IPC분류정보
국가/구분 |
United States(US) Patent
등록
|
국제특허분류(IPC7판) |
|
출원번호 |
US-0942887
(2010-11-09)
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등록번호 |
US-8507447
(2013-08-13)
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발명자
/ 주소 |
- Currie, Mark G.
- Fretzen, Angelika
- Kessler, Marco
- Zimmer, Daniel P.
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출원인 / 주소 |
- Ironwood Pharmaceuticals, Inc.
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대리인 / 주소 |
Honigman Miller Schwartz & Cohn LLP
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인용정보 |
피인용 횟수 :
7 인용 특허 :
12 |
초록
▼
The present invention provides peptides that are useful for the treatment of gastrointestinal disorders. The present invention also provides compositions and methods of treating gastrointestinal disorders and pharmaceutical compositions for accomplishing the same. In some embodiments, these pharmace
The present invention provides peptides that are useful for the treatment of gastrointestinal disorders. The present invention also provides compositions and methods of treating gastrointestinal disorders and pharmaceutical compositions for accomplishing the same. In some embodiments, these pharmaceutical compositions include oral dosage forms.
대표청구항
▼
1. A peptide or a pharmaceutically acceptable salt thereof, wherein the peptide comprises the amino acid sequence Xaa1 Xaa2 Xaa3 Xaa4 Cys5 Xaa6 Xaa7 Xaa8 Cys9 Asn10 Pro11 Ala12 Cys13 Xaa14 Gly15 Xaa16 Xaa17 (SEQ ID NO:1), or a pharmaceutically acceptable salt thereof; whereinXaa1 is Asn, D-Asn, Gln,
1. A peptide or a pharmaceutically acceptable salt thereof, wherein the peptide comprises the amino acid sequence Xaa1 Xaa2 Xaa3 Xaa4 Cys5 Xaa6 Xaa7 Xaa8 Cys9 Asn10 Pro11 Ala12 Cys13 Xaa14 Gly15 Xaa16 Xaa17 (SEQ ID NO:1), or a pharmaceutically acceptable salt thereof; whereinXaa1 is Asn, D-Asn, Gln, D-Gln, Pro, Ala, β-Ala, D-Ala, Val, D-Val, Gly, Thr, D-Thr, Asp, D-Asp, γ-carboxylated Asp, Glu, D-Glu, γ-carboxylated Glu, α-aminosuberic acid (Asu), α-aminoadipic acid (Aad), α-aminopimelic acid (Apm), or is absent;Xaa2 is Asp, γ-carboxylated Asp, Glu, γ-carboxylated Glu, Asu, Aad, Apm, or is absent;Xaa3 is Asp, γ-carboxylated Asp, Glu, γ-carboxylated Glu, Asu, Aad, Apm, or is absent;Xaa4 is Cys or D-Cys;Xaa6 is P-Ser, P-Thr, P-homo-Ser, 4-hydroxyvaline phosphate, P-homo-Thr, P-Cys or P-Tyr;Xaa7 is Tyr, Leu, Phe or Ile;Xaa8 is Cys or D-Cys;Xaa14 is Thr, Ala or Phe;Xaa16 is Cys or D-Cys; andXaa17 is Tyr, D-Tyr, or is absent;wherein:if Xaa1 is present, Xaa1 may be modified on its amino group by methyl, ethanedioic acid, propanedioic acid, butanedioic acid, pentanedioic acid, hexanedioic acid, heptanedioic acid or octanedioic acid;if Xaa1 is absent and Xaa2 is present, then Xaa2 may be modified on its amino group by methyl, ethanedioic acid, propanedioic acid, butanedioic acid, pentanedioic acid, hexanedioic acid, heptanedioic acid or octanedioic acid; orif both Xaa1 and Xaa2 are absent, then Xaa3 may be modified on its amino group by methyl, ethanedioic acid, propanedioic acid, butanedioic acid, pentanedioic acid, hexanedioic acid, heptanedioic acid or octanedioic acid. 2. The peptide or pharmaceutically acceptable salt thereof according to claim 1, wherein Xaa2 is Asp, Glu, or absent;Xaa3 is Asp, Glu, or absent;Xaa7 is Tyr or Leu;Xaa14 is Thr; andXaa17 is Tyr or is absent. 3. The peptide or pharmaceutically acceptable salt thereof according to claim 1, wherein Xaa1 is Asp, D-Asp, Glu, D-Glu, or absent; and Xaa6 is P-Ser or P-Thr. 4. The peptide or pharmaceutically acceptable salt thereof according to claim 3, wherein Xaa6 is P-Ser. 5. The peptide or pharmaceutically acceptable salt thereof according to claim 1, wherein Xaa1, Xaa2 and Xaa3 are absent. 6. The peptide or pharmaceutically acceptable salt thereof according to claim 1, wherein said peptide comprises the amino acid sequence Cys4 Cys5 P-Ser6 Xaa7 Cys8 Cys9 Asn10 Pro11 Ala12 Cys13 Thr14 Gly15 Cys16 Xaa17 (SEQ ID NO: 15),wherein Xaa7 is Tyr or Leu, and Xaa17 is Tyr, D-Tyr, or is absent. 7. The peptide or pharmaceutically acceptable salt thereof according to claim 1, wherein said peptide comprises the amino acid sequence: Asp Asp Cys Cys P-Ser Leu Cys Cys Asn Pro Ala Cys Thr Gly Cys Tyr (SEQ ID NO:2);Asp Asp Cys Cys P-Ser Leu Cys Cys Asn Pro Ala Cys Thr Gly Cys (SEQ ID NO:3);Asp Asp Cys Cys P-Ser Tyr Cys Cys Asn Pro Ala Cys Thr Gly Cys Tyr (SEQ ID NO:4);Asp Asp Cys Cys P-Ser Tyr Cys Cys Asn Pro Ala Cys Thr Gly Cys (SEQ ID NO:5);Cys Cys P-Ser Leu Cys Cys Asn Pro Ala Cys Thr Gly Cys Tyr (SEQ ID NO:6);Cys Cys P-Ser Leu Cys Cys Asn Pro Ala Cys Thr Gly Cys (SEQ ID NO:7);Cys Cys P-Ser Tyr Cys Cys Asn Pro Ala Cys Thr Gly Cys Tyr (SEQ ID NO:8); orCys Cys P-Ser Tyr Cys Cys Asn Pro Ala Cys Thr Gly Cys (SEQ ID NO:9). 8. The peptide or pharmaceutically acceptable salt thereof according to claim 1, wherein said peptide comprises no more than 50, 40, 30 or 20 amino acids. 9. The peptide or pharmaceutically acceptable salt thereof according to claim 8, wherein said peptide comprises no more than 19, 18, 17, 16, 15 or 14 amino acids. 10. A peptide consisting of the amino acid sequence Xaa1 Xaa2 Xaa3 Xaa4 Cys5 Xaa6 Xaa7 Xaa8 Cys9 Asn10 Pro11 Ala12 Cys13 Xaa14 Gly15 Xaa16 Xaa17 (SEQ ID NO:1), or a pharmaceutically acceptable salt thereof; whereinXaa1 is Asn, D-Asn, Gln, D-Gln, Pro, Ala, β-Ala, D-Ala, Val, D-Val, Gly, Thr, D-Thr, Asp, D-Asp, γ-carboxylated Asp, Glu, D-Glu, γ-carboxylated Glu, α-aminosuberic acid (Asu), α-aminoadipic acid (Aad), α-aminopimelic acid (Apm), or is absent;Xaa2 is Asp, γ-carboxylated Asp, Glu, γ-carboxylated Glu, Asu, Aad, Apm, or is absent;Xaa3 is Asp, γ-carboxylated Asp, Glu, γ-carboxylated Glu, Asu, Aad, Apm, or is absent;Xaa4 is Cys or D-Cys;Xaa6 is P-Ser, P-Thr, P-homo-Ser, 4-hydroxyvaline phosphate, P-homo-Thr, P-Cys or P-Tyr;Xaa7 is Tyr, Leu, Phe or Ile;Xaa8 is Cys or D-Cys;Xaa14 is Thr, Ala or Phe;Xaa16 is Cys or D-Cys; andXaa17 is Tyr, D-Tyr, or is absent;wherein:if Xaa1 is present, Xaa1 may be modified on its amino group by methyl, ethanedioic acid, propanedioic acid, butanedioic acid, pentanedioic acid, hexanedioic acid, heptanedioic acid or octanedioic acid;if Xaa1 is absent and Xaa2 is present, then Xaa2 may be modified on its amino group by methyl, ethanedioic acid, propanedioic acid, butanedioic acid, pentanedioic acid, hexanedioic acid, heptanedioic acid or octanedioic acid; orif both Xaa1 and Xaa2 are absent, then Xaa3 may be modified on its amino group by methyl, ethanedioic acid, propanedioic acid, butanedioic acid, pentanedioic acid, hexanedioic acid, heptanedioic acid or octanedioic acid. 11. The peptide or pharmaceutically acceptable salt thereof according to claim 10, wherein Xaa2 is Asp, Glu, or absent;Xaa3 is Asp, Glu, or absent;Xaa7 is Tyr or Leu;Xaa14 is Thr; andXaa17 is Tyr or is absent. 12. The peptide or pharmaceutically acceptable salt thereof according to claim 10, wherein Xaa1 is Asp, D-Asp, Glu, D-Glu or absent; and Xaa6 is P-Ser or P-Thr. 13. The peptide or pharmaceutically acceptable salt thereof according to claim 12, wherein Xaa6 is P-Ser. 14. The peptide or pharmaceutically acceptable salt thereof according to claim 10, wherein Xaa1, Xaa2 and Xaa3 are absent. 15. The peptide or pharmaceutically acceptable salt thereof according to claim 10, wherein said peptide comprises the amino acid sequence Cys4 Cys5 P-Ser6 Xaa7 Cys8 Cys9 Asn10 Pro11, Ala12 Cys13 Thr14 Gly15 Cys16 Xaa17 (SEQ ID NO: 15),wherein Xaa7 is Tyr or Leu, and Xaa17 is Tyr, D-Tyr, or is absent. 16. The peptide or pharmaceutically acceptable salt thereof according to claim 10, wherein said peptide consists of the amino acid sequence: Asp Asp Cys Cys P-Ser Leu Cys Cys Asn Pro Ala Cys Thr Gly Cys Tyr (SEQ ID NO:2);Asp Asp Cys Cys P-Ser Leu Cys Cys Asn Pro Ala Cys Thr Gly Cys (SEQ ID NO:3);Asp Asp Cys Cys P-Ser Tyr Cys Cys Asn Pro Ala Cys Thr Gly Cys Tyr (SEQ ID NO:4);Asp Asp Cys Cys P-Ser Tyr Cys Cys Asn Pro Ala Cys Thr Gly Cys (SEQ ID NO:5);Cys Cys P-Ser Leu Cys Cys Asn Pro Ala Cys Thr Gly Cys Tyr (SEQ ID NO:6);Cys Cys P-Ser Leu Cys Cys Asn Pro Ala Cys Thr Gly Cys (SEQ ID NO:7);Cys Cys P-Ser Tyr Cys Cys Asn Pro Ala Cys Thr Gly Cys Tyr (SEQ ID NO:8); orCys Cys P-Ser Tyr Cys Cys Asn Pro Ala Cys Thr Gly Cys (SEQ ID NO:9). 17. The peptide or pharmaceutically acceptable salt thereof according to claim 1, wherein said peptide or pharmaceutically acceptable salt thereof is isolated. 18. The peptide or pharmaceutically acceptable salt thereof according to claim 17, wherein said peptide or pharmaceutically acceptable salt thereof is purified. 19. A pharmaceutical composition comprising a peptide or pharmaceutically acceptable salt thereof according to claim 1. 20. The pharmaceutical composition according to claim 19 further comprising a pharmaceutically acceptable carrier and one or more agents selected from (i) a cation selected from Mg2+, Ca2+, Zn2+, Mn2+, K+, Na+ and Al3+, and (ii) a sterically hindered primary amine. 21. The pharmaceutical composition according to claim 20, wherein said agent is Mg2+, Ca2+, Zn2+, Mn2+, K+, Na+ or Al3+. 22. The pharmaceutical composition according to claim 20, wherein said agent is a sterically hindered primary amine. 23. The pharmaceutical composition according to claim 22, wherein the sterically hindered primary amine is an amino acid. 24. The pharmaceutical composition according to claim 19, further comprising an antioxidant selected from BHA, vitamin E and propyl gallate. 25. The pharmaceutical composition according to claim 19, further comprising a pharmaceutically acceptable binder or additive selected from polyvinyl alcohol, Polyvinylpyrrolidone (povidone), a starch, maltodextrin and a cellulose ether. 26. The pharmaceutical composition according to claim 19, further comprising a pharmaceutically acceptable filler selected from cellulose, isomalt, mannitol, lactose and dibasic calcium phosphate. 27. A peptide or a pharmaceutically acceptable salt thereof, wherein the peptide comprises the amino acid sequence Cys Cys P-Ser Leu Cys Cys Asn Pro Ala Cys Thr Gly Cys (SEQ ID NO:7). 28. A pharmaceutical composition comprising a peptide or pharmaceutically acceptable salt thereof, wherein the peptide comprises the amino acid sequence Cys Cys P-Ser Leu Cys Cys Asn Pro Ala Cys Thr Gly Cys (SEQ ID NO:7). 29. A peptide or a pharmaceutically acceptable salt thereof, wherein the peptide consists of the amino acid sequence Cys Cys P-Ser Leu Cys Cys Asn Pro Ala Cys Thr Gly Cys (SEQ ID NO:7). 30. A pharmaceutical composition comprising a peptide or pharmaceutically acceptable salt thereof, wherein the peptide consists of the amino acid sequence Cys Cys P-Ser Leu Cys Cys Asn Pro Ala Cys Thr Gly Cys (SEQ ID NO:7).
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