CS273185B2 - Method of ephidophylotoxin's derivatives production that contain nitrogen - Google Patents

Method of ephidophylotoxin's derivatives production that contain nitrogen Download PDF

Info

Publication number: CS273185B2
Authority: CS; Czechoslovakia
Prior art keywords: formula; group; defined above; mmol; dichloromethane
Prior art date: 1987-05-19

Application number

CS331288A

Other languages

Czech (cs)

English (en)

Other versions

CS331288A2 (en

Inventor

Dolatrai M Vyas

Mark G Saulnier

John R Kadow

Original Assignee

Bristol Myers Squibb Co

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.)

1987-05-19

Filing date

1988-05-17

Publication date

1991-03-12

1988-05-17 Application filed by Bristol Myers Squibb Co filed Critical Bristol Myers Squibb Co

1989-06-12 Priority to CS356589A priority Critical patent/CS273199B2/cs

1990-06-13 Publication of CS331288A2 publication Critical patent/CS331288A2/cs

1991-03-12 Publication of CS273185B2 publication Critical patent/CS273185B2/cs

Links

IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 title claims description 31
238000000034 method Methods 0.000 title claims description 23
229910052757 nitrogen Inorganic materials 0.000 title claims description 21
150000001875 compounds Chemical class 0.000 claims abstract description 58
239000003795 chemical substances by application Substances 0.000 claims abstract description 10
QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims abstract description 4
-1 amide acetals Chemical class 0.000 claims description 22
150000001412 amines Chemical class 0.000 claims description 19
JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 14
WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 claims description 13
238000006243 chemical reaction Methods 0.000 claims description 12
229910052739 hydrogen Inorganic materials 0.000 claims description 12
238000002360 preparation method Methods 0.000 claims description 10
125000004432 carbon atom Chemical group C* 0.000 claims description 8
239000001257 hydrogen Substances 0.000 claims description 8
125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 8
125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 8
239000002253 acid Substances 0.000 claims description 7
UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 7
SBLYXIKLMHGUJZ-FMEAWWTOSA-N 5-[(5s,5ar,8ar,9r)-5-[[(2r,4ar,6r,7r,8r,8as)-7,8-dihydroxy-2-methyl-4,4a,6,7,8,8a-hexahydropyrano[3,2-d][1,3]dioxin-6-yl]oxy]-8-oxo-5a,6,8a,9-tetrahydro-5h-[2]benzofuro[5,6-f][1,3]benzodioxol-9-yl]-3-methoxycyclohexa-3,5-diene-1,2-dione Chemical compound O=C1C(=O)C(OC)=CC([C@@H]2C3=CC=4OCOC=4C=C3[C@@H](O[C@H]3[C@@H]([C@@H](O)[C@@H]4O[C@H](C)OC[C@H]4O3)O)[C@@H]3[C@@H]2C(OC3)=O)=C1 SBLYXIKLMHGUJZ-FMEAWWTOSA-N 0.000 claims description 6
KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 6
125000000217 alkyl group Chemical group 0.000 claims description 6
230000008569 process Effects 0.000 claims description 6
150000003839 salts Chemical class 0.000 claims description 6
125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 4
PXHVJJICTQNCMI-UHFFFAOYSA-N Nickel Chemical compound [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 claims description 4
229910052799 carbon Inorganic materials 0.000 claims description 4
239000012954 diazonium Substances 0.000 claims description 4
IJGRMHOSHXDMSA-UHFFFAOYSA-O diazynium Chemical compound [NH+]#N IJGRMHOSHXDMSA-UHFFFAOYSA-O 0.000 claims description 4
150000002148 esters Chemical class 0.000 claims description 4
125000005842 heteroatom Chemical group 0.000 claims description 4
XLYOFNOQVPJJNP-UHFFFAOYSA-M hydroxide Chemical compound [OH-] XLYOFNOQVPJJNP-UHFFFAOYSA-M 0.000 claims description 4
125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 4
239000003960 organic solvent Substances 0.000 claims description 4
BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 claims description 4
230000009467 reduction Effects 0.000 claims description 4
125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 3
125000000852 azido group Chemical group *N=[N+]=[N-] 0.000 claims description 3
125000002485 formyl group Chemical class [H]C(*)=O 0.000 claims description 3
125000005843 halogen group Chemical group 0.000 claims description 3
239000012948 isocyanate Substances 0.000 claims description 3
150000002513 isocyanates Chemical class 0.000 claims description 3
150000004965 peroxy acids Chemical class 0.000 claims description 3
KJTLSVCANCCWHF-UHFFFAOYSA-N Ruthenium Chemical compound [Ru] KJTLSVCANCCWHF-UHFFFAOYSA-N 0.000 claims description 2
229910052783 alkali metal Inorganic materials 0.000 claims description 2
239000002168 alkylating agent Chemical class 0.000 claims description 2
229940100198 alkylating agent Drugs 0.000 claims description 2
QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 2
150000004651 carbonic acid esters Chemical class 0.000 claims description 2
239000003054 catalyst Substances 0.000 claims description 2
125000001072 heteroaryl group Chemical group 0.000 claims description 2
238000005984 hydrogenation reaction Methods 0.000 claims description 2
125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 2
229910052759 nickel Inorganic materials 0.000 claims description 2
125000002971 oxazolyl group Chemical group 0.000 claims description 2
239000001301 oxygen Chemical group 0.000 claims description 2
229910052760 oxygen Inorganic materials 0.000 claims description 2
229910052763 palladium Inorganic materials 0.000 claims description 2
229910052697 platinum Inorganic materials 0.000 claims description 2
229910052703 rhodium Inorganic materials 0.000 claims description 2
239000010948 rhodium Substances 0.000 claims description 2
MHOVAHRLVXNVSD-UHFFFAOYSA-N rhodium atom Chemical compound [Rh] MHOVAHRLVXNVSD-UHFFFAOYSA-N 0.000 claims description 2
229910052707 ruthenium Inorganic materials 0.000 claims description 2
125000001424 substituent group Chemical group 0.000 claims description 2
125000004434 sulfur atom Chemical group 0.000 claims description 2
238000006722 reduction reaction Methods 0.000 claims 2
125000004414 alkyl thio group Chemical group 0.000 claims 1
206010028980 Neoplasm Diseases 0.000 abstract description 6
YJGVMLPVUAXIQN-UHFFFAOYSA-N epipodophyllotoxin Natural products COC1=C(OC)C(OC)=CC(C2C3=CC=4OCOC=4C=C3C(O)C3C2C(OC3)=O)=C1 YJGVMLPVUAXIQN-UHFFFAOYSA-N 0.000 abstract description 5
230000002401 inhibitory effect Effects 0.000 abstract description 5
229930182478 glucoside Natural products 0.000 abstract 1
150000008131 glucosides Chemical class 0.000 abstract 1
YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 156
OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 69
239000000243 solution Substances 0.000 description 35
XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 33
239000007787 solid Substances 0.000 description 30
238000005160 1H NMR spectroscopy Methods 0.000 description 26
239000000203 mixture Substances 0.000 description 22
239000011541 reaction mixture Substances 0.000 description 18
LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 17
HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 17
VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 13
239000000741 silica gel Substances 0.000 description 12
229910002027 silica gel Inorganic materials 0.000 description 12
238000003756 stirring Methods 0.000 description 12
CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 11
WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 10
239000003480 eluent Substances 0.000 description 10
KJIFKLIQANRMOU-UHFFFAOYSA-N oxidanium;4-methylbenzenesulfonate Chemical compound O.CC1=CC=C(S(O)(=O)=O)C=C1 KJIFKLIQANRMOU-UHFFFAOYSA-N 0.000 description 10
XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 10
WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 9
UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 9
230000000259 anti-tumor effect Effects 0.000 description 9
229960005420 etoposide Drugs 0.000 description 9
VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 9
239000000047 product Substances 0.000 description 9
238000003818 flash chromatography Methods 0.000 description 8
230000008018 melting Effects 0.000 description 8
238000002844 melting Methods 0.000 description 8
125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 8
VJJPUSNTGOMMGY-MRVIYFEKSA-N etoposide Chemical compound COC1=C(O)C(OC)=CC([C@@H]2C3=CC=4OCOC=4C=C3[C@@H](O[C@H]3[C@@H]([C@@H](O)[C@@H]4O[C@H](C)OC[C@H]4O3)O)[C@@H]3[C@@H]2C(OC3)=O)=C1 VJJPUSNTGOMMGY-MRVIYFEKSA-N 0.000 description 7
241000124008 Mammalia Species 0.000 description 6
ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
238000004587 chromatography analysis Methods 0.000 description 6
URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 description 6
UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 5
PNEYBMLMFCGWSK-UHFFFAOYSA-N aluminium oxide Inorganic materials [O-2].[O-2].[O-2].[Al+3].[Al+3] PNEYBMLMFCGWSK-UHFFFAOYSA-N 0.000 description 5
125000000325 methylidene group Chemical group [H]C([H])=* 0.000 description 5
230000007935 neutral effect Effects 0.000 description 5
239000012044 organic layer Substances 0.000 description 5
238000010992 reflux Methods 0.000 description 5
239000002904 solvent Substances 0.000 description 5
NRUKOCRGYNPUPR-QBPJDGROSA-N teniposide Chemical compound COC1=C(O)C(OC)=CC([C@@H]2C3=CC=4OCOC=4C=C3[C@@H](O[C@H]3[C@@H]([C@@H](O)[C@@H]4O[C@@H](OC[C@H]4O3)C=3SC=CC=3)O)[C@@H]3[C@@H]2C(OC3)=O)=C1 NRUKOCRGYNPUPR-QBPJDGROSA-N 0.000 description 5
238000012360 testing method Methods 0.000 description 5
YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 5
210000004881 tumor cell Anatomy 0.000 description 5
AZQWKYJCGOJGHM-UHFFFAOYSA-N 1,4-benzoquinone Chemical compound O=C1C=CC(=O)C=C1 AZQWKYJCGOJGHM-UHFFFAOYSA-N 0.000 description 4
QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 4
HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
241001465754 Metazoa Species 0.000 description 4
241001529936 Murinae Species 0.000 description 4
PXIPVTKHYLBLMZ-UHFFFAOYSA-N Sodium azide Chemical compound [Na+].[N-]=[N+]=[N-] PXIPVTKHYLBLMZ-UHFFFAOYSA-N 0.000 description 4
FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
101150077651 VP35 gene Proteins 0.000 description 4
150000001408 amides Chemical class 0.000 description 4
238000004458 analytical method Methods 0.000 description 4
239000012267 brine Substances 0.000 description 4
231100000263 cytotoxicity test Toxicity 0.000 description 4
238000010828 elution Methods 0.000 description 4
238000002474 experimental method Methods 0.000 description 4
239000000284 extract Substances 0.000 description 4
208000032839 leukemia Diseases 0.000 description 4
238000001819 mass spectrum Methods 0.000 description 4
239000000843 powder Substances 0.000 description 4
239000002244 precipitate Substances 0.000 description 4
229920006395 saturated elastomer Polymers 0.000 description 4
235000017557 sodium bicarbonate Nutrition 0.000 description 4
229910000030 sodium bicarbonate Inorganic materials 0.000 description 4
LPXPTNMVRIOKMN-UHFFFAOYSA-M sodium nitrite Chemical compound [Na+].[O-]N=O LPXPTNMVRIOKMN-UHFFFAOYSA-M 0.000 description 4
HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 4
KZNICNPSHKQLFF-UHFFFAOYSA-N succinimide Chemical compound O=C1CCC(=O)N1 KZNICNPSHKQLFF-UHFFFAOYSA-N 0.000 description 4
229960001278 teniposide Drugs 0.000 description 4
238000004809 thin layer chromatography Methods 0.000 description 4
KVKKVSRXXDVRTJ-UHFFFAOYSA-N 3-octyl-5-sulfanylidenepyrrolidin-2-one Chemical compound CCCCCCCCC1CC(=S)NC1=O KVKKVSRXXDVRTJ-UHFFFAOYSA-N 0.000 description 3
HCXJFMDOHDNDCC-UHFFFAOYSA-N 5-$l^{1}-oxidanyl-3,4-dihydropyrrol-2-one Chemical group O=C1CCC(=O)[N]1 HCXJFMDOHDNDCC-UHFFFAOYSA-N 0.000 description 3
CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 3
PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 3
239000013543 active substance Substances 0.000 description 3
150000001299 aldehydes Chemical class 0.000 description 3
150000003973 alkyl amines Chemical class 0.000 description 3
125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 3
125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 3
210000004027 cell Anatomy 0.000 description 3
239000003153 chemical reaction reagent Substances 0.000 description 3
238000002784 cytotoxicity assay Methods 0.000 description 3
238000000354 decomposition reaction Methods 0.000 description 3
238000004992 fast atom bombardment mass spectroscopy Methods 0.000 description 3
239000000706 filtrate Substances 0.000 description 3
XNXVOSBNFZWHBV-UHFFFAOYSA-N hydron;o-methylhydroxylamine;chloride Chemical compound Cl.CON XNXVOSBNFZWHBV-UHFFFAOYSA-N 0.000 description 3
238000000338 in vitro Methods 0.000 description 3
238000002955 isolation Methods 0.000 description 3
229910052943 magnesium sulfate Inorganic materials 0.000 description 3
235000019341 magnesium sulphate Nutrition 0.000 description 3
239000000463 material Substances 0.000 description 3
SQDFHQJTAWCFIB-UHFFFAOYSA-N n-methylidenehydroxylamine Chemical compound ON=C SQDFHQJTAWCFIB-UHFFFAOYSA-N 0.000 description 3
239000008194 pharmaceutical composition Substances 0.000 description 3
229960001237 podophyllotoxin Drugs 0.000 description 3
YVCVYCSAAZQOJI-UHFFFAOYSA-N podophyllotoxin Natural products COC1=C(O)C(OC)=CC(C2C3=CC=4OCOC=4C=C3C(O)C3C2C(OC3)=O)=C1 YVCVYCSAAZQOJI-UHFFFAOYSA-N 0.000 description 3
YJGVMLPVUAXIQN-XVVDYKMHSA-N podophyllotoxin Chemical compound COC1=C(OC)C(OC)=CC([C@@H]2C3=CC=4OCOC=4C=C3[C@H](O)[C@@H]3[C@@H]2C(OC3)=O)=C1 YJGVMLPVUAXIQN-XVVDYKMHSA-N 0.000 description 3
125000006239 protecting group Chemical group 0.000 description 3
230000002829 reductive effect Effects 0.000 description 3
239000011780 sodium chloride Substances 0.000 description 3
229910052938 sodium sulfate Inorganic materials 0.000 description 3
235000011152 sodium sulphate Nutrition 0.000 description 3
YJGVMLPVUAXIQN-LGWHJFRWSA-N (5s,5ar,8ar,9r)-5-hydroxy-9-(3,4,5-trimethoxyphenyl)-5a,6,8a,9-tetrahydro-5h-[2]benzofuro[5,6-f][1,3]benzodioxol-8-one Chemical class COC1=C(OC)C(OC)=CC([C@@H]2C3=CC=4OCOC=4C=C3[C@@H](O)[C@@H]3[C@@H]2C(OC3)=O)=C1 YJGVMLPVUAXIQN-LGWHJFRWSA-N 0.000 description 2
WOAHJDHKFWSLKE-UHFFFAOYSA-N 1,2-benzoquinone Chemical compound O=C1C=CC=CC1=O WOAHJDHKFWSLKE-UHFFFAOYSA-N 0.000 description 2
LJCZNYWLQZZIOS-UHFFFAOYSA-N 2,2,2-trichlorethoxycarbonyl chloride Chemical compound ClC(=O)OCC(Cl)(Cl)Cl LJCZNYWLQZZIOS-UHFFFAOYSA-N 0.000 description 2
OPHQOIGEOHXOGX-UHFFFAOYSA-N 3,4,5-trimethoxybenzaldehyde Chemical compound COC1=CC(C=O)=CC(OC)=C1OC OPHQOIGEOHXOGX-UHFFFAOYSA-N 0.000 description 2
125000001541 3-thienyl group Chemical group S1C([H])=C([*])C([H])=C1[H] 0.000 description 2
XVMSFILGAMDHEY-UHFFFAOYSA-N 6-(4-aminophenyl)sulfonylpyridin-3-amine Chemical compound C1=CC(N)=CC=C1S(=O)(=O)C1=CC=C(N)C=N1 XVMSFILGAMDHEY-UHFFFAOYSA-N 0.000 description 2
ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical group [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 2
QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
206010009944 Colon cancer Diseases 0.000 description 2
VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 2
241000699670 Mus sp. Species 0.000 description 2
JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 2
229960000583 acetic acid Drugs 0.000 description 2
239000003377 acid catalyst Substances 0.000 description 2
230000009471 action Effects 0.000 description 2
150000008064 anhydrides Chemical class 0.000 description 2
239000002585 base Substances 0.000 description 2
239000006227 byproduct Substances 0.000 description 2
238000009903 catalytic hydrogenation reaction Methods 0.000 description 2
239000003638 chemical reducing agent Substances 0.000 description 2
239000000460 chlorine Substances 0.000 description 2
208000029742 colonic neoplasm Diseases 0.000 description 2
239000012043 crude product Substances 0.000 description 2
201000010099 disease Diseases 0.000 description 2
208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 2
HYBBIBNJHNGZAN-UHFFFAOYSA-N furfural Chemical compound O=CC1=CC=CO1 HYBBIBNJHNGZAN-UHFFFAOYSA-N 0.000 description 2
239000012362 glacial acetic acid Substances 0.000 description 2
150000004820 halides Chemical class 0.000 description 2
125000001841 imino group Chemical group [H]N=* 0.000 description 2
239000010410 layer Substances 0.000 description 2
238000004949 mass spectrometry Methods 0.000 description 2
BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
150000002923 oximes Chemical class 0.000 description 2
ZRSNZINYAWTAHE-UHFFFAOYSA-N p-methoxybenzaldehyde Chemical compound COC1=CC=C(C=O)C=C1 ZRSNZINYAWTAHE-UHFFFAOYSA-N 0.000 description 2
230000036961 partial effect Effects 0.000 description 2
VLTRZXGMWDSKGL-UHFFFAOYSA-N perchloric acid Chemical compound OCl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-N 0.000 description 2
239000008363 phosphate buffer Substances 0.000 description 2
238000010898 silica gel chromatography Methods 0.000 description 2
235000010288 sodium nitrite Nutrition 0.000 description 2
239000007858 starting material Substances 0.000 description 2
239000000126 substance Substances 0.000 description 2
229960002317 succinimide Drugs 0.000 description 2
125000000446 sulfanediyl group Chemical group *S* 0.000 description 2
229940124530 sulfonamide Drugs 0.000 description 2
150000003456 sulfonamides Chemical class 0.000 description 2
230000004083 survival effect Effects 0.000 description 2
JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 2
QAEDZJGFFMLHHQ-UHFFFAOYSA-N trifluoroacetic anhydride Chemical compound FC(F)(F)C(=O)OC(=O)C(F)(F)F QAEDZJGFFMLHHQ-UHFFFAOYSA-N 0.000 description 2
PYOKUURKVVELLB-UHFFFAOYSA-N trimethyl orthoformate Chemical compound COC(OC)OC PYOKUURKVVELLB-UHFFFAOYSA-N 0.000 description 2
230000004614 tumor growth Effects 0.000 description 2
125000006527 (C1-C5) alkyl group Chemical group 0.000 description 1
BCMYXYHEMGPZJN-UHFFFAOYSA-N 1-chloro-2-isocyanatoethane Chemical compound ClCCN=C=O BCMYXYHEMGPZJN-UHFFFAOYSA-N 0.000 description 1
125000000453 2,2,2-trichloroethyl group Chemical group [H]C([H])(*)C(Cl)(Cl)Cl 0.000 description 1
FFRBMBIXVSCUFS-UHFFFAOYSA-N 2,4-dinitro-1-naphthol Chemical compound C1=CC=C2C(O)=C([N+]([O-])=O)C=C([N+]([O-])=O)C2=C1 FFRBMBIXVSCUFS-UHFFFAOYSA-N 0.000 description 1
125000002941 2-furyl group Chemical group O1C([*])=C([H])C([H])=C1[H] 0.000 description 1
125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 description 1
125000000175 2-thienyl group Chemical group S1C([*])=C([H])C([H])=C1[H] 0.000 description 1
125000005809 3,4,5-trimethoxyphenyl group Chemical group [H]C1=C(OC([H])([H])[H])C(OC([H])([H])[H])=C(OC([H])([H])[H])C([H])=C1* 0.000 description 1
NHQDETIJWKXCTC-UHFFFAOYSA-N 3-chloroperbenzoic acid Chemical compound OOC(=O)C1=CC=CC(Cl)=C1 NHQDETIJWKXCTC-UHFFFAOYSA-N 0.000 description 1
RBIGKSZIQCTIJF-UHFFFAOYSA-N 3-formylthiophene Chemical compound O=CC=1C=CSC=1 RBIGKSZIQCTIJF-UHFFFAOYSA-N 0.000 description 1
ZETIVVHRRQLWFW-UHFFFAOYSA-N 3-nitrobenzaldehyde Chemical compound [O-][N+](=O)C1=CC=CC(C=O)=C1 ZETIVVHRRQLWFW-UHFFFAOYSA-N 0.000 description 1
PBZLPFKFPUVVFB-UHFFFAOYSA-N 3-pyridin-2-yl-5-sulfanylidenepyrrolidin-2-one Chemical compound O=C1NC(=S)CC1C1=CC=CC=N1 PBZLPFKFPUVVFB-UHFFFAOYSA-N 0.000 description 1
OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 1
125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 description 1
125000000339 4-pyridyl group Chemical group N1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 description 1
JRLTTZUODKEYDH-UHFFFAOYSA-N 8-methylquinoline Chemical group C1=CN=C2C(C)=CC=CC2=C1 JRLTTZUODKEYDH-UHFFFAOYSA-N 0.000 description 1
RZVAJINKPMORJF-UHFFFAOYSA-N Acetaminophen Chemical compound CC(=O)NC1=CC=C(O)C=C1 RZVAJINKPMORJF-UHFFFAOYSA-N 0.000 description 1
WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 1
PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
238000005033 Fourier transform infrared spectroscopy Methods 0.000 description 1
239000005909 Kieselgur Substances 0.000 description 1
208000008342 Leukemia P388 Diseases 0.000 description 1
206010058467 Lung neoplasm malignant Diseases 0.000 description 1
239000012359 Methanesulfonyl chloride Substances 0.000 description 1
241000699666 Mus <mouse, genus> Species 0.000 description 1
241000282887 Suidae Species 0.000 description 1
241001104043 Syringa Species 0.000 description 1
235000004338 Syringa vulgaris Nutrition 0.000 description 1
ATJFFYVFTNAWJD-UHFFFAOYSA-N Tin Chemical compound [Sn] ATJFFYVFTNAWJD-UHFFFAOYSA-N 0.000 description 1
150000001241 acetals Chemical group 0.000 description 1
125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 1
239000004480 active ingredient Substances 0.000 description 1
125000002252 acyl group Chemical group 0.000 description 1
125000003545 alkoxy group Chemical group 0.000 description 1
150000001350 alkyl halides Chemical class 0.000 description 1
150000007854 aminals Chemical class 0.000 description 1
229910021529 ammonia Inorganic materials 0.000 description 1
239000000538 analytical sample Substances 0.000 description 1
239000002246 antineoplastic agent Substances 0.000 description 1
239000008346 aqueous phase Substances 0.000 description 1
238000003556 assay Methods 0.000 description 1
125000004429 atom Chemical group 0.000 description 1
238000010533 azeotropic distillation Methods 0.000 description 1
150000001540 azides Chemical class 0.000 description 1
125000000638 benzylaminocarbonyl group Chemical group C(C1=CC=CC=C1)NC(=O)* 0.000 description 1
230000004071 biological effect Effects 0.000 description 1
230000015572 biosynthetic process Effects 0.000 description 1
GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
229910052794 bromium Inorganic materials 0.000 description 1
HQABUPZFAYXKJW-UHFFFAOYSA-N butan-1-amine Chemical compound CCCCN HQABUPZFAYXKJW-UHFFFAOYSA-N 0.000 description 1
201000011510 cancer Diseases 0.000 description 1
239000002775 capsule Substances 0.000 description 1
CVXBEEMKQHEXEN-UHFFFAOYSA-N carbaryl Chemical group C1=CC=C2C(OC(=O)NC)=CC=CC2=C1 CVXBEEMKQHEXEN-UHFFFAOYSA-N 0.000 description 1
150000001732 carboxylic acid derivatives Chemical class 0.000 description 1
230000010261 cell growth Effects 0.000 description 1
229910052801 chlorine Inorganic materials 0.000 description 1
AOGYCOYQMAVAFD-UHFFFAOYSA-N chlorocarbonic acid Chemical class OC(Cl)=O AOGYCOYQMAVAFD-UHFFFAOYSA-N 0.000 description 1
239000012141 concentrate Substances 0.000 description 1
235000008504 concentrate Nutrition 0.000 description 1
238000007796 conventional method Methods 0.000 description 1
230000008878 coupling Effects 0.000 description 1
238000010168 coupling process Methods 0.000 description 1
238000005859 coupling reaction Methods 0.000 description 1
238000012136 culture method Methods 0.000 description 1
238000012258 culturing Methods 0.000 description 1
239000012024 dehydrating agents‎ Substances 0.000 description 1
238000001514 detection method Methods 0.000 description 1
238000011161 development Methods 0.000 description 1
238000010790 dilution Methods 0.000 description 1
239000012895 dilution Substances 0.000 description 1
239000002552 dosage form Substances 0.000 description 1
229940079593 drug Drugs 0.000 description 1
239000003814 drug Substances 0.000 description 1
239000003937 drug carrier Substances 0.000 description 1
238000001035 drying Methods 0.000 description 1
230000000694 effects Effects 0.000 description 1
238000006056 electrooxidation reaction Methods 0.000 description 1
239000002786 epipodophyllotoxin derivative Substances 0.000 description 1
125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
238000001704 evaporation Methods 0.000 description 1
230000008020 evaporation Effects 0.000 description 1
230000029142 excretion Effects 0.000 description 1
239000011737 fluorine Substances 0.000 description 1
229910052731 fluorine Inorganic materials 0.000 description 1
239000006260 foam Substances 0.000 description 1
235000019253 formic acid Nutrition 0.000 description 1
VGGRCVDNFAQIKO-UHFFFAOYSA-N formic anhydride Chemical compound O=COC=O VGGRCVDNFAQIKO-UHFFFAOYSA-N 0.000 description 1
239000008187 granular material Substances 0.000 description 1
238000011141 high resolution liquid chromatography Methods 0.000 description 1
150000002431 hydrogen Chemical class 0.000 description 1
239000012433 hydrogen halide Substances 0.000 description 1
229910000039 hydrogen halide Inorganic materials 0.000 description 1
238000002513 implantation Methods 0.000 description 1
238000002329 infrared spectrum Methods 0.000 description 1
239000003112 inhibitor Substances 0.000 description 1
230000010354 integration Effects 0.000 description 1
239000007928 intraperitoneal injection Substances 0.000 description 1
229910052740 iodine Inorganic materials 0.000 description 1
239000011630 iodine Substances 0.000 description 1
YDNLNVZZTACNJX-UHFFFAOYSA-N isocyanatomethylbenzene Chemical compound O=C=NCC1=CC=CC=C1 YDNLNVZZTACNJX-UHFFFAOYSA-N 0.000 description 1
125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
229930013686 lignan Natural products 0.000 description 1
150000005692 lignans Chemical class 0.000 description 1
235000009408 lignans Nutrition 0.000 description 1
230000000670 limiting effect Effects 0.000 description 1
239000007788 liquid Substances 0.000 description 1
201000005202 lung cancer Diseases 0.000 description 1
208000020816 lung neoplasm Diseases 0.000 description 1
201000001441 melanoma Diseases 0.000 description 1
QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 1
WSFSSNUMVMOOMR-NJFSPNSNSA-N methanone Chemical compound O=[14CH2] WSFSSNUMVMOOMR-NJFSPNSNSA-N 0.000 description 1
125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 description 1
239000002808 molecular sieve Substances 0.000 description 1
PSHKMPUSSFXUIA-UHFFFAOYSA-N n,n-dimethylpyridin-2-amine Chemical compound CN(C)C1=CC=CC=N1 PSHKMPUSSFXUIA-UHFFFAOYSA-N 0.000 description 1
125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
231100000252 nontoxic Toxicity 0.000 description 1
230000003000 nontoxic effect Effects 0.000 description 1
235000016709 nutrition Nutrition 0.000 description 1
230000035764 nutrition Effects 0.000 description 1
HYDZPXNVHXJHBG-UHFFFAOYSA-N o-benzylhydroxylamine;hydron;chloride Chemical compound Cl.NOCC1=CC=CC=C1 HYDZPXNVHXJHBG-UHFFFAOYSA-N 0.000 description 1
239000012074 organic phase Substances 0.000 description 1
230000003647 oxidation Effects 0.000 description 1
238000007254 oxidation reaction Methods 0.000 description 1
NXJCBFBQEVOTOW-UHFFFAOYSA-L palladium(2+);dihydroxide Chemical compound O[Pd]O NXJCBFBQEVOTOW-UHFFFAOYSA-L 0.000 description 1
ISWSIDIOOBJBQZ-UHFFFAOYSA-N phenol group Chemical group C1(=CC=CC=C1)O ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 1
239000002504 physiological saline solution Substances 0.000 description 1
239000006187 pill Substances 0.000 description 1
239000013641 positive control Substances 0.000 description 1
230000003389 potentiating effect Effects 0.000 description 1
238000012746 preparative thin layer chromatography Methods 0.000 description 1
125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
238000000425 proton nuclear magnetic resonance spectrum Methods 0.000 description 1
BGUWFUQJCDRPTL-UHFFFAOYSA-N pyridine-4-carbaldehyde Chemical compound O=CC1=CC=NC=C1 BGUWFUQJCDRPTL-UHFFFAOYSA-N 0.000 description 1
238000001953 recrystallisation Methods 0.000 description 1
238000011160 research Methods 0.000 description 1
XMVJITFPVVRMHC-UHFFFAOYSA-N roxarsone Chemical group OC1=CC=C([As](O)(O)=O)C=C1[N+]([O-])=O XMVJITFPVVRMHC-UHFFFAOYSA-N 0.000 description 1
230000035945 sensitivity Effects 0.000 description 1
238000000935 solvent evaporation Methods 0.000 description 1
238000001228 spectrum Methods 0.000 description 1
238000010561 standard procedure Methods 0.000 description 1
239000008223 sterile water Substances 0.000 description 1
150000003458 sulfonic acid derivatives Chemical class 0.000 description 1
150000003461 sulfonyl halides Chemical class 0.000 description 1
239000000725 suspension Substances 0.000 description 1
238000003786 synthesis reaction Methods 0.000 description 1
239000006188 syrup Substances 0.000 description 1
235000020357 syrup Nutrition 0.000 description 1
239000003826 tablet Substances 0.000 description 1
230000001225 therapeutic effect Effects 0.000 description 1
125000004044 trifluoroacetyl group Chemical group FC(C(=O)*)(F)F 0.000 description 1
238000001665 trituration Methods 0.000 description 1
238000009281 ultraviolet germicidal irradiation Methods 0.000 description 1
150000003672 ureas Chemical class 0.000 description 1

Classifications

- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H17/00—Compounds containing heterocyclic radicals directly attached to hetero atoms of saccharide radicals
- C07H17/04—Heterocyclic radicals containing only oxygen as ring hetero atoms
- 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
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H17/00—Compounds containing heterocyclic radicals directly attached to hetero atoms of saccharide radicals

Landscapes

Chemical & Material Sciences (AREA)
Organic Chemistry (AREA)
Health & Medical Sciences (AREA)
General Health & Medical Sciences (AREA)
Life Sciences & Earth Sciences (AREA)
Biotechnology (AREA)
Engineering & Computer Science (AREA)
Molecular Biology (AREA)
Genetics & Genomics (AREA)
Biochemistry (AREA)
Veterinary Medicine (AREA)
Public Health (AREA)
Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
General Chemical & Material Sciences (AREA)
Animal Behavior & Ethology (AREA)
Chemical Kinetics & Catalysis (AREA)
Medicinal Chemistry (AREA)
Pharmacology & Pharmacy (AREA)
Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Saccharide Compounds (AREA)
Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)

CS331288A 1987-05-19 1988-05-17 Method of ephidophylotoxin's derivatives production that contain nitrogen CS273185B2 (en)

Priority Applications (1)

Application Number	Priority Date	Filing Date	Title
CS356589A CS273199B2 (en)	1987-05-19	1989-06-12	Method of epidophyllotoxine-glucoside's derivatives production that contain nitrogen

Applications Claiming Priority (1)

Application Number	Priority Date	Filing Date	Title
US07/051,434 US4853467A (en)	1987-05-19	1987-05-19	Nitrogen containing derivatives of epipodophyllotoxin glucosides

Publications (2)

Publication Number	Publication Date
CS331288A2 CS331288A2 (en)	1990-06-13
CS273185B2 true CS273185B2 (en)	1991-03-12

Family

ID=21971296

Family Applications (1)

Application Number	Title	Priority Date	Filing Date
CS331288A CS273185B2 (en)	1987-05-19	1988-05-17	Method of ephidophylotoxin's derivatives production that contain nitrogen

Country Status (16)

Country	Link
US (1)	US4853467A (de)
EP (1)	EP0291957A3 (de)
JP (1)	JPS63303991A (de)
KR (1)	KR900006217B1 (de)
AU (1)	AU594238B2 (de)
CA (1)	CA1295612C (de)
CS (1)	CS273185B2 (de)
DD (1)	DD270078A5 (de)
DK (1)	DK270988A (de)
FI (1)	FI87789C (de)
HU (1)	HU204838B (de)
NO (1)	NO168648C (de)
NZ (1)	NZ224565A (de)
PT (1)	PT87517B (de)
YU (1)	YU46568B (de)
ZA (1)	ZA883518B (de)

Families Citing this family (9)

* Cited by examiner, † Cited by third party
Publication number	Priority date	Publication date	Assignee	Title
US4874851A (en) *	1987-07-01	1989-10-17	Bristol-Meyers Company	3',4'-dinitrogen substituted epipodophyllotoxin glucoside derivatives
US4888419A (en) *	1987-08-31	1989-12-19	Bristol-Myers Company	3'-demethoxyepipodophyllotoxin glucoside derivatives
US4965348A (en) *	1989-05-19	1990-10-23	Bristol-Myers Company	Dimeric epipodophyllotoxin glucoside derivatives
US5036055A (en) *	1989-06-07	1991-07-30	Bristol-Myers Company	Acylated derivatives of etoposide
KR910014122A (ko) *	1990-01-19	1991-08-31	디께다 가즈히꼬	에토포시드-2-디메틸아미노 화합물의 동결건조 제제
JPH07508046A (ja) *	1993-04-13	1995-09-07	ノバルティス　アクチェンゲゼルシャフト	オルニチンデカルボキシラーゼを阻害する枝分れアミノオキシアミノアルカン誘導体
ES2100060T3 (es) *	1993-04-13	1997-06-01	Ciba Geigy Ag	Aminooxi-compuestos ciclicos inhibidores de ornitina descarboxilasa.
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
HK1049787B (en)	1999-10-01	2014-07-25	Immunogen, Inc.	Compositions and methods for treating cancer using immunoconjugates and chemotherapeutic agents

Family Cites Families (5)

* Cited by examiner, † Cited by third party
Publication number	Priority date	Publication date	Assignee	Title
NL6613143A (de) *	1965-09-21	1967-03-22
JPS6032799A (ja) *	1983-07-29	1985-02-19	Microbial Chem Res Found	新規４′−デメチル−４−エピポドフィロトキシン誘導体
US4609644A (en) *	1984-06-15	1986-09-02	St. Jude Children's Research Hospital	Epipodophyllotoxinquinone glucoside derivatives, method of production and use
US4874851A (en) *	1987-07-01	1989-10-17	Bristol-Meyers Company	3',4'-dinitrogen substituted epipodophyllotoxin glucoside derivatives
US4888419A (en) *	1987-08-31	1989-12-19	Bristol-Myers Company	3'-demethoxyepipodophyllotoxin glucoside derivatives

1987
- 1987-05-19 US US07/051,434 patent/US4853467A/en not_active Expired - Fee Related
1988
- 1988-04-26 AU AU15136/88A patent/AU594238B2/en not_active Ceased
- 1988-05-10 NZ NZ224565A patent/NZ224565A/en unknown
- 1988-05-16 NO NO882126A patent/NO168648C/no unknown
- 1988-05-16 FI FI882277A patent/FI87789C/fi not_active IP Right Cessation
- 1988-05-17 CS CS331288A patent/CS273185B2/cs unknown
- 1988-05-18 KR KR8805813A patent/KR900006217B1/ko not_active Expired
- 1988-05-18 JP JP63121675A patent/JPS63303991A/ja active Pending
- 1988-05-18 EP EP88107968A patent/EP0291957A3/de not_active Ceased
- 1988-05-18 YU YU96588A patent/YU46568B/sh unknown
- 1988-05-18 DD DD88315877A patent/DD270078A5/de not_active IP Right Cessation
- 1988-05-18 DK DK270988A patent/DK270988A/da not_active Application Discontinuation
- 1988-05-18 HU HU882483A patent/HU204838B/hu not_active IP Right Cessation
- 1988-05-18 PT PT87517A patent/PT87517B/pt not_active IP Right Cessation
- 1988-05-18 ZA ZA883518A patent/ZA883518B/xx unknown
- 1988-05-18 CA CA000567081A patent/CA1295612C/en not_active Expired - Fee Related

Also Published As

Publication number	Publication date
DK270988D0 (da)	1988-05-18
US4853467A (en)	1989-08-01
NO168648C (no)	1992-03-18
CS331288A2 (en)	1990-06-13
FI87789C (fi)	1993-02-25
CA1295612C (en)	1992-02-11
EP0291957A3 (de)	1990-08-01
PT87517A (pt)	1989-05-31
JPS63303991A (ja)	1988-12-12
HUT47126A (en)	1989-01-30
EP0291957A2 (de)	1988-11-23
NZ224565A (en)	1991-03-26
AU1513688A (en)	1988-11-24
YU96588A (en)	1989-12-31
FI882277A0 (fi)	1988-05-16
NO882126L (no)	1988-11-21
KR880013965A (ko)	1988-12-22
FI87789B (fi)	1992-11-13
HU204838B (en)	1992-02-28
DK270988A (da)	1988-11-20
NO168648B (no)	1991-12-09
FI882277A7 (fi)	1988-11-20
AU594238B2 (en)	1990-03-01
PT87517B (pt)	1992-09-30
YU46568B (sh)	1993-11-16
KR900006217B1 (ko)	1990-08-25
DD270078A5 (de)	1989-07-19
NO882126D0 (no)	1988-05-16
ZA883518B (en)	1988-11-22

Publication	Publication Date	Title
US7256209B2 (en)	2007-08-14	Pyrazole derivatives and diabetic medicine containing them
US4877776A (en)	1989-10-31	K-252 compounds
US4923986A (en)	1990-05-08	Derivatives of physiologically active substance K-252
EP2316832B1 (de)	2017-03-08	Cyclopamin Analogverbindungen, deren Herstellungsverfahren und Anwendung
JP4105592B2 (ja)	2008-06-25	フペルジンａ誘導体、その製造およびその使用
CA2661166A1 (en)	2008-02-28	Compounds and methods for inhibiting the interaction of bcl proteins with binding partners
CA2220006A1 (en)	1996-12-19	Heterocyclic substituted cyclopentane compounds
CS273185B2 (en)	1991-03-12	Method of ephidophylotoxin's derivatives production that contain nitrogen
AU618536B2 (en)	1992-01-02	Novel 3',4'-dinitrogen substituted epipodophyllotoxin glucoside derivatives
US4888419A (en)	1989-12-19	3'-demethoxyepipodophyllotoxin glucoside derivatives
PL205635B1 (pl)	2010-05-31	Nowe pochodne genisteiny i zawierające je środki farmaceutyczne
US5034380A (en)	1991-07-23	Alkoxymethylidene epipodophyllotoxin glucosides
JP4591781B2 (ja)	2010-12-01	新規ピラゾール誘導体及びそれらを含有する糖尿病治療薬
JPH0285288A (ja)	1990-03-26	ナイジエリシン誘導体およびその製法
JPS6259714B2 (de)	1987-12-12