib, p-X-Phe or is deleted;   A 32  is His or is deleted;   A 33  is Asn or is deleted;   A 34  is Phe, Tyr, Amp, Aib, β-Nal, Cha, Nle, Leu, Ile, Acc, p-X-Phe or is deleted;   A 35  is Val, Leu, Nle, Acc, Cha, Phe, Ile, β-Nal Aib, p-X-Phe or is deleted;   A 36  is Ala, Val, Aib, Acc, Nva, Abu or is deleted;   A 37  is Leu, Val, Nle, Ile, Cha, β-Nal, Trp, Pal, Acc, Phe, p-X-Phe, a lipophilic amino acid, or is deleted;   A 38  is Gly, Acc, Aib, or is deleted;
 where X for each occurrence is independently selected from the group consisting of OH, a halo and CH 3 ; 
 R 1  and R 2  are each independently selected from the group consisting of H, (C 1-30 )alkyl, (C 2-30 )alkenyl, phenyl-(C 1-30 )alkyl, naphthyl(C 1-30 )alkyl, hydroxy(C 1-30 )alkyl, hydroxy(C 2-30 )alkenyl, hydroxy-phenyl(C 1-30 )alkyl or hydroxy-naphthyl(C 1-30 )alkyl; 
 or one of R 1  or R 2  is COE 1  where E 1  is (C 1-30 )alkyl, (C 2-30 )alkenyl, phenyl(C 1-30 )alkyl, naphthyl(C 1-30 )alkyl, hydroxy(C 1-30 )alkyl, hydroxy(C 2-30 )alkenyl, hydroxy-phenyl(C 1-30 )alkyl or hydroxy-naphthyl(C 1-30 )alkyl; 
 R 3  is OH, NH 2 , (C 1-30 )alkoxy or NH—Y—CH 2 -Z, where Y is a (C 1-30 ) hydrocarbon moiety and Z is CO 2 H or CONH 2 ; 
 n for each occurrence is independently an integer from 1 to 5; and 
 R 4  for each occurrence is independently (C 1 -C 30 )alkyl, (C 1 -C 30 )acyl or —C((NH)(NH 2 )); 
   provided that the compound is not PTH(1-34)R 3 , PTH(1-35)R 3 , PTH(1-36)R 3 , PTH(1-37)R 3 , or PTH(1-38)R 3 .   
   
   
       10 . A compound of the formula (III),
   (R 1 R 2 )-A 1 -A 2 -A 3 -A 4 -A 5 -A 6 -A 7 -A 8 -A 9 -A 10 -A 11 -A 12 -A 13 -A 14 -A 15 -A 16 -A 17 -A 18 -A 19 -A 20 -A 21 -A 22 -A 23 -A 24 -A 25 -A 26 -A 27 -A 28 -A 29 -A 30 -A 31 -A 32 -A 33 -A 34 -A 35 -A 36 -A 37 -A 38 -R 3 ,  (III)   or a pharmaceutically-acceptable salt thereof wherein   A 1  is Ser, Ala, Dap, Thr, Aib or is deleted;   A 2  is Val, Leu, Ile, Phe, Nle, p-Nal, Aib, p-X-Phe, Acc, Cha, Met or is deleted;   A 3  is Ser, Thr, Aib or is deleted;   A 4  is Glu, Asp or is deleted;   A 5  is Leu, Val, Nle, Ile, Cha, P-Nal, Trp, Pal, Acc, Phe, p-X-Phe or is deleted;   A 6  is Gin, a hydrophilic amino acid or is deleted;   A 7  is Leu, Val, Nle, Ile, Cha, β-Nal, Trp, Pal, Acc, Phe, p-X-Phe, a lipophilic amino acid, or is deleted;   A 8  is Met, Nva, Leu, Val, Ile, Cha, Acc, Nle, p-X-Phe, Phe, β-Nal, Bpa, a lipophilic amino acid or is deleted;   A 9  is His, a hydrophilic amino acid or is deleted;   A 10  is Asn, a hydrophilic amino acid or is deleted;   A 11  is Leu, Val, Nle, Ile, Cha, β-Nal, Trp, Pal, Acc, Phe, p-X-Phe, a hydrophilic amino acid or is deleted;   A 12  is Gly, Acc, Aib, or is deleted;   A 13  is Lys, Arg or HN—CH((CH 2 ) n NH—R 4 )—C(O);   A 14  is His or is deleted;   A 15  is Leu, Val, Nle, Ile, Cha, β-Nal, Trp, Pal, Acc, Phe, p-X-Phe or is deleted;   A 16  is Ser, Asn, Ala, Aib or is deleted;   A 17  is Ser, Thr, Aib or is deleted;   A 18  is Met, Nva, Leu, Val; Ile, Nle, p-X-Phe, Phe, β-Nal, Acc, Cha, Aib or is deleted;   A 19  is Glu, Aib or is deleted;   A 20  is Arg, Lys, HN—CH((CH 2 ) n NH—R 4 )—C(O) or is deleted;   A 21  is Val, Leu, Ile, Phe, Nle, β-Nal, Aib, p-X-Phe, Acc, Cha, Met or is deleted;   A 22  is Acc, Aib, Glu or is deleted;   A 23  is Trp, Acc, Phe, p-X-Phe, Aib, β-Nal or Cha;   A 24  is Leu, Acc, Ile, Val, Phe, β-Nal, Nle, Aib, p-X-Phe or Cha;   A 25  is Arg, Lys or HN—CH((CH 2 ) n NH—R 4 )—C(O);   A 26  is Arg, Lys or HN—CH((CH 2 ) n NH—R 4 )—C(O);   A 27  is Lys, Aib, Leu, hArg, Gln, Acc, Arg, Cha, Nle, Ile, Val, Phe, β-Nal, or p-X-Phe,   where the Lys is optionally substituted on the e-amino group by an acyl group;   A 28  is Leu, Acc, Cha, Ile, Val, Phe, Nle, β-Nal, Aib or p-X-Phe;   A 29  is Gln, Acc or Aib;   A 30  is Asp, Lys, Arg or is deleted;   A 31  is Val, Leu, Nle, Acc, Cha, Phe, Ile, β-Nal Aib, p-X-Phe or is deleted;   A 32  is His or is deleted;   A 33  is Asn or is deleted;   A 34  is Phe, Tyr, Amp, Aib, β-Nal, Cha, Nle, Leu, Ile, Acc, p-X-Phe or is deleted;   A 35  is Val, Leu, Nle, Acc, Cha, Phe, Ile, β-Nal Aib, p-X-Phe or is deleted;   A 36  is Ala, Val, Aib, Acc, Nva, Abu or is deleted;   A 37  is Leu, Val, Nle, Ile, Cha, β-Nal, Trp, Pal, Acc, Phe, p-X-Phe, a lipophilic amino acid, or is deleted;   A 38  is Gly, Acc, Aib, or is deleted;
 where X for each occurrence is independently selected from the group consisting of OH, a halo and CH 3 ; 
 R 1  and R 2  are each independently selected from the group consisting of H, (C 1-30 )alkyl, (C 2-30 )alkenyl, phenyl-(C 1-30 )alkyl, naphthyl(C 1-30 )alkyl, hydroxy(C 1-30 )alkyl, hydroxy(C 2-30 )alkenyl, hydroxy-phenyl(C 1-30 )alkyl or hydroxy-naphthyl(C 1-30 )alkyl; 
 or one of R 1  or R 2  is COE 1  where E 1  is (C 1-30 )alkyl, (C 2-30 )alkenyl, phenyl(C 1-30 )alkyl, naphthyl(C 1-30 )alkyl, hydroxy(C 1-30 )alkyl, hydroxy(C 2-30 )alkenyl, hydroxy-phenyl(C 1-30 )alkyl or hydroxy-naphthyl(C 1-30 )alkyl; 
 R 3  is OH, NH 2 , (C 1-30 )alkoxy or NH—Y—CH 2 -Z, where Y is a (C 1-30 ) hydrocarbon moiety and Z is CO 2 H or CONH 2 ; 
 n for each occurrence is independently an integer from 1 to 5; and 
 R 4  for each occurrence is independently (C 1 -C 30 )alkyl, (C 1 -C 30 )acyl or —C((NH)(NH 2 )); 
   provided that when A 8  is not a lipophilic D-amino acid or is not deleted then at least one of A 6 , A 7 , A 9 , A 10 , A 11  and A 12  is a D-amino acid or at least one of A 6 , A 7 , A 9 , A 10 , A 11 , A 12 , A 13 , A 14 , A 15 , A 16 , A 17 , A 18 , A 19 , A 20 , A 21  and A 22  is deleted;   and further provided that when the compound contains a D-amino acid then A 36  is deleted.   
   
   
       11 . A compound according to  claim 10  wherein said compound is
 [D-Nle 8 , Nle 18 , Tyr 34 ]hPTH(1-34)NH 2 ,   [D-Nle 8 ]hPTH(1-34)NH 2 ,   [D-Leu 8 , Nle 18 , Tyr 34 ]hPTH(1-34)NH 2 ,   [D-Cha 8 , Nle 18 , Tyr 34 ]hPTH(1-34)NH 2 ,   [D-Phe 8 , Nle 18 , Tyr 34 ]hPTH(1-34)NH 2 ,   [D-Nal 8 , Nle 18 , Tyr 34 ]hPTH(1-34)NH 2 ,   [D-Abu 8  Nle 18 , Tyr 34 ]hPTH(1-34)NH 2 ,   [D-Met 8 ]hPTH(1-34)NH 2 ,   [Cha 7,11 , D-Met 8 ]hPTH(1-34)NH 2 ,   [D-Ile 8 ]hPTH(1-34)NH 2 ,   [Cha 7,11 , D-Ile 8 , Nle 18 , Tyr 34 ]hPTH(1-34)NH 2 ,   [D-Ile 8 , Nle 18 , Tyr 34 ]hPTH(1-34)NH 2 ,   [D-Leu 8 ]hPTH(1-34)NH 2 ,   [Cha 7,11 , D-Leu 8 , Nle 18 , Tyr 34 ]hPTH(1-34)NH 2 ,   [D-Val 8 ]hPTH(1-34)NH 2 ,   [Cha 7,11 , D-Val 8 , Nle 18  Tyr 34 ]hPTH(1-34)NH 2 ,   [D-Val 8 , Nle 18 , Tyr 34 ]hPTH(1-34)NH 2 ,   [D-Cha 8 ]hPTH(1-34)NH 2 ,   [Cha 7,11 , D-Cha 8 , Nle 18 , Tyr 34 ]hPTH(1-34)NH 2 ,   [D-Ala 8 ]hPTH(1-34)NH 2 ,   [Cha 7,11 , D-Ala 8 , Nle 18 , Tyr 34 ]hPTH(1-34)NH 2 ,   [D-Ala 8 , Nle 18 , Tyr 34 ]hPTH(1-34)NH 2 ,   [D-Phe 8 ]hPTH(1-34)NH 2 ,   [Cha 7,11 , D-Phe 8 , Nle 18 , Tyr 34 ]hPTH(1-34)NH 2 ,   [D-Nal 8 ]hPTH(1-34)NH 2 ,   [D-Trp 8 ]hPTH(1-34)NH 2 ,   [Cha 7,11 , D-Trp 8 , Nle 18 , Tyr 34 ]hPTH(1-34)NH 2 ,   [D-Trp 8 , Nle 18 , Tyr 34 ]hPTH(1-34)NH 2 ,   [D-Abu 8 ]hPTH(1-34)NH 2 ,   [Cha 7,11 , D-Abu 8 , Nle 18 , Tyr 34 ]hPTH(1-34)NH 2 ,   [D-Nle 8 , Nle 18 ]hPTH(1-34)NH 2 ,   [des-Met 8 ]hPTH(1-34)NH 2 ,   [Cha 7,11 , des-Met 8 ]hPTH(1-34)NH 2 ,   [Cha 7,11 , des-Met 8 , des-Met 18 , Tyr 34 ]hPTH(1-34)NH 2 ,   [des-Met 8 , des-Met 18 ]h PTH(1-34)NH 2 ,   [Cha 7,11 , des-Met 8 , des-Met 18 ]hPTH(1-34)NH 2 ,   [des-Met 8 , Nle 18 , Tyr 34 ]hPTH(1-34)NH 2 ,   [des-Met 18 ]hPTH(1-34)NH 2 ,   [Cha 7,11 , des-Met 18 ]hPTH(1-34)NH 2 ,   [Cha 7,11 , des-Met 18 , Tyr 34 ]hPTH(1-34)NH 2 ,   [D-Nle 8 , des-Met 18 , Tyr 34 ]hPTH(1-34)NH 2 ,   [des-Glu 6 , Nle 8,18 , Tyr 34 ]hPTH(1-34)NH 2 ,   [des-Leu 7 , Nle 8,18 , Tyr 34 ]hPTH(1-34)NH 2 ,   [des-His 9 , Nle 8,18 , Tyr 34 ]hPTH(1-34)NH 2 ,   [des-Asn 10 , Nle 8,18 , Tyr 34 ]hPTH(1-34)NH 2 ,   [des-Leu 11 , Nle 8,18 , Tyr 34 ]hPTH(1-34)NH 2 ,   [des-Gly 12 , Nle 8,18 , Tyr 34 ]hPTH(1-34)NH 2 ,   [des-Lys 13 , Nle 8,18 , Tyr 34 ]hPTH(1-34)NH 2 ,   [des-His 14 , Nle 8,18 , Tyr 34 ]hPTH(1-34)NH 2 ,   [des-Leu 15 , Nle 8,18 , Tyr 34 ]hPTH(1-34)NH 2 ,   [des-Asn 16 , Nle 8,18 , Tyr 34 ]hPTH(1-34)NH 2 ,   [des-Ser 17 , Nle 8,18 , Tyr 34 ]hPTH(1-34)NH 2 ,   [des-Glu 19 , Nle 8,18 , Tyr 34 ]hPTH(1-34)NH 2 ,   [des-Arg 20 , Nle 8,18 , Tyr 34 ]hPTH(1-34)NH 2 ,   [des-Val 21 , Nle 8,18 , Tyr 34 ]hPTH(1-34)NH 2 ,   [des-Glu 22 , Nle 8,18 , Tyr 34 ]hPTH(1-34)NH 2 ,   [des-Glu 6 , Cha 7,11 , Nle 8,18 , Tyr 34 ]hPTH(1-34)NH 2 ,   [des-Leu 7 , Nle 8,18 , Cha 11 , Tyr 34 ]hPTH(1-34)NH 2 ,   [Cha 7,11 , des-His 9 , Nle 8,18 , Tyr 34 ]hPTH(1-34)NH 2 ,   [des-Glu 6 , Cha 7,11 , D-Nle 8 , Nle 18 , Tyr 34 ]hPTH(1-34)NH 2 ,   [des-Leu 7 , D-Nle 8,18 , Cha 11 , Nle 18 , Tyr 34 ]hPTH(1-34)NH 2 ,   [Cha 7,11 , D-Nle 8 , des-His 9 , Nle 18 , Tyr 34 ]hPTH(1-34)NH 2 ,   [Cha 7,11 , D-Nle 8 , Nle 18 , Tyr 34 ]hPTH(1-31)NH 2 ,   [Cha 7,11 , des-Met 8 , Nle 18 , Tyr 34 ]hPTH(1-34)NH 2 ,   [Cha 7,11 , D-Nle 8 , des-Met 18 , Tyr 34 ]hPTH(1-34)NH 2 ,   [Cha 7,11  des-Met 8 , des-His 9 , des-Asn 10 ]hPTH(1-34)NH 2 ,   [Cha 7,11  des-Ser 17 , des-Met 18 , des-Glu 19 ]hPTH(1-34)NH 2 ,   [D-Met 8 , Nle 18 , Tyr 34 ]hPTH(1-34)NH 2 ,   [D-Met 8 , Tyr 34 ]hPTH(1-34)NH 2 ,   [D-Bpa 8 , Tyr 34 ]hPTH(1-34)NH 2 ,   [D-Nle 8 , Nle 18 , Tyr 34 ]hPTH(7-34)NH 2 ,   [D-Nle 8 , Nle 18 ]hPTH(7-34)NH 2  or   [D-Met 8 ]hPTH(7-34)NH 2 .   
   
   
       12 . A compound according to  claim 11  wherein said compound is
 [Cha 7,11 , des-Met 8 , Nle 18 , Tyr 34 ]hPTH-(1-34)NH 2 ,   [Cha 7,11 , D-Nle 8 , des-Met 18 , Tyr 34 ]hPTH-(1-34)NH 2 ,   [Cha 7,11 , D-Nle 8 , Nle 18 , Tyr 34 ]hPTH-(1-34)NH 2 ,   [D-Nle 8 , Nle 18 , Tyr 34 ]hPTH(1-34)NH 2  or [D-Bpa 8 , Tyr 34 ]hPTH(1-34)NH 2 .   
   
   
       13 . A PTHrP analogue of formula (IV) that selectively binds to the PTH2 receptor,
   (R 1 R 2 )-A 1 -A 2 -A 3 -A 4 -A 5 -A 6 -A 7 -A 8 -A 9 -A 10 -A 11 -A 12 -A 13 -A 14 -A 15 -A 16 -A 17 A 18 -A 19 -A 20 -A 21 -A 22 -A 23 -A 24 -A 25 -A 26 -A 27 -A 28 -A 29 -A 30 -A 31 -A 32 -A 33 -A 33 -A 35 -A 36 -A 37 -A 38 -R 3 ,  (IV)   or a pharmaceutically acceptable salt thereof, wherein   A 1  is Ala, Ser, Dap, Thr, Aib or is deleted;   A 2  is Val or is deleted;   A 3  is Ser, Aib, Thr or is deleted;   A 4  is Glu, Asp or is deleted;   A 5  is His, Ile, Acc, Val, Nle, Phe, Leu, p-X-Phe, 8-Nal, Aib, Cha or is deleted;   A 6  is Gln, a hydrophilic amino acid or is deleted;   A 7  is Leu, Val, Cha, Nle, β-Nal, Trp, Pal, Acc, Phe, p-X-Phe, Aib, a lipophilic amino acid or is deleted;   A 8  is Leu, Met, Acc, Cha, Aib, Nle, Phe, Ile, Val, β-Nal, p-X-Phe, a lipophilic amino acid or is deleted;   A 9  is His, a hydrophilic amino acid or is deleted;   A 10  is Asp, Asn, a hydrophilic amino acid or is deleted;   A 11  is Lys, Arg, Leu, Cha, Aib, p-X-Phe, Ile, Val, Nle, Acc, Phe, β-Nal, HN—CH((CH 2 ) n NH—R 4 )—C(O), a lipophilic D-amino acid, a hydrophilic amino acid or is deleted;   A 12  is Gly, Acc, Aib or is deleted;   A 13  is Lys, Arg, HN—CH((CH 2 ) n NH—R 4 )—C(O) or is deleted;   A 14  is Ser, His or is deleted;   A 15  is Ile, Acc, Cha, Leu, Phe, Nle, β-Nal, Trp, p-X-Phe, Val, Aib or is deleted;   A 16  is Gln, Aib or is deleted;   A 17  is Asp, Aib or is deleted;   A 18  is Leu, Aib, Acc, Cha, Phe, Ile, Nle, β-Nal, Val, p-X-Phe or is deleted;   A 19  is Arg, Lys, Aib, HN—CH((CH 2 ) n NH—R 4 )—C(O) or is deleted;   A 20  is Arg, Lys, HN—CH((CH 2 ) n NH—R 4 )—C(O) or is deleted;   A 21  is Arg, Lys, HN—CH((CH 2 ) n NH—R 4 )—C(O) or is deleted;   A 22  is Phe, Glu, Aib, Acc, p-X-Phe, β-Nal, Val, Leu, Ile, Nle or Cha;   A 23  is Phe, Leu, Lys, Acc, Cha, β-Nal, Aib, Nle, Ile, p-X-Phe, Val or Trp;   A 24  is Leu, Lys, Acc, Nle, Ile, Val, Phe, β-Nal, Aib, p-X-Phe, Arg or Cha;   A 25  is His, Lys, Aib, Acc, Arg or Glu;   A 26  is His, Aib, Acc, Arg or Lys;   A 27  is Leu, Lys, Acc, Arg, Ile, Val, Phe, Aib, Nle, β-Nal, p-X-Phe or Cha;   A 2 3 is Ile, Leu, Lys, Acc, Cha, Val, Phe, p-X-Phe, Nle, β-Nal, Aib or is deleted;   A 29  is Ala, Glu, Acc, Aib or is deleted;   A 30  is Glu, Leu, Nle, Cha, Aib, Acc, Lys, Arg or is deleted;   A 31  is Ile, Leu, Cha, Lys, Acc, Phe, Val, Nle, β-Nal, Arg or is deleted;   A 32  is His or is deleted;   A 33  is Thr, Ser or is deleted;   A 34  is Ala, Phe, Tyr, Cha, Val, Ile, Leu, Nle, β-Nal, Aib, Acc or is deleted;   A 35  is Glu, Asp or is deleted;   A 36  is Ile, Acc, Cha, Leu, Phe, Nle, β-Nal, Trp, p-X-Phe, Val, Aib or is deleted;   A 37  is Arg, Lys, HN—CH((CH 2 ) n NH—R 4 )—C(O) or is deleted;   A 38  is Ala, Phe, Tyr, Cha, Val, Ile, Leu, Nle, β-Nal, Aib, Acc or is deleted;
 R 1  and R 2  are each independently selected from the group consisting of H, (C 1-30 )alkyl, (C 2-30 )alkenyl, phenyl-(C 1-30 )alkyl, naphthyl(C 1-30 )alkyl, hydroxy(C 1-30 )alkyl, hydroxy(C 2-30 )alkenyl, hydroxy-phenyl(C 1-30 )alkyl or hydroxy-naphthyl(C 1-30 )alkyl; 
 or one of R 1  or R 2  is COE 1  where E 1  is (C 1-30 )alkyl, (C 2-30 )alkenyl, phenyl(C 1-30 )alkyl, naphthyl(C 1-30 )alkyl, hydroxy(C 1-30 )alkyl, hydroxy(C 2-30 )alkenyl, hydroxy-phenyl(C 1-30 )alkyl or hydroxy-naphthyl(C 1-30 )alkyl; 
 R 3  is OH, NH 2 , (C 1-30 )alkoxy or NH—Y—CH 2 -Z, where Y is a (C 1-30 ) hydrocarbon moiety and Z is CO 2 H or CONH 2 ; 
 n for each occurrence is independently an integer from 1 to 5; and 
 R 4  for each occurrence is independently (C 1 -C 30 )alkyl, (C 1 -C 30 )acyl or —C((NH)(NH 2 )); 
   provided that the compound is not PTHrP(1-34)R 3 , PTHrP(1-35)R 3 , PTHrP(1-36) 3 , PTHrP(1-37)R 3  or PTHrP(1-38)R 3 ,   and further provided that the compound is not [Ile 5 , Trp 23 ]PTHrP(1-36) or [Trp 23 ]PTHrP(1-36).   
   
   
       14 . A compound of formula (V),
   (R 1 R 2 )-A 1 -A 2 -A 3 -A 4 -A 5 -A 6 -A 7 -A 8 -A 9 -A 10 -A 11 -A 12 -A 13 -A 14 -A 15 -A 166 -A 17 -A 18 -A 19 -A 20 -A 21 -A 22 -A 23 -A 24 -A 25 -A 26 -A 27 -A 28 -A 29 -A 30 -A 31 -A 32 -A 33 -A 34 -A 35 -A 36 -A 37 -A 38 -R 3 ,  (V)   or a pharmaceutically acceptable salt thereof, wherein   A 1  is Ala, Ser, Dap, Thr, Aib or is deleted;   A 2  is Val or is deleted;   A 3  is Ser, Aib, Thr or is deleted;   A 4  is Glu, Asp or is deleted;   A 5  is His, Ile, Acc, Val, Nle, Phe, Leu, p-X-Phe, β-Nal, Aib, Cha or is deleted;   A 6  is Gln, a hydrophilic amino acid or is deleted;   A 7  is Leu, Val, Cha, Nle, β-Nal, Trp, Pal, Acc, Phe, p-X-Phe, Aib, a lipophilic amino acid or is deleted;   A 8  is Leu, Met, Acc, Cha, Aib, Nle, Phe, Ile, Val, β-Nal, p-X-Phe, a lipophilic amino acid or is deleted;   A 9  is His, a hydrophilic amino acid or is deleted;   A 10  is Asp, Asn, a hydrophilic amino acid or is deleted;   A 11  is Lys, Arg, Leu, Cha, Aib, p-X-Phe, Ile, Val, Nle, Acc, Phe, β-Nal, HN—CH((CH 2 ) n NH—R X )—C(O), a lipophilic D-amino acid, a hydrophilic amino acid or is deleted;   A 12  is Gly, Acc, Aib or is deleted;   A 13  is Lys, Arg, HN—CH((CH 2 ) n NH—R 4 )—C(O) or is deleted;   A 14  is Ser, His or is deleted;   A 15  is Ile, Acc, Cha, Leu, Phe, Nle, β-Nal, Trp, p-X-Phe, Val, Aib or is deleted;   A 16  is Gin, Aib or is deleted;   A 17  is Asp, Aib or is deleted;   A 18  is Leu, Aib, Acc, Cha, Phe, Ile, Nle, β-Nal, Val, p-X-Phe or is deleted;   A 19  is Arg, Lys, Aib, HN—CH((CH 2 ),NH—R 4 )_C(O) or is deleted;   A 20  is Arg, Lys, HN—CH((CH 2 ) n NH—R 4 )_C(O) or is deleted;   A 21  is Arg, Lys, HN—CH((CH 2 ) n NH—R 4 )—C(O) or is deleted;   A 22  is Phe, Glu, Aib, Acc, p-X-Phe, β-Nal, Val, Leu, Ile, Nle or Cha;   A 23  is Phe, Leu, Lys, Acc, Cha, β-Nal, Aib, Nle, Ile, p-X-Phe, Val or Trp;   A 24  is Leu, Lys, Acc, Nle, Ile, Val, Phe, β-Nal, Aib, p-X-Phe, Arg or Cha;   A 25  is His, Lys, Aib, Acc, Arg or Glu;   A 26  is His, Aib, Acc, Arg or Lys;   A 27  is Leu, Lys, Acc, Arg, Ile, Val, Phe, Aib, Nle, β-Nal, p-X-Phe or Cha;   A 28  is Ile, Leu, Lys, Acc, Cha, Val, Phe, p-X-Phe, Nle, β-Nal, Aib or is deleted;   A 29  is Ala, Glu, Acc, Aib or is deleted;   A 30  is Glu, Leu, Nle, Cha, Aib, Acc, Lys, Arg or is deleted;   A 31  is Ile, Leu, Cha, Lys, Acc, Phe, Val, Nle, β-Nal, Arg or is deleted;   A 32  is His or is deleted;   A 33  is Thr, Ser or is deleted;   A 34  is Ala, Phe, Tyr, Cha, Val, Ile, Leu, Nle, β-Nal, Aib, Acc or is deleted;   A 35  is Glu, Asp or is deleted;   A 36  is Ile, Acc, Cha, Leu, Phe, Nle, β-Nal, Trp, p-X-Phe, Val, Aib or is deleted;   A 37  is Arg, Lys, HN—CH((CH 2 ) n NH—R 4 )—C(O) or is deleted;   A 38  is Ala, Phe, Tyr, Cha, Val, Ile, Leu, Nle, f-Nal, Aib, Acc or is deleted;
 R 1  and R 2  are each independently selected from the group consisting of H, (C 1-30 )alkyl, (C 2-30 )alkenyl, phenyl-(C 1-30 )alkyl, naphthyl(C 1-30 )alkyl, hydroxy(C 1-30 )alkyl, hydroxy(C 2-30 )alkenyl, hydroxy-phenyl(C 1-30 )alkyl or hydroxy-naphthyl(C 1-30 )alkyl; 
 or one of R 1  or R 2  is COE 1  where E 1  is (C 1-30 )alkyl, (C 2-30 )alkenyl, phenyl(C 1-30 )alkyl, naphthyl(C 1-30 )alkyl, hydroxy(C 1-30 )alkyl, hydroxy(C 2-30 )alkenyl, hydroxy-phenyl(C 1-30 )alkyl or hydroxy-naphthyl(C 1-30 )alkyl; 
 R 3  is OH, NH 2 , (C, 30)alkoxy or NH—Y—CH 2 -Z, where Y is a (C 1-30 ) hydrocarbon moiety and Z is CO 2 H or CONH 2 ; 
 n for each occurrence is independently an integer from 1 to 5; and 
 R 4  for each occurrence is independently (C 1 -C 30 )alkyl, (C 1 -C 30 )acyl or —C((NH)(NH 2 )); 
   provided that when A 8  is not a lipophilic D-amino acid or is not deleted then at least one of A 6 , A 7 , A 9 , A 10 , A 11  and A 12  is a D-amino acid or at least one of A 6 , A 7 , A 9 , A 10 , A 11 , A 12 , A 13 , A 14 , A 15 , A 16 , A 17 , A 18 , A 19 , A 20 , A 21  and A 22  is deleted.   
   
   
       15 . A compound according to  claim 14  wherein said compound is
 [Ile 5 , D-Leu 8 ]hPTHrP(1-34)NH 2 ,   [Ile 5 , D-Leu 8 , Trp 23 ]hPTHrP(1-34)NH 2 ,   [Ile 5 , des-Leu 8 , Trp 23 ]hPTHrP(1-34)NH 2 ,   [Ile 5 , des-Leu 8 ]hPTHrP(1-34)NH 2 ,   [des-Leu 8 , Trp 23 ]hPTHrP(1-34)NH 2 ,   [Ile 5 , des-Leu 18 ]hPTHrP(1-34)NH 2 ,   [Ile 5 , des-Leu 18 , Trp 23 ]hPTHrP(1-34)NH 2 ,   [des-Leu 18 , Trp 23 ]hPTHrP(1-34)NH 2 ,   [Ile 5 , D-Leu 8 , Glu 22,25 , Leu 23,28,31 , Lys 26,30 , Aib 29 ]hPTHrP(1-34)NH 2 ,   [Ile 5 , D-Leu 8 , Glu 22,25 , Trp 23 , Lys 26,30 , Leu 28,31 , Aib 29 ]hPTHrP(1-34)NH 2 ,   [Ile 5 , D-Leu 8 , Glu 22,25,29 , Leu 23,28,31 , Lys 26,30 ]hPTHrP(1-34)NH 2 ,   [Ile 5 , D-Leu 8 , Glu 22,25,29 , Trp 23 , Lys 26,30 , Leu 28,31 ]hPTHrP(1-34)NH 2  or   [D-Leu 8 , Trp 23 ]hPTHrP(7-34)NH 2 .   
   
   
       16 . A method of selectively binding the PTH2 receptor which comprises administering to a patient in need thereof an analogue according to  claim 9  or a pharmaceutically acceptable salt thereof. 
   
   
       17 . A method of selectively binding the PTH2 receptor which comprises administering to a patient in need thereof a compound according to  claim 10  or a pharmaceutically acceptable salt thereof. 
   
   
       18 . A method of selectively binding the PTH2 receptor which comprises administering to a patient in need thereof a compound according to  claim 11  or a pharmaceutically acceptable salt thereof. 
   
   
       19 . A method of selectively binding a PTH2 receptor which comprises administering to a patient in need thereof a compound according to  claim 12  or a pharmaceutically acceptable salt thereof. 
   
   
       20 . A method of selectively binding a PTH2 receptor which comprises administering to a patient in need thereof an analogue according to  claim 13  or a pharmaceutically acceptable salt thereof. 
   
   
       21 . A method of selectively binding a PTH2 receptor which comprises administering to a patient in need thereof a compound according to  claim 14  or a pharmaceutically acceptable salt thereof. 
   
   
       22 . A method of selectively binding a PTH2 receptor which comprises administering to a patient in need thereof a compound according to  claim 15  or a pharmaceutically acceptable salt thereof. 
   
   
       23 . A pharmaceutical composition comprising an analogue according to  claim 9  or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier. 
   
   
       24 . A pharmaceutical composition comprising a compound according to  claim 10  or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier. 
   
   
       25 . A pharmaceutical composition comprising a compound according to  claim 11  or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier. 
   
   
       26 . A pharmaceutical composition comprising a compound according to  claim 12  or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier. 
   
   
       27 . A pharmaceutical composition comprising an analogue according to  claim 13  or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier. 
   
   
       28 . A pharmaceutical composition comprising a compound according to  claim 14  or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier. 
   
   
       29 . A pharmaceutical composition comprising a compound according to  claim 15  or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier. 
   
   
       30 . A method of treating a medical disorder that results from altered or excessive action of the PTH2 receptor, which comprises administering to a patient in need thereof an effective amount of an analogue according to  claim 7 , sufficient to inhibit the activation of the PTH2 receptor of said patient. 
   
   
       31 . A method of treating a medical disorder that results from altered or excessive action of the PTH2 receptor, which comprises administering to a patient in need thereof an effective amount of an analogue according to  claim 9 , sufficient to inhibit the activation of the PTH2 receptor of said patient. 
   
   
       32 . A method of treating a medical disorder that results from altered or excessive action of the PTH2 receptor, which comprises administering to a patient in need thereof an effective amount of a compound according to  claim 10 , sufficient to inhibit the activation of the PTH2 receptor of said patient. 
   
   
       33 . A method of treating a medical disorder that results from altered or excessive action of the PTH2 receptor, which comprises administering to a patient in need thereof an effective amount of a compound according to  claim 11 , sufficient to inhibit the activation of the PTH2 receptor of said patient. 
   
   
       34 . A method of treating a medical disorder that results from altered or excessive action of the PTH2 receptor, which comprises administering to a patient in need thereof an effective amount of a compound according to  claim 12 , sufficient to inhibit the activation of the PTH2 receptor of said patient. 
   
   
       35 . A method of treating a medical disorder that results from altered or excessive action of the PTH2 receptor, which comprises administering to a patient in need thereof an effective amount of an analogue according to  claim 13 , sufficient to inhibit the activation of the PTH2 receptor of said patient. 
   
   
       36 . A method of treating a medical disorder that results from altered or excessive action of the PTH2 receptor, which comprises administering to a patient in need thereof an effective amount of a compound according to  claim 14 , sufficient to inhibit the activation of the PTH2 receptor of said patient. 
   
   
       37 . A method of treating a medical disorder that results from altered or excessive action of the PTH2 receptor, which comprises administering to a patient in need thereof an effective amount of a compound according to  claim 15 , sufficient to inhibit the activation of the PTH2 receptor of said patient. 
   
   
       38 . A method according to  claim 30  wherein said medical disorder is abnormal CNS functions, abnormal pancreatic functions, divergence from normal mineral metabolism and homeostasis, male infertility, abnormal blood pressure or a hypothalmic disease. 
   
   
       39 . A method according to  claim 31  wherein said medical disorder is abnormal CNS functions, abnormal pancreatic functions, divergence from normal mineral metabolism and homeostasis, male infertility, abnormal blood pressure or a hypothalmic disease. 
   
   
       40 . A method according to  claim 32  wherein said medical disorder is abnormal CNS functions, abnormal pancreatic functions, divergence from normal mineral metabolism and homeostasis, male infertility, abnormal blood pressure or a hypothalmic disease. 
   
   
       41 . A method according to  claim 33  wherein said medical disorder is abnormal CNS functions, abnormal pancreatic functions, divergence from normal mineral metabolism and homeostasis, male infertility, abnormal blood pressure or a hypothalmic disease. 
   
   
       42 . A method according to  claim 34  wherein said medical disorder is abnormal CNS functions, abnormal pancreatic functions, divergence from normal mineral metabolism and homeostasis, male infertility, abnormal blood pressure or a hypothalmic disease. 
   
   
       43 . A method according to  claim 35  wherein said medical disorder is abnormal CNS functions, abnormal pancreatic functions, divergence from normal mineral metabolism and homeostasis, male infertility, abnormal blood pressure or a hypothalmic disease. 
   
   
       44 . A method according to  claim 36  wherein said medical disorder is abnormal CNS functions, abnormal pancreatic functions, divergence from normal mineral metabolism and homeostasis, male infertility, abnormal blood pressure or a hypothalmic disease. 
   
   
       45 . A method according to  claim 37  wherein said medical disorder is abnormal CNS functions, abnormal pancreatic functions, divergence from normal mineral metabolism and homeostasis, male infertility, abnormal blood pressure or a hypothalmic disease. 
   
   
       46 . A method of treating a medical disorder that results from altered or excessive action of the PTH2 receptor, which comprises administering to a patient in need thereof an effective amount of a PTH analogue or a truncated PTH analogue or a pharmaceutically acceptable salt thereof according to  claim 1 , sufficient to inhibit the activation of the PTH2 receptor of said patient. 
   
   
       47 . A method according to  claim 46  wherein said medical disorder is abnormal CNS functions, abnormal pancreatic functions, divergence from normal mineral metabolism and homeostasis, male infertility, abnormal blood pressure or a hypothalmic disease.