NO328280B1 - Makrocykliske analoger - Google Patents

Makrocykliske analoger Download PDF

Info

Publication number: NO328280B1
Authority: NO; Norway
Prior art keywords: mmol; added; etoac; mixture; concentrated
Prior art date: 1998-06-17

Application number

NO20006316A

Other languages

English (en)

Norwegian (no)

Other versions

NO20006316L (no

NO20006316D0 (no

Inventor

Melvin Joseph Yu

Bruce A Littlefield

Monica Palme

Boris M Seletsky

Murray J Towle

Wanjun Zheng

Original Assignee

Eisai R&D Man Co Ltd

Priority date (The priority date 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 date listed.)

1998-06-17

Filing date

2000-12-12

Publication date

2010-01-25

Family has litigation

First worldwide family litigation filed litigation Critical https://patents.darts-ip.com/?family=22219026&utm_source=google_patent&utm_medium=platform_link&utm_campaign=public_patent_search&patent=NO328280(B1) "Global patent litigation dataset” by Darts-ip is licensed under a Creative Commons Attribution 4.0 International License.

2000-12-12 Application filed by Eisai R&D Man Co Ltd filed Critical Eisai R&D Man Co Ltd

2000-12-12 Publication of NO20006316D0 publication Critical patent/NO20006316D0/no

2001-02-15 Publication of NO20006316L publication Critical patent/NO20006316L/no

2010-01-25 Publication of NO328280B1 publication Critical patent/NO328280B1/no

Links

150000001875 compounds Chemical class 0.000 claims abstract description 67
-1 azido, oxo, p-fluorophenyl Chemical group 0.000 claims description 56
125000000217 alkyl group Chemical group 0.000 claims description 21
229910052799 carbon Inorganic materials 0.000 claims description 17
125000001424 substituent group Chemical group 0.000 claims description 17
125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 16
150000002367 halogens Chemical class 0.000 claims description 9
125000000852 azido group Chemical group *N=[N+]=[N-] 0.000 claims description 8
125000004093 cyano group Chemical group *C#N 0.000 claims description 8
229910052736 halogen Inorganic materials 0.000 claims description 8
125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 8
125000000719 pyrrolidinyl group Chemical group 0.000 claims description 8
125000005036 alkoxyphenyl group Chemical group 0.000 claims description 7
125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 6
125000000171 (C1-C6) haloalkyl group Chemical group 0.000 claims description 5
229910052760 oxygen Inorganic materials 0.000 claims description 4
229930195734 saturated hydrocarbon Natural products 0.000 claims description 4
125000004043 oxo group Chemical group O=* 0.000 claims description 3
150000003839 salts Chemical class 0.000 claims description 3
125000006273 (C1-C3) alkyl group Chemical group 0.000 claims description 2
125000001183 hydrocarbyl group Chemical group 0.000 claims 4
125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims 3
125000005037 alkyl phenyl group Chemical group 0.000 claims 2
125000004432 carbon atom Chemical group C* 0.000 claims 2
125000006577 C1-C6 hydroxyalkyl group Chemical group 0.000 claims 1
101150009274 nhr-1 gene Proteins 0.000 claims 1
229930195695 Halichondrin Natural products 0.000 abstract description 6
238000002360 preparation method Methods 0.000 abstract description 4
239000000460 chlorine Substances 0.000 description 198
239000000203 mixture Substances 0.000 description 178
WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 166
239000011734 sodium Substances 0.000 description 149
239000000243 solution Substances 0.000 description 148
VLKZOEOYAKHREP-UHFFFAOYSA-N hexane Substances CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 136
XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 133
LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 124
229920006395 saturated elastomer Polymers 0.000 description 86
YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 72
239000000284 extract Substances 0.000 description 67
OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 65
210000004027 cell Anatomy 0.000 description 65
235000019439 ethyl acetate Nutrition 0.000 description 65
239000011541 reaction mixture Substances 0.000 description 60
239000012267 brine Substances 0.000 description 53
238000004440 column chromatography Methods 0.000 description 53
IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 51
HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 50
238000006243 chemical reaction Methods 0.000 description 48
RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 47
238000003818 flash chromatography Methods 0.000 description 45
238000003756 stirring Methods 0.000 description 44
150000001299 aldehydes Chemical class 0.000 description 40
238000000034 method Methods 0.000 description 39
238000012746 preparative thin layer chromatography Methods 0.000 description 37
239000000543 intermediate Substances 0.000 description 31
HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 30
150000001336 alkenes Chemical class 0.000 description 27
VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 25
150000002009 diols Chemical class 0.000 description 25
CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 24
YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 21
239000010410 layer Substances 0.000 description 18
239000012044 organic layer Substances 0.000 description 18
238000012360 testing method Methods 0.000 description 18
230000015572 biosynthetic process Effects 0.000 description 15
RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 15
JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 14
230000000394 mitotic effect Effects 0.000 description 14
JRZJOMJEPLMPRA-UHFFFAOYSA-N olefin Natural products CCCCCCCC=C JRZJOMJEPLMPRA-UHFFFAOYSA-N 0.000 description 14
239000012074 organic phase Substances 0.000 description 14
239000000047 product Substances 0.000 description 14
238000000746 purification Methods 0.000 description 14
238000003786 synthesis reaction Methods 0.000 description 14
KPUWHANPEXNPJT-UHFFFAOYSA-N disiloxane Chemical compound [SiH3]O[SiH3] KPUWHANPEXNPJT-UHFFFAOYSA-N 0.000 description 13
230000011278 mitosis Effects 0.000 description 13
229910004298 SiO 2 Inorganic materials 0.000 description 12
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 12
239000012634 fragment Substances 0.000 description 12
239000002609 medium Substances 0.000 description 12
FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 description 12
AMKGKYQBASDDJB-UHFFFAOYSA-N 9$l^{2}-borabicyclo[3.3.1]nonane Chemical compound C1CCC2CCCC1[B]2 AMKGKYQBASDDJB-UHFFFAOYSA-N 0.000 description 11
FEJUGLKDZJDVFY-UHFFFAOYSA-N 9-borabicyclo[3.3.1]nonane Substances C1CCC2CCCC1B2 FEJUGLKDZJDVFY-UHFFFAOYSA-N 0.000 description 11
238000006646 Dess-Martin oxidation reaction Methods 0.000 description 11
UREBWPXBXRYXRJ-UHFFFAOYSA-N ethyl acetate;methanol Chemical compound OC.CCOC(C)=O UREBWPXBXRYXRJ-UHFFFAOYSA-N 0.000 description 11
230000002829 reductive effect Effects 0.000 description 11
229940079593 drug Drugs 0.000 description 10
239000003814 drug Substances 0.000 description 10
239000012071 phase Substances 0.000 description 10
230000022131 cell cycle Effects 0.000 description 9
239000000706 filtrate Substances 0.000 description 9
239000000463 material Substances 0.000 description 9
239000000725 suspension Substances 0.000 description 9
RMVRSNDYEFQCLF-UHFFFAOYSA-N thiophenol Chemical compound SC1=CC=CC=C1 RMVRSNDYEFQCLF-UHFFFAOYSA-N 0.000 description 9
JXLYSJRDGCGARV-WWYNWVTFSA-N Vinblastine Natural products O=C(O[C@H]1[C@](O)(C(=O)OC)[C@@H]2N(C)c3c(cc(c(OC)c3)[C@]3(C(=O)OC)c4[nH]c5c(c4CCN4C[C@](O)(CC)C[C@H](C3)C4)cccc5)[C@@]32[C@H]2[C@@]1(CC)C=CCN2CC3)C JXLYSJRDGCGARV-WWYNWVTFSA-N 0.000 description 8
239000003080 antimitotic agent Substances 0.000 description 8
229910052739 hydrogen Inorganic materials 0.000 description 8
150000002576 ketones Chemical class 0.000 description 8
230000002441 reversible effect Effects 0.000 description 8
229960003048 vinblastine Drugs 0.000 description 8
JXLYSJRDGCGARV-XQKSVPLYSA-N vincaleukoblastine Chemical compound C([C@@H](C[C@]1(C(=O)OC)C=2C(=CC3=C([C@]45[C@H]([C@@]([C@H](OC(C)=O)[C@]6(CC)C=CCN([C@H]56)CC4)(O)C(=O)OC)N3C)C=2)OC)C[C@@](C2)(O)CC)N2CCC2=C1NC1=CC=CC=C21 JXLYSJRDGCGARV-XQKSVPLYSA-N 0.000 description 8
238000004458 analytical method Methods 0.000 description 7
239000003795 chemical substances by application Substances 0.000 description 7
238000001816 cooling Methods 0.000 description 7
150000002430 hydrocarbons Chemical group 0.000 description 7
238000001727 in vivo Methods 0.000 description 7
238000011534 incubation Methods 0.000 description 7
UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 7
OGWKCGZFUXNPDA-XQKSVPLYSA-N vincristine Chemical compound C([N@]1C[C@@H](C[C@]2(C(=O)OC)C=3C(=CC4=C([C@]56[C@H]([C@@]([C@H](OC(C)=O)[C@]7(CC)C=CCN([C@H]67)CC5)(O)C(=O)OC)N4C=O)C=3)OC)C[C@@](C1)(O)CC)CC1=C2NC2=CC=CC=C12 OGWKCGZFUXNPDA-XQKSVPLYSA-N 0.000 description 7
229960004528 vincristine Drugs 0.000 description 7
OGWKCGZFUXNPDA-UHFFFAOYSA-N vincristine Natural products C1C(CC)(O)CC(CC2(C(=O)OC)C=3C(=CC4=C(C56C(C(C(OC(C)=O)C7(CC)C=CCN(C67)CC5)(O)C(=O)OC)N4C=O)C=3)OC)CN1CCC1=C2NC2=CC=CC=C12 OGWKCGZFUXNPDA-UHFFFAOYSA-N 0.000 description 7
CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 6
WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
LFTLOKWAGJYHHR-UHFFFAOYSA-N N-methylmorpholine N-oxide Chemical compound CN1(=O)CCOCC1 LFTLOKWAGJYHHR-UHFFFAOYSA-N 0.000 description 6
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 6
230000008878 coupling Effects 0.000 description 6
238000010168 coupling process Methods 0.000 description 6
238000005859 coupling reaction Methods 0.000 description 6
229910000033 sodium borohydride Inorganic materials 0.000 description 6
239000012279 sodium borohydride Substances 0.000 description 6
229910001868 water Inorganic materials 0.000 description 6
LCGLNKUTAGEVQW-UHFFFAOYSA-N Dimethyl ether Chemical compound COC LCGLNKUTAGEVQW-UHFFFAOYSA-N 0.000 description 5
ZBLLGPUWGCOJNG-UHFFFAOYSA-N Halichondrin B Natural products CC1CC2(CC(C)C3OC4(CC5OC6C(CC5O4)OC7CC8OC9CCC%10OC(CC(C(C9)C8=C)C%11%12CC%13OC%14C(OC%15CCC(CC(=O)OC7C6C)OC%15C%14O%11)C%13O%12)CC%10=C)CC3O2)OC%16OC(CC1%16)C(O)CC(O)CO ZBLLGPUWGCOJNG-UHFFFAOYSA-N 0.000 description 5
AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 5
JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 5
DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 5
XSTXAVWGXDQKEL-UHFFFAOYSA-N Trichloroethylene Chemical compound ClC=C(Cl)Cl XSTXAVWGXDQKEL-UHFFFAOYSA-N 0.000 description 5
239000012298 atmosphere Substances 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
230000000694 effects Effects 0.000 description 5
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
238000000338 in vitro Methods 0.000 description 5
MZRVEZGGRBJDDB-UHFFFAOYSA-N n-Butyllithium Substances [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 5
239000008259 solid foam Substances 0.000 description 5
238000004809 thin layer chromatography Methods 0.000 description 5
238000010626 work up procedure Methods 0.000 description 5
YYROPELSRYBVMQ-UHFFFAOYSA-N 4-toluenesulfonyl chloride Chemical compound CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-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
150000001412 amines Chemical class 0.000 description 4
150000001721 carbon Chemical group 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
150000002148 esters Chemical class 0.000 description 4
125000001072 heteroaryl group Chemical group 0.000 description 4
APFVFJFRJDLVQX-UHFFFAOYSA-N indium atom Chemical compound [In] APFVFJFRJDLVQX-UHFFFAOYSA-N 0.000 description 4
230000002427 irreversible effect Effects 0.000 description 4
239000002953 phosphate buffered saline Substances 0.000 description 4
BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 4
125000006239 protecting group Chemical group 0.000 description 4
230000009467 reduction Effects 0.000 description 4
XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
STBLNCCBQMHSRC-BATDWUPUSA-N (2s)-n-[(3s,4s)-5-acetyl-7-cyano-4-methyl-1-[(2-methylnaphthalen-1-yl)methyl]-2-oxo-3,4-dihydro-1,5-benzodiazepin-3-yl]-2-(methylamino)propanamide Chemical compound O=C1[C@@H](NC(=O)[C@H](C)NC)[C@H](C)N(C(C)=O)C2=CC(C#N)=CC=C2N1CC1=C(C)C=CC2=CC=CC=C12 STBLNCCBQMHSRC-BATDWUPUSA-N 0.000 description 3
JDIIGWSSTNUWGK-UHFFFAOYSA-N 1h-imidazol-3-ium;chloride Chemical compound [Cl-].[NH2+]1C=CN=C1 JDIIGWSSTNUWGK-UHFFFAOYSA-N 0.000 description 3
JVSFQJZRHXAUGT-UHFFFAOYSA-N 2,2-dimethylpropanoyl chloride Chemical compound CC(C)(C)C(Cl)=O JVSFQJZRHXAUGT-UHFFFAOYSA-N 0.000 description 3
GDDNTTHUKVNJRA-UHFFFAOYSA-N 3-bromo-3,3-difluoroprop-1-ene Chemical compound FC(F)(Br)C=C GDDNTTHUKVNJRA-UHFFFAOYSA-N 0.000 description 3
WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 3
NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 3
UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
KZMGYPLQYOPHEL-UHFFFAOYSA-N Boron trifluoride etherate Chemical compound FB(F)F.CCOCC KZMGYPLQYOPHEL-UHFFFAOYSA-N 0.000 description 3
206010025323 Lymphomas Diseases 0.000 description 3
241001529936 Murinae Species 0.000 description 3
206010028980 Neoplasm Diseases 0.000 description 3
101100272976 Panax ginseng CYP716A53v2 gene Proteins 0.000 description 3
UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical class [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 3
UCKMPCXJQFINFW-UHFFFAOYSA-N Sulphide Chemical compound [S-2] UCKMPCXJQFINFW-UHFFFAOYSA-N 0.000 description 3
ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
102000004243 Tubulin Human genes 0.000 description 3
108090000704 Tubulin Proteins 0.000 description 3
125000001118 alkylidene group Chemical group 0.000 description 3
230000001093 anti-cancer Effects 0.000 description 3
238000003556 assay Methods 0.000 description 3
239000002981 blocking agent Substances 0.000 description 3
230000000903 blocking effect Effects 0.000 description 3
229940125878 compound 36 Drugs 0.000 description 3
238000010828 elution Methods 0.000 description 3
238000001914 filtration Methods 0.000 description 3
239000011491 glass wool Substances 0.000 description 3
125000001188 haloalkyl group Chemical group 0.000 description 3
125000000623 heterocyclic group Chemical group 0.000 description 3
238000005259 measurement Methods 0.000 description 3
LSEFCHWGJNHZNT-UHFFFAOYSA-M methyl(triphenyl)phosphanium;bromide Chemical compound [Br-].C=1C=CC=CC=1[P+](C=1C=CC=CC=1)(C)C1=CC=CC=C1 LSEFCHWGJNHZNT-UHFFFAOYSA-M 0.000 description 3
239000008188 pellet Substances 0.000 description 3
230000000144 pharmacologic effect Effects 0.000 description 3
239000008363 phosphate buffer Substances 0.000 description 3
XJMOSONTPMZWPB-UHFFFAOYSA-M propidium iodide Chemical compound [I-].[I-].C12=CC(N)=CC=C2C2=CC=C(N)C=C2[N+](CCC[N+](C)(CC)CC)=C1C1=CC=CC=C1 XJMOSONTPMZWPB-UHFFFAOYSA-M 0.000 description 3
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 3
238000000926 separation method Methods 0.000 description 3
239000007787 solid Substances 0.000 description 3
YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 3
210000001519 tissue Anatomy 0.000 description 3
ILJSQTXMGCGYMG-UHFFFAOYSA-N triacetic acid Chemical compound CC(=O)CC(=O)CC(O)=O ILJSQTXMGCGYMG-UHFFFAOYSA-N 0.000 description 3
229930195735 unsaturated hydrocarbon Natural products 0.000 description 3
150000000185 1,3-diols Chemical class 0.000 description 2
KQZLRWGGWXJPOS-NLFPWZOASA-N 1-[(1R)-1-(2,4-dichlorophenyl)ethyl]-6-[(4S,5R)-4-[(2S)-2-(hydroxymethyl)pyrrolidin-1-yl]-5-methylcyclohexen-1-yl]pyrazolo[3,4-b]pyrazine-3-carbonitrile Chemical compound ClC1=C(C=CC(=C1)Cl)[C@@H](C)N1N=C(C=2C1=NC(=CN=2)C1=CC[C@@H]([C@@H](C1)C)N1[C@@H](CCC1)CO)C#N KQZLRWGGWXJPOS-NLFPWZOASA-N 0.000 description 2
OBOHMJWDFPBPKD-UHFFFAOYSA-N 1-[chloro(diphenyl)methyl]-4-methoxybenzene Chemical compound C1=CC(OC)=CC=C1C(Cl)(C=1C=CC=CC=1)C1=CC=CC=C1 OBOHMJWDFPBPKD-UHFFFAOYSA-N 0.000 description 2
SJSOFNCYXJUNBT-UHFFFAOYSA-N 3,4,5-trimethoxybenzoic acid Chemical compound COC1=CC(C(O)=O)=CC(OC)=C1OC SJSOFNCYXJUNBT-UHFFFAOYSA-N 0.000 description 2
OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
206010009944 Colon cancer Diseases 0.000 description 2
238000006834 Hetero-Michael addition reaction Methods 0.000 description 2
238000006405 Nozaki-Hiyama-Kishi reaction Methods 0.000 description 2
OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 description 2
230000018199 S phase Effects 0.000 description 2
FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
SMNRFWMNPDABKZ-WVALLCKVSA-N [[(2R,3S,4R,5S)-5-(2,6-dioxo-3H-pyridin-3-yl)-3,4-dihydroxyoxolan-2-yl]methoxy-hydroxyphosphoryl] [[[(2R,3S,4S,5R,6R)-4-fluoro-3,5-dihydroxy-6-(hydroxymethyl)oxan-2-yl]oxy-hydroxyphosphoryl]oxy-hydroxyphosphoryl] hydrogen phosphate Chemical compound OC[C@H]1O[C@H](OP(O)(=O)OP(O)(=O)OP(O)(=O)OP(O)(=O)OC[C@H]2O[C@H]([C@H](O)[C@@H]2O)C2C=CC(=O)NC2=O)[C@H](O)[C@@H](F)[C@@H]1O SMNRFWMNPDABKZ-WVALLCKVSA-N 0.000 description 2
DHKHKXVYLBGOIT-UHFFFAOYSA-N acetaldehyde Diethyl Acetal Natural products CCOC(C)OCC DHKHKXVYLBGOIT-UHFFFAOYSA-N 0.000 description 2
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229910052938 sodium sulfate Inorganic materials 0.000 description 1
235000011152 sodium sulphate Nutrition 0.000 description 1
108010076287 sperm motility inhibitor 2 Proteins 0.000 description 1
238000010186 staining Methods 0.000 description 1
239000000126 substance Substances 0.000 description 1
150000003871 sulfonates Chemical class 0.000 description 1
125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 description 1
230000002459 sustained effect Effects 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
125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(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
238000010998 test method Methods 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
230000001052 transient effect Effects 0.000 description 1
HYWCXWRMUZYRPH-UHFFFAOYSA-N trimethyl(prop-2-enyl)silane Chemical compound C[Si](C)(C)CC=C HYWCXWRMUZYRPH-UHFFFAOYSA-N 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
XQWBDIAGTOWOOU-UHFFFAOYSA-K trisodium;dioxido-oxo-sulfanylidene-$l^{6}-sulfane;hydrogen carbonate Chemical compound [Na+].[Na+].[Na+].OC([O-])=O.[O-]S([O-])(=O)=S XQWBDIAGTOWOOU-UHFFFAOYSA-K 0.000 description 1
230000035899 viability Effects 0.000 description 1
229920002554 vinyl polymer Polymers 0.000 description 1
239000003039 volatile agent Substances 0.000 description 1
238000003260 vortexing Methods 0.000 description 1
238000005406 washing Methods 0.000 description 1
125000001834 xanthenyl group Chemical group C1=CC=CC=2OC3=CC=CC=C3C(C12)* 0.000 description 1

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

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Organic Chemistry (AREA)
Chemical & Material Sciences (AREA)
Health & Medical Sciences (AREA)
Veterinary Medicine (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)
Medicinal Chemistry (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)
Medicines Containing Material From Animals Or Micro-Organisms (AREA)
Steroid Compounds (AREA)
Saccharide Compounds (AREA)
Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Peptides Or Proteins (AREA)

NO20006316A 1998-06-17 2000-12-12 Makrocykliske analoger NO328280B1 (no)

Applications Claiming Priority (2)

Application Number	Priority Date	Filing Date	Title
US8968298P	1998-06-17	1998-06-17
PCT/US1999/013677 WO1999065894A1 (fr)	1998-06-17	1999-06-16	Analogues macrocycliques, leurs procedes d'utilisation et de preparation

Publications (3)

Publication Number	Publication Date
NO20006316D0 NO20006316D0 (no)	2000-12-12
NO20006316L NO20006316L (no)	2001-02-15
NO328280B1 true NO328280B1 (no)	2010-01-25

Family

ID=22219026

Family Applications (5)

Application Number	Title	Priority Date	Filing Date
NO20006316A NO328280B1 (no)	1998-06-17	2000-12-12	Makrocykliske analoger
NO20093217A NO331183B1 (no)	1998-06-17	2009-10-26	Farmasoytisk preparat omfattende en halokondrinanalog eller et farmasoytisk salt derav og en farmasoytisk akseptabel baerer
NO2011018C NO2011018I1 (no)	1998-06-17	2011-09-16	Eribulin og farmasøytisk akseptable salter derav
NO2011026C NO2011026I2 (no)	1998-06-17	2011-12-14	Eribulin eller et farmasøytisk akseptabelt salt derav
NO2022019C NO2022019I1 (no)	1998-06-17	2022-06-03	Eribulin eller et farmasøytisk akseptabelt salt derav - forlenget SPC

Family Applications After (4)

Application Number	Title	Priority Date	Filing Date
NO20093217A NO331183B1 (no)	1998-06-17	2009-10-26	Farmasoytisk preparat omfattende en halokondrinanalog eller et farmasoytisk salt derav og en farmasoytisk akseptabel baerer
NO2011018C NO2011018I1 (no)	1998-06-17	2011-09-16	Eribulin og farmasøytisk akseptable salter derav
NO2011026C NO2011026I2 (no)	1998-06-17	2011-12-14	Eribulin eller et farmasøytisk akseptabelt salt derav
NO2022019C NO2022019I1 (no)	1998-06-17	2022-06-03	Eribulin eller et farmasøytisk akseptabelt salt derav - forlenget SPC

Country Status (22)

Country	Link
US (4)	US6214865B1 (fr)
EP (4)	EP2272839B1 (fr)
JP (1)	JP4454151B2 (fr)
KR (1)	KR100798600B1 (fr)
CN (1)	CN1216051C (fr)
AT (1)	ATE502932T1 (fr)
AU (1)	AU762998B2 (fr)
BE (1)	BE2011C028I2 (fr)
BR (1)	BRPI9911326B8 (fr)
CA (3)	CA2335300C (fr)
CY (2)	CY1111516T1 (fr)
DE (2)	DE69943296D1 (fr)
DK (1)	DK1087960T3 (fr)
FR (1)	FR11C0038I2 (fr)
HU (1)	HU227912B1 (fr)
IL (1)	IL139960A0 (fr)
LU (1)	LU91854I2 (fr)
NO (5)	NO328280B1 (fr)
NZ (1)	NZ508597A (fr)
PT (1)	PT1087960E (fr)
WO (1)	WO1999065894A1 (fr)
ZA (1)	ZA200007159B (fr)

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Publication number	Publication date
CY1111516T1 (el)	2014-04-09
WO1999065894A1 (fr)	1999-12-23
US6469182B1 (en)	2002-10-22
CA2335300C (fr)	2008-10-07
JP4454151B2 (ja)	2010-04-21
NO2011026I2 (no)	2012-06-11
US6365759B1 (en)	2002-04-02
BE2011C028I2 (en)	2018-08-24
AU762998B2 (en)	2003-07-10
EP2277873A1 (fr)	2011-01-26
NO20006316L (no)	2001-02-15
BR9911326A (pt)	2001-04-03
CA2632433A1 (fr)	1999-12-23
HUP0103357A2 (hu)	2002-01-28
EP2277873B1 (fr)	2012-05-30
NO20006316D0 (no)	2000-12-12
CA2335300A1 (fr)	1999-12-23
BRPI9911326B8 (pt)	2021-05-25
KR100798600B1 (ko)	2008-01-28
EP1087960A1 (fr)	2001-04-04
AU4573999A (en)	2000-01-05
US20110172446A1 (en)	2011-07-14
DE69943296D1 (de)	2011-05-05
CN1216051C (zh)	2005-08-24
EP2272839B1 (fr)	2012-08-22
LU91854I2 (fr)	2011-10-17
ATE502932T1 (de)	2011-04-15
KR20010083050A (ko)	2001-08-31
NZ508597A (en)	2004-01-30
DK1087960T3 (da)	2011-06-14
CN1312804A (zh)	2001-09-12
DE122011100031I1 (de)	2011-12-15
NO2011018I1 (no)	2011-09-26
ZA200007159B (en)	2001-12-04
CY2011010I2 (el)	2014-04-09
RU2245335C2 (ru)	2005-01-27
CA2755266C (fr)	2014-08-12
BR9911326B1 (pt)	2015-01-06
CA2632433C (fr)	2012-02-07
HUP0103357A3 (en)	2002-10-28
EP1087960A4 (fr)	2004-12-01
EP1087960B1 (fr)	2011-03-23
NO20093217L (no)	2001-02-15
IL139960A0 (en)	2002-02-10
HK1035534A1 (en)	2001-11-30
CY2011010I1 (el)	2014-04-09
NO2022019I1 (no)	2022-06-03
EP2272840A1 (fr)	2011-01-12
HU227912B1 (en)	2012-05-29
JP2002518384A (ja)	2002-06-25
CA2755266A1 (fr)	1999-12-23
PT1087960E (pt)	2011-06-17
AU762998C (en)	2000-01-05
FR11C0038I1 (fr)	2011-10-14
NO2011026I1 (no)	2012-01-09
EP2272840B1 (fr)	2012-08-22
US6214865B1 (en)	2001-04-10
NO331183B1 (no)	2011-10-24
EP2272839A1 (fr)	2011-01-12
US8148554B2 (en)	2012-04-03
FR11C0038I2 (fr)	2013-01-11

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