JP4760712B2 - 新規ニトロフェニルマスタードおよびニトロフェニルアジリジンアルコールおよびそれらの対応するリン酸エステルおよびターゲットが決められた細胞毒性剤としてのそれらの使用 - Google Patents
新規ニトロフェニルマスタードおよびニトロフェニルアジリジンアルコールおよびそれらの対応するリン酸エステルおよびターゲットが決められた細胞毒性剤としてのそれらの使用 Download PDFInfo
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- JP4760712B2 JP4760712B2 JP2006537921A JP2006537921A JP4760712B2 JP 4760712 B2 JP4760712 B2 JP 4760712B2 JP 2006537921 A JP2006537921 A JP 2006537921A JP 2006537921 A JP2006537921 A JP 2006537921A JP 4760712 B2 JP4760712 B2 JP 4760712B2
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- Prior art keywords
- amino
- ethyl
- carbonyl
- bromoethyl
- formula
- 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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- 238000000034 method Methods 0.000 claims description 31
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- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 18
- 229910019142 PO4 Inorganic materials 0.000 claims description 17
- 239000010452 phosphate Substances 0.000 claims description 17
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 17
- 201000011510 cancer Diseases 0.000 claims description 15
- 125000000217 alkyl group Chemical group 0.000 claims description 13
- 125000004663 dialkyl amino group Chemical group 0.000 claims description 13
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- 125000002490 anilino group Chemical group [H]N(*)C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims description 8
- PLUBXMRUUVWRLT-UHFFFAOYSA-N Ethyl methanesulfonate Chemical compound CCOS(C)(=O)=O PLUBXMRUUVWRLT-UHFFFAOYSA-N 0.000 claims description 6
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- CCQRILWYQGCXNU-UHFFFAOYSA-N 2-[[2-[bis(2-chloroethyl)amino]-3,5-dinitrobenzoyl]amino]ethyl dihydrogen phosphate Chemical compound OP(O)(=O)OCCNC(=O)C1=CC([N+]([O-])=O)=CC([N+]([O-])=O)=C1N(CCCl)CCCl CCQRILWYQGCXNU-UHFFFAOYSA-N 0.000 claims description 3
- AJUYDWUWNBPUND-UHFFFAOYSA-N 2-[[2-[bis(2-iodoethyl)amino]-3,5-dinitrobenzoyl]amino]ethyl dihydrogen phosphate Chemical compound OP(O)(=O)OCCNC(=O)C1=CC([N+]([O-])=O)=CC([N+]([O-])=O)=C1N(CCI)CCI AJUYDWUWNBPUND-UHFFFAOYSA-N 0.000 claims description 3
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- HFZHSYXJPOMEFV-UHFFFAOYSA-N 3-[[5-[bis(2-bromoethyl)amino]-2,4-dinitrobenzoyl]amino]propyl dihydrogen phosphate Chemical compound OP(O)(=O)OCCCNC(=O)C1=CC(N(CCBr)CCBr)=C([N+]([O-])=O)C=C1[N+]([O-])=O HFZHSYXJPOMEFV-UHFFFAOYSA-N 0.000 claims description 3
- 125000002467 phosphate group Chemical group [H]OP(=O)(O[H])O[*] 0.000 claims description 3
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- ALNMHZYCWFICCG-UHFFFAOYSA-N 2-[[2-[bis(2-bromoethyl)amino]-3,5-dinitrobenzoyl]amino]ethyl dihydrogen phosphate Chemical compound OP(O)(=O)OCCNC(=O)C1=CC([N+]([O-])=O)=CC([N+]([O-])=O)=C1N(CCBr)CCBr ALNMHZYCWFICCG-UHFFFAOYSA-N 0.000 claims description 2
- PJTGFDFFOIQANN-UHFFFAOYSA-N 3-[[5-[bis(2-chloroethyl)amino]-2,4-dinitrobenzoyl]amino]propyl dihydrogen phosphate Chemical compound OP(O)(=O)OCCCNC(=O)C1=CC(N(CCCl)CCCl)=C([N+]([O-])=O)C=C1[N+]([O-])=O PJTGFDFFOIQANN-UHFFFAOYSA-N 0.000 claims description 2
- 230000001225 therapeutic effect Effects 0.000 claims description 2
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- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 21
- 238000010828 elution Methods 0.000 description 21
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 20
- 239000000047 product Substances 0.000 description 20
- 230000000694 effects Effects 0.000 description 16
- NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical compound CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 description 15
- 102000004459 Nitroreductase Human genes 0.000 description 15
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- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 14
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- 229940098779 methanesulfonic acid Drugs 0.000 description 13
- 230000026731 phosphorylation Effects 0.000 description 13
- 238000006366 phosphorylation reaction Methods 0.000 description 13
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 11
- 239000002253 acid Substances 0.000 description 10
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- 231100000682 maximum tolerated dose Toxicity 0.000 description 10
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- 239000002619 cytotoxin Substances 0.000 description 8
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Images
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/28—Phosphorus compounds with one or more P—C bonds
- C07F9/38—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)]
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/06—Phosphorus compounds without P—C bonds
- C07F9/08—Esters of oxyacids of phosphorus
- C07F9/09—Esters of phosphoric acids
- C07F9/091—Esters of phosphoric acids with hydroxyalkyl compounds with further substituents on alkyl
-
- 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
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
- C07C237/28—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a non-condensed six-membered aromatic ring of the carbon skeleton
- C07C237/32—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a non-condensed six-membered aromatic ring of the carbon skeleton having the nitrogen atom of the carboxamide group bound to an acyclic carbon atom of a hydrocarbon radical substituted by oxygen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C309/00—Sulfonic acids; Halides, esters, or anhydrides thereof
- C07C309/63—Esters of sulfonic acids
- C07C309/64—Esters of sulfonic acids having sulfur atoms of esterified sulfo groups bound to acyclic carbon atoms
- C07C309/65—Esters of sulfonic acids having sulfur atoms of esterified sulfo groups bound to acyclic carbon atoms of a saturated carbon skeleton
- C07C309/66—Methanesulfonates
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C317/00—Sulfones; Sulfoxides
- C07C317/44—Sulfones; Sulfoxides having sulfone or sulfoxide groups and carboxyl groups bound to the same carbon skeleton
- C07C317/48—Sulfones; Sulfoxides having sulfone or sulfoxide groups and carboxyl groups bound to the same carbon skeleton the carbon skeleton being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D203/00—Heterocyclic compounds containing three-membered rings with one nitrogen atom as the only ring hetero atom
- C07D203/04—Heterocyclic compounds containing three-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings
- C07D203/06—Heterocyclic compounds containing three-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
- C07D203/08—Heterocyclic compounds containing three-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring nitrogen atom
- C07D203/14—Heterocyclic compounds containing three-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring nitrogen atom with carbocyclic rings directly attached to the ring nitrogen atom
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Molecular Biology (AREA)
- Biochemistry (AREA)
- General Chemical & Material Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Radiation-Therapy Devices (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Applications Claiming Priority (5)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| NZ529249A NZ529249A (en) | 2003-10-31 | 2003-10-31 | Novel nitrophenyl mustard and nitrophenylaziridine alcohols and their corresponding phosphates and their use as targeted cytotoxic |
| NZ529249 | 2003-10-31 | ||
| NZ53561804 | 2004-09-28 | ||
| NZ535618 | 2004-09-28 | ||
| PCT/NZ2004/000275 WO2005042471A1 (en) | 2003-10-31 | 2004-10-29 | Novel nitrophenyl mustard and nitrophenylaziridine alcohols and their corresponding phosphates and their use as targeted cytotoxic agents |
Publications (3)
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| JP2007509928A JP2007509928A (ja) | 2007-04-19 |
| JP2007509928A5 JP2007509928A5 (enExample) | 2007-10-11 |
| JP4760712B2 true JP4760712B2 (ja) | 2011-08-31 |
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| EP (1) | EP1680394A4 (enExample) |
| JP (1) | JP4760712B2 (enExample) |
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| IL (1) | IL175000A0 (enExample) |
| RU (1) | RU2372324C2 (enExample) |
| WO (1) | WO2005042471A1 (enExample) |
Families Citing this family (25)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP4760712B2 (ja) * | 2003-10-31 | 2011-08-31 | オークランド ユニサーヴィスィズ リミテッド | 新規ニトロフェニルマスタードおよびニトロフェニルアジリジンアルコールおよびそれらの対応するリン酸エステルおよびターゲットが決められた細胞毒性剤としてのそれらの使用 |
| NZ549659A (en) * | 2006-09-04 | 2008-12-24 | Auckland Uniservices Ltd | Processes of preparing asymmetric dinitrobenzamide mustard compounds, intermediate compounds useful therein and products obtained therefrom |
| WO2008033041A1 (en) * | 2006-09-11 | 2008-03-20 | Auckland Uniservices Limited | Cancer treatment |
| WO2008033039A1 (en) * | 2006-09-11 | 2008-03-20 | Adam Vorn Patterson | Cancer treatment |
| NZ549831A (en) * | 2006-09-11 | 2009-03-31 | Auckland Uniservices Ltd | Combination of docetaxel and a nitrophenyl phosphate derivative for the treatment of cancer |
| ES2884044T3 (es) | 2006-12-26 | 2021-12-10 | Immunogenesis Inc | Profármaco alquilante de fosforamidato para el tratamiento del cáncer |
| US8309554B2 (en) * | 2008-05-15 | 2012-11-13 | Threshold Pharmaceuticals | Hypoxia activated drugs of nitrogen mustard alkylators |
| WO2010044685A1 (en) * | 2008-10-17 | 2010-04-22 | Auckland Uniservices Limited | Nitrophenyl mustard alcohols, their corresponding phosphates and their use as targeted cytotoxic agents |
| JP5765634B2 (ja) | 2008-10-21 | 2015-08-19 | スレッシュホールド ファーマシューティカルズ, インコーポレイテッド | 低酸素活性化型プロドラッグを用いるがんの処置 |
| CN101723932B (zh) | 2008-10-31 | 2013-11-20 | 北京以岭生物工程技术有限公司 | 硝基吡啶乙烯亚胺化合物、其药物组合物及其制备方法和用途 |
| RU2597844C2 (ru) | 2010-07-12 | 2016-09-20 | Тресхолд Фармасьютикалз, Инк. | Введение гипоксически активируемых пролекарств и средств, препятствующих ангиогенезу, для лечения рака |
| WO2012008860A2 (en) * | 2010-07-16 | 2012-01-19 | Auckland Uniservices Limited | Bacterial nitroreductase enzymes and methods relating thereto |
| JP6397765B2 (ja) * | 2011-11-11 | 2018-09-26 | ミレニアム ファーマシューティカルズ, インコーポレイテッドMillennium Pharmaceuticals, Inc. | プロテアソーム阻害剤に応答するバイオマーカー |
| WO2013096687A1 (en) | 2011-12-22 | 2013-06-27 | Threshold Pharmaceuticals, Inc. | Administration of hypoxia activated prodrugs in combination with chk1 inhibitors for treating cancer |
| US20150010474A1 (en) * | 2011-12-23 | 2015-01-08 | Auckland Uniservices Limited | Compounds And Methods For Selective Imaging And/Or Ablation |
| US10202408B2 (en) | 2012-08-23 | 2019-02-12 | Health Innovation Ventures B.V. | Prodrugs and methods of use thereof |
| US9505791B2 (en) | 2012-08-23 | 2016-11-29 | Health Innovation Ventures B.V. | Prodrugs and methods of use thereof |
| WO2014062856A1 (en) | 2012-10-16 | 2014-04-24 | Halozyme, Inc. | Hypoxia and hyaluronan and markers thereof for diagnosis and monitoring of diseases and conditions and related methods |
| WO2015013448A1 (en) | 2013-07-26 | 2015-01-29 | Threshold Pharmaceuticals, Inc. | Treatment of pancreatic cancer with a combination of a hypoxia-acti vated prodrug and a taxane |
| CA2990665A1 (en) | 2015-06-24 | 2016-12-29 | Threshold Pharmaceuticals, Inc. | Aziridine containing dna alkylating agents |
| US10348685B2 (en) * | 2016-04-29 | 2019-07-09 | Nicira, Inc. | Priority allocation for distributed service rules |
| CN108571241B (zh) * | 2017-03-14 | 2021-08-17 | 福特环球技术公司 | 用于推按式闩锁类型车辆抽屉的惯性锁系统 |
| WO2019125184A1 (en) | 2017-12-19 | 2019-06-27 | Auckland Uniservices Limited | Use of biomarker in cancer therapy |
| EP3774743B1 (en) * | 2018-03-29 | 2023-11-22 | Achilles Medical Limited | Prodrug compounds activated by akr1c3 and their use for treating hyperproliferative disorders |
| JP7541512B2 (ja) * | 2018-05-30 | 2024-08-28 | コンバート ファーマシューティカルズ エス.エー. | プロドラッグおよびその医学的使用 |
Citations (2)
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|---|---|---|---|---|
| JP2002541057A (ja) * | 1998-09-07 | 2002-12-03 | キャンサー リサーチ キャンペーン テクノロジー リミティド | 新規なニトロフェニルアジリジン化合物およびプロドラッグとしてのその使用 |
| JP2006502214A (ja) * | 2002-10-08 | 2006-01-19 | オークランド ユニサーヴィスィズ リミテッド | ニトロアニリン系のアルキル化剤およびそれらのプロドラッグとしての使用 |
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|---|---|---|---|---|
| NZ240785A (en) * | 1991-11-28 | 1995-08-28 | Cancer Res Campaign Tech | Substituted nitro aniline derivatives and medicaments |
| JP2005504789A (ja) * | 2001-09-13 | 2005-02-17 | シンタ ファーマスーティカルズ コーポレイション | 癌治療のための2−アロイルイミダゾール化合物 |
| JP4760712B2 (ja) * | 2003-10-31 | 2011-08-31 | オークランド ユニサーヴィスィズ リミテッド | 新規ニトロフェニルマスタードおよびニトロフェニルアジリジンアルコールおよびそれらの対応するリン酸エステルおよびターゲットが決められた細胞毒性剤としてのそれらの使用 |
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2004
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- 2004-10-29 RU RU2006118785/04A patent/RU2372324C2/ru not_active IP Right Cessation
- 2004-10-29 WO PCT/NZ2004/000275 patent/WO2005042471A1/en not_active Ceased
- 2004-10-29 KR KR1020067010566A patent/KR101167335B1/ko not_active Expired - Fee Related
- 2004-10-29 AU AU2004285831A patent/AU2004285831B2/en not_active Ceased
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- 2006-04-11 IL IL175000A patent/IL175000A0/en unknown
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2009
- 2009-08-11 US US12/461,419 patent/US20100010094A1/en not_active Abandoned
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2002541057A (ja) * | 1998-09-07 | 2002-12-03 | キャンサー リサーチ キャンペーン テクノロジー リミティド | 新規なニトロフェニルアジリジン化合物およびプロドラッグとしてのその使用 |
| JP2006502214A (ja) * | 2002-10-08 | 2006-01-19 | オークランド ユニサーヴィスィズ リミテッド | ニトロアニリン系のアルキル化剤およびそれらのプロドラッグとしての使用 |
Also Published As
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| RU2372324C2 (ru) | 2009-11-10 |
| KR20070006677A (ko) | 2007-01-11 |
| US20070032455A1 (en) | 2007-02-08 |
| US20100010094A1 (en) | 2010-01-14 |
| AU2004285831A1 (en) | 2005-05-12 |
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| AU2004285831B2 (en) | 2011-09-15 |
| CA2544335A1 (en) | 2005-05-12 |
| EP1680394A1 (en) | 2006-07-19 |
| JP2007509928A (ja) | 2007-04-19 |
| EP1680394A4 (en) | 2006-10-11 |
| RU2006118785A (ru) | 2007-12-10 |
| BRPI0416085A (pt) | 2007-01-02 |
| IL175000A0 (en) | 2006-08-20 |
| WO2005042471A1 (en) | 2005-05-12 |
| KR101167335B1 (ko) | 2012-07-19 |
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