INSULINOTROPIC PEPTIDE SYNTHESIS USING SOLID AND SOLUTION PHASE COMBINATION TECHNIQUES

• US 20110213082A1
• Filed: 05/11/2011
• Published: 09/01/2011
• Est. Priority Date: 06/23/2006
• Status: Abandoned Application

• Current Assignee: Christopher R. Roberts, Lin Chen, Yeun-Kwei Han
• Original Assignee: Christopher R. Roberts, Lin Chen, Yeun-Kwei Han
• Inventors: Chen, Lin, Roberts, Christopher R., Han, Yeun-Kwei
• Application Number:
  US13/105,435
• Publication Number:
  US 20110213082A1
• Time in Patent Office: Days
• US Class Current: 525/54.1
• CPC Class Codes: A61K 38/00 Medicinal preparations containing peptides peptides containing beta-lactam rings A61K31/00; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, A61K31/00; ergot alkaloids of the cyclic peptide type A61K31/48; containing macromolecular compounds having statistically distributed amino acid units A61K31/74; medicinal preparations containing antigens or antibodies A61K39/00; medicinal preparations characterised by the non-active ingredients, e.g. peptides as drug carriers, A61K47/00
• CPC Class Codes: C07K 14/605 Glucagons

Abstract

The present invention relates to the preparation of insulinotropic peptides that are synthesized using a solid and solution phase (“hybrid”) approach. Generally, the approach includes synthesizing three different peptide intermediate fragments using solid phase chemistry. Solution phase chemistry is then used to add additional amino acid material to one of the fragments. The fragments are then coupled together in the solid solution phase. The use of a pseudoproline in one of the fragments eases solid phase synthesis of that fragment and also eases subsequent solution phase coupling of this fragment to other fragments. The present invention is very useful for forming insulinotropic peptides such as GLP-1(7-36) and its natural and non-natural counterparts.

Claims

1. A peptide fragment having the amino acid sequence TFTSDVX^17-18YLEG (SEQ. ID No. 8) wherein the residue denoted by the symbol X^17-18 has the formula

2. The peptide fragment of claim 1 wherein R² is —

CH₂—

.

3. The peptide fragment of claim 1 wherein R¹ is

4. The peptide fragment of claim 3 wherein each of R³ and R⁴ is methyl.

5. The peptide fragment of claim 1 wherein Φ

represents serine.

6. The peptide fragment of claim 1 wherein the residue denoted by the symbol X^17-18 has the formula:

7. The peptide fragment of claim 6, wherein the serine residue at position X¹⁷

is side chain protected.

8. The peptide fragment of claim 7, wherein the serine residue at position X¹⁷

is side chain protected by a t-Bu protection group.

9. The peptide fragment of claim 1 wherein one or more of T¹¹, T¹³, S¹⁴, D¹⁵, Y¹⁹, and E²¹ is side chain protected.

10. The peptide fragment of claim 9 wherein all of T¹¹, T¹³, S¹⁴, D¹⁵, Y¹⁹, and E²¹

are side chain protected.

11. The peptide fragment of claim 9 wherein the side chain protecting groups are selected from tBu and OtBu.

12. The peptide fragment of claim 1 coupled to a synthetic resin via the C-terminal glycine.

13. A peptide resin, comprising the peptide fragment of claim 1 coupled to a synthetic resin.

14. A peptide fragment having the amino acid sequence HX⁸EX¹⁰TFTSDVX^17-18YLEG (SEQ ID NO. 11) wherein the residue denoted by the symbol X^17-18 has the formula

15. The peptide fragment of claim 14 wherein X⁸ is aminoisobutyric acid.

16. The peptide fragment of claim 14 wherein X¹⁰ is glycine.

17. The peptide fragment of claim 14 wherein X⁸ is aminoisobutyric acid, X¹⁰ is glycine, and the residue denoted by the symbol X^17-18 has the formula:

18. The peptide fragment of claim 14 coupled to a synthetic resin via the C-terminal glycine.