JP2019510740A - 抗体−リファマイシン複合体の製造プロセス - Google Patents
抗体−リファマイシン複合体の製造プロセス Download PDFInfo
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- JP2019510740A JP2019510740A JP2018540460A JP2018540460A JP2019510740A JP 2019510740 A JP2019510740 A JP 2019510740A JP 2018540460 A JP2018540460 A JP 2018540460A JP 2018540460 A JP2018540460 A JP 2018540460A JP 2019510740 A JP2019510740 A JP 2019510740A
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- Prior art keywords
- antibody
- rifamycin
- iii
- reacting
- acid
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
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- 238000000034 method Methods 0.000 title claims abstract description 58
- 230000008569 process Effects 0.000 title claims abstract description 36
- 229960003292 rifamycin Drugs 0.000 title claims description 20
- MDCULZTYOKLIGU-UHFFFAOYSA-N 2-amino-5-fluorobenzene-1,3-diol Chemical compound Nc1c(O)cc(F)cc1O MDCULZTYOKLIGU-UHFFFAOYSA-N 0.000 claims abstract description 18
- GDOPTJXRTPNYNR-UHFFFAOYSA-N methyl-cyclopentane Natural products CC1CCCC1 GDOPTJXRTPNYNR-UHFFFAOYSA-N 0.000 claims abstract description 16
- 239000007800 oxidant agent Substances 0.000 claims abstract description 15
- AZQWKYJCGOJGHM-UHFFFAOYSA-N 1,4-benzoquinone Chemical compound O=C1C=CC(=O)C=C1 AZQWKYJCGOJGHM-UHFFFAOYSA-N 0.000 claims abstract description 14
- BTVYFIMKUHNOBZ-ODRIEIDWSA-N Rifamycin S Chemical compound O=C1C(C(O)=C2C)=C3C(=O)C=C1NC(=O)\C(C)=C/C=C/[C@H](C)[C@H](O)[C@@H](C)[C@@H](O)[C@@H](C)[C@H](OC(C)=O)[C@H](C)[C@@H](OC)\C=C\O[C@@]1(C)OC2=C3C1=O BTVYFIMKUHNOBZ-ODRIEIDWSA-N 0.000 claims abstract description 14
- BTVYFIMKUHNOBZ-ZDHWWVNNSA-N Rifamycin S Natural products COC1C=COC2(C)Oc3c(C)c(O)c4C(=O)C(=CC(=O)c4c3C2=O)NC(=O)C(=C/C=C/C(C)C(O)C(C)C(O)C(C)C(OC(=O)C)C1C)C BTVYFIMKUHNOBZ-ZDHWWVNNSA-N 0.000 claims abstract description 13
- 238000002360 preparation method Methods 0.000 claims abstract description 9
- MYMOFIZGZYHOMD-UHFFFAOYSA-N Dioxygen Chemical compound O=O MYMOFIZGZYHOMD-UHFFFAOYSA-N 0.000 claims abstract description 8
- 229910001882 dioxygen Inorganic materials 0.000 claims abstract description 8
- AMWRITDGCCNYAT-UHFFFAOYSA-L hydroxy(oxo)manganese;manganese Chemical compound [Mn].O[Mn]=O.O[Mn]=O AMWRITDGCCNYAT-UHFFFAOYSA-L 0.000 claims abstract description 6
- 239000011734 sodium Substances 0.000 claims abstract description 6
- JQWHASGSAFIOCM-UHFFFAOYSA-M sodium periodate Chemical compound [Na+].[O-]I(=O)(=O)=O JQWHASGSAFIOCM-UHFFFAOYSA-M 0.000 claims abstract description 6
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 claims abstract description 5
- 239000012080 ambient air Substances 0.000 claims abstract description 4
- 238000004519 manufacturing process Methods 0.000 claims abstract description 4
- VNNDVNZCGCCIPA-FDGPNNRMSA-N (z)-4-hydroxypent-3-en-2-one;manganese Chemical compound [Mn].C\C(O)=C\C(C)=O.C\C(O)=C\C(C)=O VNNDVNZCGCCIPA-FDGPNNRMSA-N 0.000 claims abstract description 3
- 229910021589 Copper(I) bromide Inorganic materials 0.000 claims abstract description 3
- 229910021617 Indium monochloride Inorganic materials 0.000 claims abstract description 3
- 241000872931 Myoporum sandwicense Species 0.000 claims abstract description 3
- APHGZSBLRQFRCA-UHFFFAOYSA-M indium(1+);chloride Chemical compound [In]Cl APHGZSBLRQFRCA-UHFFFAOYSA-M 0.000 claims abstract description 3
- UGNWTBMOAKPKBL-UHFFFAOYSA-N tetrachloro-1,4-benzoquinone Chemical compound ClC1=C(Cl)C(=O)C(Cl)=C(Cl)C1=O UGNWTBMOAKPKBL-UHFFFAOYSA-N 0.000 claims abstract description 3
- JMMWKPVZQRWMSS-UHFFFAOYSA-N isopropanol acetate Natural products CC(C)OC(C)=O JMMWKPVZQRWMSS-UHFFFAOYSA-N 0.000 claims description 40
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 38
- 239000000203 mixture Substances 0.000 claims description 30
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 24
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 24
- -1 5-fluoro-2-nitro-1,3-phenylene Chemical group 0.000 claims description 20
- 239000002253 acid Substances 0.000 claims description 19
- 238000006243 chemical reaction Methods 0.000 claims description 19
- 229940011051 isopropyl acetate Drugs 0.000 claims description 18
- 239000003153 chemical reaction reagent Substances 0.000 claims description 16
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 15
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 14
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 12
- 239000002904 solvent Substances 0.000 claims description 12
- 239000003054 catalyst Substances 0.000 claims description 10
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical group [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 9
- 229910052751 metal Inorganic materials 0.000 claims description 8
- 239000002184 metal Substances 0.000 claims description 8
- 230000001590 oxidative effect Effects 0.000 claims description 8
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 claims description 8
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 7
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 claims description 7
- PWRFDGYYJWQIAB-UHFFFAOYSA-N 1,3,5-trifluoro-2-nitrobenzene Chemical compound [O-][N+](=O)C1=C(F)C=C(F)C=C1F PWRFDGYYJWQIAB-UHFFFAOYSA-N 0.000 claims description 6
- WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 claims description 6
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 6
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 claims description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 6
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 claims description 6
- 150000004703 alkoxides Chemical class 0.000 claims description 5
- 229910052799 carbon Inorganic materials 0.000 claims description 5
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 claims description 5
- YFJAIURZMRJPDB-UHFFFAOYSA-N n,n-dimethylpiperidin-4-amine Chemical compound CN(C)C1CCNCC1 YFJAIURZMRJPDB-UHFFFAOYSA-N 0.000 claims description 5
- 150000003335 secondary amines Chemical class 0.000 claims description 5
- HUUQNWZMQSLPMX-UHFFFAOYSA-N 1-(2-methylpropyl)piperazine Chemical compound CC(C)CN1CCNCC1 HUUQNWZMQSLPMX-UHFFFAOYSA-N 0.000 claims description 4
- FOOSVTRRNLPPCR-UHFFFAOYSA-N 5-fluoro-2-nitrobenzene-1,3-diol Chemical compound OC1=CC(F)=CC(O)=C1[N+]([O-])=O FOOSVTRRNLPPCR-UHFFFAOYSA-N 0.000 claims description 4
- ROSDSFDQCJNGOL-UHFFFAOYSA-N Dimethylamine Chemical compound CNC ROSDSFDQCJNGOL-UHFFFAOYSA-N 0.000 claims description 4
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 claims description 4
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 claims description 4
- 235000019445 benzyl alcohol Nutrition 0.000 claims description 4
- 229960004217 benzyl alcohol Drugs 0.000 claims description 4
- 229940113088 dimethylacetamide Drugs 0.000 claims description 4
- XEEYBQQBJWHFJM-UHFFFAOYSA-N iron Substances [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 claims description 4
- ZCSHNCUQKCANBX-UHFFFAOYSA-N lithium diisopropylamide Chemical compound [Li+].CC(C)[N-]C(C)C ZCSHNCUQKCANBX-UHFFFAOYSA-N 0.000 claims description 4
- 229910052763 palladium Inorganic materials 0.000 claims description 4
- 229910052697 platinum Inorganic materials 0.000 claims description 4
- MFRIHAYPQRLWNB-UHFFFAOYSA-N sodium tert-butoxide Chemical compound [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 0.000 claims description 4
- 239000010949 copper Substances 0.000 claims description 3
- 239000007789 gas Substances 0.000 claims description 3
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical group [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 claims description 3
- PVOAHINGSUIXLS-UHFFFAOYSA-N 1-Methylpiperazine Chemical compound CN1CCNCC1 PVOAHINGSUIXLS-UHFFFAOYSA-N 0.000 claims description 2
- KJTLSVCANCCWHF-UHFFFAOYSA-N Ruthenium Chemical compound [Ru] KJTLSVCANCCWHF-UHFFFAOYSA-N 0.000 claims description 2
- PNEYBMLMFCGWSK-UHFFFAOYSA-N aluminium oxide Inorganic materials [O-2].[O-2].[O-2].[Al+3].[Al+3] PNEYBMLMFCGWSK-UHFFFAOYSA-N 0.000 claims description 2
- FJDJVBXSSLDNJB-LNTINUHCSA-N cobalt;(z)-4-hydroxypent-3-en-2-one Chemical compound [Co].C\C(O)=C\C(C)=O.C\C(O)=C\C(C)=O.C\C(O)=C\C(C)=O FJDJVBXSSLDNJB-LNTINUHCSA-N 0.000 claims description 2
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 claims description 2
- SGDINNZGYDHHKM-UHFFFAOYSA-N dilithium;trimethylsilylazanide Chemical compound [Li+].[Li+].C[Si](C)(C)[NH-].C[Si](C)(C)[NH-] SGDINNZGYDHHKM-UHFFFAOYSA-N 0.000 claims description 2
- WEHWNAOGRSTTBQ-UHFFFAOYSA-N dipropylamine Chemical compound CCCNCCC WEHWNAOGRSTTBQ-UHFFFAOYSA-N 0.000 claims description 2
- RPDAUEIUDPHABB-UHFFFAOYSA-N potassium ethoxide Chemical compound [K+].CC[O-] RPDAUEIUDPHABB-UHFFFAOYSA-N 0.000 claims description 2
- BDAWXSQJJCIFIK-UHFFFAOYSA-N potassium methoxide Chemical compound [K+].[O-]C BDAWXSQJJCIFIK-UHFFFAOYSA-N 0.000 claims description 2
- WQKGAJDYBZOFSR-UHFFFAOYSA-N potassium;propan-2-olate Chemical compound [K+].CC(C)[O-] WQKGAJDYBZOFSR-UHFFFAOYSA-N 0.000 claims description 2
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 claims description 2
- WBQTXTBONIWRGK-UHFFFAOYSA-N sodium;propan-2-olate Chemical compound [Na+].CC(C)[O-] WBQTXTBONIWRGK-UHFFFAOYSA-N 0.000 claims description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 2
- QPLDLSVMHZLSFG-UHFFFAOYSA-N Copper oxide Chemical compound [Cu]=O QPLDLSVMHZLSFG-UHFFFAOYSA-N 0.000 claims 2
- 230000003197 catalytic effect Effects 0.000 claims 2
- 150000001879 copper Chemical class 0.000 claims 2
- 239000005751 Copper oxide Substances 0.000 claims 1
- 238000010924 continuous production Methods 0.000 claims 1
- 229910000431 copper oxide Inorganic materials 0.000 claims 1
- GWYFCOCPABKNJV-UHFFFAOYSA-N isovaleric acid Chemical compound CC(C)CC(O)=O GWYFCOCPABKNJV-UHFFFAOYSA-N 0.000 claims 1
- 230000002101 lytic effect Effects 0.000 claims 1
- 229910052707 ruthenium Inorganic materials 0.000 claims 1
- 239000000543 intermediate Substances 0.000 abstract description 16
- 238000010668 complexation reaction Methods 0.000 abstract description 2
- CUJRVFIICFDLGR-UHFFFAOYSA-N acetylacetonate Chemical compound CC(=O)[CH-]C(C)=O CUJRVFIICFDLGR-UHFFFAOYSA-N 0.000 abstract 1
- 239000000243 solution Substances 0.000 description 39
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 30
- 150000001875 compounds Chemical class 0.000 description 28
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 27
- GHMLBKRAJCXXBS-UHFFFAOYSA-N resorcinol Chemical compound OC1=CC=CC(O)=C1 GHMLBKRAJCXXBS-UHFFFAOYSA-N 0.000 description 26
- HJYYPODYNSCCOU-ODRIEIDWSA-N rifamycin SV Chemical compound OC1=C(C(O)=C2C)C3=C(O)C=C1NC(=O)\C(C)=C/C=C/[C@H](C)[C@H](O)[C@@H](C)[C@@H](O)[C@@H](C)[C@H](OC(C)=O)[C@H](C)[C@@H](OC)\C=C\O[C@@]1(C)OC2=C3C1=O HJYYPODYNSCCOU-ODRIEIDWSA-N 0.000 description 22
- 150000003839 salts Chemical class 0.000 description 18
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- 230000003115 biocidal effect Effects 0.000 description 14
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 13
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- 239000000126 substance Substances 0.000 description 13
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- 230000002829 reductive effect Effects 0.000 description 12
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- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 10
- 238000005481 NMR spectroscopy Methods 0.000 description 10
- 239000003814 drug Substances 0.000 description 10
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 10
- 239000000047 product Substances 0.000 description 10
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- MBLBDJOUHNCFQT-LXGUWJNJSA-N N-acetylglucosamine Natural products CC(=O)N[C@@H](C=O)[C@@H](O)[C@H](O)[C@H](O)CO MBLBDJOUHNCFQT-LXGUWJNJSA-N 0.000 description 9
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- IXSVOCGZBUJEPI-HTQYORAHSA-N Rifalazil Chemical compound CO[C@H]1\C=C\O[C@@]2(C)Oc3c(C)c(O)c4c(c5nc6c(cc(cc6=O)N6CCN(CC(C)C)CC6)oc5c(NC(=O)\C(C)=C/C=C/[C@H](C)[C@H](O)[C@@H](C)[C@@H](O)[C@@H](C)[C@H](OC(C)=O)[C@@H]1C)c4=O)c3=C2O IXSVOCGZBUJEPI-HTQYORAHSA-N 0.000 description 7
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- MYPYJXKWCTUITO-LYRMYLQWSA-N vancomycin Chemical compound O([C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@H]1OC1=C2C=C3C=C1OC1=CC=C(C=C1Cl)[C@@H](O)[C@H](C(N[C@@H](CC(N)=O)C(=O)N[C@H]3C(=O)N[C@H]1C(=O)N[C@H](C(N[C@@H](C3=CC(O)=CC(O)=C3C=3C(O)=CC=C1C=3)C(O)=O)=O)[C@H](O)C1=CC=C(C(=C1)Cl)O2)=O)NC(=O)[C@@H](CC(C)C)NC)[C@H]1C[C@](C)(N)[C@H](O)[C@H](C)O1 MYPYJXKWCTUITO-LYRMYLQWSA-N 0.000 description 1
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Images
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Abstract
の製造プロセス及び抗体との複合体化のための中間体を記載する。本発明は、例えば、 F−ベンゾキサジノリファマイシンIの製造プロセスであって、リファマイシンS II、2−アミノ−5−フルオロベンゼン−1,3−ジオールIII、と、TEMPO及びTEMPO類似体、周囲空気、酸素ガス、ベンゾキノン、酸化マンガン(MnO2)、(PhI(OTs)OH、過ヨウ素酸ナトリウム(NaIO4)、クロラニル、過酸化水素、Fe2O3、Na2S2O8、Co(acac)3、Mn(acac)2、Cu(OAc)2、CuO、CuBr2、ZnCl2、InCl3、Ag(OTf)2、Sc(OTf)3、ならびにYb(OTf)3から選択される1つ以上の酸化剤とを反応させて、Iを形成することを含む、前記製造プロセスを提供する。
【選択図】図1
Description
37CFR§1.53(b)項に基づいて提出する本通常出願は、2016年3月4日に出願された米国仮出願第62/303,556号の35USC§119(e)項の利益を主張し、その全体を参照として本明細書に援用する。
本発明は、抗体−リファマイシン複合体化合物の製造方法に関する。
がん治療におけるADCのコンセプトは、抗菌療法へ拡張されており、その場合には、薬物部分が抗生物質となり、抗体−抗生物質複合体(AAC)を生じる。抗WTAモノクローナル抗体を、1つ以上のリファマイシン型抗生物質部分(Lehar,S.et al(2015)“Novel antibody−antibiotic conjugate eliminates intracellular S.aureus”Nature 527(7578)323−328;Staben,L.R.,et al(2016)“Targeted drug delivery through the traceless release of tertiary and heteroaryl amines from antibody−drug conjugates”Nature Chemistry 8(12):1112−1119;Zhou,C.,et al(2016)“Pharmacokinetics and pharmacodynamics of DSTA4637A:A novel THIOMAB(商標) antibody antibiotic conjugate against Staphylococcus aureus in mice”MABS 8(8):1612−1619;WO2014/194247)及び他の抗生物質(WO2014/193722)への共有結合リンカーによる結合によって複合体化した。マウスにおけるS.aureusの細胞内リザーバが、バンコマイシンの存在下でさえ感染を確立できる細菌の病原性サブセットを有することが示された。抗WTAリファマイシン複合体は、細胞内のS.aureusを効果的に死滅させる新規治療薬である。有効性の高い抗生物質に複合体化したS.aureus標的化抗体からなるこの抗体−抗生物質複合体(AAC)は、ファゴリソソームのタンパク質分解環境中に放出された後にのみ活性化される。菌血症の治療に対して、この抗体−抗生物質複合体はバンコマイシンより優れており、細胞内S.aureusが侵襲性感染症の重要な構成要素であるという直接的な証拠を提供する。
用語「キラル」とは、鏡像パートナーに対して重ね合わせ不可能な性質を有する分子を指し、用語「アキラル」とは、それらの鏡像パートナーに重ね合わせ可能な分子を指す。
本発明は:
式中、Abは抗WTA(細胞壁タイコ酸)抗体であり、pは1〜約4の整数である(Lehar,S.et al(2015)“Novel antibody−antibiotic conjugate eliminates intracellular S.aureus”527(7578)323−328;WO2014/194247;WO 2014/193722、前記文献の各々の内容は参照として本明細書に援用する)。抗体は、生理学的に切断されるジペプチド(バリン−シトルリン)及びp−アミノベンジルスペーサーを含むリンカーを介してリファマイシン抗生物質部分に共有結合している(Carl,P.L.et al(1981)J.Med.Chem.24(5):479−480;Dubowchik,G.M.et al(1998)Chem.Lett.8:3341−3346;Dubowchik,G.M.et al(2002)Bioconjugate Chem.13:855−869)。リファマイシン部分の第三級アミン末端は、抗体−リファマイシン複合体化合物中に第四級アンモニウム塩を形成し、切断された場合に活性抗生物質を遊離させる。第四級アンモニウム基はまた、切断を調節し、溶解性を最適化し、複合体化合物の凝集を最小限にすることにも役立ち得る。
3.1 ベンゾキノンによる完全バッチプロセス
500mlのガラス反応器中で、ChemShuttle Inc.、Fremont、CA、US7342011;US7271165;US7547692から市販されているリファマイシンS II(13.92g、20mmol)、2−アミノ−5−フルオロベンゼン−1,3−ジオールIII(4.9g、34mol、1.6当量)及びベンゾキノン(2.38g、24mmol、1.2当量)をiPrOAc(185mL)に溶解する。溶液を25℃で40時間撹拌する。溶液を研磨濾過し、次いで濾液を蒸発乾固させて、25.3gの粗製F−ベンゾキサジノリファマイシンIを得る(収率29.2%、分析値18.93%)。MS (EI+): m/z 817.6 (M+, 15%)。HPLC (方法A): 5.32分。
HPLC方法A:
試料調製:100mlのアセトニトリル中の50mgの物質
システム:Agilent 1200、バイナリ
溶離液A:ACN/H2O 9:1+0.25%TFA
溶離液B:ACN/H2O 1:9+0.25%TFA
カラム:x−Bridge C18 4.6×50mm、2.5μm
流速:1.5ml/分
注入:10μl
λ:220nm
カラム温度:40℃
勾配:
500mlのガラス反応器中で、リファマイシンS II(20.0g、29mmol)、2−アミノ−5−フルオロベンゼン−1,3−ジオールIII(4.9g、35mmol、1.2当量)をiPrOAc(300mL)に溶解する。溶液を25℃で一晩撹拌する。次いで、溶液を−5.0℃に冷却し、ベンゾキノンのiPrOAc溶液(45mLの溶媒中、1.86g、17mmol、0.6当量)を8時間かけて添加する。次いで、追加のレゾルシノール(2.5g、17mmol、1.2当量)を25℃で添加し、混合物を一晩反応させる。この時間後、ベンゾキノンのiPrOAc溶液(0.93g、9mmol、22.5mL中0.3当量)を4時間かけて添加する。このレゾルシノールとベンゾキノンの逐次添加を、以下のように合計3サイクル繰り返す:
1.5Lのガラス反応器中で、リファマイシンS II(40.0g、58mmol)、2−アミノ−5−フルオロベンゼン−1,3−ジオールIII(20.6g、144mmol、2.5当量)をiPrOAc(600mL)に溶解する。混合物をアルゴン下、60℃で2時間撹拌する。この時間の後、2,2,6,6−テトラメチル−1−ピペリジニルオキシ、フリーラジカルTEMPO(Kaizer et al(2002)Jour.Mol.Cat.180:91−96)(0.90g、5.8mmol、0.1当量)を添加し、アルゴンを酸素ガスO2(N2中5v/v%)流(400mL/分)で置換する。反応混合物を60℃で22時間撹拌する。この混合物を室温に冷却し、その後、紙フィルターで濾過する。フィルターを酢酸エチル(300mL)で洗浄する。濾液を集め、Na2S2O3(10%w/w、100mL)及びブライン(100mL)の水溶液で抽出する。有機相を集め、蒸発乾固させる。残渣を2%v/vのMeOHを含むDCM(150mL)に溶解し、シリカゲル(250g、溶離液:2%v/vのMeOHを含むDCM)でクロマトグラフィーにかける。生成物を含む画分を蒸発乾固させて、22.3gのF−ベンゾキサジノリファマイシンI(収率45%、分析値95%)を暗赤色固体として得る。1H NMR (600 MHz, CHCl3): δ 14.42−14.33 (m, 1H), 10.29−10.00 (m, 1H), 6.77−6.62 (m, 1H), 6.58−6.48 (m, 1H), 6.39−6.35 (m, 1H), 6.10−4.60 (m, 4H), 4.04−3.90 (m, 1H), 3.61 (s, 1H), 3.50 (s, 1H), 3.35 (s, 1H), 3.11 (s, 1H), 2.33 (s, 1H), 2.29 (s, 1H), 2.23 (s, 2H), 2.16−2.11 (m, 6H), 2.05 (d, J = 18Hz, 2H), 1.78 (d, J= 12 Hz, 2H), 1.58−1.54 (m, 6H), 1.37−0.51 (m, 13H)。HRMS: m/z 818.3061 (質量の計算値: 818.3062)。HPLC (方法B): 5.86分。
HPLC方法B:
試料調製:アセトニトリル1ml中の2mgの物質
システム:Agilent 1200、バイナリ
溶離液A:H2O
溶離液B:ACN
溶離液C:H2O中の0.1%TFA
カラム:x−Bridge C18 4.6×50mm、2.5μm
流量:1.5ml/分
注入:2μl
λ:220nm
カラム温度:40℃
勾配:
二重ジャケットガラス反応器を、静的混合要素を有するフローリアクターにT字接合部を介して接続する。T字接合部の第三の端部を、酸化剤溶液の投与用ポンプに接続する。フローリアクターの出口は二重ジャケットガラス反応器に接続する。18Lのガラス反応器中で、リファマイシンS II(200.4g、288mmol)及び2−アミノ−5−フルオロベンゼン−1,3−ジオールIII(49.5g、347mmol、1.2当量)をiPrOAc(3.0L)に溶解する。溶液を25℃で一晩撹拌する。あるいは、II及びIIIをガラス反応器中でiPrOAcと20〜60℃で一晩混合する。次いで、−5.0〜5.0℃の構造化ミキサーフローリアクター(V=130ml)上でiPrOAc中のベンゾキノン溶液とともに、フローリアクターに溶液をポンプ輸送(5.2L/時)する(詳細は表を参照のこと)。次いで、得られる溶液を、25℃に保たれるバッチ式反応器にポンプで戻す。ループプロセスは、ベンゾキノン投与時間中に実施する(表参照)。その後、追加のレゾルシノール(24.7g、173mmol、0.6当量)を25℃で添加し、混合物を一晩反応させる。ベンゾキノンとレゾルシノールの逐次添加を、以下の表に従って合計3回繰り返す。
反応器にi−PrOAc(355g)、リファマイシンS II(40.0g、57.5mmol)及び2,2,6,6−テトラメチル−1−ピペリジニルオキシ、フリーラジカル(TEMPO)(9.0g、 57.6mmol)を窒素ガス下で添加した。反応器の内容物を1時間、60℃に加温した後、2−アミノ−5−フルオロベンゼン−1,3−ジオールIII(8.0g、55.9mmol)をi−PrOAc(266g)中の溶液として1時間にわたってチャージした。さらにTEMPO(9.0g、57.6mmol)を加え、混合物を60℃で1時間撹拌した。追加の2−アミノ−5−フルオロ−ベンゼン−1,3−ジオールIII(8.0g、55.9mmol)を1時間、i−PrOAc(266g)中の溶液としてチャージし、続いて温度で2時間撹拌した。さらにi−PrOAc(10g)中のTEMPO(1.8g、11.5mmol)を加え、混合物を60℃で1時間撹拌した。追加の2−アミノ−5−フルオロ−ベンゼン−1,3−ジオールIII(1.6g、11.2mmol)をi−PrOAc(60g)中の溶液として1時間にわたって添加し、続いて2時間混合した。i−PrOAc(60g)の溶液として、2−アミノ−5−フルオロ−ベンゼン−1,3−ジオールIII(1.6g、11.2mmol)の最終チャージを1時間かけて加え、続いて60℃で2時間混合した。
乾燥N−メチルピロリドン、NMP(55g)及び6−(2,5−ジオキソ−2,5−ジヒドロ−1H−ピロール−1−イル)−N−((S)−1−(((S)−1−((4−(ヒドロキシメチル)フェニル)アミノ)−1−オキソ−5−ウレイドペンタン−2−イル)アミノ)−3−メチル−1−オキソブタン−2−イル)ヘキサンアミド、MC−VC−PAB−OH(10.0g、17.5mmol)をN2下で反応器にチャージした。
抗WTA抗体のシステイン改変型(THIOMAB(商標)、Genentech)変異体の構築及び産生を、以前に他の抗体について報告されたように行った(WO2014/194247、参照により援用する;Junutula,et al.,2008b Nature Biotech.,26(8):925−932)。簡潔に述べると、システイン残基を抗WTA重鎖のAla118位で改変し、そのcys118 THIOMAB(商標)変異体(HC A118C)を作製した。抗WTA抗体−抗生物質複合体は、システイン改変した抗WTA抗体をリンカー−抗生物質VI中間体に複合体化することによって調製した。複合体化の前に、その記載を本目的のために参照として援用するWO2004/010957に記載されている方法論による標準的な方法を用いて、システイン改変型抗WTA抗体をTCEPで部分的に還元した。部分的に還元した抗体を、例えばDoronina et al.(2003)Nat.Biotechnol.21:778−784及びUS2005/0238649に記載されている方法による標準的な方法を用いてリンカー−抗生物質VI中間体に複合体化した。簡潔に述べると、部分的に還元した抗体をVIと組み合わせて、リンカー−抗生物質中間体を、抗体の還元システイン残基へ複合体化できるようにした。複合体化反応を停止させ、AACを精製した。単一のシステイン変異部位で改変した抗細胞壁タイコ酸抗体について、各AACの抗生物質負荷(抗体あたりの抗生物質部分の平均数)を測定したところ、それは約1〜約2であった。
Claims (22)
- F−ベンゾキサジノリファマイシンIの製造プロセスであって、
- 前記酸化剤が、酸素ガスを含む、請求項1に記載のプロセス。
- 前記酸素ガスが、約5%〜約100%の反応ガス相を含む、請求項2に記載のプロセス。
- 前記酸化剤が、触媒量のTEMPOを含む、請求項2に記載のプロセス。
- 前記酸化剤が、触媒量の銅塩を含む、請求項2に記載のプロセス。
- 前記銅塩が酸化銅である、請求項5に記載のプロセス。
- 前記酸化剤が、半連続プロセスによりIIIから分離され、IIがループプロセスにより改質されリサイクルされる、請求項2に記載のプロセス。
- II及びIIIの反応を、酢酸イソプロピル、酢酸エチル、トルエン、メタノール、及びテトラヒドロフランから選択される溶媒中で行う、請求項1に記載のプロセス。
- VIと抗体とを水性混合物中で反応させて抗体−リファマイシン複合体を形成することをさらに含む、請求項12に記載のプロセス。
- 前記水性混合物が、プロピレングリコール、N−メチルピロリドン(NMP)、ジメチルホルムアミド(DMF)、ジメチルアセトアミド(DMA)、及びジメチルスルホキシド(DMSO)から選択される溶媒を含む、請求項13に記載のプロセス。
- 前記抗体が抗細胞壁タイコ酸抗体である、請求項13に記載のプロセス。
- Vを水から単離する、請求項16に記載のプロセス。
- 前記アルコキシド試薬が、カリウムtert−ブトキシド、ナトリウムtert−ブトキシド、カリウムイソプロポキシド、ナトリウムイソプロポキシド、カリウムエトキシド、ナトリウムエトキシド、カリウムメトキシド、及びナトリウムメトキシドから選択される、請求項18に記載のプロセス。
- 前記アルコキシド試薬がカリウムtert−ブトキシドである、請求項18に記載のプロセス。
- 前記不均質金属触媒が、炭素またはアルミナ担体上の、パラジウム、白金、またはルテニウムから選択される、請求項18に記載のプロセス。
- IXと、水素ガス及び不均一系金属触媒とを反応させて、脱ベンジル化中間体である5−フルオロ−2−ニトロベンゼン−1,3−ジオールを形成し、これを単離し、続いて水素ガス及び異種金属触媒でさらに処理してIIIを形成する、請求項18に記載のプロセス。
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