CA2678754C - Process for the preparation and purification of thiol-containing maytansinoids - Google Patents

Process for the preparation and purification of thiol-containing maytansinoids Download PDF

Info

Publication number: CA2678754C
Authority: CA; Canada
Prior art keywords: maytansinol; methyl; mmol; ethyl acetate; solution
Prior art date: 2000-08-18
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.): Expired - Lifetime

Application number

CA2678754A

Other languages

English (en)

French (fr)

Other versions

CA2678754A1 (en

Inventor

Ravi Vankeepuram Jagannatha Chari

Wayne Charles Widdison

Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)

Immunogen Inc

Original Assignee

Immunogen Inc

Priority date (The priority date 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 date listed.)

2000-08-18

Filing date

2001-04-26

Publication date

2013-08-27

2001-04-26 Application filed by Immunogen Inc filed Critical Immunogen Inc

2002-02-28 Publication of CA2678754A1 publication Critical patent/CA2678754A1/en

2013-08-27 Application granted granted Critical

2013-08-27 Publication of CA2678754C publication Critical patent/CA2678754C/en

2021-04-26 Anticipated expiration legal-status Critical

Status Expired - Lifetime legal-status Critical Current

Links

238000000034 method Methods 0.000 title claims abstract description 42
230000008569 process Effects 0.000 title claims abstract description 33
238000000746 purification Methods 0.000 title description 21
238000002360 preparation method Methods 0.000 title description 14
125000003396 thiol group Chemical class [H]S* 0.000 title description 3
QWPXBEHQFHACTK-KZVYIGENSA-N (10e,12e)-86-chloro-12,14,4-trihydroxy-85,14-dimethoxy-33,2,7,10-tetramethyl-15,16-dihydro-14h-7-aza-1(6,4)-oxazina-3(2,3)-oxirana-8(1,3)-benzenacyclotetradecaphane-10,12-dien-6-one Chemical compound CN1C(=O)CC(O)C2(C)OC2C(C)C(OC(=O)N2)CC2(O)C(OC)\C=C\C=C(C)\CC2=CC(OC)=C(Cl)C1=C2 QWPXBEHQFHACTK-KZVYIGENSA-N 0.000 claims abstract description 111
QWPXBEHQFHACTK-UHFFFAOYSA-N Maytansinol Natural products CN1C(=O)CC(O)C2(C)OC2C(C)C(OC(=O)N2)CC2(O)C(OC)C=CC=C(C)CC2=CC(OC)=C(Cl)C1=C2 QWPXBEHQFHACTK-UHFFFAOYSA-N 0.000 claims abstract description 91
VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical class O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims abstract description 50
230000009467 reduction Effects 0.000 claims abstract description 16
239000000377 silicon dioxide Substances 0.000 claims abstract description 10
239000011230 binding agent Substances 0.000 claims abstract description 9
238000004519 manufacturing process Methods 0.000 claims abstract description 9
239000012043 crude product Substances 0.000 claims abstract description 5
230000005526 G1 to G0 transition Effects 0.000 claims abstract 4
238000004305 normal phase HPLC Methods 0.000 claims abstract 4
XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 186
YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 132
239000000243 solution Substances 0.000 description 83
239000000203 mixture Substances 0.000 description 54
OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 51
KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 49
RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 48
ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 48
238000006243 chemical reaction Methods 0.000 description 48
VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical class CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 45
XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 36
WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 36
150000002148 esters Chemical class 0.000 description 36
150000003573 thiols Chemical class 0.000 description 33
229960003767 alanine Drugs 0.000 description 32
239000011541 reaction mixture Substances 0.000 description 32
230000002829 reductive effect Effects 0.000 description 32
LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 24
DGBBXVWXOHSLTG-UMDRASRXSA-N ansamitocin p 2 Chemical compound C([C@@H]([C@@]1(O[C@H]1[C@@H]1C)C)OC(=O)CC)C(=O)N(C)C(C(=C(OC)C=2)Cl)=CC=2C\C(C)=C\C=C\[C@@H](OC)[C@]2(O)NC(=O)O[C@H]1C2 DGBBXVWXOHSLTG-UMDRASRXSA-N 0.000 description 24
239000002904 solvent Substances 0.000 description 23
210000004027 cell Anatomy 0.000 description 22
239000003638 chemical reducing agent Substances 0.000 description 22
-1 lithium aluminum hydride Chemical compound 0.000 description 22
239000003814 drug Substances 0.000 description 21
239000000047 product Substances 0.000 description 21
XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 21
PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 20
229940079593 drug Drugs 0.000 description 20
239000000741 silica gel Substances 0.000 description 20
229910002027 silica gel Inorganic materials 0.000 description 20
229910052938 sodium sulfate Inorganic materials 0.000 description 20
235000011152 sodium sulphate Nutrition 0.000 description 20
GDFAOVXKHJXLEI-VKHMYHEASA-N N-methyl-L-alanine Chemical class C[NH2+][C@@H](C)C([O-])=O GDFAOVXKHJXLEI-VKHMYHEASA-N 0.000 description 19
238000004128 high performance liquid chromatography Methods 0.000 description 19
DVOOXRTYGGLORL-VKHMYHEASA-N (2r)-2-(methylamino)-3-sulfanylpropanoic acid Chemical class CN[C@@H](CS)C(O)=O DVOOXRTYGGLORL-VKHMYHEASA-N 0.000 description 18
101150041968 CDC13 gene Proteins 0.000 description 18
HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 18
229910052786 argon Inorganic materials 0.000 description 18
YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 18
229960004592 isopropanol Drugs 0.000 description 17
QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 16
238000005481 NMR spectroscopy Methods 0.000 description 16
229940086542 triethylamine Drugs 0.000 description 16
HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 15
125000000217 alkyl group Chemical group 0.000 description 15
125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 15
239000012044 organic layer Substances 0.000 description 15
238000006722 reduction reaction Methods 0.000 description 15
GDFAOVXKHJXLEI-UHFFFAOYSA-N L-N-Boc-N-methylalanine Natural products CNC(C)C(O)=O GDFAOVXKHJXLEI-UHFFFAOYSA-N 0.000 description 14
125000002228 disulfide group Chemical group 0.000 description 14
VHJLVAABSRFDPM-QWWZWVQMSA-N dithiothreitol Chemical compound SC[C@@H](O)[C@H](O)CS VHJLVAABSRFDPM-QWWZWVQMSA-N 0.000 description 14
BWGNESOTFCXPMA-UHFFFAOYSA-N Dihydrogen disulfide Chemical compound SS BWGNESOTFCXPMA-UHFFFAOYSA-N 0.000 description 13
238000005886 esterification reaction Methods 0.000 description 13
239000011261 inert gas Substances 0.000 description 13
HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 12
206010028980 Neoplasm Diseases 0.000 description 12
YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 12
238000004587 chromatography analysis Methods 0.000 description 12
QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 11
229930126263 Maytansine Natural products 0.000 description 11
XYONNSVDNIRXKZ-UHFFFAOYSA-N S-methyl methanethiosulfonate Chemical compound CSS(C)(=O)=O XYONNSVDNIRXKZ-UHFFFAOYSA-N 0.000 description 11
239000012298 atmosphere Substances 0.000 description 11
201000011510 cancer Diseases 0.000 description 11
230000032050 esterification Effects 0.000 description 11
125000005647 linker group Chemical group 0.000 description 11
WKPWGQKGSOKKOO-RSFHAFMBSA-N maytansine Chemical compound CO[C@@H]([C@@]1(O)C[C@](OC(=O)N1)([C@H]([C@@H]1O[C@@]1(C)[C@@H](OC(=O)[C@H](C)N(C)C(C)=O)CC(=O)N1C)C)[H])\C=C\C=C(C)\CC2=CC(OC)=C(Cl)C1=C2 WKPWGQKGSOKKOO-RSFHAFMBSA-N 0.000 description 11
OPQNCARIZFLNLF-JBHFWYGFSA-N ansamitocin P3 Chemical compound CO[C@@H]([C@@]1(O)C[C@H](OC(=O)N1)[C@@H](C)[C@@H]1O[C@@]1(C)[C@@H](OC(=O)C(C)C)CC(=O)N1C)\C=C\C=C(C)\CC2=CC(OC)=C(Cl)C1=C2 OPQNCARIZFLNLF-JBHFWYGFSA-N 0.000 description 10
229910052739 hydrogen Inorganic materials 0.000 description 10
239000007787 solid Substances 0.000 description 10
FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 9
239000012300 argon atmosphere Substances 0.000 description 9
239000000562 conjugate Substances 0.000 description 9
125000004093 cyano group Chemical group *C#N 0.000 description 9
231100000433 cytotoxic Toxicity 0.000 description 9
230000001472 cytotoxic effect Effects 0.000 description 9
239000003960 organic solvent Substances 0.000 description 9
239000002245 particle Substances 0.000 description 9
238000000926 separation method Methods 0.000 description 9
FNDFHKWOXMMFIM-ZETCQYMHSA-N (2s)-2-[acetyl(methyl)amino]-2-methyl-3-sulfanylpropanedithioic acid Chemical compound CC(=O)N(C)[C@@](C)(CS)C(S)=S FNDFHKWOXMMFIM-ZETCQYMHSA-N 0.000 description 8
238000005160 1H NMR spectroscopy Methods 0.000 description 8
DKIDEFUBRARXTE-UHFFFAOYSA-N 3-mercaptopropanoic acid Chemical compound OC(=O)CCS DKIDEFUBRARXTE-UHFFFAOYSA-N 0.000 description 8
IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 8
OPQNCARIZFLNLF-UHFFFAOYSA-N ansamitocin P-3 Natural products CN1C(=O)CC(OC(=O)C(C)C)C2(C)OC2C(C)C(OC(=O)N2)CC2(O)C(OC)C=CC=C(C)CC2=CC(OC)=C(Cl)C1=C2 OPQNCARIZFLNLF-UHFFFAOYSA-N 0.000 description 8
230000015572 biosynthetic process Effects 0.000 description 8
230000007062 hydrolysis Effects 0.000 description 8
238000006460 hydrolysis reaction Methods 0.000 description 8
JIAARYAFYJHUJI-UHFFFAOYSA-L zinc dichloride Chemical compound [Cl-].[Cl-].[Zn+2] JIAARYAFYJHUJI-UHFFFAOYSA-L 0.000 description 8
STQGQHZAVUOBTE-UHFFFAOYSA-N 7-Cyan-hept-2t-en-4,6-diinsaeure Natural products C1=2C(O)=C3C(=O)C=4C(OC)=CC=CC=4C(=O)C3=C(O)C=2CC(O)(C(C)=O)CC1OC1CC(N)C(O)C(C)O1 STQGQHZAVUOBTE-UHFFFAOYSA-N 0.000 description 7
239000007832 Na2SO4 Substances 0.000 description 7
238000004440 column chromatography Methods 0.000 description 7
STQGQHZAVUOBTE-VGBVRHCVSA-N daunorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(C)=O)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 STQGQHZAVUOBTE-VGBVRHCVSA-N 0.000 description 7
229960000975 daunorubicin Drugs 0.000 description 7
125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 7
125000000623 heterocyclic group Chemical group 0.000 description 7
229920006395 saturated elastomer Polymers 0.000 description 7
125000003107 substituted aryl group Chemical group 0.000 description 7
PHMDDWYPVDXMNL-BYPYZUCNSA-N (2s)-2-(methylamino)-4-sulfanylbutanoic acid Chemical compound CN[C@H](C(O)=O)CCS PHMDDWYPVDXMNL-BYPYZUCNSA-N 0.000 description 6
WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
AOJJSUZBOXZQNB-TZSSRYMLSA-N Doxorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 AOJJSUZBOXZQNB-TZSSRYMLSA-N 0.000 description 6
108091006629 SLC13A2 Proteins 0.000 description 6
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239000008057 potassium phosphate buffer Substances 0.000 description 6
238000002953 preparative HPLC Methods 0.000 description 6
238000003786 synthesis reaction Methods 0.000 description 6
GCIZMJUHGHGRNW-UHFFFAOYSA-N 5-sulfanylpentanoic acid Chemical compound OC(=O)CCCCS GCIZMJUHGHGRNW-UHFFFAOYSA-N 0.000 description 5
GUUVPOWQJOLRAS-UHFFFAOYSA-N Diphenyl disulfide Chemical compound C=1C=CC=CC=1SSC1=CC=CC=C1 GUUVPOWQJOLRAS-UHFFFAOYSA-N 0.000 description 5
239000000611 antibody drug conjugate Substances 0.000 description 5
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239000006227 byproduct Substances 0.000 description 5
239000003795 chemical substances by application Substances 0.000 description 5
239000013078 crystal Substances 0.000 description 5
230000003013 cytotoxicity Effects 0.000 description 5
231100000135 cytotoxicity Toxicity 0.000 description 5
239000000706 filtrate Substances 0.000 description 5
230000014759 maintenance of location Effects 0.000 description 5
125000000325 methylidene group Chemical group [H]C([H])=* 0.000 description 5
229910052757 nitrogen Inorganic materials 0.000 description 5
238000012746 preparative thin layer chromatography Methods 0.000 description 5
238000003756 stirring Methods 0.000 description 5
239000000126 substance Substances 0.000 description 5
MRIUCSDUNONTSR-QMMMGPOBSA-N (2s)-2-[acetyl(methyl)amino]-2-methyl-4-sulfanylbutanedithioic acid Chemical compound CC(=O)N(C)[C@](C)(C(S)=S)CCS MRIUCSDUNONTSR-QMMMGPOBSA-N 0.000 description 4
YOETUEMZNOLGDB-UHFFFAOYSA-N 2-methylpropyl carbonochloridate Chemical compound CC(C)COC(Cl)=O YOETUEMZNOLGDB-UHFFFAOYSA-N 0.000 description 4
VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
FBOZXECLQNJBKD-ZDUSSCGKSA-N L-methotrexate Chemical compound C=1N=C2N=C(N)N=C(N)C2=NC=1CN(C)C1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 FBOZXECLQNJBKD-ZDUSSCGKSA-N 0.000 description 4
CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 4
229960000583 acetic acid Drugs 0.000 description 4
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150000001875 compounds Chemical class 0.000 description 4
230000000694 effects Effects 0.000 description 4
239000007789 gas Substances 0.000 description 4
229910052734 helium Inorganic materials 0.000 description 4
239000001307 helium Substances 0.000 description 4
SWQJXJOGLNCZEY-UHFFFAOYSA-N helium atom Chemical compound [He] SWQJXJOGLNCZEY-UHFFFAOYSA-N 0.000 description 4
150000004678 hydrides Chemical class 0.000 description 4
125000002887 hydroxy group Chemical group [H]O* 0.000 description 4
238000000338 in vitro Methods 0.000 description 4
125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 4
239000012280 lithium aluminium hydride Substances 0.000 description 4
229960000485 methotrexate Drugs 0.000 description 4
230000004048 modification Effects 0.000 description 4
238000012986 modification Methods 0.000 description 4
230000035484 reaction time Effects 0.000 description 4
CZDYPVPMEAXLPK-UHFFFAOYSA-N tetramethylsilane Chemical compound C[Si](C)(C)C CZDYPVPMEAXLPK-UHFFFAOYSA-N 0.000 description 4
235000005074 zinc chloride Nutrition 0.000 description 4
239000011592 zinc chloride Substances 0.000 description 4
IVFAPRBKBIISST-UHFFFAOYSA-N 3-[(4-nitrophenyl)disulfanyl]propanoic acid Chemical compound OC(=O)CCSSC1=CC=C([N+]([O-])=O)C=C1 IVFAPRBKBIISST-UHFFFAOYSA-N 0.000 description 3
JWUDANXWFVKRQT-UHFFFAOYSA-N 3-phenylpropanedithioic acid Chemical compound SC(=S)CCC1=CC=CC=C1 JWUDANXWFVKRQT-UHFFFAOYSA-N 0.000 description 3
NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 3
241000187747 Streptomyces Species 0.000 description 3
239000002253 acid Substances 0.000 description 3
244000309464 bull Species 0.000 description 3
BPOPGHPHBCLJOK-UHFFFAOYSA-N butanedithioic acid Chemical compound CCCC(S)=S BPOPGHPHBCLJOK-UHFFFAOYSA-N 0.000 description 3
RBHJBMIOOPYDBQ-UHFFFAOYSA-N carbon dioxide;propan-2-one Chemical compound O=C=O.CC(C)=O RBHJBMIOOPYDBQ-UHFFFAOYSA-N 0.000 description 3
150000001732 carboxylic acid derivatives Chemical class 0.000 description 3
229910052801 chlorine Inorganic materials 0.000 description 3
239000012230 colorless oil Substances 0.000 description 3
229940127089 cytotoxic agent Drugs 0.000 description 3
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AHMXOTXKQODUJH-UHFFFAOYSA-N hexanedithioic acid Chemical compound CCCCCC(S)=S AHMXOTXKQODUJH-UHFFFAOYSA-N 0.000 description 3
238000001727 in vivo Methods 0.000 description 3
239000007788 liquid Substances 0.000 description 3
230000001404 mediated effect Effects 0.000 description 3
XZOSENLGQPCENB-UHFFFAOYSA-N pentanedithioic acid Chemical compound CCCCC(S)=S XZOSENLGQPCENB-UHFFFAOYSA-N 0.000 description 3
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VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 2
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JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 2
LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 2
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XYFCBTPGUUZFHI-UHFFFAOYSA-N Phosphine Chemical compound P XYFCBTPGUUZFHI-UHFFFAOYSA-N 0.000 description 2
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DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 2
YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical compound C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 description 2
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230000010933 acylation Effects 0.000 description 2
238000005917 acylation reaction Methods 0.000 description 2
150000003862 amino acid derivatives Chemical class 0.000 description 2
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239000000427 antigen Substances 0.000 description 2
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YONPGGFAJWQGJC-UHFFFAOYSA-K titanium(iii) chloride Chemical compound Cl[Ti](Cl)Cl YONPGGFAJWQGJC-UHFFFAOYSA-K 0.000 description 1
231100000331 toxic Toxicity 0.000 description 1
231100000167 toxic agent Toxicity 0.000 description 1
230000002588 toxic effect Effects 0.000 description 1
239000003440 toxic substance Substances 0.000 description 1
230000001988 toxicity Effects 0.000 description 1
231100000419 toxicity Toxicity 0.000 description 1
239000003053 toxin Substances 0.000 description 1
231100000765 toxin Toxicity 0.000 description 1
GTZCVFVGUGFEME-UHFFFAOYSA-N trans-aconitic acid Natural products OC(=O)CC(C(O)=O)=CC(O)=O GTZCVFVGUGFEME-UHFFFAOYSA-N 0.000 description 1
239000012581 transferrin Substances 0.000 description 1
IVIIAEVMQHEPAY-UHFFFAOYSA-N tridodecyl phosphite Chemical compound CCCCCCCCCCCCOP(OCCCCCCCCCCCC)OCCCCCCCCCCCC IVIIAEVMQHEPAY-UHFFFAOYSA-N 0.000 description 1
KNXVOGGZOFOROK-UHFFFAOYSA-N trimagnesium;dioxido(oxo)silane;hydroxy-oxido-oxosilane Chemical compound [Mg+2].[Mg+2].[Mg+2].O[Si]([O-])=O.O[Si]([O-])=O.[O-][Si]([O-])=O.[O-][Si]([O-])=O KNXVOGGZOFOROK-UHFFFAOYSA-N 0.000 description 1
230000004614 tumor growth Effects 0.000 description 1
238000002211 ultraviolet spectrum Methods 0.000 description 1
229960003048 vinblastine Drugs 0.000 description 1
JXLYSJRDGCGARV-XQKSVPLYSA-N vincaleukoblastine Chemical compound C([C@@H](C[C@]1(C(=O)OC)C=2C(=CC3=C([C@]45[C@H]([C@@]([C@H](OC(C)=O)[C@]6(CC)C=CCN([C@H]56)CC4)(O)C(=O)OC)N3C)C=2)OC)C[C@@](C2)(O)CC)N2CCC2=C1NC1=CC=CC=C21 JXLYSJRDGCGARV-XQKSVPLYSA-N 0.000 description 1
239000011701 zinc Substances 0.000 description 1
229910052725 zinc Inorganic materials 0.000 description 1

Classifications

- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D498/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains three hetero rings
- C07D498/18—Bridged systems
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
- A61K47/6801—Drug-antibody or immunoglobulin conjugates defined by the pharmacologically or therapeutically active agent
- A61K47/6803—Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates
- A61K47/68033—Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates the drug being a maytansine
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
- A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Landscapes

Health & Medical Sciences (AREA)
Chemical & Material Sciences (AREA)
Engineering & Computer Science (AREA)
Bioinformatics & Cheminformatics (AREA)
Organic Chemistry (AREA)
Life Sciences & Earth Sciences (AREA)
Veterinary Medicine (AREA)
Public Health (AREA)
General Health & Medical Sciences (AREA)
Medicinal Chemistry (AREA)
Animal Behavior & Ethology (AREA)
Pharmacology & Pharmacy (AREA)
Chemical Kinetics & Catalysis (AREA)
Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
General Chemical & Material Sciences (AREA)
Immunology (AREA)
Communicable Diseases (AREA)
Oncology (AREA)
Epidemiology (AREA)
Transplantation (AREA)
Virology (AREA)
Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Agricultural Chemicals And Associated Chemicals (AREA)

CA2678754A 2000-08-18 2001-04-26 Process for the preparation and purification of thiol-containing maytansinoids Expired - Lifetime CA2678754C (en)

Applications Claiming Priority (3)

Application Number	Priority Date	Filing Date	Title
US09/641,348		2000-08-18
US09/641,348 US6333410B1 (en)	2000-08-18	2000-08-18	Process for the preparation and purification of thiol-containing maytansinoids
CA2373554A CA2373554C (en)	2000-08-18	2001-04-26	Process for the preparation and purification of thiol-containing maytansinoids

Related Parent Applications (1)

Application Number	Title	Priority Date	Filing Date
CA2373554A Division CA2373554C (en)	2000-08-18	2001-04-26	Process for the preparation and purification of thiol-containing maytansinoids

Publications (2)

Publication Number	Publication Date
CA2678754A1 CA2678754A1 (en)	2002-02-28
CA2678754C true CA2678754C (en)	2013-08-27

Family

ID=24571977

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Application Number	Title	Priority Date	Filing Date
CA2678754A Expired - Lifetime CA2678754C (en)	2000-08-18	2001-04-26	Process for the preparation and purification of thiol-containing maytansinoids
CA2373554A Expired - Lifetime CA2373554C (en)	2000-08-18	2001-04-26	Process for the preparation and purification of thiol-containing maytansinoids

Family Applications After (1)

Application Number	Title	Priority Date	Filing Date
CA2373554A Expired - Lifetime CA2373554C (en)	2000-08-18	2001-04-26	Process for the preparation and purification of thiol-containing maytansinoids

Country Status (10)

Country	Link
US (2)	US6333410B1 (2)
EP (1)	EP1313738B1 (2)
JP (1)	JP4922535B2 (2)
AT (1)	ATE313545T1 (2)
AU (1)	AU763107B2 (2)
CA (2)	CA2678754C (2)
DE (1)	DE60116113T2 (2)
DK (1)	DK1313738T3 (2)
ES (1)	ES2253371T3 (2)
WO (1)	WO2002016368A1 (2)

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2001
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- 2001-04-26 AU AU53118/01A patent/AU763107B2/en not_active Expired
- 2001-04-26 ES ES01926594T patent/ES2253371T3/es not_active Expired - Lifetime
- 2001-04-26 CA CA2678754A patent/CA2678754C/en not_active Expired - Lifetime
- 2001-04-26 CA CA2373554A patent/CA2373554C/en not_active Expired - Lifetime
- 2001-04-26 WO PCT/US2001/010816 patent/WO2002016368A1/en not_active Ceased
- 2001-04-26 DK DK01926594T patent/DK1313738T3/da active
- 2001-04-26 DE DE60116113T patent/DE60116113T2/de not_active Expired - Lifetime
- 2001-04-26 AT AT01926594T patent/ATE313545T1/de active
- 2001-04-26 JP JP2002521468A patent/JP4922535B2/ja not_active Expired - Lifetime
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USRE39151E1 (en)	2006-06-27
CA2373554A1 (en)	2002-02-28
DE60116113T2 (de)	2006-07-27
JP2004506738A (ja)	2004-03-04
US6333410B1 (en)	2001-12-25
EP1313738B1 (en)	2005-12-21
CA2373554C (en)	2011-02-15
CA2678754A1 (en)	2002-02-28
HK1056357A1 (en)	2004-02-13
DK1313738T3 (da)	2006-05-01
DE60116113D1 (de)	2006-01-26
JP4922535B2 (ja)	2012-04-25
AU763107B2 (en)	2003-07-10
ES2253371T3 (es)	2006-06-01
EP1313738A1 (en)	2003-05-28
ATE313545T1 (de)	2006-01-15
AU5311801A (en)	2002-03-04
EP1313738A4 (en)	2005-01-19
WO2002016368A1 (en)	2002-02-28

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Publication	Publication Date	Title
CA2678754C (en)	2013-08-27	Process for the preparation and purification of thiol-containing maytansinoids
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CA2417858C (en)	2011-07-12	Methods for preparation of cytotoxic conjugates of maytansinoids and cell binding agents
US5208020A (en)	1993-05-04	Cytotoxic agents comprising maytansinoids and their therapeutic use
EP0425235B1 (en)	1996-09-25	Cytotoxic agents comprising maytansinoids and their therapeutic use
US20040235840A1 (en)	2004-11-25	Cytotoxic agents comprising new maytansinoids
AU2002251880A1 (en)	2003-05-08	Method for preparation of cytotoxic conjugates of maytansinoids and cell binding agents
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HK40012682A (en)	2020-07-31	Improved cytotoxic agents comprising new maytansinoids
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