Process for the manufacture of degarelix and its intermediates

Patent metadata

Field	Value
Publication number	US-9822146-B2
Application number	US-201514747218-A
Country	US
Kind code	B2
Filing date	Jun 23, 2015
Priority date	Oct 27, 2010
Publication date	Nov 21, 2017
Grant date	Nov 21, 2017

Abstract

The present invention relates to a liquid (or solution)-phase manufacturing process for preparing the decapeptide Degarelix, its protected precursor, and other useful intermediates. The invention further relates to polypeptides useful in the solution-phase manufacturing process and to the purification of Degarelix itself. Degarelix can be obtained by subjecting a Degarelix precursor according to formula II: (P 1 )AA 1 -AA 2 -AA 3 -AA 4 (P 4 )-AA 5 -AA 6 (P 6 )-AA 7 -AA 8 (P 8 )-AA 9 -AA 10 -NH 2 (II) or a salt or solvate thereof, to a treatment with a cleaving agent in an organic solvent, wherein P 1 is an amino protecting groups; preferably acetyl; P 4 is hydrogen or a hydroxyl protecting group, preferably a hydroxyl protecting group; P 6 is hydrogen or an amino protecting groups; preferably an amino protecting groups; and P 8 is an amino protecting group.

First claim

The invention claimed is:

1. A process for preparing Degarelix having the formula Ac-AA 1 -AA 10 -NH 2 or a pharmaceutically acceptable salt or solvate thereof, wherein AA 1 is D-2Nal, AA 2 is D-4Cpa, AA 3 is D-3Pal, AA 4 is Ser, AA 5 is 4Aph(L-Hor), AA 6 is D-Aph(Cbm), AA 7 is Leu, AA 8 is Lys(iPr), AA 9 is Pro and AA 10 is D-Ala, comprising:
treating a Degarelix precursor according to formula II ((P 1 )AA 1 -AA 2 -AA 3 -AA 4 (P 4 )-AA 5 -AA 6 (P 6 )-AA 7 -AA 8 (P 8 )-AA 9 -AA 10 -NH 2 ), or a salt or solvate thereof, with a cleaving agent, wherein formula II is as follows:

wherein
P 1 is an amino protecting group;
P 4 is hydrogen or a hydroxyl protecting group;
P 6 is hydrogen or an amino protecting group;
P 8 is an amino protecting group chosen from 9-fluorenylmethyloxycarbonyl (Fmoc), benzyloxycarbonyl (Cbz or Z), 2-bromo-benzyloxycarbonyl (2-Br—Z), 2-chlorobenzyloxycarbonyl (2-Cl—Z), p-chlorobenzyloxycarbonyl, p-6-nitrobenzyloxycarbonyl, p-bromobenzyloxycarbonyl, and p-methoxybenzyloxycarbonyl, o-chlorobenzyloxycarbonyl, 2,4-dichlorobenzyloxycarbonyl, 2,6-dichlorobenzyloxycarbonyl, t-amyloxycarbonyl, isopropyloxycarbonyl, 2-(p-biphenylyl)-isopropyloxycarbonyl, cyclopentyloxycarbonyl, adamantyloxycarbonyl, cyclohexyloxycarbonyl, allyloxycarbonyl (Alloc) acetyl (Ac), benzoyl (Bz), trifluoroacetyl (Tfa), toluenesulfonyl (Tos), benzyl (Bn), triphenylmethyl (Trt), o-nitrophenyl-sulfenyl (Nps), t-butyl-dimethylsilyloxycarbonyl, [2-(3,5-dimethoxyphenyl)-propyl-2-oxycarbonyl](Ddz), 2,2,2-trichloroethyloxycarbonyl (Troc), biphenylylisopropyloxycarbonyl (Bpoc), and o-nitrobenzyloxycarbonyl; and

wherein the process is a liquid-phase process,
or
a process for preparing Degarelix having the formula Ac-AA 1 -AA 10 -NH 2 or a pharmaceutically acceptable salt or solvate thereof, wherein AA 1 is D-2Nal, AA 2 is D-4Cpa, AA 3 is D-3Pal, AA 4 is Ser, AA 5 is 4Aph(L-Hor), AA 6 is D-Aph(Cbm), AA 7 is Leu, AA 8 is Lys(iPr), AA 9 is Pro and AA 10 is D-Ala, comprising:
treating a Degarelix precursor according to formula II ((P 1 )AA 1 -AA 2 -AA 3 -AA 4 (P 4 )-AA 5 -AA 6 (P 6 )-AA 7 -AA 8 (P 8 )-AA 9 -AA 10 -NH 2 ), or a salt or solvate thereof, with a cleaving agent, wherein formula II is as follows:

wherein
P 1 is an amino protecting group;
P 4 is hydrogen or a hydroxyl protecting group;
P 6 is hydrogen or an amino protecting group chosen from C 5 -C 6 alkyl, acetyl (Ac), trityl, benzyl, p-methoxybenzyl, p-nitrobenzyl, p-chlorobenzyl, o-chlorobenzyl, 2,6-dichlorobenzyl, tetrahydropyranyl, tri(C 1 -C 6 )alkylsilyl, 2-methoxyethoxymethyl (MEM), 4-dimethylcarbamoylbenzyl, 9-fluorenylmethyl ethers, and O-phenoxyacetyl ethers;
P 8 is an amino protecting group; and

wherein the process is a liquid-phase process,
or
a process for preparing Degarelix having the formula Ac-AA 1 -AA 10 -NH 2 or a pharmaceutically acceptable salt or solvate thereof, wherein AA 1 is D-2Nal, AA 2 is D-4Cpa, AA 3 is D-3Pal, AA 4 is Ser, AA 5 is 4Aph(L-Hor), AA 6 is D-Aph(Cbm), AA 7 is Leu, AA 8 is Lys(iPr), AA 9 is Pro and AA 10 is D-Ala, comprising:
treating a Degarelix precursor according to formula II ((P 1 )AA 1 -AA 2 -AA 3 -AA 4 (P 4 )-AA 5 -AA 6 (P 6 )-AA 7 -AA 8 (P 8 )-AA 9 -AA 10 -NH 2 ), or a salt or solvate thereof, with a cleaving agent, wherein formula II is as follows:

wherein
P 1 is an amino protecting group;
P 4 is hydrogen or is a hydroxyl protecting group chosen from C 5 -C 6 alkyl, acetyl (Ac), trityl, benzyl, p-methoxybenzyl, p-nitrobenzyl, p-chlorobenzyl, o-chlorobenzyl, 2,6-dichlorobenzyl, tetrahydropyranyl, tri(C 1 -C 6 )alkylsilyl, 2-methoxyethoxymethyl (MEM), 4-dimethylcarbamoylbenzyl, 9-fluorenylmethyl ethers, and O-phenoxyacetyl ethers;
P 6 is hydrogen or an amino protecting group;
P 8 is an amino protecting group; and

wherein the process is a liquid-phase process,
or
a process for preparing Degarelix having the formula Ac-AA 1 -AA 10 -NH 2 or a pharmaceutically acceptable salt or solvate thereof, wherein AA 1 is D-2Nal, AA 2 is D-4Cpa, AA 3 is D-3Pal, AA 4 is Ser, AA 5 is 4Aph(L-Hor), AA 6 is D-Aph(Cbm), AA 7 is Leu, AA 8 is Lys(iPr), AA 9 is Pro and AA 10 is D-Ala, comprising: treating a Degarelix precursor according to formula II ((P 1 )AA 1 -AA 2 -AA 3 -AA 4 (P 4 )-AA 5 -AA 6 (P 6 )-AA 7 -AA 8 (P 8 )-AA 9 -AA 10 -NH 2 ), or a salt or solvate thereof, with a cleaving agent, wherein formula II is as follows:

wherein
P 1 is an amino protecting group;
P 4 is hydrogen or is a hydroxyl protecting group chosen from C 5 -C 6 alkyl, acetyl (Ac), trityl, benzyl, p-methoxybenzyl, p-nitrobenzyl, p-chlorobenzyl, o-chlorobenzyl, 2,6-dichlorobenzyl, tetrahydropyranyl, tri(C 1 -C 6 )alkylsilyl, 2-methoxyethoxymethyl (MEM), 4-dimethylcarbamoylbenzyl, 9-fluorenylmethyl ethers, and O-phenoxyacetyl ethers;
P 6 is hydrogen or an amino protecting group chosen from C 5 -C 6 alkyl, acetyl (Ac), trityl, benzyl, p-methoxybenzyl, p-nitrobenzyl, p-chlorobenzyl, o-chlorobenzyl, 2,6-dichlorobenzyl, tetrahydropyranyl, tri(C 1 -C 6 )alkylsilyl, 2-methoxyethoxymethyl (MEM), 4-dimethylcarbamoylbenzyl, 9-fluorenylmethyl ethers, and O-phenoxyacetyl ethers;
P 8 is an amino protecting group chosen from 9-fluorenylmethyloxycarbonyl (Fmoc), benzyloxycarbonyl (Cbz or Z), 2-bromo-benzyloxycarbonyl (2-Br—Z), 2-chlorobenzyloxycarbonyl (2-Cl—Z), p-chlorobenzyloxycarbonyl, p-6-nitrobenzyloxycarbonyl, p-bromobenzyloxycarbonyl, and p-methoxybenzyloxycarbonyl, o-chlorobenzyloxycarbonyl, 2,4-dichlorobenzyloxycarbonyl, 2,6-dichlorobenzyloxycarbonyl, t-amyloxycarbonyl, isopropyloxycarbonyl, 2-(p-biphenylyl)-isopropyloxycarbonyl, cyclopentyloxycarbonyl, adamantyloxycarbonyl, cyclohexyloxycarbonyl, allyloxycarbonyl (Alloc) acetyl (Ac), benzoyl (Bz), trifluoroacetyl (Tfa), toluenesulfonyl (Tos), benzyl (Bn), triphenylmethyl (Trt), o-nitrophenyl-sulfenyl (Nps), t-butyl-dimethylsilyloxycarbonyl, [2-(3,5-dimethoxyphenyl)-propyl-2-oxycarbonyl] (Ddz), 2,2,2-trichloroethyloxycarbonyl (Troc), biphenylylisopropyloxycarbonyl (Bpoc), and o-nitrobenzyloxycarbonyl; and

wherein the process is a liquid-phase process.

2. A process for the manufacture of a decapeptide represented by formula (II)
(P 1 )AA 1 -AA 2 -AA 3 -AA 4 (P 4 )-AA 5 -AA 6 (P 6 )-AA 7 -AA 8 (P 8 )-AA 9 -AA 10 -NH 2   (II)

wherein AA 1 is D-2Nal, AA 2 is D-4Cpa, AA 3 is D-3Pal, AA 4 is Ser, AA 5 is 4Aph(L-Hor), AA 6 is D-Aph(Cbm), AA 7 is Leu, AA 8 is Lys(iPr), AA 9 is Pro, and AA 10 is D-Ala;
P 1 is an amino protecting group or acetyl;
P 4 is hydrogen or is a hydroxyl protecting group chosen from C 5 -C 6 alkyl, acetyl (Ac), trityl, benzyl, p-methoxybenzyl, p-nitrobenzyl, p-chlorobenzyl, o-chlorobenzyl, 2,6-dichlorobenzyl, tetrahydropyranyl, tri(C 1 -C 6 )alkylsilyl, 2-methoxyethoxymethyl (MEM), 4-dimethylcarbamoylbenzyl, 9-fluorenylmethyl ethers, and O-phenoxyacetyl ethers;
P 6 is hydrogen or an amino protecting group; and
P 8 is an amino protecting group, or a pharmaceutically acceptable salt or solvate thereof, comprising the step of coupling a first polypeptide represented by formula (III):
(P 1 )AA 1 -AA 2 -AA 3   (III)

or a salt thereof, with a second polypeptide represented by formula (IV):
AA 4 (P 4 )-AA 5 -AA 6 (P 6 )-AA 7 -AA 8 (P 8 )-AA 9 -AA 10 -NH 2   (IV)

or a salt thereof, in a liquid reagent medium in the presence of a peptide coupling reagent,
wherein the process is a liquid-phase pr

Assignees

• Ferring Bv

Inventors

• Rasmusse Jon Holbech
• Fornsgaard Jens
• Hansen Stefan
• Rasmussen Palle Hedengran
• Wachs Wolfgang Oliver

Classifications

• C07K5/081

  the side chain containing O or S as heteroatoms, e.g. Cys, Ser · CPC title

• A61K38/08 Primary

  Peptides having 5 to 11 amino acids {(A61K38/043 - A61K38/046 take precedence)} · CPC title

• Y02P20/55

  Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups · CPC title

• C07K7/04

  Linear peptides containing only normal peptide links · CPC title

• C07K5/0815

  with the first amino acid being basic · CPC title