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 purificati
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: (P1)AA1-AA2-AA3-AA4(P4)-AA5-AA6(P6)-AA7-AA8(P8)-AA9-AA10-NH2 (II) or a salt or solvate thereof, to a treatment with a cleaving agent in an organic solvent, wherein P1 is an amino protecting groups; preferably acetyl; P4 is hydrogen or a hydroxyl protecting group, preferably a hydroxyl protecting group; P6 is hydrogen or an amino protecting groups; preferably an amino protecting groups; and P8 is an amino protecting group.
대표청구항▼
1. A process for preparing Degarelix having the formula Ac-AA1-AA10-NH2 or a pharmaceutically acceptable salt or solvate thereof, wherein AA1 is D-2Nal, AA2 is D-4Cpa, AA3 is D-3Pal, AA4 is Ser, AA5 is 4Aph(L-Hor), AA6 is D-Aph(Cbm), AA7 is Leu, AA8 is Lys(iPr), AA9 is Pro and AA10 is D-Ala, compris
1. A process for preparing Degarelix having the formula Ac-AA1-AA10-NH2 or a pharmaceutically acceptable salt or solvate thereof, wherein AA1 is D-2Nal, AA2 is D-4Cpa, AA3 is D-3Pal, AA4 is Ser, AA5 is 4Aph(L-Hor), AA6 is D-Aph(Cbm), AA7 is Leu, AA8 is Lys(iPr), AA9 is Pro and AA10 is D-Ala, comprising: treating a Degarelix precursor according to formula II ((P1)AA1-AA2-AA3-AA4(P4)-AA5-AA6(P6)-AA7-AA8(P8)-AA9-AA10-NH2), or a salt or solvate thereof, with a cleaving agent, wherein formula II is as follows: wherein P1 is an amino protecting group;P4 is hydrogen or a hydroxyl protecting group;P6 is hydrogen or an amino protecting group;P8 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, ora process for preparing Degarelix having the formula Ac-AA1-AA10-NH2 or a pharmaceutically acceptable salt or solvate thereof, wherein AA1 is D-2Nal, AA2 is D-4Cpa, AA3 is D-3Pal, AA4 is Ser, AA5 is 4Aph(L-Hor), AA6 is D-Aph(Cbm), AA7 is Leu, AA8 is Lys(iPr), AA9 is Pro and AA10 is D-Ala, comprising:treating a Degarelix precursor according to formula II ((P1)AA1-AA2-AA3-AA4(P4)-AA5-AA6(P6)-AA7-AA8(P8)-AA9-AA10-NH2), or a salt or solvate thereof, with a cleaving agent, wherein formula II is as follows: wherein P1 is an amino protecting group;P4 is hydrogen or a hydroxyl protecting group;P6 is hydrogen or an amino protecting group chosen from C5-C6 alkyl, acetyl (Ac), trityl, benzyl, p-methoxybenzyl, p-nitrobenzyl, p-chlorobenzyl, o-chlorobenzyl, 2,6-dichlorobenzyl, tetrahydropyranyl, tri(C1-C6)alkylsilyl, 2-methoxyethoxymethyl (MEM), 4-dimethylcarbamoylbenzyl, 9-fluorenylmethyl ethers, and O-phenoxyacetyl ethers;P8 is an amino protecting group; and wherein the process is a liquid-phase process, ora process for preparing Degarelix having the formula Ac-AA1-AA10-NH2 or a pharmaceutically acceptable salt or solvate thereof, wherein AA1 is D-2Nal, AA2 is D-4Cpa, AA3 is D-3Pal, AA4 is Ser, AA5 is 4Aph(L-Hor), AA6 is D-Aph(Cbm), AA7 is Leu, AA8 is Lys(iPr), AA9 is Pro and AA10 is D-Ala, comprising:treating a Degarelix precursor according to formula II ((P1)AA1-AA2-AA3-AA4(P4)-AA5-AA6(P6)-AA7-AA8(P8)-AA9-AA10-NH2), or a salt or solvate thereof, with a cleaving agent, wherein formula II is as follows: wherein P1 is an amino protecting group;P4 is hydrogen or is a hydroxyl protecting group chosen from C5-C6 alkyl, acetyl (Ac), trityl, benzyl, p-methoxybenzyl, p-nitrobenzyl, p-chlorobenzyl, o-chlorobenzyl, 2,6-dichlorobenzyl, tetrahydropyranyl, tri(C1-C6)alkylsilyl, 2-methoxyethoxymethyl (MEM), 4-dimethylcarbamoylbenzyl, 9-fluorenylmethyl ethers, and O-phenoxyacetyl ethers;P6 is hydrogen or an amino protecting group;P8 is an amino protecting group; and wherein the process is a liquid-phase process, ora process for preparing Degarelix having the formula Ac-AA1-AA10-NH2 or a pharmaceutically acceptable salt or solvate thereof, wherein AA1 is D-2Nal, AA2 is D-4Cpa, AA3 is D-3Pal, AA4 is Ser, AA5 is 4Aph(L-Hor), AA6 is D-Aph(Cbm), AA7 is Leu, AA8 is Lys(iPr), AA9 is Pro and AA10 is D-Ala, comprising: treating a Degarelix precursor according to formula II ((P1)AA1-AA2-AA3-AA4(P4)-AA5-AA6(P6)-AA7-AA8(P8)-AA9-AA10-NH2), or a salt or solvate thereof, with a cleaving agent, wherein formula II is as follows: wherein P1 is an amino protecting group;P4 is hydrogen or is a hydroxyl protecting group chosen from C5-C6 alkyl, acetyl (Ac), trityl, benzyl, p-methoxybenzyl, p-nitrobenzyl, p-chlorobenzyl, o-chlorobenzyl, 2,6-dichlorobenzyl, tetrahydropyranyl, tri(C1-C6)alkylsilyl, 2-methoxyethoxymethyl (MEM), 4-dimethylcarbamoylbenzyl, 9-fluorenylmethyl ethers, and O-phenoxyacetyl ethers;P6 is hydrogen or an amino protecting group chosen from C5-C6 alkyl, acetyl (Ac), trityl, benzyl, p-methoxybenzyl, p-nitrobenzyl, p-chlorobenzyl, o-chlorobenzyl, 2,6-dichlorobenzyl, tetrahydropyranyl, tri(C1-C6)alkylsilyl, 2-methoxyethoxymethyl (MEM), 4-dimethylcarbamoylbenzyl, 9-fluorenylmethyl ethers, and O-phenoxyacetyl ethers;P8 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) (P1)AA1-AA2-AA3-AA4(P4)-AA5-AA6(P6)-AA7-AA8(P8)-AA9-AA10-NH2 (II)wherein AA1 is D-2Nal, AA2 is D-4Cpa, AA3 is D-3Pal, AA4 is Ser, AA5 is 4Aph(L-Hor), AA6 is D-Aph(Cbm), AA7 is Leu, AA8 is Lys(iPr), AA9 is Pro, and AA10 is D-Ala;P1 is an amino protecting group or acetyl;P4 is hydrogen or is a hydroxyl protecting group chosen from C5-C6 alkyl, acetyl (Ac), trityl, benzyl, p-methoxybenzyl, p-nitrobenzyl, p-chlorobenzyl, o-chlorobenzyl, 2,6-dichlorobenzyl, tetrahydropyranyl, tri(C1-C6)alkylsilyl, 2-methoxyethoxymethyl (MEM), 4-dimethylcarbamoylbenzyl, 9-fluorenylmethyl ethers, and O-phenoxyacetyl ethers;P6 is hydrogen or an amino protecting group; andP8 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): (P1)AA1-AA2-AA3 (III)or a salt thereof, with a second polypeptide represented by formula (IV): AA4(P4)-AA5-AA6(P6)-AA7-AA8(P8)-AA9-AA10-NH2 (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 process,ora process for the manufacture of a decapeptide represented by formula (II) (P1)AA1-AA2-AA3-AA4 (P4)-AA5-AA6(P6)-AA7-AA8(P8)-AA9-AA10-NH2 (II)wherein AA1 is D-2Nal, AA2 is D-4Cpa, AA3 is D-3Pal, AA4 is Ser, AA5 is 4Aph(L-Hor), AA6 is D-Aph(Cbm), AA7 is Leu, AA8 is Lys(iPr), AA9 is Pro, and AA10 is D-Ala;P1 is an amino protecting group or acetyl;P4 is hydrogen or a hydroxyl protecting group;P6 is hydrogen or an amino protecting group chosen from C5-C6 alkyl, acetyl (Ac), trityl, benzyl, p-methoxybenzyl, p-nitrobenzyl, p-chlorobenzyl, o-chlorobenzyl, 2,6-dichlorobenzyl, tetrahydropyranyl, tri(C1-C6)alkylsilyl, 2-methoxyethoxymethyl (MEM), 4-dimethylcarbamoylbenzyl, 9-fluorenylmethyl ethers, and O-phenoxyacetyl ethers; andP8 is an amino protecting group, or a pharmaceutically acceptable salt or solvate thereof, comprising the step ofcoupling a first polypeptide represented by formula (III): (P1)AA1-AA2-AA3 (III)or a salt thereof, with a second polypeptide represented by formula (IV): AA4(P4)-AA5-AA6(P6)-AA7-AA8(P8)-AA9-AA10-NH2 (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 process,ora process for the manufacture of a decapeptide represented by formula (II) (P1)AA1-AA2-AA3-AA4 (P4)-AA5-AA6(P6)-AA7-AA8(P8)-AA9-AA10-NH2 (II)wherein AA1 is D-2Nal, AA2 is D-4Cpa, AA3 is D-3Pal, AA4 is Ser, AA5 is 4Aph(L-Hor), AA6 is D-Aph(Cbm), AA7 is Leu, AA8 is Lys(iPr), AA9 is Pro, and AA10 is D-Ala;P1 is an amino protecting group or acetyl;P4 is hydrogen or a hydroxyl protecting group;P6 is hydrogen or an amino protecting group; andP8 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, or a pharmaceutically acceptable salt or solvate thereof, comprising the step ofcoupling a first polypeptide represented by formula (III): (P1)AA1-AA2-AA3 (III)or a salt thereof, with a second polypeptide represented by formula (IV): AA4(P4)-AA5-AA6(P6)-AA7-AA8(P8)-AA9-AA10-NH2 (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 process,ora process for the manufacture of a decapeptide represented by formula (II) (P1)AA1-AA2-AA3-AA4 (P4)-AA5-AA6(P6)-AA7-AA8(P8)-AA9-AA10-NH2 (II)wherein AA1 is D-2Nal, AA2 is D-4Cpa, AA3 is D-3Pal, AA4 is Ser, AA5 is 4Aph(L-Hor), AA6 is D-Aph(Cbm), AA7 is Leu, AA8 is Lys(iPr), AA9 is Pro, and AA10 is D-Ala;P1 is an amino protecting group or acetyl;P4 is hydrogen or is a hydroxyl protecting group chosen from C5-C6 alkyl, acetyl (Ac), trityl, benzyl, p-methoxybenzyl, p-nitrobenzyl, p-chlorobenzyl, o-chlorobenzyl, 2,6-dichlorobenzyl, tetrahydropyranyl, tri(C1-C6)alkylsilyl, 2-methoxyethoxymethyl (MEM), 4-dimethylcarbamoylbenzyl, 9-fluorenylmethyl ethers, and O-phenoxyacetyl ethers;P6 is hydrogen or an amino protecting group chosen from C5-C6 alkyl, acetyl (Ac), trityl, benzyl, p-methoxybenzyl, p-nitrobenzyl, p-chlorobenzyl, o-chlorobenzyl, 2,6-dichlorobenzyl, tetrahydropyranyl, tri(C1-C6)alkylsilyl, 2-methoxyethoxymethyl (MEM), 4-dimethylcarbamoylbenzyl, 9-fluorenylmethyl ethers, and O-phenoxyacetyl ethers; andP8 is an amino protecting group chosen from 9-fluorenylmethyloxycarbonyl (Fmoc), benzyloxycarbonyl (Cbz or Z), 2-bromo-benzyloxycarbonyl (2-Br—Z), 2-chloro-benzyloxycarbonyl (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, or a pharmaceutically acceptable salt or solvate thereof, comprising the step ofcoupling a first polypeptide represented by formula (III): (P1)AA1-AA2-AA3 (III)or a salt thereof, with a second polypeptide represented by formula (IV): AA4(P4)-AA5-AA6(P6)-AA7-AA8(P8)-AA9-AA10- NH2 (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 process. 3. A process for preparing a polypeptide represented by formula (IV): (P4)AA4-AA5-AA6(P6)-AA7-AA8(P8)-AA9-AA10-NH2 (IV)whereinP4 is hydrogen or is a hydroxyl protecting group chosen from C5-C6 alkyl, acetyl (Ac), trityl, benzyl, p-methoxybenzyl, p-nitrobenzyl, p-chlorobenzyl, o-chlorobenzyl, 2,6-dichlorobenzyl, tetrahydropyranyl, tri(C1-C6)alkylsilyl, 2-methoxyethoxymethyl (MEM), 4-dimethylcarbamoylbenzyl, 9-fluorenylmethyl ethers, and O-phenoxyacetyl ethers;P6 is hydrogen or an amino protecting group; andP8 is an amino protecting group, comprising:coupling a polypeptide represented by formulae (V), or a salt or solvate thereof, with a polypeptide represented by formula (VI), or a salt or solvate thereof, (PN)AA4(P4)-AA5-AA6(P6)-AA7 (V)AA8(P8)-AA9-AA10-NH2 (VI)and then removing the deprotecting group PN, wherein AA4 is Ser, AA5 is 4Aph(L-Hor), AA6 is D-Aph(Cbm), AA7 is Leu, AA8 is Lys(iPr), AA9 is Pro and AA10 is D-Ala, and PN is a protecting group that can be removed by hydrogenation,wherein the process is a liquid-phase process,ora process for preparing a polypeptide represented by formula (IV): (P4)AA4-AA5-AA6(P6)-AA7-AA8(P8)-AA9-AA10-NH2 (IV)whereinP4 is hydrogen or a hydroxyl protecting group;P6 is hydrogen or an amino protecting group chosen from C5-C6 alkyl, acetyl (Ac), trityl, benzyl, p-methoxybenzyl, p-nitrobenzyl, p-chlorobenzyl, o-chlorobenzyl, 2,6-dichlorobenzyl, tetrahydropyranyl, tri(C1-C6)alkylsilyl, 2-methoxyethoxymethyl (MEM), 4-dimethylcarbamoylbenzyl, 9-fluorenylmethyl ethers, and O-phenoxyacetyl ethers; andP8 is an amino protecting group, comprising:coupling a polypeptide represented by formulae (V), or a salt or solvate thereof, with a polypeptide represented by formula (VI), or a salt or solvate thereof, (PN)AA4(P4)-AA5-AA6(P6)-AA7 (V)AA8(P8)-AA9-AA10-NH2 (VI)and then removing the deprotecting group PN, wherein AA4 is Ser, AA5 is 4Aph(L-Hor), AA6 is D-Aph(Cbm), AA7 is Leu, AA8 is Lys(iPr), AA9 is Pro and AA10 is D-Ala, and PN is a protecting group that can be removed by hydrogenation,wherein the process is a liquid-phase process,ora process for preparing a polypeptide represented by formula (IV): (P4)AA4-AA5-AA6(P6)-AA7-AA8(P8)-AA9-AA10-NH2 (IV)whereinP4 is hydrogen or a hydroxyl protecting group;P6 is hydrogen or an amino protecting group; andP8 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, comprising:coupling a polypeptide represented by formulae (V), or a salt or solvate thereof, with a polypeptide represented by formula (VI), or a salt or solvate thereof, (PN)AA4(P4)-AA5-AA6(P6)-AA7 (V)AA8(P8)-AA9-AA10-NH2 (VI)and then removing the deprotecting group PN, wherein AA4 is Ser, AA5 is 4Aph(L-Hor), AA6 is D-Aph(Cbm), AA7 is Leu, AA5 is Lys(iPr), AA9 is Pro and AA10 is D-Ala, and PN is a protecting group that can be removed by hydrogenation,wherein the process is a liquid-phase process,ora process for preparing a polypeptide represented by formula (IV): (P4)AA4-AA5-AA6(P6)-AA7-AA8(P8)-AA9-AA10-NH2 (IV)whereinP4 is hydrogen or is a hydroxyl protecting group chosen from C5-C6 alkyl, acetyl (Ac), trityl, benzyl, p-methoxybenzyl, p-nitrobenzyl, p-chlorobenzyl, o-chlorobenzyl, 2,6-dichlorobenzyl, tetrahydropyranyl, tri(C1-C6)alkylsilyl, 2-methoxyethoxymethyl (MEM), 4-dimethylcarbamoylbenzyl, 9-fluorenylmethyl ethers, and O-phenoxyacetyl ethers;P6 is hydrogen or an amino protecting group chosen from C5-C6 alkyl, acetyl (Ac), trityl, benzyl, p-methoxybenzyl, p-nitrobenzyl, p-chlorobenzyl, o-chlorobenzyl, 2,6-dichlorobenzyl, tetrahydropyranyl, tri(C1-C6)alkylsilyl, 2-methoxyethoxymethyl (MEM), 4-dimethylcarbamoylbenzyl, 9-fluorenylmethyl ethers, and O-phenoxyacetyl ethers; andP8 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-nitrobenzyloxycarbony, comprising:coupling a polypeptide represented by formulae (V), or a salt or solvate thereof, with a polypeptide represented by formula (VI), or a salt or solvate thereof, (PN)AA4(P4)-AA5-AA6(P6)-AA7 (V)AA8(P8)-AA9-AA10-N H2 (VI)and then removing the deprotecting group PN, wherein AA4 is Ser, AA5 is 4Aph(L-Hor), AA6 is D-Aph(Cbm), AA7 is Leu, AA8 is Lys(iPr), AA9 is Pro and AA10 is D-Ala, and PN is a protecting group that can be removed by hydrogenation,wherein the process is a liquid-phase process. 4. A process for producing a compound of (PN)AA4(P4)-AA5-AA6(P6)-AA7, wherein AA4 is Ser, AA5 is 4Aph(L-Hor), AA6 is D-Aph(Cbm), AA7 is Leu,P4 is hydrogen or is a hydroxyl protecting group chosen from C5-C6 alkyl, acetyl (Ac), trityl, benzyl, p-methoxybenzyl, p-nitrobenzyl, p-chlorobenzyl, o-chlorobenzyl, 2,6-dichlorobenzyl, tetrahydropyranyl, tri(C1-C6)alkylsilyl, 2-methoxyethoxymethyl (MEM), 4-dimethylcarbamoylbenzyl, 9-fluorenylmethyl ethers, and O-phenoxyacetyl ethers,P6 is chosen from hydrogen and an amino protecting group, andPN is a protecting group that can be removed by hydrogenation, comprising the following steps:(a) providing (PN2)AA5-AA6(P6)-AA7(Pc), wherein (PN2) is an N-terminal amino protecting group or hydrogen, and (Pc) is a C-terminal carboxyl protecting group that can be cleaved by hydrogenation;(b) removing the amino protecting group (PN2), if present;(c) hydrogenating H-AA5-AA6(P6)-AA7(Pc) to obtain H-AA5-AA6(P6)-AA7; and(d) reacting H-AA5-AA6(P6)-AA7 with an activated ester of (PN)AA4(P4) to provide (PN)AA4(P4)-AA5-AA6(P6)-AA7, wherein (P4) is a hydroxyl protecting group chosen from C5-C6 alkyl, acetyl (Ac), trityl, benzyl, p-methoxybenzyl, p-nitrobenzyl, p-chlorobenzyl, o-chlorobenzyl, 2,6-dichlorobenzyl, tetrahydropyranyl, tri(C1-C6)alkylsilyl, 2-methoxyethoxymethyl (MEM), 4-dimethylcarbamoylbenzyl, 9-fluorenylmethyl ethers, and O-phenoxyacetyl ethers or hydrogen, and PN is a protecting group that can be eliminated by hydrogenation,wherein the process is a liquid-phase process,ora process for producing a compound of (PN)AA4(P4)-AA5-AA6(P6)-AA7,wherein AA4 is Ser, AA5 is 4Aph(L-Hor), AA6 is D-Aph(Cbm), AA7 is Leu,P4 is chosen from hydrogen and a hydroxyl protecting group,P6 is hydrogen or an amino protecting group chosen from C5-C6 alkyl, acetyl (Ac), trityl, benzyl, p-methoxybenzyl, p-nitrobenzyl, p-chlorobenzyl, o-chlorobenzyl, 2,6-dichlorobenzyl, tetrahydropyranyl, tri(C1-C6)alkylsilyl, 2-methoxyethoxymethyl (MEM), 4-dimethylcarbamoylbenzyl, 9-fluorenylmethyl ethers, and O-phenoxyacetyl ethers, andPN is a protecting group that can be removed by hydrogenation, comprising the following steps:(a) providing (PN2)AA5-AA6(P6)-AA7(Pc), wherein (PN2) is an N-terminal amino protecting group or hydrogen, and (Pc) is a C-terminal carboxyl protecting group that can be cleaved by hydrogenation;(b) removing the amino protecting group (PN2), if present;(c) hydrogenating H-AA5-AA6(P6)-AA7(Pc) to obtain H-AA5-AA6(P6)-AA7; and(d) reacting H-AA5-AA6(P6)-AA7 with an activated ester of (PN)AA4(P4) to provide (PN)AA4(P4)-AA5-AA6(P6)-AA7, wherein (P4) is a hydroxyl protecting group or hydrogen, and PN is a protecting group that can be eliminated by hydrogenation,wherein the process is a liquid-phase process,ora process for producing a compound of (PN)AA4(P4)-AA5-AA6(P6)-AA7,wherein AA4 is Ser, AA5 is 4Aph(L-Hor), AA6 is D-Aph(Cbm), AA7 is Leu,P4 is hydrogen or is a hydroxyl protecting group chosen from C5-C6 alkyl, acetyl (Ac), trityl, benzyl, p-methoxybenzyl, p-nitrobenzyl, p-chlorobenzyl, o-chlorobenzyl, 2,6-dichlorobenzyl, tetrahydropyranyl, tri(C1-C6)alkylsilyl, 2-methoxyethoxymethyl (MEM), 4-dimethylcarbamoylbenzyl, 9-fluorenylmethyl ethers, and O-phenoxyacetyl ethers,P6 is hydrogen or an amino protecting group chosen from C5-C6 alkyl, acetyl (Ac), trityl, benzyl, p-methoxybenzyl, p-nitrobenzyl, p-chlorobenzyl, o-chlorobenzyl, 2,6-dichlorobenzyl, tetrahydropyranyl, tri(C1-C6)alkylsilyl, 2-methoxyethoxymethyl (MEM), 4-dimethylcarbamoylbenzyl, 9-fluorenylmethyl ethers, and O-phenoxyacetyl ethers, andPN is a protecting group that can be removed by hydrogenation, comprising the following steps:(a) providing (PN2)AA5-AA6(P6)-AA7(Pc), wherein (PN2) is an N-terminal amino protecting group or hydrogen, and (Pc) is a C-terminal carboxyl protecting group that can be cleaved by hydrogenation;(b) removing the amino protecting group (PN2), if present;(c) hydrogenating H-AA5-AA6(P6)-AA7(Pc) to obtain H-AA5-AA6(P6)-AA7; and(d) reacting H-AA5-AA6(P6)-AA7 with an activated ester of (PN)AA4(P4) to provide (PN)AA4(P4)-AA5-AA6(P6)-AA7, wherein (P4) is a hydroxyl protecting group chosen from C5-C6 alkyl, acetyl (Ac), trityl, benzyl, p-methoxybenzyl, p-nitrobenzyl, p-chlorobenzyl, o-chlorobenzyl, 2,6-dichlorobenzyl, tetrahydropyranyl, tri(C1-C6)alkylsilyl, 2-methoxyethoxymethyl (MEM), 4-dimethylcarbamoylbenzyl, 9-fluorenylmethyl ethers, and O-phenoxyacetyl ethers or hydrogen, and PN is a protecting group that can be eliminated by hydrogenation,wherein the process is a liquid-phase process. 5. Polypeptide compounds consisting of the following formulae: AA4(P4)-AA5-AA6(P6)-AA7-AA8(P8)-AA9-AA10-NH2,(PN)AA4(P4)-AA5-AA6(P6)-AA7-AA8(P8)-AA9-AA10-NH2,(PN)AA4(P4)-AA5-AA6(P6)-AA7, or salts or solvates,wherein AA4 is Ser, AA5 is 4Aph(L-Hor), AA6 is D-Aph(Cbm), AA7 is Leu, AA8 is Lys(iPr), AA9 is Pro, AA10 is D-Ala;P4 is hydrogen or is a hydroxyl protecting group chosen from C5-C6 alkyl, acetyl (Ac), trityl, benzyl, p-methoxybenzyl, p-nitrobenzyl, p-chlorobenzyl, o-chlorobenzyl, 2,6-dichlorobenzyl, tetrahydropyranyl, tri(C1-C6)alkylsilyl, 2-methoxyethoxymethyl (MEM), 4-dimethylcarbamoylbenzyl, 9-fluorenylmethyl ethers, and O-phenoxyacetyl ethers;P6 is hydrogen or an amino protecting groups; andP8 is an amino protecting group, andPN is a protecting group,orpolypeptide compounds represented by the following formulae: AA4(P4)-AA5-AA6(P6)-AA7-AA8(P8)-AA9-AA10-NH2,(PN)AA4(P4)-AA5-AA6(P6)-AA7-AA8(P8)-AA9-AA10-NH2,(PN)AA4(P4)-AA5-AA6(P6)-AA7, or salts or solvates,wherein AA4 is Ser, AA5 is 4Aph(L-Hor), AA6 is D-Aph(Cbm), AA7 is Leu, AA8 is Lys(iPr), AA9 is Pro, AA10 is D-Ala;P4 is hydrogen or a hydroxyl protecting group;P6 is hydrogen or an amino protecting group chosen from C5-C6 alkyl, acetyl (Ac), trityl, benzyl, p-methoxybenzyl, p-nitrobenzyl, p-chlorobenzyl, o-chlorobenzyl, 2,6-dichlorobenzyl, tetrahydropyranyl, tri(C1-C6)alkylsilyl, 2-methoxyethoxymethyl (MEM), 4-dimethylcarbamoylbenzyl, 9-fluorenylmethyl ethers, and O-phenoxyacetyl ethers; andP8 is an amino protecting group, andPN is a protecting group,orpolypeptide compounds represented by the following formulae: AA4(P4)-AA5-AA6(P6)-AA7-AA8(P8)-AA9-AA10-NH2,(PN)AA4(P4)-AA5-AA6(P6)-AA7-AA8(P8)-AA9-AA10NH2,(PN)AA4(P4)-AA5-AA6(P6)-AA7, or salts or solvates,wherein AA4 is Ser, AA5 is 4Aph(L-Hor), AA6 is D-Aph(Cbm), AA7 is Leu, AA8 is Lys(iPr), AA9 is Pro, AA1o is D-Ala;P4 is hydrogen or a hydroxyl protecting group;P6 is hydrogen or an amino protecting groups; andP8 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-nitrobenzyloxycarbony, andPN is a protecting group,orpolypeptide compounds represented by the following formulae: AA4(P4)-AA5-AA6(P6)-AA7-AA8(P8)-AA9-AA10-NH2,(PN)AA4(P4)-AA5-AA6(P6)-AA7-AA8(P8)-AA9-AA10-NH2,(PN)AA4(P4)-AA5-AA6(P6)-AA7, or salts or solvates,wherein AA4 is Ser, AA5 is 4Aph(L-Hor), AA6 is D-Aph(Cbm), AA7 is Leu, AA8 is Lys(iPr), AA9 is Pro, AA10 is D-Ala;P4 is hydrogen or is a hydroxyl group chosen from C5-C6 alkyl, acetyl (Ac), trityl, benzyl, p-methoxybenzyl, p-nitrobenzyl, p-chlorobenzyl, o-chlorobenzyl, 2,6-dichlorobenzyl, tetrahydropyranyl, tri(C1-C6)alkylsilyl, 2-methoxyethoxymethyl (MEM), 4-dimethylcarbamoylbenzyl, 9-fluorenylmethyl ethers, and O-phenoxyacetyl ethers;P6 is hydrogen or an amino protecting group chosen from C5-C6 alkyl, acetyl (Ac), trityl, benzyl, p-methoxybenzyl, p-nitrobenzyl, p-chlorobenzyl, o-chlorobenzyl, 2,6-dichlorobenzyl, tetrahydropyranyl, tri(C1-C6)alkylsilyl, 2-methoxyethoxymethyl (MEM), 4-dimethylcarbamoylbenzyl, 9-fluorenylmethyl ethers, and O-phenoxyacetyl ethers; andP8 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-nitrobenzyloxycarbony, andPN is a protecting group.
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Rivier Jean E. F. (La Jolla CA) Porter John S. (Leucadia CA) Hoeger Carl A. (San Marcos CA) Jiang Guangcheng (La Jolla CA) Rivier Catherine L. (La Jolla CA), GNRH antagonists XIII.
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