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US 2020/0399339 A1Published application
Process for the preparation of high purity glucagon
AssigneeFresenius Kabi Ipsum S.R.L.
InventorsAndrea ORLANDIN, Antonio RICCI, Walter CABRI, Steve MCINTYRE, Alex SAUNDERS
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Abstract
The present invention provides an improved process for the preparation of high purity glucagon comprising the use of Xmb-protected amino acids, wherein may Xmb include, e.g., 2,4,6-trimethoxybenzyl, 2,4-dimethoxybenzyl, or 2-hydroxy-4-methoxybenzyl. The process also comprises the use of building blocks such as pseudoprolines to avoid aggregation and obtain the product in high yield and purity.
Claims20
A process for the preparation of glucagon of formula I (SEQ ID NO:
- 1)
- (I)
- 1 5 10
- His-Ser-Gln-Gly-Thr-Phe-Thr-Ser-Asp-Tyr-
- 15 20
- Ser-Lys-Tyr-Leu-Asp-Ser-Arg-Arg-Ala-Gln-
- 25 29
- Asp-Phe-Val-Gln-Trp-Leu-Met-Asn-Thr,
- the process comprising the use of at least one Xmb-protected amino acid and at least one pseudoproline dipeptide, wherein Xmb is 2,4,6-trimethoxybenzyl (Tmb), 2,4-dimethoxybenzyl (Dmb), or 2-hydroxy-4-methoxybenzyl group (Hmb).
6 more elements
A protected glucagon sequence selected from:
- (SEQ ID NO:
- 12)
- His(P)-Ser(P)-Gln(P)-(Xmb)Gly-Thr(P)-Phe-Thr(P)-
- Ser(P)-Asp(P)-Tyr(P)-Ser(P)-Lys(P)-Tyr(P)-Leu-
- pDS-Arg(P)-Arg(P)-Ala-Gln(P)-Asp(P)-Phe-Val-
- Gln(P)-Trp(P)-Leu-Met-Asn(P)-Thr(P),
- (SEQ ID NO:
- 13)
- His(P)-Ser(P)-Gln(P)-(Xmb)Gly-Thr(P)-Phe-Thr(P)-
- Ser(P)-Asp(P)-pYS-Lys(P)-Tyr(P)-Leu-Asp(P)-
- Ser(P)-Arg(P)-Arg(P)-Ala-Gln(P)-Asp(P)-Phe-Val-
- Gln(P)-Trp(P)-Leu-Met-Asn(P)-Thr(P),
- (SEQ ID NO:
- 14)
- His(P)-Ser(P)-Gln(P)-(Xmb)Gly-Thr(P)-Phe-pTS-
- Asp(P)-Tyr(P)-Ser(P)-Lys(P)-Tyr(P)-Leu-Asp(P)-
- Ser(P)-Arg(P)-Arg(P)-Ala-Gln(P)-Asp(P)-Phe-Val-
- Gln(P)-Trp(P)-Leu-Met-Asn(P)-Thr(P),
- (SEQ ID NO:
- 15)
- His(P)-Ser(P)-Gln(P)-(Xmb)Gly-Thr(P)-Phe-pTS-
- Asp(P)-Tyr(P)-Ser(P)-Lys(P)-Tyr(P)-Leu-pDS-
- Arg(P)-Arg(P)-Ala-Gln(P)-Asp(P)-Phe-Val-Gln(P)-
- Trp(P)-Leu-Met-Asn(P)-Thr(P),
- (SEQ ID NO:
- 16)
- His(P)-Ser(P)-Gln(P)-(Xmb)Gly-Thr(P)-Phe-
- Thr(P)-Ser(P)-Asp(P)-pYS-Lys(P)-Tyr(P)-Leu-pDS-
- Arg(P)-Arg(P)-Ala-Gln(P)-Asp(P)-Phe-Val(P)-
- Gln(P)-Trp(P)-Leu-Met-Asn(P)-Thr(P),
- (SEQ ID NO:
- 17)
- His(P)-Ser(P)-Gln(P)-Gly-Thr(P)-Phe-pTS-
- Asp(P)-Tyr(P)-Ser(P)-Lys(P)-Tyr(P)-(Xmb)Leu-
- Asp(P)-Ser(P)-Arg(P)-Arg(P)-Ala-Gln(P)-
- Asp(P)-Phe-Val-Gln(P)-Trp(P)-Leu-Met-Asn(P)-
- Thr(P),
- (SEQ ID NO:
- 18)
- His(P)-Ser(P)-Gln(P)-Gly-Thr(P)-Phe-Thr(P)-
- Ser(P)-Asp(P)-pYS-Lys(P)-Tyr(P)-(Xmb)Leu-
- Asp(P)-Ser(P)-Arg(P)-Arg(P)-Ala-Gln(P)-Asp(P)-
- Phe-Val-Gln(P)-Trp(P)-Leu-Met-Asn(P)-Thr(P),
- (SEQ ID NO:
- 19)
- His(P)-Ser(P)-Gln(P)-Gly-Thr(P)-Phe-Thr(P)-
- Ser(P)-Asp(P)-Tyr(P)-Ser(P)-Lys(P)-Tyr(P)-
- Leu-pDS-Arg(P)-Arg(P)-(Xmb)Ala-Gln(P)-Asp(P)-
- Phe-Val-Gln(P)-Trp(P)-Leu-Met-Asn(P)-Thr(P),
- (SEQ ID NO:
- 20)
- His(P)-Ser(P)-Gln(P)-(Xmb)Gly-Thr(P)-Phe-
- Thr(P)-Ser(P)-Asp(P)-pYS-Lys(P)-Tyr(P)-Leu-
- Asp(P)-Ser(P)-Arg(P)-Arg(P)-(Xmb)Ala-Gln(P)-
- Asp(P)-Phe-Val-Gln(P)-Trp(P)-Leu-Met-Asn(P)-
- Thr(P),
- and
- (SEQ ID NO:
- 21)
- His(P)-Ser(P)-Gln(P)-Gly-Thr(P)-Phe-pTS-
- Asp(P)-Tyr(P)-Ser(P)-Lys(P)-Tyr(P)-Leu-
- Asp(P)-Ser(P)-Arg(P)-Arg(P)-(Xmb)Ala-
- Gln(P)-Asp(P)-Phe-Val-Gln(P)-Trp(P)-Leu-Met-
- Asn(P)-Thr(P),
- wherein Xmb is selected from Tmb, Dmb, and Hmb, pDS is Asp(P)-Ser[psi(R1, R1)pro]-OH, pYS is Tyr(P)-Ser[psi(R1, R1)pro]-OH, pTS is Thr(P)-Ser[psi(R1, R1)pro]-OH, P is a side-chain protecting group or is absent, and R1 is hydrogen or methyl.
62 more elements
Dependencies are inferred from the claim text.