ES2428088T3 - Derivados de camptotecina como agentes quimioradiosensibilizadores - Google Patents
Derivados de camptotecina como agentes quimioradiosensibilizadores Download PDFInfo
- Publication number
- ES2428088T3 ES2428088T3 ES06836448T ES06836448T ES2428088T3 ES 2428088 T3 ES2428088 T3 ES 2428088T3 ES 06836448 T ES06836448 T ES 06836448T ES 06836448 T ES06836448 T ES 06836448T ES 2428088 T3 ES2428088 T3 ES 2428088T3
- Authority
- ES
- Spain
- Prior art keywords
- lower alkyl
- cpt
- lower alkoxy
- alkyl
- carbonyloxy
- 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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- VSJKWCGYPAHWDS-FQEVSTJZSA-N camptothecin Chemical class C1=CC=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)[C@]5(O)CC)C4=NC2=C1 VSJKWCGYPAHWDS-FQEVSTJZSA-N 0.000 title description 126
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 550
- -1 RQY-LC (O) O- Chemical group 0.000 claims abstract description 509
- 125000003545 alkoxy group Chemical group 0.000 claims abstract description 378
- 150000001875 compounds Chemical class 0.000 claims abstract description 178
- 239000001257 hydrogen Substances 0.000 claims abstract description 128
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 128
- 235000000346 sugar Nutrition 0.000 claims abstract description 115
- ORTFAQDWJHRMNX-UHFFFAOYSA-N hydroxidooxidocarbon(.) Chemical group O[C]=O ORTFAQDWJHRMNX-UHFFFAOYSA-N 0.000 claims abstract description 95
- 150000002367 halogens Chemical group 0.000 claims abstract description 92
- 229910052736 halogen Inorganic materials 0.000 claims abstract description 91
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 claims abstract description 62
- 125000000623 heterocyclic group Chemical group 0.000 claims abstract description 51
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 42
- 125000004103 aminoalkyl group Chemical group 0.000 claims abstract description 33
- 125000002837 carbocyclic group Chemical group 0.000 claims abstract description 33
- YLQBMQCUIZJEEH-UHFFFAOYSA-N Furan Chemical group C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims abstract description 32
- 229910052799 carbon Inorganic materials 0.000 claims abstract description 25
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims abstract description 25
- 125000004414 alkyl thio group Chemical group 0.000 claims abstract description 23
- 125000002768 hydroxyalkyl group Chemical group 0.000 claims abstract description 19
- 125000000547 substituted alkyl group Chemical group 0.000 claims abstract description 15
- JKTCBAGSMQIFNL-UHFFFAOYSA-N 2,3-dihydrofuran Chemical group C1CC=CO1 JKTCBAGSMQIFNL-UHFFFAOYSA-N 0.000 claims abstract description 14
- 125000004665 trialkylsilyl group Chemical group 0.000 claims abstract description 13
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 claims abstract description 13
- 229920002554 vinyl polymer Polymers 0.000 claims abstract description 13
- MENHXVNCWVKFRA-UHFFFAOYSA-N 1,4-oxazin-2-one Chemical group O=C1C=NC=CO1 MENHXVNCWVKFRA-UHFFFAOYSA-N 0.000 claims abstract description 12
- 125000004448 alkyl carbonyl group Chemical group 0.000 claims abstract description 12
- 125000004985 dialkyl amino alkyl group Chemical group 0.000 claims abstract description 12
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims abstract description 11
- 125000002431 aminoalkoxy group Chemical group 0.000 claims abstract description 10
- 150000003839 salts Chemical class 0.000 claims abstract description 9
- 206010028980 Neoplasm Diseases 0.000 claims description 122
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 96
- 230000005855 radiation Effects 0.000 claims description 63
- 201000011510 cancer Diseases 0.000 claims description 59
- 239000000203 mixture Substances 0.000 claims description 58
- 238000000034 method Methods 0.000 claims description 57
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims description 54
- 238000011282 treatment Methods 0.000 claims description 52
- 125000001424 substituent group Chemical group 0.000 claims description 48
- 239000003814 drug Substances 0.000 claims description 34
- 210000004881 tumor cell Anatomy 0.000 claims description 29
- 229910052760 oxygen Inorganic materials 0.000 claims description 28
- 229910052717 sulfur Inorganic materials 0.000 claims description 27
- 125000005708 carbonyloxy group Chemical group [*:2]OC([*:1])=O 0.000 claims description 26
- 208000035269 cancer or benign tumor Diseases 0.000 claims description 25
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 21
- 241001465754 Metazoa Species 0.000 claims description 18
- 125000002947 alkylene group Chemical group 0.000 claims description 16
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 14
- 125000003118 aryl group Chemical group 0.000 claims description 12
- 125000004202 aminomethyl group Chemical group [H]N([H])C([H])([H])* 0.000 claims description 11
- 125000004432 carbon atom Chemical group C* 0.000 claims description 10
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 10
- 125000006297 carbonyl amino group Chemical group [H]N([*:2])C([*:1])=O 0.000 claims description 7
- 238000004519 manufacturing process Methods 0.000 claims description 7
- 206010070834 Sensitisation Diseases 0.000 claims description 6
- 208000035475 disorder Diseases 0.000 claims description 6
- 230000008313 sensitization Effects 0.000 claims description 6
- 230000001235 sensitizing effect Effects 0.000 claims description 6
- 125000000051 benzyloxy group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])O* 0.000 claims description 5
- 125000004663 dialkyl amino group Chemical group 0.000 claims description 5
- 238000002560 therapeutic procedure Methods 0.000 claims description 3
- 125000000587 piperidin-1-yl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 claims description 2
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 claims 2
- 150000002431 hydrogen Chemical class 0.000 abstract description 68
- 125000004356 hydroxy functional group Chemical group O* 0.000 abstract 4
- 125000004849 alkoxymethyl group Chemical group 0.000 abstract 1
- 229940127093 camptothecin Drugs 0.000 description 459
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 85
- VSJKWCGYPAHWDS-UHFFFAOYSA-N dl-camptothecin Natural products C1=CC=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)C5(O)CC)C4=NC2=C1 VSJKWCGYPAHWDS-UHFFFAOYSA-N 0.000 description 79
- KLWPJMFMVPTNCC-UHFFFAOYSA-N Camptothecin Natural products CCC1(O)C(=O)OCC2=C1C=C3C4Nc5ccccc5C=C4CN3C2=O KLWPJMFMVPTNCC-UHFFFAOYSA-N 0.000 description 77
- 210000004027 cell Anatomy 0.000 description 64
- 239000000243 solution Substances 0.000 description 55
- RTZKZFJDLAIYFH-UHFFFAOYSA-N ether Substances CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 44
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 40
- 239000002502 liposome Substances 0.000 description 38
- 150000003254 radicals Chemical group 0.000 description 38
- 229920006395 saturated elastomer Polymers 0.000 description 35
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 30
- JOERSAVCLPYNIZ-UHFFFAOYSA-N 2,4,5,7-tetranitrofluoren-9-one Chemical compound O=C1C2=CC([N+]([O-])=O)=CC([N+]([O-])=O)=C2C2=C1C=C([N+](=O)[O-])C=C2[N+]([O-])=O JOERSAVCLPYNIZ-UHFFFAOYSA-N 0.000 description 28
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 28
- 229940079593 drug Drugs 0.000 description 28
- 239000007787 solid Substances 0.000 description 27
- 239000002904 solvent Substances 0.000 description 27
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 26
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 24
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 24
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 23
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 23
- 238000005160 1H NMR spectroscopy Methods 0.000 description 22
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 22
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 22
- 239000012528 membrane Substances 0.000 description 22
- 238000001959 radiotherapy Methods 0.000 description 22
- 229910052938 sodium sulfate Inorganic materials 0.000 description 22
- 235000011152 sodium sulphate Nutrition 0.000 description 22
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 21
- 239000007832 Na2SO4 Substances 0.000 description 21
- 238000006243 chemical reaction Methods 0.000 description 21
- 230000005865 ionizing radiation Effects 0.000 description 20
- RRSNDVCODIMOFX-MPKOGUQCSA-N Fc1c(Cl)cccc1[C@H]1[C@@H](NC2(CCCCC2)[C@@]11C(=O)Nc2cc(Cl)ccc12)C(=O)Nc1ccc(cc1)C(=O)NCCCCCc1cccc2C(=O)N(Cc12)C1CCC(=O)NC1=O Chemical compound Fc1c(Cl)cccc1[C@H]1[C@@H](NC2(CCCCC2)[C@@]11C(=O)Nc2cc(Cl)ccc12)C(=O)Nc1ccc(cc1)C(=O)NCCCCCc1cccc2C(=O)N(Cc12)C1CCC(=O)NC1=O RRSNDVCODIMOFX-MPKOGUQCSA-N 0.000 description 19
- 238000000119 electrospray ionisation mass spectrum Methods 0.000 description 19
- 150000002148 esters Chemical class 0.000 description 19
- 125000001570 methylene group Chemical group [H]C([H])([*:1])[*:2] 0.000 description 19
- 230000000694 effects Effects 0.000 description 18
- 125000005842 heteroatom Chemical group 0.000 description 18
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 18
- 150000002632 lipids Chemical class 0.000 description 17
- 239000000047 product Substances 0.000 description 17
- 231100000419 toxicity Toxicity 0.000 description 17
- 230000001988 toxicity Effects 0.000 description 17
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 16
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 16
- 229910052757 nitrogen Inorganic materials 0.000 description 16
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 15
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 15
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 14
- CSCPPACGZOOCGX-WFGJKAKNSA-N acetone d6 Chemical compound [2H]C([2H])([2H])C(=O)C([2H])([2H])[2H] CSCPPACGZOOCGX-WFGJKAKNSA-N 0.000 description 14
- 235000019439 ethyl acetate Nutrition 0.000 description 14
- 239000000693 micelle Substances 0.000 description 14
- 239000002534 radiation-sensitizing agent Substances 0.000 description 14
- 239000000741 silica gel Substances 0.000 description 14
- 229910002027 silica gel Inorganic materials 0.000 description 14
- 238000003786 synthesis reaction Methods 0.000 description 14
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 12
- 239000001301 oxygen Substances 0.000 description 12
- 238000002360 preparation method Methods 0.000 description 12
- 229960000549 4-dimethylaminophenol Drugs 0.000 description 11
- 206010021143 Hypoxia Diseases 0.000 description 11
- 230000000973 chemotherapeutic effect Effects 0.000 description 11
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 11
- 235000017557 sodium bicarbonate Nutrition 0.000 description 11
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 11
- 239000012279 sodium borohydride Substances 0.000 description 11
- 229910000033 sodium borohydride Inorganic materials 0.000 description 11
- 125000005809 3,4,5-trimethoxyphenyl group Chemical group [H]C1=C(OC([H])([H])[H])C(OC([H])([H])[H])=C(OC([H])([H])[H])C([H])=C1* 0.000 description 10
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 10
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 10
- 125000003668 acetyloxy group Chemical group [H]C([H])([H])C(=O)O[*] 0.000 description 10
- 150000001412 amines Chemical class 0.000 description 10
- 125000004122 cyclic group Chemical group 0.000 description 10
- 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 description 10
- 230000004083 survival effect Effects 0.000 description 10
- 125000001981 tert-butyldimethylsilyl group Chemical group [H]C([H])([H])[Si]([H])(C([H])([H])[H])[*]C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 10
- 241000699670 Mus sp. Species 0.000 description 9
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 9
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 9
- 230000015572 biosynthetic process Effects 0.000 description 9
- 239000003638 chemical reducing agent Substances 0.000 description 9
- 238000000338 in vitro Methods 0.000 description 9
- GURKHSYORGJETM-WAQYZQTGSA-N irinotecan hydrochloride (anhydrous) Chemical compound Cl.C1=C2C(CC)=C3CN(C(C4=C([C@@](C(=O)OC4)(O)CC)C=4)=O)C=4C3=NC2=CC=C1OC(=O)N(CC1)CCC1N1CCCCC1 GURKHSYORGJETM-WAQYZQTGSA-N 0.000 description 9
- 150000002772 monosaccharides Chemical class 0.000 description 9
- 230000000637 radiosensitizating effect Effects 0.000 description 9
- 239000011593 sulfur Substances 0.000 description 9
- OKKJLVBELUTLKV-MZCSYVLQSA-N Deuterated methanol Chemical compound [2H]OC([2H])([2H])[2H] OKKJLVBELUTLKV-MZCSYVLQSA-N 0.000 description 8
- 239000012981 Hank's balanced salt solution Substances 0.000 description 8
- 229960000583 acetic acid Drugs 0.000 description 8
- 230000000118 anti-neoplastic effect Effects 0.000 description 8
- 150000005690 diesters Chemical class 0.000 description 8
- 230000002427 irreversible effect Effects 0.000 description 8
- 239000010410 layer Substances 0.000 description 8
- 125000004433 nitrogen atom Chemical group N* 0.000 description 8
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- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 7
- 125000004429 atom Chemical group 0.000 description 7
- 239000003795 chemical substances by application Substances 0.000 description 7
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- 239000000126 substance Substances 0.000 description 7
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- 210000001519 tissue Anatomy 0.000 description 7
- UCFGDBYHRUNTLO-QHCPKHFHSA-N topotecan Chemical compound C1=C(O)C(CN(C)C)=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)[C@]5(O)CC)C4=NC2=C1 UCFGDBYHRUNTLO-QHCPKHFHSA-N 0.000 description 7
- 229960000303 topotecan Drugs 0.000 description 7
- DTQVDTLACAAQTR-UHFFFAOYSA-N trifluoroacetic acid Substances OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 7
- 125000004214 1-pyrrolidinyl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 description 6
- QCQCHGYLTSGIGX-GHXANHINSA-N 4-[[(3ar,5ar,5br,7ar,9s,11ar,11br,13as)-5a,5b,8,8,11a-pentamethyl-3a-[(5-methylpyridine-3-carbonyl)amino]-2-oxo-1-propan-2-yl-4,5,6,7,7a,9,10,11,11b,12,13,13a-dodecahydro-3h-cyclopenta[a]chrysen-9-yl]oxy]-2,2-dimethyl-4-oxobutanoic acid Chemical compound N([C@@]12CC[C@@]3(C)[C@]4(C)CC[C@H]5C(C)(C)[C@@H](OC(=O)CC(C)(C)C(O)=O)CC[C@]5(C)[C@H]4CC[C@@H]3C1=C(C(C2)=O)C(C)C)C(=O)C1=CN=CC(C)=C1 QCQCHGYLTSGIGX-GHXANHINSA-N 0.000 description 6
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 6
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 125000006615 aromatic heterocyclic group Chemical group 0.000 description 6
- LNHWXBUNXOXMRL-VWLOTQADSA-N belotecan Chemical compound C1=CC=C2C(CCNC(C)C)=C(CN3C4=CC5=C(C3=O)COC(=O)[C@]5(O)CC)C4=NC2=C1 LNHWXBUNXOXMRL-VWLOTQADSA-N 0.000 description 6
- PFKFTWBEEFSNDU-UHFFFAOYSA-N carbonyldiimidazole Chemical compound C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 description 6
- 150000001735 carboxylic acids Chemical class 0.000 description 6
- 125000000753 cycloalkyl group Chemical group 0.000 description 6
- 238000001914 filtration Methods 0.000 description 6
- 238000009472 formulation Methods 0.000 description 6
- UIVFUQKYVFCEKJ-OPTOVBNMSA-N gimatecan Chemical compound C1=CC=C2C(\C=N\OC(C)(C)C)=C(CN3C4=CC5=C(C3=O)COC(=O)[C@]5(O)CC)C4=NC2=C1 UIVFUQKYVFCEKJ-OPTOVBNMSA-N 0.000 description 6
- 230000007954 hypoxia Effects 0.000 description 6
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 6
- 150000002466 imines Chemical class 0.000 description 6
- 238000007912 intraperitoneal administration Methods 0.000 description 6
- 229960004768 irinotecan Drugs 0.000 description 6
- 230000003211 malignant effect Effects 0.000 description 6
- 239000000463 material Substances 0.000 description 6
- 229910052751 metal Inorganic materials 0.000 description 6
- 239000002184 metal Substances 0.000 description 6
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical class CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 6
- 238000010992 reflux Methods 0.000 description 6
- 235000011149 sulphuric acid Nutrition 0.000 description 6
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 6
- 230000001225 therapeutic effect Effects 0.000 description 6
- QDKWLJJOYIFEBS-UHFFFAOYSA-N 1-fluoro-4-$l^{1}-oxidanylbenzene Chemical group [O]C1=CC=C(F)C=C1 QDKWLJJOYIFEBS-UHFFFAOYSA-N 0.000 description 5
- DVTXLOLRLNACCF-UHFFFAOYSA-N 2-(propan-2-ylideneamino)oxypropanoic acid Chemical compound OC(=O)C(C)ON=C(C)C DVTXLOLRLNACCF-UHFFFAOYSA-N 0.000 description 5
- 125000000954 2-hydroxyethyl group Chemical group [H]C([*])([H])C([H])([H])O[H] 0.000 description 5
- RFHNUQVGWJTISN-UHFFFAOYSA-N 2-piperazin-1-yl-n-propylacetamide Chemical compound CCCNC(=O)CN1CCNCC1 RFHNUQVGWJTISN-UHFFFAOYSA-N 0.000 description 5
- 241000124008 Mammalia Species 0.000 description 5
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 5
- 229950011276 belotecan Drugs 0.000 description 5
- 150000001721 carbon Chemical group 0.000 description 5
- DQLATGHUWYMOKM-UHFFFAOYSA-L cisplatin Chemical compound N[Pt](N)(Cl)Cl DQLATGHUWYMOKM-UHFFFAOYSA-L 0.000 description 5
- 125000004093 cyano group Chemical group *C#N 0.000 description 5
- 238000001035 drying Methods 0.000 description 5
- 125000000031 ethylamino group Chemical group [H]C([H])([H])C([H])([H])N([H])[*] 0.000 description 5
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- 230000002829 reductive effect Effects 0.000 description 5
- GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical compound CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 description 5
- 239000003981 vehicle Substances 0.000 description 5
- ITOFPJRDSCGOSA-KZLRUDJFSA-N (2s)-2-[[(4r)-4-[(3r,5r,8r,9s,10s,13r,14s,17r)-3-hydroxy-10,13-dimethyl-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1h-cyclopenta[a]phenanthren-17-yl]pentanoyl]amino]-3-(1h-indol-3-yl)propanoic acid Chemical compound C([C@H]1CC2)[C@H](O)CC[C@]1(C)[C@@H](CC[C@]13C)[C@@H]2[C@@H]3CC[C@@H]1[C@H](C)CCC(=O)N[C@H](C(O)=O)CC1=CNC2=CC=CC=C12 ITOFPJRDSCGOSA-KZLRUDJFSA-N 0.000 description 4
- AZQWKYJCGOJGHM-UHFFFAOYSA-N 1,4-benzoquinone Chemical compound O=C1C=CC(=O)C=C1 AZQWKYJCGOJGHM-UHFFFAOYSA-N 0.000 description 4
- 125000002373 5 membered heterocyclic group Chemical group 0.000 description 4
- 125000004070 6 membered heterocyclic group Chemical group 0.000 description 4
- KXDAEFPNCMNJSK-UHFFFAOYSA-N Benzamide Chemical compound NC(=O)C1=CC=CC=C1 KXDAEFPNCMNJSK-UHFFFAOYSA-N 0.000 description 4
- 201000009030 Carcinoma Diseases 0.000 description 4
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 4
- XBDQKXXYIPTUBI-UHFFFAOYSA-N Propionic acid Chemical compound CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 4
- 206010060862 Prostate cancer Diseases 0.000 description 4
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- ILMRJRBKQSSXGY-UHFFFAOYSA-N tert-butyl(dimethyl)silicon Chemical group C[Si](C)C(C)(C)C ILMRJRBKQSSXGY-UHFFFAOYSA-N 0.000 description 1
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 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
- 230000002381 testicular Effects 0.000 description 1
- 125000001935 tetracenyl group Chemical group C1(=CC=CC2=CC3=CC4=CC=CC=C4C=C3C=C12)* 0.000 description 1
- QZZGJDVWLFXDLK-UHFFFAOYSA-N tetracosanoic acid Chemical class CCCCCCCCCCCCCCCCCCCCCCCC(O)=O QZZGJDVWLFXDLK-UHFFFAOYSA-N 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- RTKIYNMVFMVABJ-UHFFFAOYSA-L thimerosal Chemical compound [Na+].CC[Hg]SC1=CC=CC=C1C([O-])=O RTKIYNMVFMVABJ-UHFFFAOYSA-L 0.000 description 1
- 229960004906 thiomersal Drugs 0.000 description 1
- 150000003577 thiophenes Chemical class 0.000 description 1
- QVMPZNRFXAKISM-UHFFFAOYSA-N tirapazamine Chemical compound C1=CC=C2[N+]([O-])=NC(=N)N(O)C2=C1 QVMPZNRFXAKISM-UHFFFAOYSA-N 0.000 description 1
- 238000006257 total synthesis reaction Methods 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 231100000440 toxicity profile Toxicity 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- 206010044412 transitional cell carcinoma Diseases 0.000 description 1
- 210000002993 trophoblast Anatomy 0.000 description 1
- 210000001635 urinary tract Anatomy 0.000 description 1
- 238000001291 vacuum drying Methods 0.000 description 1
- CILBMBUYJCWATM-PYGJLNRPSA-N vinorelbine ditartrate Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O.OC(=O)[C@H](O)[C@@H](O)C(O)=O.C1N(CC=2C3=CC=CC=C3NC=22)CC(CC)=C[C@H]1C[C@]2(C(=O)OC)C1=CC([C@]23[C@H]([C@@]([C@H](OC(C)=O)[C@]4(CC)C=CCN([C@H]34)CC2)(O)C(=O)OC)N2C)=C2C=C1OC CILBMBUYJCWATM-PYGJLNRPSA-N 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/12—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains three hetero rings
- C07D491/14—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/22—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains four or more hetero rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
-
- 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
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
Landscapes
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Organic Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Medicinal Chemistry (AREA)
- Public Health (AREA)
- Epidemiology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Applications Claiming Priority (5)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US72892405P | 2005-10-21 | 2005-10-21 | |
| US728924P | 2005-10-21 | ||
| US11/444,150 US7875602B2 (en) | 2005-10-21 | 2006-05-30 | Camptothecin derivatives as chemoradiosensitizing agents |
| US444150 | 2006-05-30 | ||
| PCT/US2006/041175 WO2007048002A2 (en) | 2005-10-21 | 2006-10-19 | Camptothecin derivatives as chemoradiosensitizing agents |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| ES2428088T3 true ES2428088T3 (es) | 2013-11-05 |
Family
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Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| ES06836448T Active ES2428088T3 (es) | 2005-10-21 | 2006-10-19 | Derivados de camptotecina como agentes quimioradiosensibilizadores |
Country Status (11)
| Country | Link |
|---|---|
| US (3) | US7875602B2 (enExample) |
| EP (1) | EP1951231B1 (enExample) |
| JP (1) | JP5328357B2 (enExample) |
| KR (1) | KR101320160B1 (enExample) |
| CN (1) | CN101300009B (enExample) |
| AU (1) | AU2006304811C1 (enExample) |
| CA (1) | CA2626032C (enExample) |
| ES (1) | ES2428088T3 (enExample) |
| NZ (2) | NZ593706A (enExample) |
| TW (1) | TWI402270B (enExample) |
| WO (1) | WO2007048002A2 (enExample) |
Families Citing this family (21)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101402640B (zh) * | 2008-09-02 | 2011-06-15 | 暨南大学 | 双酯化喜树碱衍生物及其制备方法和应用 |
| DE102009004204A1 (de) * | 2009-01-09 | 2010-07-15 | Christian-Albrechts-Universität Zu Kiel | Verfahren zur verbesserten Bioaktivierung von Arzneistoffen |
| US8168648B2 (en) * | 2009-03-06 | 2012-05-01 | Taiwan Liposome Co., Ltd. | Camptothecin derivatives and uses thereof |
| US8575188B2 (en) | 2009-06-17 | 2013-11-05 | Threshold Pharmaceuticals, Inc. | Camptothecin derivatives |
| US10391056B2 (en) | 2011-11-03 | 2019-08-27 | Taiwan Lipsome Company, LTD. | Pharmaceutical compositions of hydrophobic camptothecin derivatives |
| US10980798B2 (en) | 2011-11-03 | 2021-04-20 | Taiwan Liposome Company, Ltd. | Pharmaceutical compositions of hydrophobic camptothecin derivatives |
| US20140135357A1 (en) * | 2012-11-12 | 2014-05-15 | Taiwan Liposome Company, Ltd. | Dose regime for camptothecin derivatives |
| AU2014216178B2 (en) | 2013-02-15 | 2018-06-28 | KALA BIO, Inc. | Therapeutic compounds and uses thereof |
| US9688688B2 (en) | 2013-02-20 | 2017-06-27 | Kala Pharmaceuticals, Inc. | Crystalline forms of 4-((4-((4-fluoro-2-methyl-1H-indol-5-yl)oxy)-6-methoxyquinazolin-7-yl)oxy)-1-(2-oxa-7-azaspiro[3.5]nonan-7-yl)butan-1-one and uses thereof |
| EP2958895B1 (en) | 2013-02-20 | 2020-08-19 | Kala Pharmaceuticals, Inc. | Therapeutic compounds and uses thereof |
| US9890173B2 (en) | 2013-11-01 | 2018-02-13 | Kala Pharmaceuticals, Inc. | Crystalline forms of therapeutic compounds and uses thereof |
| CA2928658A1 (en) | 2013-11-01 | 2015-05-07 | Kala Pharmaceuticals, Inc. | Crystalline forms of therapeutic compounds and uses thereof |
| WO2015098963A1 (ja) | 2013-12-26 | 2015-07-02 | 東亞合成株式会社 | カルレティキュリンの発現促進方法および該方法に用いられる合成ペプチド |
| JP6872713B2 (ja) | 2015-05-29 | 2021-05-19 | 東亞合成株式会社 | 腫瘍細胞の放射線感受性を増大させる合成ペプチド及びその利用 |
| US10087194B2 (en) | 2015-10-27 | 2018-10-02 | California Pacific Medical Center | Podophyllotoxin derivatives and their use |
| ES2806624T3 (es) | 2015-10-27 | 2021-02-18 | California Pacific Medical Center | Derivados de podofilotoxina y su uso |
| AU2017324713B2 (en) | 2016-09-08 | 2020-08-13 | KALA BIO, Inc. | Crystalline forms of therapeutic compounds and uses thereof |
| CA3036340A1 (en) | 2016-09-08 | 2018-03-15 | Kala Pharmaceuticals, Inc. | Crystalline forms of therapeutic compounds and uses thereof |
| CA3036065A1 (en) | 2016-09-08 | 2018-03-15 | Kala Pharmaceuticals, Inc. | Crystalline forms of therapeutic compounds and uses thereof |
| CN114341141A (zh) | 2019-07-11 | 2022-04-12 | 太阳医药高级研究有限公司 | 具有二硫部分和哌嗪部分的喜树碱衍生物 |
| JP2023512214A (ja) | 2020-01-28 | 2023-03-24 | リフレクション メディカル， インコーポレイテッド | 放射性核種および外部ビーム放射線療法の共同最適化 |
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-
2006
- 2006-05-30 US US11/444,150 patent/US7875602B2/en active Active
- 2006-10-19 WO PCT/US2006/041175 patent/WO2007048002A2/en not_active Ceased
- 2006-10-19 CN CN2006800390612A patent/CN101300009B/zh not_active Expired - Fee Related
- 2006-10-19 ES ES06836448T patent/ES2428088T3/es active Active
- 2006-10-19 KR KR1020087012095A patent/KR101320160B1/ko not_active Expired - Fee Related
- 2006-10-19 AU AU2006304811A patent/AU2006304811C1/en not_active Ceased
- 2006-10-19 NZ NZ593706A patent/NZ593706A/xx not_active IP Right Cessation
- 2006-10-19 JP JP2008536850A patent/JP5328357B2/ja not_active Expired - Fee Related
- 2006-10-19 CA CA2626032A patent/CA2626032C/en active Active
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- 2006-10-19 EP EP06836448.8A patent/EP1951231B1/en active Active
- 2006-10-20 TW TW095138924A patent/TWI402270B/zh not_active IP Right Cessation
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2008
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-
2011
- 2011-01-24 US US13/012,772 patent/US8779138B2/en active Active
Also Published As
| Publication number | Publication date |
|---|---|
| CA2626032C (en) | 2011-12-06 |
| AU2006304811C1 (en) | 2012-11-01 |
| NZ593706A (en) | 2012-11-30 |
| TWI402270B (zh) | 2013-07-21 |
| NZ567454A (en) | 2011-07-29 |
| US20110184009A1 (en) | 2011-07-28 |
| JP5328357B2 (ja) | 2013-10-30 |
| TW200730532A (en) | 2007-08-16 |
| AU2006304811B2 (en) | 2012-03-22 |
| WO2007048002A2 (en) | 2007-04-26 |
| US7875602B2 (en) | 2011-01-25 |
| WO2007048002A3 (en) | 2007-09-13 |
| EP1951231A4 (en) | 2010-09-22 |
| JP2009512714A (ja) | 2009-03-26 |
| US8563537B2 (en) | 2013-10-22 |
| CA2626032A1 (en) | 2007-04-26 |
| KR101320160B1 (ko) | 2013-10-23 |
| EP1951231A2 (en) | 2008-08-06 |
| US8779138B2 (en) | 2014-07-15 |
| HK1115321A1 (en) | 2008-11-28 |
| AU2006304811A1 (en) | 2007-04-26 |
| US20070093432A1 (en) | 2007-04-26 |
| EP1951231B1 (en) | 2013-07-31 |
| CN101300009A (zh) | 2008-11-05 |
| KR20080086436A (ko) | 2008-09-25 |
| US20080318873A1 (en) | 2008-12-25 |
| CN101300009B (zh) | 2013-04-03 |
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