JP2003515601A - ブリオスタチンアナログ、合成方法および使用 - Google Patents
ブリオスタチンアナログ、合成方法および使用Info
- Publication number
- JP2003515601A JP2003515601A JP2001541898A JP2001541898A JP2003515601A JP 2003515601 A JP2003515601 A JP 2003515601A JP 2001541898 A JP2001541898 A JP 2001541898A JP 2001541898 A JP2001541898 A JP 2001541898A JP 2003515601 A JP2003515601 A JP 2003515601A
- Authority
- JP
- Japan
- Prior art keywords
- compound
- mmol
- carbon atoms
- formula
- independently
- 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.)
- Pending
Links
- MJQUEDHRCUIRLF-TVIXENOKSA-N bryostatin 1 Chemical class C([C@@H]1CC(/[C@@H]([C@@](C(C)(C)/C=C/2)(O)O1)OC(=O)/C=C/C=C/CCC)=C\C(=O)OC)[C@H]([C@@H](C)O)OC(=O)C[C@H](O)C[C@@H](O1)C[C@H](OC(C)=O)C(C)(C)[C@]1(O)C[C@@H]1C\C(=C\C(=O)OC)C[C@H]\2O1 MJQUEDHRCUIRLF-TVIXENOKSA-N 0.000 title claims abstract description 69
- 238000010189 synthetic method Methods 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims abstract description 186
- 238000000034 method Methods 0.000 claims abstract description 63
- 229960005520 bryostatin Drugs 0.000 claims abstract description 48
- 150000003839 salts Chemical class 0.000 claims abstract description 48
- MUIWQCKLQMOUAT-AKUNNTHJSA-N bryostatin 20 Natural products COC(=O)C=C1C[C@@]2(C)C[C@]3(O)O[C@](C)(C[C@@H](O)CC(=O)O[C@](C)(C[C@@]4(C)O[C@](O)(CC5=CC(=O)O[C@]45C)C(C)(C)C=C[C@@](C)(C1)O2)[C@@H](C)O)C[C@H](OC(=O)C(C)(C)C)C3(C)C MUIWQCKLQMOUAT-AKUNNTHJSA-N 0.000 claims abstract description 43
- 238000011282 treatment Methods 0.000 claims abstract description 24
- 241000124008 Mammalia Species 0.000 claims abstract description 9
- 230000007246 mechanism Effects 0.000 claims abstract description 7
- 230000003463 hyperproliferative effect Effects 0.000 claims abstract description 3
- 238000006243 chemical reaction Methods 0.000 claims description 100
- 229910052739 hydrogen Inorganic materials 0.000 claims description 83
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 63
- -1 hydroxyl compound Chemical class 0.000 claims description 50
- 125000000217 alkyl group Chemical group 0.000 claims description 42
- 125000004432 carbon atom Chemical group C* 0.000 claims description 41
- 125000003342 alkenyl group Chemical group 0.000 claims description 31
- 229910052760 oxygen Inorganic materials 0.000 claims description 26
- 125000000304 alkynyl group Chemical group 0.000 claims description 24
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 22
- 239000001301 oxygen Substances 0.000 claims description 21
- 125000003118 aryl group Chemical group 0.000 claims description 20
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 19
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 19
- 150000002148 esters Chemical class 0.000 claims description 19
- 239000001257 hydrogen Substances 0.000 claims description 19
- 125000001424 substituent group Chemical group 0.000 claims description 19
- 229910052799 carbon Inorganic materials 0.000 claims description 13
- 125000001072 heteroaryl group Chemical group 0.000 claims description 12
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 11
- 125000004475 heteroaralkyl group Chemical group 0.000 claims description 11
- 239000002243 precursor Substances 0.000 claims description 11
- 125000004429 atom Chemical group 0.000 claims description 8
- 229910002091 carbon monoxide Inorganic materials 0.000 claims description 8
- 239000008194 pharmaceutical composition Substances 0.000 claims description 8
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 8
- 229910052717 sulfur Inorganic materials 0.000 claims description 8
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 8
- 125000004122 cyclic group Chemical group 0.000 claims description 7
- 125000001624 naphthyl group Chemical group 0.000 claims description 7
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 7
- 230000001506 immunosuppresive effect Effects 0.000 claims description 2
- 125000003367 polycyclic group Chemical group 0.000 claims description 2
- 230000002194 synthesizing effect Effects 0.000 claims description 2
- 238000002560 therapeutic procedure Methods 0.000 claims description 2
- 239000013543 active substance Substances 0.000 claims 2
- 206010028980 Neoplasm Diseases 0.000 abstract description 34
- 201000011510 cancer Diseases 0.000 abstract description 27
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 abstract description 11
- 201000010099 disease Diseases 0.000 abstract description 8
- 239000002246 antineoplastic agent Substances 0.000 abstract description 6
- 238000002650 immunosuppressive therapy Methods 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 478
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical class CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 341
- 235000019439 ethyl acetate Nutrition 0.000 description 215
- 239000000203 mixture Substances 0.000 description 147
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 128
- 239000000243 solution Substances 0.000 description 122
- 238000005481 NMR spectroscopy Methods 0.000 description 105
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 92
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 80
- OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 description 75
- 230000002829 reductive effect Effects 0.000 description 75
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 74
- 239000000126 substance Substances 0.000 description 74
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 73
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 72
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 55
- 229920006395 saturated elastomer Polymers 0.000 description 54
- 239000000741 silica gel Substances 0.000 description 53
- 229910002027 silica gel Inorganic materials 0.000 description 53
- 239000000047 product Substances 0.000 description 52
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 51
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 49
- 239000002904 solvent Substances 0.000 description 49
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 46
- 239000010408 film Substances 0.000 description 45
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 45
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 44
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 42
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 42
- 239000012230 colorless oil Substances 0.000 description 42
- 239000010410 layer Substances 0.000 description 40
- 229910052938 sodium sulfate Inorganic materials 0.000 description 39
- 235000011152 sodium sulphate Nutrition 0.000 description 39
- 239000012267 brine Substances 0.000 description 38
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 38
- 210000004027 cell Anatomy 0.000 description 37
- 239000012044 organic layer Substances 0.000 description 37
- 230000015572 biosynthetic process Effects 0.000 description 36
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 36
- 229910001868 water Inorganic materials 0.000 description 36
- 238000004896 high resolution mass spectrometry Methods 0.000 description 35
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 34
- 125000005647 linker group Chemical group 0.000 description 32
- 238000003786 synthesis reaction Methods 0.000 description 32
- 238000004587 chromatography analysis Methods 0.000 description 31
- 150000001299 aldehydes Chemical class 0.000 description 27
- 239000011734 sodium Substances 0.000 description 25
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 24
- SPEUIVXLLWOEMJ-UHFFFAOYSA-N 1,1-dimethoxyethane Chemical compound COC(C)OC SPEUIVXLLWOEMJ-UHFFFAOYSA-N 0.000 description 23
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 22
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 22
- 235000017557 sodium bicarbonate Nutrition 0.000 description 22
- 238000003756 stirring Methods 0.000 description 22
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 21
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 21
- 239000003921 oil Substances 0.000 description 21
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 21
- HZNVUJQVZSTENZ-UHFFFAOYSA-N 2,3-dichloro-5,6-dicyano-1,4-benzoquinone Chemical compound ClC1=C(Cl)C(=O)C(C#N)=C(C#N)C1=O HZNVUJQVZSTENZ-UHFFFAOYSA-N 0.000 description 20
- 239000002253 acid Substances 0.000 description 20
- 230000000694 effects Effects 0.000 description 20
- 239000007787 solid Substances 0.000 description 20
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 19
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 18
- 238000003556 assay Methods 0.000 description 18
- 150000002009 diols Chemical class 0.000 description 17
- 102000003923 Protein Kinase C Human genes 0.000 description 15
- 108090000315 Protein Kinase C Proteins 0.000 description 15
- 230000001093 anti-cancer Effects 0.000 description 15
- 230000027455 binding Effects 0.000 description 15
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 14
- 239000011541 reaction mixture Substances 0.000 description 14
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 13
- 239000000725 suspension Substances 0.000 description 13
- GQHTUMJGOHRCHB-UHFFFAOYSA-N 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine Chemical compound C1CCCCN2CCCN=C21 GQHTUMJGOHRCHB-UHFFFAOYSA-N 0.000 description 12
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 12
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 12
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 12
- 239000007864 aqueous solution Substances 0.000 description 12
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 12
- 239000012043 crude product Substances 0.000 description 12
- 238000010791 quenching Methods 0.000 description 12
- 238000005160 1H NMR spectroscopy Methods 0.000 description 11
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 11
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 11
- WWZKQHOCKIZLMA-UHFFFAOYSA-N octanoic acid Chemical class CCCCCCCC(O)=O WWZKQHOCKIZLMA-UHFFFAOYSA-N 0.000 description 11
- HSJKGGMUJITCBW-UHFFFAOYSA-N 3-hydroxybutanal Chemical compound CC(O)CC=O HSJKGGMUJITCBW-UHFFFAOYSA-N 0.000 description 10
- 150000001336 alkenes Chemical class 0.000 description 10
- XXROGKLTLUQVRX-UHFFFAOYSA-N allyl alcohol Chemical compound OCC=C XXROGKLTLUQVRX-UHFFFAOYSA-N 0.000 description 10
- 239000012455 biphasic mixture Substances 0.000 description 10
- KPUWHANPEXNPJT-UHFFFAOYSA-N disiloxane Chemical compound [SiH3]O[SiH3] KPUWHANPEXNPJT-UHFFFAOYSA-N 0.000 description 10
- 229910052757 nitrogen Inorganic materials 0.000 description 10
- 238000004809 thin layer chromatography Methods 0.000 description 10
- 239000012298 atmosphere Substances 0.000 description 9
- UAOMVDZJSHZZME-UHFFFAOYSA-N diisopropylamine Chemical compound CC(C)NC(C)C UAOMVDZJSHZZME-UHFFFAOYSA-N 0.000 description 9
- 239000000543 intermediate Substances 0.000 description 9
- 239000007788 liquid Substances 0.000 description 9
- 239000000463 material Substances 0.000 description 9
- 239000012074 organic phase Substances 0.000 description 9
- 238000000746 purification Methods 0.000 description 9
- 239000012047 saturated solution Substances 0.000 description 9
- 239000000377 silicon dioxide Substances 0.000 description 9
- 125000006850 spacer group Chemical group 0.000 description 9
- 238000004440 column chromatography Methods 0.000 description 8
- 239000003814 drug Substances 0.000 description 8
- 238000003818 flash chromatography Methods 0.000 description 8
- 238000002955 isolation Methods 0.000 description 8
- 125000006239 protecting group Chemical group 0.000 description 8
- BCNZYOJHNLTNEZ-UHFFFAOYSA-N tert-butyldimethylsilyl chloride Chemical compound CC(C)(C)[Si](C)(C)Cl BCNZYOJHNLTNEZ-UHFFFAOYSA-N 0.000 description 8
- PYOKUURKVVELLB-UHFFFAOYSA-N trimethyl orthoformate Chemical compound COC(OC)OC PYOKUURKVVELLB-UHFFFAOYSA-N 0.000 description 8
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 7
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 7
- 239000011324 bead Substances 0.000 description 7
- 239000012141 concentrate Substances 0.000 description 7
- MHDVGSVTJDSBDK-UHFFFAOYSA-N dibenzyl ether Chemical compound C=1C=CC=CC=1COCC1=CC=CC=C1 MHDVGSVTJDSBDK-UHFFFAOYSA-N 0.000 description 7
- 239000000284 extract Substances 0.000 description 7
- 125000005842 heteroatom Chemical group 0.000 description 7
- 150000002576 ketones Chemical class 0.000 description 7
- 239000007858 starting material Substances 0.000 description 7
- 239000011550 stock solution Substances 0.000 description 7
- 238000012360 testing method Methods 0.000 description 7
- OZGSEIVTQLXWRO-UHFFFAOYSA-N 2,4,6-trichlorobenzoyl chloride Chemical compound ClC(=O)C1=C(Cl)C=C(Cl)C=C1Cl OZGSEIVTQLXWRO-UHFFFAOYSA-N 0.000 description 6
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 6
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 6
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 6
- 235000019270 ammonium chloride Nutrition 0.000 description 6
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 6
- 229960005539 bryostatin 1 Drugs 0.000 description 6
- 230000003197 catalytic effect Effects 0.000 description 6
- 239000003153 chemical reaction reagent Substances 0.000 description 6
- 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 6
- 229940079593 drug Drugs 0.000 description 6
- 239000003480 eluent Substances 0.000 description 6
- 238000009472 formulation Methods 0.000 description 6
- MNWFXJYAOYHMED-UHFFFAOYSA-N heptanoic acid Chemical compound CCCCCCC(O)=O MNWFXJYAOYHMED-UHFFFAOYSA-N 0.000 description 6
- 238000001727 in vivo Methods 0.000 description 6
- DQEUYIQDSMINEY-UHFFFAOYSA-M magnesium;prop-1-ene;bromide Chemical compound [Mg+2].[Br-].[CH2-]C=C DQEUYIQDSMINEY-UHFFFAOYSA-M 0.000 description 6
- 239000002808 molecular sieve Substances 0.000 description 6
- JRZJOMJEPLMPRA-UHFFFAOYSA-N olefin Natural products CCCCCCCC=C JRZJOMJEPLMPRA-UHFFFAOYSA-N 0.000 description 6
- 239000012071 phase Substances 0.000 description 6
- 239000004033 plastic Substances 0.000 description 6
- 229920003023 plastic Polymers 0.000 description 6
- 238000010898 silica gel chromatography 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
- YURNCBVQZBJDAJ-UHFFFAOYSA-N 2-heptenoic acid Chemical compound CCCCC=CC(O)=O YURNCBVQZBJDAJ-UHFFFAOYSA-N 0.000 description 5
- ZSPTYLOMNJNZNG-UHFFFAOYSA-N 3-Buten-1-ol Chemical compound OCCC=C ZSPTYLOMNJNZNG-UHFFFAOYSA-N 0.000 description 5
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 5
- 235000021360 Myristic acid Nutrition 0.000 description 5
- TUNFSRHWOTWDNC-UHFFFAOYSA-N Myristic acid Natural products CCCCCCCCCCCCCC(O)=O TUNFSRHWOTWDNC-UHFFFAOYSA-N 0.000 description 5
- OBETXYAYXDNJHR-UHFFFAOYSA-N alpha-ethylcaproic acid Natural products CCCCC(CC)C(O)=O OBETXYAYXDNJHR-UHFFFAOYSA-N 0.000 description 5
- MJQUEDHRCUIRLF-YCVQJEHTSA-N bryostatins Chemical compound C([C@@H]1CC(/[C@@H]([C@@](C(C)(C)/C=C/2)(O)O1)OC(=O)/C=C/C=C/CCC)=C\C(=O)OC)C([C@@H](C)O)OC(=O)C[C@H](O)C[C@@H](O1)C[C@H](OC(C)=O)C(C)(C)[C@]1(O)C[C@@H]1C\C(=C\C(=O)OC)C[C@H]\2O1 MJQUEDHRCUIRLF-YCVQJEHTSA-N 0.000 description 5
- 238000010790 dilution Methods 0.000 description 5
- 239000012895 dilution Substances 0.000 description 5
- 239000011159 matrix material Substances 0.000 description 5
- NXJCBFBQEVOTOW-UHFFFAOYSA-L palladium(2+);dihydroxide Chemical compound O[Pd]O NXJCBFBQEVOTOW-UHFFFAOYSA-L 0.000 description 5
- BQJRUJTZSGYBEZ-YVQNUNKESA-N phorbol 12,13-dibutanoate Chemical compound C([C@]1(O)C(=O)C(C)=C[C@H]1[C@@]1(O)[C@H](C)[C@H]2OC(=O)CCC)C(CO)=C[C@H]1[C@H]1[C@]2(OC(=O)CCC)C1(C)C BQJRUJTZSGYBEZ-YVQNUNKESA-N 0.000 description 5
- 230000001376 precipitating effect Effects 0.000 description 5
- UNILWMWFPHPYOR-KXEYIPSPSA-M 1-[6-[2-[3-[3-[3-[2-[2-[3-[[2-[2-[[(2r)-1-[[2-[[(2r)-1-[3-[2-[2-[3-[[2-(2-amino-2-oxoethoxy)acetyl]amino]propoxy]ethoxy]ethoxy]propylamino]-3-hydroxy-1-oxopropan-2-yl]amino]-2-oxoethyl]amino]-3-[(2r)-2,3-di(hexadecanoyloxy)propyl]sulfanyl-1-oxopropan-2-yl Chemical compound O=C1C(SCCC(=O)NCCCOCCOCCOCCCNC(=O)COCC(=O)N[C@@H](CSC[C@@H](COC(=O)CCCCCCCCCCCCCCC)OC(=O)CCCCCCCCCCCCCCC)C(=O)NCC(=O)N[C@H](CO)C(=O)NCCCOCCOCCOCCCNC(=O)COCC(N)=O)CC(=O)N1CCNC(=O)CCCCCN\1C2=CC=C(S([O-])(=O)=O)C=C2CC/1=C/C=C/C=C/C1=[N+](CC)C2=CC=C(S([O-])(=O)=O)C=C2C1 UNILWMWFPHPYOR-KXEYIPSPSA-M 0.000 description 4
- TWJNQYPJQDRXPH-UHFFFAOYSA-N 2-cyanobenzohydrazide Chemical compound NNC(=O)C1=CC=CC=C1C#N TWJNQYPJQDRXPH-UHFFFAOYSA-N 0.000 description 4
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 4
- ZPSJGADGUYYRKE-UHFFFAOYSA-N 2H-pyran-2-one Chemical compound O=C1C=CC=CO1 ZPSJGADGUYYRKE-UHFFFAOYSA-N 0.000 description 4
- DYAWMXSWDGPGOI-UHFFFAOYSA-N 4-hydroxy-3,3-dimethylbutan-2-one Chemical compound CC(=O)C(C)(C)CO DYAWMXSWDGPGOI-UHFFFAOYSA-N 0.000 description 4
- AOJJSUZBOXZQNB-TZSSRYMLSA-N Doxorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 AOJJSUZBOXZQNB-TZSSRYMLSA-N 0.000 description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- 108010044467 Isoenzymes Proteins 0.000 description 4
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 4
- 241000872931 Myoporum sandwicense Species 0.000 description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 4
- 238000013459 approach Methods 0.000 description 4
- 239000012131 assay buffer Substances 0.000 description 4
- 239000002585 base Substances 0.000 description 4
- 230000000903 blocking effect Effects 0.000 description 4
- 230000037396 body weight Effects 0.000 description 4
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Classifications
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- 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
- C07D493/02—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains two hetero rings
- C07D493/06—Peri-condensed systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
- A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D265/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one oxygen atom as the only ring hetero atoms
- C07D265/04—1,3-Oxazines; Hydrogenated 1,3-oxazines
- C07D265/12—1,3-Oxazines; Hydrogenated 1,3-oxazines condensed with carbocyclic rings or ring systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D309/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings
- C07D309/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
- C07D309/08—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D309/10—Oxygen atoms
- C07D309/12—Oxygen atoms only hydrogen atoms and one oxygen atom directly attached to ring carbon atoms, e.g. tetrahydropyranyl ethers
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D319/00—Heterocyclic compounds containing six-membered rings having two oxygen atoms as the only ring hetero atoms
- C07D319/04—1,3-Dioxanes; Hydrogenated 1,3-dioxanes
- C07D319/08—1,3-Dioxanes; Hydrogenated 1,3-dioxanes condensed with carbocyclic rings or ring systems
-
- 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
- C07D493/02—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains two hetero rings
- C07D493/08—Bridged systems
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- Chemical & Material Sciences (AREA)
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- Health & Medical Sciences (AREA)
- Immunology (AREA)
- Medicinal Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- General Chemical & Material Sciences (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Transplantation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Heterocyclic Compounds That Contain Two Or More Ring Oxygen Atoms (AREA)
- Pyrane Compounds (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US16818199P | 1999-11-30 | 1999-11-30 | |
| US60/168,181 | 1999-11-30 | ||
| PCT/US2000/032896 WO2001040214A1 (en) | 1999-11-30 | 2000-11-30 | Bryostatin analogues, synthetic methods and uses |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JP2003515601A true JP2003515601A (ja) | 2003-05-07 |
| JP2003515601A5 JP2003515601A5 (https=) | 2008-01-24 |
Family
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Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP2001541898A Pending JP2003515601A (ja) | 1999-11-30 | 2000-11-30 | ブリオスタチンアナログ、合成方法および使用 |
Country Status (6)
| Country | Link |
|---|---|
| US (1) | US6624189B2 (https=) |
| EP (1) | EP1233956A4 (https=) |
| JP (1) | JP2003515601A (https=) |
| AU (1) | AU784589B2 (https=) |
| CA (1) | CA2393026A1 (https=) |
| WO (1) | WO2001040214A1 (https=) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2007277197A (ja) * | 2006-04-10 | 2007-10-25 | Ube Ind Ltd | シリルエーテル基を有するβ−ジケトン化合物の製造法 |
| JP2016501224A (ja) * | 2012-11-27 | 2016-01-18 | アフィオス コーポレーション | 蘚苔地衣類組成物、その作製方法及び使用 |
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| US7256286B2 (en) * | 1999-11-30 | 2007-08-14 | The Board Of Trustees Of The Leland Stanford Junior University | Bryostatin analogues, synthetic methods and uses |
| US6825229B2 (en) | 2002-03-07 | 2004-11-30 | Blanchette Rockefeller Neurosciences Institute | Methods for Alzheimer's Disease treatment and cognitive enhancement |
| US20050065205A1 (en) * | 2002-03-07 | 2005-03-24 | Daniel Alkon | Methods for Alzheimer's disease treatment and cognitive enhance |
| US20080004332A1 (en) * | 2002-03-07 | 2008-01-03 | Alkon Daniel L | Methods for alzheimer's disease treatment and cognitive enhancement |
| PA8580301A1 (es) * | 2002-08-28 | 2005-05-24 | Pfizer Prod Inc | Nuevos derivados de benzoimidazol utiles como agentes antiproliferativos |
| US7232842B2 (en) * | 2003-01-10 | 2007-06-19 | Board Of Trustees Of The Leland Stanford Junior University | Kinase inhibitors and associated pharmaceutical compositions and methods of use |
| WO2004074249A2 (en) * | 2003-02-20 | 2004-09-02 | Board Of Regents, University Of Texas System | Synthesis of peloruside a and analogs thereof for use as antitumor agents |
| TW201206425A (en) | 2004-05-18 | 2012-02-16 | Brni Neurosciences Inst | Treatment of depressive disorders |
| US20070026488A1 (en) * | 2005-07-27 | 2007-02-01 | Targett Nancy M | Biosynthesis of bryostatins by polyketide synthases (PKS) |
| US20070054890A1 (en) | 2005-07-29 | 2007-03-08 | Alkon Daniel L | Protein synthesis required for long-term memory is induced by PKC activation on days preceding associative learning |
| CN103961347A (zh) | 2006-07-28 | 2014-08-06 | 布朗歇特洛克菲勒神经科学研究所 | 刺激细胞生长、突触重塑和巩固长期记忆的方法 |
| US20080058396A1 (en) * | 2006-07-28 | 2008-03-06 | Alkon Daniel L | Methods of stimulating cellular growth, synaptic remodelling and consolidation of long-term memory |
| EP3332797A3 (en) * | 2007-02-09 | 2018-08-01 | Blanchette Rockefeller Neurosciences Institute | Therapeutic effects of bryostatins, bryologs and other related substances on head trauma-induced memory impairment and brain injury |
| US8497385B2 (en) * | 2007-08-31 | 2013-07-30 | The Board Of Trustees Of The Leland Stanford Junior University | Bryostatin analogues, synthetic methods and uses |
| US20100280262A1 (en) * | 2007-10-19 | 2010-11-04 | Wender Paul A | Bryostatin analogues, synthetic methods and uses |
| US9994585B2 (en) | 2007-12-31 | 2018-06-12 | Aphios Corporation | Transplantation therapies |
| US9107890B2 (en) | 2010-07-08 | 2015-08-18 | Blanchette Rockefeller Neurosciences Institute | PKC activators and anticoagulant in regimen for treating stroke |
| CA2808660A1 (en) | 2010-08-19 | 2012-02-23 | Blanchette Rockefeller Neurosciences Institute | Treatment of cognitive disorders associated with abnormal dendritic spines using pkc activators |
| EP2780316B1 (en) | 2011-11-13 | 2020-04-15 | Blanchette Rockefeller Neurosciences Institute | Esters of dcpla and methods of treatment using the same |
| JP6422778B2 (ja) | 2011-11-13 | 2018-11-14 | ブランシェット・ロックフェラー・ニューロサイエンスィズ・インスティテュート | Ｐｋｃアクチベーターおよびその組合せ |
| US9034347B2 (en) | 2011-12-19 | 2015-05-19 | Arphios Corporation | Drug delivery system and method for the treatment of neuro-degenerative disease |
| WO2013162729A1 (en) | 2012-04-24 | 2013-10-31 | The Board Of Trustees Of The Leland Stanford Junior University | Method for delivery of small molecules and proteins across the cell wall of algae using molecular transporters |
| EP2925314B1 (en) | 2012-11-28 | 2020-04-01 | Aphios Corporation | Combination therapeutics and methods for the treatment of neurodegenerative and other diseases |
| WO2014145316A1 (en) | 2013-03-15 | 2014-09-18 | Alkon Daniel L | Methods for identifying neuroprotective pkc activators |
| CA2946115A1 (en) | 2014-04-18 | 2015-10-22 | Neurotrope Bioscience, Inc. | Methods and compositions for treatment of lipid storage disorders |
| WO2016183252A1 (en) | 2015-05-11 | 2016-11-17 | Alkon, Daniel, L. | Treatment of neurodegenerative conditions using pkc activators after determining the presence of the apoe4 allele |
| US20180256537A1 (en) | 2015-09-23 | 2018-09-13 | Tapan K. Khan | Methods for survival and rejuvenation of dermal fibroblasts using pkc activators |
| US20180311209A1 (en) | 2015-10-08 | 2018-11-01 | Cognitive Research Enterprises, Inc. | Dosing regimens of pkc activators |
| WO2018034318A1 (ja) | 2016-08-18 | 2018-02-22 | 国立大学法人 奈良先端科学技術大学院大学 | 免疫調節剤 |
| EP3523296A4 (en) | 2016-10-05 | 2020-04-01 | The Board of Trustees of the Leland Stanford Junior University | BRYOSTATIN COMPOUNDS AND METHOD FOR PRODUCING THE SAME |
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| WO2018187647A1 (en) | 2017-04-06 | 2018-10-11 | Neurotrope Bioscience, Inc. | Methods and compositions for treatment of neurological diseases, disorders, or conditions |
| CA3100792A1 (en) | 2018-05-18 | 2019-11-21 | Neurotrope Bioscience, Inc. | Methods and compositions for treatment of alzheimer's disease |
| US20220133687A1 (en) * | 2020-11-02 | 2022-05-05 | Synaptogenix, Inc. | Methods of treating and preventing neurodegenerative diseases with hgf activating compounds |
| WO2022115492A1 (en) | 2020-11-24 | 2022-06-02 | Lyell Immunopharma, Inc. | Methods for making, compositions comprising, and methods of using rejuvenated t cells |
| CN113773256B (zh) * | 2021-09-16 | 2022-11-18 | 精华制药集团南通有限公司 | 一种琥布宗的合成方法 |
Family Cites Families (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4560774A (en) | 1982-11-17 | 1985-12-24 | Arizona State University | Macrocyclic lactones |
| US4611066A (en) * | 1984-08-10 | 1986-09-09 | Arizona State University | Bryostatins 4 to 8 |
| US5891870A (en) | 1986-06-11 | 1999-04-06 | Procyon Pharmaceuticals, Inc. | Protein kinase C modulators Q |
| US4833257A (en) * | 1986-07-28 | 1989-05-23 | Arizona Board Of Regents | Compositions of matter and methods of using same |
| WO1997034598A1 (en) | 1996-03-20 | 1997-09-25 | The United States Of America, Represented By The Secretary, Department Of Health And Human Services | Method of treating cancer using c-26 modified bryostatin |
-
2000
- 2000-11-30 WO PCT/US2000/032896 patent/WO2001040214A1/en not_active Ceased
- 2000-11-30 CA CA002393026A patent/CA2393026A1/en not_active Abandoned
- 2000-11-30 EP EP00982401A patent/EP1233956A4/en not_active Withdrawn
- 2000-11-30 JP JP2001541898A patent/JP2003515601A/ja active Pending
- 2000-11-30 AU AU19440/01A patent/AU784589B2/en not_active Ceased
- 2000-11-30 US US09/728,929 patent/US6624189B2/en not_active Expired - Lifetime
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2007277197A (ja) * | 2006-04-10 | 2007-10-25 | Ube Ind Ltd | シリルエーテル基を有するβ−ジケトン化合物の製造法 |
| JP2016501224A (ja) * | 2012-11-27 | 2016-01-18 | アフィオス コーポレーション | 蘚苔地衣類組成物、その作製方法及び使用 |
Also Published As
| Publication number | Publication date |
|---|---|
| AU784589B2 (en) | 2006-05-04 |
| US6624189B2 (en) | 2003-09-23 |
| CA2393026A1 (en) | 2001-06-07 |
| EP1233956A4 (en) | 2006-07-05 |
| AU1944001A (en) | 2001-06-12 |
| US20020137789A1 (en) | 2002-09-26 |
| EP1233956A1 (en) | 2002-08-28 |
| WO2001040214A1 (en) | 2001-06-07 |
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