HRP20191378T1 - Poboljšani postupak dobivanja duokarmicinskih predlijekova - Google Patents
Poboljšani postupak dobivanja duokarmicinskih predlijekova Download PDFInfo
- Publication number
- HRP20191378T1 HRP20191378T1 HRP20191378T HRP20191378T1 HR P20191378 T1 HRP20191378 T1 HR P20191378T1 HR P20191378 T HRP20191378 T HR P20191378T HR P20191378 T1 HRP20191378 T1 HR P20191378T1
- Authority
- HR
- Croatia
- Prior art keywords
- compound
- formula
- reagent
- group
- process according
- Prior art date
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- 238000000034 method Methods 0.000 title claims 15
- VQNATVDKACXKTF-XELLLNAOSA-N duocarmycin Chemical compound COC1=C(OC)C(OC)=C2NC(C(=O)N3C4=CC(=O)C5=C([C@@]64C[C@@H]6C3)C=C(N5)C(=O)OC)=CC2=C1 VQNATVDKACXKTF-XELLLNAOSA-N 0.000 title claims 2
- 229960005501 duocarmycin Drugs 0.000 title 1
- 229930184221 duocarmycin Natural products 0.000 title 1
- 229940002612 prodrug Drugs 0.000 title 1
- 239000000651 prodrug Substances 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims 10
- 229910052698 phosphorus Inorganic materials 0.000 claims 6
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 claims 6
- 239000003153 chemical reaction reagent Substances 0.000 claims 5
- KWGKDLIKAYFUFQ-UHFFFAOYSA-M lithium chloride Chemical compound [Li+].[Cl-] KWGKDLIKAYFUFQ-UHFFFAOYSA-M 0.000 claims 4
- 125000006239 protecting group Chemical group 0.000 claims 4
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 claims 4
- 101100030361 Neurospora crassa (strain ATCC 24698 / 74-OR23-1A / CBS 708.71 / DSM 1257 / FGSC 987) pph-3 gene Proteins 0.000 claims 3
- 238000006243 chemical reaction Methods 0.000 claims 3
- 239000012320 chlorinating reagent Substances 0.000 claims 3
- 230000021615 conjugation Effects 0.000 claims 3
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide Substances CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 claims 2
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 claims 2
- JRNVZBWKYDBUCA-UHFFFAOYSA-N N-chlorosuccinimide Chemical compound ClN1C(=O)CCC1=O JRNVZBWKYDBUCA-UHFFFAOYSA-N 0.000 claims 2
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M Potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 claims 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims 2
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 claims 2
- 229910052799 carbon Inorganic materials 0.000 claims 2
- 125000000753 cycloalkyl group Chemical group 0.000 claims 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims 2
- 229910052736 halogen Inorganic materials 0.000 claims 2
- 150000002367 halogens Chemical group 0.000 claims 2
- 125000005842 heteroatom Chemical group 0.000 claims 2
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims 2
- 125000001979 organolithium group Chemical group 0.000 claims 2
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 claims 2
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims 1
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 claims 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims 1
- 239000007821 HATU Substances 0.000 claims 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims 1
- -1 OCH2CH3 Chemical group 0.000 claims 1
- 229910006124 SOCl2 Inorganic materials 0.000 claims 1
- 239000012317 TBTU Substances 0.000 claims 1
- 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 1
- 125000000217 alkyl group Chemical group 0.000 claims 1
- 235000019270 ammonium chloride Nutrition 0.000 claims 1
- 239000000611 antibody drug conjugate Substances 0.000 claims 1
- 229940049595 antibody-drug conjugate Drugs 0.000 claims 1
- 230000015572 biosynthetic process Effects 0.000 claims 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims 1
- 229910052794 bromium Inorganic materials 0.000 claims 1
- 229910052801 chlorine Inorganic materials 0.000 claims 1
- 230000008030 elimination Effects 0.000 claims 1
- 238000003379 elimination reaction Methods 0.000 claims 1
- 229910052731 fluorine Chemical group 0.000 claims 1
- 229910052739 hydrogen Inorganic materials 0.000 claims 1
- 229910052740 iodine Inorganic materials 0.000 claims 1
- 239000011630 iodine Substances 0.000 claims 1
- UBJFKNSINUCEAL-UHFFFAOYSA-N lithium;2-methylpropane Chemical compound [Li+].C[C-](C)C UBJFKNSINUCEAL-UHFFFAOYSA-N 0.000 claims 1
- DVSDBMFJEQPWNO-UHFFFAOYSA-N methyllithium Chemical compound C[Li] DVSDBMFJEQPWNO-UHFFFAOYSA-N 0.000 claims 1
- 229910052757 nitrogen Inorganic materials 0.000 claims 1
- 238000005580 one pot reaction Methods 0.000 claims 1
- UHZYTMXLRWXGPK-UHFFFAOYSA-N phosphorus pentachloride Chemical compound ClP(Cl)(Cl)(Cl)Cl UHZYTMXLRWXGPK-UHFFFAOYSA-N 0.000 claims 1
- FAIAAWCVCHQXDN-UHFFFAOYSA-N phosphorus trichloride Chemical compound ClP(Cl)Cl FAIAAWCVCHQXDN-UHFFFAOYSA-N 0.000 claims 1
- PAQZWJGSJMLPMG-UHFFFAOYSA-N propylphosphonic anhydride Substances CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1 PAQZWJGSJMLPMG-UHFFFAOYSA-N 0.000 claims 1
- 239000011780 sodium chloride Substances 0.000 claims 1
- 239000002904 solvent Substances 0.000 claims 1
- 238000003786 synthesis reaction Methods 0.000 claims 1
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 claims 1
- 238000007039 two-step reaction Methods 0.000 claims 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/56—Ring systems containing three or more rings
- C07D209/58—[b]- or [c]-condensed
- C07D209/60—Naphtho [b] pyrroles; Hydrogenated naphtho [b] pyrroles
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Indole Compounds (AREA)
- Saccharide Compounds (AREA)
Claims (14)
1. Postupak, naznačen time što se sastoji u prevođenju spoja formule (I)
u spoj formule (II)
reakcijom s monometalnim organolitijskim reagensom u pogodnom otapalu, gdje su P i P’ neovisno zaštitne skupine,
R1 je CH3, CH2CH3, OCH3, OCH2CH3, CF3, OCF3, Cl ili F,
R2, R3, R4 su neovisno H ili C1-6 alkil ili
R1 i R2 uzeti zajedno tvore 5- ili 6-eročlanu (hetero)cikloalkilnu skupinu i
X je halogen.
2. Postupak u skladu s patentnim zahtjevom 1, naznačen time što je R1 CH3, CH2CH3, OCH3 ili OCH2CH3, R2, R3, R4 su neovisno H ili C1-6 alkil, ili R1 i R2 uzeti zajedno tvore 5-eročlanu (hetero)cikloalkilnu skupinu.
3. Postupak u skladu s patentnim zahtjevom 1 ili 2, naznačen time što se monometalni organolitijski reagens bira iz skupine koju čine n-butillitij, tert-butillitij i metillitij.
4. Postupak u skladu s bilo kojim od patentnih zahtjeva 1-3, naznačen time što je halogen brom ili jod.
5. Postupak u skladu s bilo kojim od patentnih zahtjeva 1-4, naznačen time što se doda jaku bazu.
6. Postupak u skladu s bilo kojim od patentnih zahtjeva 1-5, naznačen time što dodatno uključuje prevođenje spoja formule (II) u spoj formule (III)
bilo reakcijom jednom koraku ili u dva koraka s klorirajućim reagensom,
gdje R1, R2, R3, P i P’ imaju značenje kao što je definirano u patentnom zahtjevu 1.
7. Postupak u skladu s patentnim zahtjevom 6, naznačen time što se klorirajući reagens bira iz skupine koju čine LiCl, KCl, NaCl, NH4Cl, HCl, AlCl3 u koncentriranom HCl, PPh3/CCl4, PPh3/NCS, SOCl2 i PCl3/PCl5.
8. Postupak u skladu s patentnim zahtjevom 7, naznačen time što je klorirajući reagens LiCl ili PPh3/CCl4.
9. Postupak u skladu s bilo kojim od patentnih zahtjeva 1-8, naznačen time što dodatno uključuje prevođenje spoja formule (III) u spoj formule (IV)
a) uklanjanjem zaštitne skupine P i
b) reakcijom sa spojem formule (V)
u prisutnosti konjugacijskog reagensa, za čim slijedi
c) eliminacija zaštitne skupine P’,
gdje R1, R2, R3, P i P’ imaju značenja definirana u patentnom zahtjevu 1,
P” je neovisno zaštitna skupina i
X1, X2, X3 su neovisno C ili N.
10. Postupak u skladu s patentnim zahtjevom 9, naznačen time što se konjugacijski reagens bira iz skupine koju čine BOP, DCC, DIC, EDC, HATU, TBTU i T3P.
11. Postupak u skladu s patentnim zahtjevom 10, naznačen time što je konjugacijski reagens EDC.
12. Postupak u skladu s bilo kojim od patentnih zahtjeva 1-11, naznačen time što je spoj formule (II)
.
13. Postupak u skladu s bilo kojim od patentnih zahtjeva 9-12, naznačen time što je spoj formule (IV)
.
14. Postupak u skladu s bilo kojim od patentnih zahtjeva 9-13, naznačen time što dodatno uključuje upotrebu spoja formule (IV) u sintezi konjugata protutijelo-lijek koji sadrže duokarmicinske analoge.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| PCT/EP2014/061701 WO2015185142A1 (en) | 2014-06-05 | 2014-06-05 | Improved process for making duocarmycin prodrugs |
| EP14728565.4A EP3152191B1 (en) | 2014-06-05 | 2014-06-05 | Improved process for making duocarmycin prodrugs |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| HRP20191378T1 true HRP20191378T1 (hr) | 2019-11-15 |
Family
ID=50896304
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| HRP20191378 HRP20191378T1 (hr) | 2014-06-05 | 2019-07-31 | Poboljšani postupak dobivanja duokarmicinskih predlijekova |
Country Status (13)
| Country | Link |
|---|---|
| US (1) | US9890159B2 (hr) |
| EP (1) | EP3152191B1 (hr) |
| JP (1) | JP6275881B2 (hr) |
| CN (1) | CN106458892B (hr) |
| CY (1) | CY1122025T1 (hr) |
| DK (1) | DK3152191T3 (hr) |
| ES (1) | ES2738211T3 (hr) |
| HR (1) | HRP20191378T1 (hr) |
| HU (1) | HUE045447T2 (hr) |
| LT (1) | LT3152191T (hr) |
| PL (1) | PL3152191T3 (hr) |
| PT (1) | PT3152191T (hr) |
| WO (1) | WO2015185142A1 (hr) |
Families Citing this family (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US9901567B2 (en) | 2007-08-01 | 2018-02-27 | Syntarga B.V. | Substituted CC-1065 analogs and their conjugates |
| DK3056203T3 (da) | 2010-04-21 | 2018-01-29 | Syntarga Bv | Konjugater af cc-1065-analoger og bifunktionelle linkere. |
| CN105899236B (zh) | 2014-01-10 | 2019-07-26 | 斯索恩生物制药有限公司 | 表现出改进的体内抗肿瘤活性的倍癌霉素adc |
| SG11201605597VA (en) | 2014-01-10 | 2016-08-30 | Synthon Biopharmaceuticals Bv | Duocarmycin adcs for use in treatment of endometrial cancer |
| SG10201913977TA (en) | 2014-05-22 | 2020-03-30 | Synthon Biopharmaceuticals Bv | Site-specific conjugation of linker drugs to antibodies and resulting adcs |
| JP7002467B2 (ja) | 2016-04-15 | 2022-01-20 | マクロジェニクス，インコーポレーテッド | 新規のｂ７‐ｈ３結合分子、その抗体薬物コンジュゲート、及びその使用方法 |
| DK3713939T3 (da) | 2017-11-24 | 2021-09-13 | Byondis Bv | Forbedret fremgangsmåde til syntese af linker-lægemidlet vc-seco |
| CN112969478B (zh) * | 2018-11-09 | 2023-10-27 | 拜奥迪斯私人有限公司 | 可滤过的含倍癌霉素抗体-药物缀合物组合物及相关方法 |
Family Cites Families (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP2173739B1 (en) | 2007-08-01 | 2013-07-31 | Syntarga B.V. | Substituted cc-1065 analogs and their conjugates |
| US9901567B2 (en) | 2007-08-01 | 2018-02-27 | Syntarga B.V. | Substituted CC-1065 analogs and their conjugates |
| PT2344478T (pt) | 2008-11-03 | 2017-11-28 | Syntarga Bv | Análogos de cc-1065 e seus conjugados |
| DK3056203T3 (da) | 2010-04-21 | 2018-01-29 | Syntarga Bv | Konjugater af cc-1065-analoger og bifunktionelle linkere. |
| PL3092010T3 (pl) | 2014-01-10 | 2019-01-31 | Synthon Biopharmaceuticals B.V. | Sposób oczyszczania połączonych cysteiną koniugatów przeciwciało-lek |
| SG10201913977TA (en) | 2014-05-22 | 2020-03-30 | Synthon Biopharmaceuticals Bv | Site-specific conjugation of linker drugs to antibodies and resulting adcs |
| EP3197919A1 (en) | 2014-09-22 | 2017-08-02 | Synthon Biopharmaceuticals B.V. | Pan-reactive antibodies to duocarmycins |
-
2014
- 2014-06-05 PL PL14728565T patent/PL3152191T3/pl unknown
- 2014-06-05 WO PCT/EP2014/061701 patent/WO2015185142A1/en active Application Filing
- 2014-06-05 US US15/316,444 patent/US9890159B2/en active Active
- 2014-06-05 PT PT14728565T patent/PT3152191T/pt unknown
- 2014-06-05 CN CN201480079537.XA patent/CN106458892B/zh active Active
- 2014-06-05 LT LTEP14728565.4T patent/LT3152191T/lt unknown
- 2014-06-05 JP JP2016570985A patent/JP6275881B2/ja active Active
- 2014-06-05 HU HUE14728565A patent/HUE045447T2/hu unknown
- 2014-06-05 ES ES14728565T patent/ES2738211T3/es active Active
- 2014-06-05 DK DK14728565.4T patent/DK3152191T3/da active
- 2014-06-05 EP EP14728565.4A patent/EP3152191B1/en active Active
-
2019
- 2019-07-30 CY CY20191100815T patent/CY1122025T1/el unknown
- 2019-07-31 HR HRP20191378 patent/HRP20191378T1/hr unknown
Also Published As
| Publication number | Publication date |
|---|---|
| JP2017516822A (ja) | 2017-06-22 |
| LT3152191T (lt) | 2019-08-26 |
| ES2738211T3 (es) | 2020-01-20 |
| EP3152191A1 (en) | 2017-04-12 |
| CY1122025T1 (el) | 2020-11-25 |
| PT3152191T (pt) | 2019-08-30 |
| DK3152191T3 (da) | 2019-08-12 |
| WO2015185142A1 (en) | 2015-12-10 |
| CN106458892A (zh) | 2017-02-22 |
| HUE045447T2 (hu) | 2019-12-30 |
| PL3152191T3 (pl) | 2019-10-31 |
| US9890159B2 (en) | 2018-02-13 |
| US20170145006A1 (en) | 2017-05-25 |
| CN106458892B (zh) | 2019-10-18 |
| JP6275881B2 (ja) | 2018-02-07 |
| EP3152191B1 (en) | 2019-05-15 |
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