CA2335300C - Macrocyclic analogs and methods and their use and preparation - Google Patents
Macrocyclic analogs and methods and their use and preparation Download PDFInfo
- Publication number
- CA2335300C CA2335300C CA002335300A CA2335300A CA2335300C CA 2335300 C CA2335300 C CA 2335300C CA 002335300 A CA002335300 A CA 002335300A CA 2335300 A CA2335300 A CA 2335300A CA 2335300 C CA2335300 C CA 2335300C
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- Prior art keywords
- mmol
- alkyl
- compound
- etoac
- added
- 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.)
- Expired - Lifetime
Links
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- -1 C6 aryl-C1-3 Chemical group 0.000 claims description 96
- 229920006395 saturated elastomer Polymers 0.000 claims description 94
- 229910052760 oxygen Inorganic materials 0.000 claims description 77
- 125000000217 alkyl group Chemical group 0.000 claims description 40
- 125000003118 aryl group Chemical group 0.000 claims description 35
- 238000012360 testing method Methods 0.000 claims description 26
- 125000001424 substituent group Chemical group 0.000 claims description 24
- 230000011278 mitosis Effects 0.000 claims description 23
- 229910052799 carbon Inorganic materials 0.000 claims description 22
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 21
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- 150000002430 hydrocarbons Chemical group 0.000 claims description 15
- 229910052770 Uranium Inorganic materials 0.000 claims description 14
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- 125000003106 haloaryl group Chemical group 0.000 claims description 14
- 125000000852 azido group Chemical group *N=[N+]=[N-] 0.000 claims description 13
- 125000001072 heteroaryl group Chemical group 0.000 claims description 13
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 13
- 230000022131 cell cycle Effects 0.000 claims description 12
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 12
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- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 3
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- 238000013270 controlled release Methods 0.000 claims description 2
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- 125000005678 ethenylene group Chemical group [H]C([*:1])=C([H])[*:2] 0.000 claims description 2
- 238000009472 formulation Methods 0.000 claims description 2
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- 238000002347 injection Methods 0.000 claims description 2
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- 238000007918 intramuscular administration Methods 0.000 claims description 2
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- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims 12
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 claims 8
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims 5
- 125000001475 halogen functional group Chemical group 0.000 claims 3
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims 2
- 125000006719 (C6-C10) aryl (C1-C6) alkyl group Chemical group 0.000 claims 2
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- 125000006583 (C1-C3) haloalkyl group Chemical group 0.000 claims 1
- 125000006274 (C1-C3)alkoxy group Chemical group 0.000 claims 1
- 125000006720 (C1-C6) alkyl (C6-C10) aryl group Chemical group 0.000 claims 1
- 125000002853 C1-C4 hydroxyalkyl group Chemical group 0.000 claims 1
- 125000006577 C1-C6 hydroxyalkyl group Chemical group 0.000 claims 1
- 125000006549 C4-C10 aryl group Chemical group 0.000 claims 1
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- 230000000694 effects Effects 0.000 abstract description 10
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- 230000001093 anti-cancer Effects 0.000 abstract description 4
- 230000002927 anti-mitotic effect Effects 0.000 abstract description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 166
- 239000000243 solution Substances 0.000 description 146
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- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 57
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- VUTBELPREDJDDH-UHFFFAOYSA-N 4-amino-5-hydroxymethyl-2-methylpyrimidine Chemical compound CC1=NC=C(CO)C(N)=N1 VUTBELPREDJDDH-UHFFFAOYSA-N 0.000 description 49
- 238000006243 chemical reaction Methods 0.000 description 49
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- NKLCNNUWBJBICK-UHFFFAOYSA-N dess–martin periodinane Chemical compound C1=CC=C2I(OC(=O)C)(OC(C)=O)(OC(C)=O)OC(=O)C2=C1 NKLCNNUWBJBICK-UHFFFAOYSA-N 0.000 description 40
- 150000001299 aldehydes Chemical class 0.000 description 38
- 238000012746 preparative thin layer chromatography Methods 0.000 description 36
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 34
- 239000000543 intermediate Substances 0.000 description 31
- 229910000033 sodium borohydride Inorganic materials 0.000 description 31
- 239000012279 sodium borohydride Substances 0.000 description 31
- FEJUGLKDZJDVFY-UHFFFAOYSA-N 9-borabicyclo[3.3.1]nonane Substances C1CCC2CCCC1B2 FEJUGLKDZJDVFY-UHFFFAOYSA-N 0.000 description 30
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 30
- AMKGKYQBASDDJB-UHFFFAOYSA-N 9$l^{2}-borabicyclo[3.3.1]nonane Chemical compound C1CCC2CCCC1[B]2 AMKGKYQBASDDJB-UHFFFAOYSA-N 0.000 description 28
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- 230000015572 biosynthetic process Effects 0.000 description 27
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- FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 description 23
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- WLLIXJBWWFGEHT-UHFFFAOYSA-N [tert-butyl(dimethyl)silyl] trifluoromethanesulfonate Chemical compound CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F WLLIXJBWWFGEHT-UHFFFAOYSA-N 0.000 description 18
- 229910052739 hydrogen Inorganic materials 0.000 description 18
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- 238000006646 Dess-Martin oxidation reaction Methods 0.000 description 17
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 17
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- KPUWHANPEXNPJT-UHFFFAOYSA-N disiloxane Chemical class [SiH3]O[SiH3] KPUWHANPEXNPJT-UHFFFAOYSA-N 0.000 description 15
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- RMVRSNDYEFQCLF-UHFFFAOYSA-N thiophenol Chemical compound SC1=CC=CC=C1 RMVRSNDYEFQCLF-UHFFFAOYSA-N 0.000 description 13
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- 230000002829 reductive effect Effects 0.000 description 11
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 10
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- GDDNTTHUKVNJRA-UHFFFAOYSA-N 3-bromo-3,3-difluoroprop-1-ene Chemical compound FC(F)(Br)C=C GDDNTTHUKVNJRA-UHFFFAOYSA-N 0.000 description 6
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- 238000003556 assay Methods 0.000 description 5
- JJNHBFYGCSOONU-UHFFFAOYSA-M carbanide;cyclopenta-1,3-diene;dimethylaluminum;titanium(4+);chloride Chemical compound [CH3-].[Ti+3]Cl.C[Al]C.C=1C=C[CH-]C=1.C=1C=C[CH-]C=1 JJNHBFYGCSOONU-UHFFFAOYSA-M 0.000 description 5
- 150000001721 carbon Chemical group 0.000 description 5
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- FXNFULJVOQMBCW-VZBLNRDYSA-N halichondrin b Chemical compound O([C@@H]1[C@@H](C)[C@@H]2O[C@@H]3C[C@@]4(O[C@H]5[C@@H](C)C[C@@]6(C[C@@H]([C@@H]7O[C@@H](C[C@@H]7O6)[C@@H](O)C[C@@H](O)CO)C)O[C@H]5C4)O[C@@H]3C[C@@H]2O[C@H]1C[C@@H]1C(=C)[C@H](C)C[C@@H](O1)CC[C@H]1C(=C)C[C@@H](O1)CC1)C(=O)C[C@H](O2)CC[C@H]3[C@H]2[C@H](O2)[C@@H]4O[C@@H]5C[C@@]21O[C@@H]5[C@@H]4O3 FXNFULJVOQMBCW-VZBLNRDYSA-N 0.000 description 5
- 125000005843 halogen group Chemical group 0.000 description 5
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- MHYGQXWCZAYSLJ-UHFFFAOYSA-N tert-butyl-chloro-diphenylsilane Chemical compound C=1C=CC=CC=1[Si](Cl)(C(C)(C)C)C1=CC=CC=C1 MHYGQXWCZAYSLJ-UHFFFAOYSA-N 0.000 description 5
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- SRBFZHDQGSBBOR-HWQSCIPKSA-N L-arabinopyranose Chemical compound O[C@H]1COC(O)[C@H](O)[C@H]1O SRBFZHDQGSBBOR-HWQSCIPKSA-N 0.000 description 4
- 238000003820 Medium-pressure liquid chromatography Methods 0.000 description 4
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 4
- 101100272976 Panax ginseng CYP716A53v2 gene Proteins 0.000 description 4
- 150000001412 amines Chemical class 0.000 description 4
- 229910002091 carbon monoxide Inorganic materials 0.000 description 4
- LOKCTEFSRHRXRJ-UHFFFAOYSA-I dipotassium trisodium dihydrogen phosphate hydrogen phosphate dichloride Chemical compound P(=O)(O)(O)[O-].[K+].P(=O)(O)([O-])[O-].[Na+].[Na+].[Cl-].[K+].[Cl-].[Na+] LOKCTEFSRHRXRJ-UHFFFAOYSA-I 0.000 description 4
- APFVFJFRJDLVQX-UHFFFAOYSA-N indium atom Chemical compound [In] APFVFJFRJDLVQX-UHFFFAOYSA-N 0.000 description 4
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- IUBQJLUDMLPAGT-UHFFFAOYSA-N potassium bis(trimethylsilyl)amide Chemical compound C[Si](C)(C)N([K])[Si](C)(C)C IUBQJLUDMLPAGT-UHFFFAOYSA-N 0.000 description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 4
- ZDYVRSLAEXCVBX-UHFFFAOYSA-N pyridinium p-toluenesulfonate Chemical compound C1=CC=[NH+]C=C1.CC1=CC=C(S([O-])(=O)=O)C=C1 ZDYVRSLAEXCVBX-UHFFFAOYSA-N 0.000 description 4
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- LRMLWYXJORUTBG-UHFFFAOYSA-N dimethylphosphorylmethane Chemical compound CP(C)(C)=O LRMLWYXJORUTBG-UHFFFAOYSA-N 0.000 description 1
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- 238000006073 displacement reaction Methods 0.000 description 1
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- DNJIEGIFACGWOD-UHFFFAOYSA-N ethanethiol Chemical compound CCS DNJIEGIFACGWOD-UHFFFAOYSA-N 0.000 description 1
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- UQEAIHBTYFGYIE-UHFFFAOYSA-N hexamethyldisiloxane Chemical compound C[Si](C)(C)O[Si](C)(C)C UQEAIHBTYFGYIE-UHFFFAOYSA-N 0.000 description 1
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- 125000000654 isopropylidene group Chemical group C(C)(C)=* 0.000 description 1
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- 229910052751 metal Inorganic materials 0.000 description 1
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- RMIODHQZRUFFFF-UHFFFAOYSA-M methoxyacetate Chemical compound COCC([O-])=O RMIODHQZRUFFFF-UHFFFAOYSA-M 0.000 description 1
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- QMMRZOWCJAIUJA-UHFFFAOYSA-L nickel dichloride Chemical compound Cl[Ni]Cl QMMRZOWCJAIUJA-UHFFFAOYSA-L 0.000 description 1
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- 238000011170 pharmaceutical development Methods 0.000 description 1
- DDBREPKUVSBGFI-UHFFFAOYSA-N phenobarbital Chemical compound C=1C=CC=CC=1C1(CC)C(=O)NC(=O)NC1=O DDBREPKUVSBGFI-UHFFFAOYSA-N 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
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- FAQJJMHZNSSFSM-UHFFFAOYSA-N phenylglyoxylic acid Chemical compound OC(=O)C(=O)C1=CC=CC=C1 FAQJJMHZNSSFSM-UHFFFAOYSA-N 0.000 description 1
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- 125000005493 quinolyl group Chemical group 0.000 description 1
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- 230000000717 retained effect Effects 0.000 description 1
- 201000006845 reticulosarcoma Diseases 0.000 description 1
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- UAWABSHMGXMCRK-UHFFFAOYSA-L samarium(ii) iodide Chemical compound I[Sm]I UAWABSHMGXMCRK-UHFFFAOYSA-L 0.000 description 1
- 230000007017 scission Effects 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 125000003548 sec-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 238000006884 silylation reaction Methods 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 239000011697 sodium iodate Substances 0.000 description 1
- 235000015281 sodium iodate Nutrition 0.000 description 1
- 235000019345 sodium thiosulphate Nutrition 0.000 description 1
- 238000010186 staining Methods 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 125000000547 substituted alkyl group Chemical group 0.000 description 1
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 description 1
- GFYHSKONPJXCDE-UHFFFAOYSA-N sym-collidine Natural products CC1=CN=C(C)C(C)=C1 GFYHSKONPJXCDE-UHFFFAOYSA-N 0.000 description 1
- ILMRJRBKQSSXGY-UHFFFAOYSA-N tert-butyl(dimethyl)silicon Chemical group C[Si](C)C(C)(C)C ILMRJRBKQSSXGY-UHFFFAOYSA-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
- GMRIOAVKKGNMMV-UHFFFAOYSA-N tetrabutylazanium;azide Chemical compound [N-]=[N+]=[N-].CCCC[N+](CCCC)(CCCC)CCCC GMRIOAVKKGNMMV-UHFFFAOYSA-N 0.000 description 1
- OSBSFAARYOCBHB-UHFFFAOYSA-N tetrapropylammonium Chemical compound CCC[N+](CCC)(CCC)CCC OSBSFAARYOCBHB-UHFFFAOYSA-N 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-M toluene-4-sulfonate Chemical compound CC1=CC=C(S([O-])(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-M 0.000 description 1
- 125000003944 tolyl group Chemical group 0.000 description 1
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- HYWCXWRMUZYRPH-UHFFFAOYSA-N trimethyl(prop-2-enyl)silane Chemical compound C[Si](C)(C)CC=C HYWCXWRMUZYRPH-UHFFFAOYSA-N 0.000 description 1
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- IIHPVYJPDKJYOU-UHFFFAOYSA-N triphenylcarbethoxymethylenephosphorane Chemical compound C=1C=CC=CC=1P(C=1C=CC=CC=1)(=CC(=O)OCC)C1=CC=CC=C1 IIHPVYJPDKJYOU-UHFFFAOYSA-N 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
- NQPDZGIKBAWPEJ-UHFFFAOYSA-M valerate Chemical compound CCCCC([O-])=O NQPDZGIKBAWPEJ-UHFFFAOYSA-M 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
- C07D493/22—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system 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
Landscapes
- Organic Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
- Medicinal Preparation (AREA)
- Steroid Compounds (AREA)
- Medicines Containing Material From Animals Or Micro-Organisms (AREA)
- Saccharide Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Peptides Or Proteins (AREA)
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CA2632433A CA2632433C (en) | 1998-06-17 | 1999-06-16 | Methods for preparing macrocyclic analogs and intermediates for preparing same |
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US8968298P | 1998-06-17 | 1998-06-17 | |
| US60/089,682 | 1998-06-17 | ||
| PCT/US1999/013677 WO1999065894A1 (en) | 1998-06-17 | 1999-06-16 | Macrocyclic analogs and methods of their use and preparation |
Related Child Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA2632433A Division CA2632433C (en) | 1998-06-17 | 1999-06-16 | Methods for preparing macrocyclic analogs and intermediates for preparing same |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CA2335300A1 CA2335300A1 (en) | 1999-12-23 |
| CA2335300C true CA2335300C (en) | 2008-10-07 |
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| CA002335300A Expired - Lifetime CA2335300C (en) | 1998-06-17 | 1999-06-16 | Macrocyclic analogs and methods and their use and preparation |
| CA2632433A Expired - Lifetime CA2632433C (en) | 1998-06-17 | 1999-06-16 | Methods for preparing macrocyclic analogs and intermediates for preparing same |
| CA2755266A Expired - Lifetime CA2755266C (en) | 1998-06-17 | 1999-06-16 | Intermediates for preparing macrocyclic analogs |
Family Applications After (2)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA2632433A Expired - Lifetime CA2632433C (en) | 1998-06-17 | 1999-06-16 | Methods for preparing macrocyclic analogs and intermediates for preparing same |
| CA2755266A Expired - Lifetime CA2755266C (en) | 1998-06-17 | 1999-06-16 | Intermediates for preparing macrocyclic analogs |
Country Status (22)
| Country | Link |
|---|---|
| US (4) | US6214865B1 (enExample) |
| EP (4) | EP1087960B1 (enExample) |
| JP (1) | JP4454151B2 (enExample) |
| KR (1) | KR100798600B1 (enExample) |
| CN (1) | CN1216051C (enExample) |
| AT (1) | ATE502932T1 (enExample) |
| AU (1) | AU762998B2 (enExample) |
| BE (1) | BE2011C028I2 (enExample) |
| BR (1) | BRPI9911326B8 (enExample) |
| CA (3) | CA2335300C (enExample) |
| CY (2) | CY1111516T1 (enExample) |
| DE (2) | DE122011100031I1 (enExample) |
| DK (1) | DK1087960T3 (enExample) |
| FR (1) | FR11C0038I2 (enExample) |
| HU (1) | HU227912B1 (enExample) |
| IL (1) | IL139960A0 (enExample) |
| LU (1) | LU91854I2 (enExample) |
| NO (5) | NO328280B1 (enExample) |
| NZ (1) | NZ508597A (enExample) |
| PT (1) | PT1087960E (enExample) |
| WO (1) | WO1999065894A1 (enExample) |
| ZA (1) | ZA200007159B (enExample) |
Families Citing this family (97)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| IL139960A0 (en) | 1998-06-17 | 2002-02-10 | Eisai Co Ltd | Macrocylic analogs and methods of their use and preparation |
| US8097648B2 (en) * | 1998-06-17 | 2012-01-17 | Eisai R&D Management Co., Ltd. | Methods and compositions for use in treating cancer |
| US6653341B1 (en) | 1998-06-17 | 2003-11-25 | Eisai Co., Ltd. | Methods and compositions for use in treating cancer |
| DE10037310A1 (de) | 2000-07-28 | 2002-02-07 | Asta Medica Ag | Neue Indolderivate und deren Verwendung als Arzneimittel |
| EP1531846A4 (en) * | 2002-02-27 | 2006-04-19 | Us Gov Health & Human Serv | Conjugates of ligand, linker and cytotoxic agent and related compositions and methods of use |
| AU2003228354B8 (en) | 2002-03-22 | 2010-03-04 | Eisai R&D Management Co., Ltd. | Hemiasterlin derivatives and uses thereof in the treatment of cancer |
| US20050075395A1 (en) * | 2003-05-28 | 2005-04-07 | Gary Gordon | Continuous dosing regimen |
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