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US 2003/0166836 A1Published application
Analogs of parathyroid hormone
AssigneeSociete de Conseils de Recherches et D'Application Scientefiques, S.A.S., a France corporation
InventorZheng Xin Dong
Life of this patent
Estimating the term…
Abstract
The present invention is directed to peptide analogues of fragment of parathyroid hormone (PTH) or parathyroid hormone-related protein (PTHrP), a method of using said analogues alone or in combination with a bisphosphonate or calcitonin to treat osteoporosis and pharmaceutical compositions comprising said analogues alone or in combination with a bisphosphonate or calcitonin.
Claims67
A peptide of the formula (I):
- 8
- wherein
- A1 is Ser, Ala, or Dap;
- A3 is Ser, Thr, or Aib;
- A5 is Leu, Nle, Ile, Cha, β-Nal, Trp, Pal, Acc, Phe or p-X-Phe, in which X is OH, a halogen, or CH3;
- A7 is Leu, Nle, Ile, Cha, β-Nal, Trp, Pal, Acc, Phe, or p-X-Phe in which X is OH, a halogen or CH3;
- A8 is Met, Nva, Leu, Val, Ile, Cha, Acc, or Nle;
- A11 is Leu, Nle, Ile, Cha, β-Nal, Trp, Pal, Acc, Phe or p-X-Phe in which X is OH, a halogen, or CH3,
- A12 is Gly, Acc, or Aib;
- A15 is Leu, Nle, Ile, Cha, β-Nal, Trp, Pal, Acc, Phe, or p-X-Phe in which X is OH, a halogen, or CH3,
- A16 is Ser, Asn, Ala, or Aib;
- A17 is Ser, Thr, or Aib,
- A18 is Met, Nva, Leu, Val, Ile, Nle, Acc, Cha, or Aib;
- A19 is Glu or Aib;
- A21 is Val, Acc, Cha, or Met;
- A22 is Acc or Glu;
- A23 is Trp, Acc, or Cha;
- A24 is Leu, Acc, or Cha;
- A27 is Lys, Aib, Leu, hArg, Gln, Acc, or Cha;
- A28 is Leu, Acc, or Cha;
- A29 is Gln, Acc, or Aib;
- A30 is Asp or Lys;
- A31 is Val, Leu, Nle, Acc, Cha, or deleted;
- A32 is His or deleted;
- A33 is Asn or deleted;
- A34 is Phe, Tyr, Amp, Aib, or deleted;
- each of R1 and R2 is, independently, H, C1-12alkyl, C2-12alkenyl, C7-20phenylalkyl, C11-20naphthylalkyl, C1-12hydroxyalkyl, C2-12hydroxyalkenyl, C7-20hydroxyphenylalkyl, or C11-20hydroxynaphthylalkyl;
- or one and only one of R1 and R2 is COE1 in which E1 is C1-12alkyl, C2-12alkenyl, C7-20phenylalkyl, C11-20naphthylalkyl, C1-12hydroxyalkyl, C2-12hydroxyalkenyl, C7-20hydroxy-phenylalkyl, or C11-20hydroxynaphthylalkyl;
- and
- R3 is OH, NH2, C1-12alkoxy, or NH—Y—CH2-Z in which Y is a C1-12hydrocarbon moiety and Z is H, OH, CO2H, or CONH2;
- provided that at least one of A5, A7, A8, A11, A12, A15, A18, A21, A22, A23, A24, A27, A28, A29, and A31 is Acc;
- or a pharmaceutically acceptable salt thereof.
29 more elements
A peptide of the formula:
- [Cha22,23, Glu25, Lys26,30Leu28, Aib29]hPTHrP(1-34)NH2;
- [Cha22,23, Glu25, Lys26,30, Aib29]hPTHrP(1-34)NH2;
- [Glu22,25, Leu23,28,31, Lys26, Aib29, Nle30]hPTHrP(1-34)NH2;
- [Glu22,25, Leu23,28,30,31, Lys26, Aib29]hPTHrP(1-34)NH2, ]Glu22,25,29, Leu23,28,30,31, Lys26]hPTHrP(1-34)NH2;
- [Glu22,25,28, Leu23,28,31, Lys26, Nle30]hPTHrP(1-34)NH2;
- [Ser1, Ile5, Met8, Asn10, Leu11,23,28,31, His14, Cha15, Glu22,25, Lys26,30, Aib29]hPTHrP(1-34)NH2;
- [Glu22,25, Cha23, Lys26, Leu28,31, Aib29, Nle30]hPTHrP(1-34)NH2, [Cha22,23, Glu25, Lys26,30, Leu28,31, Aib29]hPTHrP(1-34)NH2;
- [Cha22, Leu23,28,31, Glu25,29, Lys26, Nle30]hPTHrP(1-34)NH2;
- [Cha7,11,15]hPTHrP(1-34)NH2;
- [Cha7,8,15]hPTHrP(1-34)NH2;
- [Glu22, Cha23, Aib25,29, Lys26,30, Leu28,31]hPTHrP(1-34)NH2;
- [Glu22, Cha23, Aib25,29, Lys26, Leu28]hPTHrP(1-34)NH2;
- [Glu22, Leu23,28, Aib25,29, Lys26]hPTHrP(1-34)NH2;
- [Aib29]hPTHrP(1-34)NH2;
- [Glu22,25, Cha23, Lys26, Leu28,31, Aib29, Nle30]hPTHrP(1-34)NH2;
- [Glu22,25, Cha23, Lys26,30, Aib29, Leu31]hPTHrP(1-34)NH2;
- [Glu 22,25, Leu23,28,31, Lys26, Aib29,31]hPTHrP(1-34)NH2;
- [Glu22,25, Leu23,28,31, Lys26, Aib29]hPTHrP(1-34)NH2;
- [Glu22,25, Leu23,28,31, Aib26,29, Lys30]hPTHrP(1-34)NH2;
- [Glu22,25, Cha23, Lys26,30, Leu28,31, Aib29]hPTHrP(1-34)NH2;
- [Glu22,25, Cha23, Lys26,30, Aib29]hPTHrP(1-34)NH2;
- [Glu22,25, Cha23, Lys26,30, Leu28, Aib29]hPTHrP(1-34)NH2;
- or [Leu27, Aib29]hPTHrP(1-34)NH2;
- or a pharmaceutically acceptable salt thereof.
21 more elements
A peptide of the formula:
- [Glu22,25, Leu23,28, Lys26,30, Aib29, Ahc31]hPTHrP(1-34)NH2;
- [Glu22,25, Ahc23, Lys26,30, Leu28,31, Aib29]hPTHrP(1-34)NH2;
- [Glu22,25, Leu23,28,31, Lys26,30, Ahc27, Aib29]hPTHrP(1-34)NH2;
- [Glu22,25,29, Leu23,28,31, Lys26, Ahc30]hPTHrP(1-34)NH2;
- [Cha22, Leu23,28,31, Glu25, Lys26,30, Ahc27, Aib29]hPTHrP(1-34)NH2;
- [Glu22,25, Leu23,28,31, Ahc24, Lys26,30, Aib29]hPTHrP(1-34)NH2;
- [Glu22,29, Leu23,28,31, Aib25, Lys26,30, Ahc27]hPTHrP(1-34)NH2;
- [Glu22, Leu23,28,31, Aib25,29, Lys26,30, Ahc27]hPTHrP(1-34)NH2, [Ahc22, Leu23,28,31, Glu25, Lys26,30, Aib29]hPTHrP(1-34)NH2, [Glu22,25, Leu23,31, Lys26,30, Ahc28, Aib29]hPTHrP(1-34)NH2;
- [Cha22, Ahc23, Glu25, Lys26,30, Leu28,31, Aib29]hPTHrP(1-34)NH2;
- [Ahc22,24,27, Leu23,28,31, Glu25, Lys26,30, Aib29]hPTHrP(1-34)NH2;
- [Cha22, Leu23,28,31, Ahc24,27, Glu25, Lys26,30, Aib29]hPTHrP(1-34)NH2;
- [Glu22, Leu23,28,31, Ahc24,27, Lys25,26, Aib29]hPTHrP(1-34)NH2;
- [Ahc18,24,27, Glu22, Cha23, Lys25,26, Leu28, Aib29]hPTHrP(1-34)NH2;
- [Glu22, Cha23, Ahc24, Lyc25,26, Leu28, Aib29]hPTHrP(1-34)NH2;
- [Glu22,25, Leu23,28,31, Lys26, Ahc27, Aib29, Nle30]hPTHrP(1-34)NH2;
- [Ser1, Ile5, Cha7,11, Met8, Asn10, His14, Glu22,25, Leu23,28,31, Lys26,30, Ahc27, Aib29]hPTHrP(1-34)NH2;
- [Ser1, Ile5, Met8, Asn10, Leu11,23,28,31, His14, Cha15, Glu22,25, Lys26,30, Ahc27, Aib29]hPTHrP(1-34)NH2;
- [Cha22, Ahc23, Glu25, Lys26,30, Leu28,31, Aib29]hPTHrP(1-34)NH2;
- [Glu22, Ahc23, Aib25,29, Lys26,30, Leu28,31]hPTHrP(1-34)NH2;
- [Glu22,25, Leu23,28,31, Lys26,30, Ahc29]hPTHrP(1-34)NH2;
- [Cha22, Leu23,28,31, Ahc24, Glu25, Lys26,30, Aib29]hPTHrP(1-34)NH2;
- [Cha22, Leu23,28,31, Ahc24,27, Glu25, Lys26,30, Aib29]hPTHrP(1-34)NH2;
- [Glu22,25, Leu23,28,31, Ahc24,27, Lys26,30, Aib29]hPTHrP(1-34)NH2, [Ahc22,24,27, Leu23,28,31, Glu25, Lys26,30, Aib29]hPTHrP(1-34)NH2;
- [Cha22, Leu23,28,31, Aib25,29, Lys26,30, Ahc27]hPTHrP(1-34)NH2;
- [Ahc22,27, Leu23,28,31, Aib25,29, Lys26,30]hPTHrP(1-34)NH2;
- [Glu22, Leu23,28,31, Ahc24,27, Lys25,26,30, Aib29]hPTHrP 1-34)NH2;
- [Glu22, Leu23,28, Ahc24,27, Lys25,26,30, Aib29]hPTHrP(1-34)NH2;
- [Glu22, Cha23, Ahc24,27, Lys25,26,30, Leu28, Aib29]hPTHrP(1-34)NH2;
- [Glu22,25, Cha23, Ahc24,27, Lys26,30, Leu28,31, Aib29]hPTHrP(1-34)NH2;
- [Glu22, Cha23, Ahc24,27, Lys25,26,30, Leu28,31, Aib29]hPTHrP(1-34)NH2;
- [Glu22, Leu23,28,31, Ahc24,27, Lys25,26, Aib29]hPTHrP(1-34)NH2;
- [Glu22, Leu23,28, Ahc24,27, Lys25,26, Aib29]hPTHrP(1-34)NH2;
- [Glu22, Cha23, Ahc24,27, Lys25,26, Leu28,31, Aib29]hPTHrP(1-34)NH2, [Glu22, Cha23, Ahc24,27, Lys25,26, Leu28, Aib29]hPTHrP(1-34)NH2, [Glu22, Leu23,28, Lys25,26, Ahc27, Aib29]hPTHrP(1-34)NH2;
- [Glu22, Leu23,28,31, Lys25,26, Ahc27, Aib29]hPTHrP(1-34)NH2;
- [Glu22, Leu23,28,31, Lys25,26,30, Ahc27, Aib29]hPTHrP(1-34)NH2;
- [Glu22, Leu23,28, Lys25,26,30, Ahc27, Aib29]hPTHrP(1-34)NH2;
- [Glu22, Cha23, Ahc24, Lys25,26, Leu28, Aib29]hPTHrP(1-34)NH2;
- [Glu22,25, Leu23,28,31, Lys26, Aib29, Ahc30]hPTHrP(1-34)NH2;
- [Aib22,29, Leu23,28,31, Glu25, Lys26,30]hPTHrP(1-34)NH2;
- [Cha22, Ahc23, Glu25,29, Lys26,30, Leu28,31]hPTHrP(1-34)NH2, [Cha22, Leu23,28,31, Ahc24, Glu25,29, Lys26,30]hPTHrP(1-34)NH2;
- [Cha22, Leu23,28,31, Glu25,29, Lys26,30, Ahc27]hPTHrP(1-34)NH2;
- [Cha22, Leu23,31, Glu25,29, Lys26,30, Ahc28]hPTHrP(1-34)NH2;
- [Cha22, Leu23,28,31, Glu25,29, Lys26, Ahc30]hPTHrP(1-34)NH2;
- [Cha22, Leu23,28, Glu25,29, Lys26,30, Ahc31]hPTHrP(1-34)NH2;
- [Glu22,29, Ahc23, Aib25, Lys26,30, Leu28,31]hPTHrP(1-34)NH2, [Ahc22, Leu23,28,31, Aib25, Lys26,30, Glu29]hPTHrP(1-34)NH2;
- [Glu22,29, Leu23,28,31, Ahc24, Aib25, Lys26,30]hPTHrP(1-34)NH2;
- [Glu22,29, Leu23,31, Aib25, Lys26,30, Ahc28]hPTHrP(1-34)NH2;
- [Glu22,29, Leu23,28, Aib25, Lys26,30, Ahc31]hPTHrP(1-34)NH2;
- [Glu22,29, Leu23,28,31, Aib25, Lys26, Ahc30]hPTHrP(1-34)NH2;
- [Glu22,25,29, Leu23,28,31, Lys26, Ahc27, Aib30]hPTHrP(1-34)NH2;
- [Glu22,25,29, Leu23,28,31, Ahc24, Lys26, Aib30]hPTHrP(1-34)NH2;
- [Ahc22, Leu23,28,31, Glu25,29, Lys26, Aib30]hPTHrP(1-34)NH2;
- [Ahc22, Leu23,28, Glu25,29, Lys26,30,31]hPTHrP(1-34)NH2, [Glu22,25,29, Leu23,28, Lys26,31, Ahc30]hPTHrP(1-34)NH2;
- [Glu22,25,29, Leu23,28, Lys26,30,31, Ahc27]hPTHrP(1-34)NH2;
- [Ahc22, Cha23, Glu25, Lys26,30, Leu28,31, Aib29]hPTHrP(1-34)NH2, [Ahc22, Cha23, Lys25,26,30, Leu28,31, Aib29]hPTHrP(1-34)NH2;
- [Ahc22, Cha23, Lys25,26, Leu28,31, Aib29]hPTHrP(1-34)NH2;
- [Ahc22, Leu23,28, Lys25,26, Aib29]hPTHrP(1-34)NH2;
- [Ahc22, Leu23,28, Arg25, Lys26, Aib29]hPTHrP(1-34)NH2;
- [Ahc22,24, Leu23,28,31, Glu25, Lys26,30, Aib29]hPTHrP(1-34)NH2;
- [Ahc22,24, Leu23,28,31, Lys25,26,30, Aib29]hPTHrP(1-34)NH2;
- [Ahc22,24, Leu23,28,31, Lys25,26, Aib29]hPTHrP(1-34)NH2;
- [Ahc22,24, Leu23,28, Lys25,26, Aib29]hPTHrP(1-34)NH2;
- [Ahc22,24, Leu23,28, Arg25, Lys26, Aib29]hPTHrP(1-34)NH2;
- [Glu22, Leu23,28,31, Ahc24, Lys25,26,30, Aib29]hPTHrP(1-34)NH2;
- [Glu22, Leu23,28,31, Ahc24, Lys25,26, Aib29]hPTHrP(1-34)NH2;
- [Glu22, Leu23,28, Ahc24, Lys25,26, Aib29]hPTHrP(1-34)NH2;
- [Glu22, Leu23,28,31, Ahc24, Arg25, Lys26,30, Aib29]hPTHrP(1-34)NH2;
- [Glu22, Leu23,28,31, Ahc24, Arg25, Lys26, Aib29]hPTHrP(1-34)NH2;
- [Glu22, Leu23,28, Ahc24, Arg25, Lys26, Aib29]hPTHrP(1-34)NH2;
- [Glu22, Ahc23, Aib25,29, Lys26,30, Leu28,31]hPTHrP(1-34)NH2;
- [Glu22, Ahc23, Aib25,29, Lys26, Leu28]hPTHrP(1-34)NH2;
- [Glu22, Ahc23,31, Aib25,29, Lys26, Leu28]hPTHrP(1-34)NH2;
- [Glu22, Leu23,28, Aib25,29, Lys26,30, Ahc31]hPTHrP(1-34)NH2;
- [Glu22, Leu23,28, Aib25,29, Lys26, Ahc31]hPTHrP(1-34)NH2;
- [Glu22,25, Leu23,28, Ahc24,31, Lys26,30, Aib29]hPTHrP(1-34)NH2;
- or [Glu22, Leu23,21, Ahc24,31, Lys25,25, Aib29]hPTHrP(1-34)NH2;
- or [Glu22, Leu23,28,31, Ahc24, Aib25,29, Lys26,30]hPTHrP(1-34)NH2;
- or a pharmaceutically acceptable salt thereof.
75 more elements
A peptide of the formula (II):
- 9
- wherein
- A1 is Ser, Ala, or Dap;
- A3 is Ser, Thr, or Aib;
- A5 is Leu, Nle, Ile, Cha, β-Nal, Trp, Pal, Phe or p-X-Phe, in which X is OH, a halogen, or CH3,
- A7 is Leu, Nle, Ile, Cha, β-Nal, Trp, Pal, Phe, or p-X-Phe in which X is OH, a halogen, or CH3;
- A8 is Met, Nva, Leu, Val, Ile, Cha, or Nle;
- A11 is Leu, Nle, Ile, Cha, β-Nal, Trp, Pal, Phe or p-X-Phe in which X is OH, a halogen, or CH3;
- A12 is Gly or Aib;
- A15 is Leu, Nle, Ile, Cha, β-Nal, Trp, Pal, Phe, or p-X-Phe in which X is OH, a halogen, or CH3;
- A16 is Ser, Asn, Ala, or Aib;
- A17 is Ser, Thr, or Aib;
- A18 is Met, Nva, Leu, Val, Ile, Nle, Cha, or Aib;
- A19 is Glu or Aib;
- A21 is Val, Cha, or Met;
- A23 is Trp or Cha;
- A24 is Leu or Cha;
- A27 is Lys, Aib, Leu, hArg, Gln, or Cha;
- A28 is Leu or Cha;
- A30 is Asp or Lys;
- A31 is Val, Nle, Cha, or deleted;
- A32 is His or deleted;
- A33 is Asn or deleted;
- A34 is Phe, Tyr, Amp, Aib, or deleted;
- each of R1 and R2 is, independently, H, C1-12alkyl, C2-12alkenyl, C7-20phenylalkyl, C11-20naphthylalkyl, C1-12hydroxyalkyl, C2-12hydroxyalkenyl, C7-20hydroxyphenylalkyl, or C11-20hydroxynaphthylalkyl;
- or one and only one of R1 and R2 is COE1 in which E1 is C1-12alkyl, C2-12alkenyl, C7-20phenylalkyl, C11-20naphthylalkyl, C1-12hydroxyalkyl, C2-12hydroxyalkenyl, C7-20hydroxy-phenylalkyl, or C11-20hydroxynaphthylalkyl;
- and
- R3 is OH, NH2, C1-12alkoxy, or NH—Y—CH2-Z in which Y is a C1-12hydrocarbon moiety and Z is H, OH, CO2H, or CONH2;
- provided that at least one of A5, A7, A8, A11, A15, A18, A21, A23, A24, A27, A28, and A31 is Cha, or at least one of A3, A12, A16, A17, A18, A19, and A34 is Aib;
- and the peptide is not ]Aib12, Tyr34]hPTH(1-34)NH2, or a pharmaceutically acceptable salt thereof.
27 more elements
13 A peptide of claim 12, wherein said peptide is [Cha7,11]hPTH(1-34)NH2, [Cha7,11, Nle8,18, Tyr34]hPTH(1-34)NH2;
- [Cha11]hPTH(1-34)NH2;
- [Cha7,11,15]hPTH(1-34)NH2;
- or [Cha7]hPTH(1-34)NH2;
- or a pharmaceutically acceptable salt thereof.
1 more element
14 A peptide of claim 11, wherein at least one of A15, A23, A24, A27, A28, and A31 is Cha;
- or a pharmaceutically acceptable salt thereof.
A peptide of claim 14, wherein said peptide is [Cha23]hPTH(1-34)NH2, [Cha24]hPTH(1-34)NH2, [Nle8,18, Cha27]hPTH(1-34)NH2, [Cha28]hPTH(1-34)NH2, [Cha31]hPTH(1-34)NH2, [Cha24,28,31]hPTH(1-34)NH2;
- [Cha24,28,31, Lys30]hPTH(1-34)NH2;
- [Cha28,31]hPTH(1-34)NH2;
- or [Cha15]hPTH(1-34)NH2;
- or a pharmaceutically acceptable salt thereof.
1 more element
16 A peptide of claim 9, wherein at least one of A3, A12, A16, A17, A18, A19, and A34 is Aib;
- or a pharmaceutically acceptable salt thereof.
17 A peptide of claim 16, wherein
- A3 is Ser or Aib,
- A5 is Ile;
- A7 is Leu or Cha,
- A8 is Met, Nva, Leu, Val, Ile, or Nle,
- A11 is Leu or Cha,
- A15 is Leu or Cha;
- A16 is Asn or Aib;
- A18 is Met, Aib, or Nle;
- A21 is Val;
- A27 is Lys, Aib, Leu, hArg, or Cha;
- A31 is Val, Nle, or Cha;
- A32 is His;
- A33 is Asn;
- A34 is Phe, Tyr, Amp, or Aib;
- R1 is H, R2 is H, and R3 is NH2;
- or a pharmaceutically acceptable salt thereof.
13 more elements
18 A peptide of claim 17, wherein at least one of A3, A12, A16, A17, A19, and A34 is Aib, or a pharmaceutically acceptable salt thereof.
A peptide of claim 18, wherein said peptide is [Aib16]hPTH(1-34)NH2, [Aib19]hPTH(1-34)NH2, [Aib34]hPTH(1-34)NH2;
- [Aib16,19]hPTH(1-34)NH2;
- [Aib3]hPTH(1-34)NH2, [Aib17]hPTH(1-34)NH2;
- or [Aib12]hPTH(1-34)NH2;
- or a pharmaceutically acceptable salt thereof.
1 more element
A peptide of the formula (III):
- 10
- wherein
- A3 is Ser, Thr, or Aib;
- A5 is Leu, Nle, Ile, Cha, β-Nal, Trp, Pal, Phe or p-X-Phe, in which X is OH, a halogen, or CH3;
- A7 is Leu, Ile, Nle, Cha, β-Nal, Trp, Pal, Phe, or p-X-Phe in which X is H, OH, a halogen, or CH3;
- A8 is Met, Nva, Leu, Val, Ile, Cha, or Nle;
- A11 is Leu, Nle, Ile, Cha, β-Nal, Trp, Pal, Phe or p-X-Phe in which X is OH, a halogen, or CH3,
- A12 is Gly or Aib,
- A15 is Leu, Nle, Ile, Cha, β-Nal, Trp, Pal, Phe, or p-X-Phe in which X is OH, a halogen, or CH3;
- A16 is Ser, Asn, Ala, or Aib;
- A17 is Ser, Thr, or Aib,
- A18 is Met, Nva, Leu, Val, Ile, Nle, Cha, or Aib;
- A19 is Glu or Aib;
- A21 is Val, Cha, or Met;
- A23 is Trp or Cha;
- A24 is Leu or Cha;
- A27 is Lys, Aib, Leu, hArg, Gln, or Cha;
- A28 is Leu or Cha;
- A30 is Asp or Lys;
- A31 is Val, Nle, Cha, or deleted;
- A32 is His or deleted;
- A33 is Asn or deleted;
- A34 is Phe, Tyr, Amp, Aib, or deleted;
- each of R1 and R2 is, independently, H, C1-12alkyl, C2-12alkenyl, C7-20phenylalkyl, C11-20naphthylalkyl, C1-12hydroxyalkyl, C2-12hydroxyalkenyl, C7-20hydroxyphenylalkyl, or C11-20hydroxynaphthylalkyl;
- or one and only one of R1 and R2 is COE1 in which E1 is C1-12alkyl, C2-12alkenyl, C7-20phenylalkyl, C11-20naphthylalkyl, C1-12hydroxyalkyl, C2-12hydroxyalkenyl, C7-20hydroxy-phenylalkyl, or C11-20hydroxynaphthylalkyl;
- R3 is OH, NH2, C1-12alkoxy, or NH—Y—CH2-Z in which Y is a C1-12hydrocarbon moiety and Z is H, OH, CO2H, or CONH2;
- provided that at least A1 is Dap, A7 is β-Nal, Trp, Pal, Phe, or p-X-Phe;
- A15 is β-Nal, Trp, Pal, Phe, or p-X-Phe, A27 is hArg, or A31 is Nle;
- or a pharmaceutically acceptable salt thereof.
26 more elements
A peptide of the formula (IV):
- 11
- wherein
- A1 is Ala, Ser, or Dap;
- A3 is Ser or Aib;
- A5 is His, Ile, or Cha;
- A7 is Leu, Cha, Nle, β-Nal, Trp, Pal, Phe, or p-X-Phe in which X is OH, a halogen, or CH3;
- A8 is Leu, Met, or Cha;
- A10 is Asp or Asn;
- A11 is Lys, Leu, Cha, Phe, or β-Nal;
- A12 is Gly or Aib;
- A14 is Ser or His;
- A15 is Ile, or Cha;
- A16 is Gln or Aib;
- A17 is Asp or Aib;
- A18 is Leu, Aib, or Cha;
- A19 is Arg or Aib;
- A22 is Phe, Glu, Aib, or Cha;
- A23 is Phe, Leu, Lys, or Cha;
- A24 is Leu, Lys, or Cha;
- A25 is His, Aib, or Glu;
- A26 is His, Aib, or Lys;
- A27 is Leu, Lys, or Cha;
- A28 is Ile, Leu, Lys, or Cha;
- A29 is Ala, Glu, or Aib;
- A30 is Glu, Cha, Aib, or Lys;
- A31 is Ile, Leu, Cha, Lys, or deleted;
- A32 is His or deleted;
- A33 is Thr or deleted;
- A34 is Ala or deleted;
- each of R1 and R2 is, independently, H, C1-12alkanyl, C7-20phenylalkyl, C11-20naphthylalkyl, C1-12, hydroxyalkyl, C2-12hydroxyalkenyl, C7-20hydroxyphenylalkyl, or C11-20hydroxynaphthylalkyl;
- or one and only one of R1 and R2 is COE1 in which E1 is C1-12alkyl, C2-12alkyl, C2-12alkenyl, C7-20phenylalkyl, C11-20naphthylalkyl, C1-12hydroxyalkyl, C2-12hydroxyalkenyl, C7-20hydroxyphenylalkyl, or C11-20hydroxynaphthylalkyl;
- and
- R3 is OH, NH2 C1-12alkoxy, or NH—Y—CH2-Z in which Y is a C1-12hydrocarbon moiety and Z is H, OH, CO2H or CONH2;
- provided that at least one of A5, A7, A8, A11, A15, A18, A22, A23, A24, A27, A28, A30, or A31 is Cha, or at least one of A3, A12, A16, A17, A18, A19, A22, A25, A26, A29, A30, or A34 is Aib;
- or a pharmaceutically acceptable salt thereof.
32 more elements
36 A peptide of the formula (V):
- 12
- wherein
- A1 is Ala, Ser or Dap;
- A3 is Ser or Aib;
- A5 is His, Ile or Cha;
- A7 is Leu, Cha, Nle, β-Nal, Trp, Pal, Phe, or p-X-Phe in which X is OH, a halogen or CH3;
- A8 is Leu, Met or Cha;
- A10 is Asp or Asn;
- A11 is Lys, Leu, Cha, Phe or β-Nal;
- A12 is Gly or Aib;
- A14 is Ser or His;
- A15 is Ile or Cha;
- A16 is Gln or Aib;
- A17 is Asp or Aib;
- A18 is Leu, Aib or Cha;
- A19 is Arg or Aib;
- A22 is Phe, Glu, Aib, Acc or Cha;
- A23 is Phe, Leu, Lys, Acc or Cha;
- A24 is Leu, Lys, Acc or Cha;
- A25 is His, Aib or Glu;
- A26 is His, Aib or Lys;
- A27 is Leu, Lys, Acc or Cha;
- A28 is Ile, Leu, Lys, Acc or Cha;
- A29 is Ala, Glu or Aib;
- A30 is Glu, Cha, Aib, Acc or Lys;
- A31 is Ile, Leu, Cha, Lys, Acc or deleted;
- A32 is His or deleted;
- A33 is Thr or deleted;
- A34 is Ala or deleted;
- each of R1 and R2 is, independently, H, C1-12alkanyl, C7-20phenylalkyl, C11-20naphthylalkyl, C1-12, hydroxyalkyl, C2-12hydroxyalkenyl, C7-20hydroxyphenylalkyl, or C11-20hydroxynaphthylalkyl;
- or one and only one of R1 and R2 is COE1 in which E1 is C1-12alkyl, C2-12alkyl, C2-12alkenyl, C7-20phenylalkyl, C11-20naphthylalkyl, C1-12hydroxyalkyl, C2-12hydroxyalkenyl, C7-20hydroxyphenylalkyl, or C11-20hydroxynaphthylalkyl;
- and
- R3 is OH, NH2, C1-12alkoxy, or NH—Y—CH2-Z in which Y is a C1-12hydrocarbon moiety and Z is H, OH, CO2H or CONH2;
- provided that at least one of A23, A24, A27, A28, or A31 is Lys;
- or a pharmaceutically acceptable salt thereof.
32 more elements
A peptide of claim 36, wherein A22 is Glu, Aib, Acc, or Cha;
- A23 is Leu, Lys, Acc, or Cha;
- A25 is Aib or Glu;
- A26 is Aib or Lys;
- A28 is Leu, Lys, Acc, or Cha;
- A29 is Glu or Aib;
- A30 is Cha, Aib, Acc, or Lys;
- A31 is Leu, Cha, Acc, or Lys, A32 is His;
- A33 is Thr;
- and A34 is Ala;
- or a pharmaceutically acceptable salt thereof.
7 more elements
A method of treating osteoporosis in a patient in need thereof, which comprises administering to said patient a compound of claim 36 or a pharmaceutically acceptable salt thereof.
49 A method of treating osteoporosis in a patient in need thereof, which comprises administering to said patient a combination of a bisphosphonate or calcitonin and a compound of claim 36 or a pharmaceutically acceptable salt thereof.
54 A pharmaceutical composition comprising a compound of claim 26 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or diluent
55 A pharmaceutical composition comprising a compound of claim 26 or a pharmaceutically acceptable salt thereof, a bisphosphonate or calcitonin and a pharmaceutically acceptable carrier or diluent.
A pharmaceutical composition comprising a compound of claim 36 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or diluent.
59 A pharmaceutical composition comprising a compound of claim 36 or a pharmaceutically acceptable salt thereof, a bisphosphonate or calcitonin and a pharmaceutically acceptable carrier or diluent.
A method of treating osteoporosis in a patient in need thereof, which comprises administering to said patient a peptide of the formula [Glu22,25, Leu23,28,31, Aib29, Lys26,30]hPTHrP(1-34)NH2 or a pharmaceutically acceptable salt thereof.
A method of treating osteoporosis in a patient in need thereof, which comprises administering to said patient a combination of a bisphosphonate or calcitonin and a peptide of the formula [Glu22,25, Leu23,28,31, Aib29, Lys26,30]hPTHrP(1-34)NH2 or a pharmaceutically acceptable salt thereof.
A pharmaceutical composition comprising a peptide of the formula [Glu22,25, Leu23,28,31, Aib29, Lys26,30]hPTHrP(1-34)NH2 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or diluent.
A pharmaceutical composition comprising a peptide of the formula [Glu22,25, Leu23,28,31, Aib29, Lys26,30]hPTHrP(1-34)NH2 or a pharmaceutically acceptable salt thereof, a bisphosphonate or calcitonin, and a pharmaceutically acceptable carrier or diluent.
64 A method of treating osteoporosis in a patient in need thereof, which comprises administering to said patient a peptide of the formula (VI):
- 13
- wherein
- A1 is Ala, Ser, or Dap;
- A3 is Ser or Aib;
- A5 is His, Ile, Acc, or Cha;
- A7 is Leu, Cha, Nle, β-Nal, Trp, Pal, Acc, Phe, or p-X-Phe in which X is OH, a halogen, or CH3;
- A8 is Leu, Met, Acc, or Cha;
- A10 is Asp or Asn;
- A11 is Lys, Leu, Cha, Acc, Phe, or β-Nal;
- A12 is Gly, Acc, or Aib;
- A14 is Ser or His;
- A15 is Ile, Acc, or Cha;
- A16 is Gln or Aib;
- A17 is Asp or Aib;
- A18 is Leu, Aib, Acc, or Cha;
- A19 is Arg or Aib;
- A22 is Phe, Glu, Aib, Acc, or Cha;
- A23 is Phe, Leu, Lys, Acc, or Cha;
- A24 is Leu, Lys, Acc, or Cha;
- A25 is His, Lys, Aib, Acc, or Glu;
- A26 is His, Aib, Acc, or Lys;
- A27 is Leu, Lys, Acc, or Cha;
- A28 is Ile, Leu, Lys, Acc, or Cha;
- A29 is Ala, Glu, Acc, or Aib;
- A30 is Glu, Leu, Nle, Cha, Aib, Acc, or Lys;
- A31 is Ile, Leu, Cha, Lys, Acc, or deleted;
- A32 is His or deleted;
- A33 is Thr or deleted;
- A34 is Ala or deleted;
- each of R1 and R2 is, independently, H, C1-12alkanyl, C7-20phenylalkyl, C11-20naphthylalkyl, C1-12, hydroxyalkyl, C2-12hydroxyalkenyl, C7-20hydroxyphenylalkyl, or C11-20hydroxynaphthylalkyl;
- or one and only one of R1 and R2 is COE1 in which E1 is C1-12alkyl, C2-12alkyl, C2-12alkenyl, C7-20phenylalkyl, C11-20naphthylalkyl, C1-12hydroxyalkyl, C2-12hydroxyalkenyl, C7-20hydroxyphenylalkyl, or C11-20hydroxynaphthylalkyl;
- and
- R3 is OH, NH2, C1-12alkoxy, or NH—Y—CH2-Z in which Y is a C1-12hydrocarbon moiety and Z is H, OH, CO2H or CONH2;
- provided that at least one of A5, A7, A8, A11, A12, A15, A18, A22, A23, A24, A25, A26, A27, A28, A29, A30, or A31 is Acc;
- or a pharmaceutically acceptable salt thereof.
32 more elements
A method of treating osteoporosis in a patient in need thereof, which comprises administering to said patient a combination of a bisphosphonate or calcitonin and a peptide of the formula (VI):
- 14
- wherein
- A1 is Ala, Ser, or Dap;
- A3 is Ser or Aib;
- A5 is His, Ile, Acc, or Cha;
- A7 is Leu, Cha, Nle, β-Nal, Trp, Pal, Acc, Phe, or p-X-Phe in which X is OH, a halogen, or CH3,
- A8 is Leu, Met, Acc, or Cha;
- A10 is Asp or Asn;
- A11 is Lys, Leu, Cha, Acc, Phe, or β-Nal;
- A12 is Gly, Acc, or Aib;
- A14 is Ser or His;
- A15 is Ile, Acc, or Cha;
- A16 is Gln or Aib;
- A17 is Asp or Aib;
- A18 is Leu, Aib, Acc, or Cha;
- A19 is Arg or Aib;
- A22 is Phe, Glu, Aib, Acc, or Cha;
- A23 is Phe, Leu, Lys, Acc, or Cha;
- A24 is Leu, Lys, Acc, or Cha;
- A25 is His, Lys, Aib, Acc, or Glu;
- A26 is His, Aib, Acc, or Lys;
- A27 is Leu, Lys, Acc, or Cha;
- A28 is Ile, Leu, Lys, Acc, or Cha;
- A29 is Ala, Glu, Acc, or Aib;
- A30 is Glu, Leu, Nle, Cha, Aib, Acc, or Lys,
- A31 is Ile, Leu, Cha, Lys, Acc, or deleted;
- A32 is His or deleted;
- A33 is Thr or deleted;
- A34 is Ala or deleted;
- each of R1 and R2 is, independently, H, C1-12alkanyl, C7-20phenylalkyl, C11-20naphthylalkyl, C1-12, hydroxyalkyl, C2-12hydroxyalkenyl, C7-20hydroxyphenylalkyl, or C11-20hydroxynaphthylalkyl;
- or one and only one of R1 and R2 is COE1 in which E1 is C1-12alkyl, C2-12alkyl, C2-12alkenyl, C7-20phenylalkyl, C11-20naphthylalkyl, C1-12 hydroxyalkyl, C2-12hydroxyalkenyl, C7-20hydroxyphenylalkyl, or C11-20hydroxynaphthylalkyl;
- and
- R3 is OH, NH2, C1-12alkoxy, or NH—Y—CH2-Z in which Y is a C1-12hydrocarbon moiety and Z is H, OH, CO2H or CONH2;
- provided that at least one of A5, A7, A8, A11, A12, A15, A18, A22, A23, A24, A25, A26, A27, A28, A29, A30, or A31 is Acc;
- or a pharmaceutically acceptable salt thereof.
32 more elements
A pharmaceutical composition comprising a pharmaceutically acceptable carrier or diluent and a peptide of the following formula (VI):
- 15
- wherein
- A1 is Ala, Ser, or Dap;
- A3 is Ser or Aib;
- A5 is His, Ile, Acc, or Cha;
- A7 is Leu, Cha, Nle, β-Nal, Trp, Pal, Acc, Phe, or p-X-Phe in which X is OH, a halogen, or CH3;
- A8 is Leu, Met, Acc, or Cha;
- A10 is Asp or Asn,
- A11 is Lys, Leu, Cha, Acc, Phe, or β-Nal;
- A12 is Gly, Acc, or Aib;
- A14 is Ser or His;
- A15 is Ile, Acc, or Cha;
- A16 is Gln or Aib,
- A17 is Asp or Aib;
- A18 is Leu, Aib, Acc, or Cha;
- A19 is Arg or Aib;
- A22 is Phe, Glu, Aib, Acc, or Cha;
- A23 is Phe, Leu, Lys, Acc, or Cha;
- A24 is Leu, Lys, Acc, or Cha;
- A25 is His, Lys, Aib, Acc, or Glu;
- A26 is His, Aib, Acc, or Lys;
- A27 is Leu, Lys, Acc, or Cha;
- A28 is Ile, Leu, Lys, Acc, or Cha;
- A29 is Ala, Glu, Acc, or Aib;
- A30 is Glu, Leu, Nle, Cha, Aib, Acc, or Lys;
- A31 is Ile, Leu, Cha, Lys, Acc, or deleted;
- A32 is His or deleted;
- A33 is Thr or deleted;
- A34 is Ala or deleted;
- each of R1 and R2 is, independently, H, C1-12alkanyl, C7-20phenylalkyl, C11-20naphthylalkyl, C1-12, hydroxyalkyl, C2-12hydroxyalkenyl, C7-20hydroxyphenylalkyl, or C11-20hydroxynaphthylalkyl;
- or one and only one of R1 and R2 is COE1 in which E1 is C1-12 alkyl, C2-12alkyl, C2-12 alkenyl, C7-20phenylalkyl, C11-20naphthylalkyl, C1-12hydroxyalkyl, C2-12hydroxyalkenyl, C7-20hydroxyphenylalkyl, or C11-20hydroxynaphthylalkyl;
- and
- R3 is OH, NH2, C1-12alkoxy, or NH—Y—CH2-Z in which Y is a C1-12hydrocarbon moiety and Z is H, OH, CO2H or CONH2;
- provided that at least one of A5, A7, A8, A11, A12, A15, A18, A22, A23, A24, A25, A26, A27, A28, A29, A30, or A31 is Acc;
- or a pharmaceutically acceptable salt thereof.
32 more elements
A pharmaceutical composition comprising a bisphosphonate or calcitonin, a pharmaceutically acceptable carrier or diluent, and a peptide of the following formula (VI):
- 16
- wherein
- A1 is Ala, Ser, or Dap;
- A3 is Ser or Aib;
- A5 is His, Ile, Acc, or Cha;
- A7 is Leu, Cha, Nle, β-Nal, Trp, Pal, Acc, Phe, or p-X-Phe in which X is OH, a halogen, or CH3;
- A8 is Leu, Met, Acc, or Cha;
- A10 is Asp or Asn;
- A11 is Lys, Leu, Cha, Acc, Phe, or β-Nal;
- A12 is Gly, Acc, or Aib;
- A14 is Ser or His;
- A15 is Ile, Acc, or Cha;
- A16 is Gln or Aib;
- A17 is Asp or Aib;
- A18 is Leu, Aib, Acc, or Cha;
- A19 is Arg or Aib;
- A22 is Phe, Glu, Aib, Acc, or Cha;
- A23 is Phe, Leu, Lys, Acc, or Cha;
- A24 is Leu, Lys, Acc, or Cha;
- A25 is His, Lys, Aib, Acc, or Glu;
- A26 is His, Aib, Acc, or Lys;
- A27 is Leu, Lys, Acc, or Cha;
- A28 is Ile, Leu, Lys, Acc, or Cha;
- A29 is Ala, Glu, Acc, or Aib;
- A30 is Glu, Leu, Nle, Cha, Aib, Acc, or Lys;
- A31 is Ile, Leu, Cha, Lys, Acc, or deleted;
- A32 is His or deleted;
- A33 is Thr or deleted;
- A34 is Ala or deleted;
- each of R1 and R2 is, independently, H, C1-12alkanyl, C7-20phenylalkyl, C11-20naphthylalkyl, C1-12, hydroxyalkyl, C2-12hydroxyalkenyl, C7-20hydroxyphenylalkyl, or C11-20hydroxynaphthylalkyl, or one and only one of R1 and R2 is COE1 in which E1 is C1-12alkyl, C2-12alkyl, C2-12alkenyl, C7-20phenylalkyl, C11-20naphthylalkyl, C1-12hydroxyalkyl, C2-12hydroxyalkenyl, C7-20hydroxyphenylalkyl, or C11-20hydroxynaphthylalkyl;
- and
- R3 is OH, NH2, C1-12alkoxy, or NH—Y—CH2-Z in which Y is a C1-12hydrocarbon moiety and Z is H, OH, CO2H or CONH2;
- provided that at least one of A5, A7, A8, A11, A12, A15, A18, A22, A23, A24, A25, A26, A27, A28, A29, A30, or A31 is Acc;
- or a pharmaceutically acceptable salt thereof.
31 more elements
Dependencies are inferred from the claim text.