ES2883023T3 - Derivados de péptidos de dolaproína-dolaisoleuina citotóxicos para el tratamiento del cáncer - Google Patents
Derivados de péptidos de dolaproína-dolaisoleuina citotóxicos para el tratamiento del cáncer Download PDFInfo
- Publication number
- ES2883023T3 ES2883023T3 ES15799069T ES15799069T ES2883023T3 ES 2883023 T3 ES2883023 T3 ES 2883023T3 ES 15799069 T ES15799069 T ES 15799069T ES 15799069 T ES15799069 T ES 15799069T ES 2883023 T3 ES2883023 T3 ES 2883023T3
- Authority
- ES
- Spain
- Prior art keywords
- methyl
- methoxy
- alkyl
- methylbutanamido
- amino
- 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.)
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- 206010028980 Neoplasm Diseases 0.000 title claims description 31
- 201000011510 cancer Diseases 0.000 title claims description 27
- 108090000765 processed proteins & peptides Proteins 0.000 title description 7
- 230000001472 cytotoxic effect Effects 0.000 title description 4
- 231100000433 cytotoxic Toxicity 0.000 title description 3
- 150000001875 compounds Chemical class 0.000 claims abstract description 189
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 82
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 40
- 150000003839 salts Chemical class 0.000 claims abstract description 38
- 125000000623 heterocyclic group Chemical group 0.000 claims abstract description 29
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims abstract description 27
- 125000003342 alkenyl group Chemical group 0.000 claims abstract description 22
- 125000000304 alkynyl group Chemical group 0.000 claims abstract description 22
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims abstract description 20
- 125000000592 heterocycloalkyl group Chemical group 0.000 claims abstract description 10
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 claims abstract description 5
- 238000000034 method Methods 0.000 claims description 130
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 92
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 88
- -1 azidomethyl Chemical group 0.000 claims description 64
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 49
- RUZLIIJDZBWWSA-INIZCTEOSA-N methyl 2-[[(1s)-1-(7-methyl-2-morpholin-4-yl-4-oxopyrido[1,2-a]pyrimidin-9-yl)ethyl]amino]benzoate Chemical group COC(=O)C1=CC=CC=C1N[C@@H](C)C1=CC(C)=CN2C(=O)C=C(N3CCOCC3)N=C12 RUZLIIJDZBWWSA-INIZCTEOSA-N 0.000 claims description 38
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 29
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 20
- 239000002253 acid Substances 0.000 claims description 14
- 239000008194 pharmaceutical composition Substances 0.000 claims description 14
- 125000003831 tetrazolyl group Chemical group 0.000 claims description 8
- 125000000335 thiazolyl group Chemical group 0.000 claims description 8
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 5
- 125000004076 pyridyl group Chemical group 0.000 claims description 5
- 125000004214 1-pyrrolidinyl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 claims description 4
- 229960005190 phenylalanine Drugs 0.000 claims description 4
- 125000003386 piperidinyl group Chemical group 0.000 claims description 4
- 125000004202 aminomethyl group Chemical group [H]N([H])C([H])([H])* 0.000 claims description 3
- DNSISZSEWVHGLH-UHFFFAOYSA-N butanamide Chemical compound CCCC(N)=O DNSISZSEWVHGLH-UHFFFAOYSA-N 0.000 claims 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 245
- 238000006243 chemical reaction Methods 0.000 description 225
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 161
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 145
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 141
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 132
- 239000000243 solution Substances 0.000 description 124
- 239000011541 reaction mixture Substances 0.000 description 119
- 238000004007 reversed phase HPLC Methods 0.000 description 116
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 110
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 108
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 104
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 100
- 239000010779 crude oil Substances 0.000 description 96
- 239000000725 suspension Substances 0.000 description 84
- 235000019439 ethyl acetate Nutrition 0.000 description 71
- 239000003480 eluent Substances 0.000 description 65
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 65
- 235000019341 magnesium sulphate Nutrition 0.000 description 65
- 239000007821 HATU Substances 0.000 description 64
- 239000012267 brine Substances 0.000 description 64
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 64
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 54
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical class CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 52
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 49
- 102000004243 Tubulin Human genes 0.000 description 48
- 108090000704 Tubulin Proteins 0.000 description 48
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 46
- 238000000746 purification Methods 0.000 description 46
- 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 41
- 235000019253 formic acid Nutrition 0.000 description 41
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 39
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 37
- 125000003088 (fluoren-9-ylmethoxy)carbonyl group Chemical group 0.000 description 34
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 32
- 238000000338 in vitro Methods 0.000 description 32
- 210000004027 cell Anatomy 0.000 description 31
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 30
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 28
- 238000012360 testing method Methods 0.000 description 27
- YWWDBCBWQNCYNR-UHFFFAOYSA-N trimethylphosphine Chemical compound CP(C)C YWWDBCBWQNCYNR-UHFFFAOYSA-N 0.000 description 26
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 25
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 25
- 235000011114 ammonium hydroxide Nutrition 0.000 description 25
- 230000003013 cytotoxicity Effects 0.000 description 24
- 231100000135 cytotoxicity Toxicity 0.000 description 24
- 230000004083 survival effect Effects 0.000 description 24
- 238000002474 experimental method Methods 0.000 description 23
- 239000010410 layer Substances 0.000 description 23
- 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 21
- 239000007787 solid Substances 0.000 description 20
- 239000012043 crude product Substances 0.000 description 19
- 239000000741 silica gel Substances 0.000 description 18
- 229910002027 silica gel Inorganic materials 0.000 description 18
- 229910052763 palladium Inorganic materials 0.000 description 16
- 239000000872 buffer Substances 0.000 description 14
- 125000004432 carbon atom Chemical group C* 0.000 description 14
- 229930012538 Paclitaxel Natural products 0.000 description 13
- 239000003921 oil Substances 0.000 description 13
- 235000019198 oils Nutrition 0.000 description 13
- 229960001592 paclitaxel Drugs 0.000 description 13
- RCINICONZNJXQF-MZXODVADSA-N taxol Chemical compound O([C@@H]1[C@@]2(C[C@@H](C(C)=C(C2(C)C)[C@H](C([C@]2(C)[C@@H](O)C[C@H]3OC[C@]3([C@H]21)OC(C)=O)=O)OC(=O)C)OC(=O)[C@H](O)[C@@H](NC(=O)C=1C=CC=CC=1)C=1C=CC=CC=1)O)C(=O)C1=CC=CC=C1 RCINICONZNJXQF-MZXODVADSA-N 0.000 description 13
- 239000005909 Kieselgur Substances 0.000 description 12
- 238000004458 analytical method Methods 0.000 description 12
- 239000000126 substance Substances 0.000 description 12
- 239000000706 filtrate Substances 0.000 description 11
- HJZVHUQSQGITAM-UHFFFAOYSA-N butanamide Chemical compound CC[CH]C(N)=O HJZVHUQSQGITAM-UHFFFAOYSA-N 0.000 description 10
- 238000003818 flash chromatography Methods 0.000 description 10
- 239000000203 mixture Substances 0.000 description 10
- 239000000460 chlorine Substances 0.000 description 9
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 9
- 239000003381 stabilizer Substances 0.000 description 9
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 8
- QUSNBJAOOMFDIB-UHFFFAOYSA-N Ethylamine Chemical compound CCN QUSNBJAOOMFDIB-UHFFFAOYSA-N 0.000 description 8
- 150000003840 hydrochlorides Chemical class 0.000 description 8
- 229940117803 phenethylamine Drugs 0.000 description 8
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical group C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 7
- 239000004480 active ingredient Substances 0.000 description 7
- 229910052799 carbon Inorganic materials 0.000 description 7
- 230000034994 death Effects 0.000 description 7
- 231100000517 death Toxicity 0.000 description 7
- 125000006413 ring segment Chemical group 0.000 description 7
- 125000001424 substituent group Chemical group 0.000 description 7
- 125000004209 (C1-C8) alkyl group Chemical group 0.000 description 6
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 6
- 0 CC[C@](C)[C@@]([C@@](C1)*=C1N(CCC1)[C@@]1[C@@]([C@@]1C)*=C1N[C@@](Cc1ccccc1)C(OC)=O)N(C)C(C([C@](C)*)NC([C@](C(C)C)N(C)C)=O)=O Chemical compound CC[C@](C)[C@@]([C@@](C1)*=C1N(CCC1)[C@@]1[C@@]([C@@]1C)*=C1N[C@@](Cc1ccccc1)C(OC)=O)N(C)C(C([C@](C)*)NC([C@](C(C)C)N(C)C)=O)=O 0.000 description 6
- 238000003556 assay Methods 0.000 description 6
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- 230000003287 optical effect Effects 0.000 description 5
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- 150000003254 radicals Chemical class 0.000 description 5
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 description 4
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical group FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 4
- 239000002246 antineoplastic agent Substances 0.000 description 4
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- 239000011737 fluorine Chemical group 0.000 description 4
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- 125000005843 halogen group Chemical group 0.000 description 4
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
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- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 3
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- ASOKPJOREAFHNY-UHFFFAOYSA-N 1-Hydroxybenzotriazole Chemical compound C1=CC=C2N(O)N=NC2=C1 ASOKPJOREAFHNY-UHFFFAOYSA-N 0.000 description 3
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- SAVROPQJUYSBDD-UHFFFAOYSA-N formyl(dimethyl)azanium;chloride Chemical compound [Cl-].C[N+](C)=CO SAVROPQJUYSBDD-UHFFFAOYSA-N 0.000 description 1
- VZCYOOQTPOCHFL-OWOJBTEDSA-L fumarate(2-) Chemical class [O-]C(=O)\C=C\C([O-])=O VZCYOOQTPOCHFL-OWOJBTEDSA-L 0.000 description 1
- 230000014509 gene expression Effects 0.000 description 1
- 238000007429 general method Methods 0.000 description 1
- 230000012010 growth Effects 0.000 description 1
- 239000001963 growth medium Substances 0.000 description 1
- 229910052736 halogen Inorganic materials 0.000 description 1
- 150000002367 halogens Chemical class 0.000 description 1
- 230000003862 health status Effects 0.000 description 1
- 208000019622 heart disease Diseases 0.000 description 1
- MNWFXJYAOYHMED-UHFFFAOYSA-N heptanoic acid Chemical class CCCCCCC(O)=O MNWFXJYAOYHMED-UHFFFAOYSA-N 0.000 description 1
- KKLGDUSGQMHBPB-UHFFFAOYSA-N hex-2-ynedioic acid Chemical class OC(=O)CCC#CC(O)=O KKLGDUSGQMHBPB-UHFFFAOYSA-N 0.000 description 1
- HNDVDQJCIGZPNO-UHFFFAOYSA-N histidine Natural products OC(=O)C(N)CC1=CN=CN1 HNDVDQJCIGZPNO-UHFFFAOYSA-N 0.000 description 1
- 150000002431 hydrogen Chemical class 0.000 description 1
- SWVMLNPDTIFDDY-UHFFFAOYSA-N hydron;methyl 2-amino-3-phenylpropanoate;chloride Chemical class Cl.COC(=O)C(N)CC1=CC=CC=C1 SWVMLNPDTIFDDY-UHFFFAOYSA-N 0.000 description 1
- 238000003384 imaging method Methods 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 150000004694 iodide salts Chemical class 0.000 description 1
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 1
- 230000007794 irritation Effects 0.000 description 1
- KQNPFQTWMSNSAP-UHFFFAOYSA-N isobutyric acid Chemical class CC(C)C(O)=O KQNPFQTWMSNSAP-UHFFFAOYSA-N 0.000 description 1
- 125000004491 isohexyl group Chemical group C(CCC(C)C)* 0.000 description 1
- 150000002519 isoleucine derivatives Chemical class 0.000 description 1
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 150000003893 lactate salts Chemical class 0.000 description 1
- 238000004811 liquid chromatography Methods 0.000 description 1
- GLXDVVHUTZTUQK-UHFFFAOYSA-M lithium hydroxide monohydrate Substances [Li+].O.[OH-] GLXDVVHUTZTUQK-UHFFFAOYSA-M 0.000 description 1
- 229940040692 lithium hydroxide monohydrate Drugs 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 210000004072 lung Anatomy 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 230000014759 maintenance of location Effects 0.000 description 1
- 150000002688 maleic acid derivatives Chemical class 0.000 description 1
- 150000002690 malonic acid derivatives Chemical class 0.000 description 1
- 238000004949 mass spectrometry Methods 0.000 description 1
- 125000005341 metaphosphate group Chemical group 0.000 description 1
- 208000037819 metastatic cancer Diseases 0.000 description 1
- 208000011575 metastatic malignant neoplasm Diseases 0.000 description 1
- CEMZBWPSKYISTN-YFKPBYRVSA-N methyl (2s)-2-amino-3-methylbutanoate Chemical compound COC(=O)[C@@H](N)C(C)C CEMZBWPSKYISTN-YFKPBYRVSA-N 0.000 description 1
- QPJVMBTYPHYUOC-UHFFFAOYSA-N methyl benzoate Chemical class COC(=O)C1=CC=CC=C1 QPJVMBTYPHYUOC-UHFFFAOYSA-N 0.000 description 1
- 125000000250 methylamino group Chemical group [H]N(*)C([H])([H])[H] 0.000 description 1
- 230000008880 microtubule cytoskeleton organization Effects 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 125000002950 monocyclic group Chemical group 0.000 description 1
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 description 1
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- PSZYNBSKGUBXEH-UHFFFAOYSA-N naphthalene-1-sulfonic acid Chemical class C1=CC=C2C(S(=O)(=O)O)=CC=CC2=C1 PSZYNBSKGUBXEH-UHFFFAOYSA-N 0.000 description 1
- KVBGVZZKJNLNJU-UHFFFAOYSA-N naphthalene-2-sulfonic acid Chemical class C1=CC=CC2=CC(S(=O)(=O)O)=CC=C21 KVBGVZZKJNLNJU-UHFFFAOYSA-N 0.000 description 1
- 239000002547 new drug Substances 0.000 description 1
- WWZKQHOCKIZLMA-UHFFFAOYSA-M octanoate Chemical class CCCCCCCC([O-])=O WWZKQHOCKIZLMA-UHFFFAOYSA-M 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- 238000011275 oncology therapy Methods 0.000 description 1
- 239000010502 orange oil Substances 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 229960003104 ornithine Drugs 0.000 description 1
- 210000001672 ovary Anatomy 0.000 description 1
- 150000003891 oxalate salts Chemical class 0.000 description 1
- 210000000496 pancreas Anatomy 0.000 description 1
- 238000011170 pharmaceutical development Methods 0.000 description 1
- 239000008063 pharmaceutical solvent Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 238000009521 phase II clinical trial Methods 0.000 description 1
- DYUMLJSJISTVPV-UHFFFAOYSA-N phenyl propanoate Chemical class CCC(=O)OC1=CC=CC=C1 DYUMLJSJISTVPV-UHFFFAOYSA-N 0.000 description 1
- WLJVXDMOQOGPHL-UHFFFAOYSA-N phenylacetic acid Chemical class OC(=O)CC1=CC=CC=C1 WLJVXDMOQOGPHL-UHFFFAOYSA-N 0.000 description 1
- COLNVLDHVKWLRT-UHFFFAOYSA-N phenylalanine Natural products OC(=O)C(N)CC1=CC=CC=C1 COLNVLDHVKWLRT-UHFFFAOYSA-N 0.000 description 1
- COLNVLDHVKWLRT-QMMMGPOBSA-N phenylalanine group Chemical group N[C@@H](CC1=CC=CC=C1)C(=O)O COLNVLDHVKWLRT-QMMMGPOBSA-N 0.000 description 1
- 235000021317 phosphate Nutrition 0.000 description 1
- 150000003013 phosphoric acid derivatives Chemical class 0.000 description 1
- 229910052698 phosphorus Inorganic materials 0.000 description 1
- 239000011574 phosphorus Substances 0.000 description 1
- 125000005498 phthalate group Chemical class 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 125000003367 polycyclic group Chemical group 0.000 description 1
- 230000037048 polymerization activity Effects 0.000 description 1
- 238000006116 polymerization reaction Methods 0.000 description 1
- 238000002600 positron emission tomography Methods 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 239000000651 prodrug Substances 0.000 description 1
- 229940002612 prodrug Drugs 0.000 description 1
- KCXFHTAICRTXLI-UHFFFAOYSA-N propane-1-sulfonic acid Chemical class CCCS(O)(=O)=O KCXFHTAICRTXLI-UHFFFAOYSA-N 0.000 description 1
- UORVCLMRJXCDCP-UHFFFAOYSA-N propynoic acid Chemical class OC(=O)C#C UORVCLMRJXCDCP-UHFFFAOYSA-N 0.000 description 1
- 210000002307 prostate Anatomy 0.000 description 1
- 201000001514 prostate carcinoma Diseases 0.000 description 1
- 230000002285 radioactive effect Effects 0.000 description 1
- 230000010076 replication Effects 0.000 description 1
- 102220034815 rs199475569 Human genes 0.000 description 1
- YGSDEFSMJLZEOE-UHFFFAOYSA-N salicylic acid Chemical class OC(=O)C1=CC=CC=C1O YGSDEFSMJLZEOE-UHFFFAOYSA-N 0.000 description 1
- CXMXRPHRNRROMY-UHFFFAOYSA-N sebacic acid Chemical class OC(=O)CCCCCCCCC(O)=O CXMXRPHRNRROMY-UHFFFAOYSA-N 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 238000004611 spectroscopical analysis Methods 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- TYFQFVWCELRYAO-UHFFFAOYSA-N suberic acid Chemical class OC(=O)CCCCCCC(O)=O TYFQFVWCELRYAO-UHFFFAOYSA-N 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 150000003900 succinic acid esters Chemical class 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- LSNNMFCWUKXFEE-UHFFFAOYSA-L sulfite Chemical class [O-]S([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-L 0.000 description 1
- 125000001273 sulfonato group Chemical class [O-]S(*)(=O)=O 0.000 description 1
- 150000003467 sulfuric acid derivatives Chemical class 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 150000003892 tartrate salts Chemical class 0.000 description 1
- QOISWWBTZMFUEL-NSHDSACASA-N tert-butyl (2s)-2-amino-3-phenylpropanoate Chemical compound CC(C)(C)OC(=O)[C@@H](N)CC1=CC=CC=C1 QOISWWBTZMFUEL-NSHDSACASA-N 0.000 description 1
- FDMCEXDXULPJPG-MERQFXBCSA-N tert-butyl (2s)-2-amino-3-phenylpropanoate;hydrochloride Chemical class Cl.CC(C)(C)OC(=O)[C@@H](N)CC1=CC=CC=C1 FDMCEXDXULPJPG-MERQFXBCSA-N 0.000 description 1
- 125000001973 tert-pentyl group Chemical group [H]C([H])([H])C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 150000003512 tertiary amines Chemical class 0.000 description 1
- 238000003354 tissue distribution assay Methods 0.000 description 1
- 238000011200 topical administration Methods 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 125000002221 trityl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C([*])(C1=C(C(=C(C(=C1[H])[H])[H])[H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- 230000004614 tumor growth Effects 0.000 description 1
- 238000004704 ultra performance liquid chromatography Methods 0.000 description 1
- 210000003932 urinary bladder Anatomy 0.000 description 1
- 239000004474 valine Substances 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
- 239000012855 volatile organic compound Substances 0.000 description 1
- 230000003442 weekly effect Effects 0.000 description 1
- GDJZZWYLFXAGFH-UHFFFAOYSA-M xylenesulfonate group Chemical group C1(C(C=CC=C1)C)(C)S(=O)(=O)[O-] GDJZZWYLFXAGFH-UHFFFAOYSA-M 0.000 description 1
Classifications
-
- 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
- A61K38/03—Peptides having up to 20 amino acids in an undefined or only partially defined sequence; 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
- 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
- A61K38/00—Medicinal preparations containing peptides
- A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
- A61K38/08—Peptides having 5 to 11 amino acids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
- C07K7/02—Linear peptides containing at least one abnormal peptide link
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Medicinal Chemistry (AREA)
- Organic Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- Engineering & Computer Science (AREA)
- Biochemistry (AREA)
- Molecular Biology (AREA)
- Genetics & Genomics (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Immunology (AREA)
- Biophysics (AREA)
- Epidemiology (AREA)
- Crystallography & Structural Chemistry (AREA)
- Gastroenterology & Hepatology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Peptides Or Proteins (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US201462004084P | 2014-05-28 | 2014-05-28 | |
| PCT/US2015/032704 WO2015183978A1 (en) | 2014-05-28 | 2015-05-27 | Derivatives of dolaproine-dolaisoleuine peptides |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| ES2883023T3 true ES2883023T3 (es) | 2021-12-03 |
Family
ID=54699722
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| ES15799069T Active ES2883023T3 (es) | 2014-05-28 | 2015-05-27 | Derivados de péptidos de dolaproína-dolaisoleuina citotóxicos para el tratamiento del cáncer |
Country Status (9)
| Country | Link |
|---|---|
| US (2) | US20170190735A1 (https=) |
| EP (1) | EP3149024B9 (https=) |
| JP (3) | JP2017519740A (https=) |
| KR (1) | KR102413079B1 (https=) |
| CN (1) | CN107041139A (https=) |
| ES (1) | ES2883023T3 (https=) |
| RU (1) | RU2747989C2 (https=) |
| SG (1) | SG11201609739UA (https=) |
| WO (1) | WO2015183978A1 (https=) |
Families Citing this family (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP3149024B9 (en) * | 2014-05-28 | 2021-10-27 | Agensys, Inc. | Cytotoxic dolaproine-dolaisoleuine peptide derivatives for the treatment of cancer |
| WO2017058808A1 (en) * | 2015-10-02 | 2017-04-06 | Sirenas Llc | Anti-cancer compounds and conjugates thereof |
| EP4321522A1 (en) * | 2022-08-12 | 2024-02-14 | Seagen Inc. | Cytotoxic compounds and conjugates thereof |
| AU2024267769A1 (en) * | 2023-05-06 | 2025-10-16 | Remegen Co., Ltd. | Preparation method for intermediate of auristatin derivative |
Family Cites Families (28)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE69232552T2 (de) * | 1991-08-09 | 2002-10-31 | Teikoku Hormone Mfg. Co., Ltd. | Tetrapeptide Derivat |
| US6569834B1 (en) | 1992-12-03 | 2003-05-27 | George R. Pettit | Elucidation and synthesis of antineoplastic tetrapeptide w-aminoalkyl-amides |
| US5635483A (en) | 1992-12-03 | 1997-06-03 | Arizona Board Of Regents Acting On Behalf Of Arizona State University | Tumor inhibiting tetrapeptide bearing modified phenethyl amides |
| US5780588A (en) | 1993-01-26 | 1998-07-14 | Arizona Board Of Regents | Elucidation and synthesis of selected pentapeptides |
| JPH06234790A (ja) * | 1993-02-09 | 1994-08-23 | Teikoku Hormone Mfg Co Ltd | 新規テトラペプチドアミド誘導体 |
| KR100332254B1 (ko) * | 1993-10-01 | 2002-09-27 | 데이꼬꾸 조끼 세이야꾸 가부시키가이샤 | 신규인펩티드유도체 |
| US5521284A (en) * | 1994-08-01 | 1996-05-28 | Arizona Board Of Regents Acting On Behalf Of Arizona State University | Human cancer inhibitory pentapeptide amides and esters |
| US5530097A (en) * | 1994-08-01 | 1996-06-25 | Arizona Board Of Regents Acting On Behalf Of Arizona State University | Human cancer inhibitory peptide amides |
| US5663149A (en) | 1994-12-13 | 1997-09-02 | Arizona Board Of Regents Acting On Behalf Of Arizona State University | Human cancer inhibitory pentapeptide heterocyclic and halophenyl amides |
| US6323315B1 (en) * | 1999-09-10 | 2001-11-27 | Basf Aktiengesellschaft | Dolastatin peptides |
| US6884869B2 (en) * | 2001-04-30 | 2005-04-26 | Seattle Genetics, Inc. | Pentapeptide compounds and uses related thereto |
| ATE459364T1 (de) | 2003-10-22 | 2010-03-15 | Univ Johns Hopkins | Verbesserte bakteriolyse-kombinationstherapie für die behandlung von tumoren |
| KR20070050918A (ko) * | 2004-07-02 | 2007-05-16 | 뉴텍 파마 피엘씨 | 암의 치료 |
| WO2006132670A2 (en) | 2004-11-12 | 2006-12-14 | Seattle Genetics, Inc. | Auristatins having an aminobenzoic acid unit at the n terminus |
| CN101242816B (zh) * | 2005-06-30 | 2012-10-31 | 维罗贝股份有限公司 | Hcv抑制剂 |
| US7608592B2 (en) | 2005-06-30 | 2009-10-27 | Virobay, Inc. | HCV inhibitors |
| JP5171621B2 (ja) * | 2005-07-07 | 2013-03-27 | シアトル ジェネティックス， インコーポレイテッド | フェニルアラニン側鎖修飾をｃ末端に有するモノメチルバリン化合物 |
| CN106986926A (zh) | 2008-01-30 | 2017-07-28 | 皮里斯股份公司 | 具有对人c‑met受体酪氨酸激酶的亲和性的泪脂质运载蛋白的突变蛋白及其获得方法 |
| EP2265283B1 (en) * | 2008-03-18 | 2014-09-03 | Seattle Genetics, Inc. | Auristatin drug linker conjugates |
| EP2276509B1 (en) | 2008-04-11 | 2016-06-15 | Seattle Genetics, Inc. | Detection and tratment of pancreatic, ovarian and other cancers |
| KR102023496B1 (ko) | 2011-04-21 | 2019-09-20 | 시애틀 지네틱스, 인크. | 신규 결합제-약물 콘주게이트 (adc) 및 그의 용도 |
| RU2566693C2 (ru) * | 2011-07-08 | 2015-10-27 | Сименс Акциенгезелльшафт | Система слоев с двухслойным металлическим слоем |
| US20130190248A1 (en) * | 2011-07-26 | 2013-07-25 | Agensys, Inc. | Substituted peptide analogs |
| MY168297A (en) | 2011-11-17 | 2018-10-23 | Pfizer | Cytotoxic Peptides and Antibody Drug Conjugates Thereof |
| US9981046B2 (en) * | 2012-05-15 | 2018-05-29 | Concortis Biosystems, Corp., a wholly owned Subsidiary of Sorrento Therapeutics, Inc. | Drug-conjugates, conjugation methods, and uses thereof |
| HK1214282A1 (zh) * | 2012-11-07 | 2016-07-22 | 辉瑞公司 | 抗-notch3抗体及抗体-药物缀合物 |
| CN104936621A (zh) | 2012-11-07 | 2015-09-23 | 辉瑞公司 | 抗IL-13受体α2抗体和抗体-药物缀合物 |
| EP3149024B9 (en) * | 2014-05-28 | 2021-10-27 | Agensys, Inc. | Cytotoxic dolaproine-dolaisoleuine peptide derivatives for the treatment of cancer |
-
2015
- 2015-05-27 EP EP15799069.8A patent/EP3149024B9/en active Active
- 2015-05-27 ES ES15799069T patent/ES2883023T3/es active Active
- 2015-05-27 RU RU2016150426A patent/RU2747989C2/ru not_active Application Discontinuation
- 2015-05-27 US US15/313,906 patent/US20170190735A1/en not_active Abandoned
- 2015-05-27 KR KR1020167036764A patent/KR102413079B1/ko active Active
- 2015-05-27 CN CN201580041582.0A patent/CN107041139A/zh active Pending
- 2015-05-27 WO PCT/US2015/032704 patent/WO2015183978A1/en not_active Ceased
- 2015-05-27 JP JP2016569825A patent/JP2017519740A/ja active Pending
- 2015-05-27 SG SG11201609739UA patent/SG11201609739UA/en unknown
-
2019
- 2019-11-14 US US16/684,208 patent/US11312748B2/en active Active
-
2020
- 2020-05-07 JP JP2020081698A patent/JP6995160B2/ja active Active
-
2021
- 2021-12-14 JP JP2021202579A patent/JP7292366B2/ja active Active
Also Published As
| Publication number | Publication date |
|---|---|
| JP2017519740A (ja) | 2017-07-20 |
| KR102413079B1 (ko) | 2022-06-24 |
| RU2747989C2 (ru) | 2021-05-18 |
| WO2015183978A1 (en) | 2015-12-03 |
| EP3149024A1 (en) | 2017-04-05 |
| JP7292366B2 (ja) | 2023-06-16 |
| JP2022027896A (ja) | 2022-02-14 |
| US20220204557A1 (en) | 2022-06-30 |
| EP3149024B9 (en) | 2021-10-27 |
| US20200325170A1 (en) | 2020-10-15 |
| CN107041139A (zh) | 2017-08-11 |
| JP2020128405A (ja) | 2020-08-27 |
| RU2016150426A3 (https=) | 2018-12-20 |
| JP6995160B2 (ja) | 2022-01-14 |
| US20170190735A1 (en) | 2017-07-06 |
| US11312748B2 (en) | 2022-04-26 |
| KR20170005495A (ko) | 2017-01-13 |
| RU2016150426A (ru) | 2018-07-03 |
| EP3149024A4 (en) | 2018-06-06 |
| EP3149024B1 (en) | 2021-05-12 |
| SG11201609739UA (en) | 2016-12-29 |
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