USH1487H - Benzoate derivatives of taxol - Google Patents
Benzoate derivatives of taxol Download PDFInfo
- Publication number
- USH1487H USH1487H US08/128,949 US12894993A USH1487H US H1487 H USH1487 H US H1487H US 12894993 A US12894993 A US 12894993A US H1487 H USH1487 H US H1487H
- Authority
- US
- United States
- Prior art keywords
- compound
- alkyl
- formula
- taxol
- mmol
- 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.)
- Abandoned
Links
- 229930012538 Paclitaxel Natural products 0.000 title claims description 47
- 229960001592 paclitaxel Drugs 0.000 title claims description 46
- 150000001558 benzoic acid derivatives Chemical class 0.000 title description 2
- 150000001875 compounds Chemical class 0.000 claims abstract description 174
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 104
- -1 hydroxy, phosphono, phosphonooxy, carboxy Chemical group 0.000 claims abstract description 49
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims abstract description 42
- 150000003839 salts Chemical class 0.000 claims abstract description 27
- 239000001257 hydrogen Substances 0.000 claims abstract description 26
- 238000000034 method Methods 0.000 claims abstract description 24
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims abstract description 14
- 206010028980 Neoplasm Diseases 0.000 claims abstract description 14
- 125000006619 (C1-C6) dialkylamino group Chemical group 0.000 claims abstract description 9
- 229910052799 carbon Inorganic materials 0.000 claims abstract description 9
- 150000002431 hydrogen Chemical class 0.000 claims abstract description 7
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims abstract description 7
- 229910052736 halogen Inorganic materials 0.000 claims abstract description 6
- 150000002367 halogens Chemical class 0.000 claims abstract description 6
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims abstract description 5
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims abstract description 5
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 5
- 229910052705 radium Inorganic materials 0.000 claims abstract description 5
- 229910052701 rubidium Inorganic materials 0.000 claims abstract description 5
- 150000001721 carbon Chemical group 0.000 claims abstract 5
- RCINICONZNJXQF-MZXODVADSA-N taxol Chemical compound O([C@@H]1[C@@]2(C[C@@H](C(C)=C(C2(C)C)[C@H](C([C@]2(C)[C@@H](O)C[C@H]3OC[C@]3([C@H]21)OC(C)=O)=O)OC(=O)C)OC(=O)[C@H](O)[C@@H](NC(=O)C=1C=CC=CC=1)C=1C=CC=CC=1)O)C(=O)C1=CC=CC=C1 RCINICONZNJXQF-MZXODVADSA-N 0.000 claims description 54
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 claims description 34
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 29
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 9
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 8
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 6
- KWYHDKDOAIKMQN-UHFFFAOYSA-N N,N,N',N'-tetramethylethylenediamine Chemical compound CN(C)CCN(C)C KWYHDKDOAIKMQN-UHFFFAOYSA-N 0.000 claims description 5
- 239000003937 drug carrier Substances 0.000 claims description 5
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 4
- 229910052757 nitrogen Inorganic materials 0.000 claims description 3
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 3
- YDIYEOMDOWUDTJ-UHFFFAOYSA-M 4-(dimethylamino)benzoate Chemical compound CN(C)C1=CC=C(C([O-])=O)C=C1 YDIYEOMDOWUDTJ-UHFFFAOYSA-M 0.000 claims description 2
- 241000124008 Mammalia Species 0.000 claims description 2
- 239000003085 diluting agent Substances 0.000 claims description 2
- 239000004480 active ingredient Substances 0.000 claims 1
- 101100386054 Saccharomyces cerevisiae (strain ATCC 204508 / S288c) CYS3 gene Proteins 0.000 abstract 1
- 101150035983 str1 gene Proteins 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 145
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 90
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 90
- 239000000203 mixture Substances 0.000 description 86
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 75
- 235000019439 ethyl acetate Nutrition 0.000 description 68
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 49
- 239000000243 solution Substances 0.000 description 49
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 45
- 238000005160 1H NMR spectroscopy Methods 0.000 description 39
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 36
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 36
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 33
- KZBUYRJDOAKODT-UHFFFAOYSA-N Chlorine Chemical compound ClCl KZBUYRJDOAKODT-UHFFFAOYSA-N 0.000 description 32
- 239000002253 acid Substances 0.000 description 28
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 24
- 239000007787 solid Substances 0.000 description 24
- 239000012267 brine Substances 0.000 description 23
- 239000000741 silica gel Substances 0.000 description 23
- 229910002027 silica gel Inorganic materials 0.000 description 23
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 23
- 125000006239 protecting group Chemical group 0.000 description 21
- CSCPPACGZOOCGX-WFGJKAKNSA-N acetone d6 Chemical compound [2H]C([2H])([2H])C(=O)C([2H])([2H])[2H] CSCPPACGZOOCGX-WFGJKAKNSA-N 0.000 description 20
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 19
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 18
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 18
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 15
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 15
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 15
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 15
- 239000003921 oil Substances 0.000 description 15
- 235000019198 oils Nutrition 0.000 description 15
- 239000011541 reaction mixture Substances 0.000 description 15
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 14
- 150000003254 radicals Chemical group 0.000 description 14
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 13
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 13
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N phenol group Chemical group C1(=CC=CC=C1)O ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 13
- 125000002467 phosphate group Chemical group [H]OP(=O)(O[H])O[*] 0.000 description 13
- 239000000047 product Substances 0.000 description 13
- 229910004809 Na2 SO4 Inorganic materials 0.000 description 12
- 238000004992 fast atom bombardment mass spectroscopy Methods 0.000 description 12
- 239000012458 free base Substances 0.000 description 12
- LEHBURLTIWGHEM-UHFFFAOYSA-N pyridinium chlorochromate Chemical compound [O-][Cr](Cl)(=O)=O.C1=CC=[NH+]C=C1 LEHBURLTIWGHEM-UHFFFAOYSA-N 0.000 description 12
- 238000003786 synthesis reaction Methods 0.000 description 12
- 239000003810 Jones reagent Substances 0.000 description 11
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 11
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 11
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 10
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 10
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 10
- 239000010410 layer Substances 0.000 description 10
- 239000011734 sodium Substances 0.000 description 10
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 9
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 9
- 238000004440 column chromatography Methods 0.000 description 9
- 239000000706 filtrate Substances 0.000 description 9
- 239000000463 material Substances 0.000 description 9
- 239000000377 silicon dioxide Substances 0.000 description 9
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 9
- 239000002904 solvent Substances 0.000 description 9
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 9
- 241000699670 Mus sp. Species 0.000 description 8
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 8
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 8
- 230000015572 biosynthetic process Effects 0.000 description 8
- 238000006243 chemical reaction Methods 0.000 description 8
- 239000003153 chemical reaction reagent Substances 0.000 description 8
- 229910052681 coesite Inorganic materials 0.000 description 8
- 229910052906 cristobalite Inorganic materials 0.000 description 8
- NSBNXCZCLRBQTA-UHFFFAOYSA-N dibenzyl bis(phenylmethoxy)phosphoryl phosphate Chemical compound C=1C=CC=CC=1COP(OP(=O)(OCC=1C=CC=CC=1)OCC=1C=CC=CC=1)(=O)OCC1=CC=CC=C1 NSBNXCZCLRBQTA-UHFFFAOYSA-N 0.000 description 8
- 125000004356 hydroxy functional group Chemical group O* 0.000 description 8
- ZCSHNCUQKCANBX-UHFFFAOYSA-N lithium diisopropylamide Chemical compound [Li+].CC(C)[N-]C(C)C ZCSHNCUQKCANBX-UHFFFAOYSA-N 0.000 description 8
- 229910052682 stishovite Inorganic materials 0.000 description 8
- FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 description 8
- 229910052905 tridymite Inorganic materials 0.000 description 8
- 125000000453 2,2,2-trichloroethyl group Chemical group [H]C([H])(*)C(Cl)(Cl)Cl 0.000 description 7
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 7
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 7
- 150000007513 acids Chemical class 0.000 description 7
- 230000003647 oxidation Effects 0.000 description 7
- 238000007254 oxidation reaction Methods 0.000 description 7
- 125000001476 phosphono group Chemical group [H]OP(*)(=O)O[H] 0.000 description 7
- 239000000725 suspension Substances 0.000 description 7
- KJUGUADJHNHALS-UHFFFAOYSA-N 1H-tetrazole Chemical compound C=1N=NNN=1 KJUGUADJHNHALS-UHFFFAOYSA-N 0.000 description 6
- SGWZVZZVXOJRAQ-UHFFFAOYSA-N 2,6-Dimethyl-1,4-benzenediol Chemical compound CC1=CC(O)=CC(C)=C1O SGWZVZZVXOJRAQ-UHFFFAOYSA-N 0.000 description 6
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 6
- WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 description 6
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 125000004432 carbon atom Chemical group C* 0.000 description 6
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 6
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 5
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 5
- 239000002585 base Substances 0.000 description 5
- FODOWNHLRYKAAC-UHFFFAOYSA-N dibenzyl [2-(4-hydroxy-2-methylbutan-2-yl)-3,5-dimethylphenyl] phosphate Chemical compound CC1=CC(C)=C(C(C)(C)CCO)C(OP(=O)(OCC=2C=CC=CC=2)OCC=2C=CC=CC=2)=C1 FODOWNHLRYKAAC-UHFFFAOYSA-N 0.000 description 5
- 239000006260 foam Substances 0.000 description 5
- 238000009472 formulation Methods 0.000 description 5
- 239000012442 inert solvent Substances 0.000 description 5
- 229960004592 isopropanol Drugs 0.000 description 5
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 5
- 239000012299 nitrogen atmosphere Substances 0.000 description 5
- 239000012074 organic phase Substances 0.000 description 5
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 5
- 229910000104 sodium hydride Inorganic materials 0.000 description 5
- 229910052717 sulfur Inorganic materials 0.000 description 5
- BCNZYOJHNLTNEZ-UHFFFAOYSA-N tert-butyldimethylsilyl chloride Chemical compound CC(C)(C)[Si](C)(C)Cl BCNZYOJHNLTNEZ-UHFFFAOYSA-N 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
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 4
- ZVXWXORBQGXYPQ-UHFFFAOYSA-N 2-(4-hydroxy-2-methylbutan-2-yl)-3,5-dimethylphenol Chemical compound CC1=CC(C)=C(C(C)(C)CCO)C(O)=C1 ZVXWXORBQGXYPQ-UHFFFAOYSA-N 0.000 description 4
- CNFFXDHHVZVVMM-UHFFFAOYSA-N 3-[2-bis(phenylmethoxy)phosphoryloxy-4,6-dimethylphenyl]-3-methylbutanoic acid Chemical compound CC1=CC(C)=C(C(C)(C)CC(O)=O)C(OP(=O)(OCC=2C=CC=CC=2)OCC=2C=CC=CC=2)=C1 CNFFXDHHVZVVMM-UHFFFAOYSA-N 0.000 description 4
- NHQDETIJWKXCTC-UHFFFAOYSA-N 3-chloroperbenzoic acid Chemical compound OOC(=O)C1=CC=CC(Cl)=C1 NHQDETIJWKXCTC-UHFFFAOYSA-N 0.000 description 4
- 238000005481 NMR spectroscopy Methods 0.000 description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
- 150000001412 amines Chemical class 0.000 description 4
- 201000011510 cancer Diseases 0.000 description 4
- XMPZTFVPEKAKFH-UHFFFAOYSA-P ceric ammonium nitrate Chemical compound [NH4+].[NH4+].[Ce+4].[O-][N+]([O-])=O.[O-][N+]([O-])=O.[O-][N+]([O-])=O.[O-][N+]([O-])=O.[O-][N+]([O-])=O.[O-][N+]([O-])=O XMPZTFVPEKAKFH-UHFFFAOYSA-P 0.000 description 4
- 239000012230 colorless oil Substances 0.000 description 4
- 239000012043 crude product Substances 0.000 description 4
- 239000002274 desiccant Substances 0.000 description 4
- WQSJARQXZYHSNN-UHFFFAOYSA-N dibenzyl [2-[4-[tert-butyl(dimethyl)silyl]oxy-2-methylbutan-2-yl]-3,5-dimethylphenyl] phosphate Chemical compound CC1=CC(C)=C(C(C)(C)CCO[Si](C)(C)C(C)(C)C)C(OP(=O)(OCC=2C=CC=CC=2)OCC=2C=CC=CC=2)=C1 WQSJARQXZYHSNN-UHFFFAOYSA-N 0.000 description 4
- SBZXBUIDTXKZTM-UHFFFAOYSA-N diglyme Chemical compound COCCOCCOC SBZXBUIDTXKZTM-UHFFFAOYSA-N 0.000 description 4
- 150000002148 esters Chemical class 0.000 description 4
- 239000002198 insoluble material Substances 0.000 description 4
- 150000002596 lactones Chemical class 0.000 description 4
- 229910052751 metal Inorganic materials 0.000 description 4
- 239000002184 metal Substances 0.000 description 4
- 239000012071 phase Substances 0.000 description 4
- 230000002829 reductive effect Effects 0.000 description 4
- 238000010992 reflux Methods 0.000 description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L sodium carbonate Substances [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 4
- 239000011780 sodium chloride Substances 0.000 description 4
- 230000003595 spectral effect Effects 0.000 description 4
- 150000003892 tartrate salts Chemical class 0.000 description 4
- OTEADGQJLYVKJC-UHFFFAOYSA-N 2-(4-hydroxy-2-methylbutan-2-yl)-3,5-dimethyl-4-phenylmethoxyphenol Chemical compound CC1=CC(O)=C(C(C)(C)CCO)C(C)=C1OCC1=CC=CC=C1 OTEADGQJLYVKJC-UHFFFAOYSA-N 0.000 description 3
- TUAMRELNJMMDMT-UHFFFAOYSA-N 3,5-xylenol Chemical compound CC1=CC(C)=CC(O)=C1 TUAMRELNJMMDMT-UHFFFAOYSA-N 0.000 description 3
- SZFAEJMEHIBRMS-UHFFFAOYSA-N 4,4,5,7-tetramethyl-3h-chromen-2-one Chemical compound O1C(=O)CC(C)(C)C=2C1=CC(C)=CC=2C SZFAEJMEHIBRMS-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
- KRHYYFGTRYWZRS-UHFFFAOYSA-M Fluoride anion Chemical group [F-] KRHYYFGTRYWZRS-UHFFFAOYSA-M 0.000 description 3
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 3
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 3
- PBZCAGIVTPVHRU-UHFFFAOYSA-N [2-[4-[tert-butyl(dimethyl)silyl]oxy-2-methylbutan-2-yl]-3,5-dimethyl-4-phenylmethoxyphenyl] acetate Chemical compound CC1=C(C(C)(C)CCO[Si](C)(C)C(C)(C)C)C(OC(=O)C)=CC(C)=C1OCC1=CC=CC=C1 PBZCAGIVTPVHRU-UHFFFAOYSA-N 0.000 description 3
- UYTHXLPLGPBBTQ-UHFFFAOYSA-N [4-(chloromethyl)benzoyl] 4-(chloromethyl)benzoate Chemical compound C1=CC(CCl)=CC=C1C(=O)OC(=O)C1=CC=C(CCl)C=C1 UYTHXLPLGPBBTQ-UHFFFAOYSA-N 0.000 description 3
- 230000010933 acylation Effects 0.000 description 3
- 238000005917 acylation reaction Methods 0.000 description 3
- 150000001299 aldehydes Chemical class 0.000 description 3
- 125000003545 alkoxy group Chemical group 0.000 description 3
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 description 3
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 3
- 230000003197 catalytic effect Effects 0.000 description 3
- 229960004106 citric acid Drugs 0.000 description 3
- 239000010779 crude oil Substances 0.000 description 3
- GHZQWJJBNSBADT-UHFFFAOYSA-N dibenzyl [3,5-dimethyl-2-(2-methyl-4-oxobutan-2-yl)phenyl] phosphate Chemical compound CC1=CC(C)=C(C(C)(C)CC=O)C(OP(=O)(OCC=2C=CC=CC=2)OCC=2C=CC=CC=2)=C1 GHZQWJJBNSBADT-UHFFFAOYSA-N 0.000 description 3
- 150000002009 diols Chemical class 0.000 description 3
- 125000005982 diphenylmethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])(*)C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 3
- KPUWHANPEXNPJT-UHFFFAOYSA-N disiloxane Chemical compound [SiH3]O[SiH3] KPUWHANPEXNPJT-UHFFFAOYSA-N 0.000 description 3
- 238000010265 fast atom bombardment Methods 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- 238000007327 hydrogenolysis reaction Methods 0.000 description 3
- 239000007943 implant Substances 0.000 description 3
- 229910052500 inorganic mineral Inorganic materials 0.000 description 3
- 235000010755 mineral Nutrition 0.000 description 3
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- HVVNJUAVDAZWCB-YFKPBYRVSA-N [(2s)-pyrrolidin-2-yl]methanol Chemical compound OC[C@@H]1CCCN1 HVVNJUAVDAZWCB-YFKPBYRVSA-N 0.000 description 1
- MIUMTRMKHBSCDY-UHFFFAOYSA-N [2-(chloromethyl)benzoyl] 2-(chloromethyl)benzoate Chemical compound ClCC1=CC=CC=C1C(=O)OC(=O)C1=CC=CC=C1CCl MIUMTRMKHBSCDY-UHFFFAOYSA-N 0.000 description 1
- XAKBSHICSHRJCL-UHFFFAOYSA-N [CH2]C(=O)C1=CC=CC=C1 Chemical group [CH2]C(=O)C1=CC=CC=C1 XAKBSHICSHRJCL-UHFFFAOYSA-N 0.000 description 1
- DGYIJVNZSDYBOE-UHFFFAOYSA-N [CH2]C1=CC=NC=C1 Chemical group [CH2]C1=CC=NC=C1 DGYIJVNZSDYBOE-UHFFFAOYSA-N 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 125000001539 acetonyl group Chemical group [H]C([H])([H])C(=O)C([H])([H])* 0.000 description 1
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 1
- 125000005396 acrylic acid ester group Chemical group 0.000 description 1
- 239000002671 adjuvant Substances 0.000 description 1
- 125000003158 alcohol group Chemical group 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 125000003172 aldehyde group Chemical group 0.000 description 1
- 150000003973 alkyl amines Chemical class 0.000 description 1
- 125000005210 alkyl ammonium group Chemical group 0.000 description 1
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 150000003927 aminopyridines Chemical class 0.000 description 1
- 239000000908 ammonium hydroxide Substances 0.000 description 1
- 230000002052 anaphylactic effect Effects 0.000 description 1
- 150000001450 anions Chemical class 0.000 description 1
- 238000010719 annulation reaction Methods 0.000 description 1
- 229940044684 anti-microtubule agent Drugs 0.000 description 1
- 230000000259 anti-tumor effect Effects 0.000 description 1
- 239000002246 antineoplastic agent Substances 0.000 description 1
- 229940041181 antineoplastic drug Drugs 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- 239000000010 aprotic solvent Substances 0.000 description 1
- 229910052786 argon Inorganic materials 0.000 description 1
- 239000012300 argon atmosphere Substances 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- 239000011668 ascorbic acid Substances 0.000 description 1
- 235000010323 ascorbic acid Nutrition 0.000 description 1
- 229960005070 ascorbic acid Drugs 0.000 description 1
- 239000012298 atmosphere Substances 0.000 description 1
- 125000004429 atom Chemical group 0.000 description 1
- 229910052788 barium Inorganic materials 0.000 description 1
- DSAJWYNOEDNPEQ-UHFFFAOYSA-N barium atom Chemical compound [Ba] DSAJWYNOEDNPEQ-UHFFFAOYSA-N 0.000 description 1
- UPABQMWFWCMOFV-UHFFFAOYSA-N benethamine Chemical compound C=1C=CC=CC=1CNCCC1=CC=CC=C1 UPABQMWFWCMOFV-UHFFFAOYSA-N 0.000 description 1
- JUHORIMYRDESRB-UHFFFAOYSA-N benzathine Chemical compound C=1C=CC=CC=1CNCCNCC1=CC=CC=C1 JUHORIMYRDESRB-UHFFFAOYSA-N 0.000 description 1
- RWCCWEUUXYIKHB-UHFFFAOYSA-N benzophenone Chemical compound C=1C=CC=CC=1C(=O)C1=CC=CC=C1 RWCCWEUUXYIKHB-UHFFFAOYSA-N 0.000 description 1
- 239000012965 benzophenone Substances 0.000 description 1
- ULRXXOPTBNYPKA-VFTBNVCNSA-N benzoyltaxol Chemical group O([C@@H]1[C@@]2(C[C@@H](C(C)=C(C2(C)C)[C@H](C([C@]2(C)[C@@H](O)C[C@H]3OC[C@]3([C@H]21)OC(C)=O)=O)OC(=O)C)OC(=O)[C@H](O)[C@@H](NC(=O)C=1C=CC(=CC=1)C(=O)C=1C=CC=CC=1)C=1C=CC=CC=1)O)C(=O)C1=CC=CC=C1 ULRXXOPTBNYPKA-VFTBNVCNSA-N 0.000 description 1
- 229960002903 benzyl benzoate Drugs 0.000 description 1
- AGEZXYOZHKGVCM-UHFFFAOYSA-N benzyl bromide Chemical compound BrCC1=CC=CC=C1 AGEZXYOZHKGVCM-UHFFFAOYSA-N 0.000 description 1
- VBQDSLGFSUGBBE-UHFFFAOYSA-N benzyl(triethyl)azanium Chemical compound CC[N+](CC)(CC)CC1=CC=CC=C1 VBQDSLGFSUGBBE-UHFFFAOYSA-N 0.000 description 1
- FKPSBYZGRQJIMO-UHFFFAOYSA-M benzyl(triethyl)azanium;hydroxide Chemical compound [OH-].CC[N+](CC)(CC)CC1=CC=CC=C1 FKPSBYZGRQJIMO-UHFFFAOYSA-M 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 210000000481 breast Anatomy 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
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 description 1
- 229910000019 calcium carbonate Inorganic materials 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 239000004202 carbamide Substances 0.000 description 1
- VZGDMQKNWNREIO-UHFFFAOYSA-N carbon tetrachloride Substances ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 1
- 150000001244 carboxylic acid anhydrides Chemical class 0.000 description 1
- 150000001735 carboxylic acids Chemical class 0.000 description 1
- 238000000451 chemical ionisation Methods 0.000 description 1
- 238000007385 chemical modification Methods 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 239000003638 chemical reducing agent Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 125000002668 chloroacetyl group Chemical group ClCC(=O)* 0.000 description 1
- KOPOQZFJUQMUML-UHFFFAOYSA-N chlorosilane Chemical class Cl[SiH3] KOPOQZFJUQMUML-UHFFFAOYSA-N 0.000 description 1
- WRJWRGBVPUUDLA-UHFFFAOYSA-N chlorosulfonyl isocyanate Chemical compound ClS(=O)(=O)N=C=O WRJWRGBVPUUDLA-UHFFFAOYSA-N 0.000 description 1
- JOPOVCBBYLSVDA-UHFFFAOYSA-N chromium(6+) Chemical compound [Cr+6] JOPOVCBBYLSVDA-UHFFFAOYSA-N 0.000 description 1
- 239000002178 crystalline material Substances 0.000 description 1
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- FNIATMYXUPOJRW-UHFFFAOYSA-N cyclohexylidene Chemical group [C]1CCCCC1 FNIATMYXUPOJRW-UHFFFAOYSA-N 0.000 description 1
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 1
- 238000001212 derivatisation Methods 0.000 description 1
- 238000003795 desorption Methods 0.000 description 1
- MCVGAILPZFVZQW-UHFFFAOYSA-N dibenzyl 4-[tert-butyl(dimethyl)silyl]oxybutyl phosphate Chemical compound C=1C=CC=CC=1COP(=O)(OCCCCO[Si](C)(C)C(C)(C)C)OCC1=CC=CC=C1 MCVGAILPZFVZQW-UHFFFAOYSA-N 0.000 description 1
- MHDVGSVTJDSBDK-UHFFFAOYSA-N dibenzyl ether Chemical compound C=1C=CC=CC=1COCC1=CC=CC=C1 MHDVGSVTJDSBDK-UHFFFAOYSA-N 0.000 description 1
- TXFOLHZMICYNRM-UHFFFAOYSA-N dichlorophosphoryloxybenzene Chemical compound ClP(Cl)(=O)OC1=CC=CC=C1 TXFOLHZMICYNRM-UHFFFAOYSA-N 0.000 description 1
- ZBCBWPMODOFKDW-UHFFFAOYSA-N diethanolamine Chemical compound OCCNCCO ZBCBWPMODOFKDW-UHFFFAOYSA-N 0.000 description 1
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 description 1
- UXGNZZKBCMGWAZ-UHFFFAOYSA-N dimethylformamide dmf Chemical compound CN(C)C=O.CN(C)C=O UXGNZZKBCMGWAZ-UHFFFAOYSA-N 0.000 description 1
- 235000019329 dioctyl sodium sulphosuccinate Nutrition 0.000 description 1
- CZZYITDELCSZES-UHFFFAOYSA-N diphenylmethane Chemical compound C=1C=CC=CC=1CC1=CC=CC=C1 CZZYITDELCSZES-UHFFFAOYSA-N 0.000 description 1
- XPPKVPWEQAFLFU-UHFFFAOYSA-J diphosphate(4-) Chemical compound [O-]P([O-])(=O)OP([O-])([O-])=O XPPKVPWEQAFLFU-UHFFFAOYSA-J 0.000 description 1
- 235000011180 diphosphates Nutrition 0.000 description 1
- CETRZFQIITUQQL-UHFFFAOYSA-N dmso dimethylsulfoxide Chemical compound CS(C)=O.CS(C)=O CETRZFQIITUQQL-UHFFFAOYSA-N 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 230000001804 emulsifying effect Effects 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 239000002024 ethyl acetate extract Substances 0.000 description 1
- 229920001249 ethyl cellulose Polymers 0.000 description 1
- 235000019325 ethyl cellulose Nutrition 0.000 description 1
- LVGKNOAMLMIIKO-QXMHVHEDSA-N ethyl oleate Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OCC LVGKNOAMLMIIKO-QXMHVHEDSA-N 0.000 description 1
- 229940093471 ethyl oleate Drugs 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 235000013305 food Nutrition 0.000 description 1
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 235000011087 fumaric acid Nutrition 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- KDCIHNCMPUBDKT-UHFFFAOYSA-N hexane;propan-2-one Chemical compound CC(C)=O.CCCCCC KDCIHNCMPUBDKT-UHFFFAOYSA-N 0.000 description 1
- 238000004896 high resolution mass spectrometry Methods 0.000 description 1
- 229960001340 histamine Drugs 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 238000001802 infusion Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007928 intraperitoneal injection Substances 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 230000000670 limiting effect Effects 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 235000019341 magnesium sulphate Nutrition 0.000 description 1
- 230000014759 maintenance of location Effects 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 239000001630 malic acid Substances 0.000 description 1
- 235000011090 malic acid Nutrition 0.000 description 1
- 229960002510 mandelic acid Drugs 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 238000004949 mass spectrometry Methods 0.000 description 1
- 230000010534 mechanism of action Effects 0.000 description 1
- 230000002503 metabolic effect Effects 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- 239000012452 mother liquor Substances 0.000 description 1
- HVOYZOQVDYHUPF-UHFFFAOYSA-N n,n',n'-trimethylethane-1,2-diamine Chemical compound CNCCN(C)C HVOYZOQVDYHUPF-UHFFFAOYSA-N 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 description 1
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 1
- 125000001181 organosilyl group Chemical group [SiH3]* 0.000 description 1
- 230000002611 ovarian Effects 0.000 description 1
- 230000001590 oxidative effect Effects 0.000 description 1
- 125000003854 p-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Cl 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 150000002989 phenols Chemical class 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 230000001766 physiological effect Effects 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 229920001515 polyalkylene glycol Polymers 0.000 description 1
- 239000001205 polyphosphate Substances 0.000 description 1
- 235000011176 polyphosphates Nutrition 0.000 description 1
- 235000011181 potassium carbonates Nutrition 0.000 description 1
- NTTOTNSKUYCDAV-UHFFFAOYSA-N potassium hydride Chemical compound [KH] NTTOTNSKUYCDAV-UHFFFAOYSA-N 0.000 description 1
- 229910000105 potassium hydride Inorganic materials 0.000 description 1
- 239000012286 potassium permanganate Substances 0.000 description 1
- 159000000001 potassium salts Chemical class 0.000 description 1
- 229920001592 potato starch Polymers 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 150000003138 primary alcohols Chemical class 0.000 description 1
- MFDFERRIHVXMIY-UHFFFAOYSA-N procaine Chemical compound CCN(CC)CCOC(=O)C1=CC=C(N)C=C1 MFDFERRIHVXMIY-UHFFFAOYSA-N 0.000 description 1
- 229960004919 procaine Drugs 0.000 description 1
- 238000000425 proton nuclear magnetic resonance spectrum Methods 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- NPRDHMWYZHSAHR-UHFFFAOYSA-N pyridine;trioxochromium Chemical compound O=[Cr](=O)=O.C1=CC=NC=C1.C1=CC=NC=C1 NPRDHMWYZHSAHR-UHFFFAOYSA-N 0.000 description 1
- JUJWROOIHBZHMG-UHFFFAOYSA-O pyridinium Chemical compound C1=CC=[NH+]C=C1 JUJWROOIHBZHMG-UHFFFAOYSA-O 0.000 description 1
- 125000001453 quaternary ammonium group Chemical group 0.000 description 1
- 239000012429 reaction media Substances 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 238000012552 review Methods 0.000 description 1
- 238000007363 ring formation reaction Methods 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- RMAQACBXLXPBSY-UHFFFAOYSA-N silicic acid Chemical compound O[Si](O)(O)O RMAQACBXLXPBSY-UHFFFAOYSA-N 0.000 description 1
- 235000012239 silicon dioxide Nutrition 0.000 description 1
- 238000006884 silylation reaction Methods 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 description 1
- 235000019345 sodium thiosulphate Nutrition 0.000 description 1
- 229940035044 sorbitan monolaurate Drugs 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 150000003460 sulfonic acids Chemical class 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 125000002456 taxol group Chemical group 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- DZLFLBLQUQXARW-UHFFFAOYSA-N tetrabutylammonium Chemical compound CCCC[N+](CCCC)(CCCC)CCCC DZLFLBLQUQXARW-UHFFFAOYSA-N 0.000 description 1
- UQCWXKSHRQJGPH-UHFFFAOYSA-M tetrabutylazanium;fluoride;hydrate Chemical compound O.[F-].CCCC[N+](CCCC)(CCCC)CCCC UQCWXKSHRQJGPH-UHFFFAOYSA-M 0.000 description 1
- CBXCPBUEXACCNR-UHFFFAOYSA-N tetraethylammonium Chemical compound CC[N+](CC)(CC)CC CBXCPBUEXACCNR-UHFFFAOYSA-N 0.000 description 1
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 description 1
- 125000001412 tetrahydropyranyl group Chemical group 0.000 description 1
- CZDYPVPMEAXLPK-UHFFFAOYSA-N tetramethylsilane Chemical compound C[Si](C)(C)C CZDYPVPMEAXLPK-UHFFFAOYSA-N 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 238000004809 thin layer chromatography Methods 0.000 description 1
- 125000003944 tolyl group Chemical group 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 231100000027 toxicology Toxicity 0.000 description 1
- 238000005809 transesterification reaction Methods 0.000 description 1
- 125000005270 trialkylamine group Chemical group 0.000 description 1
- 125000004665 trialkylsilyl group Chemical group 0.000 description 1
- 229940117013 triethanolamine oleate Drugs 0.000 description 1
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
- 239000003039 volatile agent Substances 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
- 239000008096 xylene Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D305/00—Heterocyclic compounds containing four-membered rings having one oxygen atom as the only ring hetero atoms
- C07D305/14—Heterocyclic compounds containing four-membered rings having one oxygen atom as the only ring hetero atoms condensed with carbocyclic rings or ring systems
-
- 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
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/655—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having oxygen atoms, with or without sulfur, selenium, or tellurium atoms, as the only ring hetero atoms
- C07F9/6551—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having oxygen atoms, with or without sulfur, selenium, or tellurium atoms, as the only ring hetero atoms the oxygen atom being part of a four-membered ring
- C07F9/65512—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having oxygen atoms, with or without sulfur, selenium, or tellurium atoms, as the only ring hetero atoms the oxygen atom being part of a four-membered ring condensed with carbocyclic rings or carbocyclic ring systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/6558—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system
- C07F9/65586—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system at least one of the hetero rings does not contain nitrogen as ring hetero atom
Definitions
- Taxol was first isolated from the stem bark of Western Yew, Taxus brevifolia Nut. (Taxaceae) and has the following structure (with the 2'- and 7- positions indicated) ##STR5## In ongoing clinical trials sponsored by the National Cancer Institute (NCI), taxol has shown promising results in fighting advanced cases of ovarian, breast, and other cancers. A recent review article in the Journal of National Cancer Institute provides an overview on its mechanism of action, toxicology, clinical results, etc. E. Rowinsky et al., Taxol: A Novel Investigational Antimicrotubule Agent, J. Natl. Cancer Inst., 82: 1247-1259 (1990).
- taxol has been made more water soluble through the derivatization of the 2'- and/or 7-hydroxy group with a hydrophilic group resulting in a bioreversible form known as a prodrug.
- Prodrugs have been shown to improve physicochemical (e.g. solubility, lipophilicity, etc.) and biological properties of many compounds.
- One approach to form a water soluble prodrug of a hydroxy containing molecule has been to derivatize the hydroxy group into an N-substituted-(aminomethyl)benzoate ester. See for example, Bundgaard et al., J. Med.
- This invention relates to a compound of formula I ##STR6## or a pharmaceutically acceptable salt thereof, in which R 2 is a radical of the formula ##STR7## in which R a and R b are independently hydrogen or C 1-6 alkyl, said C 1-6 alkyl being optionally substituted with hydroxy, phosphono, phosphonooxy, carboxy or di(C 1-6 alkyl)amino; or NR a R b together represents a radical of the formula ##STR8## in which y is one to three, and R a is as defined above; R p and R r are independently same or different C 1-6 alkyl;
- R 1 is hydrogen or a radical Z of the formula ##STR9## in which Q is --(CH 2 ) f --, optionally substituted with one to six same or different C 1-6 alkyl or C 3-6 cycloalkyl, or a carbon atom of said --(CH 2 ) f -- radical may also be a part of C 3-6 cycloalkylidene;
- R 3 and R 4 are independently hydrogen or C 1-6 alkyl, or R 3 and R 4 taken together with the carbon atom to which they are attached form C 3-6 cycloalkylidene;
- R 5 is --OC( ⁇ O)R, --OP ⁇ O(OH) 2 or --CH 2 OP ⁇ O(OH) 2 , in which R is C 1-6 alkyl;
- R 6 , R 7 , R 8 and R 9 are independently halogen, C 1-6 alkyl, C 1-6 alkoxy or hydrogen, but when R 5 is --OC ( ⁇ O)R one of R 6 , R 7 , R 8 R 9 is --OP ⁇ O(OH) 2 ; f is 2 to 6;
- n is O, and m is 1 or 0 when R 5 is --CH 2 OP ⁇ O(OH) 2 ; and n is 1 or 0, and m is 1 when R 5 is --OC( ⁇ O)R or --OP ⁇ O(OH) 2 .
- This invention also provides pharmaceutical formulations and a method for treating mammalian tumors with a compound of formula I.
- This invention relates to a benzoate taxol derivative of formula I ##STR10## or a pharmaceutically acceptable salt thereof, in which R 2 is a radical of the formula ##STR11## in which R a and R b are independently hydrogen or C 1-6 alkyl, said C 1-6 alkyl being optionally substituted with hydroxy, phosphono, phosphonooxy, carboxy or di(C 1-6 alkyl)amino; or NR a R b together represents a radical of the formula ##STR12## in which y is one to three, and R a is as defined above; R p and R r are independently same or different C 1-6 alkyl;
- R 1 is hydrogen or a radical Z of the formula ##STR13## in which Q is --(CH 2 ) f --, optionally substituted with one to six same or different C 1-6 alkyl or C 3-6 cycloalkyl, or a carbon atom of said --(CH 2 ) f -- radical may also be a part of C 3-6 cycloalkylidene;
- R 3 and R 4 are independently hydrogen or C 1-6 alkyl, or R 3 and R 4 taken together with the carbon atom to which they are attached form C 3-6 cycloalkylidene;
- R 5 is --OC( ⁇ O)R, --OP ⁇ O(OH) 2 or --CH 2 OP ⁇ O(OH) 2 , in which R is C 1-6 alkyl;
- R 6 , R 7 , R 8 and R 9 are independently halogen, C 1-6 alkyl, C 1-6 alkoxy or hydrogen, but when R 5 is --OC( ⁇ O)R, one of R 6 , R 7 , R 8 or R 9 is --OP ⁇ O(OH) 2 ; f is 2 to 6;
- n is O, and m is 1 or 0 when R 5 is --CH 2 OP ⁇ O(OH) 2 ; and n is 1 or 0, and m is 1 when R 5 is --OC( ⁇ O)R or --OP ⁇ O(OH) 2 .
- Some compounds of formula I may form pharmaceutically acceptable metal and amine salts in which the cation does not contribute significantly to the toxicity or biological activity of the salt and are compatible with the customary pharmaceutical vehicles and adapted for oral or parenteral administration. These salts are also part of the present invention. Suitable metal salts include the sodium, potassium, calcium, barium, zinc, and aluminum salts. The sodium or potassium salts are preferred.
- Amines which are capable of forming stable salts may include trialkylamines such as triethylamine, procaine, dibenzylamine, N-benzyl- ⁇ -phenethylamine, 1-ephenamine, N,N'-dibenzylethylenediamine, dehydroabietylamine, N-ethylpiperidine, benzylamine, dicyclohexylamine, or the like amines.
- trialkylamines such as triethylamine, procaine, dibenzylamine, N-benzyl- ⁇ -phenethylamine, 1-ephenamine, N,N'-dibenzylethylenediamine, dehydroabietylamine, N-ethylpiperidine, benzylamine, dicyclohexylamine, or the like amines.
- Some compounds of formula I may also form pharmaceutically acceptable acid addition salts in which the anion does not contribute significantly to the toxicity of the salt and are compatible with the customary pharmaceutical vehicles and adapted for oral or parenteral administration.
- the pharmaceutically acceptable acid addition salts include the salts of compounds of formula I with mineral acids such as hydrochloric acid, hydrobromic acid, phosphoric acid and sulfuric acid, with organic carboxylic acids or organic sulfonic acids such as acetic acid, citric acid, maleic acid, succinic acid, benzoic acid, tartaric acid, fumaric acid, mandelic acid, ascorbic acid, malic acid, methanesulfonic acid, p-toluenesulfonic acid, and the like acids.
- Some compounds of the present invention may exist as zwitterionic forms.
- Pharmaceutically acceptable salts include not only pharmaceutically acceptable metal and amine salts and pharmaceutically acceptable acid addition salts but also zwitterionic forms, which are also within the scope of this invention.
- C 1-6 alkyl refers to straight and branched chain alkyl groups with one to six carbon atoms and such groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, n-pentyl, n-hexyl, 3-methylpentyl, or the like alkyl groups;
- C 3-6 cycloalkylidene refers to cyclopropylidene, cyclobutylidene, cyclopentylidene or cyclohexylidene;
- C 3-6 cycloalkyl refers to cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl;
- C 1-6 alkyloxy (alkoxy) refers to straight or branched alkyloxy groups such as methoxy
- a compound of formula I 1 which is within the scope of formula I compounds, may be obtained by the steps comprising: [Step (1)] reacting taxol with chloromethylbenzoic anhydride of formula XXXV to afford a compound of formula XXX; and [Step (2)] reacting the compound of formula XXX with an secondary amine of the formula
- R t and R u are independently hydrogen or C 1-6 alkyl, said C 1-6 alkyl being optionally substituted with di(C 1-6 alkyl)amino or hydroxy, or with a conventionally protected carboxy, phosphono or phosphonooxy group; or NR t R u together represents a radical of the formula ##STR14## in which y is one to three and R t is as defined above.
- An additional step [Step (3)] of removing conventional carboxy, phosphonooxy or phosphono protecting group(s) is required if either or both R t and R u contain such protecting group(s).
- conventional carboxy protecting groups which can be employed in the present invention to block or protect the carboxylic acid function are well-known to those skilled in the art and, preferably, said groups can be removed, if desired, by methods which do not result in any appreciable destruction of the remaining portion of the molecule.
- Examples of such readily removable carboxy-protecting groups include moieties such as C 1-6 alkyl, diphenylmethyl (benzyhydryl), 2-naphthylmethyl, 4-pyridylmethyl, phenacyl, acetonyl, 2,2,2-trichloroethyl, silyl such as trimethylsilyl and t-butyldimethylsilyl, phenyl, ring substituted phenyl, e.g., 4-chlorophenyl, tolyl, and t-butylphenyl, phenyl C 1-6 alkyl, ring substituted phenyl C 1-6 alkyl, e.g., benzyl, 4-methoxybenzyl, 4-nitrobenzyl (p-nitrobenzyl), 2-nitrobenzyl (o-nitrobenzyl), and triphenylmethyl (trityl), methoxymethyl, 2,2,2-trichloroethoxycarbonyl, benzyloxymethyl,
- carboxy protecting groups well known in the art which have not been disclosed above can be found in "Protective Groups in Organic Synthesis", Theodora W. Greene and Peter G. M. Wuts, John Wiley & Sons, 2nd Edition, 1991, Chapter 5.
- Particularly advantageous carboxy protecting groups are benzyl, p-nitrobenzyl, o-nitrobenzyl, 2,4-dimethoxybenzyl, 4-methoxybenzyl, allyl, substituted allyl, t-butyl or diphenylmethyl (DPM).
- a conventional phosphono or phosphonooxy protecting group can be C 1-6 alkyl, benzyl, allyl or 2,2,2-trichloroethyl, with a preferred phosphono protecting group being ethyl and a preferred phosphonooxy protecting group being benzyl, allyl or 2,2,2-trichloroethyl.
- Step (1) of Scheme I is normally conducted in the presence of a strong base, such as LDA (lithium diisopropylamide), and in an inert solvent such as 1,4-dioxane, THF, DMF, diglyme, methylene chloride, or in the like solvent under reduced temperature.
- a strong base such as LDA (lithium diisopropylamide)
- an inert solvent such as 1,4-dioxane, THF, DMF, diglyme, methylene chloride, or in the like solvent under reduced temperature.
- All three methods (Methods A-C) in Example 28 may be adapted to make any of the positional isomers of a compound of formula XXX.
- the methods for making representative 2'-[(N-substituted-4-aminomethyl)benzoate]taxols in Example 29 may be adapted to make other 2'-[(N-substituted-aminomethyl)benzoate]taxol derivative
- R a' and R b' are independently hydrogen or C 1-6 alkyl, said C 1-6 alkyl being optionally substituted with a conventionally protected carboxy, hydroxy, phosphonooxy, or phosphono group, or with a di(C 1-6 alkyl)amino group; or NR a' R b' together represents a radical of the formula ##STR16## in which y is one to three and R a' is as defined above, to afford a compound of formula XXXI.
- Step (1) of Scheme II can be conducted in the same or substantially same manner as Step (2) of Scheme I.
- R 6' , R 7' , R 8' and R 9' are independently halogen, C 1-6 alkyl, C 1-6 alkoxy or hydrogen, but when R 5' is --OC( ⁇ O)R, one of R 6' R 7' , R 8' or R 9' is --OP ⁇ O(OR 10 ) 2 ; n is O, and m is 1 or 0 when R 5' is --CH 2 OP ⁇ O(OR 10 ) 2 ; n is 1 or 0, and m is 1 when R 5' is --OC( ⁇ O)R or --OP ⁇ O(OR 10 ) 2 ; Q, R, R 3 and R 4 are as previously defined; and R 10 is a conventional phosphonooxy protecting group.
- R d is a radical of the formula ##STR18## Subsequent removal of all protecting groups from a compound of formula XXXII in Step (3) affords a compound of formula I 2 .
- R 10 group is benzyl, it can be removed by catalytic hydrogenolysis.
- conventional hydroxy protecting groups are moieties which can be employed to block or protect the hydroxy function and they are well-known to those skilled in the art.
- said groups are those which can be removed by methods resulting in no appreciable destruction to the remaining portion of the molecule.
- hydroxy protecting groups examples include chloroacetyl, methoxymethyl, 2,2,2-trichloroethyloxymethyl, 2,2,2-trichloroethyloxycarbonyl, tetrahydropyranyl, tetrahydrofuranyl, t-butyl, benzyl, p-nitrobenzyl, p-methoxybenzyl, diphenylmethyl, trialkylsilyl, triphenylsilyl, and the like.
- a particularly advantageous protecting group for the 2'-hydroxy group of taxol is benzyloxycarbonyl, which can be removed conveniently by catalytic hydrogenolysis.
- Other suitable protecting groups which may be used are found in Chapter 2 of "Protecting Groups in Organic Synthesis", Second Ed., by Theodora W. Greene and Peter G. M. Wuts (1991, John Wiley & Sons).
- acylating a hydroxy group with a carboxylic acid is well known in the art.
- Particularly useful to the present invention are those which employ dehydrating agents such as dicyclohexylcarbodiimide (DCC), alkyl chloroformate and triethylamine, pyridinium salts-Bu 3 N, phenyl dichlorophosphate, DCC and an aminopyridine, 2-chloro-1,3,5-trinitrobenzene and pyridine, polyphosphate ester, chlorosulfonyl isocyanate, chlorosilanes, MeSO 2 Cl-triethylamine, Ph 3 P-CCl 4 -triethylamine, or N,N'-carbonyldiimidazole, to name a few.
- dehydrating agents such as dicyclohexylcarbodiimide (DCC), alkyl chloroformate and triethylamine, pyridinium salts-Bu 3 N, phenyl dich
- More particularly advantageous dehydrating system is comprised of DCC and 4-dimethylaminopyridine (4-DMAP).
- a compound of formula I 3 which is within the scope of compounds of formula I, may be made by acylating the 2'-hydroxy group of taxol with an acid of formula XXXIV [Step (1), Scheme III]. Subsequent acylation of the 7-hydroxy group with an acid of formula XXV or IX in Step (2) generates a compound of formula XXXIII. Removal of all protecting groups from a compound of formula XXXIII affords a compound of formula I 4 , which is further within the scope of formula I compounds. ##STR19##
- synthesis of acids of formula IX can be made by a wide variety of methods.
- synthesis of an acid of formula IX' which is within the scope of the acids of formula IX, may be made by the sequence of steps as shown in Scheme A.
- R 6' , R 7' , R 8' , and R 9' preferably are independently hydrogen or C 1-6 alkyl; R, R 3 and R 4 are as previously defined.
- Step (a) involves acid promoted transesterification of an acrylic acid ester with a phenol derivative of formula II and subsequent ring cyclization to afford a compound of formula III.
- the reaction is usually conducted in an inert organic solvent such as benzene, toluene or xylene, and the preferred catalyst is concentrated sulfuric acid.
- the reaction is normally conducted at an elevated temperature, preferably at or above the boiling point of benzene.
- Step (b) a lactone of formula III is being reduced.
- the reduction is normally conducted in an inert solvent such as 1,4-dioxane, diglyme, tetrahydrofuran (THF) or diethyl ether.
- a suitable reducing agent is lithium aluminum hydride.
- Other metal aluminum hydrides known to reduce lactones to alcohols may be employed as well.
- Step (c) involves the protection of the free alkylhydroxy group in a compound of formula IV to afford a compound of formula V in which R 12 is a conventional hydroxy protecting group.
- R 12 is a conventional hydroxy protecting group.
- t-butyldimethylsilyl group on a hydroxy group can be accomplished by reacting the hydroxy group with t-butyldimethylsilyl chloride in an inert solvent such as diethyl ether, 1,4-dioxane, diglyme, chloroform, DMF, THF, or methylene chloride, and also in the presence of an amine base such as imidazole, 4-dimethylaminopyridine, or triethylamine, N,N-diisopropylethylamine, or any other tri(C 1-6 )alkylamines.
- an inert solvent such as diethyl ether, 1,4-dioxane, diglyme, chloroform, DMF, THF, or methylene chloride
- an amine base such as imidazole, 4-dimethylaminopyridine, or triethylamine, N,N-diisopropylethylamine, or any other tri
- Step (d) the phenolic hydroxy group of a compound of formula V is phosphorylated with a compound of formula XXIV to afford a compound of formula VI in which R 10 is a phosphonooxy protecting group defined above.
- R 10 is a phosphonooxy protecting group defined above.
- a preferred R 10 radical is benzyl.
- the addition of dibenzylphosphono group is effected by reacting a phenolic salt of a compound of formula V with tetrabenzylpyrophosphate that in turn can be made from dibenzylphosphate and at least 0.5 equivalent of DCC.
- Step (d) is normally conducted in an inert aprotic solvent, such as 1,4-dioxane, diglyme, DMF or THF.
- the cation of the phenolic salt of a compound of formula V can be sodium, potassium, lithium, calcium, benzyltriethylammonium or tetraethylammonium, tetrabutylammonium or any other tetra(C 1-6 )alkylammonium.
- the formation of the phenolic salt can be effected by removing the phenolic proton by a base such as potassium carbonate, potassium hydroxide, potassium hydride, sodium hydride, sodium hydroxide, sodium carbonate, or a quaternary ammonium hydroxide such as tetrabutylammonium hydroxide or benzyltriethylammonium hydroxide.
- Step (e) the hydroxy protecting group R 12 is removed.
- fluoride ion or mineral acid in alcohol may be used for its removal.
- the source of the fluoride ion can be from tetrabutylammonium fluoride.
- the removal with fluoride is conducted in an inert solvent such as THF, methylene chloride, 1,4-dioxane, DMF, chloroform, or in the like inert solvent; and preferably the reaction medium is buffered by a weak acid such as acetic acid.
- An example of mineral acid in alcohol is hydrochloric acid in isopropanol.
- Step (f) entails the oxidation of the hydroxy group to the aldehyde group.
- a wide array of reagents are available for oxidizing a primary alcohol to an aldehyde, which may also be used to effect Step (f).
- Some examples include: dipyridine Cr(VI) oxide (Collin's reagent), pyridinium chlorochromate (PCC), pyridinium dichromate (PDC), ceric ammonium nitrate (CAN), Na 2 Cr 2 O 7 in water, N-iodosuccinimide and Bu 4 N + I - , Ag 2 CO 3 -on-celite, N-methylmorpholine-n-oxide, a Ru complex, etc.
- Step (f) is pyridinium chlorochromate (PCC) in methylene chloride.
- Step (g) involves a further oxidation of an aldehyde of formula VIII into an acid of formula IX'.
- Many reagents are known to convert an aldehyde to an acid.
- Step (g) Some examples include: potassium permanganate, Ag 2 O-water, m-chloroperbenzoic acid, Jones reagent (chromic and sulfuric acid in water), etc.
- the oxidation in Step (g) is preferably done by using the Jones reagent in acetone.
- a compound of formula IV can be directly converted to a compound of formula VII by employing the method specified above for Step (d). Furthermore, a compound of formula VII can be directly converted to a compound of formula IX' with the Jones reagent.
- Step (a) a quinone of formula X is reduced to a hydroquinone of formula XI by a standard quinone reduction method such as by employing sodium hydrosulfite.
- the annulation in Step (b) can be effected using the same or substantially the same condition described for Step (a) of Scheme A.
- Step (c) The phenolic hydroxy group in a compound of formula XII is protected in Step (c) to afford a compound of formula XIII.
- a suitable phenol protecting group R 11 for the purpose of Step (c) is benzyl.
- Other well-known phenol protecting groups such as those enumerated in pp. 144-170 of "Protecting Groups in Organic Synthesis", Second Ed., by Theodora W. Greene and Peter G. M. Wuts (1991, John Wiley & Sons), may also be used.
- the reduction in Step (d) can be conducted in the same or substantially the same manner as described for Step (b) of Scheme A.
- Step (h) the conversion of a compound of formula XVII to a compound of formula XVIII can be effected in the same or substantially the same way as described for Step (d) of Scheme A.
- a preferred R 10 radical is again benzyl.
- the removal of R 12 hydroxy protecting group from a compound of formula XVIII can be carried out in the same or substantially same manner as described for Step (e) of Scheme A.
- the oxidation of the alcohol group to the carboxylic group in Step (j) can be done with the Jones reagent.
- a compound of formula XXII may be reacted with bis(allyloxy)(diisopropylamino)phosphine or dibenzyloxy(diisopropylamino)phosphine in the presence of a base, such as 1H-tetrazole; and the resulting addition product is subsequently oxidized, for example by m-chloroperbenzoic acid.
- a base such as 1H-tetrazole
- NMR nuclear magnetic resonance
- the nature of the shifts as to multiplicity is reported as broad singlet (bs), broad doublet (bd), broad triplet (bt), broad quartet (bq), singlet (s), multiplet (m), doublet (d), quartet (q), triplet (t), doublet of doublet (dd), doublet of triplet (dt), and doublet of quartet (dq).
- the solvents employed for taking NMR spectra are DMSO-d 6 (perdeuterodimethylsulfoxide), D 2 O (deuterated water), CDCl 3 (deuterochloroform) and other conventional deuterated solvents.
- the infrared (IR) spectral description include only absorption wave numbers (cm -1 ) having functional group identification value.
- Celite is a registered trademark of the Johns-Manville Products Corporation for diatomaceous earth.
- hexane and hexanes may be used interchangeably.
- tetrabenzylpyrophosphate (XXIVa) (14.5 g, 26.93 mmol, 1.5 eq.; pyrophosphate XXIVa was prepared from dibenzylphosphate and DCC) all at once.
- the reaction mixture was continued to be stirred at 65° C. for 10 min. Subsequently, it was diluted with EtOAc (300 mL), washed with brine (4 ⁇ 100 mL), and dried over anhydrous sodium sulfate. It was filtered and the filtrate was concentrated in vacuo to obtain compound VIa as a crude product which was purified on a silica gel column.
- the Jones reagent was prepared by dissolving CrO 3 (26.72 g) in "concentrated sulfuric acid (23 mL) and diluted with water to a volume of 100 mL" (see Fieser and Fieser “Reagents for Organic Synthesis” Vol 1, p 142, John Wiley, New York, 1967).
- Table 1 lists taxol derivatives whose specific syntheses are described in the Examples.
- mice Balb/c x DBA/2 F 1 hybrid mice were implanted intraperitoneally, as described by William Rose in Evaluation of Madison 109 Lung Carcinoma as a Model for Screening Antitumor Drugs, Cancer Treatment Reports, 65, No. 3-4 (1981), with 0.5 mL of a 2% (w/v) brei of M109 lung carcinoma.
- mice were treated with compound under study by receiving intraperitoneal injections of various doses on either Days 1, 5 and 9 post-tumor implant or Days 5 and 8 post-implant. Mice were followed daily for survival until approximately 75-90 days post-tumor implant. One group of mice per experiment remained untreated and served as the control group. Median survival times of compound-treated (T) mice were compared to the median survial time of the control (C) mice. The ratio of the two values for each compound-treated group of mice was multiplied by 100 and expressed as a percentage (i.e. % T/C) in Table 2 for certain representative compounds.
- Another aspect of the instant invention concerns with a method for inhibiting mammalian tumors sensitive to a compound of formula I or a pharmaceutically acceptable salt thereof.
- the present invention also provides pharmaceutical compositions (formulations) containing a compound of formula I in combination with one or more pharmaceutically acceptable, inert or physiologically active, carriers, excipients, diluents or adjuvants.
- pharmaceutically acceptable, inert or physiologically active, carriers, excipients, diluents or adjuvants are described in numerous literatures, for example in U.S. Pat. Nos. 4,960,790 and 4,814,470, and such examples may be followed to formulate the compounds of this invention.
- the new compounds are administrable in the form of tablets, pills, powder mixtures, capsules, injectables, solutions, suppositories, emulsions, dispersions, food premix, and in other suitable forms.
- the pharmaceutical preparation which contains the compound is conveniently admixed with a nontoxic pharmaceutical organic carrier or a nontoxic pharmaceutical inorganic carrier, usually about 0.01 mg up to 2500 mg, or higher per dosage unit, preferably 50-500 mg.
- a nontoxic pharmaceutical organic carrier or a nontoxic pharmaceutical inorganic carrier usually about 0.01 mg up to 2500 mg, or higher per dosage unit, preferably 50-500 mg.
- pharmaceutically acceptable carriers are, for example, manitol, urea, dextrans, lactose, potato and maize starches, magnesium stearate, talc, vegetable oils, polyalkylene glycols, ethyl cellulose, poly(vinylpyrrolidone), calcium carbonate, ethyl oleate, isopropyl myristate, benzyl benzoate, sodium carbonate, gelatin, potassium carbonate, silicic acid, and other conventionally employed acceptable carriers.
- the pharmaceutical preparation may also contain nontoxic auxiliary substances such as emulsifying, preserving, wetting agents, and the like as for example, sorbitan monolaurate, triethanolamine oleate, polyoxyethylene monostearate, glyceryl tripalmitate, dioctyl sodium sulfosuccinate, and the like.
- auxiliary substances such as emulsifying, preserving, wetting agents, and the like as for example, sorbitan monolaurate, triethanolamine oleate, polyoxyethylene monostearate, glyceryl tripalmitate, dioctyl sodium sulfosuccinate, and the like.
- the compounds of the invention can also be freeze dried and, if desired, combined with other pharmaceutically acceptable excipients to prepare formulations suitable for parenteral, injectable administration.
- the formulation can be reconstituted in water (normal, saline), or a mixture of water and an organic solvent, such as propylene glycol, ethanol, and the like.
- the dose to be administered whether a single dose, multiple dose, or a daily dose, will of course vary with the particular compound employed because of the varying potency of the compound, the chosen route of administration, the size of the recipient and the nature of the patient's condition.
- the dosage to be administered is not subject to definite bounds, but it will usually be an effective amount, or the equivalent on a molar basis of the pharmacologically active free form produced from a dosage formulation upon the metabolic release of the active drug to achieve its desired pharmacological and physiological effects.
- the dosage to be administered will be generally in the range of 0.8 to 8 mg/kg of body weight or about 50-275 mg/m 2 of the patient.
- An oncologist skilled in the art of cancer treatment will able to ascertain, without undue experimentations, appropriate protocols for effective administration of the compounds of this present invention by referring to the earlier studies of taxol and its derivatives.
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Abstract
This invention relates to a compound of formula I ##STR1## or a pharmaceutically acceptable salt thereof, in which R2 is a radical of the formula ##STR2## in which Ra and Rb are independently hydrogen or C1-6 alkyl, said C1-6 alkyl being optionally substituted with hydroxy, phosphono, phosphonooxy, carboxy or di(C1-6 alkyl) amino; or NRa Rb together represents a radical of the formula ##STR3## in which y is one to three, and Ra is as defined above; Rp and Rr are independently same or different C1-6 alkyl;
R1 is hydrogen or a radical Z of the formula ##STR4## in which Q is --(CH2)f --, optionally substituted with one to six same or different C1-6 alkyl or C3-6 cycloalkyl, or a carbon atom of said --(CH2)f -- radical may also be a part of C3-6 cycloalkylidene;
R3 and R4 are independently hydrogen or C1-6 alkyl, or R3 and R4 taken together with the carbon atom to which they are attached form C3-6 cycloalkylidene;
R5 is --OC(═O)R, --OP═O(OH)2 or --CH2 OP═O(OH)2, in which R is C1-6 alkyl;
R6, R7, R8 and R9 are independently halogen, C1-6 alkyl, C1-6 alkoxy or hydrogen, but when R5 is --OC(═O)R, one of R6, R7, R8 or R9 is --OP═O(OH)2 ;
f is 2 to 6;
n is O, and m is 1 or 0 when R5 is --CH2 OP═O(OH)2 ;
and n is 1 or 0, and m is 1 when R5 is --OC(═O)R or --OP═O(OH)2.
Also provided by this invention are pharmaceutical formulations and a method for treating mammalian tumors with a compound of formula I.
Description
This application is a continuation of U.S. Ser. No. 07/879,661, filed May 6, 1992, now abandoned.
Taxol was first isolated from the stem bark of Western Yew, Taxus brevifolia Nut. (Taxaceae) and has the following structure (with the 2'- and 7- positions indicated) ##STR5## In ongoing clinical trials sponsored by the National Cancer Institute (NCI), taxol has shown promising results in fighting advanced cases of ovarian, breast, and other cancers. A recent review article in the Journal of National Cancer Institute provides an overview on its mechanism of action, toxicology, clinical results, etc. E. Rowinsky et al., Taxol: A Novel Investigational Antimicrotubule Agent, J. Natl. Cancer Inst., 82: 1247-1259 (1990).
One serious problem associated with taxol is that the compound is only very slightly soluble in water and this low solubility has created significant problems in developing suitable pharmaceutical formulations useful for human therapy. Some formulations for i.v. infusion have been developed which primarily utilize cremophore EL(R) as the drug carrier to overcome low water solubility problems. Cremophore, however, is itself somewhat toxic which could cause idiosyncratic histamine release and anaphylactoid like response. Thus, any improvement to increase water solubility by chemical modification is highly desired.
In some instances, taxol has been made more water soluble through the derivatization of the 2'- and/or 7-hydroxy group with a hydrophilic group resulting in a bioreversible form known as a prodrug. Prodrugs have been shown to improve physicochemical (e.g. solubility, lipophilicity, etc.) and biological properties of many compounds. One approach to form a water soluble prodrug of a hydroxy containing molecule has been to derivatize the hydroxy group into an N-substituted-(aminomethyl)benzoate ester. See for example, Bundgaard et al., J. Med. Chem., 32, pp 2507-2509 (1989); Jensen et al., International Journal of Pharmaceutics, 58, pp 143-153 (1990); U.S. Pat. No. 4,623,486, issued to Lombardino on Nov. 18, 1986.
We have now discovered that certain 2'-N-substituted-aminomethylbenzoate or 2'-N-substituted-aminobenzoate taxol derivatives, optionally substituted with a (phosphonooxyphenyl)alkanoyloxy, (phosphonooxy)alkanoyloxy, or [(phosphonooxyalkyl)phenyl]alkanoyloxy group on the (C)7-position of taxol, have respectable water solubility and good anti-tumor activities. Thus, it is the intention of this invention to provide novel 2'-N-substituted-aminomethylbenzoate or 2'-N-substututed-aminobenzoate taxol derivatives, with or without the 7-O-(phosphonooxyphenyl)alkanoyl, (phosphonooxy)alkanoyl, or [(phosphonooxyalkyl)phenyl]alkanoyl group, which are useful in treating mammalian tumors.
This invention relates to a compound of formula I ##STR6## or a pharmaceutically acceptable salt thereof, in which R2 is a radical of the formula ##STR7## in which Ra and Rb are independently hydrogen or C1-6 alkyl, said C1-6 alkyl being optionally substituted with hydroxy, phosphono, phosphonooxy, carboxy or di(C1-6 alkyl)amino; or NRa Rb together represents a radical of the formula ##STR8## in which y is one to three, and Ra is as defined above; Rp and Rr are independently same or different C1-6 alkyl;
R1 is hydrogen or a radical Z of the formula ##STR9## in which Q is --(CH2)f --, optionally substituted with one to six same or different C1-6 alkyl or C3-6 cycloalkyl, or a carbon atom of said --(CH2)f -- radical may also be a part of C3-6 cycloalkylidene;
R3 and R4 are independently hydrogen or C1-6 alkyl, or R3 and R4 taken together with the carbon atom to which they are attached form C3-6 cycloalkylidene;
R5 is --OC(═O)R, --OP═O(OH)2 or --CH2 OP═O(OH)2, in which R is C1-6 alkyl;
R6, R7, R8 and R9 are independently halogen, C1-6 alkyl, C1-6 alkoxy or hydrogen, but when R5 is --OC (═O)R one of R6, R7, R8 R9 is --OP═O(OH)2 ; f is 2 to 6;
n is O, and m is 1 or 0 when R5 is --CH2 OP═O(OH)2 ; and n is 1 or 0, and m is 1 when R5 is --OC(═O)R or --OP═O(OH)2.
This invention also provides pharmaceutical formulations and a method for treating mammalian tumors with a compound of formula I.
This invention relates to a benzoate taxol derivative of formula I ##STR10## or a pharmaceutically acceptable salt thereof, in which R2 is a radical of the formula ##STR11## in which Ra and Rb are independently hydrogen or C1-6 alkyl, said C1-6 alkyl being optionally substituted with hydroxy, phosphono, phosphonooxy, carboxy or di(C1-6 alkyl)amino; or NRa Rb together represents a radical of the formula ##STR12## in which y is one to three, and Ra is as defined above; Rp and Rr are independently same or different C1-6 alkyl;
R1 is hydrogen or a radical Z of the formula ##STR13## in which Q is --(CH2)f --, optionally substituted with one to six same or different C1-6 alkyl or C3-6 cycloalkyl, or a carbon atom of said --(CH2)f -- radical may also be a part of C3-6 cycloalkylidene; R3 and R4 are independently hydrogen or C1-6 alkyl, or R3 and R4 taken together with the carbon atom to which they are attached form C3-6 cycloalkylidene;
R5 is --OC(═O)R, --OP═O(OH)2 or --CH2 OP═O(OH)2, in which R is C1-6 alkyl;
R6, R7, R8 and R9 are independently halogen, C1-6 alkyl, C1-6 alkoxy or hydrogen, but when R5 is --OC(═O)R, one of R6, R7, R8 or R9 is --OP═O(OH)2 ; f is 2 to 6;
n is O, and m is 1 or 0 when R5 is --CH2 OP═O(OH)2 ; and n is 1 or 0, and m is 1 when R5 is --OC(═O)R or --OP═O(OH)2.
Some compounds of formula I may form pharmaceutically acceptable metal and amine salts in which the cation does not contribute significantly to the toxicity or biological activity of the salt and are compatible with the customary pharmaceutical vehicles and adapted for oral or parenteral administration. These salts are also part of the present invention. Suitable metal salts include the sodium, potassium, calcium, barium, zinc, and aluminum salts. The sodium or potassium salts are preferred. Amines which are capable of forming stable salts may include trialkylamines such as triethylamine, procaine, dibenzylamine, N-benzyl-β-phenethylamine, 1-ephenamine, N,N'-dibenzylethylenediamine, dehydroabietylamine, N-ethylpiperidine, benzylamine, dicyclohexylamine, or the like amines.
Some compounds of formula I may also form pharmaceutically acceptable acid addition salts in which the anion does not contribute significantly to the toxicity of the salt and are compatible with the customary pharmaceutical vehicles and adapted for oral or parenteral administration. The pharmaceutically acceptable acid addition salts include the salts of compounds of formula I with mineral acids such as hydrochloric acid, hydrobromic acid, phosphoric acid and sulfuric acid, with organic carboxylic acids or organic sulfonic acids such as acetic acid, citric acid, maleic acid, succinic acid, benzoic acid, tartaric acid, fumaric acid, mandelic acid, ascorbic acid, malic acid, methanesulfonic acid, p-toluenesulfonic acid, and the like acids.
Some compounds of the present invention may exist as zwitterionic forms. Pharmaceutically acceptable salts include not only pharmaceutically acceptable metal and amine salts and pharmaceutically acceptable acid addition salts but also zwitterionic forms, which are also within the scope of this invention.
In the instant application, the numbers in subscript after the symbol "C" define the number of carbon atoms a particular group can contain. For example, C1-6 alkyl refers to straight and branched chain alkyl groups with one to six carbon atoms and such groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, n-pentyl, n-hexyl, 3-methylpentyl, or the like alkyl groups; C3-6 cycloalkylidene refers to cyclopropylidene, cyclobutylidene, cyclopentylidene or cyclohexylidene; C3-6 cycloalkyl refers to cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl; C1-6 alkyloxy (alkoxy) refers to straight or branched alkyloxy groups such as methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, t-butoxy, n-pentyloxy, n-hexyloxy, or 3-methylpentyloxy, to name a few; di(C1-6 alkyl)amino refers to amino with the same or different C1-6 alkyl groups such as N-methyl-N-ethylamino, N,N-dimethylamino, N,N-diethylamino, N-hexyl-N-isopropylamino, etc.; phosphono refers to the radical --P(═O)(OH)2 ; phosphonooxy refers to --O--P(═O)(OH)2 ; and halogen refers to fluorine, chlorine, bromine, or iodine.
The synthesis of benzoate taxol derivatives of the instant invention can be accomplished by a wide variety of methods. In one embodiment, as shown in Scheme I, a compound of formula I1, which is within the scope of formula I compounds, may be obtained by the steps comprising: [Step (1)] reacting taxol with chloromethylbenzoic anhydride of formula XXXV to afford a compound of formula XXX; and [Step (2)] reacting the compound of formula XXX with an secondary amine of the formula
HNR.sup.t R.sup.u
wherein Rt and Ru are independently hydrogen or C1-6 alkyl, said C1-6 alkyl being optionally substituted with di(C1-6 alkyl)amino or hydroxy, or with a conventionally protected carboxy, phosphono or phosphonooxy group; or NRt Ru together represents a radical of the formula ##STR14## in which y is one to three and Rt is as defined above. An additional step [Step (3)] of removing conventional carboxy, phosphonooxy or phosphono protecting group(s) is required if either or both Rt and Ru contain such protecting group(s).
As used herein, conventional carboxy protecting groups which can be employed in the present invention to block or protect the carboxylic acid function are well-known to those skilled in the art and, preferably, said groups can be removed, if desired, by methods which do not result in any appreciable destruction of the remaining portion of the molecule. Examples of such readily removable carboxy-protecting groups include moieties such as C1-6 alkyl, diphenylmethyl (benzyhydryl), 2-naphthylmethyl, 4-pyridylmethyl, phenacyl, acetonyl, 2,2,2-trichloroethyl, silyl such as trimethylsilyl and t-butyldimethylsilyl, phenyl, ring substituted phenyl, e.g., 4-chlorophenyl, tolyl, and t-butylphenyl, phenyl C1-6 alkyl, ring substituted phenyl C1-6 alkyl, e.g., benzyl, 4-methoxybenzyl, 4-nitrobenzyl (p-nitrobenzyl), 2-nitrobenzyl (o-nitrobenzyl), and triphenylmethyl (trityl), methoxymethyl, 2,2,2-trichloroethoxycarbonyl, benzyloxymethyl, C1-6 alkanoyloxy C1-6 alkyl such as acetoxymethyl, propionyloxymethyl, C2-6 alkenyl such as vinyl and allyl. Other suitable carboxy protecting groups well known in the art which have not been disclosed above can be found in "Protective Groups in Organic Synthesis", Theodora W. Greene and Peter G. M. Wuts, John Wiley & Sons, 2nd Edition, 1991, Chapter 5. Particularly advantageous carboxy protecting groups are benzyl, p-nitrobenzyl, o-nitrobenzyl, 2,4-dimethoxybenzyl, 4-methoxybenzyl, allyl, substituted allyl, t-butyl or diphenylmethyl (DPM).
A conventional phosphono or phosphonooxy protecting group can be C1-6 alkyl, benzyl, allyl or 2,2,2-trichloroethyl, with a preferred phosphono protecting group being ethyl and a preferred phosphonooxy protecting group being benzyl, allyl or 2,2,2-trichloroethyl.
Step (1) of Scheme I is normally conducted in the presence of a strong base, such as LDA (lithium diisopropylamide), and in an inert solvent such as 1,4-dioxane, THF, DMF, diglyme, methylene chloride, or in the like solvent under reduced temperature. Moreover, all three methods (Methods A-C) in Example 28 may be adapted to make any of the positional isomers of a compound of formula XXX. The methods for making representative 2'-[(N-substituted-4-aminomethyl)benzoate]taxols in Example 29 may be adapted to make other 2'-[(N-substituted-aminomethyl)benzoate]taxol derivatives.
As another example, when a compound of formula I in which Ra and/or Rb radical(s) contain(s) hydroxy group(s), the hydroxy group(s) may be reacted with (2,2,2-trichloroethyl)phosphorochloridate, and from the resulting product, 2,2,2-trichloroethyl group(s) may be removed to afford a compound of formula I which now contains phosphonooxy group(s). See Examples 31 and 32. ##STR15##
A method of making a compound of formula I2, which is further within the scope of formula I compounds, is depicted in Scheme II. In Step (1), a compound of formula XXX is reacted with an secondary amine of formula
HNR.sup.a' R.sup.b'
wherein Ra' and Rb' are independently hydrogen or C1-6 alkyl, said C1-6 alkyl being optionally substituted with a conventionally protected carboxy, hydroxy, phosphonooxy, or phosphono group, or with a di(C1-6 alkyl)amino group; or NRa' Rb' together represents a radical of the formula ##STR16## in which y is one to three and Ra' is as defined above, to afford a compound of formula XXXI. Step (1) of Scheme II can be conducted in the same or substantially same manner as Step (2) of Scheme I. The 7-hydroxy of a compound of formula XXXI is subsquently acylated with an acid of formula IX or XXV ##STR17## (an acid of formula IX or XXV is esterified with the 7-hydroxy group of a compound of formula XXXI) to afford a compound of formula XXXII. In formula IX or XXV, R5' is --OC(═O)R, --OP═O(OR10 ).sub. 2 or --CH2 OP═O(OR10)2 ; R6', R7', R8' and R9' are independently halogen, C1-6 alkyl, C1-6 alkoxy or hydrogen, but when R5' is --OC(═O)R, one of R6' R7', R8' or R9' is --OP═O(OR10)2 ; n is O, and m is 1 or 0 when R5' is --CH2 OP═O(OR10)2 ; n is 1 or 0, and m is 1 when R5' is --OC(═O)R or --OP═O(OR10)2 ; Q, R, R3 and R4 are as previously defined; and R10 is a conventional phosphonooxy protecting group. In formula XXXII, Rd is a radical of the formula ##STR18## Subsequent removal of all protecting groups from a compound of formula XXXII in Step (3) affords a compound of formula I2. When R10 group is benzyl, it can be removed by catalytic hydrogenolysis.
As used herein, conventional hydroxy protecting groups are moieties which can be employed to block or protect the hydroxy function and they are well-known to those skilled in the art. Preferably, said groups are those which can be removed by methods resulting in no appreciable destruction to the remaining portion of the molecule. Examples of such readily removable hydroxy protecting groups include chloroacetyl, methoxymethyl, 2,2,2-trichloroethyloxymethyl, 2,2,2-trichloroethyloxycarbonyl, tetrahydropyranyl, tetrahydrofuranyl, t-butyl, benzyl, p-nitrobenzyl, p-methoxybenzyl, diphenylmethyl, trialkylsilyl, triphenylsilyl, and the like. A particularly advantageous protecting group for the 2'-hydroxy group of taxol is benzyloxycarbonyl, which can be removed conveniently by catalytic hydrogenolysis. Other suitable protecting groups which may be used are found in Chapter 2 of "Protecting Groups in Organic Synthesis", Second Ed., by Theodora W. Greene and Peter G. M. Wuts (1991, John Wiley & Sons).
The art of acylating a hydroxy group with a carboxylic acid is well known in the art. Particularly useful to the present invention are those which employ dehydrating agents such as dicyclohexylcarbodiimide (DCC), alkyl chloroformate and triethylamine, pyridinium salts-Bu3 N, phenyl dichlorophosphate, DCC and an aminopyridine, 2-chloro-1,3,5-trinitrobenzene and pyridine, polyphosphate ester, chlorosulfonyl isocyanate, chlorosilanes, MeSO2 Cl-triethylamine, Ph3 P-CCl4 -triethylamine, or N,N'-carbonyldiimidazole, to name a few. References to these reagents can be found in "Advanced Organic Chemistry", 3rd Ed., by Jerry March, pp 348-351 (1985, John Wiley & Sons). More particularly advantageous dehydrating system is comprised of DCC and 4-dimethylaminopyridine (4-DMAP).
A compound of formula I3, which is within the scope of compounds of formula I, may be made by acylating the 2'-hydroxy group of taxol with an acid of formula XXXIV [Step (1), Scheme III]. Subsequent acylation of the 7-hydroxy group with an acid of formula XXV or IX in Step (2) generates a compound of formula XXXIII. Removal of all protecting groups from a compound of formula XXXIII affords a compound of formula I4, which is further within the scope of formula I compounds. ##STR19##
Any person skilled in the art would appreciate that when the removal of a conventional phosphonooxy protecting group R1° or a conventional phosphono protecting group in the above reaction Schemes (I-III) is conducted in the presence of an appropriate amount of base, the corresponding salt of the phosphonooxy or phosphono group can be obtained. For example, the presence of sodium bicarbonate during the removal affords the sodium salt.
The synthesis of acids of formula IX can be made by a wide variety of methods. For example, as a matter of illustration, synthesis of an acid of formula IX', which is within the scope of the acids of formula IX, may be made by the sequence of steps as shown in Scheme A. In the Scheme, R6', R7', R8', and R9' preferably are independently hydrogen or C1-6 alkyl; R, R3 and R4 are as previously defined.
The methods described by Amsberry et al., Journal of Organic Chemistry, 55, pp 5867-5877 (1990), for making certain compounds of formula III and IV in which R6' and R8' are hydrogen, R7' is methyl or hydrogen, and R9' is methyl may be adapted to make additional compounds of formula III and IV. More specifically, Step (a) involves acid promoted transesterification of an acrylic acid ester with a phenol derivative of formula II and subsequent ring cyclization to afford a compound of formula III. The reaction is usually conducted in an inert organic solvent such as benzene, toluene or xylene, and the preferred catalyst is concentrated sulfuric acid. The reaction is normally conducted at an elevated temperature, preferably at or above the boiling point of benzene. ##STR20##
In Step (b), a lactone of formula III is being reduced. The reduction is normally conducted in an inert solvent such as 1,4-dioxane, diglyme, tetrahydrofuran (THF) or diethyl ether. A suitable reducing agent is lithium aluminum hydride. Other metal aluminum hydrides known to reduce lactones to alcohols may be employed as well.
Step (c) involves the protection of the free alkylhydroxy group in a compound of formula IV to afford a compound of formula V in which R12 is a conventional hydroxy protecting group. Some examples of conventional hydroxy protecting groups are cited above. Here, a more desirable group for R12 is t-butyldimethylsilyl. The attachment of t-butyldimethylsilyl group on a hydroxy group can be accomplished by reacting the hydroxy group with t-butyldimethylsilyl chloride in an inert solvent such as diethyl ether, 1,4-dioxane, diglyme, chloroform, DMF, THF, or methylene chloride, and also in the presence of an amine base such as imidazole, 4-dimethylaminopyridine, or triethylamine, N,N-diisopropylethylamine, or any other tri(C1-6)alkylamines.
In Step (d), the phenolic hydroxy group of a compound of formula V is phosphorylated with a compound of formula XXIV to afford a compound of formula VI in which R10 is a phosphonooxy protecting group defined above. Here, a preferred R10 radical is benzyl. As an example, the addition of dibenzylphosphono group is effected by reacting a phenolic salt of a compound of formula V with tetrabenzylpyrophosphate that in turn can be made from dibenzylphosphate and at least 0.5 equivalent of DCC. Step (d) is normally conducted in an inert aprotic solvent, such as 1,4-dioxane, diglyme, DMF or THF. The cation of the phenolic salt of a compound of formula V can be sodium, potassium, lithium, calcium, benzyltriethylammonium or tetraethylammonium, tetrabutylammonium or any other tetra(C1-6)alkylammonium. The formation of the phenolic salt can be effected by removing the phenolic proton by a base such as potassium carbonate, potassium hydroxide, potassium hydride, sodium hydride, sodium hydroxide, sodium carbonate, or a quaternary ammonium hydroxide such as tetrabutylammonium hydroxide or benzyltriethylammonium hydroxide.
In Step (e), the hydroxy protecting group R12 is removed. When R12 is t-butyldimethylsilyl, fluoride ion or mineral acid in alcohol may be used for its removal. The source of the fluoride ion can be from tetrabutylammonium fluoride. The removal with fluoride is conducted in an inert solvent such as THF, methylene chloride, 1,4-dioxane, DMF, chloroform, or in the like inert solvent; and preferably the reaction medium is buffered by a weak acid such as acetic acid. An example of mineral acid in alcohol is hydrochloric acid in isopropanol.
Step (f) entails the oxidation of the hydroxy group to the aldehyde group. A wide array of reagents are available for oxidizing a primary alcohol to an aldehyde, which may also be used to effect Step (f). Some examples include: dipyridine Cr(VI) oxide (Collin's reagent), pyridinium chlorochromate (PCC), pyridinium dichromate (PDC), ceric ammonium nitrate (CAN), Na2 Cr2 O7 in water, N-iodosuccinimide and Bu4 N+ I-, Ag2 CO3 -on-celite, N-methylmorpholine-n-oxide, a Ru complex, etc. References to the aforementioned reagents and to some other reagents for the oxidation can be found in such text as "Advanced Organic Chemistry", 3rd Ed., by Jerry March, pp 1057-1060 and 1081-1082 (1985, John Wiley & Sons). A preferable reagent for Step (f) is pyridinium chlorochromate (PCC) in methylene chloride. Step (g) involves a further oxidation of an aldehyde of formula VIII into an acid of formula IX'. Many reagents are known to convert an aldehyde to an acid. Some examples include: potassium permanganate, Ag2 O-water, m-chloroperbenzoic acid, Jones reagent (chromic and sulfuric acid in water), etc. The oxidation in Step (g) is preferably done by using the Jones reagent in acetone.
In a more preferred embodiment, a compound of formula IV can be directly converted to a compound of formula VII by employing the method specified above for Step (d). Furthermore, a compound of formula VII can be directly converted to a compound of formula IX' with the Jones reagent.
As another example, the synthesis of acids of formula IX", within the scope of formula IX compounds, can be made by a series of steps as shown in Scheme B. In the Scheme, R6', R7', and R9' preferably are independently hydrogen or C1-6 alkyl; R, R3 and R4 are as defined previously. In Step (a), a quinone of formula X is reduced to a hydroquinone of formula XI by a standard quinone reduction method such as by employing sodium hydrosulfite. The annulation in Step (b) can be effected using the same or substantially the same condition described for Step (a) of Scheme A. The phenolic hydroxy group in a compound of formula XII is protected in Step (c) to afford a compound of formula XIII. A suitable phenol protecting group R11 for the purpose of Step (c) is benzyl. Other well-known phenol protecting groups, such as those enumerated in pp. 144-170 of "Protecting Groups in Organic Synthesis", Second Ed., by Theodora W. Greene and Peter G. M. Wuts (1991, John Wiley & Sons), may also be used. The reduction in Step (d) can be conducted in the same or substantially the same manner as described for Step (b) of Scheme A. The protection of the alkyl hydroxy group in a compound of formula XIV with R12 which has the meaning defined earlier, is conducted in the same or substantially the same way as described for Step (c) in Scheme A. The phenolic hydroxy group in a compound of formula XV is subsequently acylated in Step (f). The acylation methodologies which may be useful to the instant invention have been described hereinabove. In addition, acylation using a carboxylic anhydride of the formula (RC═O)2 O can also be particularly useful for Step (f). In Step (g), the phenolic hydroxy protecting group R11 is removed. When R11 is benzyl it can be removed by catalytic hydrogenolysis. In Step (h), the conversion of a compound of formula XVII to a compound of formula XVIII can be effected in the same or substantially the same way as described for Step (d) of Scheme A. A preferred R10 radical is again benzyl. The removal of R12 hydroxy protecting group from a compound of formula XVIII can be carried out in the same or substantially same manner as described for Step (e) of Scheme A. The oxidation of the alcohol group to the carboxylic group in Step (j) can be done with the Jones reagent.
As a further example, the synthesis of acids of formula IX'" within the scope of formula IX compounds, can be made by a series of steps as shown in Scheme C. In the Scheme, R6', R7', R8', and R9' preferably are independently hydrogen or C1-6 alkyl. The same or substantially the same reaction conditions described for Steps (c) and (e) of Scheme A can be employed to effect Steps (a) and (c), respectively, of Scheme C. For making a compound formula XXII in which R10 is allyl or benzyl, a compound of formula XXI may be reacted with bis(allyloxy)(diisopropylamino)phosphine or dibenzyloxy(diisopropylamino)phosphine in the presence of a base, such as 1H-tetrazole; and the resulting addition product is subsequently oxidized, for example by m-chloroperbenzoic acid. The oxidation of Step (d) can be accomplished with the Jones reagent.
The synthesis of acids of formula XXV can be achieved by a wide array of methods. For example, as a matter of illustration, a series of steps in Scheme D can be used to make a compound of formula XXV' in which q equals 2 to 6, which are within the scope of formula XXV compounds. In the Scheme, one hydroxy group of a diol of formula XXVI is protected with the earlier defined R12 radical to afford a compound of formula XXVII. A phosphonooxy group protected with R10 radicals can be introduced by the same or substantially the same method that was described for Step (b) of Scheme C. The same or substantially the same method of Step (e) of Scheme A can be used to remove R12 from a compound of formula XXVIII. Oxidation of a compound of formula XXIX using the Jones reagent affords a formula XXV' compound.
The structural formulae as drawn herein are believed to best represent the structures of compounds of the present invention. However, some compounds within the scope of the invention may exist as other tautomeric forms, in which hydrogen atoms are transposed to other parts of the molecules and the chemical bonds between the atoms of the molecules are consequently rearranged. It should be understood that the structural formulae represent all tautomeric forms, insofar as they may exist. ##STR21##
The specific examples which follow illustrate the synthesis of representative compounds of the instant invention and are not to be construed as limiting the invention in sphere or scope. The methods may be adapted to variations in order to produce compounds embraced by this invention but not specifically disclosed. Further, variations of the methods to produce the same compounds in somewhat different fashion will also be evident to one skilled in the art.
All temperatures are understood to be in Centigrade (C) when not specified. The nuclear magnetic resonance (NMR) spectral characteristics refer to chemical shifts (δ) expressed in parts per million (ppm) versus tetramethylsilane (TMS) as reference standard. The relative area reported for the various shifts in the proton NMR spectral data corresponds to the number of hydrogen atoms of a particular functional type in the molecule. The nature of the shifts as to multiplicity is reported as broad singlet (bs), broad doublet (bd), broad triplet (bt), broad quartet (bq), singlet (s), multiplet (m), doublet (d), quartet (q), triplet (t), doublet of doublet (dd), doublet of triplet (dt), and doublet of quartet (dq). The solvents employed for taking NMR spectra are DMSO-d6 (perdeuterodimethylsulfoxide), D2 O (deuterated water), CDCl3 (deuterochloroform) and other conventional deuterated solvents. The infrared (IR) spectral description include only absorption wave numbers (cm-1) having functional group identification value.
Celite is a registered trademark of the Johns-Manville Products Corporation for diatomaceous earth.
The abbreviations used herein are conventional abbreviations widely employed in the art. Some of which are:
______________________________________ MS Mass spectrometry HRMS High resolution mass spectrometry DMF Dimethylformamide Ac Acetyl DMSO dimethyl sulfoxide Ph phenyl Ar aryl DCI desorption chemical ionization Y yield v/v volume/volume FAB fast atom bombardment NOBA m-nitrobenzylalcohol Rt retention time min minute(s) h hour(s) tlc thin layer chromatography tBu tertiarybutyl i-PrOH isopropylalcohol Cbz Benzyloxycarbonyl Bz (when used with a Benzoyl taxol structure) ______________________________________
In the examples that follow, hexane and hexanes may be used interchangeably.
Anal. calcd for C13 H16 O2 O: C, 76.45; H, 7.90.
Found: C, 76.63; H, 7.83.
Anal. calcd for: C13 H20 O2 : C, 74.97; H, 9.68.
Found: C, 75.35; H, 9.92.
A mixture of compound IVa (6 g, 28.8 mmol), t-butyldimethylsilyl chloride (5.2 g, 34.5 mmol, 1.2 eq.), and imidazole (4.9 g, 71.97 mmol, 2.5 eq.) in anhydrous DMF (30 mL) was stirred overnight at room temperature. The reaction mixture was diluted with EtOAc (50 mL), washed with brine (5×40 mL) and dried over anhydrous sodium sulfate. The desiccant was filtered off and the filtrate was concentrated in vacuo to obtain a white solid which was recrystallized from hexane giving 8.9 g (27.59 mmol, Y: 96%) of the title compound, Va, as white crystalline material: top, 117°-118° C.; 1 H-NMR (300 MHz, acetone-d6) δ ppm: -0.15 (6H, s, Si-Me2), 0.83 (9H, s, tBu), 1.53 (6H, s, 3,3-Me2), 2.10 (3H, s, 6'-Me), 2.19 (2H, t, J=7.5 Hz, 2-H2), 2.43 (3H, s, 4'-Me), 3.51 (2H, t, J=7.5 Hz, 1-H2), 6.37 (1H, s, Ar-H), 6.50 (1H, s, Ar-H), 8.0 (1H, s, 2'-OH, exchanged with D2 O); MS (Isobutane-DCI): m/e 323 (M+H)+ ; IR (KBr) ν max: 3308 (OH), 2856, 1614, 1390, 1260 cm-1 ; UV (MeOH:H2 O, 1:1) λ max: 196 (ε 3.3×104), 284 nm (ε 1.9×102).
Anal. calcd for C19 H34 O2 Si: C, 70.75; H, 10.63.
Found: C, 70.52; H, 10.83.
Anal. calcd for C33 H47 O5 PSi: C, 68.02; H, 8.13
Found: C, 68.19; H, 7.94.
Anal. calcd for C27 H31 O5 P: C, 69.21; H,7.10.
Found: C, 68.94; H, 7.06.
Anal. calcd for C27 H31 O5 P: C, 69.51; H, 6.70.
Found: C, 69.76; H, 6.73.
To a solution of compound VIIIa (1.46 g, 3.13 mmol) in acetone (40 mL) was added Jones reagent* (3 mL) at room temperature. The reaction mixture was stirred at room temperature for 20 min. The insoluble material was filtered off and the filtrate was concentrated in vacuo. The residue thus obtained was taken into EtOAc and purified on silica gel column, being eluted with EtOAc/CH2 C12 (1:1, v/v) to obtain 1.0 g (2.07 mmol, Y:66%) of the title compound, IXa, as a gummy material: 1 H-NMR (300 MHz, acetone-d6) δ ppm: 1.6 (6H, s, 3,3-Me2), 2.12 (3H, s, 6'-Me), 2.52 (3H, s, 4'-Me), 2.93 (2H, s, 2-H2) 5.15-5.18 (4H, 2ABq, CH2 Ph), 6.72 (1H, s, Ar-H), 7.08 (1H, s, Ar-H), 7.33-7.4 (10H, m); MS (Isobutane-DCI: m/e 483 (M+H)+ ; IR (NaCl film) ν max: 1715 (C═O), 1260 (P═O), 1020 (P-O) cm-1 ; UV (MeOH: H.sub. O, 1: 1 ) λ max: 202 (ε 4.2×104), 258 nm (ε 8.3×102).
Anal. calcd for C27 H31 O6 P: C, 67.21; H, 6.48.
Found: C, 66.75; H, 6.29.
*Note: The Jones reagent was prepared by dissolving CrO3 (26.72 g) in "concentrated sulfuric acid (23 mL) and diluted with water to a volume of 100 mL" (see Fieser and Fieser "Reagents for Organic Synthesis" Vol 1, p 142, John Wiley, New York, 1967).
Sodium hydride (NaH, 1.20 g, 30 mmol; 60% in mineral oil, Aldrich) was washed with anhydrous hexanes, dried under dry nitrogen and suspended in anhydrous DMF (100 mL; Aldrich Sure Seal). To this suspension was added compound IVa (5.20 g, 25.0 mmol) and the mixture was heated at 65° C. for 5 min. To this warm mixture was added tetrabenzyl pyrophosphate (XXIVa) (20.2 g, 37.5 mmol) all at once. The reaction mixture was heated at 65° C. for 11/2 h. The cooled reaction mixture was diluted with EtOAc (450 mL), washed with H2 O (150 mL×3) and then with brine (150 mL). The organic phase was dried (Na2 SO4) and concentrated. The residue was purified by silica column chromatography being eluted with 35% EtOAc in hexanes to obtain 4.70 g (10 mmol, Y: 40.1%) of the title compound, VIIa, as a gummy oil. This material was identical to the product obtained in Example 5 as determined by 1 H-NMR (300 MHz, acetone-d6).
To a solution of the alcohol VIIa (4.90 g, 10.5 mmol) in acetone (75 mL) was added Jones reagent (10 mL) at room temperature. The reaction mixture was stirred at room temperature for 20 min. The insoluble material was filtered and the filtrate concentrated in vacuo. The residue was taken into EtOAc and purified by silica gel column chromatography, being eluted with 50% EtOAc in CH2 C2 to obtain 3.20 g (6.64 mmol, Y: 63.5%) of the title compound, IXa as a yellowish oily solid: Rf 0.44 (50% EtOAc/hexane); 1 H-NMR (300 MHz, acetone-d6 indicated that this material was identical to the product obtained in Example 7.
A solution of 2,6-dimethyl-1,4-benzoquinone (Xa) (5.66g, 42 mmol, Aldrich) in Et2 O (200 mL) was shaken vigorously in a separatory funnel with two 200 mL portions of aqueous sodium hydrosulfite solution (sodium dithionite, Na2 S2 O4, 14.5 g, 83.3 mmol) until the Et2 O layer turned bright yellow. The ether layer was washed with brine (200 mL×2), dried (MgSO4) and concentrated in vacuo to obtain 4.865g (35.3 mmol, Y: 83.9%) of the title compound as a white solid: mp, 148°-150° C. (acetone-hexane) [mp reported by L. A. Carpino, S. A. Triolo, and R. A. Berglund in J. Org. Chem., 54, 3303 (1989): 145°-148° C.]; Rf 0.47 (10% EtOAc in CH2 Cl2); IR(KBr) 3312 cm-1 (OH); 1 H-NMR (300 MHz, acetone-d6) δ ppm: 2.15 (6H, s, Me), 6.45 (2H, s, Ar-H), 6.58 (1H, s, OH), 7.47 (1H, s, OH); 13 C-NMR (75 MHz, acetone-d6) δ ppm: 16.84, 116.00, 126.45, 147.46, 151.54; MS (isobutane-DCI) m/e 139 (MH+).
A mixture of 1,4-dihydroxy-2,6-dimethylbenzene (XIa) (4.83 g, 35 mmol), ethyl β,β-dimethylacrylate (5.38g, 42 mmol; Aldrich) and concentrated sulfuric acid (2 mL) in toluene (200 mL) was heated at reflux for 3.5 h. After the mixture had cooled, it was washed successively with H2 O (200 mL×2), 5% aqueous NaHCO3 solution (200 mL×2), and then with brine (200 mL). The toluene solution was dried (MgSO4) and concentrated in vacuo. The residual solid was crystallized from toluene to obtain 4,637 g (21.1 mmol, Y: 60.2%) of the title compound as off-white solid: mp, 141°-142° [mp reported by K. L. Amsberry and R. T. Borchardt in Pharmaceutical Res., 8, 323 (1991): 140°-142° C.]; Rf 0.67 (10% EtOAc in CH2 Cl2); IR(KBr) 3418(OH), 1742 cm-1 (lactone); 1 H-NMR (300MHz, acetone-d6) δ ppm: 1.43 (6H, s, gem-Me), 2.22 (3H, s, Ar-Me), 2.38 (3H, s, Ar-Me), 2.56 (2H, s, CH2), 6.66 (1H, s, At-H), 7.19 (1H, s, OH); 13 C-NMR (75 MHz, acetone-d6) δ ppm: 15.12, 16.64, 27.94, 36.15, 46.56, 117.56, 124.49, 125.26, 129.79, 146.16, 151.45, 169.15; MS (isobutane-DCl) m/e 221 (MH+).
Anal. calcd for C13 H16 O3 : C, 70.89; H, 7.33.
Found: C, 71.21; H, 7.43.
A mixture of hydroxyhydrocoumarin XIIa (1.10 g, 5 mmol), benzyl bromide (1.28 g, 7.5 mmol; Aldrich) and anhydrous potassium carbonate (1.38 g, 10 mmol) in anhydrous DMF (10 mL; Aldrich Sure Seal) was stirred under dry nitrogen atmosphere for 3 days. The mixture, diluted with EtOAc (30 mL) and H2 O (10 mL), was washed successively with 2N hydrochloric acid (14 mL), H2 O (10 mL), 5% aqueous NaHCO3 solution (10 mL), and then with brine (15 mL). The EtOAc layer was dried (Na2 SO4) and concentrated in vacuo to dryness. The resulting solid was triturated with hexane to obtain 1.359 g (4.38 mmol, Y: 87.7%) of the title compound as off-white solid: mp, 94°-96° C. (recrystallized from isopropyl alcohol); Rf 0.57 (30% EtOAc in hexane); IR(KBr) 1768 cm-1 (lactone); 1 H-NMR (300 MHz, CDCl3 ) δ ppm: 1.43 (6H, s, gem-Me), 2.26 (3H, s, Ar-Me), 2.40 (3H, s, Ar-Me), 2.56 (2H, s, CH2), 4.73 (2H, s, OCH2), 6.76 (1H, s, At-H), 7.3-7.5 (5H, m, Ar-Hs); 13 C-NMR (75 MHz, CDCl3) δ ppm: 15.15, 16.54, 27.87, 35.78, 46.15, 74.85, 118.00, 128.38, 128.72, 129.12, 129.17, 130.31, 131.55, 137.88, 148.02, 153.44, 169.15; MS (isobutane-DCI) m/e 311 (MH+), 91.
Anal. calcd for C20 H22 O3 : C, 77.40; H, 7.15.
Found: C, 77.37; H, 7.13.
A solution of benzyloxyhydrocoumarin XIIIa (1.147 g, 3.70 mmol) in anhydrous THF (7 mL) was carefully added to a stirred suspension of LiA1H4 (281 mg, 7.4 mmol) in anhydrous THF (15 mL). The mixture was stirred at room temperature under dry nitrogen atmosphere for 20 min and then heated at reflux for 30 min by which time the tlc (30% EtOAc in hexane) indicated that the reaction was complete. The mixture was cooled in an ice-bath and to this mixture was added carefully and successively EtOAc (15 mL), 6N hydrochloric acid (5 mL), and H2 O (15 mL). The EtOAc layer was collected and the aqueous layer was extracted with EtOAc (25 mL). Both EtOAc layers were combined and washed successively with in hydrochloric acid (25 mL), saturated aqueous NaHCO3 solution (25 mL), and brine. The EtOAc layer was dried (Na2 SO4) and concentrated in vacuo to dryness to obtain 1.10 g (3.35 mmol, Y: 90.6%) of the title compound as white solid: top, 90°-91° C.; Rf 0.15 (30% EtOAc in hexane); IR(KBr) 3462, 3262, 1606 cm-1 ; 1 H-NMR (300 MHz, acetone-d6) δ ppm: 1.58 (6H, s, gem-Me), 2.16 (3H, s, Ar-Me), 2.21 (2H, t, J=7.8 Hz, CH2), 2.46 (3H, s, Ar-Me), 3.17 (1H, t, J=5 Hz, OH), 3.45-3.52 (2H, m, CH2 O), 4.69 (2H, s, OCH2 Ph), 6.55 (1H, s, Ar-H), 7.3-7.55 (5H, m, Ph-Hs), 7.85 (1H, s, Ar-OH); 13 C-NMR (75 MHz, acetone-d6) δ ppm: 16.47, 32.73, 41.00, 46.39, 61.15, 75.02, 118.03, 127.90, 129.01, 129.11, 129.46, 129.68, 131.86, 132.40, 139.68, 150.92, 153.88; MS(FAB/NOBA+NaI+KI) m/e 353 (MK+), 337 (MNa+), 314 (M+), 229, 223.
Anal. calcd for C20 H26 O3 : C, 76.41; H, 8.34.
Found: C, 76.28; H, 8.25.
A mixture of diol XIVa (1.017 g, 3.10 mmol), t-butyldimethylsilyl chloride (561 mg, 3.72 mmol; Aldrich) and imidazole (527mg, 7.75 mmol) in DMF (5 mL; Aldrich, Sure Seal) was stirred at room temperature under nitrogen atmosphere for 18 h. This mixture was diluted with EtOAc (20 mL) and successively washed with H2 O (15 mL×3) and brine (15 mL). The EtOAc phase was dried (Na2 SO4) and concentrated in vacuo to give 1.38 g (3.16 mmol, Y: ≧100%) of the title compound as a crude oil: Rf 0.72 (30% EtOAc in hexane); IR (film) 3380 cm-1 (OH); 1 H-NMR (300 MHz, acetone-d6) δ ppm: -0.03 (6H, s, SiMe2), 0.84 (9H, s, SitBu), 1.56 (6H, s, gem-Me), 2.15 (3H, s, Ar-Me), 2.20 (2H, t, J= 7.5 Hz, CH2), 2.45 (3H, s, Ar-Me), 3.56 (2H, t, J=7.5 Hz, CH2 OSi), 4.67 (2H, s, OCH2 Ph), 6.54 (1H, s, Ar-H), 7.3-7.5 (5H, m, Ph-Hs), 7.88 (1H, s, Ar-OH); MS (isobutane-DCI) m/e 429 (MH+), 337, 297, 201.
To a solution of phenol XVa (1.38 g, 3.10 mmol; crude) in pyridine (2 mL; dried over NaOH) was added acetic anhydride (1 mL, 10.6 mmol) and the solution was stirred at room temperature for 15 h. The volatiles were evaporated in vacuo and the residue, diluted with CH2 Cl2 (20 mL), was successively washed with H2 O (15 mL ×2) and brine (15 mL). The CH2 Cl2 phase was dried (Na2 SO4) and concentrated in vacuo. The residue was purified by column chromatography (SiO2, 100 g), being eluted with 12% EtOAc in hexane to obtain 1.24 g (2.64 mmol, Y: 85.2%) of the title compound as a clear oil: Rf 0.23 (10% EtOAc in hexane); IR (film): 1760 cm-1 (OAc); 1 H-NMR (300 MHz, CDCl3) δ ppm: -0.03 (6H, s, SiMe2), 0.83 (9H, s, SitBu), 1.47 (3H, s, Ar-Me), 2.05 (2H, t, J=7.5 Hz, CH2), 2.23 (3H, s, Ar-Me), 2.25 (3H, s, OAc), 2.47 (3H, s, Ar-Me), 3.50 (2H, t, J=7.5 Hz, CH2 OSi), 4.72 (2H, s, OCH2 Ph), 6.58 (1H, s, Ar-H), 7.2-7.5 (5H, m, Ph-Hs); MS (isobutane-DCI) m/e 471 (MH+), 413 , 385 , 201.
Anal. calcd for C28 H42 Si: C, 71.45, H, 9.00.
Found: 71.47; H, 9.21.
To a solution of benzyl ether XVIa (1.19 g, 2.53 mmol) in absolute EtOH (100 mL) was added 10% Pd-C (400 mg, Aldrich), and the mixture was stirred in a Parr apparatus under hydrogen atmosphere (30 psi) at room temperature for 2 h. The catalyst was removed by filtration through Celite and the filtrate was concentrated. The residue was purified by column chromatography (SiO2, 15 g), being eluted with 20% EtOAc in hexane to obtain 863 mg (2.27 mmol, Y: 97.1%) of the title compound as white solid: mp, 87°-88° C. (recrystallized from EtOAc/hexane); Rf 0.34 (20% EtOAc in hexane); IR(KBr) 3490 (OH), 1734, 1232 cm-1 (OAc); 1 H-NMR (300 MHz, acetone-d6); δ ppm: -0.03 (6H, s, SiMe2), 0.84 (9H, s, tBu), 1.46 (6H, s, gem-Me), 2.05 (2H, t, J=7.5 Hz, CH2 O), 2.16 (3H, s, Ar-Me), 2.19 (3H, s, OAc), 2.40(3H, Ar-Me), 3.53 (2H, t, J=7.5 Hz, CH2 O), 6.50 (1H, s, Ar-H), 7.10 (1H, s, Ar-OH); MS (isobutane-DCI) m/e 381 (MH+), 323, 295, 201, 145.
Anal. calcd for C21 H36 O4 Si: C, 66.28; H, 9.54.
Found: C, 66.28; H, 9.83.
NaH (120 mg, 3.0 mmol; 60% dispersion, Aldrich) was washed with anhydrous hexane to remove the oil. To a suspension of the residue in anhydrous DMF (10 mL; Aldrich Sure Seal) was added a solution of phenol XVIIa (760 mg, 2.0 mmol) in DMF (5 mL). The mixture was heated at 60°-70° C. under dry nitrogen atmosphere for 15 min and to this was added tetrabenzyl pyrophosphate (XXIVa) (1.61 g, 3.0 mmol). The mixture was continued to be heated at 60°-70° C. for 30 min. The mixture was subsequently cooled, diluted with EtOAc (30 mL), and successively washed with H2 O (20 mL×3) and brine (20 mL). The organic phase was dried (Na2 SO4) and concentrated. The residue was purified by column chromatography (SiO2, 100 g), being eluted with 20% EtOAc in hexane to obtain 1.04 g (1.63 mmol, Y: 81.6%) of the title compound as an oil: Rf 0.23 (20% EtOAc in hexane); IR (film) 1760 cm-1 (OAc); 1 H-NMR (300 MHz, CDCl3) 6 ppm: -0.04 (6H, s, SiMe2), 0.83 (9H, s, tBu), 1.42 (6H, s, gem-Me), 2.00 (2H, t, J=7.5 Hz , CH2), 2.24 (3H, s, Ar-Me), 2.25 (3H, s, OAc), 2.43 (3H., s, Ar-Me), 3.54 (2H, t, J=7.5 Hz, CH2 OSi), 5.03 (2H, s, OCH2 Ph), 5.06 (2H, s, OCH2 Ph), 6.55 (1H, s, Ar-H), 7.2-7.4 (10H, m, Ph-Hs); MS (isobutane-DCI) m/e 641 (MH+), 583,441.
Anal. calcd for C35 H49 O7 PSi: C, 65.61; H, 7.71.
Found: C, 65.68; H, 7.64.
Anal. calcd for C14 H23 O2 Si: C, 66.88; H, 9.22.
Found: C, 66.59; H, 9.58.
Anal. calcd for C20 H33 OsPSi: C, 58.23; H, 8.06; P, 7.51.
Found: C, 58.03; H, 8.05; P, 7.50.
Anal. calcd for C14 H19 OsP: C, 56.38; H, 6.43.
Found: C, 56.21; H, 6.44.
Anal. calcd for C14 H17 O6 P: C, 53.85; H, 5.49.
Found C, 53.63; H, 5.50.
This oil (171.1 mg, 0.908 mmol) in dry dichloromethane (10 mL) was treated with dibenzyloxy(diisopropylamino)phosphine [prepared as in Bannwarth, W.; Trzeciak, A. Helv. Chim. Acta, 70, p. 175 (1987)] (399 mg, 1.120 mmol) and 1H-tetrazole (191 mg, 2.270 mmol). After 3 h at room temperature the suspension was cooled to -40° C., and solid m-chloroperbenzoic acid (50-60%, 570 mg, 1.82 mmol) was added. After 1 h the temperature of the mixture reached 0° C. Work-up with ethyl acetate and 5% aqueous sodium bicarbonate solution gave a crude product that was purified by silica gel flash chromatography (being eluted with 25% ethyl acetate in hexane) to yield the title compound as a yellow oil (185 mg, Y: 45%); 1 H-NMR (CDCl3, 300 MHz) ≢ 7.40-7.26 (m, 10H) 5.00 (m, 4H) 4.01 (q, 2H) 3.57 (t, 2H) 1.72-1.47 (m, 4H) 0.87 (s, 9H) 0.02 (s, 6H).
HRMS calcd for MH+ : 465.2226, found: 465.2216.
HRMS calcd for MH+: 351.1361, found: 351.1371.
HRMS calcd for MH+ : 365.1154. Found 365.1132.
To a cold solution (-30° C.) of taxol (0.69 g, 0.8089 mmol) in dry tetrahydrofuran (30 mL) was added freshly prepared 0.1 M lithium diisopropylamide (LDA) solution (12.0 mL, 1.2 mmol). The mixture was stirred at -30° C. for 30 min. Then 4-chloromethylbenzoic anhydride (XXXVa) (0.39 g, 1.2 mmol) was added as solids and the resulting mixture was stirred at -30° C. for 4 h. It was treated with brine and ethyl acetate and the layers were separated. The aqueous layer was re-extracted with ethyl acetate, and the combined organic layers were dried (MgSO4) and evaporated to dryness to give a white foam. This was purified by silica gel chromatography (being eluted with methylene chloride and 10% and 20% acetonitrile in methylene chloride) to give 0.6 g (Y: 74%) of the title product; IR (KBr) 3432, 3066, 1728 1644, 1612, 1580, 1526, 1486, 1452, 1416, cm-1 ; MS (FAB) MH+ m/z 1006, (M+Na)+ m/z 1028; 1 H-NMR (CDCl3) δ 1.074 (s, 3H), 1.206 (s, 3H), 1.653 (s, 3H), 1.737-1.904 (m, H), 1.938 (s, 3H), 2.099-2.120 (m, H), 2.201 (s, 3H), 2.270-2.321 (m, H), 2.419 (s, 3H), 2.483-2.587 (m, H), 3.793 (d, H), 4.165 (d, H), 4.288 (d, H), 4.485 (m, H), 4.586 (s, 2H), 4.948 (d, H), 5.655 (m, 2H), 6.017 (dd, H), 6.22 (t, H), 6.272 (S, H), 7.00 (d, H), 7.29-8.10 (m, 19H).
A mixture of DMAP (0.366 g, 3.0 mmol), DCC (0.93 g, 4.5 mmol) and 4-chloromethylbenzoic acid (0.78 g, 4.5 mmol) in dry CH2 Cl2 (50 mL) was stirred at room temperature for 30 min. Taxol (2.50 g, 3.0 mmol) was added as solids and the mixture was stirred at room temperature for 18 h. The mixture was concentrated to dryness; the residue was triturated with acetone; and the insoluble material was filtered. The acetone filtrate solution was concentrated and the residue was purified on a silica gel column (being eluted with CH2 Cl2 and 10%, 20% and 30% CH2 Cl2 in CH3 CN) to give 1.80 g (Y: 60%) of the title compound. Spectral data were consistent for the compound.
To a cooled (5° C.) solution of taxol (0.43 g, 0.5 mmol) in dry CH2 Cl2 (20 mL) was added N, N-diisopropylethylamine (0.5 ml) followed by a dropwise addition of 4-chloromethylbenzoyl chloride (0.19 g, 1.0 mmol) in dry CH2 Cl2 (2 mL). The resulting mixture was stirred at 5°-15° C. for 3 h. It was washed with saturated aqueous NaHCO3 solution and brine. It was dried (MgSO4) and concentrated to give a solid residue. The residue was purified on a silica gel plate (being eluted with CH2 Cl2 : 30% CH3 CN) to give 0.5 g of the title product (Y: 100%).
To a solution of a compound of formula XXX (1 equivalent) in acetone (10-20 mL) was added NaI (0.1 equivalent). This mixture was stirred at room temperature for 30 min. Then an appropriate amine (2-20 equivalents) was added, and the mixture was stirred at room temperature for 1 to 2 days. The reaction mixture was filtered over Celite and evaporated to dryness to give a free base as a foam. This foam was purified on a silica gel column, normally being eluted with methylene chloride and 2% to 10% methanol in methylene chloride to give the desired product.
To a solution of compound XXXa (0.1 g; 0.1 mmol) in acetone (10 mL) was added NaI (20 mg). The resultant mixture was stirred at room temperature for 15 min followed by addition of diethylamine (14.6 mg; 0.002 mL; 0.2 mmol). The mixture was stirred at room temperature for 18 h and evaporated to dryness. The residue was purified on silica gel preparative plates (being eluted with 10% MeOH in CH2 Cl2) to give 73 mg (Y: 73%) of the title product.
The free base was dissolved in acetone and treated with one mole equivalent of L-tartaric acid. This solution was concentrated and treated with dry ether to give an L-tartaric acid salt of the title compound as a white solid; mp 176°-180° C. (decomposition); IR (KBr) 3450, 3064, 2970, 1728, 1670, 1610, 1582, 1484, 1452 cm-1 ; MS (FAB) MH+ m/z 1043, (M+Na)+ m/z 1043; 1 H-NMR (CDCl3) δ 1.065 (t, 6H), 1.124 (s, 3H), 1.224 (s, 3H), 1.672 (s, 3H), 1.879 (m, H), 1.962 (s, 3H), 2.147 (m, H), 2.223 (s, 3H), 2.327 (m, H), 2.433 (s, 3H), 2.553 (m, 5H), 3.655 (m, 2H), 3.799 (d, H), 4.201 (d, H), 4.325 (d, H), 4.447 (m, H), 4.956 (d, H), 5.672 (m, 2H), 6.028 (m, H), 6.266 (t, H), 6.288 (s, H), 7.052 (d, NH), 7.20-8.20 (m, 19H).
HRMS Calcd. for MH+: 1043.4541. Found: 1043.4517.
To a solution of compound XXXa (0.2 g; 0.2 mmol) in acetone (10 mL) was added NaI (20 mg). This mixture was stirred at room temperature for 15 min, followed by addition of morpholine (35 mg; 0.04 mL; 0.4 mmol). The mixture was stirred at room temperature for 18 h and evaporated to dryness. The residue was purified on a silica gel column (being eluted with CH2 Cl2 and 5% and 10% MeOH in CH2 Cl2) to give the title product in a quantitative yield.
The free base was dissolved in acetone and treated with one mole equivalent of anhydrous citric acid. The solution was concentrated and diluted with dry ether to give a citric acid salt of the title compound as a beige solid; mp 170°-172° C.; IR (KBr) 3440, 3064, 2938, 2856, 1726, 1666, 1612, 1582, 1452, 1406, 1418, 1372 cm-1 ; MS(FAB) MH+ m/z 1058, (M+K)+ m/z 1096; 1 H-NMR (CDCl3) δ 1.117 (s, 3H), 1.216 (s, 3H), 1.664 (s, 3H), 1.821 (m, H), 1.907 (S, 3H), 2.151 (m, H), 2.221 (s, 3H), 2.277 (m, H), 2.430 (s, 3H), 2.505 (m, 4H), 3.719 (m, 4H), 3.815 (d, H), 4.104 (d, H), 4.286 (d, H), 4.425 (m, H), 4.945 (d, H), 5.677 (m, 2H), 6.022 (m, H), 6.223 (t, H), 6.250 (S, H), 7.071 (d, NH), 7.200-8.200 (m, 19H).
HRMS Calcd. for MH+ : 1057.4334. Found: 1057.4346.
To a solution of compound XXXa (0.1 g; 0.1 mmol) in acetone (10 mL) was added NaI (20 mg). This mixture was stirred at room temperature for 15 min, followed by addition of piperidine (17 mg; 0.02 mL; 0.2 mmol). The mixture was stirred at room temperature for 18 h and evaporated to dryness. The residue was purified on silica gel preparative plates (being eluted with 10% MeOH in CH2 Cl2) to give 54 mg (Y: 54%) of the title compound.
The free base was dissolved in 10% methanol in methylene chloride and treated with one equivalent of cold 1N HCl in dry ether. The mixture was concentrated and filtered to give a hydrochloride salt of the title compound as a yellow solid; mp. 170° C. (decomposition); IR (KBr) 3460, 2940, 1730, 1660, 1250 cm-1 ; MS (FAB) MH+ m/z 1055; 1 H-NMR (CDCl3) δ 1.118 (s, 3H), 1.217 (s, 3H), 1.665 (m, 7H), 1.880 (m, H), 1.959 (s, 3H), 2.127 (m, H), 2.158 (S, 3H), 2.216 (s, 3H), 2.319 (m, H), 2.439 (s, 3H), 2.621 (m, 4H), 3.816 (d, H), 4.165 (d, H), 4.293 (d, H), 4.444 (m, H), 4.950 (d, H), 5.658 (m, 2H), 6.041 (m, H), 6.257 (t, H), 6.282 (s, H), 7.043 (d, NH), 7.200-8.200 (m, 19H) .
HRMS Calcd. for MH+ : 1055. 4541. Found: 1055. 4514.
To a solution of XXXa (0.41 g; 0.4075 mmol) in acetone (10 mL) was added NaI (20 mg). This mixture was stirred at room temperature for 15 min, followed by addition of diethanolamine (86 mg, 0.8150 mmol). The mixture was stirred at room temperature for 18 h and evaporated to dryness. The residue was purified on silica gel preparative plates (being eluted with 10% MeOH in CH2 Cl2) to give 0.24 g (Y: 55%) of the title compound.
The free base was dissolved in acetone and treated with one mole equivalent of anhydrous citric acid. This mixture was concentrated and treated with dry ether to give a citric acid salt of the title compound as a white solid; mp 141°-144° C.; IR (KBr) 3438, 3064, 2944, 2898, 1726, 1660, 1610, 1582 cm-1 ; MS (FAB) MH+ m/z 1075, (M+K)+ m/z 1113; 1 H-NMR (CDCl3) δ 1.118 (s, 3H), 1.211 (s, 3H), 1.659 (s, 3H), 1.894 (m, H), 1.948 (s, 3H), 2.129 (m, H), 2.203 (s, 3H), 2.306 (m, H), 2.431 (s, 3H), 2.257 (m, H), 2.693 (m, 4H), 3.648 (m, 4H), 3.781 (d, H), 4.158 (d, H), 4.305 (d, H), 4.418 (m, H), 4.937 (d, H), 5.687 (m, 2H), 6.041 (m, H), 6.239 (t, H), 6.286 (s, H), 7.216 (d, NH), 7.200-8.200 (m, 19H).
HRMS Calcd. for MH+ : 1075.4440. Found: 1075.4430.
To a solution of compound XXXa (0.33 g, 0.328 mmol) in acetone (10 mL) was added NaI (30 mg). This mixture was stirred at room temperature for 15 min followed by addition of N-methylpiperazine (0.33 g, 3.28 mmol, 0.37 mL). The mixture was stirred at room temperature for 18 h and evaporated to dryness. The residue was purified on a silica gel preparative plate (being eluted with 10% MeOH in CH2 Cl2) to give 0.22 g (Y: 63%) of the title compound.
The free base was dissolved in acetone and treated with one mole equivalent of L-tartaric acid. This mixture was concentrated and treated with dry ether to give a tartaric acid salt of the title compound as a white solid; mp 160°-163° C.; IR (KBr) 3448, 3064, 3030, 1726, 1664, 1612, 1582, 1518 cm-1 ; MS (FAB) MH+ m/z 1070, (M+Na)+ m/z 1092, (M+K)+ m/z 1108; 1 H-NMR (CDCl3) δ 1.085 (s, 3H), 1.156 (s, 3H), 1.586 (s, 3H), 1.683 (m, H), 1.894 (s, 3H), 2.063 (m, H), 2.153 (s, 3H), 2.226 (s, 3H), 2.366 (s, 3H), 2.438 (m, 8H), 3.498 (s, 2H), 3.835 (d, H), 4.132 (d, H), 4.254 (d, H), 4.384 (m, H), 4.911 (m, H), 5.617 (m, 2H), 5.974 (m, H), 6.190 (t, H), 6.225 (S, H), 6.967 (d, NH), 7.200-8.200 (m, 19H).
HRMS Calcd. for MH+ : 1070.4650. Found 1070.4676.
To a solution of compound XXXa (0.53 g; 0.5263 mmol) in acetone (30 mL) was added NaI (50 mg). This mixture was stirred at room temperature for 15 min followed by addition of 1-(2-hydroxylethyl)piperazine (0.137 g; 0.13 mL; 1.0536 mmol). The mixture was stirred at room temperature for 18 h and evaporated to dryness. The residue was purified by a silica gel preparative plate (being eluted with 10% MeOH in CH2 Cl2) to give 0.5 g of the title compound (Y: 86%).
The free base was dissolved in acetone and treated with two mole equivalents of L-tartaric acid. This mixture was concentrated and treated with dry ether to give a tartaric acid salt of the title compound as a yellow solid; mp 170°-173° C.; IR (KBr) 3422, 3064, 2940, 2818, 1724, 1652, 1534 cm-1 ; MS (FAB) MH+ m/z 1100, (M+K)+ m/z 1138; 1 H-NMR (CDCl3) δ 1.102 (s, 3H), 1.199 (s, 3H), 1.648 (s, 3H), 1.853 (m, H), 1.935 (s, 3H), 2.096 (m, H), 2.195 (s, 3H), 2.303 (m, H), 2.415 (s, 3H), 2.603-2.766 (m, 10H), 3.568 (S, 2H), 3.713 (m, 2H), 3.795 (d, H), 4.175 (d, H), 4.297 (d, H), 4.424 (m, H), 4.953 (d, H), 5.655 (m, 2H), 5.995 (m, H), 6.224 (t, H), 6.269 (S, H), 7.088 (d, NH), 7.200-8.200 (m, 19H).
HRMS Calcd. for MH+ : 1100.4756. Found: 1100.4729.
To a solution of compound XXXa (0.29 g; 0.2882 mmol) in acetone (20 mL) was added NaI (20 mg). This mixture was stirred at room temperature for 15 min followed by addition of 4-(2-hydroxyethyl)piperidine (56 mg, 0.4323 mmol). The mixture was stirred at room temperature for 18 h and evaporated to dryness. The residue was purified on silica gel preparative plates to give 0.32 g (quantitative yield) of the title compound.
The free base (0.32 g; 0.2914 mmol) was dissolved in acetone (10 mL) and treated with 0.1M L-tartaric acid in MeOH (2.9 mL; 0.29 mmol). This mixture was concentrated and treated with dry ether to give a tartaric acid salt of the title compound as a white solid; mp 178°-180° C.; IR (KBr) 3440, 3064, 3030, 2934, 2802, 1662, 1610, 1582, 1518, 1486, 1452, 1372 cm-1 ; MS (FAB) MH+ m/z 1099, (M+Na)+ m/z 1121, (M+K)+ m/z 1137; 1 H-NMR (CDCl3) δ 1.119 (s, 3H), 1.217 (s, 3H), 1.518 (m, 7H), 1.667 (s, 3H), 1.873 (m, H), 1.957 (s, 3H), 2.111 (m, H), 2.215 (s, 3H), 2.316 (m, H), 2.432 (s, 3H), 2.597 (m, H), 2.875 (m, 2H), 3.684 (m, 2H), 3.816 (d, H), 4.196 (d, H), 4.370 (d, H), 4.440 (m, H), 4.975 (d, H), 5.665 (m, 2H), 6.030 (m, H), 6.252 (t, H), 6.284 (S, H), 7.096 (d, NH), 7.200-8.700 (m, 19H) .
HRMS Calcd. for MH+ : 1099.4804. Found 1099.4767.
To a solution of compound XXXa (0.29 g, 0.2882 mmol) in acetone (10 mL) was added NaI (20 mg). This mixture was stirred at room temperature for 15 min followed by addition of L-prolinol (44 mg, 0.042 mL, 0.433 mmol). The mixture was stirred at room temperature for 18 h, evaporated to dryness and purified on silica gel preparative plates to give 0.15 g (Y: 50%) of the title compound.
The free base (0.176 g, 0.1635 mmol) was dissolved in acetone (10 mL) and treated with one mole equivalent of L-tartaric acid in methanol (0.1M, 1.60 mL; 0.160 mmol). This mixture was concentrated and treated with dry ether and filtered to give 0.18 g of a tartaric acid salt of the the title compound; mp 150°-153° C.; IR (KBr) 3438, 3064, 2944, 1726, 1662, 1612, 1582, 1486 cm-1 ; MS (FAB) MH+ m/z 1071, (M+Na)+ m/z 1093, (M+K)+ m/z 1109; 1 H-NMR (CDCl3) δ 1.112 (s, 2H), 1.218 (s, 3H), 1.705 (s, 3H), 1.804-2.116 (m, 6H), 2.221 (s, 3H), 2.373 (m, H), 2.441 (s, 3H), 2.545 (m, 3H), 3.454-3.697 (m, 4H), 3.794 (d, H), 4.170 (d, H), 4.320 (d, H), 4.445 (m, H), 4.951 (m, 2H), 5.671 (m, 2H), 6.026 (m, H), 6.250 (t, H), 6.287 (s, H), 7.098 (d, NH), 7.200-8.200 (m, 19H).
HRMS Calcd. for MH+ : 1071.4491. Found 1071.4449.
To a solution of compound XXXa (0.5 g, 0.5 mmol) in acetone (20 mL) was added NaI (0.1 g). This mixture was stirred at room temperature for 15 min, followed by addition of N,N,N'-trimethylethylenediamine (51.09 mg, 0.064 mL, 0.5 mmol), stirred at room temperature for 18 h, and evaporated to dryness. The residue was purified on a silica gel preparative plate (being eluted with 10% MeOH in CH2 Cl2) to give 0.24 g (Y: 45%) of the title compound.
The free base (0.2 g, 0.1867 mmol) was dissolved in acetone (2 mL) and methanol (1 mL) and treated with L-tartaric acid in methanol (0.1M, 3.72 mL, 0.372 mmol). This mixture was concentrated, treated with dry ether, and filtered to give an L-tartaric acid salt of the title compound as an ivory colored solid (Y: 0.14 g); mp 140°-143° C.; IR (KBr) 3432, 3062, 3030, 2944, 2816, 1724, 1660, 1610, 1580, 1486 cm-1 ; MS (FAB) MH+ m/z 1072, (M+Na)+ m/z 1094; 1 H-NMR (CDCl3) δ 1.113 (s, 3H), 1.211 (s, 3H), 1.657 (s, 3H), 1.860 (m, H), 2.025 (s, 3H), 2.076 (m, 3H), 2.204 (s, 3H), 2.243 (s, 3H), 2.437 (s, 3H), 2.584 (m, H), 2.695 (s, 6H), 2.837 (m, 2H), 3.072 (m, 2H), 3.647 (s, 2H), 3.775 (d, H), 4.182 (d, H), 4.309 (d, H), 4.346 (m, H), 5.667 (m, 2H), 6.031 (m, H), 6.217 (t, H), 6.276 (s, H), 7.224 (d, NH) , 7.200-8.200 (m, 19H) .
HRMS Calcd. for MH+ : 1072.4807. Found 1072.4767.
To a solution of compound XXXa (0.5 g; 0.5 mmol) in acetone (20 mL) was added NaI (0.1 g). This mixture was stirred at room temperature for 15 min followed by addition of N,N,N'-trimethyl-l,3-propanediamine (58.105 mg, 0.0733 mL, 0.5 mmol). The mixture was stirred at room temperature for 18 h and evaporated to dryness. The residue was purified on silica gel preparative plates (10% MeOH in CH2 Cl2) to give 0.16 g (Y: 30%) of the title compound.
The free base (0.13 g, 0.1198 mmol) was dissolved in acetone (2 mL) and methanol (1 mL), and treated with L-tartaric acid in methanol (0.1M, 2.4 mL, 0.24 mmol). The mixture was concentrated, treated with dry ether and filtered to give an L-tartaric acid salt of the title compound (Y: 0.13 g); mp 161°-164° C.; IR (KBr) 3424, 3062, 2942, 2804, 2700, 1658, 1610, 1580, 1524, 1486 cm-1 ; MS (FAB): MH+ m/z 1086, (M+K)+ m/z 1124; 1 H-NMR (CDCl3) δ 1.118 (s, 3H), 1.215 (s, 3H), 1.663 (s, 3H), 1.830-2.111 (m, 4H), 2.004 (s, 3H), 2.221 (s, 3H), 2.225 (s, 3H), 2.443 (s, 3H), 2.534 (m, 4H), 2.747 (s, 6H), 3.055 (m, 2H), 3.603 (s, 2H), 3.783 (d, H), 4.160 (d, H), 4.290 (d, H), 4.442 (m, H), 4.946 (d, H), 5.677 (m, 2H), 6.018 (m, H), 6.225 (t, H), 6.282 (s, H), 7.160 (d, NH), 7.200-8.200 (m, 19H).
HRMS Calcd. for MH+ : 1086.4963. Found: 1086.4915.
A mixture of dimethylaminobenzoic acid (0.2 g, 1.2 mmol) , DMAP (0.12 g, 1.0 mmol) and DCC (0.25 g; 1.2 mmol) in dry CH2 Cl2 (30 mL) was stirred at room temperature for 15 min. To this mixture was added taxol (0.85 g, 1.0 mmol) in dry CH2 Cl2 (5 mL) dropwise. The mixture was stirred at room temperature for 3 days and evaporated to dryness. The residue was purified on a silica gel preparative plate (being eluted with 20% CH3CN in CH2 Cl2) to give 1.0 g (Y: 92%) of the title compound.
The free base was dissolved in acetone and treated with one mole equivalent of L-tartaric acid. The mixture was concentrated and treated with dry ether to give an L-tartaric acid salt of the title compound as a white solid; mp 175°-177° C.; IR (KBr) 3446, 3328, 3064, 2930, 1716, 1668, 1628, 1580 cm-1 ; MS (FAB) MH+ m/z 1001, (M+Na)+ m/z 1023, (M+K)+ m/z 1039; 1 H-NMR (CDCl3) δ 1.112 (s, 3H), 1.217 (s, 3H), 1.658 (s, 3H), 1.922 (s, 3H), 2.092 (m, H), 2.215 (s, 3H), 2.429 (s, 3H), 2.536 (m, H), 3.058 (s, 6H), 3.799 (d, H), 4.184 (d, H), 4.302 (d, H), 4.440 (m, H), 4.962 (d, H), 5.650 (m, 2H), 5.949 (m, H), 6.233 (t, H), 6.270 (s, H), 6.632 (d, 2H), 7.175 (d, NH), 7.200-8.200 (m, 21H) .
HRMS Calcd. for MH+ : 1001.4072. Found: 1001.4061.
To compound I1 f (0.33 g, 0.3 m mol) in dry CH2 Cl2 (20 ml) was added (at room temperature) diisopropylethylamine (0.5 ml) followed by bis(2,2,2-trichloroethyl)phosphorochloridate (0.57 g, 1.5 mmol). The resulting mixture was stirred at room temperature under argon atmosphere for 3 h. It was washed with cold aqueous NaHCO3 solution, water and brine, dried (MgSO4), and concentrated to give a residue which was purified on a silica gel plate (being eluted with 10% MeOH in CH2 Cl2) to give 0.25 g (Y: 58%) of 2'-[4-[[4-[2-[bis(2,2,2-trichloroethyl)phosphonooxy]ethyl]-1-piperazinyl]methyl]benzoate]taxol (XXXIa) as a foam. NMR (CDCl3) δ: 1.10 (s, 3H), 1.20 (s, 3H), 1.65 (s, 3H), 2.0 (s, 3H), 2.20 (s, 3H), 1.80-2.40 (m, 3H), 2.4-2.8 (m, 8H), 3.5 (m, 2H), 3.80 (d, H), 4.15 (d, H), 4.30 (d, 3H), 4.40 (m, H), 4.60 (m, 2H), 4.90 (d, H), 5.65 (m, 2H), 6.0 (dd, H), 6.20 (t, H), 6.25 (s, H), 7.0 (d, NH), 7.20-8.20 (m, 19H).
Removal of 2,2,2-trichloroethyl groups from compound XXXIa affords the title compound. The removal may be effected with zinc in acetic acid/methanol.
To compound I1 d (0.20 g; 0.19 retool) in dry CH2 Cl2 (10 mL) was added at room temperature diisopropylethylamine (0.5 ml) followed by bis (2,2,2-trichloroethyl)phosphorochloridate (0.82 g, 2.16 mmol). The resulting mixture was stirred at room temperature under argon for 3 h. It was washed with cold aqueous NaHCO3 solution, water and brine, dried and concentrated to give a residue which was purified on a silica gel plate (being eluted with 10% MeOH in CH2 Cl2) to give 0.11 g (Y: 34%) of 2'-[4-[[[bis(2-phosphonooxy)ethyl]amino]methyl]benzoate]taxol, 2'-tetrakis(2,2,2-trichloroethyl) ester (XXXIb) as a foam. NMR (CHCl3) δ: 1.15 (s, 3H), 1.20 (bs, 6H), 1.70 (s, 3H), 2.25 (bs, 6H), 1.6-2.4 (m, 3H), 2.45 (m, 2H), 2.95 (m, 4H), 3.50 (m, 2H), 3.80 (m, 4H), 4.15 (d, H), 4.20 (m, 3H), 4.60 (m, 6H), 5.0 (d, 5.70 (m, 2H), 6.0 (m, H), 6.20 (t, H), 6.25 (s, H), 7.0 (d, NH), 7.20-8.20 (m, 19H).
Removal of 2,2,2-trichloroethyl groups from compound XXXIb affords the title compound. The removal may be effected with zinc in acetic acid/methanol.
Table 1 below lists taxol derivatives whose specific syntheses are described in the Examples.
TABLE 1 ______________________________________ ##STR47## I COMPOUND # A ______________________________________ I.sup.1 a ##STR48## I.sup.1 b ##STR49## I.sup.1 c ##STR50## I.sup.1 d ##STR51## I.sup.1 e ##STR52## I.sup.1 f ##STR53## I.sup.1 g ##STR54## I.sup.1 h ##STR55## I.sup.1 i ##STR56## I.sup.1 j ##STR57## I.sup.3 a ##STR58## XXXa CH.sub.2 Cl I.sup.1 k ##STR59## I.sup.1 m ##STR60## XXXIa ##STR61## XXXIb ##STR62## ______________________________________
Balb/c x DBA/2 F1 hybrid mice were implanted intraperitoneally, as described by William Rose in Evaluation of Madison 109 Lung Carcinoma as a Model for Screening Antitumor Drugs, Cancer Treatment Reports, 65, No. 3-4 (1981), with 0.5 mL of a 2% (w/v) brei of M109 lung carcinoma.
Mice were treated with compound under study by receiving intraperitoneal injections of various doses on either Days 1, 5 and 9 post-tumor implant or Days 5 and 8 post-implant. Mice were followed daily for survival until approximately 75-90 days post-tumor implant. One group of mice per experiment remained untreated and served as the control group. Median survival times of compound-treated (T) mice were compared to the median survial time of the control (C) mice. The ratio of the two values for each compound-treated group of mice was multiplied by 100 and expressed as a percentage (i.e. % T/C) in Table 2 for certain representative compounds.
TABLE 2 ______________________________________ Maximum % T/C [Cures/Total] (dose in mg/kg/injection; Compound schedule) ______________________________________ I.sup.1 b, citric acid 259 (60; d. 1, 5 & 9) salt I.sup.2 d, citric acid >663 [5/6] (60; d. 1, 5 & 9) salt I.sup.1 e, L-tartaric 234 [1/6] (60; d. 1, 5 & 9) acid salt I.sup.1 f, L-tartaric 191 (160; d. 5 & 8) acid salt I.sup.1 g, L-tartaric 150 (160; d. 5 & 8) acid salt I.sup.1 h, L-tartaric 197 (160; d. 5 & 8) acid salt I.sup.3 a, L-tartaric 203 (80; d. 5 & 8) acid salt I.sup.1 i, L-tartaric 162 (45; d. 5 & 8) acid salt I.sup.1 j, L-tartaric 135 (160; d. 5 & 8) acid salt ______________________________________
salt
The foregoing test shows that the compounds of the instant invention have tumor inhibiting activities in mammals. Thus, another aspect of the instant invention concerns with a method for inhibiting mammalian tumors sensitive to a compound of formula I or a pharmaceutically acceptable salt thereof.
The present invention also provides pharmaceutical compositions (formulations) containing a compound of formula I in combination with one or more pharmaceutically acceptable, inert or physiologically active, carriers, excipients, diluents or adjuvants. Examples of formulating taxol or its related derivatives (including a possible dosage) are described in numerous literatures, for example in U.S. Pat. Nos. 4,960,790 and 4,814,470, and such examples may be followed to formulate the compounds of this invention. For example, the new compounds are administrable in the form of tablets, pills, powder mixtures, capsules, injectables, solutions, suppositories, emulsions, dispersions, food premix, and in other suitable forms. The pharmaceutical preparation which contains the compound is conveniently admixed with a nontoxic pharmaceutical organic carrier or a nontoxic pharmaceutical inorganic carrier, usually about 0.01 mg up to 2500 mg, or higher per dosage unit, preferably 50-500 mg. Typical of pharmaceutically acceptable carriers are, for example, manitol, urea, dextrans, lactose, potato and maize starches, magnesium stearate, talc, vegetable oils, polyalkylene glycols, ethyl cellulose, poly(vinylpyrrolidone), calcium carbonate, ethyl oleate, isopropyl myristate, benzyl benzoate, sodium carbonate, gelatin, potassium carbonate, silicic acid, and other conventionally employed acceptable carriers. The pharmaceutical preparation may also contain nontoxic auxiliary substances such as emulsifying, preserving, wetting agents, and the like as for example, sorbitan monolaurate, triethanolamine oleate, polyoxyethylene monostearate, glyceryl tripalmitate, dioctyl sodium sulfosuccinate, and the like.
The compounds of the invention can also be freeze dried and, if desired, combined with other pharmaceutically acceptable excipients to prepare formulations suitable for parenteral, injectable administration. For such administration, the formulation can be reconstituted in water (normal, saline), or a mixture of water and an organic solvent, such as propylene glycol, ethanol, and the like.
The mode, dosage and schedule of administration of taxol in human cancer patients have been extensively studied. See, for example Ann. Int. Med., ill, pp 273-279 (1989). For the compounds of this invention, the dose to be administered, whether a single dose, multiple dose, or a daily dose, will of course vary with the particular compound employed because of the varying potency of the compound, the chosen route of administration, the size of the recipient and the nature of the patient's condition. The dosage to be administered is not subject to definite bounds, but it will usually be an effective amount, or the equivalent on a molar basis of the pharmacologically active free form produced from a dosage formulation upon the metabolic release of the active drug to achieve its desired pharmacological and physiological effects. The dosage to be administered will be generally in the range of 0.8 to 8 mg/kg of body weight or about 50-275 mg/m2 of the patient. An oncologist skilled in the art of cancer treatment will able to ascertain, without undue experimentations, appropriate protocols for effective administration of the compounds of this present invention by referring to the earlier studies of taxol and its derivatives.
Claims (17)
1. A compound of formula I ##STR63## or a pharmaceutically acceptable salt thereof, in which R2 is a radical of the formula ##STR64## in which Ra and Rb are independently hydrogen or C1-6 alkyl, said C1-6 alkyl being optionally substituted with hydroxy, phosphono, phosphonooxy, carboxy or di(C1-6 alkyl)amino; or NRa Rb together represents a radical of the formula ##STR65## in which y is one to three, and Ra is as defined above; Rp and Rr are independently same or different C1-6 alkyl;
R1 is hydrogen or a radical Z of the formula ##STR66## in which Q is --(CH2)f --, optionally substituted with one to six same or different C1-6 alkyl or C3-6 cycloalkyl, or a carbon atom of said --(CH2)f -- radical may also be a part of C3-6 cycloalkylidene;
R3 and R4 are independently hydrogen or C1-6 alkyl, or R3 and R4 taken together with the carbon atom to which they are attached form C3-6 cycloalkylidene;
R5 is --OC(═O)R, --OP═O(OH)2 or --CH2 OP═O(OH)2, in which R is C1-6 alkyl;
R6, R7, R8 and R9 are independently halogen, C1-6 alkyl, C1-6 alkoxy or hydrogen, but when R5 is --OC(═O)R, one of R6, R7, R8 or R9 is --OP═O(OH)2 ; f is 2 to 6;
n is O, and m is 1 or 0 when R5 is --CH2 OP═O(OH)2 ; and n is 1 or 0, and m is 1 when R5 is --OC(═O)R or --OP═O(OH)2.
2. A compound as claimed in claim 1 in which R1 is hydrogen; Ra and Rb are same or different C1-6 alkyl, said C1-6 alkyl being optionally substituted with hydroxy, phosphonooxy or di (C1-6 alkyl) amino, with the proviso that hydroxy or di(C1-6 alkyl)amino is not attached to a carbon atom adjacent to nitrogen; or NRa Rb together represents a radical of the formula ##STR67##
3. The compound of claim 2 that is 2'-[4-(diethylaminomethyl)benzoate]taxol.
4. The compound of claim 2 that is 2'-[4(morpholinomethyl)benzoate]taxol.
5. The compouud of claim 2 that is 2'-[4-[1-(piperidinyl)methyl]benzoate]taxol.
6. The compound of claim 2 that is 2'-[4-[[(diethanolamino)methyl]benzoate]taxol.
7. The compound of claim 2 that is 2'-[4-[(4-methyl-1-piperazinyl)methyl]benzoate]taxol.
8. The compound of claim 2 that is 2'-[4-[[4-(2-hydroxyethyl)-1-piperazinyl]methyl]benzoate]taxol.
9. The compound of claim 2 that is 2'-[4-[[4-(2-hydroxyethyl)-1-piperidinyl]methyl]benzoate]taxol.
10. The compound of claim 2 that is 2'-[4-[[2-S-(hydroxymethyl)-1-pyrrolidinyl]methyl]benzoate]taxol.
11. The compound of claim 2 that is 2'-[4- [(N,N,N'-trimethylethylenediamino)methyl]benzoate]taxol.
12. The compound of claim 2 that is 2'-[4-[(N,N,N'-trimethyl-1,3-propanediamino)methyl]benzoate]taxol.
13. The compound of claim 2 that is 2'-[4-(dimethylamino)benzoate]taxol.
14. The compound of claim 2 that is 2'-[4-[[4-[2-(phosphonooxy)ethyl]-1-piperazinyl]methyl]benzoate]taxol.
15. The compound of claim 2 that is 2'-[4-[[[bis(2-phosphonooxy)ethyl]amino]methyl]benzoate]taxol.
16. A pharmaceutical formulation which comprises as an active ingredient a compound as claimed in any one of claims 1 to 15, or a pharmaceutically acceptable salt thereof, associated with one or more pharmaceutically acceptable carriers, excipients or diluents therefor.
17. A method for treating mammalian tumors which comprises administering to a mammal a tumor sensitive amount of a compound as claimed in any one of claims 1 to 15.
Priority Applications (1)
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US08/128,949 USH1487H (en) | 1992-05-06 | 1993-09-29 | Benzoate derivatives of taxol |
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US87966192A | 1992-05-06 | 1992-05-06 | |
US08/128,949 USH1487H (en) | 1992-05-06 | 1993-09-29 | Benzoate derivatives of taxol |
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US08/128,949 Abandoned USH1487H (en) | 1992-05-06 | 1993-09-29 | Benzoate derivatives of taxol |
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US (1) | USH1487H (en) |
EP (1) | EP0569281A1 (en) |
JP (1) | JPH069600A (en) |
CA (1) | CA2095375A1 (en) |
Cited By (1)
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US5589502A (en) * | 1994-11-17 | 1996-12-31 | Tanabe Seiyaku Co., Ltd. | Baccatin derivatives and processes for preparing the same |
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TW467896B (en) | 1993-03-19 | 2001-12-11 | Bristol Myers Squibb Co | Novel β-lactams, methods for the preparation of taxanes and sidechain-bearing taxanes |
GB9405400D0 (en) * | 1994-03-18 | 1994-05-04 | Erba Carlo Spa | Taxane derivatives |
US5489589A (en) * | 1994-12-07 | 1996-02-06 | Bristol-Myers Squibb Company | Amino acid derivatives of paclitaxel |
US5760251A (en) * | 1995-08-11 | 1998-06-02 | Sepracor, Inc. | Taxol process and compounds |
JP3737518B2 (en) | 1996-03-12 | 2006-01-18 | ピージー−ティーエックスエル カンパニー, エル.ピー. | Water-soluble paclitaxel prodrug |
EP0868422A1 (en) * | 1996-09-24 | 1998-10-07 | Marigen S.A. | Ultramicroemulsion of spontaneously dispersible concentrates of esters of baccatin-iii compounds with antitumor and antiviral effect |
WO1998017656A1 (en) | 1996-10-24 | 1998-04-30 | Institute Armand-Frappier | A family of canadensol taxanes, the semi-synthetic preparation and therapeutic use thereof |
HUP0600533A2 (en) | 2001-11-30 | 2006-11-28 | Bristol Myers Squibb Co | Paclitaxel solvates |
WO2009141738A2 (en) | 2008-05-23 | 2009-11-26 | The University Of British Columbia | Modified drugs for use in liposomal nanoparticles |
CN102617517B (en) * | 2011-01-27 | 2015-11-18 | 李勤耕 | 7,10-O, O-diformazan Taxotere alcohol derivate and the application thereof that one class is new |
CN111004195B (en) * | 2019-12-03 | 2022-01-28 | 沈阳药科大学 | Cabazitaxel alkalescent derivative and preparation thereof |
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- 1993-04-30 JP JP5103820A patent/JPH069600A/en active Pending
- 1993-05-03 CA CA002095375A patent/CA2095375A1/en not_active Abandoned
- 1993-05-03 EP EP93401140A patent/EP0569281A1/en not_active Withdrawn
- 1993-09-29 US US08/128,949 patent/USH1487H/en not_active Abandoned
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Cited By (2)
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US5608073A (en) * | 1994-11-17 | 1997-03-04 | Tanabe Seiyaku Co., Ltd. | Baccatin derivatives and processes for preparing the same |
Also Published As
Publication number | Publication date |
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CA2095375A1 (en) | 1993-11-07 |
EP0569281A1 (en) | 1993-11-10 |
JPH069600A (en) | 1994-01-18 |
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