JPS63104969A - Sulfur-containing heterocyclic compound - Google Patents
Sulfur-containing heterocyclic compoundInfo
- Publication number
- JPS63104969A JPS63104969A JP61253158A JP25315886A JPS63104969A JP S63104969 A JPS63104969 A JP S63104969A JP 61253158 A JP61253158 A JP 61253158A JP 25315886 A JP25315886 A JP 25315886A JP S63104969 A JPS63104969 A JP S63104969A
- Authority
- JP
- Japan
- Prior art keywords
- group
- compound
- methoxyphenyl
- acetyl
- lower alkyl
- 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.)
- Granted
Links
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 title 1
- 150000002391 heterocyclic compounds Chemical class 0.000 title 1
- 229910052717 sulfur Inorganic materials 0.000 title 1
- 239000011593 sulfur Substances 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims abstract description 54
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 38
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 24
- 125000003545 alkoxy group Chemical group 0.000 claims abstract description 17
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims abstract description 11
- 125000004093 cyano group Chemical group *C#N 0.000 claims abstract description 5
- 125000001624 naphthyl group Chemical group 0.000 claims abstract description 5
- 125000002071 phenylalkoxy group Chemical group 0.000 claims abstract description 5
- 125000004414 alkyl thio group Chemical group 0.000 claims abstract description 3
- 125000005236 alkanoylamino group Chemical group 0.000 claims abstract 2
- 125000005843 halogen group Chemical group 0.000 claims description 15
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 14
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 7
- 125000002252 acyl group Chemical group 0.000 claims description 6
- 239000000126 substance Substances 0.000 claims description 4
- 125000004429 atom Chemical group 0.000 claims description 3
- 150000003839 salts Chemical class 0.000 claims description 2
- WOHLSTOWRAOMSG-UHFFFAOYSA-N 2,3-dihydro-1,3-benzothiazole Chemical compound C1=CC=C2SCNC2=C1 WOHLSTOWRAOMSG-UHFFFAOYSA-N 0.000 abstract description 29
- 230000002213 calciumantagonistic effect Effects 0.000 abstract description 3
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N phenol group Chemical group C1(=CC=CC=C1)O ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 abstract description 3
- 150000001732 carboxylic acid derivatives Chemical class 0.000 abstract description 2
- 229910052736 halogen Inorganic materials 0.000 abstract 2
- 150000002367 halogens Chemical class 0.000 abstract 2
- 125000001589 carboacyl group Chemical group 0.000 abstract 1
- 239000000463 material Substances 0.000 abstract 1
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 73
- 238000002844 melting Methods 0.000 description 22
- 230000008018 melting Effects 0.000 description 22
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 18
- 239000000243 solution Substances 0.000 description 14
- 238000003756 stirring Methods 0.000 description 12
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 10
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 9
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 9
- 238000000034 method Methods 0.000 description 8
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 7
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 7
- IOJUPLGTWVMSFF-UHFFFAOYSA-N benzothiazole Chemical class C1=CC=C2SC=NC2=C1 IOJUPLGTWVMSFF-UHFFFAOYSA-N 0.000 description 7
- 239000012044 organic layer Substances 0.000 description 7
- 239000002904 solvent Substances 0.000 description 7
- UJVBZCCNLAAMOV-UHFFFAOYSA-N 2h-1,2-benzothiazine Chemical compound C1=CC=C2C=CNSC2=C1 UJVBZCCNLAAMOV-UHFFFAOYSA-N 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 238000001816 cooling Methods 0.000 description 6
- 230000005389 magnetism Effects 0.000 description 6
- -1 methoxy, ethoxy, propoxy, hexyloxy Chemical group 0.000 description 6
- 239000000203 mixture Substances 0.000 description 6
- 238000010898 silica gel chromatography Methods 0.000 description 6
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 6
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 5
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 5
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 description 5
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 4
- 125000004432 carbon atom Chemical group C* 0.000 description 4
- 238000006243 chemical reaction Methods 0.000 description 4
- 239000013078 crystal Substances 0.000 description 4
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 4
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 4
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 125000005530 alkylenedioxy group Chemical group 0.000 description 3
- SLUNEGLMXGHOLY-UHFFFAOYSA-N benzene;hexane Chemical compound CCCCCC.C1=CC=CC=C1 SLUNEGLMXGHOLY-UHFFFAOYSA-N 0.000 description 3
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 3
- 239000000543 intermediate Substances 0.000 description 3
- 238000004519 manufacturing process Methods 0.000 description 3
- 239000012299 nitrogen atmosphere Substances 0.000 description 3
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- XLUXHEZIGIDTCC-UHFFFAOYSA-N acetonitrile;ethyl acetate Chemical compound CC#N.CCOC(C)=O XLUXHEZIGIDTCC-UHFFFAOYSA-N 0.000 description 2
- 239000013543 active substance Substances 0.000 description 2
- 125000004423 acyloxy group Chemical group 0.000 description 2
- SYWUAPJQKHSVPQ-UHFFFAOYSA-N benzene;ethyl acetate;hexane Chemical compound CCCCCC.CCOC(C)=O.C1=CC=CC=C1 SYWUAPJQKHSVPQ-UHFFFAOYSA-N 0.000 description 2
- 125000004106 butoxy group Chemical group [*]OC([H])([H])C([H])([H])C(C([H])([H])[H])([H])[H] 0.000 description 2
- 239000011575 calcium Substances 0.000 description 2
- 238000004440 column chromatography Methods 0.000 description 2
- 229940125904 compound 1 Drugs 0.000 description 2
- FAMRKDQNMBBFBR-BQYQJAHWSA-N diethyl azodicarboxylate Substances CCOC(=O)\N=N\C(=O)OCC FAMRKDQNMBBFBR-BQYQJAHWSA-N 0.000 description 2
- 201000010099 disease Diseases 0.000 description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 2
- 150000002148 esters Chemical class 0.000 description 2
- FAMRKDQNMBBFBR-UHFFFAOYSA-N ethyl n-ethoxycarbonyliminocarbamate Chemical compound CCOC(=O)N=NC(=O)OCC FAMRKDQNMBBFBR-UHFFFAOYSA-N 0.000 description 2
- 230000004907 flux Effects 0.000 description 2
- 239000005457 ice water Substances 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- OPMNROCQHKJDAQ-FKSUSPILSA-N loline Chemical compound C1C[C@@H]2O[C@H]3[C@H](NC)[C@@H]2N1C3 OPMNROCQHKJDAQ-FKSUSPILSA-N 0.000 description 2
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 description 2
- 239000002244 precipitate Substances 0.000 description 2
- 125000002572 propoxy group Chemical group [*]OC([H])([H])C(C([H])([H])[H])([H])[H] 0.000 description 2
- 125000004076 pyridyl group Chemical group 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- 229920006395 saturated elastomer Polymers 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- 239000000741 silica gel Substances 0.000 description 2
- 229910002027 silica gel Inorganic materials 0.000 description 2
- 235000017557 sodium bicarbonate Nutrition 0.000 description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 2
- 239000012312 sodium hydride Substances 0.000 description 2
- 229910000104 sodium hydride Inorganic materials 0.000 description 2
- KZNICNPSHKQLFF-UHFFFAOYSA-N succinimide Chemical compound O=C1CCC(=O)N1 KZNICNPSHKQLFF-UHFFFAOYSA-N 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
- AOSZTAHDEDLTLQ-AZKQZHLXSA-N (1S,2S,4R,8S,9S,11S,12R,13S,19S)-6-[(3-chlorophenyl)methyl]-12,19-difluoro-11-hydroxy-8-(2-hydroxyacetyl)-9,13-dimethyl-6-azapentacyclo[10.8.0.02,9.04,8.013,18]icosa-14,17-dien-16-one Chemical compound C([C@@H]1C[C@H]2[C@H]3[C@]([C@]4(C=CC(=O)C=C4[C@@H](F)C3)C)(F)[C@@H](O)C[C@@]2([C@@]1(C1)C(=O)CO)C)N1CC1=CC=CC(Cl)=C1 AOSZTAHDEDLTLQ-AZKQZHLXSA-N 0.000 description 1
- 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 1
- WWTBZEKOSBFBEM-SPWPXUSOSA-N (2s)-2-[[2-benzyl-3-[hydroxy-[(1r)-2-phenyl-1-(phenylmethoxycarbonylamino)ethyl]phosphoryl]propanoyl]amino]-3-(1h-indol-3-yl)propanoic acid Chemical compound N([C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)O)C(=O)C(CP(O)(=O)[C@H](CC=1C=CC=CC=1)NC(=O)OCC=1C=CC=CC=1)CC1=CC=CC=C1 WWTBZEKOSBFBEM-SPWPXUSOSA-N 0.000 description 1
- ULTHEAFYOOPTTB-UHFFFAOYSA-N 1,4-dibromobutane Chemical compound BrCCCCBr ULTHEAFYOOPTTB-UHFFFAOYSA-N 0.000 description 1
- ROSJMNJJOXFJGH-UHFFFAOYSA-N 1-[2-(2-hydroxy-5-methoxyphenyl)-2h-1,3-benzothiazol-3-yl]ethanone Chemical compound COC1=CC=C(O)C(C2N(C3=CC=CC=C3S2)C(C)=O)=C1 ROSJMNJJOXFJGH-UHFFFAOYSA-N 0.000 description 1
- 101150072531 10 gene Proteins 0.000 description 1
- LEVUYFUCJRHCNR-UHFFFAOYSA-N 2-(2-methoxyphenyl)-1,3-thiazolidine-4-carboxylic acid Chemical compound COC1=CC=CC=C1C1SCC(C(O)=O)N1 LEVUYFUCJRHCNR-UHFFFAOYSA-N 0.000 description 1
- YOETUEMZNOLGDB-UHFFFAOYSA-N 2-methylpropyl carbonochloridate Chemical compound CC(C)COC(Cl)=O YOETUEMZNOLGDB-UHFFFAOYSA-N 0.000 description 1
- 241000251468 Actinopterygii Species 0.000 description 1
- WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- 208000024172 Cardiovascular disease Diseases 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- 229940126657 Compound 17 Drugs 0.000 description 1
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 1
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical group C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- 108010021119 Trichosanthin Proteins 0.000 description 1
- LNUFLCYMSVYYNW-ZPJMAFJPSA-N [(2r,3r,4s,5r,6r)-2-[(2r,3r,4s,5r,6r)-6-[(2r,3r,4s,5r,6r)-6-[(2r,3r,4s,5r,6r)-6-[[(3s,5s,8r,9s,10s,13r,14s,17r)-10,13-dimethyl-17-[(2r)-6-methylheptan-2-yl]-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1h-cyclopenta[a]phenanthren-3-yl]oxy]-4,5-disulfo Chemical compound O([C@@H]1[C@@H](COS(O)(=O)=O)O[C@@H]([C@@H]([C@H]1OS(O)(=O)=O)OS(O)(=O)=O)O[C@@H]1[C@@H](COS(O)(=O)=O)O[C@@H]([C@@H]([C@H]1OS(O)(=O)=O)OS(O)(=O)=O)O[C@@H]1[C@@H](COS(O)(=O)=O)O[C@H]([C@@H]([C@H]1OS(O)(=O)=O)OS(O)(=O)=O)O[C@@H]1C[C@@H]2CC[C@H]3[C@@H]4CC[C@@H]([C@]4(CC[C@@H]3[C@@]2(C)CC1)C)[C@H](C)CCCC(C)C)[C@H]1O[C@H](COS(O)(=O)=O)[C@@H](OS(O)(=O)=O)[C@H](OS(O)(=O)=O)[C@H]1OS(O)(=O)=O LNUFLCYMSVYYNW-ZPJMAFJPSA-N 0.000 description 1
- CDXSJGDDABYYJV-UHFFFAOYSA-N acetic acid;ethanol Chemical compound CCO.CC(O)=O CDXSJGDDABYYJV-UHFFFAOYSA-N 0.000 description 1
- ZULJYVVAYGFYKU-UHFFFAOYSA-N acetonitrile;chloroform Chemical compound CC#N.ClC(Cl)Cl ZULJYVVAYGFYKU-UHFFFAOYSA-N 0.000 description 1
- AUALQMFGWLZREY-UHFFFAOYSA-N acetonitrile;methanol Chemical compound OC.CC#N AUALQMFGWLZREY-UHFFFAOYSA-N 0.000 description 1
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 150000008065 acid anhydrides Chemical class 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 238000005904 alkaline hydrolysis reaction Methods 0.000 description 1
- 125000002947 alkylene group Chemical group 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- WPUJEWVVTKLMQI-UHFFFAOYSA-N benzene;ethoxyethane Chemical compound CCOCC.C1=CC=CC=C1 WPUJEWVVTKLMQI-UHFFFAOYSA-N 0.000 description 1
- RTEXIPZMMDUXMR-UHFFFAOYSA-N benzene;ethyl acetate Chemical compound CCOC(C)=O.C1=CC=CC=C1 RTEXIPZMMDUXMR-UHFFFAOYSA-N 0.000 description 1
- 229960004217 benzyl alcohol Drugs 0.000 description 1
- MDHYEMXUFSJLGV-UHFFFAOYSA-N beta-phenethyl acetate Natural products CC(=O)OCCC1=CC=CC=C1 MDHYEMXUFSJLGV-UHFFFAOYSA-N 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 208000015606 cardiovascular system disease Diseases 0.000 description 1
- 239000007810 chemical reaction solvent Substances 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 238000004140 cleaning Methods 0.000 description 1
- 229940125773 compound 10 Drugs 0.000 description 1
- 229940125797 compound 12 Drugs 0.000 description 1
- 229940126208 compound 22 Drugs 0.000 description 1
- 229940126214 compound 3 Drugs 0.000 description 1
- 239000013256 coordination polymer Substances 0.000 description 1
- 125000000753 cycloalkyl group Chemical group 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- AVAACINZEOAHHE-VFZPANTDSA-N doripenem Chemical compound C=1([C@H](C)[C@@H]2[C@H](C(N2C=1C(O)=O)=O)[C@H](O)C)S[C@@H]1CN[C@H](CNS(N)(=O)=O)C1 AVAACINZEOAHHE-VFZPANTDSA-N 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- LJQKCYFTNDAAPC-UHFFFAOYSA-N ethanol;ethyl acetate Chemical compound CCO.CCOC(C)=O LJQKCYFTNDAAPC-UHFFFAOYSA-N 0.000 description 1
- OAYLNYINCPYISS-UHFFFAOYSA-N ethyl acetate;hexane Chemical compound CCCCCC.CCOC(C)=O OAYLNYINCPYISS-UHFFFAOYSA-N 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- OPMNROCQHKJDAQ-UHFFFAOYSA-N festucine Natural products C1CC2OC3C(NC)C2N1C3 OPMNROCQHKJDAQ-UHFFFAOYSA-N 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 125000001153 fluoro group Chemical group F* 0.000 description 1
- 238000010575 fractional recrystallization Methods 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 239000000499 gel Substances 0.000 description 1
- 125000003104 hexanoyl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- ZLVXBBHTMQJRSX-VMGNSXQWSA-N jdtic Chemical compound C1([C@]2(C)CCN(C[C@@H]2C)C[C@H](C(C)C)NC(=O)[C@@H]2NCC3=CC(O)=CC=C3C2)=CC=CC(O)=C1 ZLVXBBHTMQJRSX-VMGNSXQWSA-N 0.000 description 1
- 125000005948 methanesulfonyloxy group Chemical group 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 239000012452 mother liquor Substances 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- PFPYHYZFFJJQFD-UHFFFAOYSA-N oxalic anhydride Chemical compound O=C1OC1=O PFPYHYZFFJJQFD-UHFFFAOYSA-N 0.000 description 1
- UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Natural products O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 description 1
- 125000004193 piperazinyl group Chemical group 0.000 description 1
- 125000003386 piperidinyl group Chemical group 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 238000006722 reduction reaction Methods 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 229960002317 succinimide Drugs 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
Landscapes
- Thiazole And Isothizaole Compounds (AREA)
- Nitrogen- Or Sulfur-Containing Heterocyclic Ring Compounds With Rings Of Six Or More Members (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
Description
「産業上の利用分野」
本発明化合物は新規化合物であり、その光学活性体はカ
ルシウム拮抗作用を有すふ光学活性なベンゾチアジン及
びベンゾチアゾリン化合物の合成中間体として有用なも
のである。
「従来の技術」
循環器官系疾患に有用なベンゾチアジン誘導体を開示し
た文献には、特開昭５９−１４８７７１号、同６０−１
５６６７９号、同６０−１６６６７４号があり、ベンゾ
チアゾリン誘導体につ−ては特開昭５８−４６０７９号
、同５９−６７２７６号、同６０−１３９６７９号、同
６１−８３１７５号がある。これらの文献は光学活性体
を含む化合物を開示しており、光学活性体の製法として
は、クロマトグラフィーによる分離、光学活性な酸と塩
を形成させ分割する方法などが記載されて粘る。
「発明が解決しようとする問題点および問題を解決する
ための手段」
本発明者等らは光学活性なベンゾチアジンおよびベンゾ
チアゾリン誘導体を得る方法をさらに鋭意検討した結果
、下記式（Ｉｌｌで表わ嘔れる化合物から容易に導くこ
とができる事を見論出した。この式［Ｉ）で表わされる
化合物は新規化合物であり。
循環器官系疾患に有用なベンゾチアジンおよびベンゾチ
アゾリン誘導体の合成中間体として侵れて〔式中 Ｒ１
け水素原子、低級アルキル基、低級アルコキシ基、ハロ
ゲン原子″！たはニトロ基から選択ぢれる１個または複
数の基を示す。
Ｒ２は水素原子、低級アルカノイル基または低級アルキ
ル基を示す。
Ｒ３は水素原子、低級アルキル基、低級アルコキシ基、
ハロゲン原子またはニトロ基から選択されｂ１個１たけ
複数の基を示す。
Ｒ４およびＲ５け同一かまたは異なって、水素原子もし
くけ低級アルキル基を示す。
Ｒ’＃−を水素原子、低級アルキル基、フェニル基また
けナフチル基を示し、フェニル基およびナフチル基は低
級アルキル基、低級アルコキシ基、ヒドロキシ基、ニト
ロ基またはハロゲン原子から選択される１個ま念は複数
の基で置換されていてもより０
Ｒ７は低級アルキル基、フェニルアルコキシ基またはフ
ェニル基を示し、フェニルアルコキシ基およびフェニル
基のフェニル環は低級アルキル基。
低級アルコキシ基、ニトロ基またはハロゲンＭ子から選
択される１個または複数の基で置換されていて本よい。
Ｒ８は水素原子、低級アルキル基、低級アルコキシｉ、
低ｉアルキルチオ基、ハロゲン原子、シアノ基または低
級アルカノイルアミン基を示す。
ｎはｏｉたＩｒ１ｌｆｔ示す。
ＸけＳまなＦｉｃ鴇を示す。以下同じ。〕上記で規定し
之基をさらに（わしく説明すると。
低級アルキル基とはメチル基、エチル基、プロピル基、
ヘキシル基等の１〜６個の炭素原子を有するアルキル基
を示し、ハロゲン原子とはフッ素。
塩素、臭素等を示し、低級アルコキシ基とはメトキシ基
、エトキシ基、プロポキシ基、ヘキシルオキシ基等の１
〜６個の炭素原子を有するアルコキシ基を示し、低級ア
ルカノイル基とはアセチル基。
ゾロビオニル基、ヘキサノイル基等の１〜６ｆｍの炭素
原子を有するアルカノイル基全示す。
本発明化合物は例えば、下記の方法によって製造するこ
とができる。すなわち、一般式［ｎ）で示されるラセミ
フェノール体と一般式〔ｍ〕で示される光学活性カルボ
ン酸を、混合酸無水物法、活性エステル法、ＤＣＣ法等
によシ縮合でせた後、得られたエステルのジアステレオ
マー混合物を分別再結晶、カラムクロマトグラフィー等
の方法により分離し２本発明化合物〔工〕を得ることが
できる。
〔ｎ ） 〔１１１］
「作用」
本発明化合物ＣＩ）はアルカリ加水分解、あるいは還元
反応によって光学活性なフェノール体〔■〕に導くこと
ができる。
〔Ｉ〕
ＣＰ！〕
石らに、光学活性フェノール体ＣＩＶ）は特開昭５９−
６７２７６号、特開昭５９−１４８７７１号等に開示し
てηる方法に従って循環器官系疾患に有用なベンゾチア
ジン及びベンゾチアゾリン誘導体（式〔■〕）に導くこ
とができる。以下にその概略の一例を示す。
〔■〕〔ｖ〕
ＶＤ
〔■〕
〔式中、Ｒ９，Ｒ１ｏＦｉ同一か又は異なって水素原子
。
低級アルキル基、シクロアルキル基、低級アルカノイル
基、フェニルカルボニル基、フェニル基又は置換低級ア
ルキル基を示し、フェニル基は低級アルキル基、ヒドロ
キシ基、低級アルコキシ基。
低級アルキレンジオキシ基、ハロゲン原子、ニトロ基、
シアノ基又は低級アルカノイルオキシ基で置換式れでい
てもよい。置換低級アルキル基の置換基はヒドロキシ基
、フェニル基、フェニルオキシ基、フェニルカルボニル
基又はピリジル基を示し、該フェニル基、フェニルオキ
シ基、フェニルカルボニル基のフェニル環およびピリジ
ル基は更に低級アルキル基、ヒドロキシ基、低級アルコ
キシ基、低級アルキレンジオキシ基、）１０ゲン原子。
ニトロ基、シアノ基又は低級アルカノイルオキシ基から
選択される１個又は複数の基で置換でれていてもよい。
又、Ｒ９とＨｌｏがいっしょになってモルホリン環、ピ
ペリジン環、ピペラジン環を形成してもよい。これらの
環は低級アルキル基、フェニル基、ヒドロキシ低級アル
キル基、フェニル低級アルキル基、フェニルカルボニル
基、フェニルカルボニル低級アルキル基、フェニル−（
ヒドロキシ）低級アルキル基を示し、該フェニル環は低
級アルキル基、低級アルコキシ基、低級アルキレンジオ
キシ基又はハロゲン原子で置換てれていてもよい。
Ｙはハロゲン原子、メタンスルホニルオキシ基またはヒ
ドロキシ基を示す。
Ｙ′はハロゲン原子を示す。
２は１〜６個の炭素原子を有する直鎖又は分枝のアルキ
レンを示す。
ｍはＯ又は１を示す。
ｐ＃ｉｏ又はｌ全示す。〕
「実施例」
実施例１
（＋）及び←）−３−アセチル−２−Ｃ２−［（２５）
−１−（ベンジルオキシカルボニル）ピロリジン−２−
イルカルボニルオキシ〕−５−メトキシフェニル〕ベン
ゾチアゾリン（、（＋）体：化合物１１ｍ１゜（ハ）体
：化合物ＮＩＩＬ２）の製造
士−３−アセチル−２−（２−ヒドロキシ−５＝メトキ
シフエニル）ベンゾチアゾリン（３６，２ｙ）の無水Ｄ
ＭＦ（１（１０ｄ）溶液を、６０％水素化ナトリウム（
５，３ｙ）の無水ＤＭＦ （５Ｍ’）懸濁液に窒素雰曲
気下、水冷撹拌しながら滴下する。滴下終了後室温で３
０分間撹拌する（Ａ液〕。
Ｎ−ベンジルオキシカルボニル−Ｌ−７’ロリン（３２
，９ｆ ）の無水Ｔ）ｉＦ （２００ｄ ）溶液に。
トリエチルアミン（１８，４ｄ ）を加え、窒素雰曲気
下、塩−氷の寒剤で冷却しながら、クロル炭酸イソブチ
ル（１７，１ｔｘｔ’）を滴下する。滴下終了後。
その温度でさらに４０分間撹拌する。反応液をＰ遇し、
そのｐ液を塩−氷の寒剤で冷却したＡ液に加える。反応
液を室温で３時間撹拌後減圧濃縮し。
残渣を氷水ｌｌ中に注ぎ、酢酸エチルで抽出する。
有機層を水、飽和食塩水で洗浄後、無水硫酸マグネシウ
ムで脱水する。溶媒を減圧留去して得られる油状物をシ
リカゲルカラムクロマトで精製し。
（＋）体１５．６ ｆ （収率２４．０％）及び（ハ）
体］ ３．Ｏｐ（収率２０．０％）ｆ得る。
（＋）体 Ｃｔｘ〕Ｄ＋ ３６２．６°（ｃ＝１．０．
メタノール）ＩＲ（ＫＢｒ、ａｍ−’、以下特記なき限
シ同シ。）１７６３．１６７０，１４９８，１４５８，
１３５０゜１３１８．１２９７，１２７１．１１７８．
１１２９゜（へ）体 〔α〕Ｄ −４５９，５°（ｃ＝
１．０．メタノール）ＩＲ：１７５７，１６６７．１４
８６，１４５７゜１４４８．１３７５，１３４８，１３
１６，１２９６゜１２７０．１１７２，１１２６．７４
３実施例２
（＋）及び（ハ）−３−アセチル−２−［２−（２Ｒ１
４Ｒ）−３−アセチル−２−（ｌ−ナフチル）チアゾリ
ジン−４−イルカルボニルオキシクー５−メトキシフエ
ニル〕ベンゾチアゾリン（（＋）体：化合物磁３．（ハ
）体：化合物阻４）の製造６０％水素化ナトリウム（１
０，５ｙ） の無水ＤＭＦ（１５０ｒｌｌ）Ｍ濁液に、
ｍ −３−７セ−ｙ−／Ｌ／−２−（２−ヒドロキシ−
５−メトキシフェニル〕ベンゾチアゾリン（７５，３９
）の無水ＤＭＦ（２００ｄ）溶液を水冷撹拌下滴下する
。滴下終了後水冷下さらに３０分間撹拌したのち、スク
シンイミドＣ２Ｒ，４Ｒ）−３−７セチルー２−（ｌ−
ナフチル）−４−チアゾリジンカルボキシレート（１９
９，２１？）の無水ＤＭＦ （１，５１）溶液を、一度
に加える０室温下２時間撹拌後氷水（約１０１）中に注
ぎ、酢酸エチルで抽出でる。有機層を飽和食塩水で洗浄
後、無水硫酸マグネシウムで脱水する。溶媒を減圧留去
して得られる油状物をシリ刀ゲルカラムクロマトで精製
し、（＋）体５８．Ｏｆ！ （収率４０．０％）および
（→体３９．５ ｆ （収率２７．ｏチ）を得る。
（＋）体 融点：１９８．５〜１９９．５℃（アセトニ
トリル）〔α〕Ｄ ＋６４４．（１°（ｃ＝１．１．ク
ロロホルム）ＩＲ：１７６３，１６４４，１４８７，１
３８１゜１３４１．１３２２．１３００．１２７３，１
２３Ｂ。
１１８０．１１３３，１０３０，７８１，７４３（へ）
体 〔α〕Ｄ−７８．０°（ｃ＝＝１．０．クロロホル
ム〕ＩＲ：１７５７，１６４９．１４８８，１４５８゜
１３７５．１３１ｇ、１２７２．１１７２，１１３８゜
実施例３
（→及び（→−３−アセチルー２−Ｃ２−Ｃ＜ ２Ｓ
。
４Ｓ）−３−アセチル−２−（２−メトキシフェニル）
チアゾリジン−４−イルカルボニルオキシクー５−メト
キシフエニル〕ベンゾチアゾリン（（＋）体：化合物Ｎ
ｃｔ５．（−３体：化合物階６）の製造Ｃ！：）−ａ−
アセチル−２−（２−ヒドロキシ−５−メ）キシフェニ
ル）ベンゾチアゾリン（３，９ｐ）及びＣ２３，４５）
−３−アセチル−２−"Industrial Application Field" The compound of the present invention is a new compound, and its optically active form is useful as a synthetic intermediate for optically active benzothiazine and benzothiazoline compounds having calcium antagonistic activity. "Prior Art" Documents disclosing benzothiazine derivatives useful for circulatory system diseases include JP-A-59-148771 and JP-A-60-1.
56679 and 60-166674, and regarding benzothiazoline derivatives, there are JP-A-58-46079, 59-67276, 60-139679, and 61-83175. These documents disclose compounds containing optically active substances, and the methods for producing optically active substances include separation by chromatography, separation by forming salts with optically active acids, and the like. "Problems to be Solved by the Invention and Means for Solving the Problems" The present inventors have further studied methods for obtaining optically active benzothiazine and benzothiazoline derivatives, and have found that the following formula (Ill) It was found that the compound represented by formula [I] is a new compound. It is used as a synthetic intermediate for benzothiazine and benzothiazoline derivatives useful for cardiovascular system diseases [in the formula R1
Represents one or more groups selected from a hydrogen atom, a lower alkyl group, a lower alkoxy group, a halogen atom or a nitro group. R2 represents a hydrogen atom, a lower alkanoyl group or a lower alkyl group. R3 represents a hydrogen atom, a lower alkanoyl group or a lower alkyl group. Hydrogen atom, lower alkyl group, lower alkoxy group,
b1 represents one or more groups selected from a halogen atom or a nitro group. R4 and R5 are the same or different and represent a hydrogen atom or a lower alkyl group. R'#- represents a hydrogen atom, a lower alkyl group, a phenyl group or a naphthyl group, and the phenyl group and the naphthyl group are one or more atoms selected from a lower alkyl group, a lower alkoxy group, a hydroxy group, a nitro group, or a halogen atom. R7 represents a lower alkyl group, a phenylalkoxy group or a phenyl group, and the phenyl ring of the phenylalkoxy group and the phenyl group is a lower alkyl group. It may be substituted with one or more groups selected from a lower alkoxy group, a nitro group, or a halogen group. R8 is a hydrogen atom, a lower alkyl group, a lower alkoxy i,
It represents a low i alkylthio group, a halogen atom, a cyano group, or a lower alkanoylamine group. n indicates oiIr1lft. Showing XkeS Mana Fic Toshi. same as below. ] The groups defined above are further defined (to explain in detail. Lower alkyl groups include methyl, ethyl, propyl,
It refers to an alkyl group having 1 to 6 carbon atoms such as a hexyl group, and the halogen atom is fluorine. Indicates chlorine, bromine, etc., and lower alkoxy groups include methoxy, ethoxy, propoxy, hexyloxy, etc.
It represents an alkoxy group having ~6 carbon atoms, and the lower alkanoyl group is an acetyl group. All alkanoyl groups having 1 to 6 fm carbon atoms such as zolobionyl group and hexanoyl group are shown. The compound of the present invention can be produced, for example, by the method described below. That is, after condensing the racemic phenol represented by the general formula [n] and the optically active carboxylic acid represented by the general formula [m] by a mixed acid anhydride method, an active ester method, a DCC method, etc., The diastereomer mixture of the obtained esters can be separated by methods such as fractional recrystallization and column chromatography to obtain the two compounds of the present invention. [n) [111] "Function" The compound CI) of the present invention can be converted into an optically active phenol compound [■] by alkaline hydrolysis or reduction reaction. [I] CP! ] Ishi et al. reported that the optically active phenolic substance CIV)
Benzothiazine and benzothiazoline derivatives (formula [■]) useful for circulatory system diseases can be derived according to the method disclosed in Japanese Patent Publication No. 67276, JP-A-59-148771, etc. An example of the outline is shown below. [■] [v] VD [■] [In the formula, R9 and R1oFi are the same or different and are hydrogen atoms. It represents a lower alkyl group, a cycloalkyl group, a lower alkanoyl group, a phenylcarbonyl group, a phenyl group, or a substituted lower alkyl group, and the phenyl group is a lower alkyl group, a hydroxy group, or a lower alkoxy group. Lower alkylene dioxy group, halogen atom, nitro group,
It may be substituted with a cyano group or a lower alkanoyloxy group. The substituent of the substituted lower alkyl group is a hydroxy group, phenyl group, phenyloxy group, phenylcarbonyl group, or pyridyl group, and the phenyl ring and pyridyl group of the phenyl group, phenyloxy group, and phenylcarbonyl group are further lower alkyl groups, Hydroxy group, lower alkoxy group, lower alkylene dioxy group,) 10 gene atoms. It may be substituted with one or more groups selected from a nitro group, a cyano group, or a lower alkanoyloxy group. Furthermore, R9 and Hlo may be combined to form a morpholine ring, a piperidine ring, or a piperazine ring. These rings are lower alkyl groups, phenyl groups, hydroxy lower alkyl groups, phenyl lower alkyl groups, phenylcarbonyl groups, phenylcarbonyl lower alkyl groups, phenyl-(
hydroxy) represents a lower alkyl group, and the phenyl ring may be substituted with a lower alkyl group, a lower alkoxy group, a lower alkylene dioxy group, or a halogen atom. Y represents a halogen atom, a methanesulfonyloxy group or a hydroxy group. Y' represents a halogen atom. 2 represents a straight-chain or branched alkylene having 1 to 6 carbon atoms. m represents O or 1. p#io or l is shown in full. ] “Example” Example 1 (+) and ←)-3-acetyl-2-C2-[(25)
-1-(benzyloxycarbonyl)pyrrolidine-2-
Manufacturer of ylcarbonyloxy]-5-methoxyphenyl]benzothiazoline (, (+) form: compound 11m1゜(c) form: compound NIIL2) -3-acetyl-2-(2-hydroxy-5=methoxyphenyl) ) Anhydrous D of benzothiazoline (36,2y)
MF (1 (10d) solution was dissolved in 60% sodium hydride (
5,3y) in anhydrous DMF (5M') under a nitrogen atmosphere while cooling with water and stirring. 3 at room temperature after completion of dropping.
Stir for 0 minutes (liquid A). N-benzyloxycarbonyl-L-7'loline (32
,9f) in anhydrous T)iF (200d) solution. Triethylamine (18,4d) is added, and isobutyl chlorocarbonate (17,1txt') is added dropwise under a nitrogen atmosphere while cooling with a salt-ice cryogen. After the dripping is finished. Stir at that temperature for an additional 40 minutes. Treat the reaction solution with P,
Add the P solution to A solution cooled with a salt-ice cryogen. The reaction solution was stirred at room temperature for 3 hours and then concentrated under reduced pressure. Pour the residue into 1 liter of ice water and extract with ethyl acetate. The organic layer is washed with water and saturated brine, and then dehydrated with anhydrous magnesium sulfate. The oil obtained by distilling off the solvent under reduced pressure was purified using silica gel column chromatography. (+) body 15.6 f (yield 24.0%) and (c)
body] 3. Op (yield 20.0%) f is obtained. (+) body Ctx]D+ 362.6° (c=1.0.
methanol) IR (KBr, am-', the same hereinafter unless otherwise specified) 1763.1670, 1498, 1458,
1350°1318.1297,1271.1178.
1129° (he) body [α]D -459,5° (c=
1.0. methanol) IR: 1757, 1667.14
86,1457°1448.1375,1348,13
16,1296°1270.1172,1126.74
3 Example 2 (+) and (c)-3-acetyl-2-[2-(2R1
4R)-3-acetyl-2-(l-naphthyl)thiazolidin-4-ylcarbonyloxycu-5-methoxyphenyl]benzothiazoline ((+) form: Compound 3. (C) form: Compound 4) Manufacture 60% sodium hydride (1
0.5y) in anhydrous DMF (150 rll) M suspension,
m -3-7se-y-/L/-2-(2-hydroxy-
5-Methoxyphenyl]benzothiazoline (75,39
) in anhydrous DMF (200d) was added dropwise to the mixture under water cooling and stirring. After the dropwise addition was completed, the mixture was further stirred for 30 minutes under water cooling, and then succinimide C2R,4R)-3-7 cetyl-2-(l-
naphthyl)-4-thiazolidinecarboxylate (19
9,21? ) in anhydrous DMF (1,51) is added at once and stirred at room temperature for 2 hours, then poured into ice water (approximately 101) and extracted with ethyl acetate. The organic layer is washed with saturated brine and then dehydrated with anhydrous magnesium sulfate. The oil obtained by distilling off the solvent under reduced pressure was purified using silica gel column chromatography to obtain (+) form 58. Of! (yield: 40.0%) and (→-isomer: 39.5 f (yield: 27.ochi). (1° (c=1.1.chloroform) IR: 1763, 1644, 1487, 1
381°1341.1322.1300.1273,1
23B. 1180.1133,1030,781,743(to)
Body [α]D-78.0° (c==1.0.Chloroform] IR: 1757, 1649.1488, 1458° 1375.131g, 1272.1172, 1138° Example 3 (→ and (→-3 -acetyl-2-C2-C<2S
. 4S)-3-acetyl-2-(2-methoxyphenyl)
Thiazolidin-4-ylcarbonyloxycu-5-methoxyphenyl]benzothiazoline ((+) form: Compound N
ct5. Production C of (-3 bodies: compound level 6)! :)-a-
Acetyl-2-(2-hydroxy-5-meth)xyphenyl)benzothiazoline (3,9p) and C23,45)
-3-acetyl-2-
【２−メトキシフェニル】−４−
チアゾリジンカルボン酸（４，Ｏｆ ）のＤＭＦ （２
０ｄ）溶液に、Ｎ、Ｎ′−ジシクロへキシルカルボジイ
ミド（２−９９）及Ｕ４−ジメチルアミノピリジン（０
，３９ｆ ）を加える。
反応液を室温で１．５時間撹拌後、無水シュウ酸（０，
１６９）を加え室温でぢらに３０分間撹拌し友後、析出
物を戸別する。ｐ液に飽和重曹水を加え酢酸エチルで抽
出し、有機層を飽和重曹水１次論で飽和食塩水で洗浄後
無水硫酸マグネシウムで脱水する。溶媒を減圧留去し、
残渣にベンゼン−メタノール混液を加えて析出する結晶
を戸数し、←）体の結晶２．３９ （収率３２．０％）
を得る。
母液を減圧濃縮後／リカゲルカラムクロマトで精製し、
（＋）体の粉末３．２ ｙ（収率４３．０％）を得る。
（＋）体 〔α〕Ｄ ＋２０７．８°（ｃ＝１．０．ク
ロロホルム）ＩＲ：］７５８，１６４７，１５９６，１
５８７゜１４８７．１３１９，１２９６，１２７３，１
２４１゜１１７２．１１３９，１１０３，１０２２．７
４６に）体 融点：２２２．５〜２２３．５°Ｃ（クロ
ロホルム−アセトニトリル〕
〔α〕 −５７６，５（（Ｈ＝ｌ、Ｑ、クロロホルム）
ＩＲ：１７６４，１６４７．１４８９．１３ｇ３゜１３
２４．１２９９．１２７１，１２４１，１１８２゜１１
３６．１０２５．７５０
同様にして以下の化合物が得られる。
（＋）−３−アセチル−２−Ｃ２−ＣＣ２Ｒ，４Ｒ）−
３−ベンジルオキシカルボニル−２−ナフチルチアゾリ
ジン−４−イルカルボニルオキシシー５−メトキシフエ
ニル〕ベンゾチアゾリン（化合物隘７）
融点＝１２６〜１２９℃（アセトニトリル）Ｃｒｔ〕：
” ＋ ４７０．０°（ｃ＝１．９．クロロホルム）Ｉ
Ｒ： ３３２０．２９１６，１７６３，１６８３゜１６
２３．１５７１，１４５８，１３８１，１３４０゜１３
０７．１２７２，１１３９．７４５Ｈ−３−アセチル−
２−（２−（（２Ｒ、４Ｊ？ ）−３−ベンジルオキシ
カルボニル−２−ナフチルチアゾリジン−４−イルカル
ボニルオキシシー５−メトキシフエニル〕ベンゾチアゾ
リン（化合物Ｎ１８）
融点＝９７〜１０２℃（了セトニトリル）（α、：］Ｄ
ｌ ｌ ７−２°（ｃ＝１．０．クロロホルム）
ＩＲ：３３８８．１７５９．］６７６．１４８９゜１４
６１．１３７９．１３］３，１２７２，１１７３゜１１
４０．１０２６，７７６．７４４
（＋３−３−アセチル−２−Ｃ２−Ｃ＜ ２Ｊ？、４７
？）−３−ベンゾイル−２−（ｌ−ナフチル）チアゾリ
ジン−４−イルカルボニルオキシ］−５−メトキシフェ
ニル〕ベンゾチアゾリン（化合９／Ｉｔｋｇ）融点：
１４５〜１４７℃（酢酸二チル−エタノール）
ＣαｌＤ＋ ４８６．４°（ｃ＝１．０．クロロホルム
）ＩＲ：１７６４，１６６４，１６２９，１４８９゜１
４６２．１３７０，１３４６，１３］７，１２９９゜１
２７３．１２２８，１１７９，１１５２．１１２４゜（
＋）−３−アセチル−２−（２−Ｃ（２ｘ、４ｎ）−３
−ベンジルオキシカルボニル−２−（２−ヒドロキシフ
ェニル）チアゾリジン−４−イルカルボニルオキシシー
５−メトキシフエニル〕ペンツチアゾリンＡ（化合物隘
１０）
融点：１４５〜１４７−５℃（ベンゼン−酢酸エチル）
〔α］Ｄ ＋３９２．９°（ｃ＝１．０．クロロホルム
）ＩＲ：３３６ｇ、１６８５，１６４７，１４９１゜１
３９６．１３５０，１３２５，１２７３，１２４３゜１
２２７．１１８９，１１７７．７４６ＴＬＣ：Ｒｆ Ｏ
，２７（シリカゲル、ｎ−ヘキサン−ベンゼン−酢酸エ
チル＝１：５：１゜以下同じ）
（＋）−３−アセチル−２−Ｃ２−（（２Ｒ，４Ｒ）−
３−ベンジルオキシカルボニル−２−（２−ヒドロキシ
フェニル）千アプリジンー４−イル刀ルボニルオキシ〕
−５−メトキシフェニル〕ベンゾチアゾリンＢ（化合物
磁１１）
〔α〕Ｄ ＋１７４．７Ｌ′（ｃ＝０．５．クロロホル
ム）ＩＲ：１７５７，１６７３，１４４８．１３１９゜
１２７２．１２４４．１２３２，１１２９，１０９１゜
ＴＬＣ：Ｒｆ ０．１７
得られる２ａ［のジアステレオマーの旋光度〔α〕。
が同一の符号を示す場合は、シリカゲルＴＬＣ上。
ｎ−ヘキサン−ベンゼン−酢酸エチル＝１：５：１で展
開する時Ｒｆ値の大きいもの１ｋＲｆ大、小さいものを
Ｒｆ小と記載。
（→−３−７セチルー２−Ｃ２−Ｃ（２ｘ、４ｘ＞−３
−アセチル−２−フェニルチアゾリジン−４−（ルヵル
ボニルオキシ〕−５−メトキシフェニル〕ベンゾチアゾ
リン（化合物隘１２）ＭＡ：２１２〜２１３℃（酢酸エ
チル−了セトニ ト リ ル ）
〔α）Ｄ ＋５３１．４°（ｃ＝１．０．クロロホルム
）ＩＲ：３３７２，３１２４．２９８０．１７６２゜１
６５４．１４５７，１３８８．１３２５．１１３４Ｈ−
３−アセチル−２−Ｃ２−Ｃ： （２Ｒ，４Ｒ）−３−
アセチル−２−フェニルチアゾリジン−４−イルカルボ
ニルオキシヨー５−メトキシフエニル〕ベンゾチアゾリ
ン（化合物％１３）融点：１６５〜１６７℃（イノプロ
ピルエーテル−ベンゼン〕
〔α：ｌ −３５８，３° （ｃ＝１．０．クロロ
ホｌレム〕ＩＲ： １７５２．１６５４．１４６２，１
３８０゜１３４２．１２７２．１１５０
（＋１−３−アセチル−２−（２−Ｃ（２Ｒ，４Ｒ）−
３−ベンジルオキシカルボニル−
トキシフェニル）チアゾリジン−４−イルカルボニルオ
キシ〕ー５ーメトキシフェニル〕ベンゾチアゾリン（化
合＠ＮＩ１１４）
融点： １ ５ ５．５〜１５７℃（酢酸エチル−アセ
トニトリル）
〔α） ＋４４２．２°（ｃ＝１．０，クロロホｌ
レム）ＩＲ：１７６３，１ ６７６、１ ４５８，］
３８５。
１３５２、１３２２．１１４０
（へ）−３−アセチル−２−Ｃ ２−Ｃ （ ２Ｒ，４
Ｒ）−３−ベンジルオキシカルボニル−２−（２−メト
キシフェニル）チアゾリジン−４−イルカルボニルオキ
シヨー５−メトキシフエニル〕ベンゾチアゾリン[2-methoxyphenyl]-4-
Thiazolidinecarboxylic acid (4,Of) in DMF (2
0d) N,N'-dicyclohexylcarbodiimide (2-99) and U4-dimethylaminopyridine (0
, 39f). After stirring the reaction solution at room temperature for 1.5 hours, oxalic anhydride (0,
169) was added and stirred for 30 minutes at room temperature, and then the precipitate was removed. Add saturated aqueous sodium bicarbonate to the p solution, extract with ethyl acetate, wash the organic layer with saturated aqueous sodium bicarbonate and saturated brine, and then dehydrate over anhydrous magnesium sulfate. Remove the solvent under reduced pressure,
Add benzene-methanol mixture to the residue, count the number of crystals that precipitate, and obtain 2.39 crystals of ← (yield 32.0%)
get. After concentrating the mother liquor under reduced pressure/purifying it with licage gel column chromatography,
(+) powder 3.2 y (yield 43.0%) was obtained. (+) body [α]D +207.8° (c=1.0.chloroform) IR:]758,1647,1596,1
587°1487.1319,1296,1273,1
241°1172.1139,1103,1022.7
46) body Melting point: 222.5-223.5°C (chloroform-acetonitrile] [α] -576,5 ((H=l, Q, chloroform)
IR:1764,1647.1489.13g3゜13
24.1299.1271,1241,1182゜11
36.1025.750 The following compound is obtained in the same manner. (+)-3-acetyl-2-C2-CC2R,4R)-
3-benzyloxycarbonyl-2-naphthylthiazolidin-4-ylcarbonyloxy-5-methoxyphenyl]benzothiazoline (compound 7) Melting point = 126-129°C (acetonitrile) Crt]:
” + 470.0° (c=1.9.chloroform) I
R: 3320.2916, 1763, 1683°16
23.1571, 1458, 1381, 1340°13
07.1272,1139.745H-3-acetyl-
2-(2-((2R,4J?)-3-benzyloxycarbonyl-2-naphthylthiazolidin-4-ylcarbonyloxy-5-methoxyphenyl)benzothiazoline (Compound N18) Melting point = 97-102°C (Compound N18) Setonitrile) (α, :]D
l l 7-2° (c=1.0.chloroform)
IR:3388.1759. ]676.1489°14
61.1379.13] 3,1272,1173°11
40.1026,776.744 (+3-3-acetyl-2-C2-C< 2J?, 47
? )-3-benzoyl-2-(l-naphthyl)thiazolidin-4-ylcarbonyloxy]-5-methoxyphenyl]benzothiazoline (compound 9/Itkg) Melting point:
145-147°C (dityl acetate-ethanol) CαID+ 486.4° (c=1.0.chloroform) IR: 1764, 1664, 1629, 1489°1
462.1370,1346,13]7,1299゜1
273.1228, 1179, 1152.1124゜(
+)-3-acetyl-2-(2-C(2x,4n)-3
-benzyloxycarbonyl-2-(2-hydroxyphenyl)thiazolidin-4-ylcarbonyloxy-5-methoxyphenyl] pentthiazoline A (compound 10) Melting point: 145-147-5°C (benzene-ethyl acetate) [ α]D +392.9° (c=1.0.chloroform) IR: 336g, 1685, 1647, 1491°1
396.1350, 1325, 1273, 1243゜1
227.1189, 1177.746TLC:Rf O
, 27 (silica gel, n-hexane-benzene-ethyl acetate = 1:5:1°, the same below) (+)-3-acetyl-2-C2-((2R,4R)-
3-benzyloxycarbonyl-2-(2-hydroxyphenyl)thousandyloxycarbonyloxy]
-5-methoxyphenyl]benzothiazoline B (compound magnetic 11) [α]D +174.7L' (c=0.5.chloroform) IR: 1757, 1673, 1448.1319° 1272.1244.1232, 1129, 1091 °TLC: Rf 0.17 Optical rotation [α] of the diastereomer of 2a obtained. on silica gel TLC if show the same sign. When developing with n-hexane-benzene-ethyl acetate = 1:5:1, the one with a large Rf value is described as 1kRf high, and the one with a small Rf value is described as small Rf. (→-3-7 Cetyl-2-C2-C (2x, 4x>-3
-Acetyl-2-phenylthiazolidine-4-(carbonyloxy]-5-methoxyphenyl]benzothiazoline (compound 12) MA: 212-213°C (ethyl acetate-acetonitrile) [α) D +531 .4° (c=1.0.chloroform) IR: 3372, 3124.2980.1762°1
654.1457, 1388.1325.1134H-
3-acetyl-2-C2-C: (2R,4R)-3-
Acetyl-2-phenylthiazolidin-4-ylcarbonyloxyyo5-methoxyphenyl]benzothiazoline (compound% 13) Melting point: 165-167°C (inopropyl ether-benzene) [α: l -358,3° (c =1.0.chlorophorem]IR: 1752.1654.1462,1
380°1342.1272.1150 (+1-3-acetyl-2-(2-C(2R,4R)-
3-benzyloxycarbonyl-toxyphenyl)thiazolidin-4-ylcarbonyloxy]-5-methoxyphenyl]benzothiazoline (compound @ NI114) Melting point: 1 5 5.5-157°C (ethyl acetate-acetonitrile) [α) +442 .2° (c=1.0, chlorophor
Rem) IR: 1763, 1 676, 1 458,]
385. 1352, 1322.1140 (to)-3-acetyl-2-C2-C (2R,4
R)-3-benzyloxycarbonyl-2-(2-methoxyphenyl)thiazolidin-4-ylcarbonyloxy-5-methoxyphenyl]benzothiazoline
【化合
動磁１５】
〔α） −２０７．９°（ｃ＝１．０，クロロホルム
）ＩＲ：１７６３．１６７４，１４８９，１３８０。
１３５０、 １３２０， １２９４， １ ２７３，
］ ２４２。
１２２７、１１８９，１１７２．１１４１，１１０２。
（＋１−３−アセチル−２−１： ２−（ （ ２Ｒ，
４Ｒ）−３−アセチル−２−（２−メトキシフェニル）
チアゾリジン−４−イルカルボニルオキシヨー５−メト
キシフエニル〕ベンゾチアゾリン（化合物ｌｋＬ１６）
融点＝２２３〜２２４℃（酢酸エチル−エタノール）
〔α） ＋５０７．０°（ｃ＝１．（１，クロロホル
ム）ＩＲ： １７６３，１ｆｔ４６．１４８７．１４
５９。
１３８３、１３２２，１２７３，１２４０．１１８２。
１１３４、１１０４，ｌ ０２０，７４９Ｈ−３−アセ
チル−２−Ｃ ２−（ （ ２Ｒ，４Ｒ ）−３−アセ
チル−２−（２−メトキシフェニル）−チアゾリジン−
４−イルカルボニルオキシヨー５−メトキシフエニル〕
ベンゾチアゾリン（化合物阻１７）
〔α）Ｄ−２ ０ ８．７°（ｃ＝１．０，クロロホル
ム）ＩＲ：１７５８．］６５４，１４８７，１４５９。
１３７７、１３１９，１２７３，１２４１，１１７１。
１１３８、１１０３，１０２１．７４５（＋１−３−ア
セチル−２−Ｃ２−ＣＣ２５，４Ｂ）−３−アセチル−
５．５−ジメチル−２−（２−メトキシフェニルフチア
ゾリジン−４−イルカルボニルオキシヨー５−メトキシ
フエニル〕ベンゾチアゾリン（化合物阻１８）
〔α：］ ＋２１９．５°（ｃ＝１．１，クロロホ
ルム）ＩＲ：１７５２，１６５３，１６４７，１４８７
。
］４５８，ｌ：（７６、１３２０，］２７３，１２４２
。
１１７１、１１３９，１１０５，１０２２．７４６に）
−３−アセチル−２−（：２−Ｃ ＜ｚｓ，４ｓ）−３
−アセチル−５．５−ジメチル−２−（２−メトキシフ
ェニル）チアゾリジン−４−イルカルボニルオキシヨー
５−メトキシフエニル〕ベンゾチアゾリン（化合動磁１
９）
融点＝１９４〜２００℃（アセトニトリル）ＣａＪＤ−
ｓ ２ ７．８°（ｃ＝１．ｏ，クロロホルム〕ＩＲ：
１７７４，１６７０．１６３７．１５８Ｂ。
１４８３、１３８０．１３０１，１２７０，１２４０。
１１２３、１１０８，１０２３．７４５（＋）−３−ア
セチル−２−［２−Ｃ （２５，４５）−３−ベンジル
オキシカルボニル−５．５−−）メチル−２−（２−メ
トキシフェニル）チアゾリジン−４−イルカルボニルオ
キシヨー５−メトキシフエニル〕ベンゾチアゾリン（化
合物１に２０）〔α〕Ｄ ＋２５１．９°（Ｃ＝１．０
，クロロホルム）ＩＲ：３３８８，２９２４．１７５０
，１６７５。
１５８７、１４８９，１４５８，１３８０．１３２０。
１２７５、１２４２，１１７３，１１３１，１０２４。
Ｈ−３−丁セチル−２−ｆ：２−（（２５，４５）−３
−ベンジルオキシ方ルボニルー５，５−ジメチル−２−
（２−メトキシフエニｌしフチアゾリジン−４−イルカ
ルボニルオキシ〕−５−メトキシフェニル〕ベンゾチア
ゾリン（化合動磁２１）〔αｌ：］Ｄ−３９９．７°（
ｃ＝１．１．クロロホルム）ＩＲ：３３７６．２９２０
．１７６４，１６７６゜１５８６．１４８８，１４５９
，１３８２，１３２１゜１２７３．１２４１，１１７７
．１１３１，１０２４゜（＋）−３−アセチル−２−Ｃ
２−Ｃ（２５，４Ｓ）−３−アセチル−５，５−ジメチ
ル−２−フェニルチアゾリジン−４−イルカルボニルオ
キシフ−５−メトキシフエニル〕ベンゾチアゾリン（化
合物を敏２２）
〔α：ｌＤ＋２７７．１°（ｃ＝１．０．クロロホルム
）ＩＲ：１７５１，１６３９．１４８７，１３７４゜１
３２０．１２７２，１１７１，１１２７，１０２６゜←
）−３−アセチル−２−（２−ＣＣ２ｓ、４ｓ＞−３−
アセチル−５，５−ジメチル−２−フェニルチアゾリジ
ン−４−イルカルボニルオキシフ−５−メトキシフエニ
ル〕ベンゾチアゾリン−メタノール（１／ｌ）（化合物
Ｎ１２３）
融点＝１２５〜１２７℃（分解）（アセトニトリル−メ
タノール〕
（α）Ｄ−４ｇ ７．９°（ｃ＝１．１．クロロホルム
）ＩＲ：１７６４，１６３７．１４Ｂ５，１４５６゜１
３７５．１３２０，１２７１，１１７５，１１２３゜１
０２７．７３７
（＋）−３−アセチル−２−Ｃ２−ＣＣ２Ｓ、４Ｓ）−
３−アセチル−２−フェニルチアソリシン−４−イルカ
ルボニルオキシ］−５−メトキシフェニル〕ベンゾチア
ゾリン（化合動磁２４）Ｃａ〕Ｄ＋３２７．３°（ｃ＝
１．０．クロロホルム）ＩＲ：３４］２，２９２０．ｌ
’７５ｇ、１６５１゜１６４７．１４６１，１３７６．
１１７６．１１３７゜１０２７．７４４，７２６
（−１−３−アセチル−２−Ｃ２−〔（２Ｓ、４Ｓ）−
３−アセチル−２−フェニルチアソリシン−４−（ルカ
ルボニルオキシ〕−５−メトキシフェニル〕ベンゾチア
ゾリン（化合物１ＩｋＬ２５）融点：１９９〜２０２℃
（アセトニトリル）〔α）ｎ ４３１−１’ （ｃ
＝１−０−クロロホルム〕ＩＲ：３３２０．２９２０
．１７６３，１６５３゜１４６０．１３８８，１１７９
，１１３４，１０２９゜また、ω−３−アセチル−２−
（２−ヒドロキシ−５−メトキシフェニル）ベンゾチア
ゾリンのかわりに、Ｃ：）−’３．４−ジヒドロー２−
（２−ヒドロキシ−５−メトキシフェニル）−４−メチ
ル−３−オキソ−２）ｉ−１，４−ベンゾチアジンを用
ηて、実施例１〜３０方法と同様に操作して以下の化合
物を得る。
（−）−２−Ｃ２−Ｃ（２Ｓ、４Ｓ）−３−アセチル−
５，５−ジメチル−２−（２−メトキシフェニル）チア
ゾリジン−４−イルカルボニルオキシフ−５−メトキシ
フェニル）−３，４−ジヒドロ−４−メチル−３−オキ
ソ−２Ｈ−１，４−ベンゾチアジン（化合動磁２６（Ｒ
ｆ大）、化合物１１ｋＬ２７（Ｒｆ小））Ｒｆ大 Ｃ（
ｔ〕Ｄ−１０８，６°（ｃ ＝ １．０ 、、クロロホ
ルム）ＩＲ： １７５５，１６４６，１４５７．１３７
６゜１３５３．１３２８．１２７９，１２４２，１１８
９゜１１３６．１１０５，１０２４．７４８Ｒｆ小融点
：１６５〜１６６℃（ｎ−ヘキサン−ベンゼン）
〔α］Ｄ −１０８，３６（ｃ＝１．０．クロロホルム
）ＩＲ：１７５６，１６５３，１４８８．１４５７゜１
３７３．１３３１，１２８０．１２４４，１１９２゜１
１７７．１１３９，１１０６，１０２５．７４８（→−
２−Ｃ２−Ｃ（２Ｒ，４Ｒ）−３−アセチル−２−フェ
ニルチアゾリジン−４−イルカルボニルオキシフ−５−
メトキシフェニル］−３，４−ジヒドロ−４−メチル−
３−オキソ−２Ｈ−１，４−ベンゾチアジン（化合物％
２８（Ｒｆ大）、化合動磁２９（Ｒｆ小））
Ｒｆ大大魚点１４８〜１５０℃（ｎ−ヘキサンーペンゼ
／）
〔α：ｌＤ＋ ］ ｌ ７．９° （ｃ＝１．０．クロ
ロホルム）ＩＲ：１７７０．１６４Ｂ、１３９０，１３
５２゜１１９７，１１４１，７５１，７２７
Ｒｆ小 〔α：）Ｄ＋０．８°（ｃ＝１．１．クロロホ
ルム〕ＩＲ： １７５９．ｌ ６５３，１３８３，１３
５１゜１１９４．１１４０．７４８
（＋）−２−（２−Ｃ（ｚｘ、４ｘ）−ａ−了セチル−
２−（２−ヒドロキシフェニル）チアゾリジン−４−イ
ルカルボニルオキシフ−５−メトキシフェニル）−３，
４−ジヒドロ−４−メチル−３−オキソ−２）１−１．
４−ベンゾチアジン（化合物Ｎ１１３０（Ｒｆ大））
〔α〕っ ＋１８５．２°（ｃ＝１．ｏ、クロロホルム
）ＩＲ：１７５９，１６４９．１５Ｂ４，１４５７゜］
３８４，１３４８，１２８０．１２４２，１１９２゜１
１３５．１１０３，１０２２．７４８Ｈ−３，４−ジヒ
ドロ−２−〔２−（（２Ｓ、４Ｓ）−３−アセチル−５
，５−ジメチル−２−フェニルチアゾリジン−４−イル
カルボニルオキシフ−５−メトキシフェニル〕−４−メ
チル−３−オキソ−２１４−１，４−ベンゾチアジン（
化合物Ｎ１３１ＣＲｆ大）、化合動磁３２（Ｒｆ小））
Ｒｆ大融点：２０２〜２０３．５℃（酢酸エチル）〔α
） −６７，６°（ｃ＝０．５．クロロホルム）ＩＲ
： １７７１，１６３９，１４４８．］ ３５８゜１３
３６．１２９０，１２５１，１１７６．１１１２゜１０
３０．７３１
Ｒｆ小融点：１８８〜１８９．５℃（ｎ−へキサン−ベ
ンゼン）
Ｃａ〕Ｄ−８６，７°（ｃ＝０．６．クロロホルム）Ｉ
Ｒ：］７５７，１６５２，１４７９，１４４７゜１３６
１．１３２９，１１９１．１１７３参考例１
（＋）−３−丁セチル−２−（２−ヒドロキシ−５−メ
）キシフェニル）ベンゾチアゾリン（化合動磁３３）の
製造
実施例２で得られる（＋１−３−アセチル−２−〔２−
Ｃｔｚｘ、４ｘ〕−ａ−アセチル−２−（１−ナフチル
）千アプリジンー４−イルカルボニルオキシ〕−５−メ
トキシフェニル〕ベンゾチアゾリン（化合物１ｋＬ３）
（２８，Ｏｙ）のＤＭＦ（５００１１Ｉｌ）ｆＩ！Ｉ液
に、水冷撹拌下、ＩＮ水酸化ナトリウム水溶液（１４４
ｍ）を加え水冷下５分間９欠論で室温で１５分間撹拌す
み。反応液に０．５ Ｎ塩＠（１，５／ ）を加え酢酸
エチルで抽出する。有機層を飽和重曹水、ｌＮｊ！醗、
飽和食塩水の順に況浄したのち、無水硫酸マグネシウム
で脱水する。溶媒を減圧留去して得られる油状物にクロ
ロホルム−シクロヘキサンの混液を加え結晶を得、イソ
プロピルエーテルから再結晶して標記化合物１３．３９
・（収＄ ９２．０％）を得る。
融点：１３０〜］ ３１．５℃（イソプロピルエーテル
）
〔α）Ｄ＋４１６．５°（ｃ＝１．０．クロロホルム）
ＩＲ：３３３２，１６３７，１５０２，１４６４゜１４
２９．１３８１，１３５１，１２７２．１２０２゜本化
ｆ物（化合４１ｆｆＦｋＬ３３ ）は化合１ｍ！ｋＬ３
のかわりに化化合動磁１．５，７，９，１０，１２，１
４゜１６．１ｇ、２０．２２″′！たは２４を用論参考
例１と同様に操作することによっても得られる。
化合動磁３のかわシ〈化合物Ｎ１２，４，６，８゜１１
．１３，１５，１７，１９，２１，２３まなは２５を用
す参考例１と同様に操作し、Ｈ−３−丁セチル−２−（
２−ヒドロキシ−５−メトキシフェニル）ベンゾチアゾ
リン（化合物Ｎ１３４）を得る。
融点：１３１．５〜１３３℃（酢酸エチル−ｎ−ヘキサ
ン〕
（：α） −４３６，２°（ｃ＝１．０．りｏｏホル
ム）ＩＲ二３３２０． １６３６． １５０２． １４
６３゜１４２９．１３７Ｂ、１３４９，１２７１，１２
０１゜化合動磁３のかわりに化合物Ｎ１２７．２９また
は３２を用す参考例１と同様に操作し、（＋） −３４
−ジヒドロ−２−（２−ヒドロキシ−５−メトキシフェ
ニル）−４−メチル−３−オキソ−２）１−１゜４−ベ
ンゾチアジン（化合物１１＆Ｌ３５）を得る。
融点＝１６２〜１６３℃（ベンゼン−ｎ−へキサン）
〔α）Ｄ＋３８．９°（ｃ＝１．０．クロロホルム）Ｉ
Ｒ：３２０８．１６２４．１５８２，１４２８゜１３６
５．１２６４，１２１８．１２００化合物磁３のかわシ
に化合動磁２６，２８．３０また＃−ｔ３１を用す参考
例１と同様に操作し、Ｈ−３，４−ジヒドロ−２−（２
−ヒドロキシ−５−メトキシフェニル）−４−メチル−
３−オキソ−２Ｈ−１，４−ベンゾチアジン（化合物１
虹３６）を得る。
融点：１６０．０〜１６１”Ｃ（ベンゼン）〔α）
−４２，０°（ｃ＝１．３．クロロホルム）ＩＲ：３２
０４，１６２４，１５７９．１４２８゜１３６５．１２
６３．１１９９
参考例２
（＋１−３−アセチル−２−〔５−メトヤシ−２−（４
−ＣＮ−メチル−Ｎ−（３，４，５−トリットキシフェ
ネチル〕アミノ〕ブトキシ〕フェニル〕ベンゾチアゾリ
ン塩酸塩（化合物１１ｈ３７）の製造６０チ水素化ナト
リウム（４４０Ｍ９）の無水ＤＭＦ（１０ゴ）懸濁液に
、水冷撹拌下、参考例１で得られた（＋）−３−アセチ
ル−２−（２−ヒドロキシ−５−メトキシフェニル）ベ
ンゾチアゾリン（化合物ｌｌ＆Ｌ３３，３．０１？）の
無水ＤＭＦ （６ｄ）溶液を滴下し、室温で１０分間撹
拌する。反応液に１，４−ジブロモブタン（１１，８ｒ
ｎｌ）を加え。
室温で３０分間撹拌後水中に注ぎ、エーテルで抽出する
。有機層を水、ＩＮ水酸化ナトＩＪウム、飽和食塩水の
順に洗浄後無水硫酸マグネシウムで脱水する。溶媒を減
圧留去して得られる油状物をシリカゲルカラムクロマト
で精製し、（＋）−ａ−アセチル−２−（２−（４−ブ
ロモブトキシクー５−メトキシフエニル〕ベンゾチアゾ
リン３．８０ ？ （収率８７．０％）を得る。
融点：８４．５〜８５．５℃（エタノール）〔α）Ｄ
＋６４９．３°（ｃ＝１．０ 、クロロホルム）ＩＲ：
１６７４．３４９９，１４６３，１３７８゜１２１４．
１０４３．７５１
さらに、上で得られた（＋）−ブロマイド（２，１０ｙ
）及びＮ−メチル−３，４，５−トリットキシフェネチ
ルアミン（１，２０ｙ）のＤＭＦ （７，：Ｍ）溶液に
炭酸方すウム１，３０ｙ１ｒ：加え、６０℃で２時間撹
拌する。反応混合物全水中に注ぎ、クロロホルムで抽出
し、有機層を水、飽和食塩水の順に洗浄後、無水硫酸マ
グネシウムで脱水する。溶媒を減圧留去して得られる油
状物をシリカゲルカラムクロマトで精製後、塩酸塩とし
、標記化合物２．３０ｙ（収率７７．０チ）を得る。
〔α） ＋４４６．９°（ｃ＝１．１．クロロホルム
）ＩＲ：１６６４，１５８９，１４９６，１４６２゜１
４２４．１３７７、］２７５，１２３６，１２０７゜同
様にして、（−）−３−アセチル−２−〔５−メトキシ
−２−Ｃ４−ＣＮ−メチル−Ｎ−（３，４゜５−トリッ
トキシフェネチル）アミノ〕ブトキシ〕フェニル〕ペン
ゾチ了ゾリン塩酸塩（化合動磁３８）を、Ｈ−３−アセ
チル−２−（２−ヒドロキシ−５−メトキシフェニル）
ベンゾチアゾリン（化合物１１＆１Ｌ３４）から得るこ
とができる。
（α’）Ｄ−４４１，２°（ｃ＝１．０．クロロホルム
）ＩＲ：１６６３，１５８９，１４９３，１４６０゜１
４２３．１３７６．１２７４，１２３５．１２０７゜参
考例３
（＋）−３，４−ジヒドロ−２−〔５−メトキシ−２−
Ｃ３−ＣＮ−メチル−Ｎ −Ｃ２−ｒ（３，４−メチレ
ンジオキシ）フェノキシ〕エチル〕アミノ〕プロポキシ
〕フェニル〕−４−メチル−３−オキ７−２Ｈ−１，４
−ベンゾチアジン フマル醒塩（化合動磁３９）の製造
参考例１で得られた（＋）−３，４−ジヒドロ−２−（
２−ヒドロキシ−５−メトキシフェニル）−４−メチル
−３−オキソ−２Ｈ−１，４−ベンゾチアジン（化合物
Ｎ１３５．１．００ ｙ）、３−ブロモ−１−プロパツ
ール（０，４６？ ）およびトリフェニルホスフィン（
０，８７ｙ）のＴＨＦ （２０ｔｔｔ’）溶液に、窒素
雰囲気下、アゾジカルボン酸ジエチル（０，５Ｗｔｌ）
１ｊｒ室温で滴下する。室温１時間撹拌後。
トリフェニルホスフィン（０，８７ｙ）およびアゾジカ
ルボン酸ジエチル（０，５ｄ）を加える。さらに室温１
時間撹拌後１反応溶媒を減圧留去丁ゐ。
析出結晶をｐ別後、Ｐ液をシリカゲルカラムクロマトで
精製し、（＋）−２−（２−（３−ブロモプロボキシ）
−５−メトキシフェニル］−３，４−ジヒドロ−４−メ
チル−３−オキソ−２Ｈ−１，４−ベンゾチアジン０．
５６ ’；！ （収率４０．２％〕を得る。
融点： ７８．０〜７９．０℃（エタノール）〔α〕Ｄ
＋１９７．７°（ｃ＝１．０．クロロホルム）ＩＲ：
１６４７，１５８４．１４９２，１４６５゜１３５７．
１２７１，１２４０．１２０１，１１４８゜１０４５．
７９９，７４６
嘔らに、上で得られた（＋）−ブロマイド（０，４２ｆ
）。
Ｎ−メチル−Ｎ−Ｃ２−ＣＣ３，４−メチレンジオキシ
）フェノキシ〕エチル〕アミン（０，２０Ｐ）およびト
リエチルアミン（０，１０’／ ）のＤＭＦ （１５−
）溶液全５０℃で３時間撹拌する。反応混合物を水中に
注ぎ、酢酸エチルで抽出し、有機層を飽和食塩水で洗浄
後、無水硫酸マグネシウムで脱水する。溶媒を減圧留去
して得られる油状物をシリカゲルカラムクロマトで精製
後、フマル酸で処理し、標記化合物Ｑ、４５ｙ（収率６
９．２チ）１−得る。
融点＝１３３〜ｌ ３３，５℃（エタノール）〔α）Ｄ
＋１９４．２°（（！＝１．０．ジメチルスルホキシド
）
ＩＲ：１６５３，１４７０，１３５７，１２６７゜１２
３９．１１８３，１１３９．１１０６．１０３４゜同様
にして、Ｈ−３，４−ジヒドロ−２−（５−メトキシ−
２−１：３−（Ｎ−メチル−Ｎ−Ｃ２−Ｃ（３，４−メ
チレンジオキシ）フェノキシ〕エチル〕アミノ〕プロポ
キシ〕フェニル〕−４−メチル−３−オキソ−２Ｈ−１
，４−ベンゾチアジンフマル酸塩（化合物Ｎ１４０）を
、（ハ）−３，４−ジヒドロ−２−（２−ヒドロキク−
５−メトキシフェニル）−４−メチル−３−オキソ−２
Ｈ−１，４−ベンゾチアジン（化合動磁３６）から得る
ことができる。
融点：１３３〜１３３．５℃（エタノール）〔α：１Ｄ
−１９５，５°（ｃ＝１．０．ジメチルスルホキシド）
ＩＲ： １６５３．１４６６．１３５７．１２６７゜１
２３９、１１８３．１１３９．１１０６．１０３３゜「
発明の効果」
本発明はカルシウム拮抗作用等を有する光学活性なベン
ゾチアジン及びベンゾチアゾリン化合−の有用な合成中
間体全提供するものである。[Combined magnetism 15] [α) -207.9° (c=1.0, chloroform) IR: 1763.1674, 1489, 1380. 1350, 1320, 1294, 1 273,
] 242. 1227, 1189, 1172. 1141, 1102. (+1-3-acetyl-2-1: 2-( (2R,
4R)-3-acetyl-2-(2-methoxyphenyl)
Thiazolidin-4-ylcarbonyloxyyo-5-methoxyphenyl]benzothiazoline (compound lkL16) Melting point = 223-224°C (ethyl acetate-ethanol) [α) +507.0° (c = 1. (1, chloroform) IR : 1763, 1ft46.1487.14
59. 1383, 1322, 1273, 1240.1182. 1134,1104,l 020,749H-3-acetyl-2-C2-((2R,4R)-3-acetyl-2-(2-methoxyphenyl)-thiazolidine-
4-ylcarbonyloxyyo-5-methoxyphenyl]
Benzothiazoline (Compound 17) [α) D-2 0 8.7° (c=1.0, chloroform) IR: 1758. ] 654, 1487, 1459. 1377, 1319, 1273, 1241, 1171. 1138, 1103, 1021.745 (+1-3-acetyl-2-C2-CC25,4B)-3-acetyl-
5.5-dimethyl-2-(2-methoxyphenylphthiazolidin-4-ylcarbonyloxy-5-methoxyphenyl)benzothiazoline (compound 18) [α:] +219.5° (c=1.1, Chloroform) IR: 1752, 1653, 1647, 1487
. ]458,l:(76,1320,]273,1242
. 1171, 1139, 1105, 1022.746)
-3-acetyl-2-(:2-C <zs, 4s)-3
-acetyl-5,5-dimethyl-2-(2-methoxyphenyl)thiazolidin-4-ylcarbonyloxy-5-methoxyphenyl]benzothiazoline (compound magnetokinetic 1
9) Melting point = 194-200°C (acetonitrile) CaJD-
s 2 7.8° (c=1.o, chloroform) IR:
1774, 1670.1637.158B. 1483, 1380.1301, 1270, 1240. 1123, 1108, 1023.745(+)-3-acetyl-2-[2-C (25,45)-3-benzyloxycarbonyl-5.5--)methyl-2-(2-methoxyphenyl)thiazolidine -4-ylcarbonyloxyyo5-methoxyphenyl]benzothiazoline (20 to compound 1) [α]D +251.9° (C=1.0
, chloroform) IR: 3388, 2924.1750
, 1675. 1587, 1489, 1458, 1380.1320. 1275, 1242, 1173, 1131, 1024. H-3-chocetyl-2-f:2-((25,45)-3
-benzyloxycarbonyl-5,5-dimethyl-2-
(2-methoxyphenylphthiazolidin-4-ylcarbonyloxy]-5-methoxyphenyl]benzothiazoline (compound magnetism 21) [αl:] D-399.7° (
c=1.1. Chloroform) IR: 3376.2920
．． 1764,1676゜1586.1488,1459
,1382,1321゜1273.1241,1177
．． 1131,1024゜(+)-3-acetyl-2-C
2-C(25,4S)-3-acetyl-5,5-dimethyl-2-phenylthiazolidin-4-ylcarbonyloxyph-5-methoxyphenyl]benzothiazoline (Compound 22) [α: 1D+277. 1° (c=1.0.chloroform) IR: 1751, 1639.1487, 1374°1
320.1272,1171,1127,1026゜←
)-3-acetyl-2-(2-CC2s, 4s>-3-
Acetyl-5,5-dimethyl-2-phenylthiazolidin-4-ylcarbonyloxyph-5-methoxyphenyl]benzothiazoline-methanol (1/l) (compound N123) Melting point = 125-127°C (decomposition) (acetonitrile -methanol] (α) D-4g 7.9° (c=1.1.chloroform) IR: 1764, 1637.14B5, 1456°1
375.1320,1271,1175,1123゜1
027.737 (+)-3-acetyl-2-C2-CC2S,4S)-
3-acetyl-2-phenylthiasoricin-4-ylcarbonyloxy]-5-methoxyphenyl]benzothiazoline (combined magnetic flux 24)Ca]D+327.3° (c=
1.0. Chloroform) IR:34]2,2920. l
'75g, 1651°1647.1461,1376.
1176.1137°1027.744,726 (-1-3-acetyl-2-C2-[(2S,4S)-
3-Acetyl-2-phenylthiasoricin-4-(carbonyloxy]-5-methoxyphenyl]benzothiazoline (Compound 1IkL25) Melting point: 199-202°C
(acetonitrile) [α)n 431-1' (c
=1-0-chloroform]IR:3320.2920
．． 1763,1653゜1460.1388,1179
,1134,1029゜Also, ω-3-acetyl-2-
(2-hydroxy-5-methoxyphenyl)benzothiazoline instead of C:)-'3,4-dihydro2-
Using (2-hydroxy-5-methoxyphenyl)-4-methyl-3-oxo-2)i-1,4-benzothiazine, the following compounds are obtained by operating in the same manner as in Examples 1 to 30. . (-)-2-C2-C(2S,4S)-3-acetyl-
5,5-dimethyl-2-(2-methoxyphenyl)thiazolidin-4-ylcarbonyloxyph-5-methoxyphenyl)-3,4-dihydro-4-methyl-3-oxo-2H-1,4-benzothiazine (Combined dynamic magnetism 26 (R
f large), compound 11kL27 (Rf small)) Rf large C(
t]D-108,6° (c = 1.0, chloroform) IR: 1755, 1646, 1457.137
6゜1353.1328.1279,1242,118
9゜1136.1105,1024.748Rf Small melting point: 165-166℃ (n-hexane-benzene) [α]D -108,36 (c=1.0.chloroform) IR: 1756,1653,1488.1457゜1
373.1331, 1280.1244, 1192゜1
177.1139, 1106, 1025.748 (→-
2-C2-C(2R,4R)-3-acetyl-2-phenylthiazolidin-4-ylcarbonyloxyph-5-
methoxyphenyl]-3,4-dihydro-4-methyl-
3-oxo-2H-1,4-benzothiazine (compound %
28 (large Rf), combined magnetism 29 (small Rf)) Rf large large fish point 148-150°C (n-hexane-penze/) [α:lD+] l 7.9° (c=1.0.chloroform) IR: 1770.164B, 1390,13
52゜1197,1141,751,727 Rf small [α:)D+0.8°(c=1.1.Chloroform]IR: 1759.l 653,1383,13
51゜1194.1140.748 (+)-2-(2-C(zx,4x)-a-Ryocetyl-
2-(2-hydroxyphenyl)thiazolidin-4-ylcarbonyloxyph-5-methoxyphenyl)-3,
4-dihydro-4-methyl-3-oxo-2) 1-1.
4-Benzothiazine (compound N1130 (large Rf)) [α] +185.2° (c = 1.o, chloroform) IR: 1759, 1649.15B4, 1457°]
384,1348,1280.1242,1192゜1
135.1103,1022.748H-3,4-dihydro-2-[2-((2S,4S)-3-acetyl-5
,5-dimethyl-2-phenylthiazolidin-4-ylcarbonyloxyph-5-methoxyphenyl]-4-methyl-3-oxo-214-1,4-benzothiazine (
Compound N131CRf large), compound dynamic magnetism 32 (Rf small))
Rf large melting point: 202-203.5°C (ethyl acetate) [α
) -67,6° (c=0.5.chloroform) IR
: 1771, 1639, 1448. ] 358°13
36.1290,1251,1176.1112゜10
30.731 Rf low melting point: 188-189.5°C (n-hexane-benzene) Ca]D-86,7° (c = 0.6.chloroform) I
R:]757,1652,1479,1447°136
Reference Example 1 (+1 -3-acetyl-2-[2-
Ctzx, 4x]-a-acetyl-2-(1-naphthyl)thousandaplidin-4-ylcarbonyloxy]-5-methoxyphenyl]benzothiazoline (compound 1kL3)
(28, Oy) DMF (50011Il)fI! IN sodium hydroxide aqueous solution (144
Add m) and stir at room temperature for 5 minutes under water cooling for 15 minutes. Add 0.5N salt@(1,5/) to the reaction solution and extract with ethyl acetate. The organic layer was diluted with saturated sodium bicarbonate solution, lNj! Alcohol,
After cleaning with saturated saline solution, dehydrate with anhydrous magnesium sulfate. A mixture of chloroform and cyclohexane was added to the oil obtained by distilling off the solvent under reduced pressure to obtain crystals, which were recrystallized from isopropyl ether to obtain the title compound 13.39.
- Obtain (yield $92.0%). Melting point: 130~] 31.5°C (isopropyl ether) [α) D + 416.5° (c = 1.0.chloroform)
IR: 3332, 1637, 1502, 1464°14
29.1381,1351,1272.1202゜F compound (compound 41ffFkL33) is compound 1m! kL3
Instead, compound dynamic magnetism 1.5, 7, 9, 10, 12, 1
4゜16.1g, 20.22'''! or 24 can also be obtained by operating in the same manner as in Practical Reference Example 1. Compound N12,4,6,8゜11
．． H-3-chocetyl-2-(
2-Hydroxy-5-methoxyphenyl)benzothiazoline (compound N134) is obtained. Melting point: 131.5-133°C (ethyl acetate-n-hexane) (:α) -436,2° (c=1.0.riooform) IR23320.1636.1502.14
63°1429.137B, 1349,1271,12
01° Compound N127.29 or 32 was used instead of compound N127.29 or 32.
-dihydro-2-(2-hydroxy-5-methoxyphenyl)-4-methyl-3-oxo-2) 1-1°4-benzothiazine (compounds 11 & L35) are obtained. Melting point = 162-163°C (benzene-n-hexane) [α) D + 38.9° (c = 1.0.chloroform) I
R:3208.1624.1582,1428°136
5.1264, 1218.1200 Compound magnetic flux 26, 28.30 and #-t31 were used in the same manner as in Reference example 1, and H-3,4-dihydro-2-(2
-Hydroxy-5-methoxyphenyl)-4-methyl-
3-oxo-2H-1,4-benzothiazine (compound 1
Rainbow 36) is obtained. Melting point: 160.0-161"C (benzene) [α)
-42,0° (c=1.3.chloroform) IR:32
04,1624,1579.1428°1365.12
63.1199 Reference Example 2 (+1-3-acetyl-2-[5-methoyac-2-(4
-CN-Methyl-N-(3,4,5-tritoxyphenethyl]amino]butoxy]phenyl]benzothiazoline hydrochloride (compound 11h37) The (+)-3-acetyl-2-(2-hydroxy-5-methoxyphenyl)benzothiazoline (compound ll&L33, 3.01?) obtained in Reference Example 1 was added to the cloudy liquid under water-cooling and stirring in anhydrous DMF ( 6d) Add the solution dropwise and stir for 10 minutes at room temperature.Add 1,4-dibromobutane (11,8r
Add nl). After stirring for 30 minutes at room temperature, it is poured into water and extracted with ether. The organic layer was sequentially washed with water, IN sodium hydroxide, and saturated brine, and then dehydrated with anhydrous magnesium sulfate. The oily substance obtained by distilling off the solvent under reduced pressure was purified by silica gel column chromatography to obtain (+)-a-acetyl-2-(2-(4-bromobutoxycou-5-methoxyphenyl)benzothiazoline 3.80 ? (yield 87.0%) Melting point: 84.5-85.5°C (ethanol) [α)D
+649.3° (c=1.0, chloroform) IR:
1674.3499, 1463, 1378°1214.
1043.751 Furthermore, (+)-bromide (2,10y
) and N-methyl-3,4,5-tritoxyphenethylamine (1,20y) in DMF (7,:M), 1,30y1r of sodium carbonate was added, and the mixture was stirred at 60°C for 2 hours. The reaction mixture was poured into total water, extracted with chloroform, and the organic layer was washed with water and saturated brine in that order, and then dried over anhydrous magnesium sulfate. The oil obtained by evaporating the solvent under reduced pressure is purified by silica gel column chromatography and converted into a hydrochloride to obtain the title compound 2.30y (yield: 77.0y). [α) +446.9° (c=1.1.chloroform) IR: 1664, 1589, 1496, 1462°1
424.1377,]275,1236,1207゜Similarly, (-)-3-acetyl-2-[5-methoxy-2-C4-CN-methyl-N-(3,4゜5-tritoxyphenethyl ) Amino]butoxy]phenyl]penzotyrozoline hydrochloride (compound dynamic 38) was converted into H-3-acetyl-2-(2-hydroxy-5-methoxyphenyl)
It can be obtained from benzothiazolines (compounds 11 & 1L34). (α') D-441,2° (c=1.0.chloroform) IR:1663,1589,1493,1460°1
423.1376.1274, 1235.1207° Reference Example 3 (+)-3,4-dihydro-2-[5-methoxy-2-
C3-CN-methyl-N -C2-r(3,4-methylenedioxy)phenoxy]ethyl]amino]propoxy]phenyl]-4-methyl-3-ox7-2H-1,4
Production of (+)-3,4-dihydro-2-(+)-3,4-dihydro-2-(
2-hydroxy-5-methoxyphenyl)-4-methyl-3-oxo-2H-1,4-benzothiazine (compound N135.1.00 y), 3-bromo-1-propatol (0,46?) and Triphenylphosphine (
Diethyl azodicarboxylate (0.5 Wtl) was added to a THF (20ttt') solution of 0.87y) under a nitrogen atmosphere.
Add 1 jr dropwise at room temperature. After stirring at room temperature for 1 hour. Add triphenylphosphine (0,87y) and diethyl azodicarboxylate (0,5d). Furthermore, room temperature 1
After stirring for an hour, the reaction solvent was distilled off under reduced pressure. After separating the precipitated crystals, the P solution was purified by silica gel column chromatography to obtain (+)-2-(2-(3-bromoproboxy)
-5-methoxyphenyl]-3,4-dihydro-4-methyl-3-oxo-2H-1,4-benzothiazine0.
56';! (yield 40.2%). Melting point: 78.0-79.0°C (ethanol) [α]D
+197.7° (c=1.0.chloroform) IR:
1647, 1584.1492, 1465°1357.
1271, 1240.1201, 1148°1045.
799,746 Furthermore, the (+)-bromide obtained above (0,42f
). DMF (15-
) Stir the entire solution at 50°C for 3 hours. The reaction mixture was poured into water, extracted with ethyl acetate, and the organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate. The oily substance obtained by distilling off the solvent under reduced pressure was purified by silica gel column chromatography, and then treated with fumaric acid to obtain the title compound Q, 45y (yield: 6
9.2 Ch) 1- Obtain. Melting point = 133~l 33,5℃ (ethanol) [α)D
+194.2° ((!=1.0.dimethylsulfoxide) IR:1653,1470,1357,1267°12
39.1183, 1139.1106.1034° Similarly, H-3,4-dihydro-2-(5-methoxy-
2-1:3-(N-methyl-N-C2-C(3,4-methylenedioxy)phenoxy]ethyl]amino]propoxy]phenyl]-4-methyl-3-oxo-2H-1
,4-benzothiazine fumarate (compound N140) was converted into (c)-3,4-dihydro-2-(2-hydro-
5-methoxyphenyl)-4-methyl-3-oxo-2
It can be obtained from H-1,4-benzothiazine (Compound Kinetic 36). Melting point: 133-133.5°C (ethanol) [α: 1D
-195,5° (c=1.0.dimethylsulfoxide) IR: 1653.1466.1357.1267°1
239, 1183.1139.1106.1033゜
Effects of the Invention The present invention provides all useful synthetic intermediates for optically active benzothiazine and benzothiazoline compounds having calcium antagonistic effects.
Claims (1)
コキシ基、ハロゲン原子またはニトロ基から選択される
１個または複数の基を示す。 Ｒ＾２は水素原子、低級アルカノイル基または低級アル
キル基を示す。 Ｒ＾３は水素原子、低級アルキル基、低級アルコキシ基
、ハロゲン原子またはニトロ基から選択される１個また
は複数の基を示す。 Ｒ＾４およびＲ＾５は同一かまたは異なって、水素原子
もしくは低級アルキル基を示す。 Ｒ＾６は水素原子、低級アルキル基、フェニル基または
ナフチル基を示し、フェニル基およびナフチル基は低級
アルキル基、低級アルコキシ基、ヒドロキシ基、ニトロ
基またはハロゲン原子から選択される１個または複数の
基で置換されていてもよい。 Ｒ＾７は低級アルキル基、フェニルアルコキシ基または
フェニル基を示し、フェニルアルコキシ基およびフェニ
ル基のフェニル環は低級アルキル基、低級アルコキシ基
、ニトロ基またはハロゲン原子から選択される１個また
は複数の基で置換されていてもよい。 Ｒ＾８は水素原子、低級アルキル基、低級アルコキシ基
、低級アルキルチオ基、ハロゲン原子、シアノ基または
低級アルカノイルアミノ基を示す。 ｎは０または１を示す。 ＸはＳまたはＣＨ＿２を示す。〕[Claims] A compound represented by formula [I] and salts thereof. ▲There are mathematical formulas, chemical formulas, tables, etc.▼ [I] [In the formula, R^1 represents one or more groups selected from a hydrogen atom, a lower alkyl group, a lower alkoxy group, a halogen atom, or a nitro group. R^2 represents a hydrogen atom, a lower alkanoyl group or a lower alkyl group. R^3 represents one or more groups selected from a hydrogen atom, a lower alkyl group, a lower alkoxy group, a halogen atom, or a nitro group. R^4 and R^5 are the same or different and represent a hydrogen atom or a lower alkyl group. R^6 represents a hydrogen atom, a lower alkyl group, a phenyl group, or a naphthyl group, and the phenyl group and the naphthyl group are one or more atoms selected from a lower alkyl group, a lower alkoxy group, a hydroxy group, a nitro group, or a halogen atom. It may be substituted with a group. R^7 represents a lower alkyl group, a phenylalkoxy group, or a phenyl group, and the phenyl ring of the phenylalkoxy group and the phenyl group is one or more groups selected from a lower alkyl group, a lower alkoxy group, a nitro group, or a halogen atom. may be replaced with . R^8 represents a hydrogen atom, a lower alkyl group, a lower alkoxy group, a lower alkylthio group, a halogen atom, a cyano group, or a lower alkanoylamino group. n represents 0 or 1. X represents S or CH_2. ]
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP61253158A JPS63104969A (en) | 1986-10-23 | 1986-10-23 | Sulfur-containing heterocyclic compound |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP61253158A JPS63104969A (en) | 1986-10-23 | 1986-10-23 | Sulfur-containing heterocyclic compound |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPS63104969A true JPS63104969A (en) | 1988-05-10 |
| JPH0560833B2 JPH0560833B2 (en) | 1993-09-03 |
Family
ID=17247337
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP61253158A Granted JPS63104969A (en) | 1986-10-23 | 1986-10-23 | Sulfur-containing heterocyclic compound |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPS63104969A (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1990015607A1 (en) * | 1989-06-16 | 1990-12-27 | Santen Pharmaceutical Co., Ltd. | Drug for improving brain function |
| US6673815B2 (en) * | 2001-11-06 | 2004-01-06 | Bristol-Myers Squibb Company | Substituted acid derivatives useful as antidiabetic and antiobesity agents and method |
-
1986
- 1986-10-23 JP JP61253158A patent/JPS63104969A/en active Granted
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1990015607A1 (en) * | 1989-06-16 | 1990-12-27 | Santen Pharmaceutical Co., Ltd. | Drug for improving brain function |
| US6673815B2 (en) * | 2001-11-06 | 2004-01-06 | Bristol-Myers Squibb Company | Substituted acid derivatives useful as antidiabetic and antiobesity agents and method |
Also Published As
| Publication number | Publication date |
|---|---|
| JPH0560833B2 (en) | 1993-09-03 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| EP0591528B1 (en) | PYRAZOLO[1,5-a]PYRIMIDINE DERIVATIVE AND ANTI-INFLAMMATORY CONTAINING THE SAME | |
| JPH05345771A (en) | Saccharin derivative proteolytic enzyme inhibitor | |
| SU629880A3 (en) | Method of obtaining 7-d-(-)-2-formyloxy-2-(4-acyloxyphenylacetamido)-cephalosporanic acids or salts thereof | |
| JPS5834474B2 (en) | Method for producing thiazolidine derivatives | |
| JPH10511084A (en) | Polyarylcarbamoylaza and carbamoylalkanediacid | |
| JPH08119964A (en) | Method of preparing benzoic acid derivative intermediate andbenzothiophene pharmaceutical | |
| JPS62294681A (en) | Thiazolylacetic acid derivative | |
| JPS6360992A (en) | Novel oxime derivative of 3-substituted 7-aminothiazolylacetamide cephalosporinic acid | |
| JP2016164143A (en) | Processes and intermediates for preparing macrocyclic protease inhibitor of hcv | |
| EP0149419B1 (en) | Acylindole derivatives and pharmaceutical compositions containing them | |
| AU695575B2 (en) | Novel process for preparing 2,3-dihydro-benzofuranol derivatives | |
| JPS63104969A (en) | Sulfur-containing heterocyclic compound | |
| JP4954421B2 (en) | Purification method of clavulanate | |
| EP0338895A1 (en) | Heteroarotinoid derivatives, their processes of preparation and pharmaceutical compositions containing them | |
| JP3187905B2 (en) | Process for producing racemic and optically active 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid and precursors thereof | |
| RU2073680C1 (en) | Crystalline acid additive salts of pure diastereomers of 1-(2,2-dimethyl propionyloxy)-ethyl ester of 3-cephem-4-carboxylic acid and method for their production | |
| EP0337885B1 (en) | Trienic derivatives with chromenic structure, their processes of preparation and pharmaceutical compositions containing them | |
| EP0580378B1 (en) | Substituted benzoate derivatives | |
| FR2477548A1 (en) | 7A-METHOXYCEPHALOSPORINE DERIVATIVES, PROCESS FOR PREPARING THEM AND THEIR THERAPEUTIC APPLICATION | |
| AU705004B2 (en) | 2,3-dihydro-benzofuranol derivatives and process for resolving the same | |
| US5041620A (en) | Method for producing optically active 2-cyclopenten-4-one-1-ol esters, 2-cyclopenteno-4-one-1-ol ester and complexes thereof with optically active 1,6-diphenyl-2,4-hexadiyne-1,6-diol | |
| JPH07196598A (en) | Hydroxamic acid derivative and medicine composition containing the same as active ingredient | |
| JP3669724B2 (en) | Process for producing optically active 3- (p-alkoxyphenyl) glycidic acid ester derivative | |
| JPH0717655B2 (en) | Oral cefalosporin compound | |
| SU1431678A3 (en) | Method of producing optically active ketals |