JP2014515735A - Nカルボキシアルキルオーリスタチンおよびその使用 - Google Patents
Nカルボキシアルキルオーリスタチンおよびその使用 Download PDFInfo
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- JP2014515735A JP2014515735A JP2013558400A JP2013558400A JP2014515735A JP 2014515735 A JP2014515735 A JP 2014515735A JP 2013558400 A JP2013558400 A JP 2013558400A JP 2013558400 A JP2013558400 A JP 2013558400A JP 2014515735 A JP2014515735 A JP 2014515735A
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- Prior art keywords
- formula
- methyl
- phenyl
- compound
- salts
- 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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- 125000004181 carboxyalkyl group Chemical group 0.000 title abstract description 4
- 108010044540 auristatin Proteins 0.000 title description 8
- 238000000034 method Methods 0.000 claims abstract description 131
- 206010028980 Neoplasm Diseases 0.000 claims abstract description 37
- 239000003814 drug Substances 0.000 claims abstract description 27
- 201000011510 cancer Diseases 0.000 claims abstract description 18
- 230000002265 prevention Effects 0.000 claims abstract description 6
- 238000004519 manufacturing process Methods 0.000 claims abstract description 5
- 150000001875 compounds Chemical class 0.000 claims description 162
- -1 propene-1,3-diyl Chemical group 0.000 claims description 97
- 150000003839 salts Chemical class 0.000 claims description 44
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 claims description 35
- 239000012453 solvate Substances 0.000 claims description 33
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 29
- 239000002904 solvent Substances 0.000 claims description 22
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 20
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 18
- 235000019253 formic acid Nutrition 0.000 claims description 18
- 125000004432 carbon atom Chemical group C* 0.000 claims description 17
- 229910052757 nitrogen Inorganic materials 0.000 claims description 17
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 15
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 15
- 239000001257 hydrogen Substances 0.000 claims description 15
- 229910052739 hydrogen Inorganic materials 0.000 claims description 15
- 239000002253 acid Substances 0.000 claims description 12
- 125000004185 ester group Chemical group 0.000 claims description 12
- 239000012442 inert solvent Substances 0.000 claims description 10
- 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 claims description 8
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 8
- 150000001732 carboxylic acid derivatives Chemical class 0.000 claims description 7
- 125000000814 indol-3-yl group Chemical group [H]C1=C([H])C([H])=C2N([H])C([H])=C([*])C2=C1[H] 0.000 claims description 7
- 238000002360 preparation method Methods 0.000 claims description 7
- 125000006163 5-membered heteroaryl group Chemical group 0.000 claims description 6
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 claims description 6
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 6
- 239000004480 active ingredient Substances 0.000 claims description 6
- 125000000217 alkyl group Chemical group 0.000 claims description 6
- 230000006806 disease prevention Effects 0.000 claims description 6
- 238000007796 conventional method Methods 0.000 claims description 5
- 125000005678 ethenylene group Chemical group [H]C([*:1])=C([H])[*:2] 0.000 claims description 5
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 5
- 125000004504 1,2,4-oxadiazolyl group Chemical class 0.000 claims description 4
- 125000000094 2-phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])* 0.000 claims description 4
- 238000005804 alkylation reaction Methods 0.000 claims description 4
- 125000005842 heteroatom Chemical group 0.000 claims description 4
- 125000002883 imidazolyl group Chemical class 0.000 claims description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 4
- 125000003226 pyrazolyl group Chemical class 0.000 claims description 4
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 3
- 230000029936 alkylation Effects 0.000 claims description 3
- 229910052799 carbon Inorganic materials 0.000 claims description 3
- 239000003638 chemical reducing agent Substances 0.000 claims description 3
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 claims description 3
- 231100000252 nontoxic Toxicity 0.000 claims description 3
- 230000003000 nontoxic effect Effects 0.000 claims description 3
- 125000001781 1,3,4-oxadiazolyl group Chemical class 0.000 claims description 2
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 claims description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 claims description 2
- 239000000825 pharmaceutical preparation Substances 0.000 claims description 2
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 claims description 2
- ITMCEJHCFYSIIV-UHFFFAOYSA-M triflate Chemical compound [O-]S(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-M 0.000 claims description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-M Formate Chemical compound [O-]C=O BDAGIHXWWSANSR-UHFFFAOYSA-M 0.000 claims 1
- 241001465754 Metazoa Species 0.000 claims 1
- 229940127557 pharmaceutical product Drugs 0.000 claims 1
- MFRNYXJJRJQHNW-DEMKXPNLSA-N (2s)-2-[[(2r,3r)-3-methoxy-3-[(2s)-1-[(3r,4s,5s)-3-methoxy-5-methyl-4-[methyl-[(2s)-3-methyl-2-[[(2s)-3-methyl-2-(methylamino)butanoyl]amino]butanoyl]amino]heptanoyl]pyrrolidin-2-yl]-2-methylpropanoyl]amino]-3-phenylpropanoic acid Chemical group CN[C@@H](C(C)C)C(=O)N[C@@H](C(C)C)C(=O)N(C)[C@@H]([C@@H](C)CC)[C@H](OC)CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@H](C(O)=O)CC1=CC=CC=C1 MFRNYXJJRJQHNW-DEMKXPNLSA-N 0.000 abstract description 19
- 108010059074 monomethylauristatin F Chemical group 0.000 abstract description 18
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 abstract description 17
- 229940079593 drug Drugs 0.000 abstract description 17
- 201000010099 disease Diseases 0.000 abstract description 15
- IEDXPSOJFSVCKU-HOKPPMCLSA-N [4-[[(2S)-5-(carbamoylamino)-2-[[(2S)-2-[6-(2,5-dioxopyrrolidin-1-yl)hexanoylamino]-3-methylbutanoyl]amino]pentanoyl]amino]phenyl]methyl N-[(2S)-1-[[(2S)-1-[[(3R,4S,5S)-1-[(2S)-2-[(1R,2R)-3-[[(1S,2R)-1-hydroxy-1-phenylpropan-2-yl]amino]-1-methoxy-2-methyl-3-oxopropyl]pyrrolidin-1-yl]-3-methoxy-5-methyl-1-oxoheptan-4-yl]-methylamino]-3-methyl-1-oxobutan-2-yl]amino]-3-methyl-1-oxobutan-2-yl]-N-methylcarbamate Chemical group CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@H](C)[C@@H](O)c1ccccc1)OC)N(C)C(=O)[C@@H](NC(=O)[C@H](C(C)C)N(C)C(=O)OCc1ccc(NC(=O)[C@H](CCCNC(N)=O)NC(=O)[C@@H](NC(=O)CCCCCN2C(=O)CCC2=O)C(C)C)cc1)C(C)C IEDXPSOJFSVCKU-HOKPPMCLSA-N 0.000 abstract description 11
- 230000003463 hyperproliferative effect Effects 0.000 abstract description 3
- 238000009097 single-agent therapy Methods 0.000 abstract description 3
- 230000001225 therapeutic effect Effects 0.000 abstract description 3
- 230000002491 angiogenic effect Effects 0.000 abstract description 2
- 238000002483 medication Methods 0.000 abstract 1
- 239000000543 intermediate Substances 0.000 description 84
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 57
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 54
- 238000004128 high performance liquid chromatography Methods 0.000 description 52
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical class OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 43
- 239000000203 mixture Substances 0.000 description 39
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 36
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 35
- 125000004214 1-pyrrolidinyl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 description 33
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 31
- 210000004027 cell Anatomy 0.000 description 31
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 30
- 239000003480 eluent Substances 0.000 description 28
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 27
- 239000000243 solution Substances 0.000 description 26
- 238000006243 chemical reaction Methods 0.000 description 25
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 24
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 24
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 24
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 22
- 230000015572 biosynthetic process Effects 0.000 description 22
- 238000003786 synthesis reaction Methods 0.000 description 22
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 21
- 125000006239 protecting group Chemical group 0.000 description 21
- 239000000126 substance Substances 0.000 description 21
- UIUJIQZEACWQSV-UHFFFAOYSA-N succinic semialdehyde Chemical compound OC(=O)CCC=O UIUJIQZEACWQSV-UHFFFAOYSA-N 0.000 description 20
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical class CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 19
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 18
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 18
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 18
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 17
- DTQVDTLACAAQTR-UHFFFAOYSA-M Trifluoroacetate Chemical compound [O-]C(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-M 0.000 description 17
- 238000012360 testing method Methods 0.000 description 17
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 15
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 14
- 239000007864 aqueous solution Substances 0.000 description 13
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 13
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 12
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 12
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 12
- 239000012074 organic phase Substances 0.000 description 12
- BEOOHQFXGBMRKU-UHFFFAOYSA-N sodium cyanoborohydride Chemical compound [Na+].[B-]C#N BEOOHQFXGBMRKU-UHFFFAOYSA-N 0.000 description 12
- 239000007787 solid Substances 0.000 description 12
- 238000005481 NMR spectroscopy Methods 0.000 description 11
- 230000000694 effects Effects 0.000 description 11
- 238000002953 preparative HPLC Methods 0.000 description 11
- 230000008569 process Effects 0.000 description 11
- 238000000825 ultraviolet detection Methods 0.000 description 11
- 102100033350 ATP-dependent translocase ABCB1 Human genes 0.000 description 10
- 238000003556 assay Methods 0.000 description 10
- 239000002585 base Substances 0.000 description 10
- 238000005859 coupling reaction Methods 0.000 description 10
- 239000003826 tablet Substances 0.000 description 10
- 239000003643 water by type Substances 0.000 description 10
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 9
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 9
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 9
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 9
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical class OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 9
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 9
- 235000019341 magnesium sulphate Nutrition 0.000 description 9
- 108010093470 monomethyl auristatin E Proteins 0.000 description 9
- 210000001519 tissue Anatomy 0.000 description 9
- VOXZDWNPVJITMN-ZBRFXRBCSA-N 17β-estradiol Chemical compound OC1=CC=C2[C@H]3CC[C@](C)([C@H](CC4)O)[C@@H]4[C@@H]3CCC2=C1 VOXZDWNPVJITMN-ZBRFXRBCSA-N 0.000 description 8
- 238000005160 1H NMR spectroscopy Methods 0.000 description 8
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 8
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 8
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 8
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 8
- OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 description 8
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 8
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- 239000007858 starting material Substances 0.000 description 8
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- 125000003088 (fluoren-9-ylmethoxy)carbonyl group Chemical group 0.000 description 7
- 0 *C(Cc1ccccc1)N Chemical compound *C(Cc1ccccc1)N 0.000 description 7
- 239000002246 antineoplastic agent Substances 0.000 description 7
- PFKFTWBEEFSNDU-UHFFFAOYSA-N carbonyldiimidazole Chemical compound C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 description 7
- 239000003054 catalyst Substances 0.000 description 7
- 238000004896 high resolution mass spectrometry Methods 0.000 description 7
- 230000035699 permeability Effects 0.000 description 7
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 7
- 238000004704 ultra performance liquid chromatography Methods 0.000 description 7
- ASOKPJOREAFHNY-UHFFFAOYSA-N 1-Hydroxybenzotriazole Chemical compound C1=CC=C2N(O)N=NC2=C1 ASOKPJOREAFHNY-UHFFFAOYSA-N 0.000 description 6
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 6
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 6
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 6
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- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 6
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 6
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- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 description 6
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- MQLACMBJVPINKE-UHFFFAOYSA-N 10-[(3-hydroxy-4-methoxyphenyl)methylidene]anthracen-9-one Chemical compound C1=C(O)C(OC)=CC=C1C=C1C2=CC=CC=C2C(=O)C2=CC=CC=C21 MQLACMBJVPINKE-UHFFFAOYSA-N 0.000 description 4
- JKMHFZQWWAIEOD-UHFFFAOYSA-N 2-[4-(2-hydroxyethyl)piperazin-1-yl]ethanesulfonic acid Chemical compound OCC[NH+]1CCN(CCS([O-])(=O)=O)CC1 JKMHFZQWWAIEOD-UHFFFAOYSA-N 0.000 description 4
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 description 4
- AOJJSUZBOXZQNB-VTZDEGQISA-N 4'-epidoxorubicin 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-VTZDEGQISA-N 0.000 description 4
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 4
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- UBOXGVDOUJQMTN-UHFFFAOYSA-N trichloroethylene Natural products ClCC(Cl)Cl UBOXGVDOUJQMTN-UHFFFAOYSA-N 0.000 description 1
- ITMCEJHCFYSIIV-UHFFFAOYSA-N triflic acid Chemical compound OS(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-N 0.000 description 1
- 229960001670 trilostane Drugs 0.000 description 1
- KVJXBPDAXMEYOA-CXANFOAXSA-N trilostane Chemical compound OC1=C(C#N)C[C@]2(C)[C@H]3CC[C@](C)([C@H](CC4)O)[C@@H]4[C@@H]3CC[C@@]32O[C@@H]31 KVJXBPDAXMEYOA-CXANFOAXSA-N 0.000 description 1
- 125000003258 trimethylene group Chemical group [H]C([H])([*:2])C([H])([H])C([H])([H])[*:1] 0.000 description 1
- WOPGHMKDMNSLIR-UHFFFAOYSA-M triphenyl(2-phenylethyl)phosphanium;bromide Chemical compound [Br-].C=1C=CC=CC=1CC[P+](C=1C=CC=CC=1)(C=1C=CC=CC=1)C1=CC=CC=C1 WOPGHMKDMNSLIR-UHFFFAOYSA-M 0.000 description 1
- 230000004614 tumor growth Effects 0.000 description 1
- 229950009811 ubenimex Drugs 0.000 description 1
- 238000000870 ultraviolet spectroscopy Methods 0.000 description 1
- 208000024722 urethra neoplasm Diseases 0.000 description 1
- AUFUWRKPQLGTGF-FMKGYKFTSA-N uridine triacetate Chemical compound CC(=O)O[C@@H]1[C@H](OC(C)=O)[C@@H](COC(=O)C)O[C@H]1N1C(=O)NC(=O)C=C1 AUFUWRKPQLGTGF-FMKGYKFTSA-N 0.000 description 1
- 210000003932 urinary bladder Anatomy 0.000 description 1
- 208000029584 urinary system neoplasm Diseases 0.000 description 1
- 206010046766 uterine cancer Diseases 0.000 description 1
- 208000012991 uterine carcinoma Diseases 0.000 description 1
- 210000001215 vagina Anatomy 0.000 description 1
- 239000006216 vaginal suppository Substances 0.000 description 1
- 229960002730 vapreotide Drugs 0.000 description 1
- 108700029852 vapreotide Proteins 0.000 description 1
- 239000003981 vehicle Substances 0.000 description 1
- 229960001722 verapamil Drugs 0.000 description 1
- 229960003895 verteporfin Drugs 0.000 description 1
- ZQFGRJWRSLZCSQ-ZSFNYQMMSA-N verteporfin Chemical compound C=1C([C@@]2([C@H](C(=O)OC)C(=CC=C22)C(=O)OC)C)=NC2=CC(C(=C2C=C)C)=NC2=CC(C(=C2CCC(O)=O)C)=NC2=CC2=NC=1C(C)=C2CCC(=O)OC ZQFGRJWRSLZCSQ-ZSFNYQMMSA-N 0.000 description 1
- 229950005577 vesnarinone Drugs 0.000 description 1
- NMDYYWFGPIMTKO-HBVLKOHWSA-N vinflunine Chemical compound C([C@@](C1=C(C2=CC=CC=C2N1)C1)(C2=C(OC)C=C3N(C)[C@@H]4[C@@]5(C3=C2)CCN2CC=C[C@]([C@@H]52)([C@H]([C@]4(O)C(=O)OC)OC(C)=O)CC)C(=O)OC)[C@H]2C[C@@H](C(C)(F)F)CN1C2 NMDYYWFGPIMTKO-HBVLKOHWSA-N 0.000 description 1
- 229960000922 vinflunine Drugs 0.000 description 1
- 210000003905 vulva Anatomy 0.000 description 1
- 201000004916 vulva carcinoma Diseases 0.000 description 1
- 208000013013 vulvar carcinoma Diseases 0.000 description 1
- 235000012431 wafers Nutrition 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
- 238000010626 work up procedure Methods 0.000 description 1
- 239000000230 xanthan gum Substances 0.000 description 1
- 229920001285 xanthan gum Polymers 0.000 description 1
- 235000010493 xanthan gum Nutrition 0.000 description 1
- 229940082509 xanthan gum Drugs 0.000 description 1
- 229960004276 zoledronic acid Drugs 0.000 description 1
- XRASPMIURGNCCH-UHFFFAOYSA-N zoledronic acid Chemical compound OP(=O)(O)C(P(O)(O)=O)(O)CN1C=CN=C1 XRASPMIURGNCCH-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
- A61K38/07—Tetrapeptides
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
-
- 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
- A61P35/00—Antineoplastic agents
- A61P35/02—Antineoplastic agents specific for leukemia
-
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/02—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link
- C07K5/0205—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link containing the structure -NH-(X)3-C(=0)-, e.g. statine or derivatives thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
-
- 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
- A61K47/62—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 a protein, peptide or polyamino acid
- A61K47/64—Drug-peptide, drug-protein or drug-polyamino acid conjugates, i.e. the modifying agent being a peptide, protein or polyamino acid which is covalently bonded or complexed to a therapeutically active agent
- A61K47/6415—Toxins or lectins, e.g. clostridial toxins or Pseudomonas exotoxins
Abstract
Description
Lは、メチルで最大で4回置換されていてよく、かつその中で(a)2個の炭素原子が互いに1,2−、1,3−もしくは1,4−の関係で、任意選択でそれらの間に炭素原子を含むことによって橋掛けされて(C3〜C6)−シクロアルキル環またはフェニル環を形成していてよい、あるいは(b)互いに近接していない最大で3つのCH2基が−O−で置き換えられていてよい直鎖状(C1〜C12)−アルカンジイルを表し、かつ
Tは、式:
**はそれぞれの基Tの基とのそれぞれの結合部位を示し、
Aは直鎖状(C1〜C4)−アルカンジイルまたは直鎖状(C2〜C4)−アルケンジイルを表し、
R3は(C1〜C4)−アルコキシカルボニルまたはカルボキシルで置換されていてよいフェニルを表し、
nは0、1または2の数を表し、
R4は、フェニル基において(C1〜C4)−アルコキシカルボニルまたはカルボキシルで置換されていてよいフェニル、ベンジルまたは2−フェニルエチルを表し、
Hetは、N、Oおよび/またはSのシリーズからの最大で3個の環ヘテロ原子を有する二価5員ヘテロアリール環を表し、かつ
R5は、フェニルで置換されていてよい(C3〜C6)−シクロアルキル、フェニルまたは(C1〜C4)−アルキルを表し、ここで、上記フェニル基は、(C1〜C4)−アルコキシカルボニルまたはカルボキシルで置換されていてよい。
(C1〜C4)−アルキルは、本発明の範囲内で、1〜4個の炭素原子を有する直鎖状または分岐状アルキル基を表す。以下のもの、好ましくは例えば:メチル、エチル、n−プロピル、イソプロピル、n−ブチル、イソブチル、sec−ブチルおよびtert−ブチルを挙げることができる。
Lが、(a)2個の炭素原子が互いに1,3−もしくは1,4−の関係で、それらの間に炭素原子の1個もしくは2個を含むことによって橋掛けされてフェニル環を形成していてよい、あるいは(b)互いに近接していない最大で2つのCH2基が−O−で置き換えられていてよい直鎖状(C1〜C8)−アルカンジイルを表し、かつ
Tが式:
**はそれぞれの基Tの基との結合部位を示し、
Aはエテン−1,2−ジイルまたはプロペン−1,3−ジイルを示し、
R3は(C1〜C4)−アルコキシカルボニルまたはカルボキシルで置換されていてよいフェニルを表し、
Hetはピラゾリル、イミダゾリル、1,3−オキサゾリル、1,3−チアゾリル、1,2,4−オキサジアゾリルおよび1,3,4−オキサジアゾリルのシリーズから選択される二価5員ヘテロアリール環であり、かつ
R5は(C1〜C4)−アルコキシカルボニルまたはカルボキシルで置換されていてよいフェニルを表す。
Lが直鎖状(C1〜C6)−アルカンジイルを表し、かつ
Tが式:
**はそれぞれの基Tの基との結合部位を示し、
Aはエテン−1,2−ジイルを示し、
R3はメトキシカルボニルまたはカルボキシルで置換されていてよいフェニルを示し、
Hetは1,3,4−オキサジアゾール−2,5−イルであり、かつ
R5はメトキシカルボニルまたはカルボキシルで置換されていてよいフェニルである。
Lがプロパン−1,3−ジイルを表す。
Tが式:
E1は水素、(C1〜C4)−アルキルまたはベンジルを表し、かつ
Xはクロリド、ブロミド、ヨージド、メシレート、トリフレートまたはトシレートなどの離脱基を表す)
と反応させて式(IV)の化合物
を形成し、次いでE1が(C1〜C4)−アルキルまたはベンジルを表す場合、このエステル基を従来の方法で分割し、それによって、式(III)のE1が水素を表す場合のような式(I)のカルボン酸
に転換させ、次いでE1が(C1〜C4)−アルキルまたはベンジルを表す場合、このエステル基を従来の方法で分割し、それによって、式(V)のE1が水素を表す場合のような式(I−A)のカルボン酸
を得、
得られた式(I)および/または(I−A)の化合物を任意選択でそれらの鏡像異性体および/またはジアステレオマーに分離する、かつ/または対応する(i)溶媒および/または(ii)塩基または酸と反応させてそれらの溶媒和物、塩および/またはその塩の溶媒和物を形成させること
を特徴とする、本発明による式(I)の化合物を調製するための方法である。
を不活性溶媒中、(VII)のカルボキシル官能基を活性化させて、
[C]最初に式(VIII)の化合物
を形成させ、次いで(XVIII)のエステル基−C(O)O−E3を、通常の方法で反応させて遊離カルボン酸(VII)を形成させることによって合成することができる。
・単一の薬物での治療と比較して、腫瘍の成長を遅延させる、そのサイズを縮小させる、さらにはそれを完全に排除する効能の改善;
・単剤療法より少ない用量での化学療法薬を使用する可能性;
・単一用量と比較して、有害作用をほとんど伴わない許容される治療の可能性;
・より広範な腫瘍の治療の可能性;
・治療に対するより高い応答率の達成;
・今日の標準的治療と比較して、より長い患者生存時間。
abs. 絶対
Ac アセチル
aq. 水性、水溶液
Boc tert−ブトキシカルボニル
br. 広幅(NMRにおいて)
Bsp. 実施例
ca. 約(circa、approx.)
CI 化学イオン化(MSにおいて)
d 二重線(NMRにおいて)
d 日
TLC 薄層クロマトグラフィー
DCI 直接化学イオン化(MSにおいて)
dd 二重線の二重線(NMRにおいて)
DMAP 4−N,N−ジメチルアミノピリジン
DME 1,2−ジメトキシエタン
DMF N,N−ジメチルホルムアミド
DMSO ジメチルスルホキシド
DPBS ダルベッコリン酸緩衝食塩水
dt 三重線の二重線(NMRにおいて)
theor. 理論値の
EDC N’−(3−ジメチルアミノプロピル)−N−エチルカルボジイミド塩酸塩
EI 電子衝突イオン化(MSにおいて)
eq. 当量
ESI エレクトロンスプレーイオン化(MSにおいて)
FCS ウシ胎仔血清
Fmoc (9H−フルオレン−9−イルメトキシ)カルボニル
GC−MS ガスクロマトグラフィー連結型質量分析
sat. 飽和(した)
GTP グアノシン5’−三リン酸
h 時間
HATU O−(7−アザベンゾトリアゾール−1−イル−N,N,N’,
N’−テトラメチルウロニウムヘキサフルオロホスフェート
HEPES 4−(2−ヒドロキシエチル)ピペラジン−1−エタンスルホン酸
HOAc 酢酸
HOBt 1−ヒドロキシ−1H−ベンゾトリアゾール水和物
HOSu N−ヒドロキシスクシンイミド
HPLC 高圧高速液体クロマトグラフィー
HR−MS 高分解能質量分析
conc. 濃縮(された)
LC−MS 液体クロマトグラフィー連結型質量分析
m 多重線(NMRにおいて)
min 分
MS 質量分析
MTBE メチル−tert−ブチルエーテル
MTT 3−(4,5−ジメチルチアゾール−2−イル)−2,5−ジフ
ェニル−2H−テトラゾリウムブロミド
NMM N−メチルモルホリン
NMP N−メチル−2−ピロリジノン
NMR 核磁気共鳴分析法
PBS リン酸緩衝食塩水
Pd/C 活性炭担持パラジウム
quant. 定量的(収率において)
quart 四重線(NMRにおいて)
quint 五重線(NMRにおいて)
Rf 保持指数(TLCにおいて)
RT 室温
Rt 保持時間(HPLCにおいて)
s 一重線(NMRにおいて)
t 三重線(NMRにおいて)
tert 第三
TFA トリフルオロ酢酸
THF テトラヒドロフラン
UV 紫外分光法
v/v 体積対体積比(溶液の)
Z ベンゾキシカルボニル
tog. 一緒に 。
方法1(LC−MS)
機器:Waters Acquity SQD UPLCシステム;カラム:Waters Acquity UPLC HSS T3 1.8μ 50mm×1mm;溶離液A:1リットル水+0.25mL 99%ギ酸;溶離液B:1リットル アセトニトリル+0.25mL 99%ギ酸;勾配:0.0min 90%A→1.2min 5%A→2.0min 5%A;流量:0.40mL/min;オーブン:50℃;UV検出:210〜400nm。
機器:Waters UPLC Acquityを備えたMicromass Quattro Premier;カラム:Thermo Hypersil GOLD 1.9μ 50mm×1mm;溶離液A:1リットル水+0.5mL 50%ギ酸;溶離液B:1リットル アセトニトリル+0.5mL 50%ギ酸;勾配:0.0min 90%A→0.1min 90%A→1.5min 10%A→2.2min 10%A;流量:0.33mL/min;オーブン:50℃;UV検出:210nm。
機器:HPLC Agilentシリーズ1100を備えたMicromass Quattro Micro MS;カラム:Thermo Hypersil GOLD 3μ 20mm×4mm;溶離液A:1リットル水+0.5mL 50%ギ酸;溶離液B:1リットル アセトニトリル+0.5mL 50%ギ酸;勾配:0.0min 100%A→3.0min 10%A→4.0min 10%A→4.01min 100%A(流量:2.5mL/min)→5.00min 100%A;オーブン:50℃;流量:2mL/min;UV検出:210nm。
機器タイプ MS:Micromass ZQ;機器タイプ HPLC:HP1100シリーズ;UV DAD;カラム:Phenomenex Gemini 3μ 30mm×3.00mm;溶離液A:1リットル水+0.5mL 50%ギ酸;溶離液B:1リットル アセトニトリル+0.5mL 50%ギ酸;勾配:0.0min 90%A→2.5min 30%A→3.0min 5%A→4.5min 5%A;流量:0.0min 1mL/min)→2.5min/3.0min/4.5min 2mL/min;オーブン:50℃;UV検出:210nm。
機器:HP1090シリーズII;カラム:Merck Chromolith Speed ROD RP−18e、50mm×4.6mm;プレカラム:Merck Chromolith guardカートリッジキットRP−18e、5mm×4.6mm;注入体積:5μL;溶離液A:水に70%HClO4(4mL/L);溶離液B:アセトニトリル;勾配:0.00min 20%B→4.00min 20%B;流量:5mL/min;カラム温度:40℃。
機器:DAD 996を備えたWaters 2695;カラム:Merck Chromolith Speed ROD RP−18e、50mm×4.6mm;プレカラム:Merck Chromolith GuardカートリッジキットRP−18c、5mm×4.6mm;溶離液A:水に70%HCLO4(4mL/L);溶離液B:アセトニトリル;勾配:0.00min 5%B→3.00min 95%B→4.00min 95%B;流量:5mL/min。
機器タイプ:Waters ZQ;機器タイプ HPLC:Agilent1100シリーズ;UV DAD;カラム:Thermo Hypersil GOLD 3μ 20mm×4mm;溶離液A:1リットル水+0.5mL 50%ギ酸;溶離液B:1リットル アセトニトリル+0.5mL 50%ギ酸;勾配:0.0min 100%A→3.0min 10%A→4.0min 10%A→4.1min 100%A(流量:2.5mL/min);オーブン:55℃;流量:2mL/min;UV検出:210nm。
機器タイプ MS:Waters ZQ;機器タイプ HPLC:Agilent1100シリーズ;UV DAD;カラム:Thermo Hypersil GOLD 3μ 20mm×4mm;溶離液A:1リットル水+0.5mL 50%ギ酸;溶離液B:1リットル アセトニトリル+0.5mL 50%ギ酸;勾配:0.0min 100%A→2.0min 60%A→2.3min 40%A→3.0min 20%A→4.0min 10%A→4.2min 100%A(流量:2.5mL/min);オーブン:55℃;流量:2mL/min;UV検出:210nm。
機器:Waters Acquity SQD UPLCシステム;カラム:Waters Acquity UPLC HSS T3 1.8μ 50mm×1mm;溶離液A:1リットル水+0.25mL 99%ギ酸;溶離液B:1リットル アセトニトリル+0.25mL 99%ギ酸;勾配:0.0min 95%A→6.0min 5%A→7.5min 5%A;オーブン:50℃;流量:0.35mL/min;UV検出:210〜400nm。
機器:Agilent 1200シリーズ;カラム:Agilent Eclipse XDB−C18 5μ 4.6mm×150mm;プレカラム:Phenomenex KrudKatcher型使い捨てプレカラム;注入体積:5μL;溶離液A:1リットル水+0.01%トリフルオロ酢酸;溶離液B:1リットル アセトニトリル;勾配:0.0min 10%B→1.00min 10%B→1.50min 90%B→5.5min 10%B;流量:2mL/min;カラム温度:30℃。
機器:Waters Acquity SQD UPLCシステム;カラム:Waters Acquity UPLC HSS T3 1.8μ 30mm×2mm;溶離液A:1リットル水+0.25mL 99%ギ酸;溶離液B:1リットル アセトニトリル+0.25mL 99%ギ酸;勾配:0.0min 90%A→1.2min 5%A→2.0min 5%A;流量:0.60mL/min;オーブン:50℃;UV検出:208〜400nm。
機器:Micromass GCT、GC 6890;カラム:Restek RTX−35、15m×200μm×0.33μm;一定流量のヘリウム:0.88mL/min;オーブン:70℃;入口:250℃;勾配:70℃、30℃/min→310℃(3min保持)。
機器:Thermo Scientific LTQ Orbitrap XL;FTMS ESIポジティブ 。
出発化合物1
(2R,3R)−3−[(2S)−1−(tert−ブトキシカルボニル)ピロリジン−2−イル]−3−メトキシ−2−メチルプロパン酸(Boc−ドラプロイン(Dolaproin))ジシクロヘキシルアミン塩
tert−ブチル−(3R,4S,5S)−3−メトキシ−5−メチル−4−(メチルアミノ)ヘプタノエート塩酸塩(ドライソロイシン(Dolaisoleucin)OtBu×HCl)
tert−ブチル−(3R,4S,5S)−4−[{N−[(ベンジルオキシ)カルボニル]−L−バリル}(メチル)アミノ]−3−メトキシ−5−メチルヘプタノエート
HPLC(方法5):Rt=2.5min;
LC−MS(方法1):Rt=1.45min;MS(ESIpos):m/z=493(M+H)+。
tert−ブチル−(3R,4S,5S)−3−メトキシ−5−メチル−4−[メチル(L−バリル)アミノ)ヘプタノエート
HPLC(方法5):Rt=1.59min;
LC−MS(方法1):Rt=0.74min;MS(ESIpos):m/z=359(M+H)+。
N−[(9H−フルオレン−9−イルメトキシ)カルボニル]−N−メチル−L−バリル−N−[(3R,4S,5S)−1−tert−ブトキシ−3−メトキシ−5−メチル−1−オキソヘプタン−4−イル]−N−メチル−L−バリンアミド
収量:660mg(理論値の68%)
HPLC(方法5):Rt=3.0min;
LC−MS(方法1):Rt=1.61min;MS(ESIpos):m/z=694(M+H)+。
N−[(9H−フルオレン−9−イルメトキシ)カルボニル]−N−メチル−L−バリル−N−[(2R,3S,4S)−1−カルボキシ−2−メトキシ−4−メチルヘキサン−3−イル]−N−メチル−L−バリンアミド
HPLC(方法5):Rt=2.4min;
LC−MS(方法2):Rt=1.51min;MS(ESIpos):m/z=638(M+H)+。
N−tert−ブトキシカルボニル)−N−メチル−L−バリル−N−[(2R,3S,4S)−1−カルボキシ−2−メトキシ−4−メチル−ヘキサン−3−イル]−N−メチル−L−バリンアミド
HPLC(方法6):Rt=2.2min;
LC−MS(方法2):Rt=1.32min;MS(ESIpos):m/z=516(M+H)+。
ベンジル−(2R,3S)−メトキシ−2−メチル−3−[(2S)−ピロリジン−2−イル]プロパノエートトリフルオロ酢酸塩
HPLC(方法5):Rt=1.5min;
LC−MS(方法1):Rt=0.59min;MS(ESIpos):m/z=278(M+H)+。
N−(tert−ブトキシカルボニル)−N−メチル−L−バリル−N−[(3R,4S,5S)−1−{(2S)−2−[(1R,2R)−2−カルボキシ−1−メトキシプロピル]ピロリジン−1−イル}−3−メトキシ−5−メチル−1−オキソヘプタン−4−イル]−N−メチル−L−バリンアミド
LC−MS(方法1):Rt=1.56min;MS(ESIpos):m/z=775(M+H)+。
HPLC(方法5):Rt=2.1min;
LC−MS(方法1):Rt=1.24min;MS(ESIpos):m/z=685(M+H)+。
Nα−(tert−ブトキシカルボニル)−N−メトキシ−N−メチル−L−フェニルアラニンアミド
LC−MS(方法1):Rt=1.02min;MS(ESIpos):m/z=309(M+H)+。
tert−ブチル−[(2S)−1−オキソ−3−フェニルプロパン−2−イル]カルバメート
GC−MS(方法12):Rt=5.61mm;MS(ESIpos):m/z=220(M−29)+
1H−NMR(500MHz, DMSO−d6): δ [ppm]=1.15−1.42(m, 9H), 7.11−7.39(m, 5H), 9.52(s, 1H)[追加的なシグナルは溶媒ピークの下に隠れた]
中間体10
(2S,3Z)−1,5−ジフェニルペンタ−3−エン−2−アミントリフルオロ酢酸塩
1H−NMR(400MHz, DMSO−d6): δ [ppm]=1.16−1.46(m, 9H), 2.62(dd, J=13.20Hz, 7.34Hz, 1H), 2.73−3.18(m, 1H), 4.56(t, J=7.46Hz, 1H), 5.27−5.57(m, 1H), 6.98−7.32(m, 10H)[追加的なシグナルは溶媒ピークの下に隠れた]。
LC−MS(方法1):Rt=0.74min;MS(ESIpos):m/z=238(M+H)+。
1H−NMR(400MHz, DMSO−d6): δ [ppm]=2.64−2.83(m, 1H), 2.88−3.22(m, 2H), 4.00−4.55(m, 1H), 5.16−5.46(m, 1H), 5.48−5.78(m, 1H), 6.60−6.89(m, 2H), 7.14(s, 3H), 7.22−7.36(m, 5H), 7.89−8.27(m, 2H).
中間体11
(2S)−1−(ベンジルスルホニル)−3−フェニルプロパン−2−アミン
HPLC(方法10):Rt=2.63min;
LC−MS(方法1):Rt=0.67min;MS(ESIpos):m/z=258(M+H)+。
HPLC(方法10):Rt=2.40min;
LC−MS(方法1):Rt=0.65min;MS(ESIpos):m/z=290(M+H)+。
(2S,3Z)−1,4−ジフェニルブタ−3−エン−2−アミン
HPLC(方法10):Rt=2.46min;
LC−MS(方法1):Rt=0.75min;MS(ESIpos):m/z=224(M+H)+。
1H−NMR(400MHz, DMSO−d6): δ [ppm]=2.71(d, J=6.60Hz, 2H), 3.73−3.95(m, 1H), 5.42−5.67(m, 1H), 6.21−6.50(m, 1H), 7.08−7.38(m, 10H)[追加的なシグナルは溶媒ピークの下に隠れた]。
(2S,3E)−1,4−ジフェニルブタ−3−エン−2−アミン
1H−NMR(400MHz, DMSO−d6): δ [ppm]=2.62−2.83(m, 2H), 3.52−3.71(m, 1H), 6.18−6.30(m, 1H), 6.34−6.46(m, 1H), 6.98−7.57(m, 10H)[追加的なシグナルは溶媒ピークの下に隠れた]。
(1S)−2−フェニル−1−(5−フェニル−1,3,4−オキサジアゾール−2−イル)エタンアミントリフルオロ酢酸塩
HPLC(方法10):Rt=3.01min;
LC−MS(方法1):Rt=1.15min;MS(ESIpos):m/z=366(M+H)+。
HPLC(方法10):Rt=2.43min;
LC−MS(方法1):Rt=0.62min;MS(ESIpos):m/z=266(M+H)+。
(1R)−2−フェニル−1−(5−フェニル−1,3,4−オキサジアゾール−2−イル)エタンアミントリフルオロ酢酸塩
HPLC(方法10):Rt=3.01min;
LC−MS(方法2):Rt=1.36min;MS(ESIpos):m/z=366(M+H)+。
HPLC(方法10):Rt=2.41min。
メチル−4−[(1E,3S)−3−アミノ−4−フェニルブタ−1−エン−1−イル)ベンゾエートトリフルオロ酢酸塩
HPLC(方法10):Rt=3.23min;
LC−MS(方法11):Rt=1.32min;MS(ESIpos):m/z=382(M+H)+。
N−メチル−L−バリル−N−[(3R,4S,5S)−1−{(2S)−2−[(1R,2R)−3−{[(2S,3Z)−1,5−ジフェニルペンタ−3−エン−2−イル]アミノ}−1−メトキシ−2−メチル−3−オキソプロピル]ピロリジン−1−イル}−3−メトキシ−5−メチル−1−オキソヘプタン−4−イル]−N−メチル−L−バリンアミドトリフルオロ酢酸塩
HPLC(方法10):Rt=4.74min;
LC−MS(方法11):Rt=1.58min;MS(ESIpos):m/z=905(M+H)+。
HPLC(方法10):Rt=2.66min;
LC−MS(方法1):Rt=1.03min;MS(ESIpos):m/z=805(M+H)+。
N−メチル−L−バリル−N−[(3R,4S,5S)−1−{(2S)−2−[(1R,2R)−3−{[(2S,3Z)−1,4−ジフェニルブタ−3−エン−2−イル]アミノ}−1−メトキシ−2−メチル−3−オキソプロピル]ピロリジン−1−イル}−3−メトキシ−5−メチル−1−オキソヘプタン−4−イル]−N−メチル−L−バリンアミドトリフルオロ酢酸塩
収量:9.2mg(理論値の35%)
HPLC(方法10):Rt=4.52min;
LC−MS(方法1):Rt=1.54min;MS(ESIpos):m/z=891(M+H)+。
HPLC(方法10):Rt=2.58min;
LC−MS(方法1):Rt=0.97min;MS(ESIpos):m/z=791(M+H)+。
N−メチル−L−バリル−N−[(3R,4S,5S)−1−{(2S)−2−[(1R,2R)−3−{[(2S,3E)−1,4−ジフェニルブタ−3−エン−2−イル]アミノ}−1−メトキシ−2−メチル−3−オキソプロピル]ピロリジン−1−イル}−3−メトキシ−5−メチル−1−オキソヘプタン−4−イル]−N−メチル−L−バリンアミドトリフルオロ酢酸塩
収量:15.1mg(理論値の58%)
HPLC(方法10):Rt=4.2min;
LC−MS(方法1):Rt=1.51min;MS(ESIpos):m/z=891(M+H)+。
HPLC(方法10):Rt=2.62min;
LC−MS(方法1):Rt=0.97min;MS(ESIpos):m/z=791(M+H)+。
N−メチル−L−バリル−N−[(3R,4S,5S)−1−{(2S)−2−[(1R,2R)−3−{[(2S)−1−ベンジルスルホニル)−3−フェニルプロパン−2−イル]アミノ}−1−メトキシ−2−メチル−3−オキソプロピル]ピロリジン−1−イル}−3−メトキシ−5−メチル−1−オキソヘプタン−4−イル]−N−メチル−L−バリンアミドトリフルオロ酢酸塩
収量:19.2mg(理論値の68%)
HPLC(方法10):Rt=3.5min;
LC−MS(方法1):Rt=1.41min;MS(ESIpos):m/z=957(M+H)+。
HPLC(方法10):Rt=2.52min;
LC−MS(方法1):Rt=0.86min;MS(ESIpos):m/z=857(M+H)+。
N−メチル−L−バリル−N−[(3R,4S,5S)−3−メトキシ−1−{(2S)−2−[(1R,2R)−1−メトキシ−2−メチル−3−オキソ−3−{[(1S)−2−フェニル−1−(5−フェニル−1,3,4−オキサジアゾール−2−イル)エチル]アミノ}プロピル]ピロリジン−1−イル}−5−メチル−1−オキソヘプタン−4−イル]−N−メチル−L−バリンアミドトリフルオロ酢酸塩
収量:22mg(理論値の81%)
HPLC(方法10):Rt=3.74min;
LC−MS(方法1):Rt=1.45min;MS(ESIpos):m/z=933(M+H)+。
HPLC(方法10):Rt=2.52min;
LC−MS(方法1):Rt=0.85min;MS(ESIpos):m/z=833(M+H)+。
N−メチル−L−バリル−N−[(3R,4S,5S)−3−メトキシ−1−{(2S)−2−[(1R,2R)−1−メトキシ−2−メチル−3−オキソ−3−{[(1R)−2−フェニル−1−(5−フェニル−1,3,4−オキサジアゾール−2−イル)エチル]アミノ}プロピル]ピロリジン−1−イル}−5−メチル−1−オキソヘプタン−4−イル]−N−メチル−L−バリンアミドトリフルオロ酢酸塩
収量:17mg(理論値の64%)
HPLC(方法10):Rt=3.74min;
LC−MS(方法1):Rt=1.45min;MS(ESIpos):m/z=933(M+H)+。
HPLC(方法10):Rt=2.55min;
LC−MS(方法11):Rt=0.85min;MS(ESIpos):m/z=833(M+H)+。
N−メチル−L−バリル−N−[(3R,4S,5S)−3−メトキシ−1−{(2S)−2−[(1R,2R)−1−メトキシ−3−{[(2S,3E)−4−[4−(メトキシカルボニル)フェニル]−1−フェニルブタ−3−エン−2−イル}アミノ)−2−メチル−3−オキソプロピル]ピロリジン−1−イル}−5−メチル−1−オキソヘプタン−4−イル]−N−メチル−L−バリンアミドトリフルオロ酢酸塩
収量:8.8mg(理論値の32%)
LC−MS(方法1):Rt=1.53min;MS(ESIpos):m/z=949(M+H)+。
LC−MS(方法1):Rt=1.00min;MS(ESIpos):m/z=849(M+H)+。
N−メチル−L−バリル−N−[(3R,4S,5S)−1−{(2S)−2−[(1R,2R)−3−{[2−(1H−インドール−3−イル)エチル]アミノ}−1−メトキシ−2−メチル−3−オキソプロピル]ピロリジン−1−イル}−3−メトキシ−5−メチル−1−オキソヘプタン−4−イル]−N−メチル−L−バリンアミドトリフルオロ酢酸塩
LC−MS(方法1):Rt=1.32min;m/z=828(M+H)+。
LC−MS(方法1):Rt=0.84min;MS(ESIpos):m/z=728(M+H)+。
N−メチル−L−バリル−N−[(3R,4S,5S)−1−{(2S)−2−[(1R,2R)−1−メトキシ−2−メチル−3−オキソ−3−[(2−フェニルエチル)アミノ]プロピル}ピロリジン−1−イル]−5−メチル−1−オキソヘプタン−4−イル}−N−メチル−L−バリンアミドトリフルオロ酢酸塩
HPLC(方法5):Rt=2.71min;
LC−MS(方法1):Rt=0.80min;MS(ESIpos):m/z=689(M+H)+。
(実施例1)
N−(3−カルボキシプロピル)−N−メチル−L−バリル−N−[(3R,4S,5S)−1−{(2S)−2−[(1R,2R)−3−{[(2S,3Z)−1,5−ジフェニルペンタ−3−エン−2−イル]アミノ}−1−メトキシ−2−メチル−3−オキソプロピル]ピロリジン−1−イル}−3−メトキシ−5−メチル−1−オキソヘプタン−4−イル]−N−メチル−L−バリンアミド
HPLC(方法10):Rt=2.63min;
LC−MS(方法1):Rt=1.01min;MS(ESIpos):m/z=891(M+H)+。
N−(3−カルボキシプロピル)−N−メチル−L−バリル−N−[(3R,4S,5S)−1−{(2S)−2−[(1R,2R)−3−{[(2S,3Z)−1,4−ジフェニルブタ−3−エン−2−イル]アミノ}−1−メトキシ−2−メチル−3−オキソプロピル]ピロリジン−1−イル}−3−メトキシ−5−メチル−1−オキソヘプタン−4−イル]−N−メチル−L−バリンアミド
HPLC(方法10):Rt=2.61min;
LC−MS(方法11):Rt=0.94min;MS(ESIpos):m/z=877(M+H)+。
HR−MS(方法13):m/z=876.5。
N−(3−カルボキシプロピル)−N−メチル−L−バリル−N−[(3R,4S,5S)−1−{(2S)−2−[(1R,2R)−3−{[(2S,3E)−1,4−ジフェニルブタ−3−エン−2−イル]アミノ}−1−メトキシ−2−メチル−3−オキソプロピル]ピロリジン−1−イル}−3−メトキシ−5−メチル−1−オキソヘプタン−4−イル]−N−メチル−L−バリンアミド
HPLC(方法10):Rt=2.59min;
LC−MS(方法11):Rt=0.94min;MS(ESIpos):m/z=877(M+H)+。
HR−MS(方法13):m/z=876.6;
1H−NMR(500MHz, ジクロロメタン−d2): δ [ppm]=0.72−1.21(m, 18H), 1.23−1.47(m, 3H), 1.51−2.22(m, 8H), 2.25−2.54(m, 5H), 2.65−2.86(m, 2H), 2.90−3.47(m, 16H), 3.53−4.46(m, 6H), 4.71−5.27(m, 4H), 5.46−5.72(m, 1H), 6.10−6.36(m, 1H), 6.44−6.67(m, 2H), 7.03−7.67(m, 10H), 9.13(br. s, 1H) 。
N−(3−カルボキシプロピル)−N−メチル−L−バリル−N−[(3R,4S,5S)−1−{(2S)−2−[(1R,2R)−3−{[(2S)−1−(ベンジルスルファニル)−3−フェニルプロパン−2−イル]アミノ}−1−メトキシ−2−メチル−3−オキソプロピル]ピロリジン−1−イル}−3−メトキシ−5−メチル−1−オキソヘプタン−4−イル]−N−メチル−L−バリンアミド
LC−MS(方法11):Rt=0.85min;MS(ESIpos):m/z=943(M+H)+。
HR−MS(方法13):m/z=942.6;
1H−NMR(500MHz, ジクロロメタン−d2): δ [ppm]=0.72−1.23(m, 18H), 1.26−1.56(m, 2H), 1.60−1.94(m, 4H), 1.95−2.17(m, 3H), 2.22−2.54(m, 5H), 2.69−2.87(m, 2H), 2.90−3.27(m, 11H), 3.31−3.53(m, 8H), 3.58−4.20(m, 7H), 4.25−4.54(m, 3H), 4.59−5.15(m, 4H), 6.22(br. s, 1H), 6.97−8.00(m, 10H), 9.13(br. s, 1H) 。
N−(3−カルボキシプロピル)−N−メチル−L−バリル−N−[(3R,4S,5S)−3−メトキシ−1−{(2S)−2−[(1R,2R)−1−メトキシ−2−メチル−3−オキソ−3−{[(1S)−2−フェニル−1−(5−フェニル−1,3,4−オキサジアゾール−2−イル)エチル]アミノ}プロピル]ピロリジン−1−イル}−5−メチル−1−オキソヘプタン−4−イル]−N−メチル−L−バリンアミド
HPLC(方法10):Rt=2.54min;
LC−MS(方法1):Rt=0.94min;MS(ESIpos):m/z=919(M+H)+。
HR−MS(方法13):m/z=918.6;
1H−NMR(500MHz, ジクロロメタン−d2): δ [ppm]=0.58−1.21(m, 20H), 1.25−1.52(m, 2H), 1.62−2.19(m, 8H), 2.28−2.50(m, 5H), 2.64−2.84(m, 2H), 2.89−3.16(m, 6H), 3.19−3.52(m, 10H), 3.59−4.00(m, 4H), 4.02−4.40(m, 3H), 4.66−5.13(m, 3H), 5.61(d, 1H), 7.32(d, 5H), 7.49−7.69(m, 3H), 7.93−8.16(m, 2H), 9.07(br. s, 1H) 。
N−(3−カルボキシプロピル)−N−メチル−L−バリル−N−[(3R,4S,5S)−3−メトキシ−1−{(2S)−2−[(1R,2R)−1−メトキシ−2−メチル−3−オキソ−3−{[(1R)−2−フェニル−1−(5−フェニル−1,3,4−オキサジアゾール−2−イル)エチル]アミノ}プロピル]ピロリジン−1−イル}−5−メチル−1−オキソヘプタン−4−イル]−N−メチル−L−バリンアミド
HPLC(方法10):Rt=2.54min;
LC−MS(方法1):Rt=0.92min;MS(ESIpos):m/z=919(M+H)+。
N−(3−カルボキシプロピル)−N−メチル−L−バリル−N−[(3R,4S,5S)−1−{(2S)−2−[(1R,2R)−3−{[2−(1H−インドール−3−イル)エチル]アミノ}−1−メトキシ−2−メチル−3−オキソプロピル]ピロリジン−1−イル}−3−メトキシ−5−メチル−1−オキソヘプタン−4−イル]−N−メチル−L−バリンアミド
収量:50mg(理論値の49%)
LC−MS(方法1):Rt=0.87min;MS(ESIpos):m/z=814(M+H)+。
N−(3−カルボキシプロピル)−N−メチル−L−バリル−N−[(3R,4S,5S)−3−メトキシ−1−{(2S)−2−[(1R,2R)−1−メトキシ−2−メチル−3−オキソ−3−[(2−フェニルエチル)アミノ]プロピル}ピロリジン−1−イル}−5−メチル−1−オキソヘプタン−4−イル]−N−メチル−L−バリンアミド
収量:10mg(理論値の19%)
LC−MS(方法1):Rt=0.85min;MS(ESIpos):m/z=775(M+H)+。
N−(3−カルボキシプロピル)−N−メチル−L−バリル−N−[(3R,4S,5S)−1−{(2S)−2−[(1R,2R)−3−{[(1S,2R)−1−ヒドロキシ−1−フェニルプロパン−2−イル]アミノ}−1−メトキシ−2−メチル−3−オキソプロピル]ピロリジン−1−イル}−3−メトキシ−5−メチル−1−オキソヘプタン−4−イル]−N−メチル−L−バリンアミド
収量:94mg(理論値の84%)
LC−MS(方法1):Rt=0.79min;MS(ESIpos):m/z=805(M+H)+。
N−(3−カルボキシプロピル)−N−メチル−L−バリル−N−[(3R,4S,5S)−3−メトキシ−1−{(2S)−2−[(1R,2R)−1−メトキシ−3−({(2S,3E)−4−[4−(メトキシカルボニル)フェニル]−1−フェニルブタ−3−エン−2−イル}アミノ)−2−メチル−3−オキソプロピル]ピロリジン−1−イル}−5−メチル−1−オキソヘプタン−4−イル]−N−メチル−L−バリンアミド
収量:33.9mg(理論値の78%)
LC−MS(方法1):Rt=1.02min;MS(ESIpos):m/z=933(M+H)+。
N−(3−カルボキシプロピル)−N−メチル−L−バリル−N−[(3R,4S,5S)−1{(2S)−2−[(1R,2R)−3−{[2S,3E)−4−(4−カルボキシフェニル)−1−フェニルブタ−3−エン−2−イル]アミノ}−1−メトキシ−2−メチル−3−オキソプロピル]ピロリジン−1−イル}−3−メトキシ−5−メチル−1−オキソヘプタン−4−イル]−N−メチル−L−バリンアミド
LC−MS(方法9):Rt=4.98min;MS(ESIpos):m/z=919(M+H)+。
本発明による化合物の生物学的活性は、当業者に知られているものなどのインビトロおよびインビボでの試験で実証することができる。例えば、化合物の薬理学的および薬物動態的特性は、以下で説明するアッセイの助けを得て本発明にしたがって測定することができる。
規定の細胞数のヒト結腸癌腫細胞系HT29wt(野生型)を、96ウェルマイクロタイタープレート中で完全培地(10%FCS−RPMI)(2500細胞/ウェル)に播種し、37℃/5%CO2で終夜インキュベートした。18時間後、播種培地を、10%FCSを含む新鮮培地で置き換えた。それぞれのテスト物質を加えて処理を開始させた。試験する物質について、10−5M〜10−14Mの範囲の濃度(1:10希釈系列)で用量効果曲線を決定した。48h〜96hのインキュベーション時間を選択した。増殖を、MTTアッセイ(ATCC、Manassas、Virginia、USA、カタログ番号30−1010K)の助けを得て検出した。選択したインキュベーション時間が終了した後、MTT試薬を細胞とともに4hインキュベートし、次いで洗浄剤を加えて細胞の溶解を終夜かけて実施した。形成された色素を570nmで検出した。テスト物質を含まないこと以外は同様に処理した細胞での増殖を100%値と規定した。このテストで得られたデータは3連の測定値を表し、少なくとも2つの独立した実験を実施した。
がん細胞は、細胞分裂の増大によって腫瘍の成長をしばしばもたらす変性または新生細胞である。微小管は、紡錘体装置の紡錘糸を形成するものであり、細胞周期の必須構成要素である。微小管の制御された構築および破壊は娘細胞への染色体の正確な分配を可能にし、これは連続的な動的過程を示す。これらの動力学における混乱は不完全な細胞分裂をもたらし、最終的に細胞死をもたらす。しかし、がん細胞の細胞分裂の増大は、それらを、化学療法の固定成分である紡錘糸毒(Spindelfasergift)の影響を特に受け易くする。パクリタキセルまたはエポチロンなどの紡錘糸毒は微小管の重合速度の著しい増大をもたらすが、ビンカアルカロイドまたはモノメチルオーリスタチンE(MMAE)は微小管の重合速度の著しい低下をもたらことになる。どちらの場合でも、細胞周期の必要な動力学は混乱に対して敏感である。本発明の関連で検討する化合物は、微小管の重合速度の低下をもたらす。
方法A:
それぞれのテスト物質1mgを0.5mLアセトニトリル/DMSO(9:1)に溶解した。この溶液20μLを取り出し、37℃で1mLのラット血漿およびヒト血漿(Liヘパリンを含む雄性ウィスター系ラットの血漿、Harlan & Winkelmannおよび/または全血標本からの新鮮なヒト白血球除去血漿)に加えた。標本を加えた直後(参照変数としての初期値)、次いで5、10、30、60、120、180および240分後に、また任意選択で24時間後にも、100μLのアリコートを取り、300μLアセトニトリルに加えた。沈澱した血漿タンパク質を5000rpmで10分間遠心分離にかけ、次いで30μLの上清をHPLCで分析してその未変化テスト物質含量を測定した。結果を、対応するピークの面積パーセントをもとにして定量化した。
機器:DAD、バイナリポンプ、オートサンプラー、カラムオーブンおよびサーモスタットを備えたAgilent1200;カラム:Kromasil100 C18、250mm×4mm、5μm;カラム温度:45℃;溶離液A:5mL過塩素酸/L水;溶離液B:アセトニトリル;勾配:0〜8min 98%A、2%B:8〜15min 56%A、44%B;15〜20min 10%A、90%B;20〜21min 10%A、90%B;21〜23min 98%A、2%B;23〜25min 98%A、2%B;流量:2mL/min;UV検出:220nm。
機器:DAD、バイナリポンプ、オートサンプラー、カラムオーブンおよびサーモスタットを備えたAgilent1100;カラム:Kromasil100 C18、250mm×4mm、5μm;カラム温度:45℃;溶離液A:5mL過塩素酸/L水;溶離液B:アセトニトリル;勾配:0〜3min 98%A、2%B;3〜10min 65%A、35%B;10〜15min 40%A、60%B;15〜21min 10%A、90%B;21〜22min 10%A、90%B;22〜24min 98%A、2%B;24〜26min 98%A、2%B;流量2mL/min;UV検出:220nm。
それぞれのテスト物質をラット血漿および/またはヒト血漿中で、かるく撹拌しながら37℃で5hインキュベートした。種々の時間点(0、2、5、10、20、30、60、120、180および300分間)で、100μLのアリコートを取った。内部標準(10μL)を加えた後、200μLのアセトニトリルを加えてタンパク質を沈澱させ、混合物をエッペンドルフ型遠心分離機で5分間遠心分離にかけた。150μL酢酸アンモニウム緩衝液、pH3を150μLの上清に加えた後、未変化テスト物質含量をLC/MSMSで分析した。
物質の細胞透過性は、Caco−2細胞を用いたフラックスアッセイで、インビトロでテストすることによって分析することができる[M.D.Troutman and D.R.Thakker、Pharm.Res.20巻(8号)、1210〜1224頁(2003年)]。そうするために、細胞を24穴フィルタープレート上で15〜16日間培養した。透過を測定するために、それぞれのテスト物質をHEPES緩衝液中で、頂端部(A)または基底部(B)で細胞に添加し、2hインキュベートした。0hおよび2h後に、シス位およびトランス位の区画からサンプルを採取した。サンプルを、逆相カラムを用いてHPLC(Agilent1200、Boeblingen、Germany)で分離した。HPLCシステムを、ターボイオンスプレーインターフェースを介してAPI4000三連四重極質量分析計(Applied Biosystems Applera、Darmstadt、Germany)に連結した。透過性を、Schwabら[D.Schwabら、J.Med.Chem.46巻、1717〜1725頁(2003年)]によって公開されている式を用いて計算したPapp値をもとにして評価した。Papp(B−A) 対 Papp(A−B)の比が2超または0.5未満であった場合、その物質を、能動的に輸送されていると分類した。
多くの腫瘍細胞は、しばしば細胞増殖抑制剤に対する耐性の進行と関係する、活性な成分および薬物のためのトランスポータータンパク質を発現する。したがって、P−糖タンパク質(P−gp)またはBCRPなどのそうしたトランスポータータンパク質の基質ではない物質は、改善された効果プロファイルを有する可能性がある。
本発明による化合物は、以下の方法で医薬調製物に転換させることができる:
錠剤:
組成:
100mgの本発明による化合物、50mgラクトース(一水和物)、50mgトウモロコシデンプン(未変性)、10mgポリビニルピロリドン(PVP25)(BASF、Ludwigshafen、Germany)および2mgステアリン酸マグネシウム
錠剤重量212mg;直径8mm;曲率半径12mm。
本発明による化合物、ラクトースおよびデンプンの混合物をPVPの5%水溶液(w/w)で顆粒化する。乾燥した後、顆粒をステアリン酸マグネシウムと5分間混合する。この混合物を慣用的な錠剤プレス(錠剤の形式については上記を参照)で圧縮する。15kNの圧縮力を、錠剤を圧縮するための指針値として用いた。
組成:
1000mgの本発明による化合物、1000mgエタノール(96%)、400mg Rhodigel(登録商標)(FMC、Pennsylvania、USAからのキサンタンガム)および99g水。
組成:
500mgの本発明による化合物、2.5gポリソルベートおよび97gポリエチレングリコール400。20gの経口液剤は100mgの本発明による化合物の単一用量に相当する。
本発明による化合物を、撹拌しながら、ポリエチレングリコールとポリソルベートの混合液中に懸濁させる。撹拌プロセスを、本発明による化合物が完全に溶解するまで続行する。
本発明による化合物を、飽和溶解度未満の濃度で生理学的に許容される溶媒(例えば、等張食塩水、グルコース溶液5%および/またはPEG400溶液30%)に溶解させる。この溶液を滅菌ろ過し、滅菌したパイロジェンフリーの注射用バイアルに瓶詰する。
Claims (11)
- 式(I):
Lは、メチルで最大で4回置換されていてよく、かつその中で(a)2個の炭素原子が互いに1,2−、1,3−もしくは1,4−の関係で、任意選択でそれらの間に炭素原子を含むことによって橋掛けされて(C3〜C6)−シクロアルキル環またはフェニル環を形成していてよい、あるいは(b)互いに近接していない最大で3つのCH2基が−O−で置き換えられていてよい直鎖状(C1〜C12)−アルカンジイルを表し、かつ
Tは、式:
*は窒素原子との結合部位を示し、
R1はフェニルまたは1H−インドール−3−イルを表し、
R2は水素または式:
**はそれぞれの基Tの基とのそれぞれの結合部位を示し、
Aは直鎖状(C1〜C4)−アルカンジイルまたは直鎖状(C2〜C4)−アルケンジイルを表し、
R3は(C1〜C4)−アルコキシカルボニルまたはカルボキシルで置換されていてよいフェニルを表し、
nは0、1または2の数を表し、
R4は、フェニル基において(C1〜C4)−アルコキシカルボニルまたはカルボキシルで置換されていてよいフェニル、ベンジルまたは2−フェニルエチルを表し、
Hetは、N、Oおよび/またはSのシリーズからの最大で3個の環ヘテロ原子を有する二価5員ヘテロアリール環を表し、かつ
R5は、フェニルで置換されていてよい(C3〜C6)−シクロアルキル、フェニルまたは(C1〜C4)−アルキルを表し、ここで、前記フェニル基は、次に(C1〜C4)−アルコキシカルボニルまたはカルボキシルで置換されていてよい、
化合物ならびにそれらの塩および溶媒和物、および前記塩の溶媒和物。 - Lが、(a)2個の炭素原子が互いに1,3−もしくは1,4−の関係で、それらの間に炭素原子の1個もしくは2個を含むことによって橋掛けされてフェニル環を形成していてよい、あるいは(b)互いに近接していない最大で2つのCH2基が−O−で置き換えられていてよい直鎖状(C1〜C8)−アルカンジイルを表し、かつ
Tが、式:
*は窒素原子との結合部位を示し、
R1はフェニルまたは1H−インドール−3−イルを示し、かつ
R2は水素または式:
**はそれぞれの基Tの基との結合部位を示し、
Aはエテン−1,2−ジイルまたはプロペン−1,3−ジイルを示し、
R3は(C1〜C4)−アルコキシカルボニルまたはカルボキシルで置換されていてよいフェニルを表し、
Hetはピラゾリル、イミダゾリル、1,3−オキサゾリル、1,3−チアゾリル、1,2,4−オキサジアゾリルおよび1,3,4−オキサジアゾリルのシリーズから選択される二価5員ヘテロアリール環であり、かつ
R5は(C1〜C4)−アルコキシカルボニルまたはカルボキシルで置換されていてよいフェニルを表す、
請求項に1記載の式(I)の化合物ならびにそれらの塩および溶媒和物、および前記塩の溶媒和物。 - 請求項1から3に記載の式(I)の化合物を調製するための方法であって、
式(II)の化合物:
を不活性溶媒中で、以下
[A]塩基誘発アルキル化によって、式(III)の化合物:
E1は水素、(C1〜C4)−アルキルまたはベンジルを表し、かつ
Xはクロリド、ブロミド、ヨージド、メシレート、トリフレートまたはトシレートなどの離脱基を表す)
と反応させて式(IV)の化合物:
を形成し、次いでE1が(C1〜C4)−アルキルまたはベンジルを表す場合、このエステル基を従来の方法で分割し、それによって、式(III)のE1が水素を表す場合のような式(I)のカルボン酸
を得るか、あるいは、
[B]適切な還元剤の存在下で式(V)の化合物:
LAは請求項1から3で示したLの意味を有するが、アルキル鎖長において1つのCH2単位だけ短縮されている)
と反応させて式(VI)の化合物:
に転換させ、次いでE1が(C1〜C4)−アルキルまたはベンジルを表す場合、このエステル基を従来の方法で分割し、それによって、式(V)のE1が水素を表す場合のような式(I−A)のカルボン酸:
を得、
得られた式(I)および/または(I−A)の化合物を任意選択でそれらの鏡像異性体および/またはジアステレオマーに分離する、かつ/または対応する(i)溶媒および/または(ii)塩基または酸と反応させてそれらの溶媒和物、塩および/または前記塩の溶媒和物を形成させることを特徴とする、方法。 - 疾患の治療および/または予防のための、請求項1から3に記載の化合物。
- がんおよび腫瘍状態の治療および/または予防の方法において使用するための、請求項1から3に記載の化合物。
- がんおよび腫瘍状態の治療および/または予防のための医薬品を調製するための、請求項1から3のいずれか一項に記載の化合物の使用。
- 1つまたは複数の不活性で非毒性の薬学的に適切な賦形剤と組み合わせて、請求項1から3のいずれか一項に記載の化合物を含む医薬品。
- 1つまたは複数の追加の活性成分と組み合わせて、請求項1から3のいずれか一項に記載の化合物を含む医薬品。
- がんおよび腫瘍状態の治療および/または予防のための、請求項8または9に記載の医薬品。
- 活性量の請求項1から3のいずれか一項に記載の少なくとも1つの化合物または請求項8から10のいずれか一項に記載の医薬品を用いる、ヒトおよび動物におけるがんおよび腫瘍状態の治療および/または予防のための方法。
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JP2007514652A (ja) * | 2003-11-06 | 2007-06-07 | シアトル ジェネティックス, インコーポレイテッド | リガンドに結合体化可能なモノメチルバリン化合物 |
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JP2014512375A (ja) * | 2011-04-21 | 2014-05-22 | シアトル ジェネティックス, インコーポレイテッド | 新規な結合剤−薬物複合体(adc)およびそれらの使用 |
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JP2016175941A (ja) * | 2011-04-21 | 2016-10-06 | シアトル ジェネティックス, インコーポレイテッド | 新規な結合剤−薬物複合体(adc)およびそれらの使用 |
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HK1191034A1 (en) | 2014-07-18 |
CN103764667A (zh) | 2014-04-30 |
US9029406B2 (en) | 2015-05-12 |
CA2829736A1 (en) | 2012-09-20 |
CA2829736C (en) | 2020-07-21 |
JP2016185987A (ja) | 2016-10-27 |
CN103764667B (zh) | 2017-06-20 |
WO2012123423A1 (de) | 2012-09-20 |
ES2543888T3 (es) | 2015-08-25 |
EP2686336A1 (de) | 2014-01-22 |
JP6023097B2 (ja) | 2016-11-09 |
US20140080763A1 (en) | 2014-03-20 |
EP2686336B1 (de) | 2015-05-06 |
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