FI89923B - Foerfarande foer framstaellning av farmaceutiskt aktiva, vattenloesliga kamptotesinanaloger - Google Patents
Foerfarande foer framstaellning av farmaceutiskt aktiva, vattenloesliga kamptotesinanaloger Download PDFInfo
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- FI89923B FI89923B FI885569A FI885569A FI89923B FI 89923 B FI89923 B FI 89923B FI 885569 A FI885569 A FI 885569A FI 885569 A FI885569 A FI 885569A FI 89923 B FI89923 B FI 89923B
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- hydroxy
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- 230000000694 effects Effects 0.000 title description 48
- 150000001875 compounds Chemical class 0.000 claims abstract description 248
- 238000002360 preparation method Methods 0.000 claims abstract description 42
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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
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Animal Behavior & Ethology (AREA)
- Medicinal Chemistry (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Steroid Compounds (AREA)
- Semiconductor Lasers (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
- Medicines Containing Material From Animals Or Micro-Organisms (AREA)
Claims (17)
1. Förfarande för framställning av en farmaceutiskt aktiv förening med formeln I eller ett farmaceutiskt acceptabelt sait, hydrat eller soivat därav: R x\i° I9 I A || B I C N_^0 d) \ I ch3 oh väri: X är hydroxi; väte; cyan; -CH2NH2; eller formyl; R är väte dä X är cyan, CH2NH2 eller formyl; eller R är formyl; cyanmetyl eller -C^R1 dä X är väte eller hydroxi; R1 är -0-R2; -S-R2; -N-R2(R3); eller -N+-R2 (R3) (R4) , förutsatt att dä R1 är -N+-R2 (R3) (R4) , är föreningen förenad med en far-maceutiskt acceptabel anjon; R2, R3 och R4 är lika eller oli-ka och är valda bland H; Cj.g-alkyl; C2.6-hydroxialkyl; C^.g-dialkylamino; C^.g-dialkylamino-C^.g-alkyl; C^.g-alkylamino-C2_6-alkyl; C2.6-aminoalkyl eller en 3-7 ledad osubstituerad eller substituerad karbocyklisk ring; och dä R1 är -N-R2(R3) kan kan R2- och R3-grupperna vara förenade med kväveatomen vid vilken de är bundna för att bilda en heterocyklisk ring som ytterligare kan innehälla en syre- eller kväveatom och som kan vara substituerad med t.ex. en alkyl- eller piperi-dingrupp, kännetecknat av att förfarandet omfattar: (a) kondensation av 10-hydroxikamptotesin med formaldehyd och en lämplig primär eller sekundär amin, varvid man erhäl-ler samtliga föreningar med formeln I förutom föreningen väri X är väte, cyan eller formyl, och R1 är -N-R2(R3) och R2 och R3 är lika och betecknar H; eller (b) formylering av 10-hydroxikamptotesin, varvid man erhäl-ler 9 - formyl-10 -hydroxikamptotesin som därefter utsätts för kondensation med lämpliga aminer med efterföljande reduktion med natriumcyanborohydrid eller katalytisk reduktion; eller 11 71 39923 (c) behandling av lämpliga föreningar med formeln I väri R1 är -N-R2(R3) med ett alkyleringsmedel, varvid man erhäller motsvarande föreningar med formeln I väri R1 är -N+-R2(R3) (R1) och R2, R3 och R1 icke är väte, eller (d) uppvärmning av 9-dimetylaminometyl-10-hydroxikamptotesin eller ett salt därav med en lämplig alkohol eller tiol i ett inert losningsmedel under bildning av föreningar med formeln I väri R1 är -0-R2 eller -S-R2; eller (e) utsättande av trifluormetylsulfonatet av 10-hydroxikamp-totesin för palladium-katalyserad karbonylering; eller (f) omsättning av en förening med formeln I väri R är -CH2-N+R2(R3) (R1) med en cyanid, varvid man erhäller motsvarande förening med formeln I väri R är cyanmetyl; eller (g) reducering av en förening med formeln I väri R är cyanmetyl , varvid man erhäller motsvarande förening med formeln I väri R är aminometyl.
2. Förfarande enligt patentkravet 1, kannetecknat av att man framställer en förening med formeln I väri X är hydroxi och R är dimetylaminometyl, N-morfolinometyl, N-metylpiper-azinylmetyl, (4'-piperidin)N-piperidinylmetyl, (2'-hydroxi-etyl)aminometyl, trimetylamrnoniummetyl, cyklohexylaminome-tyl, N-metylanilinmetyl, etoximetyl, cyklopropylaminometyl, N,N-dimetylaminoetyloximetyl, N,N-dimetylaminoetyltiometyl, Ν,Ν-dimetylaminoetylaminometyl, cyanmetyl, aminometyl eller formyl eller väri R är väte och X är cyan, formyl eller aminometyl, eller väri X är väte och R är dimetylaminometyl eller N-morfolinometyl.
3. Förfarande enligt patentkravet 1, kännetecknat av att man framställer S-isomeren av en förening med formeln I. Förfarande enligt patentkravet 1, kännetecknat av att man framställer den rasemiska blandningen av en förening med formeln I. :‘i r\ -7 η 2 ·> y >' L 3
5. Förfarande enligt patentkravet 1, kännetecknat av att man framställer S-isomeren av en förening med formeln I vari X är hydroxi och R är dimetylaminometyl.
6. Förfarande enligt patentkravet 5, kännetecknat av att man framställer acetatsaltet av föreningen.
7. Förfarande enligt patentkravet 5, kännetecknat av att man framställer monohydroklorid-, dihydroklorid- eller nat-riumsaltet av föreningen.
8. Förfarande enligt patentkravet 1, kännetecknat av att man framställer S-isomeren av en förening med formeln I vari X är hydroxi och R är trimetylammoniummetyl.
9. Förfarande enligt patentkravet 1, kännetecknat av att man framställer S-isomeren av en förening med formeln I vari X är hydroxi och R är N-metylpiperazinylmetyl.
10. Förfarande enligt patentkravet 1, kännetecknat av att man framställer S-isomeren av en förening med formeln I vari X är hydroxi och R är N-metylanilinmetyl.
11. Förfarande enligt patentkravet 1, kännetecknat av att man framställer S-isomeren av en förening med formeln I vari X är hydroxi och R är cyklohexylaminometyl.
12. Förfarande enligt patentkravet 1, kännetecknat av att man framställer S-isomeren av en förening med formeln I vari X är hydroxi och R är N,N-dimetylaminoetyloximetyl.
13. Förfarande enligt patentkravet 1, kännetecknat av att man framställer S-isomeren av en förening med formeln I vari X är hydroxi och R är cyanmetyl.
14. Förfarande enligt patentkravet 1, kännetecknat av att man framställer S-isomeren av en förening med formeln I vari X är hydroxi och R är morfolinometyl. II ·; '·; 92 3
73 J 7 L °
15. Förfarande enligt patentkravet 1, kännetecknat av att man framstSller S-isomeren av en förening med formeln I vari X är hydroxi och R Sr aminometyl.
16. Förfarande enligt patentkravet 1, kännetecknat av att man framstSller S-isomeren av en förening med formeln I vari X Sr hydroxi och R Sr N-cyklopropylaminometyl.
17. Förening med formeln CF3SO2-O^i0 y'A ij B^Tc N__^0 d)—V II '-\ E/° oh
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US12714887A | 1987-12-01 | 1987-12-01 | |
| US12714887 | 1987-12-01 |
Publications (4)
| Publication Number | Publication Date |
|---|---|
| FI885569A0 FI885569A0 (fi) | 1988-11-30 |
| FI885569L FI885569L (fi) | 1989-06-02 |
| FI89923B true FI89923B (fi) | 1993-08-31 |
| FI89923C FI89923C (sv) | 1993-12-10 |
Family
ID=22428545
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| FI885569A FI89923C (sv) | 1987-12-01 | 1988-11-30 | Förfarande för framställning av farmaceutiskt aktiva, vattenlösliga ka mptotesinanaloger |
Country Status (25)
| Country | Link |
|---|---|
| US (1) | US5004758A (sv) |
| EP (1) | EP0321122B1 (sv) |
| JP (1) | JPH0633268B2 (sv) |
| KR (1) | KR930009357B1 (sv) |
| CN (3) | CN1027265C (sv) |
| AT (1) | ATE143368T1 (sv) |
| AU (1) | AU612735B2 (sv) |
| CA (1) | CA1308102C (sv) |
| CY (1) | CY2017A (sv) |
| DE (2) | DE19775017I2 (sv) |
| DK (1) | DK173034B1 (sv) |
| ES (1) | ES2094721T3 (sv) |
| FI (1) | FI89923C (sv) |
| GR (1) | GR3021990T3 (sv) |
| HK (1) | HK81097A (sv) |
| IE (1) | IE74873B1 (sv) |
| IL (1) | IL88517A (sv) |
| LU (2) | LU90026I2 (sv) |
| MX (1) | MX9203744A (sv) |
| NL (1) | NL970017I2 (sv) |
| NO (2) | NO170487C (sv) |
| NZ (1) | NZ227124A (sv) |
| PT (1) | PT89111B (sv) |
| SG (1) | SG66254A1 (sv) |
| ZA (1) | ZA888938B (sv) |
Families Citing this family (141)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5106742A (en) * | 1987-03-31 | 1992-04-21 | Wall Monroe E | Camptothecin analogs as potent inhibitors of topoisomerase I |
| US5227380A (en) * | 1987-03-31 | 1993-07-13 | Research Triangle Institute | Pharmaceutical compositions and methods employing camptothecins |
| US5053512A (en) * | 1987-04-14 | 1991-10-01 | Research Triangle Institute | Total synthesis of 20(S) and 20(R)-camptothecin and compthothecin derivatives |
| US5122526A (en) * | 1987-03-31 | 1992-06-16 | Research Triangle Institute | Camptothecin and analogs thereof and pharmaceutical compositions and method using them |
| US5364858A (en) * | 1987-03-31 | 1994-11-15 | Research Triangle Institute | Camptothecin analogs as potent inhibitors of topoisomerase I |
| US5180722A (en) * | 1987-04-14 | 1993-01-19 | Research Triangle Institute | 10,11-methylenedioxy-20(RS)-camptothecin and 10,11-methylenedioxy-20(S)-camptothecin analogs |
| US5340817A (en) * | 1987-04-14 | 1994-08-23 | Research Triangle Institute | Method of treating tumors with anti-tumor effective camptothecin compounds |
| US5049668A (en) * | 1989-09-15 | 1991-09-17 | Research Triangle Institute | 10,11-methylenedioxy-20(RS)-camptothecin analogs |
| US5122606A (en) * | 1987-04-14 | 1992-06-16 | Research Triangle Institute | 10,11-methylenedioxy camptothecins |
| US4939255A (en) * | 1987-06-24 | 1990-07-03 | Daiichi Pharmaceutical Co., Ltd. | Hexa-cyclic camptothecin derivatives |
| US5552154A (en) * | 1989-11-06 | 1996-09-03 | The Stehlin Foundation For Cancer Research | Method for treating cancer with water-insoluble s-camptothecin of the closed lactone ring form and derivatives thereof |
| JP2684104B2 (ja) * | 1990-02-09 | 1997-12-03 | 株式会社ヤクルト本社 | 新規なカンプトテシン誘導体 |
| CZ51593A3 (en) * | 1990-09-28 | 1994-01-19 | Smithkline Beecham Corp | Water-soluble analogs of camptothecine, process of their preparation and use |
| US5883255A (en) * | 1990-10-31 | 1999-03-16 | Smithkline Beecham Corporation | Substituted indolizino 1,2-b!quinolinones |
| KR930702984A (ko) * | 1991-02-21 | 1993-11-29 | 스튜어트 알. 슈터 | 비-소세포 폐암의 치료 |
| DE69233793D1 (de) * | 1991-02-21 | 2010-09-16 | Glaxosmithkline Llc | Pharmazeutische Zusammensetzung zur Verwendung in der Behandlung von Eierstockkrebs |
| EP0572563A4 (en) * | 1991-02-21 | 1993-12-29 | Smithkline Beecham Corporation | Treatment of esophageal cancer |
| US5559235A (en) * | 1991-10-29 | 1996-09-24 | Glaxo Wellcome Inc. | Water soluble camptothecin derivatives |
| ES2086643T3 (es) * | 1991-10-29 | 1996-07-01 | Glaxo Wellcome Inc | Derivados de camptotecina solubles en agua. |
| ZA928771B (en) | 1991-11-15 | 1993-09-08 | Smithkline Beecham Corp | Combination chemotherapy |
| CA2125293A1 (en) * | 1991-12-10 | 1993-06-24 | Randall Keith Johnson | Treatment of colorectal cancer |
| US6080751A (en) * | 1992-01-14 | 2000-06-27 | The Stehlin Foundation For Cancer Research | Method for treating pancreatic cancer in humans with water-insoluble S-camptothecin of the closed lactone ring form and derivatives thereof |
| US5446047A (en) * | 1992-07-23 | 1995-08-29 | Sloan-Kettering Institute For Cancer Research | Camptothecin analogues |
| US5391745A (en) * | 1992-07-23 | 1995-02-21 | Sloan-Kettering Institute For Cancer Research | Methods of preparation of camptothecin analogs |
| US5614549A (en) * | 1992-08-21 | 1997-03-25 | Enzon, Inc. | High molecular weight polymer-based prodrugs |
| EP0655919A4 (en) * | 1992-08-21 | 1995-10-18 | Dana Farber Cancer Inst Inc | TREATING VIRUS INFECTIONS IN HUMANS. |
| US5342947A (en) * | 1992-10-09 | 1994-08-30 | Glaxo Inc. | Preparation of water soluble camptothecin derivatives |
| AP9300587A0 (en) * | 1992-11-12 | 1995-05-05 | Glaxo Inc | Water soluble camptothecin derivatives. |
| US5674872A (en) * | 1993-08-20 | 1997-10-07 | Smithkline Beecham Corporation | Treatment of ovarian cancer |
| US5880131A (en) * | 1993-10-20 | 1999-03-09 | Enzon, Inc. | High molecular weight polymer-based prodrugs |
| JPH09504033A (ja) * | 1993-10-20 | 1997-04-22 | エンゾン，インコーポレーテッド | ２’−及び／又は７−置換タキソイド類 |
| US5436243A (en) * | 1993-11-17 | 1995-07-25 | Research Triangle Institute Duke University | Aminoanthraquinone derivatives to combat multidrug resistance |
| US5447936A (en) * | 1993-12-22 | 1995-09-05 | Bionumerik Pharmaceuticals, Inc. | Lactone stable formulation of 10-hydroxy 7-ethyl camptothecin and methods for uses thereof |
| GB9402934D0 (en) * | 1994-02-16 | 1994-04-06 | Erba Carlo Spa | Camptothecin derivatives and process for their preparation |
| US5468754A (en) * | 1994-04-19 | 1995-11-21 | Bionumerik Pharmaceuticals, Inc. | 11,7 substituted camptothecin derivatives and formulations of 11,7 substituted camptothecin derivatives and methods for uses thereof |
| US5604233A (en) * | 1994-04-28 | 1997-02-18 | Bionumerik Pharmaceuticals, Inc. | Lactone stable formulation of 7-ethyl camptothecin and methods for uses thereof |
| US5597829A (en) * | 1994-05-09 | 1997-01-28 | Bionumerik Pharmaceuticals, Inc. | Lactone stable formulation of camptothecin and methods for uses thereof |
| CA2188297C (en) * | 1994-04-28 | 2006-12-19 | Frederick Herman Hausheer | Lactone stable formulation of camptothecin or 7-ethyl camptothecin |
| US5491237A (en) | 1994-05-03 | 1996-02-13 | Glaxo Wellcome Inc. | Intermediates in pharmaceutical camptothecin preparation |
| US5834442A (en) * | 1994-07-07 | 1998-11-10 | Barbara Ann Karmanos Cancer Institute | Method for inhibiting cancer metastasis by oral administration of soluble modified citrus pectin |
| US5646159A (en) * | 1994-07-20 | 1997-07-08 | Research Triangle Institute | Water-soluble esters of camptothecin compounds |
| US6504029B1 (en) * | 1995-04-10 | 2003-01-07 | Daiichi Pharmaceutical Co., Ltd. | Condensed-hexacyclic compounds and a process therefor |
| GB9510716D0 (en) * | 1995-05-26 | 1995-07-19 | Pharmacia Spa | Substituted camptothecin derivatives and process for their preparation |
| US5670500A (en) * | 1995-05-31 | 1997-09-23 | Smithkline Beecham Corporation | Water soluble camptothecin analogs |
| US5663177A (en) * | 1995-05-31 | 1997-09-02 | Smithkline Beecham Corporation | Water soluble camptothecin analogs |
| EP0835303A4 (en) * | 1995-06-07 | 2000-09-13 | Univ Jefferson | Anti-fungal agents and methods of identifying and using the same |
| AU7732996A (en) * | 1995-11-22 | 1997-06-11 | Research Triangle Institute | Camptothecin compounds with combined topoisomerase i inhibition and dna alkylation properties |
| US6395541B1 (en) | 1996-05-23 | 2002-05-28 | The Rockefeller University | Methods for the identification of compounds capable of inhibiting HIV-1 viral replication employing murine cell lines expressing human topoisomerase I |
| CA2262745C (en) * | 1996-08-19 | 2006-04-04 | Bionumerik Pharmaceuticals, Inc. | Highly lipophilic camptothecin derivatives |
| US6013505A (en) | 1996-10-08 | 2000-01-11 | Smithkline Beecham Corporation | Topoisomerase I |
| US6025156A (en) * | 1996-10-15 | 2000-02-15 | Smithkline Beecham Corporation | Topoisomerase III |
| US5962303A (en) * | 1996-10-15 | 1999-10-05 | Smithkline Beecham Corporation | Topoisomerase III |
| US6559309B2 (en) | 1996-11-01 | 2003-05-06 | Osi Pharmaceuticals, Inc. | Preparation of a camptothecin derivative by intramolecular cyclisation |
| DK1017675T3 (da) * | 1997-02-14 | 2006-10-16 | Bionumerik Pharmaceuticals Inc | Stærkt lipofile camptothecinderivater |
| US6207673B1 (en) | 1997-03-12 | 2001-03-27 | The University Of North Carolina At Chapel Hill | Covalent conjugates of topoisomerase I and topoisomerase II inhibitors |
| ID23424A (id) | 1997-05-14 | 2000-04-20 | Bayer Ag | Glikokonjugat dari 20(s)-kamptotesin |
| US6046209A (en) * | 1997-05-27 | 2000-04-04 | Smithkline Beecham Corporation | Water soluble camptothecin analogs |
| TW458974B (en) * | 1997-07-17 | 2001-10-11 | Kuraray Co | Process for producing chromans |
| US6011042A (en) * | 1997-10-10 | 2000-01-04 | Enzon, Inc. | Acyl polymeric derivatives of aromatic hydroxyl-containing compounds |
| US6214821B1 (en) | 1998-03-05 | 2001-04-10 | Washington State University Research Foundation | Methods and composition for the inhibition of cancer cells |
| HUP0103314A3 (en) * | 1998-08-05 | 2002-07-29 | Aventis Pharma Sa | Use of camptothecin derivatives, with reduced gastrointestinal toxicity |
| WO2001024763A2 (en) | 1999-10-01 | 2001-04-12 | Immunogen, Inc. | Compositions and methods for treating cancer using immunoconjugates and chemotherapeutic agents |
| FR2801309B1 (fr) * | 1999-11-18 | 2002-01-04 | Adir | Nouveaux composes analogues de la camptothecine, leur procede de preparation et les compositions pharmaceutiques qui les contiennent |
| US6288072B1 (en) * | 1999-12-29 | 2001-09-11 | Monroe E. Wall | Camptothecin β-alanine esters with topoisomerase I inhibition |
| HUP0300848A3 (en) | 2000-02-28 | 2005-03-29 | Aventis Pharma Sa | A composition comprising camptothecin and a pyrimidine derivative for the treatment of cancer |
| US6548488B2 (en) | 2000-03-17 | 2003-04-15 | Aventis Pharma S.A. | Composition comprising camptothecin or a camptothecin derivative and an alkylating agent for the treatment of cancer |
| US6545010B2 (en) | 2000-03-17 | 2003-04-08 | Aventis Pharma S.A. | Composition comprising camptothecin or a camptothecin derivative and a platin derivative for the treatment of cancer |
| AR027687A1 (es) * | 2000-03-22 | 2003-04-09 | Yakult Honsha Kk | Procedimiento para preparar camptotecina |
| US6486320B2 (en) | 2000-09-15 | 2002-11-26 | Aventis Pharma S.A. | Preparation of camptothecin and of its derivatives |
| KR100742524B1 (ko) | 2000-10-27 | 2007-08-02 | 아방티 파르마 소시에테 아노님 | 캄프토테신과 스틸벤 유도체를 포함하는 암 치료용 약제학적 병용제제 |
| WO2002040653A2 (en) * | 2000-11-14 | 2002-05-23 | Emerald Biostructures, Inc. | Chrystal compositions comprising topoisomerase i |
| JP4625637B2 (ja) | 2002-02-22 | 2011-02-02 | シャイア エルエルシー | 活性物質送達系及び活性物質を保護し投与する方法 |
| DE60238874D1 (de) * | 2002-03-26 | 2011-02-17 | Tsutomu Kagiya | Chromanol glucoside zur verbesserung der chemischen krebsbehandlung |
| ITRM20020306A1 (it) * | 2002-05-31 | 2003-12-01 | Sigma Tau Ind Farmaceuti | Esteri in posizione 20 di camptotecine. |
| US20040062748A1 (en) * | 2002-09-30 | 2004-04-01 | Mountain View Pharmaceuticals, Inc. | Polymer conjugates with decreased antigenicity, methods of preparation and uses thereof |
| US8129330B2 (en) * | 2002-09-30 | 2012-03-06 | Mountain View Pharmaceuticals, Inc. | Polymer conjugates with decreased antigenicity, methods of preparation and uses thereof |
| US8034831B2 (en) * | 2002-11-06 | 2011-10-11 | Celgene Corporation | Methods for the treatment and management of myeloproliferative diseases using 4-(amino)-2-(2,6-Dioxo(3-piperidyl)-isoindoline-1,3-dione in combination with other therapies |
| US7563810B2 (en) * | 2002-11-06 | 2009-07-21 | Celgene Corporation | Methods of using 3-(4-amino-1-oxo-1,3-dihydroisoindol-2-yl)-piperidine-2,6-dione for the treatment and management of myeloproliferative diseases |
| WO2004055020A1 (en) * | 2002-12-16 | 2004-07-01 | Council Of Scientific And Industrial Research | Process for the direct preparation of 5-alkoxy and 5-acyloxy analogues of campthothecins or mappicene ketones |
| FR2852606A1 (fr) * | 2003-03-18 | 2004-09-24 | Inst Nat Sante Rech Med | Moyens pour inhiber simultanement l'expression de plusieurs genes impliques dans une pathologie |
| JP4477510B2 (ja) * | 2003-03-31 | 2010-06-09 | カウンシル オブ サイエンティフィク アンド インダストリアル リサーチ | １０−ヒドロキシ−４−（ｓ）カンプトテンシンからトポテカンを調製する方法 |
| CN100406460C (zh) * | 2003-11-10 | 2008-07-30 | 中国科学院上海药物研究所 | 喜树碱的新衍生物、制备方法和用途 |
| TWI333492B (en) * | 2003-11-12 | 2010-11-21 | Smithkline Beecham Cork Ltd | Crystalline topotecan hydrochloride product and preparation thereof |
| ATE507240T1 (de) * | 2004-03-05 | 2011-05-15 | Vegenics Pty Ltd | Materialien und verfahren für wachstumsfaktorbindende konstrukte |
| CN1946421B (zh) * | 2004-04-27 | 2013-07-17 | 威尔斯达特生物制剂公司 | 使用病毒和喜树碱进行的癌症治疗 |
| US20050267141A1 (en) | 2004-05-28 | 2005-12-01 | Phytogen Life Sciences Inc. | Process to prepare camptothecin derivatives |
| US20050272757A1 (en) * | 2004-06-04 | 2005-12-08 | Phytogen Life Sciences Inc. | Process to prepare camptothecin derivatives and novel intermediate and compounds thereof |
| US7122700B2 (en) * | 2004-07-30 | 2006-10-17 | Xerox Corporation | Arylamine processes |
| US20090104254A1 (en) | 2004-12-22 | 2009-04-23 | Rutgers, The State University Of New Jersey | Controlled Release Hydrogels |
| AU2006207321B2 (en) | 2005-01-21 | 2012-09-06 | Astex Therapeutics Limited | Pharmaceutical compounds |
| JP5106098B2 (ja) * | 2005-02-28 | 2012-12-26 | エーザイ・アール・アンド・ディー・マネジメント株式会社 | スルホンアミド化合物の抗癌剤との新規併用 |
| KR20080039344A (ko) * | 2005-07-14 | 2008-05-07 | 웰스테트 바이올로직스 코포레이션 | 바이러스, 플루오로피리미딘 및 캄토테신을 이용한 암치료방법 |
| WO2007042799A1 (en) * | 2005-10-10 | 2007-04-19 | Cipla Limited | Novel crystalline forms |
| WO2007075492A1 (en) * | 2005-12-16 | 2007-07-05 | Sonus Pharmaceuticals, Inc. | Lipophilic anticancer drug compounds |
| US7547785B2 (en) | 2005-12-26 | 2009-06-16 | Dr. Reddy's Laboratories Limited | Process for preparing topotecan |
| WO2007085370A1 (en) * | 2006-01-25 | 2007-08-02 | Heidelberg Pharma Ag | 9-(dimethylamino)-methyl-10-hydroxy-camptothecin lipidester derivatives |
| CN101033230B (zh) * | 2006-03-10 | 2010-12-08 | 中国科学院上海药物研究所 | 一类喜树碱衍生物及其应用 |
| AU2007232206B2 (en) | 2006-03-30 | 2013-04-04 | Drais Pharmaceuticals, Inc. | Camptothecin-cell penetrating peptide conjugates and pharmaceutical compositions containing the same |
| EP2023949A4 (en) * | 2006-04-26 | 2009-08-26 | Univ California | COMPOSITIONS AND METHODS FOR CONVECTION-REINFORCED RELEASE OF NEUROTHERAPEUTICS WITH HIGH MOLECULAR WEIGHT |
| US20110028536A1 (en) * | 2006-08-18 | 2011-02-03 | Gjerset Ruth A | Methods and compositions for topoisomerase i modulated tumor suppression |
| JP5528807B2 (ja) | 2006-10-12 | 2014-06-25 | アステックス、セラピューティックス、リミテッド | 複合薬剤 |
| WO2008044041A1 (en) | 2006-10-12 | 2008-04-17 | Astex Therapeutics Limited | Pharmaceutical combinations |
| US7977483B2 (en) * | 2007-04-11 | 2011-07-12 | Scinopharm Taiwan, Ltd. | Process for making topotecan |
| US20080255175A1 (en) * | 2007-04-16 | 2008-10-16 | Lam Marina K | Anti-cancer agents, compositions and methods of treating cancers |
| CA2684599C (en) * | 2007-04-19 | 2013-07-02 | Scinopharm Taiwan Ltd. | Crystalline forms of topotecan hydrochloride and processes for making the same |
| US8026249B2 (en) * | 2007-09-14 | 2011-09-27 | Deutena Pharmaceuticals, Inc. | Deuterium-enriched topotecan |
| ITMI20072268A1 (it) | 2007-12-04 | 2009-06-05 | Antibioticos Spa | Polimorfi cristallini di topotecan cloridrato con elevato grado di purezza e metodi per la loro preparazione |
| CN102046634B (zh) * | 2008-05-29 | 2013-04-24 | 日本迈科洛生物制药有限公司 | 喜树碱衍生物的制备方法 |
| US8173621B2 (en) | 2008-06-11 | 2012-05-08 | Gilead Pharmasset Llc | Nucleoside cyclicphosphates |
| TW201026715A (en) | 2008-12-23 | 2010-07-16 | Pharmasset Inc | Nucleoside phosphoramidates |
| TW201026716A (en) * | 2008-12-23 | 2010-07-16 | Pharmasset Inc | Nucleoside analogs |
| US8716263B2 (en) | 2008-12-23 | 2014-05-06 | Gilead Pharmasset Llc | Synthesis of purine nucleosides |
| EP2547359B1 (en) | 2010-03-15 | 2016-03-09 | The Board of Trustees of the University of Illionis | Inhibitors of beta integrin-g protein alpha subunit binding interactions |
| PT3290428T (pt) | 2010-03-31 | 2021-12-27 | Gilead Pharmasset Llc | Comprimido compreendendo 2-(((s)-(((2r,3r,4r,5r)-5-(2,4-dioxo-3,4-dihidropirimidin-1-(2h)-il)¿4¿fluoro¿3¿hidroxi¿4¿metiltetrahidrofuran¿2¿il)metoxi) (fenoxi)fosforil)amino)propanoato de (s)- isopropil cristalino |
| US20140086975A1 (en) | 2010-10-15 | 2014-03-27 | Rutgers, The State University Of New Jersey | Hydrogel formulation for dermal and ocular delivery |
| RU2447076C1 (ru) * | 2010-12-09 | 2012-04-10 | Закрытое Акционерное Общество "Фарм-Синтез" | Способ получения топотекана |
| WO2012082337A2 (en) | 2010-12-17 | 2012-06-21 | Glaxo Wellcome Manufacturing Pte Ltd | Combination |
| WO2012083197A1 (en) | 2010-12-17 | 2012-06-21 | Nektar Therapeutics | Water-soluble polymer conjugates of topotecan |
| EP2655401B1 (en) | 2010-12-20 | 2016-03-09 | The Regents of the University of Michigan | Inhibitors of the epidermal growth factor receptor-heat shock protein 90 binding interaction |
| EP2672969A4 (en) | 2011-02-01 | 2014-07-16 | Glaxosmithkline Intellectual Property Ltd | COMBINATION |
| US10047116B2 (en) | 2011-10-03 | 2018-08-14 | Mx Adjuvac Ab | Nanoparticles, process for preparation and use thereof as carrier for amphipatic and hydrophobic molecules in fields of medicine including cancer treatment and food related compounds |
| PL235836B1 (pl) * | 2012-10-25 | 2020-11-02 | Inst Chemii Organicznej Polskiej Akademii Nauk | Pochodne kamptotecyny, sposób ich otrzymywania i zastosowanie |
| CN103113381B (zh) * | 2013-02-26 | 2014-12-10 | 大连理工大学 | 系列水溶性羟基喜树碱环烷胺醇衍生物及其制法与用途 |
| WO2014163558A1 (en) | 2013-04-01 | 2014-10-09 | Moreinx Ab | Nanoparticles, composed of sterol and saponin from quillaja saponaria molina process for preparation and use thereof as carrier for amphipatic of hydrphobic molecules in fields of medicine including cancer treatment and food related compounds |
| WO2016123143A1 (en) | 2015-01-26 | 2016-08-04 | The University Of Chicago | CAR T-CELLS RECOGNIZING CANCER-SPECIFIC IL 13Rα2 |
| CN107683289B (zh) | 2015-01-26 | 2021-08-06 | 芝加哥大学 | IL13Rα2结合剂和其在癌症治疗中的用途 |
| JP6877049B2 (ja) | 2015-09-25 | 2021-05-26 | ゼットワイ セラピューティクス インク．Ｚｙ Ｔｈｅｒａｐｅｕｔｉｃｓ Ｉｎｃ． | 多糖類−ビタミン共役体を含む粒状物に基づく薬物製剤 |
| SG10201913331VA (en) | 2016-03-15 | 2020-03-30 | Oryzon Genomics Sa | Combinations of lsd1 inhibitors for use in the treatment of solid tumors |
| EP3854393A1 (en) * | 2016-05-17 | 2021-07-28 | Scandion Oncology A/S | Ns3728 for use in combination with temozolomide for the treatment of glioblastoma |
| TW201912173A (zh) | 2017-08-07 | 2019-04-01 | 美商安進公司 | 三陰性乳癌或結腸直腸癌伴隨肝轉移之治療 |
| EP3669890A1 (en) | 2018-12-18 | 2020-06-24 | Croda International PLC | Filamentous nanoparticles having vaccine adjuvant effect |
| EP3941946B1 (en) | 2019-03-20 | 2024-12-25 | The Regents of the University of California | Claudin-6 antibodies and drug conjugates |
| CN114206934A (zh) | 2019-03-20 | 2022-03-18 | 加利福尼亚大学董事会 | 密封蛋白-6双特异性抗体 |
| US20220160872A1 (en) | 2019-04-09 | 2022-05-26 | The Board Of Trustees Of The University Of Illinois | Drug Adsorbed Highly Porous Activated Carbon for Enhanced Drug Delivery |
| AU2020266083A1 (en) | 2019-04-30 | 2021-09-23 | Instituto de Medicina Molecular João Lobo Antunes | Rank pathway inhibitors in combination with CDK inhibitors |
| JP7763666B2 (ja) | 2019-06-24 | 2025-11-04 | アムジェン インコーポレイテッド | 癌治療のためのＳＩＲＰγの阻害 |
| US20220265659A1 (en) | 2019-09-02 | 2022-08-25 | Inserm (Institut National De La Santé Et De Al Recherche Médicale) | Methods and compositions for treating pax6-deficiency related disease |
| AU2021226341A1 (en) * | 2020-02-25 | 2022-09-29 | Mediboston Limited | Camptothecin derivatives and conjugates thereof |
| JP2025516629A (ja) | 2022-05-11 | 2025-05-30 | セルジーン コーポレーション | Ｔ細胞療法に関連する方法および使用、ならびにその生成 |
| CN116478174B (zh) * | 2022-07-29 | 2025-09-16 | 杭州爱科瑞思生物医药有限公司 | 喜树碱衍生物及其制备方法和应用 |
| CN117045655A (zh) * | 2023-03-09 | 2023-11-14 | 兰州大学 | 喜树碱类衍生物在制备治疗膀胱癌药物中的应用 |
Family Cites Families (14)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4399282A (en) * | 1979-07-10 | 1983-08-16 | Kabushiki Kaisha Yakult Honsha | Camptothecin derivatives |
| US4342776A (en) * | 1979-11-05 | 1982-08-03 | Merck & Co., Inc. | 4-Substituted-3-hydroxy-3-pyrroline-2,5-dione inhibitors of glycolic acid oxidase |
| US4473692A (en) * | 1981-09-04 | 1984-09-25 | Kabushiki Kaisha Yakult Honsha | Camptothecin derivatives and process for preparing same |
| JPS58134095A (ja) * | 1982-02-05 | 1983-08-10 | Yakult Honsha Co Ltd | 新規なカンプトテシン誘導体 |
| JPS58154582A (ja) * | 1982-03-10 | 1983-09-14 | Yakult Honsha Co Ltd | 新規なカンプトテシン誘導体およびその製造法 |
| JPS58154584A (ja) * | 1982-03-10 | 1983-09-14 | Yakult Honsha Co Ltd | ５位ヒドロキシ置換カンプトテシン誘導体の製造法 |
| JPS5951289A (ja) * | 1982-09-17 | 1984-03-24 | Yakult Honsha Co Ltd | 新規な９−置換−カンプトテシン誘導体 |
| JPS59227884A (ja) * | 1983-06-09 | 1984-12-21 | Yakult Honsha Co Ltd | 新規な７−ヒドロキシアルキルカンプトテシン誘導体 |
| JPS6019790A (ja) * | 1983-07-14 | 1985-01-31 | Yakult Honsha Co Ltd | 新規なカンプトテシン誘導体 |
| US4775759A (en) * | 1984-11-27 | 1988-10-04 | The United States Of America As Represented By The Department Of Health And Human Services | Synthesis and utilization of 17-methyl and 17-cyclopropylmethyl-3,14-dihydroxy-4,5α-epoxy 6β-fluoromorphinans (foxy and cyclofoxy) as (18F)-labeled opioid ligands for position emission transaxial tomography (PETT) |
| US4820816A (en) * | 1985-08-02 | 1989-04-11 | President And Fellows Of Harvard College | 3-trifuoromethylsulfonyloxy-substituted 1-carbacephalosporins as intermediates for antibiotics |
| JPH0615546B2 (ja) * | 1986-02-24 | 1994-03-02 | 株式会社ヤクルト本社 | 新規なカンプトテシン誘導体 |
| US4894456A (en) * | 1987-03-31 | 1990-01-16 | Research Triangle Institute | Synthesis of camptothecin and analogs thereof |
| JP3431931B2 (ja) * | 1992-07-16 | 2003-07-28 | 旭電化工業株式会社 | 銅及び銅合金の表面処理方法 |
-
1988
- 1988-11-02 US US07/266,460 patent/US5004758A/en not_active Expired - Lifetime
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- 1988-11-28 IL IL8851788A patent/IL88517A/en not_active IP Right Cessation
- 1988-11-29 ZA ZA888938A patent/ZA888938B/xx unknown
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- 1988-11-29 NZ NZ227124A patent/NZ227124A/en unknown
- 1988-11-30 LU LU90026C patent/LU90026I2/fr unknown
- 1988-11-30 DE DE1997175017 patent/DE19775017I2/de active Active
- 1988-11-30 ES ES88311366T patent/ES2094721T3/es not_active Expired - Lifetime
- 1988-11-30 EP EP88311366A patent/EP0321122B1/en not_active Expired - Lifetime
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- 1988-12-01 KR KR1019880015971A patent/KR930009357B1/ko not_active Expired - Lifetime
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1992
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1993
- 1993-02-27 CN CN93102886A patent/CN1035380C/zh not_active Expired - Lifetime
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1996
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1997
- 1997-03-27 NL NL970017C patent/NL970017I2/nl unknown
- 1997-04-16 LU LU90053C patent/LU90053I2/fr unknown
- 1997-06-12 HK HK81097A patent/HK81097A/en not_active IP Right Cessation
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