JPH07116193B2 - Novel antitumor compound - Google Patents
Novel antitumor compoundInfo
- Publication number
- JPH07116193B2 JPH07116193B2 JP20718087A JP20718087A JPH07116193B2 JP H07116193 B2 JPH07116193 B2 JP H07116193B2 JP 20718087 A JP20718087 A JP 20718087A JP 20718087 A JP20718087 A JP 20718087A JP H07116193 B2 JPH07116193 B2 JP H07116193B2
- Authority
- JP
- Japan
- Prior art keywords
- compound
- added
- water
- methanol
- nmr
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Lifetime
Links
- 150000001875 compounds Chemical class 0.000 title description 122
- 230000000259 anti-tumor effect Effects 0.000 title description 15
- -1 azido, amino Chemical group 0.000 claims description 17
- 239000001257 hydrogen Substances 0.000 claims description 7
- 229910052739 hydrogen Inorganic materials 0.000 claims description 7
- 125000003282 alkyl amino group Chemical group 0.000 claims description 6
- 125000004414 alkyl thio group Chemical group 0.000 claims description 5
- 125000003545 alkoxy group Chemical group 0.000 claims description 4
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 4
- 125000000687 hydroquinonyl group Chemical group C1(O)=C(C=C(O)C=C1)* 0.000 claims description 4
- 125000004356 hydroxy functional group Chemical group O* 0.000 claims description 4
- 125000005110 aryl thio group Chemical group 0.000 claims description 3
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims 1
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 156
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 108
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 57
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 54
- 239000000243 solution Substances 0.000 description 47
- 238000003756 stirring Methods 0.000 description 43
- 239000000203 mixture Substances 0.000 description 37
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 36
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 36
- 238000003786 synthesis reaction Methods 0.000 description 33
- 230000015572 biosynthetic process Effects 0.000 description 32
- 238000006243 chemical reaction Methods 0.000 description 27
- 150000003839 salts Chemical class 0.000 description 26
- SQGYOTSLMSWVJD-UHFFFAOYSA-N silver(1+) nitrate Chemical compound [Ag+].[O-]N(=O)=O SQGYOTSLMSWVJD-UHFFFAOYSA-N 0.000 description 22
- 238000011097 chromatography purification Methods 0.000 description 19
- IHSLHAZEJBXKMN-UHFFFAOYSA-L potassium nitrosodisulfonate Chemical compound [K+].[K+].[O-]S(=O)(=O)N([O])S([O-])(=O)=O IHSLHAZEJBXKMN-UHFFFAOYSA-L 0.000 description 19
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 16
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 15
- 238000004587 chromatography analysis Methods 0.000 description 15
- 239000002904 solvent Substances 0.000 description 15
- 239000008351 acetate buffer Substances 0.000 description 14
- RDOXTESZEPMUJZ-UHFFFAOYSA-N anisole Chemical compound COC1=CC=CC=C1 RDOXTESZEPMUJZ-UHFFFAOYSA-N 0.000 description 14
- 239000012043 crude product Substances 0.000 description 14
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 12
- DNJIEGIFACGWOD-UHFFFAOYSA-N ethanethiol Chemical compound CCS DNJIEGIFACGWOD-UHFFFAOYSA-N 0.000 description 12
- 239000012442 inert solvent Substances 0.000 description 12
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 11
- 229910001961 silver nitrate Inorganic materials 0.000 description 11
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 10
- 229940125904 compound 1 Drugs 0.000 description 10
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 10
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 9
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 9
- XHFGWHUWQXTGAT-UHFFFAOYSA-N dimethylamine hydrochloride Natural products CNC(C)C XHFGWHUWQXTGAT-UHFFFAOYSA-N 0.000 description 8
- IQDGSYLLQPDQDV-UHFFFAOYSA-N dimethylazanium;chloride Chemical compound Cl.CNC IQDGSYLLQPDQDV-UHFFFAOYSA-N 0.000 description 8
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 8
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 7
- 239000003054 catalyst Substances 0.000 description 7
- UZKWTJUDCOPSNM-UHFFFAOYSA-N methoxybenzene Substances CCCCOC=C UZKWTJUDCOPSNM-UHFFFAOYSA-N 0.000 description 7
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium on carbon Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 6
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical class CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- ILAHWRKJUDSMFH-UHFFFAOYSA-N boron tribromide Chemical compound BrB(Br)Br ILAHWRKJUDSMFH-UHFFFAOYSA-N 0.000 description 6
- 238000004440 column chromatography Methods 0.000 description 6
- 150000005208 1,4-dihydroxybenzenes Chemical class 0.000 description 5
- OPFJDXRVMFKJJO-ZHHKINOHSA-N N-{[3-(2-benzamido-4-methyl-1,3-thiazol-5-yl)-pyrazol-5-yl]carbonyl}-G-dR-G-dD-dD-dD-NH2 Chemical compound S1C(C=2NN=C(C=2)C(=O)NCC(=O)N[C@H](CCCN=C(N)N)C(=O)NCC(=O)N[C@H](CC(O)=O)C(=O)N[C@H](CC(O)=O)C(=O)N[C@H](CC(O)=O)C(N)=O)=C(C)N=C1NC(=O)C1=CC=CC=C1 OPFJDXRVMFKJJO-ZHHKINOHSA-N 0.000 description 5
- 239000007864 aqueous solution Substances 0.000 description 5
- 229940126086 compound 21 Drugs 0.000 description 5
- 238000004128 high performance liquid chromatography Methods 0.000 description 5
- 238000000034 method Methods 0.000 description 5
- 229910000027 potassium carbonate Inorganic materials 0.000 description 5
- 238000000746 purification Methods 0.000 description 5
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 5
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 4
- LSDPWZHWYPCBBB-UHFFFAOYSA-N Methanethiol Chemical compound SC LSDPWZHWYPCBBB-UHFFFAOYSA-N 0.000 description 4
- ITLHXEGAYQFOHJ-UHFFFAOYSA-N [diazo(phenyl)methyl]benzene Chemical compound C=1C=CC=CC=1C(=[N+]=[N-])C1=CC=CC=C1 ITLHXEGAYQFOHJ-UHFFFAOYSA-N 0.000 description 4
- 229940125782 compound 2 Drugs 0.000 description 4
- OPQARKPSCNTWTJ-UHFFFAOYSA-L copper(ii) acetate Chemical compound [Cu+2].CC([O-])=O.CC([O-])=O OPQARKPSCNTWTJ-UHFFFAOYSA-L 0.000 description 4
- IWZSHWBGHQBIML-ZGGLMWTQSA-N (3S,8S,10R,13S,14S,17S)-17-isoquinolin-7-yl-N,N,10,13-tetramethyl-2,3,4,7,8,9,11,12,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-3-amine Chemical compound CN(C)[C@H]1CC[C@]2(C)C3CC[C@@]4(C)[C@@H](CC[C@@H]4c4ccc5ccncc5c4)[C@@H]3CC=C2C1 IWZSHWBGHQBIML-ZGGLMWTQSA-N 0.000 description 3
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 3
- TVTJUIAKQFIXCE-HUKYDQBMSA-N 2-amino-9-[(2R,3S,4S,5R)-4-fluoro-3-hydroxy-5-(hydroxymethyl)oxolan-2-yl]-7-prop-2-ynyl-1H-purine-6,8-dione Chemical compound NC=1NC(C=2N(C(N(C=2N=1)[C@@H]1O[C@@H]([C@H]([C@H]1O)F)CO)=O)CC#C)=O TVTJUIAKQFIXCE-HUKYDQBMSA-N 0.000 description 3
- QBWKPGNFQQJGFY-QLFBSQMISA-N 3-[(1r)-1-[(2r,6s)-2,6-dimethylmorpholin-4-yl]ethyl]-n-[6-methyl-3-(1h-pyrazol-4-yl)imidazo[1,2-a]pyrazin-8-yl]-1,2-thiazol-5-amine Chemical compound N1([C@H](C)C2=NSC(NC=3C4=NC=C(N4C=C(C)N=3)C3=CNN=C3)=C2)C[C@H](C)O[C@H](C)C1 QBWKPGNFQQJGFY-QLFBSQMISA-N 0.000 description 3
- 241000124008 Mammalia Species 0.000 description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 3
- KGNDCEVUMONOKF-UGPLYTSKSA-N benzyl n-[(2r)-1-[(2s,4r)-2-[[(2s)-6-amino-1-(1,3-benzoxazol-2-yl)-1,1-dihydroxyhexan-2-yl]carbamoyl]-4-[(4-methylphenyl)methoxy]pyrrolidin-1-yl]-1-oxo-4-phenylbutan-2-yl]carbamate Chemical compound C1=CC(C)=CC=C1CO[C@H]1CN(C(=O)[C@@H](CCC=2C=CC=CC=2)NC(=O)OCC=2C=CC=CC=2)[C@H](C(=O)N[C@@H](CCCCN)C(O)(O)C=2OC3=CC=CC=C3N=2)C1 KGNDCEVUMONOKF-UGPLYTSKSA-N 0.000 description 3
- 125000004432 carbon atom Chemical group C* 0.000 description 3
- 229940125833 compound 23 Drugs 0.000 description 3
- 229940125846 compound 25 Drugs 0.000 description 3
- 229940125851 compound 27 Drugs 0.000 description 3
- 229940126214 compound 3 Drugs 0.000 description 3
- 238000002347 injection Methods 0.000 description 3
- 239000007924 injection Substances 0.000 description 3
- 230000000527 lymphocytic effect Effects 0.000 description 3
- 239000007800 oxidant agent Substances 0.000 description 3
- 239000001301 oxygen Substances 0.000 description 3
- 229910052760 oxygen Inorganic materials 0.000 description 3
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 3
- SUVIGLJNEAMWEG-UHFFFAOYSA-N propane-1-thiol Chemical compound CCCS SUVIGLJNEAMWEG-UHFFFAOYSA-N 0.000 description 3
- 239000011541 reaction mixture Substances 0.000 description 3
- 159000000000 sodium salts Chemical class 0.000 description 3
- RMVRSNDYEFQCLF-UHFFFAOYSA-N thiophenol Chemical compound SC1=CC=CC=C1 RMVRSNDYEFQCLF-UHFFFAOYSA-N 0.000 description 3
- UAOUIVVJBYDFKD-XKCDOFEDSA-N (1R,9R,10S,11R,12R,15S,18S,21R)-10,11,21-trihydroxy-8,8-dimethyl-14-methylidene-4-(prop-2-enylamino)-20-oxa-5-thia-3-azahexacyclo[9.7.2.112,15.01,9.02,6.012,18]henicosa-2(6),3-dien-13-one Chemical compound C([C@@H]1[C@@H](O)[C@@]23C(C1=C)=O)C[C@H]2[C@]12C(N=C(NCC=C)S4)=C4CC(C)(C)[C@H]1[C@H](O)[C@]3(O)OC2 UAOUIVVJBYDFKD-XKCDOFEDSA-N 0.000 description 2
- GLGNXYJARSMNGJ-VKTIVEEGSA-N (1s,2s,3r,4r)-3-[[5-chloro-2-[(1-ethyl-6-methoxy-2-oxo-4,5-dihydro-3h-1-benzazepin-7-yl)amino]pyrimidin-4-yl]amino]bicyclo[2.2.1]hept-5-ene-2-carboxamide Chemical compound CCN1C(=O)CCCC2=C(OC)C(NC=3N=C(C(=CN=3)Cl)N[C@H]3[C@H]([C@@]4([H])C[C@@]3(C=C4)[H])C(N)=O)=CC=C21 GLGNXYJARSMNGJ-VKTIVEEGSA-N 0.000 description 2
- SZUVGFMDDVSKSI-WIFOCOSTSA-N (1s,2s,3s,5r)-1-(carboxymethyl)-3,5-bis[(4-phenoxyphenyl)methyl-propylcarbamoyl]cyclopentane-1,2-dicarboxylic acid Chemical compound O=C([C@@H]1[C@@H]([C@](CC(O)=O)([C@H](C(=O)N(CCC)CC=2C=CC(OC=3C=CC=CC=3)=CC=2)C1)C(O)=O)C(O)=O)N(CCC)CC(C=C1)=CC=C1OC1=CC=CC=C1 SZUVGFMDDVSKSI-WIFOCOSTSA-N 0.000 description 2
- GHYOCDFICYLMRF-UTIIJYGPSA-N (2S,3R)-N-[(2S)-3-(cyclopenten-1-yl)-1-[(2R)-2-methyloxiran-2-yl]-1-oxopropan-2-yl]-3-hydroxy-3-(4-methoxyphenyl)-2-[[(2S)-2-[(2-morpholin-4-ylacetyl)amino]propanoyl]amino]propanamide Chemical compound C1(=CCCC1)C[C@@H](C(=O)[C@@]1(OC1)C)NC([C@H]([C@@H](C1=CC=C(C=C1)OC)O)NC([C@H](C)NC(CN1CCOCC1)=O)=O)=O GHYOCDFICYLMRF-UTIIJYGPSA-N 0.000 description 2
- QFLWZFQWSBQYPS-AWRAUJHKSA-N (3S)-3-[[(2S)-2-[[(2S)-2-[5-[(3aS,6aR)-2-oxo-1,3,3a,4,6,6a-hexahydrothieno[3,4-d]imidazol-4-yl]pentanoylamino]-3-methylbutanoyl]amino]-3-(4-hydroxyphenyl)propanoyl]amino]-4-[1-bis(4-chlorophenoxy)phosphorylbutylamino]-4-oxobutanoic acid Chemical compound CCCC(NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@@H](NC(=O)CCCCC1SC[C@@H]2NC(=O)N[C@H]12)C(C)C)P(=O)(Oc1ccc(Cl)cc1)Oc1ccc(Cl)cc1 QFLWZFQWSBQYPS-AWRAUJHKSA-N 0.000 description 2
- WZZBNLYBHUDSHF-DHLKQENFSA-N 1-[(3s,4s)-4-[8-(2-chloro-4-pyrimidin-2-yloxyphenyl)-7-fluoro-2-methylimidazo[4,5-c]quinolin-1-yl]-3-fluoropiperidin-1-yl]-2-hydroxyethanone Chemical compound CC1=NC2=CN=C3C=C(F)C(C=4C(=CC(OC=5N=CC=CN=5)=CC=4)Cl)=CC3=C2N1[C@H]1CCN(C(=O)CO)C[C@@H]1F WZZBNLYBHUDSHF-DHLKQENFSA-N 0.000 description 2
- UNILWMWFPHPYOR-KXEYIPSPSA-M 1-[6-[2-[3-[3-[3-[2-[2-[3-[[2-[2-[[(2r)-1-[[2-[[(2r)-1-[3-[2-[2-[3-[[2-(2-amino-2-oxoethoxy)acetyl]amino]propoxy]ethoxy]ethoxy]propylamino]-3-hydroxy-1-oxopropan-2-yl]amino]-2-oxoethyl]amino]-3-[(2r)-2,3-di(hexadecanoyloxy)propyl]sulfanyl-1-oxopropan-2-yl Chemical compound O=C1C(SCCC(=O)NCCCOCCOCCOCCCNC(=O)COCC(=O)N[C@@H](CSC[C@@H](COC(=O)CCCCCCCCCCCCCCC)OC(=O)CCCCCCCCCCCCCCC)C(=O)NCC(=O)N[C@H](CO)C(=O)NCCCOCCOCCOCCCNC(=O)COCC(N)=O)CC(=O)N1CCNC(=O)CCCCCN\1C2=CC=C(S([O-])(=O)=O)C=C2CC/1=C/C=C/C=C/C1=[N+](CC)C2=CC=C(S([O-])(=O)=O)C=C2C1 UNILWMWFPHPYOR-KXEYIPSPSA-M 0.000 description 2
- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical class NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 description 2
- YSUIQYOGTINQIN-UZFYAQMZSA-N 2-amino-9-[(1S,6R,8R,9S,10R,15R,17R,18R)-8-(6-aminopurin-9-yl)-9,18-difluoro-3,12-dihydroxy-3,12-bis(sulfanylidene)-2,4,7,11,13,16-hexaoxa-3lambda5,12lambda5-diphosphatricyclo[13.2.1.06,10]octadecan-17-yl]-1H-purin-6-one Chemical compound NC1=NC2=C(N=CN2[C@@H]2O[C@@H]3COP(S)(=O)O[C@@H]4[C@@H](COP(S)(=O)O[C@@H]2[C@@H]3F)O[C@H]([C@H]4F)N2C=NC3=C2N=CN=C3N)C(=O)N1 YSUIQYOGTINQIN-UZFYAQMZSA-N 0.000 description 2
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 2
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 2
- QIGBRXMKCJKVMJ-UHFFFAOYSA-N Hydroquinone Chemical compound OC1=CC=C(O)C=C1 QIGBRXMKCJKVMJ-UHFFFAOYSA-N 0.000 description 2
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical class C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 2
- 229910002651 NO3 Inorganic materials 0.000 description 2
- NHNBFGGVMKEFGY-UHFFFAOYSA-N Nitrate Chemical compound [O-][N+]([O-])=O NHNBFGGVMKEFGY-UHFFFAOYSA-N 0.000 description 2
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 2
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical class C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 2
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 2
- PXIPVTKHYLBLMZ-UHFFFAOYSA-N Sodium azide Chemical compound [Na+].[N-]=[N+]=[N-] PXIPVTKHYLBLMZ-UHFFFAOYSA-N 0.000 description 2
- HEMHJVSKTPXQMS-DYCDLGHISA-M Sodium hydroxide-d Chemical compound [Na+].[2H][O-] HEMHJVSKTPXQMS-DYCDLGHISA-M 0.000 description 2
- LJOOWESTVASNOG-UFJKPHDISA-N [(1s,3r,4ar,7s,8s,8as)-3-hydroxy-8-[2-[(4r)-4-hydroxy-6-oxooxan-2-yl]ethyl]-7-methyl-1,2,3,4,4a,7,8,8a-octahydronaphthalen-1-yl] (2s)-2-methylbutanoate Chemical compound C([C@H]1[C@@H](C)C=C[C@H]2C[C@@H](O)C[C@@H]([C@H]12)OC(=O)[C@@H](C)CC)CC1C[C@@H](O)CC(=O)O1 LJOOWESTVASNOG-UFJKPHDISA-N 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 229910052783 alkali metal Inorganic materials 0.000 description 2
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 2
- XRWSZZJLZRKHHD-WVWIJVSJSA-N asunaprevir Chemical compound O=C([C@@H]1C[C@H](CN1C(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)(C)C)OC1=NC=C(C2=CC=C(Cl)C=C21)OC)N[C@]1(C(=O)NS(=O)(=O)C2CC2)C[C@H]1C=C XRWSZZJLZRKHHD-WVWIJVSJSA-N 0.000 description 2
- 239000007853 buffer solution Substances 0.000 description 2
- 229910052799 carbon Inorganic materials 0.000 description 2
- 229940125797 compound 12 Drugs 0.000 description 2
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- 229940125758 compound 15 Drugs 0.000 description 2
- 229940125961 compound 24 Drugs 0.000 description 2
- 229940127204 compound 29 Drugs 0.000 description 2
- 229940125877 compound 31 Drugs 0.000 description 2
- 239000012649 demethylating agent Substances 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
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- 230000000694 effects Effects 0.000 description 2
- 238000002451 electron ionisation mass spectrometry Methods 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 239000008103 glucose Substances 0.000 description 2
- 150000002431 hydrogen Chemical class 0.000 description 2
- 239000005457 ice water Substances 0.000 description 2
- 239000002198 insoluble material Substances 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 239000012046 mixed solvent Substances 0.000 description 2
- 150000007530 organic bases Chemical class 0.000 description 2
- 230000003647 oxidation Effects 0.000 description 2
- 238000007254 oxidation reaction Methods 0.000 description 2
- 239000008194 pharmaceutical composition Substances 0.000 description 2
- 239000008363 phosphate buffer Substances 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 239000001632 sodium acetate Substances 0.000 description 2
- 235000017281 sodium acetate Nutrition 0.000 description 2
- GGCZERPQGJTIQP-UHFFFAOYSA-N sodium;9,10-dioxoanthracene-2-sulfonic acid Chemical compound [Na+].C1=CC=C2C(=O)C3=CC(S(=O)(=O)O)=CC=C3C(=O)C2=C1 GGCZERPQGJTIQP-UHFFFAOYSA-N 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- WMXCDAVJEZZYLT-UHFFFAOYSA-N tert-butylthiol Chemical compound CC(C)(C)S WMXCDAVJEZZYLT-UHFFFAOYSA-N 0.000 description 2
- 238000004809 thin layer chromatography Methods 0.000 description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
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Landscapes
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
【発明の詳細な説明】 産業上の利用分野 本発明は新規な抗腫瘍性化合物に関する。TECHNICAL FIELD The present invention relates to a novel antitumor compound.
従来の技術 DC-52は式 で表される抗生物質であり、各種細菌に抗菌活性を示す
ほか、リンホサイティック・リューケミアP388等に抗腫
瘍活性を示す（特開昭57-17089）。Conventional technology DC-52 is a formula It has an antibacterial activity against various bacteria and an antitumor activity against lymphocytic leukemia P388 and the like (JP-A-57-17089).
一方、DC-52の誘導体として、式 で表され、抗腫瘍活性を有するDX-52-1が知られている
（特開昭59-210086）。On the other hand, as a derivative of DC-52, the formula And DX-52-1 having antitumor activity is known (JP-A-59-210086).
発明が解決しようとする問題点 他の抗腫瘍抗生物質と同様、さらに優れた抗腫瘍活性を
有するDC-52誘導体は常に求められている。Problems to be Solved by the Invention As with other antitumor antibiotics, there is a constant need for DC-52 derivatives that have even better antitumor activity.
問題点を解決するための手段 本発明の優れた抗腫瘍活性を有する化合物は次の式
（Ｉ） （式中、R1、R2は同一もしくは異なって水素、低級アル
コキシ、アジド、アミノ、低級アルキルアミノ、ジ低級
アルキルアミノ、環状アミノ、低級アルキルチオ又は非
置換もしくは置換のアリールチオであり、Ｘ、ＹはＸが
ヒドロキシでＹがシアノであるか、または両者一体とな
って−Ｘ−Ｙ−として−Ｏ−を表す）〔以下、化合物
（Ｉ）という。他の式番号の化合物についても同様〕で
表されるか、又はそのヒドロキノン型として表される。Means for Solving the Problems The compounds having excellent antitumor activity of the present invention are represented by the following formula (I): (Wherein R 1 and R 2 are the same or different and each is hydrogen, lower alkoxy, azido, amino, lower alkylamino, dilower alkylamino, cyclic amino, lower alkylthio or unsubstituted or substituted arylthio, and X, Y Is hydroxy and Y is cyano, or they are combined together to represent -O- as -XY-) [hereinafter referred to as compound (I). The same applies to compounds of other formula numbers] or its hydroquinone form.
式（Ｉ）のR1、R2の定義中、低級アルコキシは炭素数１
〜４のアルコキシ、例えば、メトキシ、エトキシ、ｉ−
プロポキシ、ｎ−プロポキシ、ｎ−ブチロキシ等、低級
アルキルアミノは炭素数１〜３のアルキルアミノ、例え
ばメチルアミノ、プロピルアミノ等、ジ低級アルキルア
ミノは炭素数１〜３のジアルキルアミノ、例えば、ジメ
チルアミノ、ジエチルアミノ等、環状アミノは３〜６員
環の環状アミノ、例えば、アジリジノ、アゼチジノ、ピ
ロリジノ、ピペリジノ等、低級アルキルチオは炭素数１
〜４のアルキルチオ、例えば、メチルチオ、エチルチ
オ、ｎ−プロピルチオ、ｉ−プロピルチオ、ｎ−ブチル
チオ等、非置換もしくは置換のアリールチオはフェニル
チオ、ｐ−フルオロフェニルチオ、ｐ−メトキシフェニ
ルチオ等を包含する。In the definition of R 1 and R 2 in formula (I), lower alkoxy has 1 carbon atom.
~ 4 alkoxy, for example, methoxy, ethoxy, i-
Lower alkylamino such as propoxy, n-propoxy, n-butyroxy and the like is alkylamino having 1 to 3 carbon atoms, for example, methylamino, propylamino and the like; , Diethylamino, etc., cyclic amino is a 3- to 6-membered cyclic amino, for example, aziridino, azetidino, pyrrolidino, piperidino, etc., lower alkylthio has 1 carbon atom.
~ 4 alkylthio, such as methylthio, ethylthio, n-propylthio, i-propylthio, n-butylthio and the like, unsubstituted or substituted arylthio includes phenylthio, p-fluorophenylthio, p-methoxyphenylthio and the like.
化合物（Ｉ）又はそのヒドロキノン体の薬理上許容され
る塩も化合物（Ｉ）又はそのヒドロキノン体と同様優れ
た抗腫瘍活性を有する。かかる塩は薬理上許容される酸
付加塩、アルカリ金属塩、アルカリ土類金属塩、アンモ
ニウム塩及び薬理上許容される有機塩基付加塩を包含す
る。薬理上許容される酸付加塩は薬理上許容される無機
酸付加塩例えば、塩酸塩、臭化水素酸塩、ヨウ化水素酸
塩、硫酸塩、リン酸塩、硝酸塩等、及び薬理上許容され
る有機酸付加塩例えば酢酸塩、安息香酸塩、マレイン酸
塩、フマル酸塩、コハク酸塩、酒石酸塩、クエン酸塩、
シュウ酸塩、グリオキシル酸塩、アスパラギン酸塩、メ
タンスルホン酸塩、エタンスルホン酸塩、プロパンスル
ホン酸塩、メタンジスルホン酸塩、α，β−エタンジス
ルホン酸塩、ベンゼンスルホン酸塩等を包含する。アル
カリ金属塩はナトリウム塩、カリウム塩等、アルカリ土
類金属塩はカルシウム塩、マグネシウム塩等を包含す
る。薬理上許容される有機塩基付加塩はエタノールアミ
ン、トリエチルアミン、モルホリン、ピペリジン等の付
加塩を包含する。The pharmacologically acceptable salt of compound (I) or its hydroquinone form also has excellent antitumor activity as in compound (I) or its hydroquinone form. Such salts include pharmaceutically acceptable acid addition salts, alkali metal salts, alkaline earth metal salts, ammonium salts and pharmaceutically acceptable organic base addition salts. The pharmacologically acceptable acid addition salt is a pharmacologically acceptable inorganic acid addition salt, for example, hydrochloride, hydrobromide, hydroiodide, sulfate, phosphate, nitrate, and the like. Organic acid addition salts such as acetate, benzoate, maleate, fumarate, succinate, tartrate, citrate,
It includes oxalate, glyoxylate, aspartate, methanesulfonate, ethanesulfonate, propanesulfonate, methanedisulfonate, α, β-ethanedisulfonate, benzenesulfonate and the like. The alkali metal salt includes sodium salt, potassium salt and the like, and the alkaline earth metal salt includes calcium salt, magnesium salt and the like. The pharmaceutically acceptable organic base addition salts include addition salts of ethanolamine, triethylamine, morpholine, piperidine and the like.
次に化合物（Ｉ）及びそのヒドロキノン体の製造法につ
いて説明する。Next, a method for producing the compound (I) and its hydroquinone derivative will be described.
化合物（Ｉ）及びそのヒドロキノン体は次の工程によっ
て製造することができる。なお工程中（Ｉ−１）、（Ｉ
−２）等は化合物（Ｉ）の定義に包含されることを示
す。Compound (I) and its hydroquinone derivative can be produced by the following steps. During the process (I-1), (I
-2) and the like are included in the definition of compound (I).
〔式中、R1′及びR2′はそれぞれ水素を除くR1及びR2で
あり、R1、R2、Ｘ及びＹは式（Ｉ）におけると同義であ
る。又、化合物（Ｉ−４）は化合物（Ｉ−１）＋（Ｉ−
２）＋（Ｉ−３）、化合物（Ｉ）は化合物（Ｉ−４）＋
（Ｉ−５）、化合物（Ｉ′）は化合物（Ｉ）のヒドロキ
ノン型化合物である〕 工程１ まず、DX-52-1とデメチル化剤とを不活性溶媒中で反応
させ、ついで反応液を氷水中に注ぐことにより化合物
（II）を製造する。デメチル化剤は三臭化ホウ素、三塩
化ホウ素、塩化アルミニウム−エタンチオール等を包含
し、通常DX-52-1の３〜７当量使用する。不活性溶媒は
塩化メチレン、クロロホルム等のハロゲン化アルカン、
トルエン等の芳香族炭化水素等を包含する。反応は通常
−78〜30℃で行い、数時間〜２日間で終了する。ついで
反応液を氷水に注ぎ、水層のpHを6.5〜7.5に調整した
後、青酸ソーダを加え、水層を分離濃縮し、カラムクロ
マトグラフィーに付すことにより化合物（II）を得る。 [In the formula, R 1 ′ and R 2 ′ are R 1 and R 2 excluding hydrogen, respectively, and R 1 , R 2 , X and Y have the same meanings as in formula (I). Further, the compound (I-4) is the compound (I-1) + (I-
2) + (I-3), compound (I) is compound (I-4) +
(I-5) and compound (I ′) are hydroquinone type compounds of compound (I)] Step 1 First, DX-52-1 and a demethylating agent are reacted in an inert solvent, and then the reaction solution is Compound (II) is produced by pouring into ice water. The demethylating agent includes boron tribromide, boron trichloride, aluminum chloride-ethanethiol, etc., and is usually used in 3 to 7 equivalents of DX-52-1. Inert solvents are halogenated alkanes such as methylene chloride and chloroform,
Including aromatic hydrocarbons such as toluene. The reaction is usually performed at -78 to 30 ° C and is completed in several hours to 2 days. Then, the reaction solution is poured into ice water, the pH of the aqueous layer is adjusted to 6.5 to 7.5, sodium cyanide is added, the aqueous layer is separated and concentrated, and subjected to column chromatography to obtain the compound (II).
工程２ 化合物（II）を不活性溶媒中フレミー塩（ニトロソジス
ルホン酸カリウム）で酸化することにより化合物（Ｉ−
１）を製造する。フレミー塩は通常化合物（II）の２〜
５当量使用する。Step 2 Compound (II) was oxidized with a Fremy salt (potassium nitrosodisulfonate) in an inert solvent to give compound (I-
1) is manufactured. Fremy's salt is usually 2 to 3 of the compound (II).
Use 5 equivalents.
不活性溶媒としては、アセトニトリル、メタノール、エ
タノール、テトラヒドロフラン、ジオキサン、ジメトキ
シエタン等の有機溶媒と水との混合溶媒が用いられる。
反応は通常室温で行い、１〜10時間で終了する。精製は
カラムクロマトグラフィーやHPLGにより行う。As the inert solvent, a mixed solvent of water with an organic solvent such as acetonitrile, methanol, ethanol, tetrahydrofuran, dioxane or dimethoxyethane is used.
The reaction is usually performed at room temperature and is completed in 1 to 10 hours. Purification is performed by column chromatography or HPLG.
工程３ 本工程は実際には次の２段階反応で進行する。Step 3 This step actually proceeds in the following two-step reaction.
すなわち化合物（Ｉ−１）と化合物（III）とを不活性
溶媒中で反応させ、反応液中に酸化剤を添加して酸化す
るか、化合物（Ｉ−１）と化合物（III）との反応を酸
化剤の存在下に行うことによって化合物（Ｉ−２）を得
る。化合物（III）は通常化合物（Ｉ−１）の１〜６当
量使用する。不活性溶媒としては水、アセトニトリル、
テトラヒドロフラン、ジオキサン、ジメトキシエタン、
メタノール、エタノール、ジメチルホルムアミド等が、
単独又は混合して用いられる。酸化剤はフレミー塩、塩
化第二鉄、四酢酸鉛、三トリフルオロ酢酸タリウム、硝
酸第二セリウムアンモニウム、酸素、酢酸第二銅等を包
含し、通常化合物（Ｉ−１）の１〜３当量使用する。化
合物（Ｉ−１）と化合物（III）との反応にひきつづき
酸化する場合、反応は通常−10〜30℃で30分〜３時間行
い、続く酸化は通常同様の温度で30分〜４時間行う。ま
た酸化条件下に化合物（Ｉ−１）と化合物（III）とを
反応させる場合は反応は通常−10〜50℃で１時間〜15日
間行う。 That is, the compound (I-1) and the compound (III) are reacted in an inert solvent and an oxidizing agent is added to the reaction solution to oxidize, or the compound (I-1) and the compound (III) are reacted. Is carried out in the presence of an oxidizing agent to obtain the compound (I-2). The compound (III) is usually used in 1 to 6 equivalents of the compound (I-1). Water, acetonitrile, as an inert solvent,
Tetrahydrofuran, dioxane, dimethoxyethane,
Methanol, ethanol, dimethylformamide, etc.
Used alone or as a mixture. The oxidizing agent includes Flemmy's salt, ferric chloride, lead tetraacetate, thallium trifluoroacetate, ammonium ceric nitrate, oxygen, cupric acetate, etc., and is usually 1 to 3 equivalents of compound (I-1). use. When oxidation is continued following the reaction between compound (I-1) and compound (III), the reaction is usually carried out at -10 to 30 ° C for 30 minutes to 3 hours, and the subsequent oxidation is usually carried out at the same temperature for 30 minutes to 4 hours. . When compound (I-1) and compound (III) are reacted under oxidizing conditions, the reaction is usually carried out at -10 to 50 ° C for 1 hour to 15 days.
反応の後処理は、反応液にpH3〜４の緩衝液を加え、減
圧下に濃縮するか、またはクロロホルム、酢酸エチル等
の非水溶性溶媒で抽出し、飽和食塩水等で洗浄した後、
抽出液を濃縮してから精製する。精製はカラムクロマト
グラフィー、TLC、HPLC等によって行うことができる。For the post-treatment of the reaction, after adding a buffer solution having a pH of 3 to 4 to the reaction solution and concentrating it under reduced pressure, or extracting with a non-water-soluble solvent such as chloroform or ethyl acetate, and washing with a saturated saline solution or the like,
The extract is concentrated and then purified. Purification can be performed by column chromatography, TLC, HPLC and the like.
工程４ 化合物（IV）を用いて工程３と同様の操作を行って化合
物（Ｉ−３）を得る。精製も同様でよい。Step 4 Using the compound (IV), the same operation as in Step 3 is performed to obtain the compound (I-3). Purification may be the same.
工程５ 本工程はは次の２段階反応で進行する。Step 5 This step proceeds in the following two-step reaction.
まず化合物（Ｉ−４）を水又は親水性溶媒中銀塩の存在
下保持することにより化合物（Ｉ−５′）とする。 First, the compound (I-4) is retained in water or a hydrophilic solvent in the presence of a silver salt to give a compound (I-5 ′).
親水性溶媒はアセトニトリル、メタノール、エタノー
ル、テトラヒドロフラン、ジオキサン等を包含し、これ
らは単独もしくは組み合わせて用いられる。銀塩は硝酸
銀、塩素酸銀、過塩素酸銀、フッ化銀等を包含する。銀
塩の使用量は通常ＸがヒドロキシでＹがシアノである化
合物（Ｉ−４）の１当量でよいが、反応時間の短縮、化
合物（Ｉ−５′）の収率向上のために３当量ぐらいまで
過剰に用いてもよい。反応は通常０〜30℃で行い、30分
〜数時間で終了する。The hydrophilic solvent includes acetonitrile, methanol, ethanol, tetrahydrofuran, dioxane and the like, and these are used alone or in combination. Silver salts include silver nitrate, silver chlorate, silver perchlorate, silver fluoride and the like. The silver salt may be used in an amount of 1 equivalent of the compound (I-4) in which X is hydroxy and Y is cyano, but 3 equivalents are used for shortening the reaction time and improving the yield of the compound (I-5 ′). It may be used in excess. The reaction is usually carried out at 0 to 30 ° C and is completed in 30 minutes to several hours.
反応後、反応液を過後、濃縮し、カラムクロマトグラ
フィー、TLC、HPLC等によって精製を行う。After the reaction, the reaction solution is filtered, concentrated, and purified by column chromatography, TLC, HPLC and the like.
化合物（Ｉ−５′）は乾燥すると分子内脱水して化合物
（Ｉ−５）となる。When the compound (I-5 ') is dried, it undergoes intramolecular dehydration to give the compound (I-5).
工程６ 化合物（Ｉ）を不活性溶媒中接触水素添加することによ
り化合物（Ｉ′）を得る。本反応に用いられる触媒は、
Pd-C、PtO2等を包含する。触媒は化合物（Ｉ）の20〜40
％（w/w）使用する。不活性溶媒としては水、メタノー
ル、エタノール、アセトニトリル、テトラヒドロフラ
ン、酢酸等が単独もしくは混合して用いられる。反応は
通常０〜40℃で行い、15分〜３時間で終了する。Step 6 Compound (I ') is obtained by catalytic hydrogenation of compound (I) in an inert solvent. The catalyst used in this reaction is
Pd-C, PtO 2 and the like are included. The catalyst is 20-40 of compound (I)
% (W / w) used. As the inert solvent, water, methanol, ethanol, acetonitrile, tetrahydrofuran, acetic acid, etc. may be used alone or in combination. The reaction is usually carried out at 0 to 40 ° C and is completed in 15 minutes to 3 hours.
工程７（別法） 以上の工程の他に化合物（II）のカルボキシルをエステ
ル化した後工程２〜６と同様に操作して、最後に脱エス
テル化して化合物（Ｉ）もしくは（Ｉ′）を得てもよ
い。かかる方法の採用により反応の円滑化、収率の向
上、単離精製の容易化が図られる場合がある。すなわ
ち、まず化合物（II）とジフェニルジアゾメタンとを不
活性溶媒中反応させて式（II′） で表される化合物を製造する。ジフェニルジアゾメタン
は通常化合物（II）の１〜４当量使用する。不活性溶媒
としてはクロロホルム、塩化メチレン、メタノール、エ
タノール、テトラヒドロフラン等が単独もしくは混合し
て用いられる。Step 7 (Alternative Method) In addition to the steps above, esterification of the carboxyl of compound (II) is followed by the same procedure as steps 2 to 6, and finally deesterification to give compound (I) or (I ′). You may get it. Adopting such a method may facilitate the reaction, improve the yield, and facilitate the isolation and purification. That is, first, the compound (II) and diphenyldiazomethane are reacted in an inert solvent to give the compound of the formula (II ′) A compound represented by Diphenyldiazomethane is usually used in 1 to 4 equivalents of compound (II). As the inert solvent, chloroform, methylene chloride, methanol, ethanol, tetrahydrofuran, etc. may be used alone or in combination.
反応は通常室温で行い１〜数時間で終了する。精製はク
ロマトグラフィーや再結晶により行う。一方、化合物
（Ｉ）又は（Ｉ′）のジフェニルメチルエステルは通常
の酸加水分解反応に付すことにより化合物（Ｉ）または
（Ｉ′）にそれぞれ変換することができる。このような
方法は例えばグリーン著、プロテクティブ・グループス
・イン・オーガニック・シンセシス174（1981）（ジョ
ンウイリー・アンド・サンズインコーポレイテッド）に
記載されている。好ましくは化合物（Ｉ）又は（Ｉ′）
のジフェニルメチルエステルとトリフルオロ酢酸とを無
溶媒で又は不活性溶媒中反応させることによりそれぞれ
化合物（Ｉ）又は（Ｉ′）を得る。不活性溶媒は塩化メ
チレン、トルエン等を包含する。トリフルオロ酢酸は原
料化合物の５〜100当量使用するのが適当である。本反
応を原料化合物の１〜50当量のアニソール、フェノー
ル、ハイドロキノン、エタンチオール等の存在下に行う
場合には好ましくない副産物の生成を抑えることができ
る。反応は通常０℃から室温で行い30分〜８時間で終了
する。The reaction is usually performed at room temperature and is completed in 1 to several hours. Purification is performed by chromatography or recrystallization. On the other hand, the diphenylmethyl ester of the compound (I) or (I ′) can be converted into the compound (I) or (I ′) by subjecting it to an ordinary acid hydrolysis reaction. Such a method is described, for example, in Green, Protective Groups in Organic Synthesis 174 (1981) (John Willie and Sons Incorporated). Preferably compound (I) or (I ′)
The compound (I) or (I ′) is obtained by reacting the diphenylmethyl ester of 1 with trifluoroacetic acid without solvent or in an inert solvent. Inert solvents include methylene chloride, toluene and the like. Trifluoroacetic acid is suitably used in an amount of 5 to 100 equivalents of the starting compound. When this reaction is carried out in the presence of 1 to 50 equivalents of the starting compound in the presence of anisole, phenol, hydroquinone, ethanethiol or the like, the production of undesirable by-products can be suppressed. The reaction is usually carried out at 0 ° C to room temperature and is completed in 30 minutes to 8 hours.
反応終了後、反応液を濃縮しカラムクロマトグラフィ
ー、HPLC等によって精製を行う。あるいは反応液を濃縮
後pH4の緩衝液を加え、クロロホルム、酢酸エチル等の
非水溶性溶媒で化合物（Ｉ）又は（Ｉ′）を抽出し、抽
出液を濃縮後カラムクロマトグラフィー、HPLC等に付し
て精製を行う。After completion of the reaction, the reaction solution is concentrated and purified by column chromatography, HPLC and the like. Alternatively, after concentrating the reaction solution, a buffer solution of pH 4 is added, the compound (I) or (I ′) is extracted with a non-water-soluble solvent such as chloroform or ethyl acetate, and the extract is concentrated and subjected to column chromatography, HPLC, etc. And purify.
化合物（Ｉ）、そのヒドロキノン体及びそれらの薬理上
許容される塩はリンホサイティック・リューケミアP-38
8等に対し強い抗腫瘍活性を有し、人を含む哺乳動物の
抗腫瘍剤として有用であると考えられる。かかる本発明
化合物中、式（Ｉ）でR1、R2が同一もしくは異なった低
級アルキルチオでＸがヒドロキシでＹがシアノであるか
又は両者一体となって−Ｘ−Ｙ−として−Ｏ−である化
合物及びその薬理上許容される塩は抗腫瘍活性が特に優
れている。Compound (I), its hydroquinone derivative and their pharmacologically acceptable salts are Lymphocytic rheuchemia P-38.
It has a strong antitumor activity against 8 etc. and is considered to be useful as an antitumor agent for mammals including humans. In the compound of the present invention, in formula (I), R 1 and R 2 are the same or different lower alkylthio, X is hydroxy and Y is cyano, or both are combined to form —X—Y— which is —O—. Certain compounds and their pharmaceutically acceptable salts have particularly good antitumor activity.
次に化合物（Ｉ）の薬理活性を実験例で説明する。Next, the pharmacological activity of compound (I) will be described with reference to experimental examples.
実験例１ 抗腫瘍活性 代表的化合物（Ｉ）のリンホサイティック・リューケミ
アP-388に対する抗腫瘍活性を第１表に示す。Experimental Example 1 Antitumor activity Table 1 shows the antitumor activity of the representative compound (I) against Lymphocytic rheuchemia P-388.
実験方法は以下の通りである。体重約22gのCDF雄マウス
１群５匹に、リンホサイティック・リューケミアP-388
腫瘍細胞１×106個を腹腔内移植した。移植後24時間後
に、薬剤のリン酸緩衝生理食塩水溶液0.2mlを１回腹腔
内に投与した。薬剤の延命効果をT/Cで示した。 The experimental method is as follows. Five CDF male mice each weighing about 22 g were treated with Lymphocytic rheuchemia P-388.
1 × 10 6 tumor cells were intraperitoneally transplanted. Twenty-four hours after transplantation, 0.2 ml of a phosphate buffered saline solution of the drug was intraperitoneally administered once. The life-prolonging effect of the drug was shown by T / C.
化合物（Ｉ）又はその薬理上許容される塩は単独で又は
通常少なくとも１種の製剤上許容される補助剤と共に抗
腫瘍組成物として用いることができる。例えば化合物
（Ｉ）もしくはその塩を生理食塩水やグルコース、ラク
トース、マンニトール等の水溶液に溶解して注射剤とし
て適当な医薬組成物とする。又は化合物（Ｉ）又はその
塩を常法に従って凍結乾燥し、これに塩化ナトリウムを
加えることによって粉末注射剤を作成する。本医薬組成
物は必要に応じ、製剤分野で周知の添加剤、例えば製剤
上許容される塩等を含有することができる。本組成物の
投与量は患者の年令、症状等によって異なるが人を含む
哺乳動物に対し化合物（Ｉ）として0.003〜1mg/kg/day
投与する。投与は例えば１日１回（単回投与又は連日投
与）又は間欠的に１週間に１〜３回、2,3週間に１回静
脈注射により投与する。望まれる場合は同様の投与量・
投与方法で経口投与も可能である。経口投与形態は錠
剤、カプセル剤、粉末剤、顆粒剤、アンプル剤等を包含
し、これらは製薬分野で周知の医薬補助剤を含む。又、
望まれる場合は同様の投与量・投与形態で動脈内投与、
腹腔内投与、胸腔内投与等も可能である。The compound (I) or a pharmaceutically acceptable salt thereof can be used alone or together with at least one pharmaceutically acceptable auxiliary agent as an antitumor composition. For example, compound (I) or a salt thereof is dissolved in physiological saline or an aqueous solution of glucose, lactose, mannitol or the like to give a pharmaceutical composition suitable as an injection. Alternatively, compound (I) or a salt thereof is freeze-dried according to a conventional method, and sodium chloride is added thereto to prepare a powder injection. The pharmaceutical composition may contain additives well known in the field of formulation, such as pharmaceutically acceptable salts, if necessary. The dose of this composition varies depending on the age, symptoms, etc. of the patient, but 0.003 to 1 mg / kg / day as compound (I) for mammals including humans
Administer. The administration is, for example, once a day (single administration or continuous administration) or intermittently by intravenous injection once to three times a week and once every a few weeks. Similar dosage if desired
Oral administration is also possible. Oral dosage forms include tablets, capsules, powders, granules, ampoules and the like, which contain the pharmaceutical auxiliaries well known in the pharmaceutical field. or,
If desired, intraarterial administration with similar dose and dosage form,
Intraperitoneal administration, intrathoracic administration, etc. are also possible.
本抗腫瘍組成物は人を含む哺乳動物の白血病、胃癌、大
腸癌、肺癌、乳癌、子宮癌等に効果があると期待され
る。The antitumor composition is expected to be effective against leukemia, gastric cancer, colon cancer, lung cancer, breast cancer, uterine cancer and the like in mammals including humans.
実施例 代表的化合物（Ｉ）の構造及び化合物番号を第２表に示
す。Examples Structures and compound numbers of representative compounds (I) are shown in Table 2.
以下の実施例及び参考例で示される物理化学的データは
次の機器類によって測定された。 The physicochemical data shown in the following examples and reference examples were measured by the following instruments.
IR 日本分光 IR-810 NMR バリアン EM-390（90MHz） 日本電子 FX-100（100MHz） ブルーカー AM400（400MHz） MS 日立B-80 実施例1.化合物１の合成 参考例１で得られた化合物a4gを水40mlに溶解し1N酢酸
ナトリウム溶液12mlを加える。フレミー塩12.9gの水400
ml溶液を室温で滴下する。滴下後室温で40分攪拌後塩酸
を加えてpH4.0に調整する。濃縮後クロマト精製（ダイ
ヤイオンHP-20 水：メタノール＝1:0〜3:1）して化合物
1 2.08g（53.2％）を得る。13 C NMR（D2O）187.1、187.0、176.2、141.8、138.9、1
37.8、137.1、115.9、70.2、65.8、63.4、57.3、55.7、
54.8、41.0、40.4、28.5、24.21 H NMR（CD3OD）6.78（ｄ、1H、Ｊ＝10.2Hz）、6.75
（ｄ、1H、Ｊ＝10.2Hz）、4.27（ｄ、1H、Ｊ＝2.9H
z）、3.82（ｍ、1H）、3.79（dd、1H、Ｊ＝11.4、2.3H
z）、3.61（dd、1H、Ｊ＝11.4、3.7Hz）、3.52（dd、1
H、Ｊ＝6.4、2.6Hz）、3.51（bs、1H）、3.22（dd、1
H、Ｊ＝9.7、5.9Hz）、2.78（ｍ、1H）、2.73（ddd、1
H、Ｊ＝17.3、2.9、1.1Hz）、2.59（dt、1H）、2.33
（ｓ、3H）、2.15（ddd、1H、Ｊ＝17.3、10.9、2.6H
z）、2.02（dd、1H、Ｊ＝13.4、9.7Hz） SIMS 360（Ｍ＋３）＋ 実施例2.化合物２の合成 実施例１で得られた化合物1 3.0gをアセトニトリル80ml
とpH4.0 0.2Mの酢酸緩衝液80mlの混合溶媒に溶解す
る。メチルメルカプタンのナトリウム塩の15％水溶液4.
5mlを加えて室温で１時間攪拌する。フレミー塩4.5gと
水140mlを加える。40分攪拌後酢酸緩衝液20mlとメチル
メルカプタンのナトリウム塩水溶液3.0mlを加える。50
分攪拌後フレミー塩2.0gと水50mlを加える。30分攪拌後
さらにフレミー塩2.3gを加える。30分攪拌後、減圧濃縮
して過剰のメチルメルカプタンとアセトニトリルを留去
する。酢酸エチルで２回抽出し、飽和食塩水で洗浄、無
水硫酸ナトリウムで乾燥後、減圧濃縮して粗生成物3.56
gを得る。クロマト精製（ワコーゲルC-200 450mlクロロ
ホルム：メタノール＝1:0〜20:1）して化合物２ 3.22g
（85.5％）を得る。1 H NMR（CDCl3‐CD3OD）4.05（ｄ、1H、Ｊ＝2.7Hz）、
3.95（ｍ、1H）、3.79（dd、1H、Ｊ＝11.7、2.8Hz）、
3.65（dd、1H、Ｊ＝11.7、3.3Hz）、3.53（bs、1H）、
3.52（ｍ、1H）、3.05（dd、1H、Ｊ＝9.6、5.8Hz）、2.
91（bd、1H、Ｊ＝11.0Hz）、2.81（ddd、1H、Ｊ＝18.
0、3.0、1.2Hz）、2.63（ｍ、1H）、2.63（ｓ、3H）、
2.61（ｓ、3H）、2.36（ｓ、3H）、2.12（ddd、1H、Ｊ
＝18.0、11.0、2.8Hz）、1.95（dd、1H、Ｊ＝13.6、9.7
Hz） SIMS:452（Ｍ＋３）＋ 13 C NMR（CDCl3‐CD3OD）178.9、178.8、177.3、145.
4、144.9、142.6、140.0、116.9、69.8、64.6、63.2、5
8.1、56.8、56.1、42.5、41.8、28.7、25.4、18.2、18.
1 実施例3.化合物３の合成 実施例２で得られた化合物2 1.0gをアセトニトリル30ml
に溶解し、硝酸銀560mgを加えて室温で攪拌する。１時
間後硝酸銀をさらに300mg加えて40分攪拌し水を10ml加
える。セライトを用いて不溶物を減圧過し、液を濃
縮する。クロマト精製（ダイヤイオンHP-20 100ml水：
メタノール＝1:0〜1:1）して化合物3 769mg（81.8％）
を得る。1 H NMR（CD3OD）4.48（ｄ、1H、Ｊ＝3.2Hz）、4.22
（ｍ、1H）、4.14（bd、1H、Ｊ＝8.0Hz）、4.12（bs、1
H）、3.79（dd、1H、Ｊ＝11.5、2.8Hz）、3.56（dd、1
H、Ｊ＝11.5、3.9Hz）、3.27〜3.31（ｍ、2H）、2.83
（dd、1H、Ｊ＝17.3、2.3Hz）、2.78（ｓ、3H）、2.62
（ｍ、1H）、2.57（ｓ、3H）、2.55（ｓ、3H）、2.28
（dd、1H、Ｊ＝14.0、10.5Hz）、2.18（ddd、1H、Ｊ＝1
7.2、11.2、2.2Hz） SIMS:425（Ｍ＋３）＋ 13 C NMR（CD3OD）180.7、180.2、146.8、146.7、143.
8、142.7、90.9、72.7、66.5、64.9、56.2、54.3、43.
1、41.2、28.5、26.2、18.5 実施例4.化合物15の合成 実施例２で得られた化合物2 500mgをメタノール20mlに
溶解する。５％Pd-C 150mgを加え、水素気流下室温で
１時間攪拌する。セライトを用いて触媒を減圧過し、
液を溶媒留去して化合物15 486mg（96.7％）を得る。1 H NMR（CDCl3）4.21（ｍ、1H）、4.10（ｄ、1H、Ｊ＝
2.6Hz）、3.82（dd、1H、Ｊ＝11.1、2.8Hz）、3.70（d
d、1H、Ｊ＝11.1、3.5Hz）、3.56（ｓ、1H）、3.51
（ｍ、1H）、3.21（dd、1H、Ｊ＝9.3、5.8Hz）、2.98〜
3.02（ｍ、2H）、2.63（dt、1H、Ｊ＝13.2、6.6Hz）、
2.35〜2.40（ｍ、1H）、2.354（ｓ、6H）、2.347（ｓ、
3H）、2.04（dd、1H、Ｊ＝13.2、9.8Hz） SIMS:452（Ｍ＋１）＋ 13 C NMR（CDCl3‐CD3OD）178.2、147.9、147.2、124.
5、123.0、122.3、122.0、117.6、70.1、64.8、64.4、5
8.3、57.7、56.8、42.5、41.6、28.6、26.7、19.7、19.
6 実施例5.化合物16の合成 実施例３で得られた化合物3 200mgをメタノール3mlに溶
解し、pH4.0の酢酸緩衝液2mlを加える。10％Pd-C 60mg
を加え、水素気流下室温で１時間15分攪拌する。減圧
過で触媒を除き、液を濃縮後クロマト精製（ダイヤイ
オンHP-20 20ml水：メタノール＝1:0〜1:1）して化合物
16 160mg（79.6％）を得る。1 H NMR（CD3OD）4.57（ｄ、1H、Ｊ＝3.1Hz）、4.53（d
d、1H、Ｊ＝6.3、3.0Hz）、4.15（bs、1H）、4.12
（ｍ、1H）、3.75（dd、1H、Ｊ＝10.9、3.0Hz）、3.50
（dd、1H、Ｊ＝10.9、6.4Hz）、3.39（dd、1H、Ｊ＝10.
5、5.1Hz）、3.37（bd、1H、Ｊ＝12.3Hz）、3.08（dd、
1H、Ｊ＝15.4、2.6Hz）、2.80（ｓ、3H）、2.63（ｍ、1
H）、2.46（dd、1H、Ｊ＝14.0、10.6Hz）、2.43（dd、1
H、Ｊ＝15.2、12.0Hz）、2.33（ｓ、3H）、2.32（ｓ、3
H） SIMS:425（Ｍ＋１）＋ 13 C NMR（CD3OD）179.3、149.6、149.1、125.9、125.
4、124.9、124.4、92.1、73.1、67.3、66.7、56.7、55.
0、42.8、40.6、28.2、27.0、20.0、19.8 実施例6.化合物５の合成 実施例２で得られた化合物2 300mgをアセトニトリル3ml
に溶解する。ジメチルアミン塩酸塩の1M溶液3mlと炭酸
カリウムの1M溶液1.5mlを加え室温で攪拌する。４時間
後ジメチルアミン塩酸塩1M溶液1mlと炭酸カリウム1M溶
液0.5mlを加え、更に４時間攪拌する。pH4.0の酢酸緩衝
液5mlを加えアセトニトリルを留去後、酢酸エチルで３
回抽出する。飽和食塩水で洗浄、無水硫酸ナトリウムで
乾燥後、溶媒留去して粗生成物330mgを得る。これをク
ロマト精製（ワコーゲルC-200クロロホルム：メタノー
ル＝1:0〜50:1）して化合物5 174.5mg（58.6％）を得
る。1 H NMR（CD3OD）4.25（ｍ、1H）、3.86（ｍ、1H）、3.7
9（dd、0.4H、Ｊ＝11.4、2.3Hz）、3.75（dd、0.6H、Ｊ
＝11.7、2.6Hz）、3.61（dd、0.6H、Ｊ＝11.6、3.6H
z）、3.60（dd、0.4H、Ｊ＝11.5、3.6Hz）、3.52（dd、
1H、Ｊ＝6.2、2.3Hz）、3.50（bs、1H）、3.19（ｓ、2.
4H）、3.18（ｓ、3.6H）、3.17〜3.21（ｍ、1H）、2.65
〜2.80（ｍ、2H）、2.58（ｍ、1H）、2.32（ｓ、3H）、
2.16（ｓ、1.8H）、2.15（ｓ、1.2H）、2.08〜2.14
（ｍ、1H）、2.02（dd、0.4H、Ｊ＝13.4、9.6Hz）、2.0
0（dd、0.6H、Ｊ＝13.3、9.6Hz） SIMS:449（Ｍ＋３）＋ 実施例7.化合物４の合成 実施例１で得られた化合物1 1.0gを水20mlとアセトニト
リル20mlに溶解する。エタンチオール0.42mlを加え、室
温で攪拌する。40分後フレミー塩1.5gと水40mlを加え攪
拌を続ける。１時間後フレミー塩1gと水20mlを加える。
１時間後フレミー塩400mgを加え、さらに30分攪拌す
る。IR JASCO IR-810 NMR Varian EM-390 (90MHz) JEOL FX-100 (100MHz) Bruker AM400 (400MHz) MS Hitachi B-80 Example 1. Synthesis of Compound 1 Compound a4g obtained in Reference Example 1 Is dissolved in 40 ml of water and 12 ml of 1N sodium acetate solution is added. Fremy salt 12.9g water 400
The ml solution is added dropwise at room temperature. After dropping, stir at room temperature for 40 minutes and add hydrochloric acid to adjust the pH to 4.0. After concentration, chromatographic purification (Diaion HP-20 water: methanol = 1: 0 to 3: 1) was performed and the compound
1 2.08 g (53.2%) is obtained. 13 C NMR (D 2 O) 187.1, 187.0, 176.2, 141.8, 138.9, 1
37.8, 137.1, 115.9, 70.2, 65.8, 63.4, 57.3, 55.7,
54.8, 41.0, 40.4, 28.5, 24.2 1 H NMR (CD 3 OD) 6.78 (d, 1H, J = 10.2 Hz), 6.75
(D, 1H, J = 10.2Hz), 4.27 (d, 1H, J = 2.9H)
z), 3.82 (m, 1H), 3.79 (dd, 1H, J = 11.4, 2.3H
z), 3.61 (dd, 1H, J = 11.4, 3.7Hz), 3.52 (dd, 1
H, J = 6.4, 2.6Hz), 3.51 (bs, 1H), 3.22 (dd, 1
H, J = 9.7, 5.9Hz), 2.78 (m, 1H), 2.73 (ddd, 1
H, J = 17.3, 2.9, 1.1Hz), 2.59 (dt, 1H), 2.33
(S, 3H), 2.15 (ddd, 1H, J = 17.3, 10.9, 2.6H
z), 2.02 (dd, 1H, J = 13.4, 9.7 Hz) SIMS 360 (M + 3) + Example 2. Synthesis of compound 2 3.0 g of compound 1 obtained in Example 1 was added to 80 ml of acetonitrile.
Dissolve in a mixed solvent of 80 ml of pH 4.0 0.2M acetate buffer. 15% aqueous solution of methyl mercaptan sodium salt 4.
Add 5 ml and stir at room temperature for 1 hour. Add 4.5g Fremy's salt and 140ml water. After stirring for 40 minutes, 20 ml of acetate buffer and 3.0 ml of an aqueous sodium salt solution of methyl mercaptan are added. 50
After stirring for a minute, 2.0 g of Fremy's salt and 50 ml of water are added. After stirring for 30 minutes, 2.3 g of Fremy's salt was added. After stirring for 30 minutes, the mixture is concentrated under reduced pressure to remove excess methyl mercaptan and acetonitrile. Extracted twice with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a crude product 3.56.
get g. Chromatographic purification (Wakogel C-200 450 ml chloroform: methanol = 1: 0 to 20: 1) and compound 2 3.22 g
(85.5%) is obtained. 1 H NMR (CDCl 3 -CD 3 OD) 4.05 (d, 1H, J = 2.7 Hz),
3.95 (m, 1H), 3.79 (dd, 1H, J = 11.7, 2.8Hz),
3.65 (dd, 1H, J = 11.7, 3.3Hz), 3.53 (bs, 1H),
3.52 (m, 1H), 3.05 (dd, 1H, J = 9.6, 5.8Hz), 2.
91 (bd, 1H, J = 11.0Hz), 2.81 (ddd, 1H, J = 18.
0, 3.0, 1.2Hz), 2.63 (m, 1H), 2.63 (s, 3H),
2.61 (s, 3H), 2.36 (s, 3H), 2.12 (ddd, 1H, J
= 18.0, 11.0, 2.8Hz), 1.95 (dd, 1H, J = 13.6, 9.7
Hz) SIMS: 452 (M + 3) + 13 C NMR (CDCl 3 -CD 3 OD) 178.9, 178.8, 177.3, 145.
4, 144.9, 142.6, 140.0, 116.9, 69.8, 64.6, 63.2, 5
8.1, 56.8, 56.1, 42.5, 41.8, 28.7, 25.4, 18.2, 18.
1 Example 3. Synthesis of Compound 3 1.0 g of the compound 2 obtained in Example 2 was added to 30 ml of acetonitrile.
, 560 mg of silver nitrate is added, and the mixture is stirred at room temperature. After 1 hour, another 300 mg of silver nitrate was added, and the mixture was stirred for 40 minutes and 10 ml of water was added. The insoluble material is depressurized with Celite and the solution is concentrated. Chromatographic purification (Diaion HP-20 100 ml water:
Methanol = 1: 0 to 1: 1) and compound 3 769mg (81.8%)
To get 1 H NMR (CD 3 OD) 4.48 (d, 1 H, J = 3.2 Hz), 4.22
(M, 1H), 4.14 (bd, 1H, J = 8.0Hz), 4.12 (bs, 1
H), 3.79 (dd, 1H, J = 11.5, 2.8Hz), 3.56 (dd, 1
H, J = 11.5, 3.9Hz), 3.27 to 3.31 (m, 2H), 2.83
(Dd, 1H, J = 17.3, 2.3Hz), 2.78 (s, 3H), 2.62
(M, 1H), 2.57 (s, 3H), 2.55 (s, 3H), 2.28
(Dd, 1H, J = 14.0, 10.5Hz), 2.18 (ddd, 1H, J = 1
7.2, 11.2, 2.2 Hz) SIMS: 425 (M + 3) + 13 C NMR (CD 3 OD) 180.7, 180.2, 146.8, 146.7, 143.
8, 142.7, 90.9, 72.7, 66.5, 64.9, 56.2, 54.3, 43.
1, 41.2, 28.5, 26.2, 18.5 Example 4. Synthesis of Compound 15 500 mg of the compound 2 obtained in Example 2 is dissolved in 20 ml of methanol. Add 150 mg of 5% Pd-C and stir at room temperature for 1 hour under hydrogen stream. Depressurize the catalyst with Celite,
The solvent was distilled off to obtain 486 mg of compound 15 (96.7%). 1 H NMR (CDCl 3 ) 4.21 (m, 1H), 4.10 (d, 1H, J =
2.6Hz), 3.82 (dd, 1H, J = 11.1, 2.8Hz), 3.70 (d
d, 1H, J = 11.1, 3.5Hz), 3.56 (s, 1H), 3.51
(M, 1H), 3.21 (dd, 1H, J = 9.3, 5.8Hz), 2.98 ~
3.02 (m, 2H), 2.63 (dt, 1H, J = 13.2, 6.6Hz),
2.35 ~ 2.40 (m, 1H), 2.354 (s, 6H), 2.347 (s,
3H), 2.04 (dd, 1H, J = 13.2, 9.8 Hz) SIMS: 452 (M + 1) + 13 C NMR (CDCl 3 -CD 3 OD) 178.2, 147.9, 147.2, 124.
5, 123.0, 122.3, 122.0, 117.6, 70.1, 64.8, 64.4, 5
8.3, 57.7, 56.8, 42.5, 41.6, 28.6, 26.7, 19.7, 19.
6 Example 5. Synthesis of Compound 16 200 mg of the compound 3 obtained in Example 3 is dissolved in 3 ml of methanol, and 2 ml of acetate buffer having a pH of 4.0 is added. 10% Pd-C 60mg
Is added and the mixture is stirred under a hydrogen stream at room temperature for 1 hour and 15 minutes. After removing the catalyst under reduced pressure, the liquid was concentrated and then purified by chromatography (Diaion HP-20 20 ml water: methanol = 1: 0 to 1: 1) to give the compound.
16 160 mg (79.6%) are obtained. 1 H NMR (CD 3 OD) 4.57 (d, 1 H, J = 3.1 Hz), 4.53 (d
d, 1H, J = 6.3, 3.0Hz), 4.15 (bs, 1H), 4.12
(M, 1H), 3.75 (dd, 1H, J = 10.9, 3.0Hz), 3.50
(Dd, 1H, J = 10.9, 6.4Hz), 3.39 (dd, 1H, J = 10.
5, 5.1Hz), 3.37 (bd, 1H, J = 12.3Hz), 3.08 (dd,
1H, J = 15.4, 2.6Hz), 2.80 (s, 3H), 2.63 (m, 1
H), 2.46 (dd, 1H, J = 14.0, 10.6Hz), 2.43 (dd, 1
H, J = 15.2, 12.0Hz), 2.33 (s, 3H), 2.32 (s, 3)
H) SIMS: 425 (M + 1) + 13 C NMR (CD 3 OD) 179.3, 149.6, 149.1, 125.9, 125.
4, 124.9, 124.4, 92.1, 73.1, 67.3, 66.7, 56.7, 55.
0, 42.8, 40.6, 28.2, 27.0, 20.0, 19.8 Example 6. Synthesis of compound 5 300 mg of the compound 2 obtained in Example 2 was added to 3 ml of acetonitrile.
Dissolve in. Add 3 ml of a 1M solution of dimethylamine hydrochloride and 1.5 ml of a 1M solution of potassium carbonate and stir at room temperature. After 4 hours, 1 ml of a 1M solution of dimethylamine hydrochloride and 0.5 ml of a 1M solution of potassium carbonate were added, and the mixture was further stirred for 4 hours. Add 5 ml of pH 4.0 acetate buffer and distill off the acetonitrile, then add 3 ml of ethyl acetate.
Extract twice. The extract is washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent is distilled off to obtain 330 mg of a crude product. This is purified by chromatography (Wakogel C-200 chloroform: methanol = 1: 0 to 50: 1) to obtain 174.5 mg (58.6%) of compound 5. 1 H NMR (CD 3 OD) 4.25 (m, 1H), 3.86 (m, 1H), 3.7
9 (dd, 0.4H, J = 11.4, 2.3Hz), 3.75 (dd, 0.6H, J
= 11.7, 2.6Hz), 3.61 (dd, 0.6H, J = 11.6, 3.6H
z), 3.60 (dd, 0.4H, J = 11.5, 3.6Hz), 3.52 (dd,
1H, J = 6.2, 2.3Hz), 3.50 (bs, 1H), 3.19 (s, 2.
4H), 3.18 (s, 3.6H), 3.17 to 3.21 (m, 1H), 2.65
~ 2.80 (m, 2H), 2.58 (m, 1H), 2.32 (s, 3H),
2.16 (s, 1.8H), 2.15 (s, 1.2H), 2.08 to 2.14
(M, 1H), 2.02 (dd, 0.4H, J = 13.4, 9.6Hz), 2.0
0 (dd, 0.6H, J = 13.3, 9.6 Hz) SIMS: 449 (M + 3) + Example 7. Synthesis of Compound 4 1.0 g of the compound 1 obtained in Example 1 is dissolved in 20 ml of water and 20 ml of acetonitrile. Add 0.42 ml of ethanethiol and stir at room temperature. After 40 minutes, 1.5 g of Fremy's salt and 40 ml of water are added and stirring is continued. After 1 hour, add 1 g of Fremy's salt and 20 ml of water.
After 1 hour, 400 mg of Fremy's salt is added, and the mixture is stirred for another 30 minutes.
エタンチオールとアセトニトリルを留去し、酢酸エチル
で４回抽出する。飽和食塩水で洗浄、無水硫酸ナトリウ
ムで乾燥、溶媒留去して粗生成物1.17gを得る。これを
クロマト精製（ワコーゲルC-200 180mlクロロホルム：
メタノール＝1:0〜50:1）して化合物4 1.14g（85.3％）
を得る。1 H NMR（CDCl3‐CD3OD）4.12（ｄ、1H、Ｊ＝2.9Hz）、
3.94（ｍ、1H）、3.79（dd、1H、Ｊ＝11.6、2.7Hz）、
3.61（dd、1H、Ｊ＝11.6、3.8Hz）、3.53（bs、1H）、
3.51（dd、1H、Ｊ＝6.3、2.4Hz）、3.16〜3.23（ｍ、4
H）、3.08（dd、1H、Ｊ＝9.6、5.8Hz）、2.89（ｍ、1
H）、2.82（ｍ、1H）、2.61（dt、1H、Ｊ＝13.3、6.3H
z）、2.35（ｓ、3H）、2.13（ddd、1H、Ｊ＝17.8、10.
9、2.9Hz）、1.97（dd、1H、Ｊ＝13.5、9.7Hz）、1.302
（ｔ、3H、Ｊ＝7.4Hz）、1.296（ｔ、3H、Ｊ＝7.4Hz） SIMS:480（Ｍ＋３）＋ 13 C NMR（CDCl3‐CD3OD）179.2、179.1、177.5、145.
4、145.0、142.6、140.2、117.1、69.9、64.7、63.5、5
8.2、57.0、56.3、42.6、41.8、29.23、29.15、28.6、2
5.5、15.3 実施例8.化合物17の合成 実施例７で得られた化合物4 500mgをメタノール20mlに
溶解し５％Pd-C 150mgを加え、水素気流下室温で１時間
攪拌する。触媒を過し、液を溶媒留去して粗生成物
460mgを得る。これをクロマト精製（ワコーゲルC-200 5
0mlクロロホルム：メタノール＝1:0〜50:1）して化合物
17 396mg（78.8％）を得る。1 H NMR（CDCl3）4.23（ｍ、1H）、4.06（bs、1H）、3.8
2（dd、1H、Ｊ＝11.1、3.1Hz）、3.75（dd、1H、Ｊ＝1
1.1、4.0Hz）、3.58（bs、1H）、3.54（ｍ、1H）、3.24
（dd、1H、Ｊ＝9.3、5.7Hz）、3.06（ｍ、1H）、3.01
（ｍ、1H）、2.82（ｑ、2H、Ｊ＝7.4Hz）、2.81（ｑ、2
H、Ｊ＝7.4Hz）、2.65（dt、1H、Ｊ＝13.7、6.5Hz）、
2.39（ｓ、3H）、2.37（ｍ、1H）、2.04（dd、1H、Ｊ＝
13.7、9.3Hz）、1.214（ｔ、3H、Ｊ＝7.4Hz）、1.210
（ｔ、3H、Ｊ＝7.4Hz） SIMS:480（Ｍ＋１）＋ 13 C NMR（CDCl3）179.8、148.7、147.9、124.1、122.
8、120.9、120.7、117.5、70.3、64.8、64.5、58.5、5
7.5、56.7、42.7、41.7、31.0、30.9、28.8、26.9、14.
9、14.8 実施例9.化合物６の合成 実施例７で得られた化合物4 50mgをアセトニトリル1ml
と水1mlに溶解する。ジメチルアミン塩酸塩の1M溶液0.5
mlと炭酸カリウムの1M溶液0.25mlを加え室温で攪拌す
る。４時間30分後さらにジメチルアミン塩酸塩1M溶液0.
15mlと炭酸カリウムの1M溶液75μｌを加え攪拌を続け
る。５時間後ジメチルアミン塩酸塩1M溶液0.2mlと炭酸
カリウム1M溶液0.1mlを加えさらに２時間攪拌する。pH
4.0の酢酸緩衝液を3ml加えアセトニトリルを減圧下留去
する。酢酸エチルで抽出し、飽和食塩水で洗浄、無水硫
酸ナトリウムで乾燥、溶媒留去する。得られた粗生成物
をクロマト精製（ワコーゲルC-200 10mlクロロホルム：
メタノール＝1:0〜50:1）して化合物6 24.3mg（50.4
％）を得る。1 H NMR（CDCl3）4.03（ｄ、0.4H、Ｊ＝2.6Hz）、4.00
（ｄ、0.6H、Ｊ＝2.5Hz）、3.96（ｍ、0.4H）、3.94
（ｍ、0.6H）、3.80（ｍ、1H）、3.69（ｍ、1H）、3.53
（bs、2H）、3.18（ｓ、6H）、3.11（dd、1H、Ｊ＝9.
4、5.9Hz）、2.78〜2.94（ｍ、2H）、2.60〜2.71（ｍ、
3H）、2.36（ｓ、3H）、2.04〜2.19（ｍ、1H）、1.95
（dd、1H、Ｊ＝13.2、9.8Hz）、1.20（ｔ、1.2H、Ｊ＝
7.4Hz）、1.19（ｔ、1.8H、Ｊ＝7.4Hz） SIMS:463（Ｍ＋３）＋ 実施例10.化合物７及び化合物８の合成 ジメチルアミン塩酸塩457mgと炭酸カリウム232mgと酢酸
銅224mgをメタノール13mlに溶解する。その溶液へ実施
例１で得られた化合物1 400mgのメタノール26ml溶液を
室温で滴下する。滴下後酸素雰囲気下に室温で40分攪拌
する。pH4.0の酢酸緩衝液20mlを加え減圧下にメタノー
ルを留去する。クロマト精製（ダイヤイオンHP-20 70ml
水：メタノール＝1:0〜1:1）して粗生成物344mgを得
る。The ethanethiol and acetonitrile are distilled off and the mixture is extracted 4 times with ethyl acetate. The extract is washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent is distilled off to obtain 1.17 g of a crude product. This was purified by chromatography (Wako Gel C-200 180 ml chloroform:
Methanol = 1: 0 to 50: 1) and then compound 4 1.14 g (85.3%)
To get 1 H NMR (CDCl 3 -CD 3 OD) 4.12 (d, 1H, J = 2.9 Hz),
3.94 (m, 1H), 3.79 (dd, 1H, J = 11.6, 2.7Hz),
3.61 (dd, 1H, J = 11.6, 3.8Hz), 3.53 (bs, 1H),
3.51 (dd, 1H, J = 6.3, 2.4Hz), 3.16 to 3.23 (m, 4
H), 3.08 (dd, 1H, J = 9.6, 5.8Hz), 2.89 (m, 1
H), 2.82 (m, 1H), 2.61 (dt, 1H, J = 13.3, 6.3H
z), 2.35 (s, 3H), 2.13 (ddd, 1H, J = 17.8, 10.
9, 2.9Hz), 1.97 (dd, 1H, J = 13.5, 9.7Hz), 1.302
(T, 3H, J = 7.4 Hz), 1.296 (t, 3H, J = 7.4 Hz) SIMS: 480 (M + 3) + 13 C NMR (CDCl 3 -CD 3 OD) 179.2, 179.1, 177.5, 145.
4, 145.0, 142.6, 140.2, 117.1, 69.9, 64.7, 63.5, 5
8.2, 57.0, 56.3, 42.6, 41.8, 29.23, 29.15, 28.6, 2
5.5, 15.3 Example 8. Synthesis of Compound 17 500 mg of the compound 4 obtained in Example 7 was dissolved in 20 ml of methanol, 150 mg of 5% Pd-C was added, and the mixture was stirred at room temperature under a hydrogen stream for 1 hour. Pass the catalyst and evaporate the liquid to remove the crude product.
You get 460 mg. Chromatographic purification (Wakogel C-200 5
Compound with 0 ml chloroform: methanol = 1: 0 to 50: 1)
Yields 17 396 mg (78.8%). 1 H NMR (CDCl 3 ) 4.23 (m, 1H), 4.06 (bs, 1H), 3.8
2 (dd, 1H, J = 11.1, 3.1Hz), 3.75 (dd, 1H, J = 1
1.1, 4.0Hz), 3.58 (bs, 1H), 3.54 (m, 1H), 3.24
(Dd, 1H, J = 9.3, 5.7Hz), 3.06 (m, 1H), 3.01
(M, 1H), 2.82 (q, 2H, J = 7.4Hz), 2.81 (q, 2
H, J = 7.4Hz), 2.65 (dt, 1H, J = 13.7, 6.5Hz),
2.39 (s, 3H), 2.37 (m, 1H), 2.04 (dd, 1H, J =
13.7, 9.3Hz), 1.214 (t, 3H, J = 7.4Hz), 1.210
(T, 3H, J = 7.4 Hz) SIMS: 480 (M + 1) + 13 C NMR (CDCl 3 ) 179.8, 148.7, 147.9, 124.1, 122.
8, 120.9, 120.7, 117.5, 70.3, 64.8, 64.5, 58.5, 5
7.5, 56.7, 42.7, 41.7, 31.0, 30.9, 28.8, 26.9, 14.
9, 14.8 Example 9. Synthesis of Compound 6 50 mg of the compound 4 obtained in Example 7 was added to 1 ml of acetonitrile.
And dissolve in 1 ml of water. 1M solution of dimethylamine hydrochloride 0.5
ml and 0.25 ml of 1M potassium carbonate solution are added and stirred at room temperature. After 4 hours and 30 minutes, a 1M solution of dimethylamine hydrochloride was added.
Add 15 ml and 75 μl of 1M potassium carbonate solution and continue stirring. After 5 hours, 0.2 ml of a 1M solution of dimethylamine hydrochloride and 0.1 ml of a 1M solution of potassium carbonate were added, and the mixture was further stirred for 2 hours. pH
Add 3 ml of 4.0 acetate buffer and distill off the acetonitrile under reduced pressure. Extract with ethyl acetate, wash with saturated brine, dry over anhydrous sodium sulfate, and evaporate the solvent. The resulting crude product was purified by chromatography (Wako Gel C-200 10 ml chloroform:
Methanol = 1: 0 to 50: 1) and compound 6 24.3 mg (50.4
%). 1 H NMR (CDCl 3 ) 4.03 (d, 0.4H, J = 2.6Hz), 4.00
(D, 0.6H, J = 2.5Hz), 3.96 (m, 0.4H), 3.94
(M, 0.6H), 3.80 (m, 1H), 3.69 (m, 1H), 3.53
(Bs, 2H), 3.18 (s, 6H), 3.11 (dd, 1H, J = 9.
4, 5.9Hz), 2.78 ~ 2.94 (m, 2H), 2.60 ~ 2.71 (m,
3H), 2.36 (s, 3H), 2.04 to 2.19 (m, 1H), 1.95
(Dd, 1H, J = 13.2, 9.8Hz), 1.20 (t, 1.2H, J =
7.4Hz), 1.19 (t, 1.8H, J = 7.4Hz) SIMS: 463 (M + 3) + Example 10. Synthesis of compound 7 and compound 8 457 mg of dimethylamine hydrochloride, 232 mg of potassium carbonate and 224 mg of copper acetate, 13 ml of methanol Dissolve in. A solution of 400 mg of the compound 1 obtained in Example 1 in 26 ml of methanol is added dropwise to the solution at room temperature. After the dropping, the mixture is stirred under an oxygen atmosphere at room temperature for 40 minutes. Add 20 ml of pH 4.0 acetate buffer and distill off the methanol under reduced pressure. Chromatographic purification (Diaion HP-20 70ml
Water: methanol = 1: 0 to 1: 1) to obtain 344 mg of a crude product.
これをHPLC（Nucleosil 10 C18 φ20×250 10％アセト
ニトリル−0.01M酢酸アンモニウム）で分取して化合物7
170mg（38％）及び化合物8 131mg（29％）を得る。This was separated by HPLC (Nucleosil 10 C 18 φ20 × 250 10% acetonitrile-0.01 M ammonium acetate) to give compound 7
170 mg (38%) and compound 8 131 mg (29%) are obtained.
化合物７1 H NMR（D2O）5.55（ｓ、0.7H）、4.60（ｄ、1H、Ｊ＝
2.5Hz）、4.15（ｍ、1H）、4.03（bs、1H）、3.96
（ｍ、1H）、3.80（dd、1H、Ｊ＝12.1、2.4Hz）、3.65
（dd、1H、Ｊ＝12.1、3.6Hz）、3.20〜3.28（ｍ、1
H）、3.17（ｓ、6H）、3.06（bd、1H、Ｊ＝9.3Hz）、2.
80（ｍ、1H）、2.64〜2.70（ｍ、1H）、2.64（ｓ、3
H）、2.28（ｍ、1H）、2.20（ｍ、1H） SIMS:403（Ｍ＋３）＋ 13 C NMR（D2O）184.3、183.7、153.7、143.8、136.6、1
17.4、101.1、70.8、65.6、62.7、57.7、56.6、55.7、4
3.3、43.3、41.3、29.6、25.2 化合物８1 H NMR（D2O）5.51（ｓ、0.7H）、4.55（ｄ、1H、Ｊ＝
2.7Hz）、4.08（ｍ、1H）、3.96（bs、1H）、3.89
（ｍ、1H）、3.85（dd、1H、Ｊ＝11.8、2.4Hz）、3.67
（dd、1H、Ｊ＝11.8、3.4Hz）、3.18〜3.23（ｍ、1
H）、3.17（ｓ、6H）、3.00（bd、1H、Ｊ＝9.0Hz）、2.
79（ｍ、1H）、2.65（ｍ、1H）、2.58（ｓ、3H）、2.24
（dd、1H、Ｊ＝14.1、10.4Hz）、2.17（ddd、1H、Ｊ＝1
7.2、10.8、2.3Hz） SIMS:403（Ｍ＋３）＋ 13 C NMR（D2O）184.4、184.2、153.2、140.1、139.5、1
17.6、101.5、70.8、65.6、63.4、58.1、56.7、56.0、4
3.2、43.2、41.4、29.6、25.1 実施例11.化合物９の合成 実施例１で得られた化合物1 200mgをメタノール20mlに
溶解し、チオフェノール46μｌを加える。室温で１時間
攪拌後、水10mlとフレミー塩300mgを加える。１時間50
分攪拌後、pH4.0の酢酸緩衝液15mlを加え、減圧下メタ
ノールを留去する。酢酸エチルで３回抽出し飽和食塩水
で洗浄無水硫酸ナトリウムで乾燥、溶媒留去して粗生成
物220mgを得る。これをクロマト精製（ワコーゲルC-200
40mlクロロホルム：メタノール＝100:1）して化合物9
121.5mg（46.6％）を得る。1 H NMR（CD3OD‐D2O）7.55〜7.61（ｍ、5H）、5.79
（ｓ、0.9H）、5.75（ｓ、0.1H）、4.36（ｄ、1H、Ｊ＝
2.8Hz）、3.88（ｍ、1H）、3.86（dd、1H、Ｊ＝11.6、
2.2Hz）、3.68（dd、1H、Ｊ＝11.6、3.4Hz）、3.67
（ｍ、1H）、3.63（bs、1H）、3.11（dd、1H、Ｊ＝9.
7、5.6Hz）、2.82（bd、1H、Ｊ＝10.1Hz）、2.74（dd、
1H、Ｊ＝17.9、2.3Hz）、2.60（dt、1H、Ｊ＝13.1、6.3
Hz）、2.36（ｓ、3H）、2.16（dd、1H、Ｊ＝17.9、11.0
Hz）、2.09（dd、1H、Ｊ＝13.5、10.0Hz） SIMS:468（Ｍ＋３）＋ 13 C NMR（CD3OD‐D2O）184.1、183.9、181.9、179.3、1
56.3、145.0、139.8、136.8、132.1、131.8、128.2、12
6.6、118.8、71.0、65.9、63.6、59.0、58.1、57.3、4
4.9、42.4、30.3、26.3 実施例12.化合物10の合成 参考例４で得られた化合物d 250mgを塩化メチレン10ml
に溶解し、アニソール0.5mlとトリフルオロ酢酸1mlを加
え室温で２時間攪拌する。反応液を濃縮しクロマト精製
（ダイヤイオンHP-20 30ml水：メタノール＝1:0〜3:7）
して化合物10 114mg（64.5％）を得る。1 H NMR（D2O）6.57（bs、0.3H）、6.39（bs、0.7H）、
4.41（ｍ、1H）、4.28（bs、1H）、4.00（ｍ、1H）、3.
87（dd、1H、Ｊ＝12.0、2.3Hz）、3.68（dd、1H、Ｊ＝1
2.1、3.9Hz）、3.41（dd、1H、Ｊ＝10.5、5.6Hz）、3.1
8（bd、1H、Ｊ＝8.7Hz）、2.81〜2.93（ｍ、1H）、2.83
（ｓ、3H）、2.75（ｍ、1H）、2.43（dd、1H、Ｊ＝14.
5、10.7Hz） SIMS:401（Ｍ＋３）＋ 実施例13.化合物11の合成 参考例５で得られた化合物e 300mgを塩化メチレン15ml
に溶解し、アニソール0.8mlとトリフルオロ酢酸1.2mlを
加え、室温で１時間40分攪拌する。反応液を濃縮し、ク
ロマト精製（ダイヤイオンHP-20 40ml水：メタノール＝
1:0〜1:1）して化合物11 147mg（70.0％）を得る。1 H NMR（D2O）6.02（ｓ、0.6H）、5.99（ｓ、0.4H）、
4.73（ｄ、1H、Ｊ＝2.9Hz）、4.36（ｍ、1H）、4.23（b
s、1H）、3.94（ｍ、1H）、3.82（ｍ、1H）、3.80
（ｓ、3H）、3.63（dd、1H、Ｊ＝12.1、3.8Hz）、3.36
（dd、1H、Ｊ＝10.4、5.5Hz）、3.14（bd、1H、Ｊ＝10.
7Hz）、2.86（ｍ、1H）、2.79（ｓ、3H）、2.72（ｍ、1
H）、2.38（dd、1H、Ｊ＝14.4、10.6Hz）、2.24（ｍ、1
H） SIMS:390（Ｍ＋３）＋ 実施例14.化合物12の合成 参考例６で得られた化合物f 220mgを塩化メチレン6mlに
溶解し、アニソール0.2mlとトリフルオロ酢酸0.6ml加え
て室温で１時間攪拌する。反応液を濃縮してクロマト精
製（ダイヤイオンHP-20 20ml水：メタノール＝1:0〜1:
2）して化合物12 143mg（88.8％）を得る。1 H NMR（D2O）4.41（bd、1H、Ｊ＝6.6Hz）、4.28（bs、
1H）、4.09（ｓ、3H）、4.02（ｍ、1H）、3.86（dd、1
H、Ｊ＝12.0、2.5Hz）、3.40（dd、1H、Ｊ＝10.5、5.5H
z）、3.17（ｍ、1H）、2.98（ｍ、2H）、2.93（ｍ、1
H）、2.83（ｓ、3H）、2.75（ｍ、1H）、2.42（dd、1
H、Ｊ＝14.5、10.5Hz）、2.30（ddd、1H、Ｊ＝17.5、1
0.7、2.4Hz）、1.21（ｔ、3H、Ｊ＝7.4Hz） SIMS:450（Ｍ＋３）＋ 13 C NMR（D2O）184.6、180.6、179.5、159.1、141.1、1
39.7、129.5、116.4、71.0、66.0、63.4、62.2、57.9、
56.0、55.1、42.6、41.1、29.3、28.4、24.5、15.2 実施例15.化合物13の合成 参考例６で得られた化合物g 358mgを塩化メチレン10ml
に溶解しアニソール0.3mlとトリフルオロ酢酸1mlを加え
室温で１時間10分攪拌する。反応液を濃縮してクロマト
精製（ダイヤイオンHP-20 50ml水：メタノール＝1:0〜
1:2）して化合物13 200mg（77.0％）を得る。1 H NMR（CD3OD）4.55（ｄ、1H、Ｊ＝2.7Hz）、4.03
（ｓ、3H）、3.96（ｍ、1H）、3.91（bs、1H）、3.83
（dd、1H、Ｊ＝11.6、2.3Hz）、3.64（dd、1H、Ｊ＝11.
6、4.1Hz）、3.43（dd、1H、Ｊ＝10.0、5.7Hz）、3.07
（ｑ、2H、Ｊ＝7.4Hz）、2.97（ｍ、1H）、2.84（dd、1
H、Ｊ＝17.5、2.1Hz）、2.71（ｍ、1H）、2.61（ｓ、3
H）、2.24（dd、1H、Ｊ＝13.8、10.2Hz）、2.20（ddd、
1H、Ｊ＝17.6、10.9、2.5Hz）、1.25（ｔ、3H、Ｊ＝7.4
Hz） SIMS:450（Ｍ＋３）＋ 13 C NMR（CD3OD）184.1、180.4、177.0、158.1、142.
9、138.6、130.9、117.2、71.3、66.3、64.1、61.6、5
8.7、57.3、56.6、42.2、41.7、29.2、28.0、25.9、15.
6 実施例16.化合物14の合成 実施例１で得られた化合物1 300mgをpH4.0の酢酸緩衝液
20mlに溶解し、10％Pd-C 100mgを加え、水素雰囲気下で
３時間30分攪拌する。触媒を過して除き、液を濃縮
してクロマト精製（ダイヤイオンHP-20 40ml水only）し
て化合物14 89mg（29.2％）を得る。Compound 7 1 H NMR (D 2 O) 5.55 (s, 0.7H), 4.60 (d, 1H, J =
2.5Hz), 4.15 (m, 1H), 4.03 (bs, 1H), 3.96
(M, 1H), 3.80 (dd, 1H, J = 12.1, 2.4Hz), 3.65
(Dd, 1H, J = 12.1, 3.6Hz), 3.20-3.28 (m, 1
H), 3.17 (s, 6H), 3.06 (bd, 1H, J = 9.3Hz), 2.
80 (m, 1H), 2.64 to 2.70 (m, 1H), 2.64 (s, 3
H), 2.28 (m, 1H), 2.20 (m, 1H) SIMS: 403 (M + 3) + 13 C NMR (D 2 O) 184.3, 183.7, 153.7, 143.8, 136.6, 1
17.4, 101.1, 70.8, 65.6, 62.7, 57.7, 56.6, 55.7, 4
3.3, 43.3, 41.3, 29.6, 25.2 Compound 8 1 H NMR (D 2 O) 5.51 (s, 0.7H), 4.55 (d, 1H, J =
2.7Hz), 4.08 (m, 1H), 3.96 (bs, 1H), 3.89
(M, 1H), 3.85 (dd, 1H, J = 11.8, 2.4Hz), 3.67
(Dd, 1H, J = 11.8, 3.4Hz), 3.18 to 3.23 (m, 1
H), 3.17 (s, 6H), 3.00 (bd, 1H, J = 9.0Hz), 2.
79 (m, 1H), 2.65 (m, 1H), 2.58 (s, 3H), 2.24
(Dd, 1H, J = 14.1, 10.4Hz), 2.17 (ddd, 1H, J = 1
7.2, 10.8, 2.3 Hz) SIMS: 403 (M + 3) + 13 C NMR (D 2 O) 184.4, 184.2, 153.2, 140.1, 139.5, 1
17.6, 101.5, 70.8, 65.6, 63.4, 58.1, 56.7, 56.0, 4
3.2, 43.2, 41.4, 29.6, 25.1 Example 11. Synthesis of Compound 9 200 mg of the compound 1 obtained in Example 1 is dissolved in 20 ml of methanol and 46 μl of thiophenol is added. After stirring for 1 hour at room temperature, 10 ml of water and 300 mg of Fremy's salt are added. 1 hour 50
After stirring for 15 minutes, 15 ml of pH 4.0 acetate buffer is added, and methanol is distilled off under reduced pressure. It is extracted 3 times with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent is evaporated to obtain 220 mg of a crude product. Chromatographic purification (Wako Gel C-200
40 ml chloroform: methanol = 100: 1) and compound 9
Obtained 121.5 mg (46.6%). 1 H NMR (CD 3 OD-D 2 O) 7.55 to 7.61 (m, 5H), 5.79
(S, 0.9H), 5.75 (s, 0.1H), 4.36 (d, 1H, J =
2.8Hz), 3.88 (m, 1H), 3.86 (dd, 1H, J = 11.6,
2.2Hz), 3.68 (dd, 1H, J = 11.6, 3.4Hz), 3.67
(M, 1H), 3.63 (bs, 1H), 3.11 (dd, 1H, J = 9.
7, 5.6Hz), 2.82 (bd, 1H, J = 10.1Hz), 2.74 (dd,
1H, J = 17.9, 2.3Hz), 2.60 (dt, 1H, J = 13.1, 6.3
Hz), 2.36 (s, 3H), 2.16 (dd, 1H, J = 17.9, 11.0
Hz), 2.09 (dd, 1H, J = 13.5, 10.0 Hz) SIMS: 468 (M + 3) + 13 C NMR (CD 3 OD-D 2 O) 184.1, 183.9, 181.9, 179.3, 1
56.3, 145.0, 139.8, 136.8, 132.1, 131.8, 128.2, 12
6.6, 118.8, 71.0, 65.9, 63.6, 59.0, 58.1, 57.3, 4
4.9, 42.4, 30.3, 26.3 Example 12. Synthesis of Compound 10 250 mg of the compound d obtained in Reference Example 4 was added to 10 ml of methylene chloride.
Dissolve in, add 0.5 ml of anisole and 1 ml of trifluoroacetic acid, and stir at room temperature for 2 hours. Chromatographic purification by concentrating the reaction mixture (Diaion HP-20 30 ml water: methanol = 1: 0 to 3: 7)
To give 114 mg (64.5%) of compound 10. 1 H NMR (D 2 O) 6.57 (bs, 0.3H), 6.39 (bs, 0.7H),
4.41 (m, 1H), 4.28 (bs, 1H), 4.00 (m, 1H), 3.
87 (dd, 1H, J = 12.0, 2.3Hz), 3.68 (dd, 1H, J = 1
2.1, 3.9Hz), 3.41 (dd, 1H, J = 10.5, 5.6Hz), 3.1
8 (bd, 1H, J = 8.7Hz), 2.81 to 2.93 (m, 1H), 2.83
(S, 3H), 2.75 (m, 1H), 2.43 (dd, 1H, J = 14.
5, 10.7 Hz) SIMS: 401 (M + 3) + Example 13. Synthesis of Compound 11 300 mg of the compound e obtained in Reference Example 5 was mixed with 15 ml of methylene chloride.
0.8 ml of anisole and 1.2 ml of trifluoroacetic acid are added, and the mixture is stirred at room temperature for 1 hour and 40 minutes. The reaction mixture is concentrated and purified by chromatography (Diaion HP-20 40 ml water: methanol =
1: 0 to 1: 1) to give 147 mg (70.0%) of compound 11. 1 H NMR (D 2 O) 6.02 (s, 0.6H), 5.99 (s, 0.4H),
4.73 (d, 1H, J = 2.9Hz), 4.36 (m, 1H), 4.23 (b
s, 1H), 3.94 (m, 1H), 3.82 (m, 1H), 3.80
(S, 3H), 3.63 (dd, 1H, J = 12.1, 3.8Hz), 3.36
(Dd, 1H, J = 10.4, 5.5Hz), 3.14 (bd, 1H, J = 10.
7Hz), 2.86 (m, 1H), 2.79 (s, 3H), 2.72 (m, 1)
H), 2.38 (dd, 1H, J = 14.4, 10.6Hz), 2.24 (m, 1
H) SIMS: 390 (M + 3) + Example 14. Synthesis of Compound 12 220 mg of the compound f obtained in Reference Example 6 was dissolved in 6 ml of methylene chloride, 0.2 ml of anisole and 0.6 ml of trifluoroacetic acid were added, and the mixture was stirred at room temperature for 1 hour. Stir. Chromatographic purification by concentrating the reaction solution (Diaion HP-20 20 ml water: methanol = 1: 0 to 1:
2) to give 143 mg (88.8%) of compound 12. 1 H NMR (D 2 O) 4.41 (bd, 1H, J = 6.6 Hz), 4.28 (bs,
1H), 4.09 (s, 3H), 4.02 (m, 1H), 3.86 (dd, 1
H, J = 12.0, 2.5Hz), 3.40 (dd, 1H, J = 10.5, 5.5H
z), 3.17 (m, 1H), 2.98 (m, 2H), 2.93 (m, 1)
H), 2.83 (s, 3H), 2.75 (m, 1H), 2.42 (dd, 1
H, J = 14.5, 10.5Hz), 2.30 (ddd, 1H, J = 17.5, 1
0.7, 2.4 Hz), 1.21 (t, 3H, J = 7.4 Hz) SIMS: 450 (M + 3) + 13 C NMR (D 2 O) 184.6, 180.6, 179.5, 159.1, 141.1, 1
39.7, 129.5, 116.4, 71.0, 66.0, 63.4, 62.2, 57.9,
56.0, 55.1, 42.6, 41.1, 29.3, 28.4, 24.5, 15.2 Example 15. Synthesis of compound 13 358 mg of the compound g obtained in Reference Example 6 was added to 10 ml of methylene chloride.
0.3 ml of anisole and 1 ml of trifluoroacetic acid are added and the mixture is stirred at room temperature for 1 hour and 10 minutes. Chromatographic purification by concentrating the reaction solution (Diaion HP-20 50 ml water: methanol = 1: 0〜
1: 2) to give 200 mg (77.0%) of compound 13. 1 H NMR (CD 3 OD) 4.55 (d, 1 H, J = 2.7 Hz), 4.03
(S, 3H), 3.96 (m, 1H), 3.91 (bs, 1H), 3.83
(Dd, 1H, J = 11.6, 2.3Hz), 3.64 (dd, 1H, J = 11.
6, 4.1Hz), 3.43 (dd, 1H, J = 10.0, 5.7Hz), 3.07
(Q, 2H, J = 7.4Hz), 2.97 (m, 1H), 2.84 (dd, 1
H, J = 17.5, 2.1Hz), 2.71 (m, 1H), 2.61 (s, 3
H), 2.24 (dd, 1H, J = 13.8, 10.2Hz), 2.20 (ddd,
1H, J = 17.6, 10.9, 2.5Hz), 1.25 (t, 3H, J = 7.4
Hz) SIMS: 450 (M + 3) + 13 C NMR (CD 3 OD) 184.1, 180.4, 177.0, 158.1, 142.
9, 138.6, 130.9, 117.2, 71.3, 66.3, 64.1, 61.6, 5
8.7, 57.3, 56.6, 42.2, 41.7, 29.2, 28.0, 25.9, 15.
6 Example 16. Synthesis of Compound 14 300 mg of the compound 1 obtained in Example 1 was mixed with acetate buffer of pH 4.0.
Dissolve in 20 ml, add 10% Pd-C 100 mg, and stir under hydrogen atmosphere for 3 hours and 30 minutes. The catalyst is removed by filtration, and the solution is concentrated and purified by chromatography (Diaion HP-20 40 ml water only) to obtain 89 mg (29.2%) of compound 14.
SIMS 360（Ｍ＋１）＋ 1 H NMR（CD3OD）6.53（ｓ、2H）、4.27（ｄ、1H）、4.1
7（ｍ、1H）、3.52（bs、1H）、3.3〜3.9（ｍ、3H）、
3.13（ｍ、1H）、2.4〜3.0（ｍ、4H）、2.35（ｓ、3
H）、2.12（ｍ、1H） 実施例17.化合物18の合成 実施例７で得られた化合物4 300mgをアセトニトリル6ml
とメタノール3mlに溶解し、硝酸銀267mgを加え室温で３
時間攪拌する。1N塩酸6mlを加えセライトを用いて不溶
物を減圧過し、液を濃縮する。クロマト精製（ダイ
ヤイオンHP-20 40ml水：メタノール＝1:0〜3:7）して化
合物18 218mg（77.0％）を得る。1 H NMR（CD3OD）:4.48（d,1H,J＝3.2Hz）,4.23（m,1
H）,4.13（m,1H）,4.11（bs,1H）,3.80（dd,1H,J＝11.
5,2.8Hz）,3.56（dd,1H,J＝11.5,3.9Hz）,3.05〜3.21
（m,4H）,2.85（dd,1H,J＝17.2,2.3Hz）2.78（s,3H）,
2.61（m,1H）,2.28（dd,1H,J＝14.0,10.5Hz）,2.19（dd
d,1H,J＝17.1,11.1,2.4Hz）,1.25（t,6H,J＝7.4Hz） SIMS:453（Ｍ＋３）＋ 実施例18.化合物19の合成 実施例１で得られた化合物1 500mgをアセトニトリル5ml
と水10mlに溶解し、ｎ−プロパンチオール0.19mlを加え
る。室温で１時間攪拌後、フレミー塩750mgを加える。3
0分後さらにｎ−プロパンチオール0.19mlを加え攪拌を
続ける。さらに30分後フレミー塩750mgと水10ml,アセト
ニトリル5mlを加え攪拌を続ける。１時間後フレミー塩
を200mg、さらに30分後フレミー塩を750mg加え50分攪拌
した後、過剰のｎ−プロパンチオール，アセトニトリル
を減圧下留去する。pH4.0の酢酸緩衝液を加え酢酸エチ
ルで２回抽出し、飽和食塩水で洗浄後、無水硫酸ナトリ
ウムで乾燥後、減圧濃縮して粗生成物710mgを得る。こ
れをクロマト精製（ワコーゲルC-200 60mlクロロホル
ム：メタノール＝1:0〜50:1）して化合物19 509mg（71.
9％）を得る。1 H NMR（CD3OD）:4.16（d,1H,J＝2.9Hz）,3.78（m,1
H）,3.68（dd,1H,J＝11.4,2.6Hz）,3.51（dd,1H,J＝11.
4,3.7Hz）,3.43（m,1H）,3.40（bs,1H）,2.91〜3.20
（m,5H）,2.66〜2.70（m,2H）,2.50（m,1H）,2.23（s,3
H）,2.05（ddd,1H,J＝18.0,11.4,2.9Hz）,1.91（dd,1H,
J＝13.2,9.5Hz）,1.51（m,4H）,0.912（t,3H,J＝7.3H
z）,0.907（t,3H,J＝7.3Hz） SIMS:508（Ｍ＋３）＋ 実施例19.化合物20の合成 実施例18で得られた化合物19 300mgをアセトニトリル6m
lとメタノール3mlに溶解し、硝酸銀252mgを加え室温で
２時間50分攪拌する。硝酸銀80mgをさらに加え、室温で
50分攪拌し、1N塩酸を加える。セライトを用いて不溶物
を減圧過で除去し、液を濃縮する。クロマト精製
（ダイヤイオンHP-20 40ml水：メタノール＝1:0〜3:7）
して化合物20 228mg（80.2％）を得る。1 H NMR（CD3OD）:4.48（d,1H,J＝3.2Hz）,4.23（m,1
H）,4.14（m,1H）,4.11（bs,1H）,3.79（dd,1H,J＝11.
5,2.8Hz）,3.55（dd,1H,J＝11.5,3.9Hz）,2.99〜3.20
（m,4H）,2.85（dd,1H,J＝17.3,2.3Hz）,2.78（s,3H）,
2.62（m,1H）,2.28（dd,1H,J＝14.0,10.5Hz）,2.18（dd
d,1H,J＝17.2,11.1,2.4Hz）,1.60（m,4H）,1.997（t,3
H,J＝7.4Hz）,1.996（t,3H,J＝7.4Hz） SIMS:481（Ｍ＋３）＋ 実施例20.化合物21の合成 実施例１で得られた化合物1 500mgをアセトニトリル5ml
と水10mlに溶解する。ｉ−プロパンチオール0.26mlを加
え室温で１時間攪拌後、フレミー塩1.07gを加える。15
分攪拌後ｉ−プロパンチオール0.13mlを加え、45分後に
フレミー塩1.07gと水10mlをさらに加える。１時間30分
攪拌後水3mlとフレミー塩300mgをさらに加え、30分攪拌
を続ける。過剰のｉ−プロパンチオールとアセトニトリ
ルを減圧下留去し、pH4.0の酢酸緩衝液を加え、酢酸エ
チルで２回抽出する。飽和食塩水で洗浄、無水硫酸ナト
リウムで乾燥後、溶媒留去して粗生成物580mgを得る。
これをクロマト精製（ワコーゲルC-200 60mlクロロホル
ム：メタノール＝1:0〜50:1）して化合物21 518mg（73.
2％）を得る。1 H NMR（CD3OD）:4.26（d,1H,J＝2.9Hz）,4.01〜4.11
（m,2H）,3.89（m,1H）,3.79（dd,1H,J＝11.5,2.4Hz）,
3.62（dd,1H,J＝11.5,3.7Hz）,3.53（m,1H）,3.51（bs,
1H）,3.22（dd,1H,J＝9.7,5.7Hz）,2.77〜2.82（m,2
H）,2.60（m,1H）,2.33（s,3H）,2.17（ddd,1H,J＝18.
0,11.3,2.8Hz）,2.02（dd,1H,J＝13.4,9.7Hz）,1.23〜
1.30（m,12H） SIMS:508（Ｍ＋３）＋ 実施例21.化合物22の合成 実施例20で得られた化合物21 300mgをアセトニトリル6m
lとメタノール3mlに溶解する。硝酸銀250mgを加え室温
で１時間20分攪拌後、さらに硝酸銀80mgを加えて２時間
50分攪拌する。1N塩酸を加え、不溶物をセライトを用い
た減圧過で除去し液を濃縮する。クロマト精製（ダ
イヤイオンHP-20水：メタノール＝1:0〜3:7）して化合
物22 238mg（83.8％）を得る。1 H NMR（CD3OD）:4.49（d,1H,J＝3.2Hz）,4.25（m,1
H）,4.13（m,1H）,4.12（bs,1H）,4.00〜4.11（m,2H）,
3.81（dd,1H,J＝11.4,2.8Hz）,3.57（dd,1H,J＝11.4,3.
9Hz）,2.87（dd,1H,J＝17.3,2.2Hz）,2.78（s,3H）,2.6
2（m,1H）,2.29（dd,1H,J＝14.1,10.5Hz）,2.21（ddd,1
H,J＝17.3,11.1,2.5Hz）,1.23〜1.29（m,2H） SIMS:481（Ｍ＋３）＋ 実施例22.化合物23の合成 実施例20で得られた化合物21 1.11gをアセトニトリル18
mlに溶解し、1Mジメチルアミン塩酸塩水溶液20mlと1M炭
酸カリウム水溶液10mlを加えて室温で攪拌する。３時間
30分後、さらに1Mジメチルアミン塩酸塩水溶液4mlと1M
炭酸カリウム水溶液2mlを加え、さらに室温で19時間攪
拌する。pH4の酢酸緩衝液を加え濃縮後、クロマト精製
（ダイヤイオンHP-20 150ml水：メタノール＝1:0〜1:
2）して化合物23 302mg（29％）を得る。SIMS 360 (M + 1) + 1 H NMR (CD 3 OD) 6.53 (s, 2H), 4.27 (d, 1H), 4.1
7 (m, 1H), 3.52 (bs, 1H), 3.3 to 3.9 (m, 3H),
3.13 (m, 1H), 2.4-3.0 (m, 4H), 2.35 (s, 3
H), 2.12 (m, 1H) Example 17. Synthesis of compound 18 300 mg of the compound 4 obtained in Example 7 was added to 6 ml of acetonitrile.
And dissolve in 3 ml of methanol, add 267 mg of silver nitrate, and mix at room temperature for 3
Stir for hours. 6 ml of 1N hydrochloric acid was added, the insoluble matter was decompressed with Celite, and the solution was concentrated. Chromatographic purification (Diaion HP-20 40 ml water: methanol = 1: 0-3: 7) gives compound 218 mg (77.0%). 1 H NMR (CD 3 OD): 4.48 (d, 1H, J = 3.2Hz), 4.23 (m, 1
H), 4.13 (m, 1H), 4.11 (bs, 1H), 3.80 (dd, 1H, J = 11.
5,2.8Hz), 3.56 (dd, 1H, J = 11.5,3.9Hz), 3.05 to 3.21
(M, 4H), 2.85 (dd, 1H, J = 17.2,2.3Hz) 2.78 (s, 3H),
2.61 (m, 1H), 2.28 (dd, 1H, J = 14.0, 10.5Hz), 2.19 (dd
d, 1H, J = 17.1,11.1,2.4Hz), 1.25 (t, 6H, J = 7.4Hz) SIMS: 453 (M + 3) + Example 18. Synthesis of compound 19 Compound 1 obtained in Example 1 500 mg 5 ml of acetonitrile
And dissolve in 10 ml of water and add 0.19 ml of n-propanethiol. After stirring for 1 hour at room temperature, 750 mg of Fremy's salt is added. 3
After 0 minutes, 0.19 ml of n-propanethiol was further added and stirring was continued. After another 30 minutes, 750 mg of Flemie salt, 10 ml of water and 5 ml of acetonitrile are added and stirring is continued. After 1 hour, 200 mg of Fremy's salt was added, and after 30 minutes, 750 mg of Fremy's salt was added and stirred for 50 minutes, and then excess n-propanethiol and acetonitrile were distilled off under reduced pressure. A pH 4.0 acetate buffer was added, the mixture was extracted twice with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 710 mg of a crude product. This was purified by chromatography (Wako Gel C-200 60 ml chloroform: methanol = 1: 0 to 50: 1) to give 509 mg of compound 19 (71.
9%). 1 H NMR (CD 3 OD): 4.16 (d, 1H, J = 2.9Hz), 3.78 (m, 1
H), 3.68 (dd, 1H, J = 11.4, 2.6Hz), 3.51 (dd, 1H, J = 11.
4,3.7Hz), 3.43 (m, 1H), 3.40 (bs, 1H), 2.91 to 3.20
(M, 5H), 2.66 to 2.70 (m, 2H), 2.50 (m, 1H), 2.23 (s, 3
H), 2.05 (ddd, 1H, J = 18.0,11.4,2.9Hz), 1.91 (dd, 1H,
J = 13.2,9.5Hz), 1.51 (m, 4H), 0.912 (t, 3H, J = 7.3H
z), 0.907 (t, 3H, J = 7.3 Hz) SIMS: 508 (M + 3) + Example 19. Synthesis of compound 20 300 mg of the compound 19 obtained in Example 18 was added to 6 m of acetonitrile.
It is dissolved in 1 ml of methanol and 3 ml of methanol, 252 mg of silver nitrate is added, and the mixture is stirred at room temperature for 2 hours and 50 minutes. Add 80 mg of silver nitrate at room temperature
Stir for 50 minutes and add 1N hydrochloric acid. The insoluble material is removed under reduced pressure using Celite, and the solution is concentrated. Chromatographic purification (Diaion HP-20 40 ml water: methanol = 1: 0 to 3: 7)
Compound 228 mg (80.2%) is obtained. 1 H NMR (CD 3 OD): 4.48 (d, 1H, J = 3.2Hz), 4.23 (m, 1
H), 4.14 (m, 1H), 4.11 (bs, 1H), 3.79 (dd, 1H, J = 11.
5,2.8Hz), 3.55 (dd, 1H, J = 11.5,3.9Hz), 2.99 to 3.20
(M, 4H), 2.85 (dd, 1H, J = 17.3,2.3Hz), 2.78 (s, 3H),
2.62 (m, 1H), 2.28 (dd, 1H, J = 14.0, 10.5Hz), 2.18 (dd
d, 1H, J = 17.2,11.1,2.4Hz), 1.60 (m, 4H), 1.997 (t, 3
H, J = 7.4Hz), 1.996 (t, 3H, J = 7.4Hz) SIMS: 481 (M + 3) + Example 20. Synthesis of compound 21 500 mg of the compound 1 obtained in Example 1 was added to 5 ml of acetonitrile.
And dissolve in 10 ml of water. After adding 0.26 ml of i-propanethiol and stirring at room temperature for 1 hour, 1.07 g of Flemmy salt is added. 15
After stirring for a minute, 0.13 ml of i-propanethiol was added, and after 45 minutes, 1.07 g of Flemie salt and 10 ml of water were further added. After stirring for 1 hour and 30 minutes, 3 ml of water and 300 mg of Fremy's salt were further added, and stirring was continued for 30 minutes. Excess i-propanethiol and acetonitrile are distilled off under reduced pressure, an acetate buffer of pH 4.0 is added, and the mixture is extracted twice with ethyl acetate. The extract is washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent is distilled off to give a crude product (580 mg).
Chromatographic purification (Wakogel C-200 60 ml chloroform: methanol = 1: 0 to 50: 1) was performed to obtain 518 mg of compound 21 (73.
2%). 1 H NMR (CD 3 OD): 4.26 (d, 1H, J = 2.9Hz), 4.01 to 4.11
(M, 2H), 3.89 (m, 1H), 3.79 (dd, 1H, J = 11.5,2.4Hz),
3.62 (dd, 1H, J = 11.5,3.7Hz), 3.53 (m, 1H), 3.51 (bs,
1H), 3.22 (dd, 1H, J = 9.7,5.7Hz), 2.77 to 2.82 (m, 2
H), 2.60 (m, 1H), 2.33 (s, 3H), 2.17 (ddd, 1H, J = 18.
0,11.3,2.8Hz), 2.02 (dd, 1H, J = 13.4,9.7Hz), 1.23〜
1.30 (m, 12H) SIMS: 508 (M + 3) + Example 21. Synthesis of compound 22 300 mg of compound 21 obtained in Example 20 was added to 6 m of acetonitrile.
Dissolve l and 3 ml of methanol. Add 250 mg of silver nitrate and stir at room temperature for 1 hour 20 minutes, then add 80 mg of silver nitrate for 2 hours.
Stir for 50 minutes. 1N hydrochloric acid is added, the insoluble matter is removed under reduced pressure using Celite, and the solution is concentrated. Chromatographic purification (Diaion HP-20 water: methanol = 1: 0 to 3: 7) gives compound 238 mg (83.8%). 1 H NMR (CD 3 OD): 4.49 (d, 1H, J = 3.2Hz), 4.25 (m, 1
H), 4.13 (m, 1H), 4.12 (bs, 1H), 4.00 to 4.11 (m, 2H),
3.81 (dd, 1H, J = 11.4,2.8Hz), 3.57 (dd, 1H, J = 11.4,3.
9Hz), 2.87 (dd, 1H, J = 17.3,2.2Hz), 2.78 (s, 3H), 2.6
2 (m, 1H), 2.29 (dd, 1H, J = 14.1,10.5Hz), 2.21 (ddd, 1
H, J = 17.3,11.1,2.5Hz), 1.23 to 1.29 (m, 2H) SIMS: 481 (M + 3) + Example 22. Synthesis of compound 23 1.11 g of the compound 21 obtained in Example 20 was added to acetonitrile 18
Dissolve in 1 ml, add 20 ml of 1M dimethylamine hydrochloride aqueous solution and 10 ml of 1M potassium carbonate aqueous solution, and stir at room temperature. 3 hours
After 30 minutes, an additional 4 ml of 1M dimethylamine hydrochloride solution and 1M
2 ml of aqueous potassium carbonate solution is added, and the mixture is further stirred at room temperature for 19 hours. After adding pH 4 acetate buffer and concentrating, chromatographic purification (Diaion HP-20 150 ml water: methanol = 1: 0 to 1:
2) to give 302 mg (29%) of compound 23.
SIMS:477（Ｍ＋３）＋ 実施例23.化合物24の合成 実施例１で得られた化合物1 600mgをアセトニトリル15m
lと水30mlに溶解し、ｔ−ブチルメルカプタン0.28mlを
加え、室温で30分攪拌する。フレミー塩1.29gを加え、5
0分攪拌後アセトニトリル10mlとｔ−ブチルメルカプタ
ン0.28mlを加える。35分攪拌後フレミー塩1.29gと水20m
l,アセトニトリル10mlを加え、さらに35分攪拌後、フレ
ミー塩300mgと水10mlを加える。１時間攪拌後過剰のｔ
−ブチルメルカプタンとアセトニトリルを減圧下留去
し、酢酸エチルで２回抽出する。飽和食塩水で洗浄、無
水硫酸ナトリウムで乾燥、溶媒留去して粗生成物680mg
を得る。これをクロマト精製（ワコーゲルC-200 60mlク
ロロホルム：メタノール＝1:0〜50:1して化合物24 475m
g（53.0％）を得る。1 H NMR（CDCl3‐CD3OD）:4.27（d,1H,J＝2.4Hz）,3.92
（m,1H）,3.54〜3.90（m,2H）,3.53（m,2H）,3.23（dd,
1H,J＝9.5,5.6Hz）,2.75〜2.97（m,2H）,2.59（m,1H）,
2.35（s,3H）,1.91〜2.27（m,2H）,1.416（s,9H）,1.41
1（s,9H） SIMS:536（Ｍ＋３）＋ 実施例24.化合物25の合成 参考例７で得られた化合物i 625mgを塩化メチレン18ml
に溶解し、アニソール1mlとトリフルオロ酢酸1.8mlを加
え、室温で２時間20分攪拌する。反応液を濃縮してクロ
マト精製（ダイヤイオンHP-20 70ml水：メタノール＝1:
0〜3:7）して化合物25 400mg（87.0％）を得る。1 H NMR（CD3OD）:4.25（d,1H,J＝2.9Hz）,4.04（s,3
H）,3.85（m,1H）,3.83（m,1H）,3.79（dd,1H,J＝11.5,
2.3Hz）,3.64（dd,1H,J＝11.6,3.6Hz）,3.52（dd,1H,J
＝6.4,2.5Hz）,3.49（bs,1H）,3.20（dd,1H,J＝9.7,5.7
Hz）,2.73〜2.78（m,2H）,2.59（m,1H）,2.32（s,3H）,
2.14（ddd,1H,J＝18.0,11.3,2.8Hz）,2.01（dd,1H,J＝1
3.4,9.7Hz）,1.24（d,6H,J＝6.7Hz） SIMS:464（Ｍ＋３）＋ 実施例25.化合物26の合成 実施例24で得られた化合物25 129mgをアセトニトリル3m
lと水2mlに溶解し、硝酸銀119mgを加え、室温で４時間
攪拌する。不溶物をセライトを用いた減圧過で除き、
液を濃縮しクロマト精製して（ダイヤイオンHP-20 10
ml水：メタノール＝1:0〜1:1）化合物26 99.6mg（82.0
％）を得る。1 H NMR（CD3OD）:4.48（d,1H,J＝3.2Hz）,4.20（m,1
H）,4.14（m,1H）,4.11（bs,1H）,4.04（s,3H）,3.88
（m,1H）,3.82（dd,1H,J＝11.5,2.7Hz）,3.59（dd,1H,J
＝11.5,3.8Hz）,3.27（m,1H）,2.84（dd,1H,J＝17.2,2.
3Hz）,2.78（s,3H）,2.62（m,1H）,2.29（dd,1H,J＝14.
1,10.5Hz）,2.19（ddd,1H,J＝17.2,11.1,2.6Hz）,1.246
（d,3H,J＝6.7Hz）,1.244（d,3H,J＝6.7Hz） SIMS:437（Ｍ＋３）＋ 実施例26.化合物27の合成 参考例７で得られた化合物h 423mgを塩化メチレン12ml
に溶解し、アニソール0.6ml,トリフルオロ酢酸1.2mlを
加え、室温で１時間30分攪拌する。反応液を濃縮し、ク
ロマト精製（ダイヤイオンHP-20 50ml水：メタノール＝
1:0〜3:7）して化合物27 239mg（76.9％）を得る。1 H NMR（CD3OD）:4.25（d,1H,J＝2.9Hz）,4.05（s,3
H）,3.86（m,1H）,3.85（m,1H）,3.78（dd,1H,J＝11.5,
2.3Hz）,3.59（dd,1H,J＝11.5,3.8Hz）,3.52（dd,1H,J
＝6.2,2.4Hz）,3.50（bs,1H）,3.20（dd,1H,J＝9.7,5.7
Hz）,2.71〜2.79（m,2H）,2.59（m,1H）,2.32（s,3H）,
2.13（ddd,1H,J＝16.7,10.1,2.7Hz）,2.01（dd,1H,J＝1
3.4,9.7Hz）,1.25（d,3H,J＝6.7Hz）,1.22（d,3H,J＝6.
7Hz） SIMS:464（Ｍ＋３）＋ 実施例27.化合物28の合成 実施例26で得られた化合物27 110mgをアセトニトリル2.
5mlと水1.5mlに溶解し、硝酸銀102mgを加えて室温で４
時間攪拌する。不溶物を別し、液を濃縮してクロマ
ト精製（ダイヤイオンHP-20 10ml水：メタノール＝1:0
〜1:1）して化合物28 88.4mg（85.4％）を得る。1 H NMR（CD3OD）:4.49（d,1H,J＝3.3Hz）,4.21（m,1
H）,4.14（m,1H）,4.11（bs,1H）,4.06（s,3H）,3.84
（m,1H）,3.80（dd,1H,J＝11.5,2.6Hz）,3.53（dd,1H,J
＝11.5,3.9Hz）,3.27（m,1H）,2.82（dd,1H,J＝17.1,2.
4Hz）,2.78（s,3H）,2.62（m,1H）,2.30（dd,1H,J＝14.
1,10.5Hz）,2.18（ddd,1H,J＝17.1,11.1,2.5Hz）,1.25
（d,3H,J＝6.7Hz）,1.23（d,3H,J＝6.6Hz） SIMS:437（Ｍ＋３）＋ 実施例28.化合物29の合成 実施例22で得られた化合物23 240mgをアセトニトリル8m
lとメタノール2mlに溶解し、硝酸銀217mgを加えて室温
で１時間攪拌する。水を加えた後不溶物を別し、液
を濃縮してクロマト精製（ダイヤイオンHP-20 40ml水：
メタノール＝1:0〜1:1）して化合物29 147mg（64.9％）
を得る。SIMS: 477 (M + 3) + Example 23. Synthesis of compound 24 600 mg of the compound 1 obtained in Example 1 was converted into acetonitrile 15 m.
1 and water (30 ml), t-butyl mercaptan (0.28 ml) is added, and the mixture is stirred at room temperature for 30 minutes. Add 1.29g of Fremy's salt and add 5
After stirring for 0 minutes, 10 ml of acetonitrile and 0.28 ml of t-butyl mercaptan are added. After stirring for 35 minutes, 1.29 g of Fremy salt and 20 m of water
l, 10 ml of acetonitrile are added, and after stirring for 35 minutes, 300 mg of Flemie salt and 10 ml of water are added. Excess t after stirring for 1 hour
-Butyl mercaptan and acetonitrile are distilled off under reduced pressure and extracted twice with ethyl acetate. Wash with saturated brine, dry over anhydrous sodium sulfate, evaporate the solvent to give 680 mg of crude product.
To get Chromatographic purification (Wako Gel C-200 60 ml chloroform: methanol = 1: 0 to 50: 1 was carried out to give compound 24 475 m
Get g (53.0%). 1 H NMR (CDCl 3 -CD 3 OD): 4.27 (d, 1H, J = 2.4Hz), 3.92
(M, 1H), 3.54 to 3.90 (m, 2H), 3.53 (m, 2H), 3.23 (dd,
1H, J = 9.5,5.6Hz), 2.75 to 2.97 (m, 2H), 2.59 (m, 1H),
2.35 (s, 3H), 1.91 to 2.27 (m, 2H), 1.416 (s, 9H), 1.41
1 (s, 9H) SIMS: 536 (M + 3) + Example 24. Synthesis of compound 25 625 mg of compound i obtained in Reference Example 7 was added to 18 ml of methylene chloride.
Dissolve in, add 1 ml of anisole and 1.8 ml of trifluoroacetic acid, and stir at room temperature for 2 hours and 20 minutes. Chromatographic purification by concentrating the reaction solution (Diaion HP-20 70 ml water: methanol = 1:
0-3: 7) to give 400 mg (87.0%) of compound 25. 1 H NMR (CD 3 OD): 4.25 (d, 1H, J = 2.9Hz), 4.04 (s, 3
H), 3.85 (m, 1H), 3.83 (m, 1H), 3.79 (dd, 1H, J = 11.5,
2.3Hz), 3.64 (dd, 1H, J = 11.6,3.6Hz), 3.52 (dd, 1H, J
= 6.4,2.5Hz), 3.49 (bs, 1H), 3.20 (dd, 1H, J = 9.7,5.7
Hz), 2.73 to 2.78 (m, 2H), 2.59 (m, 1H), 2.32 (s, 3H),
2.14 (ddd, 1H, J = 18.0,11.3,2.8Hz), 2.01 (dd, 1H, J = 1
3.4,9.7 Hz), 1.24 (d, 6H, J = 6.7 Hz) SIMS: 464 (M + 3) + Example 25. Synthesis of compound 26 129 mg of compound 25 obtained in Example 24 was added to 3 m of acetonitrile.
It is dissolved in 1 ml of water and 2 ml of water, 119 mg of silver nitrate is added, and the mixture is stirred at room temperature for 4 hours. The insoluble matter was removed by decompression using Celite,
The solution is concentrated and purified by chromatography (Diaion HP-20 10
ml water: methanol = 1: 0 to 1: 1) Compound 26 99.6 mg (82.0
%). 1 H NMR (CD 3 OD): 4.48 (d, 1H, J = 3.2Hz), 4.20 (m, 1
H), 4.14 (m, 1H), 4.11 (bs, 1H), 4.04 (s, 3H), 3.88
(M, 1H), 3.82 (dd, 1H, J = 11.5,2.7Hz), 3.59 (dd, 1H, J
= 11.5, 3.8Hz), 3.27 (m, 1H), 2.84 (dd, 1H, J = 17.2, 2.
3Hz), 2.78 (s, 3H), 2.62 (m, 1H), 2.29 (dd, 1H, J = 14.
1,10.5Hz), 2.19 (ddd, 1H, J = 17.2,11.1,2.6Hz), 1.246
(D, 3H, J = 6.7Hz), 1.244 (d, 3H, J = 6.7Hz) SIMS: 437 (M + 3) + Example 26. Synthesis of compound 27 423 mg of compound h obtained in Reference Example 7 was methylene chloride. 12 ml
0.6 ml of anisole and 1.2 ml of trifluoroacetic acid are added, and the mixture is stirred at room temperature for 1 hour and 30 minutes. The reaction mixture is concentrated and purified by chromatography (Diaion HP-20 50 ml water: methanol =
1: 0 to 3: 7) to obtain 239 mg (76.9%) of compound 27. 1 H NMR (CD 3 OD): 4.25 (d, 1H, J = 2.9Hz), 4.05 (s, 3
H), 3.86 (m, 1H), 3.85 (m, 1H), 3.78 (dd, 1H, J = 11.5,
2.3Hz), 3.59 (dd, 1H, J = 11.5,3.8Hz), 3.52 (dd, 1H, J
= 6.2,2.4Hz), 3.50 (bs, 1H), 3.20 (dd, 1H, J = 9.7,5.7
Hz), 2.71 to 2.79 (m, 2H), 2.59 (m, 1H), 2.32 (s, 3H),
2.13 (ddd, 1H, J = 16.7,10.1,2.7Hz), 2.01 (dd, 1H, J = 1
3.4,9.7Hz), 1.25 (d, 3H, J = 6.7Hz), 1.22 (d, 3H, J = 6.
7 Hz) SIMS: 464 (M + 3) + Example 27. Synthesis of compound 28 110 mg of compound 27 obtained in Example 26 was added to acetonitrile 2.
Dissolve in 5 ml of water and 1.5 ml of water, add 102 mg of silver nitrate, and add 4 at room temperature.
Stir for hours. Insoluble matter is removed, and the solution is concentrated and purified by chromatography (Diaion HP-20 10 ml water: methanol = 1: 0
~ 1: 1) to give 88.4 mg (85.4%) of compound 28. 1 H NMR (CD 3 OD): 4.49 (d, 1H, J = 3.3Hz), 4.21 (m, 1
H), 4.14 (m, 1H), 4.11 (bs, 1H), 4.06 (s, 3H), 3.84
(M, 1H), 3.80 (dd, 1H, J = 11.5,2.6Hz), 3.53 (dd, 1H, J
= 11.5,3.9Hz), 3.27 (m, 1H), 2.82 (dd, 1H, J = 17.1,2.
4Hz), 2.78 (s, 3H), 2.62 (m, 1H), 2.30 (dd, 1H, J = 14.
1,10.5Hz), 2.18 (ddd, 1H, J = 17.1,11.1,2.5Hz), 1.25
(D, 3H, J = 6.7Hz), 1.23 (d, 3H, J = 6.6Hz) SIMS: 437 (M + 3) + Example 28. Synthesis of compound 29 240 mg of the compound 23 obtained in Example 22 was added to 8 m of acetonitrile.
It is dissolved in 1 ml of methanol and 2 ml of methanol, 217 mg of silver nitrate is added, and the mixture is stirred at room temperature for 1 hour. After adding water, insoluble matter is removed, and the solution is concentrated and purified by chromatography (Diaion HP-20 40 ml water:
Methanol = 1: 0 to 1: 1) and compound 29 147mg (64.9%)
To get
SIMS:450（Ｍ＋３）＋ 実施例29.化合物30の合成 実施例20で得られた化合物21 90mgをアセトニトリル1ml
に溶解し、pH7.7のリン酸緩衝液2mlを加える。エチレン
イミンの水溶液0.3mlを加え、室温で１時間40分攪拌す
る。反応液を濃縮後、クロマト精製（ダイヤイオンHP-2
0 15ml水：メタノール＝1:0〜3:2）して化合物30 57mg
（67.8％）を得る。1 H NMR（CD3OD）:4.24（m,1H）,3.87（m,0.4H）,3.81
（m,0.6H）,3.78（m,1H）,3.69（m,1H）,3.63（dd,0.6
H,J＝11.4,3.6Hz）,3.57（dd,0.4H,J＝11.4,3.9Hz）,3.
50（bs,1H）,3.49（m,1H）,3.12（m,1H）,2.73〜2.81
（m,2H）,2.58（m,1H）,2.43〜2.47（m,4H）,2.32（s,3
H）,2.13（m,1H）,1.99（m,1H）,1.20〜1.25（m,6H） SIMS:475（Ｍ＋３）＋ 実施例30.化合物31の合成 実施例20で得られた化合物21 223mgをメタノール8mlに
溶解し５％Pd-C 60mgを加え、水素雰囲気下、室温で15
分間攪拌する。触媒を別後、液を濃縮して化合物31
225mg（定量的）を得る。1 H NMR（CD3OD）:4.33（d,1H,J＝2.6Hz）,4.19（dd,1H,
J＝6.0,2.6Hz）,3.84（dd,1H,J＝10.8,2.6Hz）,3.55（d
d,1H,J＝10.8,6.0Hz）,3.52（bs,1H）,3.51（m,1H）,3.
28〜3.38（m,3H）,3.00（dd,1H,J＝15.7,2.5Hz）,2.86
（bd,1H,J＝11.0Hz）,2.61（m,1H）,2.40（dd,1H,J＝1
5.8,11.7Hz）,2.34（s,3H）,2.13（dd,1H,J＝13.2,9.8H
z）,1.19〜1.22（m,12H） SIMS:508（Ｍ＋１）＋ 以下に示す参考例で得られる化合物の構造及び化合物番
号を以下に示す。以下で例えば 参考例１ 化合物ａの合成 DX-52-1 15gを塩化メチレン150mlに懸濁させる。−78℃
に冷却下三臭化ホウ素の塩化メチレン溶液（50g/200m
l）を150ml滴下する。滴下後−78℃〜室温で22時間攪拌
する。再び−78℃に冷却し三臭化ホウ素の塩化メチレン
溶液（25g/200ml）を100ml滴下し−78℃〜室温で７時間
攪拌する。氷を加え、NaOH溶液で水層のpHを7.2としNaC
N3.87gを加える。水層を分液後濃縮してクロマト精製し
て〔ダイヤイオンHP-20 2l水：メタノール＝1:0〜9:1
（v/v）〕化合物ａのナトリウム塩11.17gを得る。これ
を水80mlに溶解し、塩酸を加えてpHを3.5に調整する。
生成する沈澱物を濾取して乾燥し化合物a10.4g（76.6
％）を得る。1 H NMR（D2O、NaOD、PD＝9.3）7.13（ｍ、1H）、6.75
（ｍ、2H）、4.24（ｄ、1H、Ｊ＝2.7Hz）、4.13（ｍ、1
H）、3.70（ｍ、2H）、3.57（ｍ、1H）、3.51（bs、1
H）、3.10（dd、1H、Ｊ＝10.0、5.4Hz）、2.40〜2.84
（ｍ、4H）、2.22（ｓ、3H）、2.03（dd、1H、Ｊ＝10.
5、13.2Hz） SIMS:344（Ｍ＋１）＋ 13 C NMR（D2O、NaOD、PD＝9.3）184.4、154.6、138.6、
128.9、121.9、120.1、119.7、114.8、70.7、65.0、65.
0、58.6、45.3、41.9、33.3、30.0 参考例２ 化合物ｂの合成 参考例１で得られた化合物a 8gをクロロホルム133mlと
メタノール36mlに溶解しジフェニルジアゾメタン5.42g
のクロロホルム25ml溶液を加え室温で攪拌する。１時間
40分後さらにジフェニルジアゾメタン4.53gのクロロホ
ルム20ml溶液を加える。１時間攪拌後、酢酸を赤紫色が
消失するまで徐々に加える。クロロホルムを加えて希釈
し、飽和NaHCO3溶液、飽和食塩水で洗浄し無水硫酸ナト
リウムで乾燥後溶媒留去する。これをクロマト精製して
（ワコーゲルC-200 500mlヘキサン：酢酸エチル＝2:1）
化合物b 10.2g（86％）を得る。1 H NMR（CDCl3）7.33（ｍ、10H）、6.97（ｍ、1H）、6.
88（ｓ、1H）、6.63（ｍ、2H）、4.18（ｍ、1H）、3.93
（ｄ、1H）、3.65（ｍ、2H）、3.44（bs、1H）、3.38
（ｍ、1H）、3.19（dd、1H）、3.02（ｍ、1H）、2.47〜
2.83（ｍ、3H）、2.11（ｓ、3H）、1.93（dd、1H） SIMS:510（Ｍ＋１）＋ 参考例３ 化合物ｃの合成 参考例２で得られた化合物b 1.43gをアセトニトリル80m
lに溶解し1N酢酸ナトリウム溶液10mlと水80mlを加え
る。フレミー塩1.5gを加え室温で攪拌する。１時間後フ
レミー塩1.5gと水80ml、アセトニトリル20mlを加えて攪
拌を続ける。１時間20分後さらにフレミー塩を750mg加
えて攪拌し、１時間20分後さらにフレミー塩750mgを加
えてさらに１時間20分攪拌する。反応液を酢酸エチルで
抽出し、飽和食塩水で洗浄、無水硫酸ナトリウムで乾燥
後、溶媒留去して粗生成物1.57gを得る。これをクロマ
ト精製（ワコーゲルC-200 220mlクロロホルム：メタノ
ール＝1:0〜50:1）して化合物c 1.16g（78.8％）を得
る。また原料b 127mg（8.9％）を回収する。1 H NMR（CDCl3）7.25〜7.43（ｍ、10H）、6.89（ｓ、1
H）、6.72（ｓ、2H）、3.87〜4.03（ｍ、2H）、3.73
（ｍ、2H）、3.52（bs、1H）、3.45（ｍ、1H）、2.50〜
3.23（ｍ、4H）、2.12〜2.33（ｍ、1H）、2.14（ｓ、3
H）、1.93（dd、1H） SIMS:526（Ｍ＋３）＋ 参考例4.化合物ｄの合成 参考例３で得られた化合物c 250mgをアセトニトリル8ml
に溶解し、pH4.0の酢酸緩衝液8mlを加える。アジ化ナト
リウム94mgを加え室温で１時間30分攪拌する。フレミー
塩386mgと水3mlを加え攪拌を続ける。２時間後フレミー
塩120mgを加え室温で更に１時間10分攪拌する。生成し
た結晶を減圧過し、水洗した後減圧乾燥して化合物d
183mg（68.0％）を得る。1 H NMR（CDCl3）7.20〜7.47（ｍ、10H）、6.88（ｓ、1
H）、6.23（ｓ、1H）、3.98（ｍ、2H）、3.77（ｍ、2
H）、3.51（bs、1H）、3.47（ｍ、1H）、2.5〜3.3
（ｍ、4H）、2.10〜2.35（ｍ、1H）、2.13（ｓ、3H）、
1.93（ｍ、1H） SIMS:567（Ｍ＋３）＋ IR νmax（KBr）3450、2110、1726、1657、1636、1596 参考例5.化合物ｅの合成 参考例３で得られた化合物c 600mgをメタノール30mlに
溶解し、酢酸銅230mg、トリエチルアミン80μｌを加
え、酸素雰囲気下室温で10日間攪拌する。pH4.0の酢酸
緩衝液20mlを加え、減圧下メタノールを留去する。酢酸
エチルで抽出し、飽和食塩水で乾燥後、溶媒留去して粗
生成物710mgを得る。これをクロマト精製（ワコーゲルC
-200 60ml n−ヘキサン：酢酸エチル＝3:2〜1:1）して
化合物e 356mg（56.1％）を得る。また原料c 133mg（2
2.1％）を回収する。1 H NMR（CDCl3）7.23〜7.43（ｍ、10H）、6.88（ｓ、1
H）、5.89（ｓ、0.6H）、5.85（ｓ、0.4H）、3.87〜4.0
3（ｍ、2H）、3.79（ｓ、3H）、3.70（ｍ、2H）、3.50
（bs、1H）、3.45（ｍ、1H）、3.15（dd、1H）、2.50〜
3.00（ｍ、3H）、2.13〜2.33（ｍ、1H）、2.13（ｓ、3
H）、1.93（ｍ、1H） SIMS:556（Ｍ＋３）＋ 参考例6.化合物ｆ及びｇの合成 参考例５で得られた化合物e 600mgをアセトニトリル10m
lと水10mlに溶解し、エタンチオール0.12mlを加え室温
で攪拌する。30分後エタンチオールをさらに0.12ml加え
攪拌を続ける。２時間後pH4.0の酢酸緩衝液3mlを加え、
さらに室温で17時間攪拌後フレミー塩580mgを加え室温
で40分攪拌する。減圧下過剰のエタンチオールを留去
し、水を加えて酢酸エチルで抽出する。pH7.7のリン酸
緩衝液及び飽和食塩水で洗浄し、無水硫酸ナトリウムで
乾燥後、溶媒留去して粗生成物630mgを得る。これをク
ロマト精製（ワコーゲルC-200 100ml n−ヘキサン：酢
酸エチル＝4:1〜2:1）して化合物f 143mg（21.5％）及
び化合物g 211mg（33.3％）を得る。SIMS: 450 (M + 3) + Example 29. Synthesis of compound 30 90 mg of the compound 21 obtained in Example 20 was mixed with 1 ml of acetonitrile.
Dissolve in and add 2 ml of pH 7.7 phosphate buffer. 0.3 ml of an aqueous solution of ethyleneimine is added, and the mixture is stirred at room temperature for 1 hour and 40 minutes. After concentrating the reaction solution, chromatographic purification (Diaion HP-2
0 15ml water: methanol = 1: 0 to 3: 2) and compound 30 57mg
(67.8%) is obtained. 1 H NMR (CD 3 OD): 4.24 (m, 1H), 3.87 (m, 0.4H), 3.81
(M, 0.6H), 3.78 (m, 1H), 3.69 (m, 1H), 3.63 (dd, 0.6
H, J = 11.4,3.6Hz), 3.57 (dd, 0.4H, J = 11.4,3.9Hz), 3.
50 (bs, 1H), 3.49 (m, 1H), 3.12 (m, 1H), 2.73 to 2.81
(M, 2H), 2.58 (m, 1H), 2.43 to 2.47 (m, 4H), 2.32 (s, 3
H), 2.13 (m, 1H), 1.99 (m, 1H), 1.20 to 1.25 (m, 6H) SIMS: 475 (M + 3) + Example 30. Synthesis of compound 31 Compound 223 mg obtained in Example 20 Is dissolved in 8 ml of methanol and 60 mg of 5% Pd-C is added.
Stir for minutes. After removing the catalyst, the solution was concentrated to give compound 31.
225 mg (quantitative) are obtained. 1 H NMR (CD 3 OD): 4.33 (d, 1H, J = 2.6Hz), 4.19 (dd, 1H,
J = 6.0, 2.6Hz), 3.84 (dd, 1H, J = 10.8, 2.6Hz), 3.55 (d
d, 1H, J = 10.8,6.0Hz), 3.52 (bs, 1H), 3.51 (m, 1H), 3.
28 ~ 3.38 (m, 3H), 3.00 (dd, 1H, J = 15.7, 2.5Hz), 2.86
(Bd, 1H, J = 11.0Hz), 2.61 (m, 1H), 2.40 (dd, 1H, J = 1)
5.8,11.7Hz), 2.34 (s, 3H), 2.13 (dd, 1H, J = 13.2,9.8H
z), 1.19 to 1.22 (m, 12H) SIMS: 508 (M + 1) + The structures and compound numbers of the compounds obtained in the reference examples shown below are shown below. For example Reference Example 1 Synthesis of compound a 15 g of DX-52-1 is suspended in 150 ml of methylene chloride. -78 ° C
Boron tribromide in methylene chloride solution (50g / 200m under cooling)
l) of 150 ml is dropped. After dropping, the mixture is stirred at -78 ° C to room temperature for 22 hours. The mixture was again cooled to -78 ° C, 100 ml of a methylene chloride solution of boron tribromide (25 g / 200 ml) was added dropwise, and the mixture was stirred at -78 ° C to room temperature for 7 hours. Add ice and adjust the pH of the aqueous layer to 7.2 with NaOH solution.
Add 3.87 g of N. The aqueous layer is separated, concentrated and chromatographed [Diaion HP-20 2l water: methanol = 1: 0-9: 1].
(V / v)] 11.17 g of the sodium salt of compound a is obtained. This is dissolved in 80 ml of water and hydrochloric acid is added to adjust the pH to 3.5.
The resulting precipitate was collected by filtration and dried to obtain 10.4 g of compound a (76.6
%). 1 H NMR (D 2 O, NaOD, PD = 9.3) 7.13 (m, 1H), 6.75
(M, 2H), 4.24 (d, 1H, J = 2.7Hz), 4.13 (m, 1
H), 3.70 (m, 2H), 3.57 (m, 1H), 3.51 (bs, 1
H), 3.10 (dd, 1H, J = 10.0, 5.4Hz), 2.40-2.84
(M, 4H), 2.22 (s, 3H), 2.03 (dd, 1H, J = 10.
5, 13.2 Hz) SIMS: 344 (M + 1) + 13 C NMR (D 2 O, NaOD, PD = 9.3) 184.4, 154.6, 138.6,
128.9, 121.9, 120.1, 119.7, 114.8, 70.7, 65.0, 65.
0, 58.6, 45.3, 41.9, 33.3, 30.0 Reference Example 2 Synthesis of Compound b 8 g of the compound a obtained in Reference Example 1 was dissolved in 133 ml of chloroform and 36 ml of methanol to obtain 5.42 g of diphenyldiazomethane.
25 ml of chloroform solution is added and stirred at room temperature. 1 hour
After 40 minutes, a solution of 4.53 g of diphenyldiazomethane in 20 ml of chloroform is added. After stirring for 1 hour, acetic acid is gradually added until the reddish purple color disappears. Chloroform is added to dilute, washed with saturated NaHCO 3 solution and saturated saline, dried over anhydrous sodium sulfate, and the solvent is distilled off. This was purified by chromatography (Wako Gel C-200 500 ml hexane: ethyl acetate = 2: 1)
10.2 g (86%) of compound b is obtained. 1 H NMR (CDCl 3 ) 7.33 (m, 10H), 6.97 (m, 1H), 6.
88 (s, 1H), 6.63 (m, 2H), 4.18 (m, 1H), 3.93
(D, 1H), 3.65 (m, 2H), 3.44 (bs, 1H), 3.38
(M, 1H), 3.19 (dd, 1H), 3.02 (m, 1H), 2.47 ~
2.83 (m, 3H), 2.11 (s, 3H), 1.93 (dd, 1H) SIMS: 510 (M + 1) + Reference Example 3 Synthesis of compound c 1.43 g of the compound b obtained in Reference Example 2 was added to 80 m of acetonitrile.
Dissolve in 1 l and add 10 ml of 1N sodium acetate solution and 80 ml of water. Add 1.5 g of Fremy's salt and stir at room temperature. After 1 hour, 1.5 g of Fremy's salt, 80 ml of water and 20 ml of acetonitrile are added and stirring is continued. After 1 hour and 20 minutes, 750 mg of Fremy's salt was further added and stirred, and after 1 hour and 20 minutes, 750 mg of Fremy's salt was added and further stirred for 1 hour and 20 minutes. The reaction solution is extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent is distilled off to obtain 1.57 g of a crude product. This is purified by chromatography (Wakogel C-200 220 ml chloroform: methanol = 1: 0 to 50: 1) to obtain 1.16 g (78.8%) of compound c. Also collect 127 mg (8.9%) of raw material b. 1 H NMR (CDCl 3 ) 7.25 to 7.43 (m, 10 H), 6.89 (s, 1
H), 6.72 (s, 2H), 3.87 to 4.03 (m, 2H), 3.73
(M, 2H), 3.52 (bs, 1H), 3.45 (m, 1H), 2.50 ~
3.23 (m, 4H), 2.12 to 2.33 (m, 1H), 2.14 (s, 3
H), 1.93 (dd, 1H) SIMS: 526 (M + 3) + Reference Example 4. Synthesis of Compound d 250 mg of the compound c obtained in Reference Example 3 was added to 8 ml of acetonitrile.
And add 8 ml of pH 4.0 acetate buffer. 94 mg of sodium azide is added, and the mixture is stirred at room temperature for 1 hour and 30 minutes. Add 386 mg of Fremy's salt and 3 ml of water and continue stirring. After 2 hours, 120 mg of Fremy's salt was added, and the mixture was stirred at room temperature for 1 hour and 10 minutes. The crystals formed were passed under reduced pressure, washed with water and dried under reduced pressure to give compound d
Obtain 183 mg (68.0%). 1 H NMR (CDCl 3 ) 7.20 to 7.47 (m, 10 H), 6.88 (s, 1
H), 6.23 (s, 1H), 3.98 (m, 2H), 3.77 (m, 2
H), 3.51 (bs, 1H), 3.47 (m, 1H), 2.5 to 3.3
(M, 4H), 2.10 to 2.35 (m, 1H), 2.13 (s, 3H),
1.93 (m, 1H) SIMS: 567 (M + 3) + IR ν max (KBr) 3450, 2110, 1726, 1657, 1636, 1596 Reference Example 5. Synthesis of Compound e 600 mg of Compound c obtained in Reference Example 3 was added to methanol. Dissolve in 30 ml, add 230 mg of copper acetate and 80 μl of triethylamine, and stir for 10 days at room temperature under oxygen atmosphere. 20 ml of pH 4.0 acetate buffer is added, and methanol is distilled off under reduced pressure. It is extracted with ethyl acetate, dried over saturated saline, and then the solvent is distilled off to obtain 710 mg of a crude product. Chromatographic purification (Wako Gel C
-200 60 ml n-hexane: ethyl acetate = 3: 2-1: 1) to obtain compound 356 mg (56.1%). Raw material c 133 mg (2
2.1%) is recovered. 1 H NMR (CDCl 3 ) 7.23 to 7.43 (m, 10 H), 6.88 (s, 1
H), 5.89 (s, 0.6H), 5.85 (s, 0.4H), 3.87 ~ 4.0
3 (m, 2H), 3.79 (s, 3H), 3.70 (m, 2H), 3.50
(Bs, 1H), 3.45 (m, 1H), 3.15 (dd, 1H), 2.50 ~
3.00 (m, 3H), 2.13 to 2.33 (m, 1H), 2.13 (s, 3
H), 1.93 (m, 1H) SIMS: 556 (M + 3) + Reference Example 6. Synthesis of Compounds f and g 600 mg of the compound e obtained in Reference Example 5 was added to 10 m of acetonitrile.
Dissolve l and 10 ml of water, add 0.12 ml of ethanethiol and stir at room temperature. After 30 minutes, add 0.12 ml of ethanethiol and continue stirring. After 2 hours, add 3 ml of pH 4.0 acetate buffer,
After further stirring at room temperature for 17 hours, 580 mg of Flemie salt is added and the mixture is stirred at room temperature for 40 minutes. Excess ethanethiol is distilled off under reduced pressure, water is added, and the mixture is extracted with ethyl acetate. It is washed with a phosphate buffer of pH 7.7 and saturated saline, dried over anhydrous sodium sulfate, and then the solvent is distilled off to obtain 630 mg of a crude product. This is purified by chromatography (Wako Gel C-200 100 ml n-hexane: ethyl acetate = 4: 1 to 2: 1) to obtain 143 mg (21.5%) of compound f and 211 mg (33.3%) of compound g.
化合物f SIMS 616（Ｍ＋３）＋ 化合物g SIMS 616（Ｍ＋３）＋ 参考例7.化合物ｈおよびｉの合成 参考例５で得られた化合物e 1.2gをアセトニトリル20ml
に溶解し、pH4.0の酢酸緩衝液5mlとｉ−プロパンチオー
ル1.0mlを加えて室温で24時間攪拌する。フレミー塩1.6
9gと水20ml,アセトニトリル10mlを加え、さらに室温で
３時間40分攪拌する。過剰のｉ−プロパンチオールを留
去し、酢酸エチルで抽出、飽和食塩水で洗浄後、無水硫
酸ナトリウムで乾燥、溶媒留去して粗生成物1.24gを得
る。これをクロマト精製（ワコーゲルC-200 100ml n−
ヘキサン：酢酸エチル＝4:1〜2:1）して化合物h 391mg
（28.7％）及び化合物i 629mg（46.2％）を得る。Compound f SIMS 616 (M + 3) + Compound g SIMS 616 (M + 3) + Reference Example 7. Synthesis of Compounds h and i 1.2 g of the compound e obtained in Reference Example 5 was added to 20 ml of acetonitrile.
The solution is dissolved in the above solution, 5 ml of an acetic acid buffer of pH 4.0 and 1.0 ml of i-propanethiol are added, and the mixture is stirred at room temperature for 24 hours. Fremy salt 1.6
9 g, 20 ml of water and 10 ml of acetonitrile are added, and the mixture is further stirred at room temperature for 3 hours and 40 minutes. Excessive i-propanethiol was distilled off, extracted with ethyl acetate, washed with saturated saline, dried over anhydrous sodium sulfate, and the solvent was distilled off to obtain 1.24 g of a crude product. Chromatographic purification (Wakogel C-200 100 ml n-
Hexane: ethyl acetate = 4: 1 to 2: 1) to give compound h 391mg
(28.7%) and Compound i 629 mg (46.2%) are obtained.
化合物ｈ EIMS:627（Ｍ＋）,629（Ｍ＋２）＋,598 化合物ｉ EIMS:627（Ｍ＋）,629（Ｍ＋２）＋,598 参考例8.注射剤 化合物3 0.1g及びグルコース50gに蒸留水を加え１の
溶液とする。この溶液を0.22μの孔径を有するメンブラ
ンフィルター（ミリポア社、FGLD14200）及びN2ガスを
用いて加圧（0.5kg/cm2）下に過する。液を20mlの
白色アンプルに10mlあて分注し常法でシールする。これ
により注射剤を得る。Compound h EIMS: 627 (M + ), 629 (M + 2) + , 598 Compound i EIMS: 627 (M + ), 629 (M + 2) + , 598 Reference Example 8. Injectable Compound 3 0.1 g and glucose 50 g in distilled water. To prepare a solution of 1. The solution is passed under pressure (0.5 kg / cm 2 ) with a membrane filter having a pore size of 0.22 μ (Millipore FGLD14200) and N 2 gas. Dispense 10 ml of the solution into a 20 ml white ampoule and seal it in the usual way. This gives an injection.
発明の効果 化合物（Ｉ）、そのヒドロキノン体及びそれらの薬理上
許容される塩は優れた抗腫瘍活性を有する。EFFECTS OF THE INVENTION Compound (I), its hydroquinone derivative and their pharmacologically acceptable salts have excellent antitumor activity.
Claims (1)
コキシ、アジド、アミノ、低級アルキルアミノ、ジ低級
アルキルアミノ、環状アミノ、低級アルキルチオ又は非
置換もしくは置換のアリールチオであり、Ｘ、ＹはＸが
ヒドロキシでＹがシアノであるか又は両者一体となって
−Ｘ−Ｙ−として−Ｏ−を表す）で表されるか、又はそ
のヒドロキノン型として表される化合物。1. A formula (Wherein R 1 and R 2 are the same or different and each is hydrogen, lower alkoxy, azido, amino, lower alkylamino, dilower alkylamino, cyclic amino, lower alkylthio or unsubstituted or substituted arylthio, and X, Y Is X is hydroxy and Y is cyano, or both are represented by -X-Y- representing -O-) or its hydroquinone form.
Priority Applications (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US07/102,359 US4822882A (en) | 1986-10-03 | 1987-09-29 | DC-52 derivatives and their antitumor use |
| CA000548413A CA1307274C (en) | 1986-10-03 | 1987-10-01 | Quinone and hydroquinone derivatives |
| EP87308770A EP0262984B1 (en) | 1986-10-03 | 1987-10-02 | Antitumor compounds |
| DE8787308770T DE3783697T2 (en) | 1986-10-03 | 1987-10-02 | ANTITUMOR CONNECTIONS. |
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP23585886 | 1986-10-03 | ||
| JP61-235858 | 1986-12-02 | ||
| JP61-287212 | 1986-12-02 | ||
| JP28721286 | 1986-12-02 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPS63264482A JPS63264482A (en) | 1988-11-01 |
| JPH07116193B2 true JPH07116193B2 (en) | 1995-12-13 |
Family
ID=26532369
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP20718087A Expired - Lifetime JPH07116193B2 (en) | 1986-10-03 | 1987-08-20 | Novel antitumor compound |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPH07116193B2 (en) |
-
1987
- 1987-08-20 JP JP20718087A patent/JPH07116193B2/en not_active Expired - Lifetime
Also Published As
| Publication number | Publication date |
|---|---|
| JPS63264482A (en) | 1988-11-01 |
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