DK2632934T3 - Fremgangsmåde til fremstilling af Degarelix og dets mellemprodukter - Google Patents
Fremgangsmåde til fremstilling af Degarelix og dets mellemprodukter Download PDFInfo
- Publication number
- DK2632934T3 DK2632934T3 DK11776156.9T DK11776156T DK2632934T3 DK 2632934 T3 DK2632934 T3 DK 2632934T3 DK 11776156 T DK11776156 T DK 11776156T DK 2632934 T3 DK2632934 T3 DK 2632934T3
- Authority
- DK
- Denmark
- Prior art keywords
- coupling
- protecting group
- process according
- degarelix
- peptide
- Prior art date
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- MEUCPCLKGZSHTA-XYAYPHGZSA-N degarelix Chemical compound C([C@H](C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCCNC(C)C)C(=O)N1[C@@H](CCC1)C(=O)N[C@H](C)C(N)=O)NC(=O)[C@H](CC=1C=CC(NC(=O)[C@H]2NC(=O)NC(=O)C2)=CC=1)NC(=O)[C@H](CO)NC(=O)[C@@H](CC=1C=NC=CC=1)NC(=O)[C@@H](CC=1C=CC(Cl)=CC=1)NC(=O)[C@@H](CC=1C=C2C=CC=CC2=CC=1)NC(C)=O)C1=CC=C(NC(N)=O)C=C1 MEUCPCLKGZSHTA-XYAYPHGZSA-N 0.000 title claims description 47
- 108010052004 acetyl-2-naphthylalanyl-3-chlorophenylalanyl-1-oxohexadecyl-seryl-4-aminophenylalanyl(hydroorotyl)-4-aminophenylalanyl(carbamoyl)-leucyl-ILys-prolyl-alaninamide Proteins 0.000 title claims description 45
- 229960002272 degarelix Drugs 0.000 title claims description 44
- 238000000034 method Methods 0.000 title claims description 39
- 230000008569 process Effects 0.000 title claims description 27
- 238000002360 preparation method Methods 0.000 title claims description 14
- 239000000543 intermediate Substances 0.000 title description 11
- 238000005859 coupling reaction Methods 0.000 claims description 58
- 230000008878 coupling Effects 0.000 claims description 48
- 238000010168 coupling process Methods 0.000 claims description 48
- 125000006239 protecting group Chemical group 0.000 claims description 48
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical group O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 38
- -1 hexafluorophosphate Chemical compound 0.000 claims description 36
- 239000002585 base Substances 0.000 claims description 29
- 108090000765 processed proteins & peptides Proteins 0.000 claims description 28
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-diisopropylethylamine Substances CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 23
- 102000004196 processed proteins & peptides Human genes 0.000 claims description 21
- 239000007821 HATU Substances 0.000 claims description 19
- 239000007791 liquid phase Substances 0.000 claims description 19
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical group OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 18
- 238000006243 chemical reaction Methods 0.000 claims description 18
- 125000003088 (fluoren-9-ylmethoxy)carbonyl group Chemical group 0.000 claims description 17
- 239000000654 additive Substances 0.000 claims description 17
- FPIRBHDGWMWJEP-UHFFFAOYSA-N 1-hydroxy-7-azabenzotriazole Chemical compound C1=CN=C2N(O)N=NC2=C1 FPIRBHDGWMWJEP-UHFFFAOYSA-N 0.000 claims description 16
- 238000004519 manufacturing process Methods 0.000 claims description 16
- 150000001412 amines Chemical class 0.000 claims description 14
- 239000003153 chemical reaction reagent Substances 0.000 claims description 14
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical group [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 claims description 13
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 claims description 13
- 239000001257 hydrogen Substances 0.000 claims description 13
- 229910052739 hydrogen Inorganic materials 0.000 claims description 13
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 13
- 239000003960 organic solvent Substances 0.000 claims description 13
- 239000002243 precursor Substances 0.000 claims description 13
- 230000000996 additive effect Effects 0.000 claims description 12
- ASOKPJOREAFHNY-UHFFFAOYSA-N 1-Hydroxybenzotriazole Chemical compound C1=CC=C2N(O)N=NC2=C1 ASOKPJOREAFHNY-UHFFFAOYSA-N 0.000 claims description 11
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 11
- 239000002904 solvent Substances 0.000 claims description 11
- BGRWYRAHAFMIBJ-UHFFFAOYSA-N diisopropylcarbodiimide Natural products CC(C)NC(=O)NC(C)C BGRWYRAHAFMIBJ-UHFFFAOYSA-N 0.000 claims description 10
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 10
- 150000003839 salts Chemical class 0.000 claims description 10
- BDNKZNFMNDZQMI-UHFFFAOYSA-N 1,3-diisopropylcarbodiimide Chemical compound CC(C)N=C=NC(C)C BDNKZNFMNDZQMI-UHFFFAOYSA-N 0.000 claims description 9
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 9
- 238000003776 cleavage reaction Methods 0.000 claims description 9
- 230000007017 scission Effects 0.000 claims description 9
- 239000007790 solid phase Substances 0.000 claims description 9
- 239000012453 solvate Substances 0.000 claims description 9
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 8
- 238000005897 peptide coupling reaction Methods 0.000 claims description 8
- 229920001184 polypeptide Polymers 0.000 claims description 8
- 150000001875 compounds Chemical class 0.000 claims description 7
- 239000012026 peptide coupling reagents Substances 0.000 claims description 7
- CLZISMQKJZCZDN-UHFFFAOYSA-N [benzotriazol-1-yloxy(dimethylamino)methylidene]-dimethylazanium Chemical compound C1=CC=C2N(OC(N(C)C)=[N+](C)C)N=NC2=C1 CLZISMQKJZCZDN-UHFFFAOYSA-N 0.000 claims description 6
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 5
- 239000012317 TBTU Substances 0.000 claims description 5
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 4
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 4
- 239000007822 coupling agent Substances 0.000 claims description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-M hydroxide Chemical compound [OH-] XLYOFNOQVPJJNP-UHFFFAOYSA-M 0.000 claims description 4
- 230000000397 acetylating effect Effects 0.000 claims description 3
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 claims description 3
- HJBLUNHMOKFZQX-UHFFFAOYSA-N 3-hydroxy-1,2,3-benzotriazin-4-one Chemical compound C1=CC=C2C(=O)N(O)N=NC2=C1 HJBLUNHMOKFZQX-UHFFFAOYSA-N 0.000 claims description 2
- 230000003301 hydrolyzing effect Effects 0.000 claims description 2
- MJZMSEWWBGCBFM-UHFFFAOYSA-N 2-(2-acetamidopropanoylamino)propanoic acid Chemical compound OC(=O)C(C)NC(=O)C(C)NC(C)=O MJZMSEWWBGCBFM-UHFFFAOYSA-N 0.000 claims 2
- NOFZMNUYEFQMBS-UHFFFAOYSA-N 1-(1,3-dimethylimidazolidin-2-yl)oxybenzotriazole Chemical compound CN1CCN(C)C1ON1C2=CC=CC=C2N=N1 NOFZMNUYEFQMBS-UHFFFAOYSA-N 0.000 claims 1
- PZBQVZFITSVHAW-UHFFFAOYSA-N 5-chloro-2h-benzotriazole Chemical compound C1=C(Cl)C=CC2=NNN=C21 PZBQVZFITSVHAW-UHFFFAOYSA-N 0.000 claims 1
- 235000013312 flour Nutrition 0.000 claims 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 51
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 51
- 239000000243 solution Substances 0.000 description 39
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 30
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 25
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 24
- 239000007787 solid Substances 0.000 description 23
- 239000000047 product Substances 0.000 description 22
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 20
- 239000000203 mixture Substances 0.000 description 20
- 239000011541 reaction mixture Substances 0.000 description 20
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 14
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 12
- 150000001413 amino acids Chemical class 0.000 description 12
- 230000015572 biosynthetic process Effects 0.000 description 12
- MTCFGRXMJLQNBG-REOHCLBHSA-N (2S)-2-Amino-3-hydroxypropansäure Chemical compound OC[C@H](N)C(O)=O MTCFGRXMJLQNBG-REOHCLBHSA-N 0.000 description 11
- 239000012535 impurity Substances 0.000 description 11
- 238000003786 synthesis reaction Methods 0.000 description 11
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 10
- 239000012044 organic layer Substances 0.000 description 10
- 239000011347 resin Substances 0.000 description 10
- 229920005989 resin Polymers 0.000 description 10
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 9
- 229940024606 amino acid Drugs 0.000 description 9
- 235000001014 amino acid Nutrition 0.000 description 9
- 239000012071 phase Substances 0.000 description 9
- 238000003756 stirring Methods 0.000 description 9
- 239000000725 suspension Substances 0.000 description 9
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 8
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 8
- 239000003795 chemical substances by application Substances 0.000 description 8
- RLSSMJSEOOYNOY-UHFFFAOYSA-N m-cresol Chemical compound CC1=CC=CC(O)=C1 RLSSMJSEOOYNOY-UHFFFAOYSA-N 0.000 description 8
- 239000002244 precipitate Substances 0.000 description 8
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 8
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 7
- WYURNTSHIVDZCO-UHFFFAOYSA-N tetrahydrofuran Substances C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 7
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 6
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 6
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 6
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 6
- 108010037444 diisopropylglutathione ester Proteins 0.000 description 6
- 229940079593 drug Drugs 0.000 description 6
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- 238000000746 purification Methods 0.000 description 6
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 5
- MTCFGRXMJLQNBG-UHFFFAOYSA-N Serine Natural products OCC(N)C(O)=O MTCFGRXMJLQNBG-UHFFFAOYSA-N 0.000 description 5
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 5
- WJRBRSLFGCUECM-UHFFFAOYSA-N hydantoin Chemical compound O=C1CNC(=O)N1 WJRBRSLFGCUECM-UHFFFAOYSA-N 0.000 description 5
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- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 5
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- 238000012216 screening Methods 0.000 description 5
- 229960001153 serine Drugs 0.000 description 5
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 4
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- 125000006282 2-chlorobenzyl group Chemical group [H]C1=C([H])C(Cl)=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
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- A61K38/09—Luteinising hormone-releasing hormone [LHRH], i.e. Gonadotropin-releasing hormone [GnRH]; Related peptides
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Claims (19)
1. Væskefase-fremgangsmåde til fremstilling af Degarelix med formlen Ac~ AA1AA10NH2:
eller et farmaceutisk acceptabelt salt eller solvat deraf; omfattende trinnet at kobie (P4)Ac-AAiAA4 med (PejAAsAAioNHz eller koble Ac-AAiAAb med (Pa) (Ρε)ΑΑ4ΑΑιοΝΗ2 i et organisk opløsningsmiddel omfattende de to peptider, et peptidkoblingsreagens og en organisk aminbase opløst deri hvor Ρε er en e-amino-beskytteisesgruppe og P4 er en hydroxylbeskytteisesgruppe eller hydrogen, hvor peptidkoblingsmidlet I tilfælde af kobling af (p4)Ac-AA:iAA4 med (Ρε) AAsAAioINSPb er valgt blandt en eller flere af o-(7-azabenzotriazol-l-yi)-1,1,3,3-tetramethyiuroniumhexafiuorphosphat (HATU) og 2-(benzotriazoi-l-yi) oxy-l,3-dimethylimidazolidiniumhexf!uorphosphat (BOP), og peptiderne er repræsenteret nedenfor:
ti! tilvejebringelse afen beskyttet Degareiix-precursor med formlen (P4)(Pe)AcAAiAAioNH2:
og omfattende trinnet at spalte ε-aminobeskyttelsesgruppen Pe fra en Degareiix-precursor med formlen (Ρ4)(Ρε)Αο-ΑΑ:ιΑΑιοίΜΗ2 i et organisk opløsningsmiddel omfattende precursoren og et spaitnlngsmiddel opløst deri for at tilvejebringe Degarelix,
2« Fremgangsmåde ifølge krav l, hvor spaltningsmidiet er trifluoreddikesyre og/eiler piperidin.
3, Fremgangsmåde ifølge et hvilket som helst af kravene 1 til 2, hvor Ρε er valgt fra gruppen bestående af t-butoxycarbony! (Boc), 9-fiuorenyimethyioxycarbonyi (Fmoc) og allyloxycarbønyi (Alloc).
4, Fremgangsmåde ifølge et hvilket som helst af kravene i til 3, hvor Ρε-beskyttelsesgruppen er Fmoc og/eller hvor det organiske opløsningsmiddel er DMF.
5, Fremgangsmåde ifølge et hvilket som helst af kravene 1 til 4, hvor, I tilfælde af kobling af A0AA1AA3 med (P4)(Ρε)AA4AA10NHz, peptidkoblingsreagenset er valgt blandt en eller flere af ø-(7-azabenzctriazoi~l-yi)-1.,1,3,3-tetramethyluroniumhexafiuorphosphat (HATU), o-(benzotriazoi~l~yi)-l,l,3,3~ tetramethyluroniumhexafluorphosphat (HBTU) og o-(benzotriazoi-l-yi)-l, 1,3,3-tetramethyluroniumtetrafiuorborat (TBTU) og i-ethy!-3-(3-dimethyl3minopropyi) ca rbod i i m id hyd roch i ro rid (EDC.HC!), (2-(6-chlor-l-H-benzotriazol~l~yl)-l, 1,3,3-tetramethylamlnium)hexafluorphosphat (HCTU), 2-(benzotriazoi-l-yi)oxy-l,3-dimethylimidazoiidiniurnhexfluorphosphat (BOP), og diisopropylcarbodiimid (DIC).
6, Fremgangsmåde ifølge et hvilket som helst af kravene 1 eller 5, hvor den organiske aminbase er vaigt blandt en eller flere af Ν,Ν'-diisopropyiethyiamin (DIPEA), N-methyimorphoiin (NMM), triethylamin (TEA) eller 2,4,6-trimethylpyrldin.
7, Fremgangsmåde Ifølge et hvilket som helst af kravene 1 til 6, hvor opløsningen yderligere omfatter et koblingtilsætningsstof valgt blandt 3,4-dihydro-3-hydroxy4-oxo-l,2,3-benzotriazin (HOOBt), l-hydroxy-7 aza-benzotriazol (HOAt) eller 1-hydroxybenzotriazoi (HOBt) opløst deri.
8« Fremgangsmåde Ifølge et hvilket som helst af kravene 1 tli 7, hvor den organiske aminbase er DIPEA og peptidkobiingsreagenset er HATU, og/eiler hvor den organiske aminbase er DIPEA og peptid køb li ngsad d itivet er HOAt, og/eller hvor peptidkobiingsreagenset er HATU og peptidkoblingsadditivet er HOAt, og/eller hvor den organiske aminbase er DIPEA, peptidkobiingsreagenset er HATU og peptidkoblingsadditivet er HOAt.
9. Fremgangsmåde ifølge et hvilket som helst af kravene 1 til 8, hvor den organiske aminbase anvendes i en mængde på 2,5 til 3,5, fortrinsvis omkring 3, moiækvivaienter AA5-AA10 hexapeptid.
10. Fremgangsmåde Ifølge et hvilket som helst af kravene i til 9, hvor det organiske opløsningsmiddel afkøles til en temperatur på -10° C eller derunder, fortrinsvis -15° C eller derunder, og reaktionen derefter udføres ved den temperatur.
11. Fremgangsmåde Ifølge et hvilket som helst af kravene 1 til 10, hvor peptiderne og koblingsadditivet først opløses I det organiske opløsningsmiddel før tilsætning af koblingsreagenset og den organiske amin.
12. Væskefase-fremgangsmåde tli fremstilling af et Degareiix-mellemprodukt med formlen (Ρ4)Αο-ΑΑιΑΑ4:
eller et farmaceutisk acceptabelt salt eller soivat deraf, hvilken fremgangsmåde omfatter trinnet at hydrolysere en forbindelse med formlen (P4)Ac-AAiAA4-R med et alkalisk hydroxid, hvor R betegner en carboxylbeskytteisesgruppe, fortrinsvis en Ci-C4-alkyl eller benzyl, P4 betegner hydrogen eller en hydroxyl beskytteisesg ruppe:
og hvor det alkaiiske hydroxid er LiOH,
13« Væskefase-fremgangsmåde til fremstilling af hexapeptidet (Ρε)ΑΑ5ΑΑιοΝΗ2 omfattende kobling af (Ρε)ΑΑ6ΑΑιοΝΗ?. og (PxJAAs, hvor Px er en aminobeskytteisesgruppe og AAs ti! AAio og Ρε har samme betydning som i krav 1, ti! tilvejebringelse af (Ρχ)(Ρε)ΑΑ5ΑΑ:ο!\ΙΗ2; og spaltning af Px med TFA til tilvejebringelse af (Ρε)ΑΑδΑΑι.οΝΗ2, hvor (Ρχ)(Ρε)ΑΑ5ΑΑιοΝΗ2.(Ρε)ΑΑ6ΑΑιοΝΗ2 og (Px)AAs har følgende strukturer:
14« Fremgangsmåde ifølge krav 12 og/eiier 13 efterfulgt afen hvilken som helst af fremgangsmåderne i kravene 1 til 13,
15« Fremgangsmåde ifølge krav 12 eller 14, hvor forbindelsen med formlen Ac-AA;AA4--R først fremstilles ved kobling af Ac-AAiAA.? med (PføAA^-R eller kobling af Ac-AAiAAi. med (P4)AA?AA4-R, Idet peptiderne er repræsenteret nedenfor
16« Fremgangsmåde ifølge et hvilket som helst af kravene 12 og 14 til lb? hvor R er methyl eller benzyl·
17« Meiiemprodukt-poiypeptider med formlerne:
hvor R er en carboxy i beskytte isesg ru ppe, fortrinsvis en Ci-Graikyi eller benzyl, Ρε er en am inobeskyttelsesg ru ppe, og P4 er hydrogen eller en hydroxyl beskyttelsesgruppe.
18. Fastfase-fremgangsmåde til fremstilling af et Degarelix-meliemprodukt med formlen (P/f)Ac-AAj.AÅ/f:
eller et farmaceutisk acceptabelt salt eller solvat deraf, omfattende trinnene: a) at omsætte (PN)AA2 med (P4) AA3AA4-
for at give (P4,PN)AA2AA4-
b) at fjerne PN fra (P4,PN)AA2AA4-'
for at give (P4)AA2AA4-
c) at omsætte (PN)AAl med (P4)AA2AA4-
for at give (P4,PN)AAiAA4-
d) hvis PIM Ikke er acetyl, fjernelse af PN fra (Ρ4,ΡΝ)ΑΑιΑΑ4-
for at give (P4)AAiAA4-
og efterfølgende at acetylere (P4)AAiAA4-'
for at give (P4)Ac-AAiAA4-
; og e) at spalte (Ρ4)ΑοΑΑιΑΑ4-
I for at give (P4)Ac-AAiAA4, hvor P4 er H eller en hydroxyIbeskyttelsesgruppe på AA4, og PN er en aminobeskyttelsesg ruppe.
19. Væskefase-fremgangsmåde tit fremstilling af hexapeptidet (PejAAsAAioNHa ved kobling af (PSjAAsAA? med (PalAAsAAioNHy for at give (PS, Pe)AAsAAioNH2 og efterfølgende fraspaltning af Ρ5 for at tilvejebringe (Ρε)ΑΑδΑΑιοΝΗ2, (hvor P5 er en aminobeskyttelsesgruppe på AAs og Ρε er en sidekædeaminobeskytteisesgruppe på AA6), hvor fremgangsmåden eventueit efterfølges af kobling af (P4)Ac-AAiAA4 til (Ρε)ΑΑςΑΑ:ιοΝΗ?., hvor AAi ti i AAio bar den samme betydning som i krav 1,
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| EP10189011 | 2010-10-27 | ||
| PCT/EP2011/068733 WO2012055903A1 (en) | 2010-10-27 | 2011-10-26 | Process for the manufacture of degarelix and its intermediates |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| DK2632934T3 true DK2632934T3 (da) | 2017-01-23 |
Family
ID=43534715
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| DK11776156.9T DK2632934T3 (da) | 2010-10-27 | 2011-10-26 | Fremgangsmåde til fremstilling af Degarelix og dets mellemprodukter |
Country Status (12)
| Country | Link |
|---|---|
| US (1) | US9260480B2 (da) |
| EP (1) | EP2632934B1 (da) |
| DK (1) | DK2632934T3 (da) |
| ES (1) | ES2617336T3 (da) |
| HR (1) | HRP20161746T1 (da) |
| HU (1) | HUE031113T2 (da) |
| LT (1) | LT2632934T (da) |
| PL (1) | PL2632934T3 (da) |
| PT (1) | PT2632934T (da) |
| RS (1) | RS55457B1 (da) |
| SI (1) | SI2632934T1 (da) |
| WO (1) | WO2012055903A1 (da) |
Families Citing this family (15)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB0117057D0 (en) * | 2001-07-12 | 2001-09-05 | Ferring Bv | Pharmaceutical composition |
| TWI539959B (zh) | 2008-02-11 | 2016-07-01 | 菲瑞茵國際中心股份有限公司 | 治療轉移階段攝護腺癌的方法 |
| MX2011011431A (es) * | 2009-05-01 | 2012-02-23 | Ferring Bv | Composicion para el tratamiento de cancer de prostata. |
| US20110039787A1 (en) * | 2009-07-06 | 2011-02-17 | Ferring International Center S.A. | Compositions, kits and methods for treating benign prostate hyperplasia |
| EP2447276A1 (en) | 2010-10-27 | 2012-05-02 | Ferring B.V. | Process for the manufacture of Degarelix and its intermediates |
| LT2632934T (lt) | 2010-10-27 | 2017-01-10 | Ferring B.V. | Degarelikso ir jo tarpinių darinių gamybos būdas |
| JO3755B1 (ar) | 2011-01-26 | 2021-01-31 | Ferring Bv | تركيبات تستوستيرون |
| PL4512390T1 (pl) | 2012-06-01 | 2025-09-01 | Ferring B.V. | Wytwarzanie degareliksu |
| US11168114B2 (en) | 2015-12-17 | 2021-11-09 | Fresenius Kabi iPSUM S.r.l | Process for the manufacture of degarelix and its intermediates |
| CN107022002B (zh) * | 2017-05-26 | 2020-04-14 | 济南康和医药科技有限公司 | 一种固液结合制备地加瑞克的方法 |
| US20220177521A1 (en) * | 2019-03-07 | 2022-06-09 | Fresenius Kabi Ipsum S.R.L. | Process for the preparation of degarelix |
| CN114938646B (zh) * | 2019-12-05 | 2026-03-27 | 费森尤斯卡比有限责任公司 | 分析地加瑞克及其相关产物的方法 |
| CN112175043A (zh) * | 2020-10-12 | 2021-01-05 | 湖南津安生物科技有限公司 | 一种改进的鲑鱼促性腺激素释放激素的固相合成方法 |
| EP4296275A3 (en) | 2020-12-11 | 2024-03-13 | Fresenius Kabi iPSUM S.r.l. | Method for the fmoc group cleavage |
| WO2026068660A1 (en) | 2024-09-26 | 2026-04-02 | Ferring B.V. | Lipidated gonadotropin releasing hormone analogues |
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| US3773919A (en) | 1969-10-23 | 1973-11-20 | Du Pont | Polylactide-drug mixtures |
| DE2862341D1 (en) | 1977-12-26 | 1983-11-24 | Ihara Chemical Ind Co | Process for producing aromatic monocarboxylic acid |
| DE69214818T2 (de) | 1991-04-25 | 1997-02-27 | Romano S.-Cergue Deghenghi | LHRH-Antagonisten |
| EP0556034B2 (en) | 1992-02-12 | 2004-07-21 | Daikyo Gomu Seiko Ltd. | A medical instrument |
| SI9300468A (en) | 1992-10-14 | 1994-06-30 | Hoffmann La Roche | Injectable composition for the sustained release of biologically active compounds |
| US5506207A (en) | 1994-03-18 | 1996-04-09 | The Salk Institute For Biological Studies | GNRH antagonists XIII |
| US5595760A (en) | 1994-09-02 | 1997-01-21 | Delab | Sustained release of peptides from pharmaceutical compositions |
| US5710246A (en) | 1996-03-19 | 1998-01-20 | Abbott Laboratories | Process for intermediates for the synthesis of LHRH antagonists |
| US5860957A (en) | 1997-02-07 | 1999-01-19 | Sarcos, Inc. | Multipathway electronically-controlled drug delivery system |
| US5925730A (en) | 1997-04-11 | 1999-07-20 | Ferring Bv | GnRH antagonists |
| US5821230A (en) | 1997-04-11 | 1998-10-13 | Ferring Bv | GnRH antagonist decapeptides |
| US5977302A (en) | 1997-11-20 | 1999-11-02 | Ortho-Mcneil Pharmaceutical, Inc. | Liquid phase process for the preparation of GnRH peptides |
| FR2776520B1 (fr) | 1998-03-25 | 2000-05-05 | Sod Conseils Rech Applic | Nouvelles compositions pharmaceutiques destinees a la liberation prolongee de peptides et leur procede de preparation |
| US20040198706A1 (en) | 2003-03-11 | 2004-10-07 | Carrara Dario Norberto R. | Methods and formulations for transdermal or transmucosal application of active agents |
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| SE0104463D0 (sv) * | 2001-12-29 | 2001-12-29 | Carlbiotech Ltd As | Mellanprodukter för syntes af LHRH-antagonister, sätt att framställa dem och sätt för framställning av LHRH-antagonister |
| CN1411803A (zh) | 2002-08-29 | 2003-04-23 | 四川大学 | 制备前体脂质体的方法及其装置 |
| AR042815A1 (es) | 2002-12-26 | 2005-07-06 | Alza Corp | Dispositivo de suministro de agente activo que tiene miembros compuestos |
| EP1674082A1 (de) | 2004-12-22 | 2006-06-28 | Zentaris GmbH | Verfahren zur Herstellung von sterilen Suspensionen oder Lyophilisaten schwerlöslicher basischer Peptidkomplexe, diese enthaltende pharmazeutische Formulierungen sowie ihre Verwendung als Arzneimittel |
| WO2007130809A2 (en) | 2006-05-06 | 2007-11-15 | Volodymyr Brodskyy | An automatic injectable drug mixing device |
| EP1891964A1 (en) | 2006-08-08 | 2008-02-27 | AEterna Zentaris GmbH | Application of initial doses of LHRH analogues and maintenance doses of LHRH antagonists for the treatment of hormone-dependent cancers and corresponding pharmaceutical kits |
| EP1967202A1 (en) | 2007-03-05 | 2008-09-10 | AEterna Zentaris GmbH | Use of LHRH Antagonists for the Treatment of Lower Urinary Tract Symptoms, in particular Overactive Bladder and/or Detrusor Overactivity |
| IL182922A0 (en) | 2007-05-02 | 2007-09-20 | Medimop Medical Projects Ltd | Automatic liquid drug reconstitution apparatus |
| TWI539959B (zh) | 2008-02-11 | 2016-07-01 | 菲瑞茵國際中心股份有限公司 | 治療轉移階段攝護腺癌的方法 |
| ES2589322T3 (es) | 2008-02-11 | 2016-11-11 | Safety Syringes, Inc. | Jeringa con protector de seguridad de aguja y clip para evitar la liberación del protector durante un proceso de reconstitución |
| WO2010121835A1 (en) * | 2009-04-24 | 2010-10-28 | Polypeptide Laboratories A/S | Method for the manufacture of degarelix |
| MX2011011431A (es) | 2009-05-01 | 2012-02-23 | Ferring Bv | Composicion para el tratamiento de cancer de prostata. |
| TW201043221A (en) | 2009-05-06 | 2010-12-16 | Ferring Int Ct Sa | Kit and method for preparation of a Degarelix solution |
| US20110039787A1 (en) | 2009-07-06 | 2011-02-17 | Ferring International Center S.A. | Compositions, kits and methods for treating benign prostate hyperplasia |
| LT2632934T (lt) | 2010-10-27 | 2017-01-10 | Ferring B.V. | Degarelikso ir jo tarpinių darinių gamybos būdas |
| EP2447276A1 (en) | 2010-10-27 | 2012-05-02 | Ferring B.V. | Process for the manufacture of Degarelix and its intermediates |
| JO3755B1 (ar) | 2011-01-26 | 2021-01-31 | Ferring Bv | تركيبات تستوستيرون |
| KR20140063602A (ko) | 2011-07-15 | 2014-05-27 | 훼링 비.브이. | 피코설페이트 조성물을 투여하여 대장내시경의 시술 시기를 조절하는 방법 |
-
2011
- 2011-10-26 LT LTEP11776156.9T patent/LT2632934T/lt unknown
- 2011-10-26 PL PL11776156T patent/PL2632934T3/pl unknown
- 2011-10-26 PT PT117761569T patent/PT2632934T/pt unknown
- 2011-10-26 EP EP11776156.9A patent/EP2632934B1/en active Active
- 2011-10-26 ES ES11776156.9T patent/ES2617336T3/es active Active
- 2011-10-26 HU HUE11776156A patent/HUE031113T2/en unknown
- 2011-10-26 US US13/881,751 patent/US9260480B2/en active Active
- 2011-10-26 RS RS20161175A patent/RS55457B1/sr unknown
- 2011-10-26 SI SI201131060A patent/SI2632934T1/sl unknown
- 2011-10-26 WO PCT/EP2011/068733 patent/WO2012055903A1/en not_active Ceased
- 2011-10-26 DK DK11776156.9T patent/DK2632934T3/da active
- 2011-10-26 HR HRP20161746TT patent/HRP20161746T1/hr unknown
Also Published As
| Publication number | Publication date |
|---|---|
| SI2632934T1 (sl) | 2017-02-28 |
| US9260480B2 (en) | 2016-02-16 |
| US20130281662A1 (en) | 2013-10-24 |
| EP2632934B1 (en) | 2016-11-30 |
| ES2617336T3 (es) | 2017-06-16 |
| PL2632934T3 (pl) | 2017-06-30 |
| WO2012055903A1 (en) | 2012-05-03 |
| HRP20161746T1 (hr) | 2017-02-10 |
| PT2632934T (pt) | 2017-01-06 |
| RS55457B1 (sr) | 2017-04-28 |
| HUE031113T2 (en) | 2017-06-28 |
| LT2632934T (lt) | 2017-01-10 |
| EP2632934A1 (en) | 2013-09-04 |
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