JP2002275157A - New naphthalene derivative - Google Patents
New naphthalene derivativeInfo
- Publication number
- JP2002275157A JP2002275157A JP33174798A JP33174798A JP2002275157A JP 2002275157 A JP2002275157 A JP 2002275157A JP 33174798 A JP33174798 A JP 33174798A JP 33174798 A JP33174798 A JP 33174798A JP 2002275157 A JP2002275157 A JP 2002275157A
- Authority
- JP
- Japan
- Prior art keywords
- compound
- formula
- acid
- methyl
- oxadiazol
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- 150000002790 naphthalenes Chemical class 0.000 title abstract description 5
- 239000003527 fibrinolytic agent Substances 0.000 claims abstract description 20
- 229960000103 thrombolytic agent Drugs 0.000 claims abstract description 13
- -1 salt compounds Chemical class 0.000 claims description 160
- 150000001875 compounds Chemical class 0.000 claims description 140
- 125000000217 alkyl group Chemical group 0.000 claims description 18
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 9
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 9
- 125000001424 substituent group Chemical group 0.000 claims description 9
- 125000003545 alkoxy group Chemical group 0.000 claims description 6
- 125000004430 oxygen atom Chemical group O* 0.000 claims description 6
- 229940126214 compound 3 Drugs 0.000 claims description 5
- 239000012453 solvate Substances 0.000 claims description 5
- 229910052717 sulfur Inorganic materials 0.000 claims description 5
- 125000004434 sulfur atom Chemical group 0.000 claims description 5
- 125000005843 halogen group Chemical group 0.000 claims description 4
- 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 claims description 3
- 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 claims description 3
- 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 claims description 3
- 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 claims description 3
- KQZLRWGGWXJPOS-NLFPWZOASA-N 1-[(1R)-1-(2,4-dichlorophenyl)ethyl]-6-[(4S,5R)-4-[(2S)-2-(hydroxymethyl)pyrrolidin-1-yl]-5-methylcyclohexen-1-yl]pyrazolo[3,4-b]pyrazine-3-carbonitrile Chemical compound ClC1=C(C=CC(=C1)Cl)[C@@H](C)N1N=C(C=2C1=NC(=CN=2)C1=CC[C@@H]([C@@H](C1)C)N1[C@@H](CCC1)CO)C#N KQZLRWGGWXJPOS-NLFPWZOASA-N 0.000 claims description 3
- ONBQEOIKXPHGMB-VBSBHUPXSA-N 1-[2-[(2s,3r,4s,5r)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]oxy-4,6-dihydroxyphenyl]-3-(4-hydroxyphenyl)propan-1-one Chemical compound O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1OC1=CC(O)=CC(O)=C1C(=O)CCC1=CC=C(O)C=C1 ONBQEOIKXPHGMB-VBSBHUPXSA-N 0.000 claims description 3
- 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 claims description 3
- 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 claims 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 claims description 3
- NPRYCHLHHVWLQZ-TURQNECASA-N 2-amino-9-[(2R,3S,4S,5R)-4-fluoro-3-hydroxy-5-(hydroxymethyl)oxolan-2-yl]-7-prop-2-ynylpurin-8-one Chemical compound NC1=NC=C2N(C(N(C2=N1)[C@@H]1O[C@@H]([C@H]([C@H]1O)F)CO)=O)CC#C NPRYCHLHHVWLQZ-TURQNECASA-N 0.000 claims description 3
- 229940126657 Compound 17 Drugs 0.000 claims description 3
- 229940126639 Compound 33 Drugs 0.000 claims description 3
- 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 claims description 3
- PNUZDKCDAWUEGK-CYZMBNFOSA-N Sitafloxacin Chemical compound C([C@H]1N)N(C=2C(=C3C(C(C(C(O)=O)=CN3[C@H]3[C@H](C3)F)=O)=CC=2F)Cl)CC11CC1 PNUZDKCDAWUEGK-CYZMBNFOSA-N 0.000 claims description 3
- 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 claims 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 claims description 3
- 229940125797 compound 12 Drugs 0.000 claims description 3
- 229940126543 compound 14 Drugs 0.000 claims description 3
- 229940125758 compound 15 Drugs 0.000 claims description 3
- 229940126142 compound 16 Drugs 0.000 claims description 3
- 229940125782 compound 2 Drugs 0.000 claims description 3
- 229940125810 compound 20 Drugs 0.000 claims description 3
- 229940126086 compound 21 Drugs 0.000 claims description 3
- 229940126208 compound 22 Drugs 0.000 claims description 3
- 229940125833 compound 23 Drugs 0.000 claims description 3
- 229940125851 compound 27 Drugs 0.000 claims description 3
- 229940127204 compound 29 Drugs 0.000 claims description 3
- 229940125877 compound 31 Drugs 0.000 claims description 3
- 229940125898 compound 5 Drugs 0.000 claims description 3
- JAXFJECJQZDFJS-XHEPKHHKSA-N gtpl8555 Chemical compound OC(=O)C[C@H](N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](C(C)C)C(=O)N1CCC[C@@H]1C(=O)N[C@H](B1O[C@@]2(C)[C@H]3C[C@H](C3(C)C)C[C@H]2O1)CCC1=CC=C(F)C=C1 JAXFJECJQZDFJS-XHEPKHHKSA-N 0.000 claims description 3
- KLTISGBWMJIHHU-UHFFFAOYSA-N C1=CC2=CC(OCC(=O)O)=CC=C2C=C1C1=CC=CC=N1 Chemical compound C1=CC2=CC(OCC(=O)O)=CC=C2C=C1C1=CC=CC=N1 KLTISGBWMJIHHU-UHFFFAOYSA-N 0.000 claims description 2
- UIGVJTKMWIIUGN-UHFFFAOYSA-N C1=CC2=CC(OCC(=O)O)=CC=C2C=C1C=1C=NNN=1 Chemical compound C1=CC2=CC(OCC(=O)O)=CC=C2C=C1C=1C=NNN=1 UIGVJTKMWIIUGN-UHFFFAOYSA-N 0.000 claims description 2
- DTOSWNJUMDVECW-UHFFFAOYSA-N CN1N=NN=C1C1=CC=C(C=C(OCC(O)=O)C=C2)C2=C1 Chemical compound CN1N=NN=C1C1=CC=C(C=C(OCC(O)=O)C=C2)C2=C1 DTOSWNJUMDVECW-UHFFFAOYSA-N 0.000 claims description 2
- DJBLFKLQOKLIOV-UHFFFAOYSA-N N1(C=NCC1)C=1C=C2C=CC(=CC2=CC1)OCC(=O)O Chemical compound N1(C=NCC1)C=1C=C2C=CC(=CC2=CC1)OCC(=O)O DJBLFKLQOKLIOV-UHFFFAOYSA-N 0.000 claims description 2
- 125000002252 acyl group Chemical group 0.000 claims description 2
- 125000003282 alkyl amino group Chemical group 0.000 claims description 2
- 125000003277 amino group Chemical group 0.000 claims description 2
- 229940125904 compound 1 Drugs 0.000 claims description 2
- 229940125773 compound 10 Drugs 0.000 claims description 2
- 229910052736 halogen Inorganic materials 0.000 claims description 2
- 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 claims description 2
- 239000008194 pharmaceutical composition Substances 0.000 claims description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 2
- 125000003396 thiol group Chemical group [H]S* 0.000 claims description 2
- ZWLPBLYKEWSWPD-UHFFFAOYSA-N o-toluic acid Chemical compound CC1=CC=CC=C1C(O)=O ZWLPBLYKEWSWPD-UHFFFAOYSA-N 0.000 claims 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 claims 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 claims 1
- GDSLUYKCPYECNN-UHFFFAOYSA-N 3-[4-(aminomethyl)-6-(trifluoromethyl)pyridin-2-yl]oxy-N-[(4-fluorophenyl)methyl]benzamide Chemical compound NCC1=CC(=NC(=C1)C(F)(F)F)OC=1C=C(C(=O)NCC2=CC=C(C=C2)F)C=CC=1 GDSLUYKCPYECNN-UHFFFAOYSA-N 0.000 claims 1
- 239000003146 anticoagulant agent Substances 0.000 abstract description 8
- 229960004676 antithrombotic agent Drugs 0.000 abstract description 7
- 230000000694 effects Effects 0.000 abstract description 6
- 239000000243 solution Substances 0.000 description 126
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 75
- 238000006243 chemical reaction Methods 0.000 description 73
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 64
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 63
- 230000002829 reductive effect Effects 0.000 description 60
- 238000000034 method Methods 0.000 description 53
- 239000000203 mixture Substances 0.000 description 53
- 239000007787 solid Substances 0.000 description 52
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 48
- 238000002360 preparation method Methods 0.000 description 42
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 34
- 238000005160 1H NMR spectroscopy Methods 0.000 description 33
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 33
- 238000004992 fast atom bombardment mass spectroscopy Methods 0.000 description 33
- 238000001914 filtration Methods 0.000 description 29
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 26
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 26
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 26
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 24
- 239000000741 silica gel Substances 0.000 description 24
- 229910002027 silica gel Inorganic materials 0.000 description 24
- NFHFRUOZVGFOOS-UHFFFAOYSA-N palladium;triphenylphosphane Chemical compound [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 NFHFRUOZVGFOOS-UHFFFAOYSA-N 0.000 description 22
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 21
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 20
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 20
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 18
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 17
- 229910000027 potassium carbonate Inorganic materials 0.000 description 17
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 16
- 239000008213 purified water Substances 0.000 description 16
- 125000000524 functional group Chemical group 0.000 description 14
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 13
- 238000010992 reflux Methods 0.000 description 13
- 229910052739 hydrogen Inorganic materials 0.000 description 12
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 12
- OAYLNYINCPYISS-UHFFFAOYSA-N ethyl acetate;hexane Chemical compound CCCCCC.CCOC(C)=O OAYLNYINCPYISS-UHFFFAOYSA-N 0.000 description 11
- 229920006395 saturated elastomer Polymers 0.000 description 11
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 10
- PXIPVTKHYLBLMZ-UHFFFAOYSA-N Sodium azide Chemical compound [Na+].[N-]=[N+]=[N-] PXIPVTKHYLBLMZ-UHFFFAOYSA-N 0.000 description 10
- 208000007536 Thrombosis Diseases 0.000 description 10
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 10
- 235000013772 propylene glycol Nutrition 0.000 description 10
- 150000003839 salts Chemical class 0.000 description 10
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 10
- 235000017557 sodium bicarbonate Nutrition 0.000 description 10
- NAWXUBYGYWOOIX-SFHVURJKSA-N (2s)-2-[[4-[2-(2,4-diaminoquinazolin-6-yl)ethyl]benzoyl]amino]-4-methylidenepentanedioic acid Chemical compound C1=CC2=NC(N)=NC(N)=C2C=C1CCC1=CC=C(C(=O)N[C@@H](CC(=C)C(O)=O)C(O)=O)C=C1 NAWXUBYGYWOOIX-SFHVURJKSA-N 0.000 description 8
- LKPGFFPTRSEILK-UHFFFAOYSA-N CCCC[Sn](CCCC)(CCCC)C1=CC2=C(C=C1)C=C(C=C2)OCC(=O)OC Chemical compound CCCC[Sn](CCCC)(CCCC)C1=CC2=C(C=C1)C=C(C=C2)OCC(=O)OC LKPGFFPTRSEILK-UHFFFAOYSA-N 0.000 description 8
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 8
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 8
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 8
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 8
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 description 7
- 239000002585 base Substances 0.000 description 7
- 239000002904 solvent Substances 0.000 description 7
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 6
- DLFVBJFMPXGRIB-UHFFFAOYSA-N Acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 description 6
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 6
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- 230000003480 fibrinolytic effect Effects 0.000 description 6
- 239000001863 hydroxypropyl cellulose Substances 0.000 description 6
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 description 6
- MHWHOXZQKUHWFE-UHFFFAOYSA-N methyl 2-(6-cyanonaphthalen-2-yl)oxyacetate Chemical compound C(#N)C=1C=C2C=CC(=CC2=CC1)OCC(=O)OC MHWHOXZQKUHWFE-UHFFFAOYSA-N 0.000 description 6
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- 229930195712 glutamate Natural products 0.000 description 1
- 239000001087 glyceryl triacetate Substances 0.000 description 1
- 235000013773 glyceryl triacetate Nutrition 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 150000004820 halides Chemical class 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 150000002391 heterocyclic compounds Chemical class 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
- 239000001257 hydrogen Substances 0.000 description 1
- 239000001341 hydroxy propyl starch Substances 0.000 description 1
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 1
- UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC2C(C(O)C(OC3C(C(O)C(O)C(CO)O3)O)C(CO)O2)O)C(CO)O1 UFVKGYZPFZQRLF-UHFFFAOYSA-N 0.000 description 1
- 235000013828 hydroxypropyl starch Nutrition 0.000 description 1
- 230000001771 impaired effect Effects 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 150000007529 inorganic bases Chemical class 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 230000000302 ischemic effect Effects 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- JMMWKPVZQRWMSS-UHFFFAOYSA-N isopropanol acetate Natural products CC(C)OC(C)=O JMMWKPVZQRWMSS-UHFFFAOYSA-N 0.000 description 1
- 229940011051 isopropyl acetate Drugs 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 239000007951 isotonicity adjuster Substances 0.000 description 1
- GWYFCOCPABKNJV-UHFFFAOYSA-N isovaleric acid Chemical compound CC(C)CC(O)=O GWYFCOCPABKNJV-UHFFFAOYSA-N 0.000 description 1
- 235000019860 lauric fat Nutrition 0.000 description 1
- 231100000518 lethal Toxicity 0.000 description 1
- 230000001665 lethal effect Effects 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 229940031703 low substituted hydroxypropyl cellulose Drugs 0.000 description 1
- 230000002101 lytic effect Effects 0.000 description 1
- ZLNQQNXFFQJAID-UHFFFAOYSA-L magnesium carbonate Chemical compound [Mg+2].[O-]C([O-])=O ZLNQQNXFFQJAID-UHFFFAOYSA-L 0.000 description 1
- 239000001095 magnesium carbonate Substances 0.000 description 1
- 229910000021 magnesium carbonate Inorganic materials 0.000 description 1
- 235000014380 magnesium carbonate Nutrition 0.000 description 1
- 159000000003 magnesium salts Chemical class 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 230000010534 mechanism of action Effects 0.000 description 1
- GBMDVOWEEQVZKZ-UHFFFAOYSA-N methanol;hydrate Chemical compound O.OC GBMDVOWEEQVZKZ-UHFFFAOYSA-N 0.000 description 1
- AQBJGAUQEJFPKZ-UHFFFAOYSA-N methyl 4-(aminomethyl)benzoate Chemical compound COC(=O)C1=CC=C(CN)C=C1 AQBJGAUQEJFPKZ-UHFFFAOYSA-N 0.000 description 1
- FVHXBZJAKXMJTN-UHFFFAOYSA-N methyl acetate;hydrobromide Chemical compound Br.COC(C)=O FVHXBZJAKXMJTN-UHFFFAOYSA-N 0.000 description 1
- NQMRYBIKMRVZLB-UHFFFAOYSA-N methylamine hydrochloride Chemical compound [Cl-].[NH3+]C NQMRYBIKMRVZLB-UHFFFAOYSA-N 0.000 description 1
- OCLFNQJKQFFHHK-UHFFFAOYSA-N methylsulfanylbenzene;2,2,2-trifluoroacetic acid;trifluoromethanesulfonic acid Chemical compound OC(=O)C(F)(F)F.CSC1=CC=CC=C1.OS(=O)(=O)C(F)(F)F OCLFNQJKQFFHHK-UHFFFAOYSA-N 0.000 description 1
- 239000012046 mixed solvent Substances 0.000 description 1
- 239000002808 molecular sieve Substances 0.000 description 1
- 238000010172 mouse model Methods 0.000 description 1
- 208000010125 myocardial infarction Diseases 0.000 description 1
- DILRJUIACXKSQE-UHFFFAOYSA-N n',n'-dimethylethane-1,2-diamine Chemical compound CN(C)CCN DILRJUIACXKSQE-UHFFFAOYSA-N 0.000 description 1
- JVXXKQIRGQDWOJ-UHFFFAOYSA-N naphthalene-2-carboxamide Chemical class C1=CC=CC2=CC(C(=O)N)=CC=C21 JVXXKQIRGQDWOJ-UHFFFAOYSA-N 0.000 description 1
- 150000004780 naphthols Chemical class 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 125000004433 nitrogen atom Chemical group N* 0.000 description 1
- LYGJENNIWJXYER-UHFFFAOYSA-N nitromethane Chemical compound C[N+]([O-])=O LYGJENNIWJXYER-UHFFFAOYSA-N 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- AICOOMRHRUFYCM-ZRRPKQBOSA-N oxazine, 1 Chemical compound C([C@@H]1[C@H](C(C[C@]2(C)[C@@H]([C@H](C)N(C)C)[C@H](O)C[C@]21C)=O)CC1=CC2)C[C@H]1[C@@]1(C)[C@H]2N=C(C(C)C)OC1 AICOOMRHRUFYCM-ZRRPKQBOSA-N 0.000 description 1
- GNWXVOQHLPBSSR-UHFFFAOYSA-N oxolane;toluene Chemical compound C1CCOC1.CC1=CC=CC=C1 GNWXVOQHLPBSSR-UHFFFAOYSA-N 0.000 description 1
- 239000003002 pH adjusting agent Substances 0.000 description 1
- ZOUWOGOTHLRRLS-UHFFFAOYSA-N palladium;phosphane Chemical compound P.[Pd] ZOUWOGOTHLRRLS-UHFFFAOYSA-N 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 239000008363 phosphate buffer Substances 0.000 description 1
- 239000002504 physiological saline solution Substances 0.000 description 1
- 229920001495 poly(sodium acrylate) polymer Polymers 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 230000002335 preservative effect Effects 0.000 description 1
- 230000002250 progressing effect Effects 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 230000002685 pulmonary effect Effects 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 230000010410 reperfusion Effects 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 239000001509 sodium citrate Substances 0.000 description 1
- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 description 1
- 235000010267 sodium hydrogen sulphite Nutrition 0.000 description 1
- RYYKJJJTJZKILX-UHFFFAOYSA-M sodium octadecanoate Chemical compound [Na+].CCCCCCCCCCCCCCCCCC([O-])=O RYYKJJJTJZKILX-UHFFFAOYSA-M 0.000 description 1
- NNMHYFLPFNGQFZ-UHFFFAOYSA-M sodium polyacrylate Chemical compound [Na+].[O-]C(=O)C=C NNMHYFLPFNGQFZ-UHFFFAOYSA-M 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 238000007711 solidification Methods 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 238000007910 systemic administration Methods 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- WMOVHXAZOJBABW-UHFFFAOYSA-N tert-butyl acetate Chemical compound CC(=O)OC(C)(C)C WMOVHXAZOJBABW-UHFFFAOYSA-N 0.000 description 1
- BCNZYOJHNLTNEZ-UHFFFAOYSA-N tert-butyldimethylsilyl chloride Chemical compound CC(C)(C)[Si](C)(C)Cl BCNZYOJHNLTNEZ-UHFFFAOYSA-N 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 125000000437 thiazol-2-yl group Chemical group [H]C1=C([H])N=C(*)S1 0.000 description 1
- CBDKQYKMCICBOF-UHFFFAOYSA-N thiazoline Chemical compound C1CN=CS1 CBDKQYKMCICBOF-UHFFFAOYSA-N 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 238000000844 transformation Methods 0.000 description 1
- 230000001052 transient effect Effects 0.000 description 1
- 229960002622 triacetin Drugs 0.000 description 1
- UKTDFYOZPFNQOQ-UHFFFAOYSA-N tributyl(thiophen-2-yl)stannane Chemical compound CCCC[Sn](CCCC)(CCCC)C1=CC=CS1 UKTDFYOZPFNQOQ-UHFFFAOYSA-N 0.000 description 1
- 125000005951 trifluoromethanesulfonyloxy group Chemical group 0.000 description 1
- 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 1
- 238000007631 vascular surgery Methods 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D291/00—Heterocyclic compounds containing rings having nitrogen, oxygen and sulfur atoms as the only ring hetero atoms
- C07D291/02—Heterocyclic compounds containing rings having nitrogen, oxygen and sulfur atoms as the only ring hetero atoms not condensed with other rings
- C07D291/04—Five-membered rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Diabetes (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Pharmacology & Pharmacy (AREA)
- Engineering & Computer Science (AREA)
- Animal Behavior & Ethology (AREA)
- Hematology (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Pyridine Compounds (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
- Heterocyclic Compounds Containing Sulfur Atoms (AREA)
- Quinoline Compounds (AREA)
- Other In-Based Heterocyclic Compounds (AREA)
- Furan Compounds (AREA)
Abstract
Description
【0001】[0001]
【発明の属する技術分野】本発明は、線溶促進作用を有
し、血栓溶解剤、抗血栓剤として有用なナフタレン誘導
体に関する。TECHNICAL FIELD The present invention relates to a naphthalene derivative having a fibrinolytic accelerating action and useful as a thrombolytic agent and an antithrombotic agent.
【0002】[0002]
【従来の技術】血栓を溶解させるためには、プラスミノ
ーゲンアクチベータ(PA)類を投与する療法、すなわ
ち血栓溶解療法(線溶療法)が、現在広く実施されてい
る。線溶系の活性化は、血液線溶系調節因子の前駆体で
あるプラスミノーゲンをPAがプラスミンに活性化する
ことによって開始され、生じたプラスミンが酵素作用を
発現して血栓の構成成分であるフィブリンを分解するこ
とによって血栓溶解が進行する。現在、この線溶療法に
使用される血栓溶解剤として、ウロキナーゼ(UK)、
組織プラスミノーゲンアクチベータ(t−PA)などの
生体内物質、ストレプトキナーゼ(SK)、スタフィロ
キナーゼ(SAK)などの菌体産生物質およびそれらの
遺伝子組換え体等が知られている。しかし、これら既存
の血栓溶解薬はすべて蛋白製剤であるため、血中半減期
が短く、速やかに肝臓で代謝され、かつ、生体内に阻害
因子が存在するため、血栓の生じている局所において血
栓溶解作用を発現させるためには大量投与を必要とす
る。臨床において、投与量が多いほど再潅流率が高いこ
とが報告されているが、このような血栓溶解剤の一過性
の大量投与は、全身的に血栓溶解活性を著しく高め、血
栓塞栓部位を開通させることが期待される一方、副作用
として重篤な出血症状が認められる。また、これらの血
栓溶解剤の投与により一時的に塞栓部位を開通させて
も、再閉塞を生じ易いことが大きな問題となっている。
さらに、治療に用いる場合の投与法が静脈内全身投与法
若しくは冠動脈内投与法であり、血管内への直接投与で
あることから、長期投与する場合には患者の負担が大き
いという問題もある。そのため、新たな作用機序に基づ
く血栓溶解剤の開発が望まれている。2. Description of the Related Art In order to dissolve blood clots, therapy for administering plasminogen activators (PA), that is, thrombolytic therapy (fibrinolytic therapy) is currently widely practiced. Activation of the fibrinolytic system is initiated by the activation of plasminogen, which is a precursor of a blood fibrinolytic regulatory factor, to plasmin, and the resulting plasmin expresses an enzymatic action to produce fibrin, a component of thrombus. Decomposes to promote thrombolysis. Currently, urokinase (UK), a thrombolytic agent used in this fibrinolytic therapy,
In vivo substances such as tissue plasminogen activator (t-PA), bacterial cell producing substances such as streptokinase (SK) and staphylokinase (SAK), and recombinants thereof are known. However, since these existing thrombolytic drugs are all protein preparations, they have a short half-life in blood, are rapidly metabolized in the liver, and have an inhibitory factor in the living body. In order to exert the lytic effect, a large amount of administration is required. In clinical practice, it has been reported that the higher the dose, the higher the reperfusion rate.However, such a transient large dose of a thrombolytic agent significantly enhances the thrombolytic activity systemically, causing While it is expected to be opened, severe side effects of bleeding are observed. Further, even if the embolization site is temporarily opened by administration of these thrombolytic agents, reocclusion tends to occur easily, which is a major problem.
Furthermore, the administration method used for treatment is intravenous systemic administration method or intracoronary administration method, which is a direct administration into a blood vessel, so that there is a problem that a long-term administration requires a heavy burden on a patient. Therefore, development of a thrombolytic agent based on a new mechanism of action is desired.
【0003】[0003]
【発明が解決しようとする課題】本発明の目的は、線溶
促進作用を有し、経口投与可能な抗血栓剤、血栓溶解剤
を提供することにある。SUMMARY OF THE INVENTION An object of the present invention is to provide an orally administrable antithrombotic agent and a thrombolytic agent which have a fibrinolytic promoting action.
【0004】[0004]
【課題を解決するための手段】本発明者等は、上記課題
を解決すべく鋭意研究した結果、下記新規ナフタレン誘
導体が優れた線溶促進作用を有し、抗血栓剤、血栓溶解
剤として極めて有用であることを見出した。すなわち、
本発明は、下記式(I)式(I)The present inventors have conducted intensive studies to solve the above-mentioned problems. As a result, the following novel naphthalene derivatives have an excellent fibrinolysis-promoting action and are extremely useful as antithrombotic agents and thrombolytic agents. I found it useful. That is,
The present invention relates to the following formula (I):
【化5】 (式中、R1は水素原子、R2−カルボニル低級アルキ
ル基またはR3−低級アルキル基を表わし、R2は水酸
基、低級アルコキシ基、置換基を有する低級アルキルア
ミノ基、低級アルキル基を表わし、R3は置換基を有す
るフェニル基、置換基を有するアミノ基または水酸基を
表わし、AはEmbedded image (Wherein, R1 represents a hydrogen atom, an R2-carbonyl lower alkyl group or an R3-lower alkyl group, R2 represents a hydroxyl group, a lower alkoxy group, a lower alkylamino group having a substituent or a lower alkyl group, and R3 represents a substituent. A represents a phenyl group having a group, an amino group having a substituent or a hydroxyl group, and A represents
【化6】 を表わし、R4は水素原子または低級アシル基を表わ
し、Xは酸素原子または硫黄原子を表わし、R5はハロ
ゲン、水酸基、メルカプト基、−OR6または−SR6
を表わし、R6は低級アルキル基またはR7−カルボニ
ル低級アルキル基を表わし、R7は水酸基または低級ア
ルコキシ基を表わし、R8は水素原子または低級アルキ
ル基を表わし、Yは−(CH2)n−(n=2または
3)または−CH=CH−を表わし、Pは−NH−、酸
素原子または硫黄原子を表わす。) (ただし、R1が水素原子を表わすとき、AがEmbedded image R4 represents a hydrogen atom or a lower acyl group, X represents an oxygen atom or a sulfur atom, and R5 represents a halogen, a hydroxyl group, a mercapto group, -OR6 or -SR6.
R6 represents a lower alkyl group or an R7-carbonyl lower alkyl group, R7 represents a hydroxyl group or a lower alkoxy group, R8 represents a hydrogen atom or a lower alkyl group, and Y represents-(CH2) n- (n = 2 or 3) or -CH = CH-, and P represents -NH-, an oxygen atom or a sulfur atom. (Provided that when R1 represents a hydrogen atom,
【化7】 (Yが−(CH2)n−、n=2でPが酸素原子または
−NH−)を表わす場合を除く。)で表わされる化合
物、それらの塩化合物およびそれらの溶媒和物、並びに
それらを有効成分とする抗血栓剤、血栓溶解剤に関す
る。さらに、本発明の式(II)Embedded image (Y is-(CH2) n-, n = 2 and P represents an oxygen atom or -NH-). ), Their salt compounds and their solvates, and antithrombotic agents and thrombolytic agents containing them as active ingredients. Further, the compound of formula (II) of the present invention
【化8】 を表わす。)で表わされる化合物は、前記式(I)で表
わされる化合物の合成中間体として有用である。Embedded image Represents The compound represented by the formula (1) is useful as a synthetic intermediate for the compound represented by the formula (I).
【0005】[0005]
【発明の実施の形態】本発明において、低級アルキル基
および低級アルコキシ基の一部としての低級アルキル基
とは、炭素数1〜6の直鎖および分枝鎖アルキル基を意
味し、具体的には例えばメチル基、エチル基、プロピル
基、イソプロピル基、ブチル基、イソブチル基、sec
−ブチル基、tert−ブチル基、ペンチル基およびヘ
キシル基などが挙げられる。ハロゲン原子としては、フ
ッ素原子、塩素原子、臭素原子、ヨウ素原子などが挙げ
られる。本発明の前記式(I)で表わされる化合物は、
必要に応じて薬理学的に許容し得る塩に変換すること
も、あるいは生成した塩から遊離塩基あるいは遊離酸に
変換することもできる。さらにそれらの化合物を溶媒和
物とすることもできる。塩としては、薬理学的に許容し
得る酸付加塩、金属塩、アンモニウム塩、有機アミン
塩、アミノ酸付加塩が挙げられる。具体的には酸付加塩
としては塩酸塩、リン酸塩、硫酸塩等の無機酸塩、酢酸
塩、クエン酸塩、メタンスルホン酸塩等の有機酸塩が挙
げられ、金属塩としてはナトリウム塩、カリウム塩等の
アルカリ金属、マグネシウム塩、カルシウム塩等のアル
カリ土類金属塩、アルミニウム塩等が挙げられ、アンモ
ニウム塩としてはアンモニウム等の塩が挙げられ、有機
アミン塩付加塩としてはモルホリン、ピペリジン等の付
加塩が挙げられ、アミノ酸付加塩としては、グリシン、
リジン等の付加塩が挙げられる。溶媒和物としては、水
和物等が挙げられる。BEST MODE FOR CARRYING OUT THE INVENTION In the present invention, a lower alkyl group as a part of a lower alkyl group and a lower alkoxy group means a straight-chain or branched-chain alkyl group having 1 to 6 carbon atoms. Are, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec
-Butyl group, tert-butyl group, pentyl group, hexyl group and the like. Examples of the halogen atom include a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom. The compound represented by the formula (I) of the present invention is
If necessary, the compound can be converted into a pharmacologically acceptable salt, or the resulting salt can be converted into a free base or a free acid. Further, those compounds may be solvates. Salts include pharmacologically acceptable acid addition salts, metal salts, ammonium salts, organic amine salts, amino acid addition salts. Specific examples of the acid addition salt include inorganic acid salts such as hydrochloride, phosphate and sulfate, and organic acid salts such as acetate, citrate and methanesulfonate. And alkaline earth metal salts such as magnesium salts and calcium salts, aluminum salts and the like, ammonium salts and the like, ammonium salts and the like, and organic amine salt addition salts as morpholine and piperidine. And the like. Among the amino acid addition salts, glycine,
And addition salts such as lysine. Hydrate etc. are mentioned as a solvate.
【0006】本発明の前記式(I)で表わされる化合物
は、いずれも公知の方法により合成することができる。The compounds of the present invention represented by the formula (I) can be synthesized by known methods.
【化9】 [式(3)および式(7)中、R9はハロゲン原子また
はトリフルオロメタンスルホニルオキシ基などを表わ
し、式(4)および式(6)中、Buはブチル基を表わ
す。式(3)および式(4)中、R1は前記の通りであ
り、式(5)、式(6)および式(7)中、Aは前記の
通りである]Embedded image [In formulas (3) and (7), R9 represents a halogen atom or a trifluoromethanesulfonyloxy group, and in formulas (4) and (6), Bu represents a butyl group. In the formulas (3) and (4), R1 is as described above, and in the formulas (5), (6) and (7), A is as described above.
【0007】工程1 式(1)で表わされる化合物は、式(3)で表わされる
化合物および式(5)で表わされる化合物を用いて、S
ommai Pivsa−Artらの方法[Bull.
Chem.Soc.Jpn.,71,467(199
8).]により製造することができる。例えば、式
(3)で表わされる化合物として6−ブロモ−2−ナフ
トール誘導体、式(5)で表わされる化合物として各種
複素環化合物、例えばN−メチルベンゾイミダゾール、
ベンゾチオフェン、ベンゾオキサゾールあるいはベンゾ
チアゾールなどを用いると、式(1)で表わされる化合
物として、対応する6−(1−メチルベンゾイミダゾー
ル−2−イル)−2−ナフトール誘導体、6−(ベンゾ
チオフェン−2−イル)−2−ナフトール誘導体、6−
(ベンゾオキサゾール−2−イル)−2−ナフトール誘
導体あるいは6−(ベンゾチアゾール−2−イル)−2
−ナフトール誘導体を得ることができる。式(3)中、
R1が水素原子の場合は、あらかじめ適当な保護基で保
護し、該反応後、脱保護し目的の官能基に変換すること
ができる。得られた式(1)で表わされる化合物は、必
要に応じて官能基を変換し、目的の化合物とすることも
できる。Step 1 A compound represented by the formula (1) is prepared by using a compound represented by the formula (3) and a compound represented by the formula (5)
ommai Pivsa-Art et al. [Bull.
Chem. Soc. Jpn. , 71, 467 (199
8). ] Can be produced. For example, as the compound represented by the formula (3), a 6-bromo-2-naphthol derivative, as the compound represented by the formula (5), various heterocyclic compounds, for example, N-methylbenzimidazole,
When benzothiophene, benzoxazole, benzothiazole, or the like is used, as a compound represented by the formula (1), the corresponding 6- (1-methylbenzimidazol-2-yl) -2-naphthol derivative, 6- (benzothiophene- 2-yl) -2-naphthol derivative, 6-
(Benzoxazol-2-yl) -2-naphthol derivative or 6- (benzothiazol-2-yl) -2
-Naphthol derivatives can be obtained. In equation (3),
When R1 is a hydrogen atom, it can be protected with an appropriate protecting group in advance, and after the reaction, deprotected and converted into a desired functional group. The obtained compound represented by the formula (1) can be converted into a functional group, if necessary, to obtain a target compound.
【0008】本発明において、塩基とは、ナトリウム、
アルコキシアルカリ金属(例えばナトリウムメトキシ
ド)あるいは炭酸カリウム、炭酸ナトリウム、水酸化ナ
トリウムなどの無機塩基あるいはトリエチルアミン、ピ
リジンなどの有機塩基を表わす。有機合成化学で常用さ
れる保護基の導入および脱離法としては、例えば、T.
W.Green,“Protective Group
s in Organic Synthesis,2n
d Ed.”,John Wiley & Sons,
1991.に記載の方法がある。目的の官能基への変換
反応としては、例えば水酸基の場合、適当な溶媒中で塩
基存在下、置換もしくは非置換のハロゲン化低級アルキ
ルと反応させることにより、置換もしくは非置換の低級
アルコキシ基とする反応がある。このほか公知の方法と
して例えば、 R.C.Larock,“Compre
hensive Organic Transform
ations.”, VHC Publishers,
Inc.1989.に記載の方法を用いることもでき
る。上記の方法は例であり、その他の既知の方法を用い
ることもできる。In the present invention, the base is sodium,
Inorganic bases such as alkoxyalkali metal (for example, sodium methoxide), potassium carbonate, sodium carbonate, and sodium hydroxide; and organic bases such as triethylamine and pyridine. Methods for introducing and removing protective groups commonly used in organic synthetic chemistry include, for example, T.I.
W. Green, “Protective Group
s in Organic Synthesis, 2n
d Ed. ", John Wiley & Sons,
1991. There is a method described in. As the conversion reaction to the desired functional group, for example, in the case of a hydroxyl group, in the presence of a base in an appropriate solvent, by reacting with a substituted or unsubstituted lower alkyl halide, a substituted or unsubstituted lower alkoxy group is obtained. There is a reaction. Other known methods include, for example, R.I. C. Larock, “Compre
Hensive Organic Transform
ations. ", VHC Publishers,
Inc. 1989. Can also be used. The above method is an example, and other known methods can be used.
【0009】工程2 式(1)で表わされる化合物は、式(3)で表わされる
化合物および式(6)で表わされる化合物を用いて、S
tilleら[T.N.Mitchell, Synt
hesis, 803(1992).]の方法により、
製造することもできる。例えば、式(3)で表わされる
化合物として6−ブロモ−2−ナフトール誘導体を、式
(6)で表わされる化合物としてトリブチルスタニル基
を有する各種複素環誘導体、例えば、2−トリブチルス
タニルフラン若しくは2−トリブチルスタニルチオフェ
ンなどを用いることにより、式(1)で表わされる化合
物として、対応する6−(2−フリル)−2−ナフトー
ル誘導体若しくは6−チエニル−2−ナフトール誘導体
を得ることができる。式(3)中、R1は工程1と同様
な反応を行うことにより、目的とする式(1)で表わさ
れる化合物を製造することができる。上記の方法は例で
あり、その他の既知の方法を用いることもできる。Step 2 The compound represented by the formula (1) is prepared by using the compound represented by the formula (3) and the compound represented by the formula (6)
Tille et al. [T. N. Mitchell, Synt
hesis, 803 (1992). ] Method,
It can also be manufactured. For example, a 6-bromo-2-naphthol derivative is used as the compound represented by the formula (3), and various heterocyclic derivatives having a tributylstannyl group are used as the compound represented by the formula (6), for example, 2-tributylstannylfuran or 2 By using -tributylstannylthiophene or the like, a corresponding 6- (2-furyl) -2-naphthol derivative or 6-thienyl-2-naphthol derivative can be obtained as the compound represented by the formula (1). In the formula (3), the target compound represented by the formula (1) can be produced by subjecting R1 to the same reaction as in step 1. The above method is an example, and other known methods can be used.
【0010】工程3−1 中間体(6−トリブチルスタニル−2−ナフトール誘導
体)[式(4)]の製造 式(3)で表わされる化合物およびビス(トリブチルス
ズ)を、テトラキス(トリフェニル)ホスフィンパラジ
ウム存在下、適当な溶媒中で加熱することにより式
(4)で表わされる化合物が製造できる。例えば、式
(3)で表わされる化合物として、メチル 6−ブロモ
−2−ナフチルオキシアセタートを用い、これとテトラ
キス(トリフェニル)ホスフィンパラジウムのジオキサ
ン溶液にビス(トリブチルスズ)を加え、加熱還流し、
反応液を減圧下で濃縮したのち、シリカゲルカラム(へ
キサン−酢酸エチル)で精製することにより、式(4)
で表わされる化合物であるメチル 6−トリブチルスタ
ニル−2−ナフチルオキシアセタートを得ることができ
る。式(3)中、R1は工程1と同様な反応を行うこと
もできる。Step 3-1 Preparation of Intermediate (6-Tributylstannyl-2-naphthol Derivative) [Formula (4)] A compound represented by the formula (3) and bis (tributyltin) are converted to tetrakis (triphenyl) phosphine The compound represented by the formula (4) can be produced by heating in a suitable solvent in the presence of palladium. For example, as the compound represented by the formula (3), methyl 6-bromo-2-naphthyloxyacetate is used, bis (tributyltin) is added to a dioxane solution of tetrakis (triphenyl) phosphinepalladium, and the mixture is heated under reflux.
The reaction solution is concentrated under reduced pressure, and then purified by a silica gel column (hexane-ethyl acetate) to obtain the compound of formula (4).
To obtain methyl 6-tributylstannyl-2-naphthyloxyacetate. In the formula (3), R1 can perform the same reaction as in step 1.
【0011】工程3−2 式(1)で表わされる化合物は、式(4)で表わされる
化合物および式(7)で表わされる化合物を用いて、前
記のStilleらの方法に従い製造することもでき
る。例えば、式(4)で表わされる化合物としてメチル
6−トリブチルスタニル−2−ナフチルオキシアセタ
ート、式(7)で表わされる化合物として各種複素環誘
導体、例えば、2−ブロモピリジン、3−ブロモピリジ
ン、4−ブロモピリジン、3−ブロモフラン、3−ブロ
モチオフェン、5−ブロモピリミジン、2−ブロモ−
1,3−チアゾール、3−ブロモキノリン、4−ブロモ
イソキノリン、N−アセチル−4−ブロモピラゾール、
5−ブロモ−2−メチルベンゾチアゾール若しくは4−
ブロモアンチピリンなどを用いることにより、対応する
メチル 6−(2−ピリジル)−2−ナフチルオキシア
セタート、メチル 6−(3−ピリジル)−2−ナフチ
ルオキシアセタート、メチル 6−(4−ピリジル)−
2−ナフチルオキシアセタート、メチル 6−(3−フ
リル)−2−ナフチルオキシアセタート、メチル 6−
(3−チエニル)−2−ナフチルオキシアセタート、メ
チル 6−(5−ピリミジニル)−2−ナフチルオキシ
アセタート、メチル 6−(1,3−チアゾール−2−
イル)−2−ナフチルオキシアセタート、メチル 6−
(3−キノリル)−2−ナフチルオキシアセタート、メ
チル6−(4−イソキノリル)−2−ナフチルオキシア
セタート、メチル 6−(N−アセチル−4−ピラゾリ
ル)−2−ナフチルオキシアセタート、メチル 6−
[5−(2−メチル−1,3−ベンゾチアゾリル)]−
2−ナフチルオキシアセタート若しくはメチル 6−
(2,3−ジメチル−1−フェニル−3−ピラゾリン−
5−オン−4−イル)−2−ナフチルオキシアセタート
を得ることができる。得られた式(1)で表わされる化
合物は、必要に応じて工程1に記載の方法で官能基を変
換し、目的の化合物とすることもできる。上記の方法は
例であり、その他の既知の方法を用いることもできる。Step 3-2 The compound represented by the formula (1) can also be produced from the compound represented by the formula (4) and the compound represented by the formula (7) according to the method of Stille et al. . For example, methyl 6-tributylstannyl-2-naphthyloxyacetate as the compound represented by the formula (4), and various heterocyclic derivatives as the compound represented by the formula (7), for example, 2-bromopyridine, 3-bromopyridine , 4-bromopyridine, 3-bromofuran, 3-bromothiophene, 5-bromopyrimidine, 2-bromo-
1,3-thiazole, 3-bromoquinoline, 4-bromoisoquinoline, N-acetyl-4-bromopyrazole,
5-bromo-2-methylbenzothiazole or 4-
By using bromoantipyrine or the like, the corresponding methyl 6- (2-pyridyl) -2-naphthyloxyacetate, methyl 6- (3-pyridyl) -2-naphthyloxyacetate, methyl 6- (4-pyridyl) −
2-naphthyloxyacetate, methyl 6- (3-furyl) -2-naphthyloxyacetate, methyl 6-
(3-thienyl) -2-naphthyloxyacetate, methyl 6- (5-pyrimidinyl) -2-naphthyloxyacetate, methyl 6- (1,3-thiazole-2-
Yl) -2-naphthyloxyacetate, methyl 6-
(3-quinolyl) -2-naphthyloxyacetate, methyl 6- (4-isoquinolyl) -2-naphthyloxyacetate, methyl 6- (N-acetyl-4-pyrazolyl) -2-naphthyloxyacetate, methyl 6-
[5- (2-methyl-1,3-benzothiazolyl)]-
2-naphthyloxyacetate or methyl 6-
(2,3-dimethyl-1-phenyl-3-pyrazoline-
5-on-4-yl) -2-naphthyloxyacetate can be obtained. The obtained compound represented by the formula (1) can be converted into a desired compound by converting a functional group by the method described in Step 1 as necessary. The above method is an example, and other known methods can be used.
【0012】[0012]
【化10】 (式(8)、式(9)、式(10)、式(11)、式
(12)、式(13)および式(14)中、R1は前記
の通りであり、式(13)中、R5は前記の通りであ
る) 工程4 式(8)で表わされる化合物およびクロロカルボニルス
ルホニルクロリドを用いて、 Paul C.Unan
gstらの方法[J.Med.Chem.,35,36
91(1992).]に従い、式(9)で表わされる化
合物を製造することができる。例えば、式(8)で表わ
される化合物として6−ヒドロキシナフタレン−2−カ
ルボキサミドを用いると、式(9)で表わされる化合物
として5−(6−ヒドロキシ−2−ナフチル)−2−オ
キソ−1,3,4−オキサチアゾールが得られる。得ら
れた式(9)で表わされる化合物は、必要に応じて工程
1に記載の方法により官能基を変換し、目的の化合物と
することもできる。上記の方法は例であり、その他の既
知の方法を用いることもできる。Embedded image (In the formula (8), the formula (9), the formula (10), the formula (11), the formula (12), the formula (13) and the formula (14), R1 is as described above, and in the formula (13) , R5 are as defined above. Step 4 Using a compound represented by the formula (8) and chlorocarbonylsulfonyl chloride, Paul C.I. Unan
gst et al. [J. Med. Chem. , 35,36
91 (1992). ], The compound represented by the formula (9) can be produced. For example, when 6-hydroxynaphthalene-2-carboxamide is used as the compound represented by the formula (8), 5- (6-hydroxy-2-naphthyl) -2-oxo-1, 3,4-oxathiazole is obtained. The obtained compound represented by the formula (9) can be converted into a desired compound by converting a functional group according to the method described in Step 1 as necessary. The above method is an example, and other known methods can be used.
【0013】工程5−1 中間体(2−ヒドロキシアミジノ−2−ナフトール誘導
体)[式(11)]の製造 式(10)で表わされる化合物は、式(8)で表わされ
る化合物を塩化チオニルなどで処理することにより得ら
れる。もしくは2−シアノ−6−ナフトールから工程1
に記載した官能基変換反応によっても誘導できる。例え
ば、2−シアノ−6−ナフトールを適当な溶媒中で炭酸
カリウムあるいは炭酸ナトリウムなどの塩基存在下、臭
化酢酸メチルと反応させると、式(10)で表わされる
化合物としてメチル 6−シアノ−2−ナフチルオキシ
アセタートが得られる。得られた式(10)で表わされ
る化合物およびヒドロキシルアミンを用いて、 前記の
Paul C.Unangst らの方法に従い、式
(11)で表わされる化合物を製造することができる。
例えば、式(10)で表わされる化合物として、メチル
6−シアノ−2−ナフチルオキシアセタートを用いる
と、式(11)で表わされる化合物としてメチル 6−
ヒドロキシアミジノ−2−ナフチルオキシアセタートが
得られる。Step 5-1 Preparation of Intermediate (2-Hydroxyamidino-2-naphthol Derivative) [Formula (11)] The compound represented by the formula (10) is obtained by converting the compound represented by the formula (8) into thionyl chloride or the like. Obtained by treating Alternatively, Step 1 from 2-cyano-6-naphthol
Can also be induced by the functional group conversion reaction described in (1). For example, when 2-cyano-6-naphthol is reacted with methyl bromide acetate in a suitable solvent in the presence of a base such as potassium carbonate or sodium carbonate, methyl 6-cyano-2 is obtained as a compound represented by the formula (10). -Naphthyl oxyacetate is obtained. Using the obtained compound represented by the formula (10) and hydroxylamine, the above Paul C.I. According to the method of Unangst et al., The compound represented by the formula (11) can be produced.
For example, when methyl 6-cyano-2-naphthyloxyacetate is used as the compound represented by the formula (10), methyl 6-cyano-2-naphthyloxyacetate is used as the compound represented by the formula (11).
Hydroxyamidino-2-naphthyloxy acetate is obtained.
【0014】工程5−2 式(11)で表わされる化合物、塩化チオニルおよびピ
リジンを用いて、Y.Koharaらの方法[ J.M
ed.Chem.,39,5228(1996).]に
より、式(12)で表わされる化合物を製造することが
できる。例えば、式(11)で表わされる化合物とし
て、前記工程5−1で記載したメチル 6−ヒドロキシ
アミジノ−2−ナフチルオキシアセタートを用いると、
式(12)で表わされる化合物としてメチル 6−(2
−オキソ−3H−1,2,3,5−オキサチアジアゾー
ル−4−イル)−2−ナフチルオキシアセタートが得ら
れる。上記の方法は例であり、その他の既知の方法を用
いることもできる。Step 5-2 Using a compound represented by the formula (11), thionyl chloride and pyridine, Y. Kohara et al. [J. M
ed. Chem. , 39, 5228 (1996). ], The compound represented by the formula (12) can be produced. For example, when methyl 6-hydroxyamidino-2-naphthyloxyacetate described in the above step 5-1 is used as the compound represented by the formula (11),
As the compound represented by the formula (12), methyl 6- (2
-Oxo-3H-1,2,3,5-oxathiadiazol-4-yl) -2-naphthyloxyacetate is obtained. The above method is an example, and other known methods can be used.
【0015】工程5−3 式(11)で表わされる化合物およびクロロぎ酸エチル
を用いて前記のY.Koharaらの方法に従い、式
(13)で表わされる化合物を製造することができる。
例えば、式(11)中、R1に2−メトキシエトキシメ
チル基あるいはメトキシカルボニルメチル基などが導入
された化合物を用いると、式(13)で表わされる化合
物として、それぞれ対応する、3−(2−メトキシエト
キシメトキシ−6−ナフチル)−1,2,4−オキサジ
アゾール−5−オールあるいはメチル6−(5−ヒドロ
キシ−1,2,4−オキサジアゾール−3−イル)−2
−ナフチルオキシアセタートが得られる。得られた3−
(2−メトキシエトキシメトキシ−6−ナフチル)−
1,2,4−オキサジアゾール−5−オールは酸、例え
ば、塩酸あるいはトリフルオロ酢酸などで処理をする
と、2−(6−ヒドロキシナフチル)−1,2,4−オ
キサジアゾール−5−オールが得られ、メチル 6−
(5−ヒドロキシ−1,2,4−オキサジアゾール−3
−イル)−2−ナフチルオキシアセタートは適当な溶媒
中、塩基、例えば、水酸化ナトリウムあるいは水酸化カ
リウムなどで処理をすると6−(5−ヒドロキシ−1,
2,4−オキサジアゾール−3−イル)−2−ナフチル
オキシ酢酸が得られる。得られた6−(5−ヒドロキシ
−1,2,4−オキサジアゾール−3−イル)−2−ナ
フトール誘導体[式(13)]は、6−(4H−1,
2,4−オキサジアゾール−5−オン−3−イル)−2
−ナフトール誘導体と互変異性の関係にあり、両化合物
は等価である。本発明において記載する5−ヒドロキシ
−1,2,4−オキサジアゾール誘導体は、特にことわ
らないかぎり互変異性体の両方を示し、いずれの異性体
も本発明の範囲に含まれる。式(13)中、R1および
R5は、工程1に記載した方法および前記のPaul
C.Unangst らの方法により目的の官能基へ変
換できる。得られた、6−(5−メルカプト−1,2,
4−オキサジアゾール−3−イル)−2−ナフトール誘
導体は、6−(5−チオキソ−4H−1,2,4−オキ
サジアゾール−3−イル)−2−ナフトール誘導体と互
変異性の関係にあり、両化合物は等価である。本発明に
おいて記載する5−メルカプト−1,2,4−オキサジ
アゾール誘導体は、特にことわらないかぎり互変異性体
の両方を示し、いずれの異性体も本発明の範囲に含まれ
る。上記の方法は例であり、その他の既知の方法を用い
ることもできる。Step 5-3 Using the compound represented by the formula (11) and ethyl chloroformate, According to the method of Kohara et al., The compound represented by the formula (13) can be produced.
For example, in the formula (11), when a compound in which a 2-methoxyethoxymethyl group or a methoxycarbonylmethyl group is introduced into R1 is used, as a compound represented by the formula (13), 3- (2- Methoxyethoxymethoxy-6-naphthyl) -1,2,4-oxadiazol-5-ol or methyl 6- (5-hydroxy-1,2,4-oxadiazol-3-yl) -2
-Naphthyl oxyacetate is obtained. The obtained 3-
(2-methoxyethoxymethoxy-6-naphthyl)-
1,2,4-oxadiazol-5-ol can be treated with an acid such as hydrochloric acid or trifluoroacetic acid to give 2- (6-hydroxynaphthyl) -1,2,4-oxadiazole-5-ol. All is obtained, methyl 6-
(5-Hydroxy-1,2,4-oxadiazole-3
-Yl) -2-naphthyloxyacetate can be treated with a base such as sodium hydroxide or potassium hydroxide in a suitable solvent to give 6- (5-hydroxy-1,
2,4-oxadiazol-3-yl) -2-naphthyloxyacetic acid is obtained. The obtained 6- (5-hydroxy-1,2,4-oxadiazol-3-yl) -2-naphthol derivative [formula (13)] is obtained by adding 6- (4H-1,
2,4-oxadiazol-5-one-3-yl) -2
-Has a tautomeric relationship with the naphthol derivative, and both compounds are equivalent. The 5-hydroxy-1,2,4-oxadiazole derivative described in the present invention shows both tautomers unless otherwise specified, and both isomers are included in the scope of the present invention. In the formula (13), R1 and R5 are the same as those described in the step 1 and the aforementioned Paul.
C. It can be converted to the desired functional group by the method of Ungst et al. The resulting 6- (5-mercapto-1,2,2,
The 4-oxadiazol-3-yl) -2-naphthol derivative is tautomeric with the 6- (5-thioxo-4H-1,2,4-oxadiazol-3-yl) -2-naphthol derivative. In a relationship, both compounds are equivalent. The 5-mercapto-1,2,4-oxadiazole derivative described in the present invention shows both tautomers unless otherwise specified, and both isomers are included in the scope of the present invention. The above method is an example, and other known methods can be used.
【0016】工程6 式(10)で表わされる化合物、アジ化ナトリウムおよ
び塩化アンモニウムを用いることにより、式(14)で
表わされる化合物を製造することができる。例えば、式
(10)で表わされる化合物としてメチル 6−シアノ
−2−ナフチルオキシアセタートを用いると、式(1
4)で表わされる化合物としてメチル 6−(5−テト
ラゾリル)−2−ナフチルオキシアセタートが得られ
る。得られた式(14)で表わされる化合物は、必要に
応じて工程1に記載の方法により官能基を変換し、目的
の化合物とすることもできる。上記方法は例であり、そ
の他既知の方法を用いることもできる。Step 6 The compound represented by the formula (14) can be produced by using the compound represented by the formula (10), sodium azide and ammonium chloride. For example, when methyl 6-cyano-2-naphthyloxyacetate is used as the compound represented by the formula (10), the compound represented by the formula (1)
Methyl 6- (5-tetrazolyl) -2-naphthyloxyacetate is obtained as the compound represented by 4). The obtained compound represented by the formula (14) may be converted into a functional group by the method described in Step 1 as necessary to obtain a target compound. The above method is an example, and other known methods can also be used.
【0017】中間体(2−アミジノ−6−ナフトール誘
導体)[式(15)]の製造Preparation of intermediate (2-amidino-6-naphthol derivative) [formula (15)]
【化11】 [式(15)、(16)および(17)中、R1は前記
の通りである]式(8)で表わされる化合物およびトリ
アルキルオキソニウムテトラフルオロボレートを用い
て、Meerweinら[R.F.Borch, Te
trahedronLett., 61(196
8).]の方法によりカルバモイル基をアルコキシカル
ボンイミドリル基へ変換させたのち、アンモニアを反応
させることにより式(15)で表わされる化合物を製造
することができる。あるいは、式(10)で表わされる
化合物を用いて、Pinnerらの方法により、式(1
5)で表わされる化合物を製造することができる。式
(8)および式(10)中、R1は工程1と同様な反応
を行うことができる。Embedded image [In the formulas (15), (16) and (17), R1 is as defined above] Using the compound represented by the formula (8) and a trialkyloxonium tetrafluoroborate, Meerwein et al. F. Borch, Te
trahedron Lett. , 61 (196
8). ], The carbamoyl group is converted to an alkoxycarboximidolyl group, and then reacted with ammonia to produce a compound represented by the formula (15). Alternatively, using the compound represented by the formula (10) and the method of Pinner et al.
The compound represented by 5) can be produced. In the formulas (8) and (10), R1 can perform the same reaction as in the step 1.
【0018】工程7 式(15)で表わされる化合物、アセトアミドおよび
1,1−ジメトキシトリメチルアミンをジオキサンに溶
解し、塩基存在下、例えば、カリウム t−ブトキシド
などを用いて、加熱することにより式(16)で表わさ
れる化合物を製造することができる。例えば、式(1
5)で表わされる化合物として2−アミジノ−6−ナフ
トール・メタンスルホン酸塩を用いると、式(16)で
表わされる化合物として6−(1,3,5−トリアジン
−2−イル)−2−ナフトールが得られる。得られた式
(16)で表わされる化合物は、必要に応じて工程1に
記載の方法により官能基を変換し、目的の化合物とする
こともできる。上記の方法は例であり、その他の既知の
方法を用いることもできる。Step 7 The compound represented by the formula (15), acetamide and 1,1-dimethoxytrimethylamine are dissolved in dioxane, and heated by using, for example, potassium t-butoxide in the presence of a base to obtain the compound represented by the formula (16). ) Can be produced. For example, the expression (1
When 2-amidino-6-naphthol methanesulfonate is used as the compound represented by 5), 6- (1,3,5-triazin-2-yl) -2- as a compound represented by the formula (16). Naphthol is obtained. The obtained compound represented by the formula (16) may be converted into a functional group by the method described in Step 1 as necessary to obtain a target compound. The above method is an example, and other known methods can be used.
【0019】工程8 式(15)で表わされる化合物および臭化アセトアルデ
ヒドジエチルアセタールを用いて、J.W.Cornf
orthらの方法[J.Chem.Soc.,1960
(1948).]により式(17)で表わされる化合物
を製造することができる。例えば、式(15)で表わさ
れる化合物としてエチル 6−アミジノ−2−ナフチル
オキシアセタート・酢酸塩を用いると、式(17)で表
わされる化合物としてエチル 6−イミダゾリル−2−
ナフチルオキシアセタートが得られる。得られた式(1
7)で表わされる化合物は、必要に応じて工程1に記載
の方法により官能基を変換し、目的の化合物とすること
もできる。上記の方法は例であり、その他の既知の方法
を用いることもできる。Step 8 Using a compound represented by the formula (15) and acetaldehyde bromide diethyl acetal, W. Cornf
Orth et al. [J. Chem. Soc. , 1960
(1948). To produce a compound represented by the formula (17). For example, when ethyl 6-amidino-2-naphthyloxyacetate / acetate is used as the compound represented by the formula (15), ethyl 6-imidazolyl-2- as the compound represented by the formula (17)
Naphthyloxy acetate is obtained. The obtained equation (1)
The compound represented by 7) may be converted into a functional group by the method described in Step 1 as necessary to obtain a target compound. The above method is an example, and other known methods can be used.
【0020】工程9Step 9
【化12】 [式(18)および式(19)中、R1は前記の通りで
ある]式(18)で表わされる化合物、ニトロメタンお
よびアジ化ナトリウムを用いてN.S.Zefirov
ら[Chem.Commun.,1001(197
1).]の方法により式(19)で表わされる化合物を
製造することができる。例えば、式(18)で表わされ
る化合物としてt−ブチル 6−ホルミル−2−ナフチ
ルオキシアセタートを用いて反応を行うことにより、式
(19)で表わされる化合物としてt−ブチル 6−
(1,2,3−トリアゾール−4−イル)−2−ナフチ
ルオキシアセタートが得られる。式(18)中、R1は工
程1と同様な反応を行うことができる。式(19)中、
R1は工程1に記載の方法で官能基を変換し目的の化合
物とすることもできる。上記の方法は例であり、その他
の既知の方法を用いることもできる。Embedded image [In the formulas (18) and (19), R1 is as defined above.] A compound represented by the formula (18), S. Zefirov
[Chem. Commun. , 1001 (197
1). ], The compound represented by the formula (19) can be produced. For example, by performing a reaction using t-butyl 6-formyl-2-naphthyloxyacetate as the compound represented by the formula (18), t-butyl 6-
(1,2,3-Triazol-4-yl) -2-naphthyloxyacetate is obtained. In the formula (18), R1 can perform the same reaction as in Step 1. In equation (19),
R1 may be converted to a functional group by the method described in Step 1 to obtain a target compound. The above method is an example, and other known methods can be used.
【0021】工程10 中間体(2−ナフトエ酸誘導体)[式(21)]の製造Step 10 Preparation of Intermediate (2-Naphthoic Acid Derivative) [Formula (21)]
【化13】 [式(21)中、R10は低級アルキルあるいはアリー
ルアルキルを表わし、式(22)中、R11は置換の低
級アルキルを表わす。式(23)中、Yは−(CH2)
n−(n=2〜3)を表わし、式(24)中、Pおよび
Qは同一あるいは異なって、窒素原子、NH若しくは硫
黄原子を表わす。式(20)、(21)、(22)、
(23)、(24)および(25)中、R1は前記の通
りである]式(20)で表わされる化合物として6−ヒ
ドロキシ−2−ナフトエ酸を用いて、適当な溶媒に溶解
後、適当な塩基存在下、置換もしくは非置換のハロゲン
化低級アルキルあるいはハロゲン化アリールアルキルを
反応させることにより、式(21)で表わされる化合物
を製造することができる。例えば、ハロゲン化低級アル
キルとしてヨウ化エチル、ハロゲン化アリールアルキル
として臭化ベンジルを用いると、式(21)で表わされ
る化合物として、それぞれ対応する、エチル 6−ヒド
ロキシ−2−ナフタート、ベンジル 6−ヒドロキシ−
2−ナフタートが得られる。用いる塩基およびハロゲン
化物を過剰量用いると、R1およびR10の両方がアル
キル基あるいはアリールアルキル基で置換された式(2
1)で表わされる化合物が製造できる。上記の方法は例
であり、その他の既知の方法を用いることもできる。Embedded image [In formula (21), R10 represents lower alkyl or arylalkyl, and in formula (22), R11 represents substituted lower alkyl. In the formula (23), Y is-(CH2)
In the formula (24), P and Q are the same or different and represent a nitrogen atom, NH or a sulfur atom. Equations (20), (21), (22),
In the formulas (23), (24) and (25), R1 is as defined above.] Using 6-hydroxy-2-naphthoic acid as the compound represented by the formula (20), the compound is dissolved in a suitable solvent, and then dissolved. The compound represented by the formula (21) can be produced by reacting a substituted or unsubstituted halogenated lower alkyl or arylalkyl halide in the presence of a basic base. For example, when ethyl iodide is used as the lower alkyl halide and benzyl bromide is used as the arylalkyl halide, the corresponding compound represented by the formula (21) is ethyl 6-hydroxy-2-naphthalate and benzyl 6-hydroxy, respectively. −
2-Naphthate is obtained. When an excess amount of the base and halide used is used, the compound represented by the formula (2) in which both R1 and R10 are substituted with an alkyl group or an arylalkyl group is used.
The compound represented by 1) can be produced. The above method is an example, and other known methods can be used.
【0022】工程11 中間体(2−ナフタレンカルボキサミド誘導体)[式
(22)]の製造 式(21)で表わされる化合物および置換基を有する低
級アルキルアミンを、溶媒中あるいは無溶媒で加熱する
ことにより、式(22)で表わされる化合物を製造する
ことができる。例えば、式(21)で表わされる化合物
としてエチル 6−ヒドロキシ−2−ナフタート、置換
基を有する低級アルキルアミンとして2−アミノエタノ
ール若しくは3−アミノ−1−プロパノールを用いる
と、式(22)で表わされる化合物として、それぞれ対
応する、6−ヒドロキシ−N−(2−ヒドロキシエチ
ル)−2−ナフタレンカルボキサミドるいは6−ヒドロ
キシ−N−(3−ヒドロキシプロピル)−2−ナフタレ
ンカルボキサミドが製造できる。Step 11 Preparation of Intermediate (2-Naphthalenecarboxamide Derivative) [Formula (22)] , A compound represented by the formula (22) can be produced. For example, when ethyl 6-hydroxy-2-naphthate is used as the compound represented by the formula (21) and 2-aminoethanol or 3-amino-1-propanol is used as the lower alkylamine having a substituent, the compound represented by the formula (22) is obtained. 6-Hydroxy-N- (2-hydroxyethyl) -2-naphthalenecarboxamide or 6-hydroxy-N- (3-hydroxypropyl) -2-naphthalenecarboxamide, respectively, can be produced.
【0023】工程12 式(22)で表わされる化合物および塩化チオニルを用
いて、Guy D.Dianaらの方法[J.Med.
Chem.,30,383(1987).]により式
(23)で表わされる化合物を製造することができる。
例えば、式(22)で表わされる化合物として、工程1
1で得られる6−ヒドロキシ−N−(2−ヒドロキシエ
チル)−2−ナフタレンカルボキサミド若しくは6−ヒ
ドロキシ−N−(3−ヒドロキシプロピル)−2−ナフ
タレンカルボキサミドを用いると、式(23)で表わさ
れる化合物として、それぞれ対応する、6−(4,5−
ジヒドロ−1,3−オキサゾール−2−イル)−2−ナ
フトールあるいは6−(5,6−ジヒドロ−4H−1,
3−オキサジン−2−イル)−2−ナフトールが製造で
きる。式(23)中、R1は工程1に記載の方法により
官能基を変換し、目的の化合物とすることもできる。上
記の方法は例であり、その他の既知の方法を用いること
もできる。Step 12 Using the compound represented by the formula (22) and thionyl chloride, Guy D. Diana et al. [J. Med.
Chem. , 30, 383 (1987). To produce a compound represented by the formula (23).
For example, as a compound represented by the formula (22),
When 6-hydroxy-N- (2-hydroxyethyl) -2-naphthalenecarboxamide or 6-hydroxy-N- (3-hydroxypropyl) -2-naphthalenecarboxamide obtained in 1 is used, the compound is represented by the formula (23). As compounds, the corresponding 6- (4,5-
Dihydro-1,3-oxazol-2-yl) -2-naphthol or 6- (5,6-dihydro-4H-1,
3-Oxazin-2-yl) -2-naphthol can be produced. In the formula (23), R1 can be converted to a functional group by the method described in Step 1 to obtain a target compound. The above method is an example, and other known methods can be used.
【0024】工程13 式(21)で表わされる化合物、置換基を有する低級ア
ルキルアミンおよびトリアルキルアルミニウムを用い
て、Carl A.Busaccaらの方法[Tetr
ahedron Lett.,37,2935(199
6).]もしくはGunter Neefらの方法
[J.Org.Chem.,46,2824(198
1).]により式(24)で表わされる化合物を製造す
ることができる。例えば、式(21)で表わされる化合
物としてベンジル 6−ベンジルオキシ−2−ナフター
ト、置換基を有する低級アルキルアミンとしてエチレン
ジアミンまたは2−アミノエタンチオールを用いると、
式(24)で表わされる化合物として、それぞれ対応す
る、2−ベンジルオキシ−6−(2−イミダゾリニル)
ナフタレンまたは2−ベンジルオキシ−6−(4,5−
ジヒドロ−1,3−チアゾリン−2−イル)ナフタレン
が製造できる。式(24)中、R1は工程1に記載の方
法により官能基を変換し、目的の化合物とすることもで
きる。上記の方法は例であり、その他の既知の方法を用
いることもできる。Step 13 Using a compound represented by the formula (21), a lower alkylamine having a substituent and a trialkylaluminum, Carl A.S. Busacca et al. [Tetr
ahedron Lett. , 37, 2935 (199
6). ] Or the method of Gunter Neef et al. [J. Org. Chem. , 46, 2824 (198
1). To produce a compound represented by the formula (24). For example, when benzyl 6-benzyloxy-2-naphthalate is used as the compound represented by the formula (21) and ethylenediamine or 2-aminoethanethiol is used as the lower alkylamine having a substituent,
As the compound represented by the formula (24), 2-benzyloxy-6- (2-imidazolinyl)
Naphthalene or 2-benzyloxy-6- (4,5-
Dihydro-1,3-thiazolin-2-yl) naphthalene can be produced. In the formula (24), R1 can be converted to a functional group by the method described in Step 1 to obtain a target compound. The above method is an example, and other known methods can be used.
【0025】工程14 式(22)で表わされる化合物、アジ化ナトリウムおよ
びトリフルオロメタンスルホン酸無水物を用いて、Ed
ward W.Thomasの方法[Synthesi
s,767(1993).]により式(25)で表わさ
れる化合物を製造することができる。例えば、式(2
2)で表わされる化合物としてR11がメチル基の化合
物を用いると、式(25)で表わされる化合物が製造で
きる。式(25)中、R1は工程1に記載の方法により
官能基を変換し、目的の化合物とすることもできる。上
記の方法は例であり、その他の既知の方法を用いること
もできる。Step 14 Using a compound represented by the formula (22), sodium azide and trifluoromethanesulfonic anhydride,
ward. The method of Thomas [Synthesi
s, 767 (1993). To produce a compound represented by the formula (25). For example, equation (2)
When a compound in which R11 is a methyl group is used as the compound represented by 2), a compound represented by the formula (25) can be produced. In formula (25), R1 can be converted into a target compound by converting a functional group by the method described in Step 1. The above method is an example, and other known methods can be used.
【0026】このようにして製造される一般式(I)で
表わされる新規ナフタレン誘導体およびその塩化合物あ
るいはそれらの溶媒和物を有効成分とする医薬は、通
常、哺乳類(ヒト患者を含む)に対し、錠剤、カプセル
剤、散剤、細粒剤、シロップ剤等の経口投与剤、直腸投
与剤、あるいは注射剤として投与することができる。ま
た、本発明化合物は1個の治療剤として、あるいは他の
治療剤との混合物として投与することができる。それら
は単体で投与しても良いが、一般的には医薬組成物の形
態で投与する。それらの製剤は薬理学的、製剤学的に許
容し得る添加物を加え、常法により製造することができ
る。すなわち、経口剤には、通常の賦形剤、滑沢剤、結
合剤、崩壊剤、湿潤剤、コーティング剤等の添加剤を用
いることができる。経口用液剤は、水性または油性懸濁
液、溶液、乳濁液、シロップ、エリキシル等の形態であ
っても良く、あるいは使用前水または他の適当な溶媒で
調製するドライシロップとして供されても良い。前記の
液剤は、懸濁化剤、香料、希釈剤あるいは乳化剤のよう
な通常の添加剤を含有できる。直腸内投与する場合は、
坐剤として投与することができる。坐剤は、カカオ脂、
ラウリン脂、マクロゴール、グリセロゼラチン、ウィテ
ップゾール、ステアリン酸ナトリウムまたはそれらの混
合物など、適当な物質を基剤とし、必要に応じて乳化
剤、懸濁化剤、保存剤等を加えることができる。注射剤
は、水性あるいは用時溶解型剤形を構成し得る注射用蒸
留水、生理食塩水、5%ブドウ糖溶液、プロピレングリ
コール等の溶解剤ないし溶解補助剤、pH調節剤、等張
化剤、安定化剤等の製剤成分が使用される。The medicament containing the novel naphthalene derivative represented by the general formula (I) and its salt compound or a solvate thereof as an active ingredient is usually used for mammals (including human patients). , Tablets, capsules, powders, fine granules, syrups, and the like, orally, rectally, or injected. The compounds of the present invention can be administered as one therapeutic agent or as a mixture with another therapeutic agent. They may be administered alone, but are generally administered in the form of a pharmaceutical composition. These preparations can be produced by a conventional method by adding pharmacologically and pharmaceutically acceptable additives. That is, for the oral preparation, additives such as ordinary excipients, lubricants, binders, disintegrants, wetting agents, and coating agents can be used. Oral solutions may be in the form of an aqueous or oily suspension, solution, emulsion, syrup, elixir, or the like, or may be presented as a dry syrup prepared with water or other suitable solvent before use. . Said solutions may contain usual additives such as suspending agents, flavors, diluents or emulsifiers. If administered rectally,
It can be administered as a suppository. Suppositories are cocoa butter,
Based on a suitable substance such as lauric fat, macrogol, glycerogelatin, witepsol, sodium stearate or a mixture thereof, an emulsifier, a suspending agent, a preservative and the like can be added as necessary. Injectables may be dissolved or auxiliary agents such as distilled water for injection, physiological saline, 5% dextrose solution, propylene glycol or the like, which may constitute an aqueous or ready-to-use dosage form, a pH adjusting agent, an isotonic agent, Formulation ingredients such as stabilizers are used.
【0027】上記組成物で用いられる賦形剤等の具体例
を以下に挙げる。賦形剤:リン酸水素カルシウム、合成
ケイ酸アルミニウム、メタケイ酸アルミン酸マグネシウ
ム、水酸化アルミニウム・マグネシウム、ケイ酸マグネ
シウム、炭酸カルシウム、炭酸マグネシウム、リン酸水
素カルシウム、軽質無水ケイ酸、無水ケイ酸、アビセ
ル、各種デンプン、デキストリン、カルボキシメチルス
ターチ(CMS)、乳糖等。結合剤:エチルセルロース
(EC)、カルボキシメチルセルロースNa(CMC−
Na)、低置換度ヒドロキシプロピルセルロース(L−
HPC)、ヒドロキシプロピルメチルセルロース(HP
MC)、メチルセルロース(MC)、ヒドロキシプロピ
ルセルロース(HPC)、各種デンプン、デキストリ
ン、アルギン酸ナトリウム、ゼラチン、ポリビニルアル
コール(PVA)、ポリビニルピロリドン(PVP)
等。崩壊剤:合成ケイ酸アルミニウム、メタケイ酸アル
ミン酸マグネシウム、CMC−Ca、CMC、アビセ
ル、L−HPC、HPMC、MC、各種デンプン、CM
S、ヒドロキシプロピルスターチ(CPS)等。固化防
止剤:軽質無水ケイ酸、合成ケイ酸アルミニウム等。滑
沢剤:合成ケイ酸アルミニウム、無水ケイ酸、タルク、
アビセル等。矯味剤:マンニトール、クエン酸、クエン
酸Na、砂糖等。乳化剤:ゼラチン、クエン酸、クエン
酸Na、ポリオキシエチレン硬化ヒマシ油、マクロゴー
ル(PEG)、プロピレングリコール脂肪酸エステル、
ポリオキシエチレンポリオキシプロピレングリコール、
プロピレングリコール、ラウリル硫酸Na、リン脂質
等。安定化剤:亜硫酸水素ナトリウム、ポリオキシエチ
レン硬化ヒマシ油、PEG、プロピレングリコール脂肪
酸エステル、ポリオキシエチレンポリオキシプロピレン
グリコール、プロピレングリコール、ラウリル硫酸N
a、各種天然・合成シクロデキストリン、リン脂質等。
吸収促進剤:ポリオキシエチレン硬化ヒマシ油、PE
G、プロピレングリコール脂肪酸エステル、ポリオキシ
エチレンポリオキシプロピレングリコール、プロピレン
グリコール、ラウリル硫酸Na、各種天然・合成シクロ
デキストリン、中鎖脂肪酸トリグリセリド等。溶解補助
剤:エタノール、ポリオキシエチレン硬化ヒマシ油、P
EG、プロピレングリコール脂肪酸エステル、ポリオキ
シエチレンポリオキシプロピレングリコール、プロピレ
ングリコール、ラウリル硫酸Na、各種天然・合成シク
ロデキストリン等。懸濁化剤:CMC−Na、HPM
C、MC、HPC、アルギン酸ナトリウム、ゼラチン、
プロピレングリコール、ラウリル硫酸Na等。被覆剤:
EC、ケイ酸マグネシウム、タルク、酸化チタン、炭酸
カルシウム、トリアセチン、カルボキシメチルエチルセ
ルロース(CMEC)、酢酸フタル酸セルロース(CA
P)、HPMC、ヒドロキシプロピルメチルセルロース
フタレート(HPMCP)、MC、HPC、アルギン酸
ナトリウム、ポリビニルアセタールジエチルアミノアセ
テート、ポリアクリル酸Na、各種アクリル酸メタクリ
ル酸誘導体のコポリマー、ポリグリコール酸Na等。着
色剤:酸化チタン、タール色素、カラメル等。Specific examples of excipients and the like used in the above composition are shown below. Excipients: calcium hydrogen phosphate, synthetic aluminum silicate, magnesium metasilicate aluminate, aluminum magnesium hydroxide, magnesium silicate, calcium carbonate, magnesium carbonate, calcium hydrogen phosphate, light anhydrous silicic acid, silicic anhydride, Avicel, various starches, dextrin, carboxymethyl starch (CMS), lactose and the like. Binder: ethyl cellulose (EC), carboxymethyl cellulose Na (CMC-
Na), low-substituted hydroxypropylcellulose (L-
HPC), hydroxypropyl methylcellulose (HP
MC), methylcellulose (MC), hydroxypropylcellulose (HPC), various starches, dextrin, sodium alginate, gelatin, polyvinyl alcohol (PVA), polyvinylpyrrolidone (PVP)
etc. Disintegrator: synthetic aluminum silicate, magnesium metasilicate aluminate, CMC-Ca, CMC, Avicel, L-HPC, HPMC, MC, various starches, CM
S, hydroxypropyl starch (CPS) and the like. Anti-solidification agents: light anhydrous silicic acid, synthetic aluminum silicate, etc. Lubricants: synthetic aluminum silicate, silicic anhydride, talc,
Avicel and others. Flavoring agents: mannitol, citric acid, sodium citrate, sugar and the like. Emulsifiers: gelatin, citric acid, Na citrate, polyoxyethylene hydrogenated castor oil, macrogol (PEG), propylene glycol fatty acid ester,
Polyoxyethylene polyoxypropylene glycol,
Propylene glycol, sodium lauryl sulfate, phospholipids and the like. Stabilizer: sodium bisulfite, polyoxyethylene hydrogenated castor oil, PEG, propylene glycol fatty acid ester, polyoxyethylene polyoxypropylene glycol, propylene glycol, lauryl sulfate N
a, various natural and synthetic cyclodextrins, phospholipids and the like.
Absorption accelerator: Polyoxyethylene hydrogenated castor oil, PE
G, propylene glycol fatty acid esters, polyoxyethylene polyoxypropylene glycol, propylene glycol, sodium lauryl sulfate, various natural and synthetic cyclodextrins, medium-chain fatty acid triglycerides and the like. Dissolution aid: ethanol, polyoxyethylene hydrogenated castor oil, P
EG, propylene glycol fatty acid ester, polyoxyethylene polyoxypropylene glycol, propylene glycol, sodium lauryl sulfate, various natural and synthetic cyclodextrins, and the like. Suspending agent: CMC-Na, HPM
C, MC, HPC, sodium alginate, gelatin,
Propylene glycol, sodium lauryl sulfate and the like. Coating agent:
EC, magnesium silicate, talc, titanium oxide, calcium carbonate, triacetin, carboxymethylethylcellulose (CMEC), cellulose acetate phthalate (CA)
P), HPMC, hydroxypropylmethylcellulose phthalate (HPMCP), MC, HPC, sodium alginate, polyvinyl acetal diethylaminoacetate, sodium polyacrylate, copolymers of various acrylic acid methacrylic acid derivatives, sodium polyglycolate, and the like. Colorant: titanium oxide, tar dye, caramel and the like.
【0028】本発明化合物をヒトに投与する場合の投与
量は、患者の症状および本発明化合物の使用目的にもよ
るが、通常成人の場合、経口剤あるいは直腸内投与剤で
1mg〜500mg/人/日程度、注射剤で0.1〜1
00mg/人/日程度である。しかし、これらの数値は
あくまでも例示であり、投与量は患者の症状等種々の条
件によって適宜増減される。The dose of the compound of the present invention when administered to humans depends on the condition of the patient and the purpose of use of the compound of the present invention. / Day about 0.1 ~ 1 by injection
It is about 00 mg / person / day. However, these numerical values are merely examples, and the dose may be appropriately adjusted depending on various conditions such as the patient's symptoms.
【0029】[0029]
【実施例】次に実施例および試験例を挙げて本発明を具
体的に説明するが、本発明はこれらの例によって限定さ
れるものではない。EXAMPLES The present invention will now be described specifically with reference to examples and test examples, but the present invention is not limited to these examples.
【0030】参考例1 メチル 6−ブロモ−2−ナフチルオキシアセタートの
製造 6−ブロモ−2−ナフトール(22.3g)および無水
炭酸カリウム(17.9g)のDMF(200ml)懸
濁液に臭化酢酸メチル(11.4ml)を加えて1時間
攪拌する。反応液を減圧下で濃縮後、残留物に精製水を
加え、析出した固体をろ取して、メチル 6−ブロモ−
2−ナフチルオキシアセタートを得た。Reference Example 1 Preparation of methyl 6-bromo-2-naphthyloxyacetate Odor was added to a suspension of 6-bromo-2-naphthol (22.3 g) and anhydrous potassium carbonate (17.9 g) in DMF (200 ml). Methyl acetate (11.4 ml) was added and stirred for 1 hour. After the reaction solution was concentrated under reduced pressure, purified water was added to the residue, and the precipitated solid was collected by filtration to give methyl 6-bromo-
2-Naphthyloxy acetate was obtained.
【0031】参考例2 メチル 6−トリブチルスタニル−2−ナフチルオキシ
アセタートの製造 メチル 6−ブロモ−2−ナフチルオキシアセタート
(5.9g)およびテトラキス(トリフェニルホスフィ
ン)パラジウム(461mg)のジオキサン(50m
l)溶液にビス(トリブチルチン)ヘキサブチルジチン
(13.1ml)を加え、10時間加熱還流した。反応
液を減圧下で濃縮したのち、シリカゲルカラム(へキサ
ン−酢酸エチル)で精製して、メチル 6−トリブチル
スタニル−2−ナフチルオキシアセタートを得た。Reference Example 2 Preparation of methyl 6-tributylstannyl-2-naphthyloxyacetate Dioxane of methyl 6-bromo-2-naphthyloxyacetate (5.9 g) and tetrakis (triphenylphosphine) palladium (461 mg) (50m
l) Bis (tributyltin) hexabutylditin (13.1 ml) was added to the solution, and the mixture was heated under reflux for 10 hours. After concentrating the reaction solution under reduced pressure, the residue was purified by a silica gel column (hexane-ethyl acetate) to obtain methyl 6-tributylstannyl-2-naphthyloxyacetate.
【0032】参考例3 メチル 6−シアノ−2−ナフチルオキシアセタートの
製造 2−シアノ−6−ナフトール(5g)および無水炭酸カ
リウム(12.3g)のDMF(30ml)懸濁液に、
臭化酢酸メチル(3.3ml)を加えて2時間攪拌し
た。反応液を減圧下で濃縮後、残留物にメタノールを加
え、析出した固体をろ取して、メチル 6−シアノ−2
−ナフチルオキシアセタートを得た。Reference Example 3 Preparation of methyl 6-cyano-2-naphthyloxyacetate A suspension of 2-cyano-6-naphthol (5 g) and anhydrous potassium carbonate (12.3 g) in DMF (30 ml) was prepared.
Methyl acetate bromide (3.3 ml) was added and the mixture was stirred for 2 hours. After concentrating the reaction solution under reduced pressure, methanol was added to the residue, and the precipitated solid was collected by filtration to give methyl 6-cyano-2.
-Naphthyloxy acetate was obtained.
【0033】実施例1 6−(2−フリル)−2−ナフチルオキシ酢酸(化合物
1)の製造 メチル 6−ブロモ−2−ナフチルオキシアセタート
(294mg)およびテトラキス(トリフェニルホスフ
ィン)パラジウム(58mg)のジオキサン(10m
l)溶液に2−(トリブチルスタニル)フラン(0.9
4ml)を加え、2時間加熱還流した。反応液を減圧下
で濃縮したのち、シリカゲルカラム(へキサン−酢酸エ
チル)で精製して、メチル 6−(2−フリル)−2−
ナフチルオキシアセタートを得た。得られたメチル 6
−(2−フリル)−2−ナフチルオキシアセタートをエ
タノール(9ml)に懸濁し、2規定水酸化ナトリウム
水溶液(1.0ml)を加えて20分間攪拌した。反応
液を希塩酸で中和後、減圧下で濃縮した。析出した固体
をろ取したのち、精製水で洗浄して、化合物1を得た。 1H−NMR(DMSO−d6/TMS):δ=4.6
0 (2H,s)、 6.62 (1H,dd,J=1.
7,3.3Hz)、 6.99 (1H,d,J=3.3
Hz)、 7.17−7.20 (2H,m)、 7.7
7 (3H,s)、7.86 (1H,d,J=9.6H
z)、 8.12 (1H,s)。FABMS(m/
z):269 (M+1)+。Example 1 Preparation of 6- (2-furyl) -2-naphthyloxyacetic acid (compound 1) Methyl 6-bromo-2-naphthyloxyacetate (294 mg) and tetrakis (triphenylphosphine) palladium (58 mg) Dioxane (10m
l) Add 2- (tributylstannyl) furan (0.9
4 ml) and heated under reflux for 2 hours. After the reaction solution was concentrated under reduced pressure, it was purified by a silica gel column (hexane-ethyl acetate) to give methyl 6- (2-furyl) -2-.
Naphthyloxy acetate was obtained. The resulting methyl 6
-(2-Furyl) -2-naphthyloxyacetate was suspended in ethanol (9 ml), 2N aqueous sodium hydroxide solution (1.0 ml) was added, and the mixture was stirred for 20 minutes. After the reaction solution was neutralized with dilute hydrochloric acid, it was concentrated under reduced pressure. After the precipitated solid was collected by filtration, the solid was washed with purified water to obtain Compound 1. 1H-NMR (DMSO-d6 / TMS): δ = 4.6
0 (2H, s), 6.62 (1H, dd, J = 1.
7, 3.3 Hz), 6.99 (1H, d, J = 3.3)
Hz), 7.17-7.20 (2H, m), 7.7
7 (3H, s), 7.86 (1H, d, J = 9.6H)
z), 8.12 (1H, s). FABMS (m /
z): 269 (M + 1) +.
【0034】実施例2 6−(2−チエニル)−2−ナフチルオキシ酢酸(化合
物2)の製造 メチル 6−ブロモ−2−ナフチルオキシアセタート
(588mg)、テトラキス(トリフェニルホスフィ
ン)パラジウム(116mg)、および2−(トリブチ
ルスタニル)チオフェン(1.5ml)を用いて実施例
1と同様の操作を行い、メチル 6−(2−チエニル)
−2−ナフチルオキシアセタートを得た。得られた、メ
チル 6−(2−チエニル)−2−ナフチルオキシアセ
タート(150mg)に対し、実施例1と同様に2規定
水酸化ナトリウム水溶液との反応を行い、化合物2を白
色固体として得た。 1H−NMR(DMSO−d6/TMS):δ=4.6
9 (2H,s)、 7.14−7.23 (3H,
m)、 7.53−7.59 (2H,m)、 7.74
−7.83 (2H,m)、 7.88 (1H,d,J
=8.9Hz)、 8.09 (1H,s)。 FABMS(m/z):283 (M−1)−。Example 2 Preparation of 6- (2-thienyl) -2-naphthyloxyacetic acid (compound 2) Methyl 6-bromo-2-naphthyloxyacetate (588 mg), tetrakis (triphenylphosphine) palladium (116 mg) , And 2- (tributylstannyl) thiophene (1.5 ml) to carry out the same operation as in Example 1 to obtain methyl 6- (2-thienyl).
-2-Naphthyloxy acetate was obtained. The obtained methyl 6- (2-thienyl) -2-naphthyloxyacetate (150 mg) was reacted with a 2N aqueous sodium hydroxide solution in the same manner as in Example 1 to obtain Compound 2 as a white solid. Was. 1H-NMR (DMSO-d6 / TMS): δ = 4.6
9 (2H, s), 7.14-7.23 (3H,
m), 7.53-7.59 (2H, m), 7.74
−7.83 (2H, m), 7.88 (1H, d, J)
= 8.9 Hz), 8.09 (1H, s). FABMS (m / z): 283 (M-1)-.
【0035】実施例3 6−(2−ピリジル)−2−ナフチルオキシ酢酸(化合
物3)の製造 メチル 6−トリブチルスタニル−2−ナフチルオキシ
アセタート(505mg)およびテトラキス(トリフェ
ニルホスフィン)パラジウム(58mg)のジオキサン
(10ml)溶液に2−臭化ピリジン(0.29ml)
を加え、48時間加熱還流した。反応液を減圧下で濃縮
したのち、シリカゲルカラム(へキサン−酢酸エチル)
で精製して、メチル 6−(2−ピリジル)−2−ナフ
チルオキシアセタートを得た。得られた、メチル 6−
(2−ピリジル)−2−ナフチルオキシアセタート(1
20mg)をエタノール(9ml)に懸濁し、2規定水
酸化ナトリウム水溶液(1.0ml)を加えて20分間
攪拌した。反応液を希塩酸で中和後、減圧下で濃縮し
た。残留物に精製水を加えて析出した固体をろ取して、
化合物3を得た。 1H−NMR(DMSO−d6/TMS):δ=4.8
2 (2H,s)、 7.23−7.38 (3H,
m)、 7.88−8.00 (3H,m)、 8.09
(1H,d,J=7.6Hz)、 8.21 (1H,
d,J=8.6Hz)、8.60 (1H,s)、 8.
69 (1H,d,J=4.6Hz)、 13.1(1
H,br)。 FABMS(m/z):280 (M+1)+。Example 3 Preparation of 6- (2-pyridyl) -2-naphthyloxyacetic acid (compound 3) Methyl 6-tributylstannyl-2-naphthyloxyacetate (505 mg) and tetrakis (triphenylphosphine) palladium ( 2-bromopyridine (0.29 ml) in a dioxane (10 ml) solution of 58 mg).
Was added and heated under reflux for 48 hours. After concentrating the reaction solution under reduced pressure, a silica gel column (hexane-ethyl acetate)
To give methyl 6- (2-pyridyl) -2-naphthyloxyacetate. The resulting methyl 6-
(2-pyridyl) -2-naphthyloxyacetate (1
20 mg) was suspended in ethanol (9 ml), 2N aqueous sodium hydroxide solution (1.0 ml) was added, and the mixture was stirred for 20 minutes. After the reaction solution was neutralized with dilute hydrochloric acid, it was concentrated under reduced pressure. The solid precipitated by adding purified water to the residue was collected by filtration,
Compound 3 was obtained. 1H-NMR (DMSO-d6 / TMS): δ = 4.8
2 (2H, s), 7.23-7.38 (3H,
m), 7.88-8.00 (3H, m), 8.09
(1H, d, J = 7.6 Hz), 8.21 (1H,
7. d, J = 8.6 Hz), 8.60 (1H, s),
69 (1H, d, J = 4.6 Hz), 13.1 (1
H, br). FABMS (m / z): 280 (M + 1) +.
【0036】実施例4 6−(3−チエニル)−2−ナフチルオキシ酢酸(化合
物4)の製造 メチル 6−トリブチルスタニル−2−ナフチルオキシ
アセタート(505mg)、テトラキス(トリフェニル
ホスフィン)パラジウム(58mg)、および3−臭化
チオフェン(0.28ml)を用いて実施例3と同様の
操作を行い、メチル 6−(3−チエニル)−2−ナフ
チルオキシアセタートを得た。得られたメチル 6−
(3−チエニル)−2−ナフチルオキシアセタート(1
50mg)に対し、実施例3と同様に2規定水酸化ナト
リウム水溶液との反応を行い、化合物4を得た。 1H−NMR(DMSO−d6/TMS):δ=4.4
2(2H,s)、7.13−7.16(2H,m)、
7.65−7.66(2H,m)、7.74−7.91
(3H,m)、8.13(1H,s)。 FABMS(m/z):283 (M−1)−。Example 4 Preparation of 6- (3-thienyl) -2-naphthyloxyacetic acid (compound 4) Methyl 6-tributylstannyl-2-naphthyloxyacetate (505 mg), tetrakis (triphenylphosphine) palladium ( The same operation as in Example 3 was performed using 58 mg) and 3-thiophene bromide (0.28 ml) to obtain methyl 6- (3-thienyl) -2-naphthyloxyacetate. The resulting methyl 6-
(3-thienyl) -2-naphthyloxyacetate (1
50 mg) was reacted with a 2N aqueous sodium hydroxide solution in the same manner as in Example 3 to obtain Compound 4. 1H-NMR (DMSO-d6 / TMS): δ = 4.4
2 (2H, s), 7.13-7.16 (2H, m),
7.65-7.66 (2H, m), 7.74-7.91
(3H, m), 8.13 (1H, s). FABMS (m / z): 283 (M-1)-.
【0037】実施例5 6−(5−ピリミジニル)−2−ナフチルオキシ酢酸
(化合物5)の製造 メチル 6−トリブチルスタニル−2−ナフチルオキシ
アセタート(505mg)、テトラキス(トリフェニル
ホスフィン)パラジウム(58mg)、および5−臭化
ピリミジン(0.48ml)を用いて実施例3と同様の
操作を行い、メチル 6−(5−ピリミジニル)−2−
ナフチルオキシアセタートを得た。得られた、メチル
6−(5−ピリミジニル)−2−ナフチルオキシアセタ
ート(180mg)に対し、実施例3と同様に2規定水
酸化ナトリウム水溶液との反応を行い、化合物5を得
た。 1H−NMR(DMSO−d6/TMS):δ=4.2
1 (2H,s)、 7.14−7.21 (2H,
m)、 7.86−7.89 (3H,m)、 8.30
(1H,s)、 9.17 (1H,s)、 9.26
(2H,s)。 FABMS(m/z):281 (M+1)+。Example 5 Preparation of 6- (5-pyrimidinyl) -2-naphthyloxyacetic acid (compound 5) Methyl 6-tributylstannyl-2-naphthyloxyacetate (505 mg), tetrakis (triphenylphosphine) palladium ( 58 mg) and 5-bromopyrimidine (0.48 ml), and the same operation as in Example 3 was carried out to give methyl 6- (5-pyrimidinyl) -2-
Naphthyloxy acetate was obtained. Obtained methyl
6- (5-Pyrimidinyl) -2-naphthyloxyacetate (180 mg) was reacted with a 2N aqueous sodium hydroxide solution in the same manner as in Example 3 to obtain Compound 5. 1H-NMR (DMSO-d6 / TMS): δ = 4.2
1 (2H, s), 7.14-7.21 (2H, s)
m), 7.86-7.89 (3H, m), 8.30
(1H, s), 9.17 (1H, s), 9.26
(2H, s). FABMS (m / z): 281 (M + 1) +.
【0038】実施例6 6−(3−キノリル)−2−ナフチルオキシ酢酸(化合
物6)の製造 メチル 6−トリブチルスタニル−2−ナフチルオキシ
アセタート(505mg)、テトラキス(トリフェニル
ホスフィン)パラジウム(58mg)、および3−臭化
キノリン(0.41ml)を用いて実施例3と同様の操
作を行い、メチル 6−(3−キノリル)−2−ナフチ
ルオキシアセタートを得た。得られた、メチル 6−
(3−キノリル)−2−ナフチルオキシアセタート(1
40mg)に対し、実施例3と同様に2規定水酸化ナト
リウム水溶液との反応を行い、化合物6を固体として得
た。 1H−NMR(DMSO−d6/TMS):δ=4.8
4 (2H,s)、 7.29 (1H,dd,J=2.
6,8.9Hz)、 7.36 (1H,d,J=2.3
Hz)、 7.67 (1H,m)、 7.78 (1H,
m)、 7.96−8.01 (3H,m)、 8.04
−8.10 (2H,m)、 8.43 (1H,s)、
8.77 (1H,d,J=2.3Hz)、 9.40
(1H,d,J=2.3Hz)、 13.07 (1H,
br)。 FABMS(m/z):330 (M+1)+。Example 6 Preparation of 6- (3-quinolyl) -2-naphthyloxyacetic acid (compound 6) Methyl 6-tributylstannyl-2-naphthyloxyacetate (505 mg), tetrakis (triphenylphosphine) palladium ( 58 mg) and 3-bromoquinoline (0.41 ml), and the same operation as in Example 3 was performed to obtain methyl 6- (3-quinolyl) -2-naphthyloxyacetate. The resulting methyl 6-
(3-quinolyl) -2-naphthyloxyacetate (1
40 mg) was reacted with a 2N aqueous sodium hydroxide solution in the same manner as in Example 3 to obtain Compound 6 as a solid. 1H-NMR (DMSO-d6 / TMS): δ = 4.8
4 (2H, s), 7.29 (1H, dd, J = 2.
6,8.9 Hz), 7.36 (1H, d, J = 2.3)
Hz), 7.67 (1H, m), 7.78 (1H,
m), 7.96-8.01 (3H, m), 8.04
−8.10 (2H, m), 8.43 (1H, s),
8.77 (1H, d, J = 2.3 Hz), 9.40
(1H, d, J = 2.3 Hz), 13.07 (1H, d, J = 2.3 Hz)
br). FABMS (m / z): 330 (M + 1) +.
【0039】実施例7 6−(4−イソキノリル)−2−ナフチルオキシ酢酸
(化合物7)の製造 メチル 6−トリブチルスタニル−2−ナフチルオキシ
アセタート(505mg)、テトラキス(トリフェニル
ホスフィン)パラジウム(58mg)、および4−臭化
イソキノリン(624mg)を用いて実施例3と同様の
操作を行い、メチル 6−(4−イソキノリル)−2−
ナフチルオキシアセタートを得た。得られた、メチル
6−(4−イソキノリル)−2−ナフチルオキシアセタ
ート(110mg)に対し、実施例3と同様に2規定水
酸化ナトリウム水溶液との反応を行い、化合物7を固体
として得た。 1H−NMR(DMSO−d6/TMS):δ=4.8
4 (2H,s)、 7.29 (1H,dd,J=2.
3,8.9Hz)、 7.40 (1H,d,J=2.3
Hz)、 7.64 (1H, dd,J=1.7,8.
3Hz )、 7.72−7.83 (2H,m)、 7.
89−7.99 (3H,m)、 8.04(1H,
s)、 8.25 (1H,dd,J=2.0,9.2H
z)、 8.53 (1H,s)、 9.37 (1H,
s)。 FABMS(m/z):330 (M+1)+。Example 7 Preparation of 6- (4-isoquinolyl) -2-naphthyloxyacetic acid (compound 7) Methyl 6-tributylstannyl-2-naphthyloxy acetate (505 mg), tetrakis (triphenylphosphine) palladium ( 58 mg) and 4-bromoisoquinoline (624 mg), and the same operation as in Example 3 was carried out to give methyl 6- (4-isoquinolyl) -2-.
Naphthyloxy acetate was obtained. Obtained methyl
6- (4-Isoquinolyl) -2-naphthyloxyacetate (110 mg) was reacted with a 2N aqueous sodium hydroxide solution in the same manner as in Example 3 to obtain Compound 7 as a solid. 1H-NMR (DMSO-d6 / TMS): δ = 4.8
4 (2H, s), 7.29 (1H, dd, J = 2.
3,8.9 Hz), 7.40 (1H, d, J = 2.3)
Hz), 7.64 (1H, dd, J = 1.7, 8.
3 Hz), 7.72-7.83 (2H, m), 7.
89-7.99 (3H, m), 8.04 (1H,
s), 8.25 (1H, dd, J = 2.0, 9.2H)
z), 8.53 (1H, s), 9.37 (1H,
s). FABMS (m / z): 330 (M + 1) +.
【0040】実施例8 6−(2,3−ジメチル−1−フェニル−3−ピラゾリ
ン−5−オン−4−イル)−2−ナフチルオキシ酢酸
(化合物8)の製造 メチル 6−トリブチルスタニル−2−ナフチルオキシ
アセタート(505mg)、テトラキス(トリフェニル
ホスフィン)パラジウム(58mg)、および4−ブロ
モアンチピリン(801mg)を用いて実施例3と同様
の操作を行い、メチル 6−(2,3−ジメチル−1−
フェニル−3−ピラゾリン−5−オン−4−イル)−2
−ナフチルオキシアセタートを得た。得られた、メチル
6−(2,3−ジメチル−1−フェニル−3−ピラゾ
リン−5−オン−4−イル)−2−ナフチルオキシアセ
タート(80mg)に対し、実施例3と同様に2規定水
酸化ナトリウム水溶液との反応を行い、化合物8を固体
として得た。 1H−NMR(DMSO−d6/TMS):δ=2.4
4 (3H,s)、 3.18 (3H,s)、 4.77
(2H,s)、 7.18−7.29 (2H,m)、
7.35 (1H,m)、 7.41−7.44 (2
H,m)、 7.50−7.53 (2H,m)、 7.
63 (1H,m)、 7.78−7.86(2H,
m)、 7.96 (1H,m)。 FABMS(m/z):389 (M+1)+。Example 8 Preparation of 6- (2,3-dimethyl-1-phenyl-3-pyrazolin-5-one-4-yl) -2-naphthyloxyacetic acid (compound 8) Methyl 6-tributylstannyl- The same operation as in Example 3 was performed using 2-naphthyloxyacetate (505 mg), tetrakis (triphenylphosphine) palladium (58 mg), and 4-bromoantipyrine (801 mg) to give methyl 6- (2,3- Dimethyl-1-
Phenyl-3-pyrazolin-5-one-4-yl) -2
-Naphthyloxy acetate was obtained. The obtained methyl 6- (2,3-dimethyl-1-phenyl-3-pyrazolin-5-one-4-yl) -2-naphthyloxyacetate (80 mg) was treated with 2 in the same manner as in Example 3. Reaction with a normal aqueous sodium hydroxide solution was carried out to obtain Compound 8 as a solid. 1H-NMR (DMSO-d6 / TMS): δ = 2.4
4 (3H, s), 3.18 (3H, s), 4.77
(2H, s), 7.18-7.29 (2H, m),
7.35 (1H, m), 7.41-7.44 (2
H, m), 7.50-7.53 (2H, m), 7.
63 (1H, m), 7.78-7.86 (2H,
m), 7.96 (1H, m). FABMS (m / z): 389 (M + 1) +.
【0041】実施例9 6−(4−ピラゾリル)−2−ナフチルオキシ酢酸(化
合物9)の製造 4−臭化ピラゾ−ル(1.5g)をピリジン(20m
l)に溶解し、無水酢酸(4.7ml)を加えて室温で
30分間攪拌した。反応液をクロロホルム−飽和炭酸水
素ナトリウム水溶液で分配後、クロロホルム層を無水硫
酸マグネシウムで乾燥し、減圧下で濃縮した。析出した
固体をろ取し、ヘキサンで洗浄して、N−アセチル−4
−臭化ピラゾ−ルを得た。得られたN−アセチル−4−
臭化ピラゾ−ル(567mg)、メチル 6−トリブチ
ルスタニル−2−ナフチルオキシアセタート(505m
g)、およびテトラキス(トリフェニルホスフィン)パ
ラジウム(58mg)を用いて実施例3と同様の操作を
行い、メチル 6−(N−アセチル−4−ピラゾリル)
−2−ナフチルオキシアセタートを得た。得られた、メ
チル 6−(N−アセチル−4−ピラゾリル)−2−ナ
フチルオキシアセタート(110mg)に対し、実施例
3と同様に2規定水酸化ナトリウム水溶液との反応を行
い、化合物9を固体として得た。 1H−NMR(DMSO−d6/TMS):δ=4.7
7 (2H,s)、 7.18 (1H,dd,J=2.
6,8.9Hz)、 7.23 (1H,d,J=2.6
Hz)、 7.75−7.81 (3H,m)、 8.0
5 (1H,s)、8.14 (2H,s)、 13.0
0 (1H,br)。 FABMS(m/z):269 (M+1)+。 実施例10 メチル 6−(5−テトラゾリル)−2−ナフチルオキ
シアセタート(化合物10)の製造 メチル 6−シアノ−2−ナフチルオキシアセタート
(1.0g)のDMF(20ml)溶液にアジ化ナトリ
ウム(650mg)および塩化アンモニウム(535m
g)を加え、100℃で12時間攪拌した。反応液をろ
過し、ろ液を減圧下で濃縮したのち、シリカゲルカラム
(クロロホルム−メタノール)で精製して、化合物10
を固体として得た。 1H−NMR(DMSO−d6/TMS):δ=3.7
6 (3H,s)、 4.99 (2H,s)、 7.35
(1H,dd,J=2.3,8.9Hz)、 7.43
(1H,d,J=2.3Hz)、 8.00−8.11
(3H,m)、8.60 (1H,s)。 FABMS(m/z):285 (M+1)+。Example 9 Preparation of 6- (4-pyrazolyl) -2-naphthyloxyacetic acid (compound 9) Pyrazol 4-bromide (1.5 g) was added to pyridine (20 m
l), acetic anhydride (4.7 ml) was added, and the mixture was stirred at room temperature for 30 minutes. After partitioning the reaction solution with chloroform-saturated aqueous sodium hydrogen carbonate solution, the chloroform layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The precipitated solid was collected by filtration and washed with hexane to give N-acetyl-4.
-Pyrazole bromide was obtained. The resulting N-acetyl-4-
Pyrazol bromide (567 mg), methyl 6-tributylstannyl-2-naphthyloxyacetate (505 m
g) and tetrakis (triphenylphosphine) palladium (58 mg), and the same operation as in Example 3 was performed to obtain methyl 6- (N-acetyl-4-pyrazolyl).
-2-Naphthyloxy acetate was obtained. The obtained methyl 6- (N-acetyl-4-pyrazolyl) -2-naphthyloxyacetate (110 mg) was reacted with a 2N aqueous sodium hydroxide solution in the same manner as in Example 3 to give Compound 9. Obtained as a solid. 1H-NMR (DMSO-d6 / TMS): δ = 4.7
7 (2H, s), 7.18 (1H, dd, J = 2.
6,8.9 Hz), 7.23 (1H, d, J = 2.6)
Hz), 7.75-7.81 (3H, m), 8.0
5 (1H, s), 8.14 (2H, s), 13.0
0 (1H, br). FABMS (m / z): 269 (M + 1) +. Example 10 Preparation of Methyl 6- (5-tetrazolyl) -2-naphthyloxyacetate (Compound 10) Sodium azide was added to a solution of methyl 6-cyano-2-naphthyloxyacetate (1.0 g) in DMF (20 ml). (650 mg) and ammonium chloride (535 m
g) was added and the mixture was stirred at 100 ° C. for 12 hours. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure.
Was obtained as a solid. 1H-NMR (DMSO-d6 / TMS): δ = 3.7
6 (3H, s), 4.99 (2H, s), 7.35
(1H, dd, J = 2.3, 8.9 Hz), 7.43
(1H, d, J = 2.3 Hz), 8.00-8.11
(3H, m), 8.60 (1H, s). FABMS (m / z): 285 (M + 1) +.
【0042】実施例11 メチル 6−(5−ヒドロキシ−1,2,4−オキサジ
アゾール−3−イル)−2−ナフチルオキシアセタート
(化合物11)の製造 ヒドロキシルアミン・塩酸塩(1.2g)の水(50m
l)溶液に炭酸ナトリウム(880mg)を加え、室温
で5分間攪拌したのち、メチル 6−シアノ−2−ナフ
チルオキシアセタート(2.0g)のエタノール(50
ml)溶液を加え、5時間加熱還流した。反応液を氷冷
し、析出した固体をろ取したのち、精製水で洗浄して、
メチル 6−ヒドロキシアミジノ−2−ナフチルオキシ
アセタートを白色固体として得た。得られたメチル 6
−ヒドロキシアミジノ−2−ナフチルオキシアセタート
(800mg)をピリジン(5ml)に溶解し、塩化ギ
酸エチル(0.34ml)を加え、1昼夜加熱還流し
た。反応液を減圧下で濃縮したのち、残留物を少量のク
ロロホルムに溶解し、エーテルを加えて析出した固体を
ろ取して、化合物11を得た。 1H−NMR(DMSO−d6/TMS):δ=3.7
5 (3H,s)、 4.99 (2H,s)、 7.35
(1H,dd,J=2.6,8.9Hz)、 7.43
(1H,d,J=2.3Hz)、 7.83 (1H,
dd,J=1.7,8.6Hz)、 7.95−7.9
8 (2H,m)、 8.35 (1H,d,J=1.0
Hz)、 13.03 (1H,br)。 FABMS(m/z):301 (M+1)+。Example 11 Preparation of methyl 6- (5-hydroxy-1,2,4-oxadiazol-3-yl) -2-naphthyloxyacetate (Compound 11) Hydroxylamine hydrochloride (1.2 g) ) Water (50m
l) To the solution was added sodium carbonate (880 mg), and the mixture was stirred at room temperature for 5 minutes, and then methyl 6-cyano-2-naphthyloxyacetate (2.0 g) in ethanol (50 g)
ml) solution and heated to reflux for 5 hours. The reaction solution was cooled on ice, and the precipitated solid was collected by filtration and washed with purified water.
Methyl 6-hydroxyamidino-2-naphthyloxyacetate was obtained as a white solid. The resulting methyl 6
-Hydroxyamidino-2-naphthyloxyacetate (800 mg) was dissolved in pyridine (5 ml), ethyl formate (0.34 ml) was added, and the mixture was heated under reflux for one day. After the reaction solution was concentrated under reduced pressure, the residue was dissolved in a small amount of chloroform, ether was added, and the precipitated solid was collected by filtration to obtain Compound 11. 1H-NMR (DMSO-d6 / TMS): δ = 3.7
5 (3H, s), 4.99 (2H, s), 7.35
(1H, dd, J = 2.6, 8.9 Hz), 7.43
(1H, d, J = 2.3 Hz), 7.83 (1H, d, J = 2.3 Hz)
dd, J = 1.7, 8.6 Hz), 7.95-7.9
8 (2H, m), 8.35 (1H, d, J = 1.0
Hz), 13.03 (1H, br). FABMS (m / z): 301 (M + 1) +.
【0043】実施例12 6−(5−ヒドロキシ−1,2,4−オキサジアゾール
−3−イル)−2−ナフチルオキシ酢酸(化合物12)
の製造 メチル 6−(5−ヒドロキシ−1,2,4−オキサジ
アゾール−3−イル)−2−ナフチルオキシアセタート
(190mg)をメタノール(5ml)に溶解し、1規
定水酸化ナトリウム水溶液(1.6ml)を加え、室温
で1.5時間攪拌した。反応液をクエン酸で中和し、析
出した固体をろ取して、化合物12を得た。 1H−NMR(DMSO−d6/TMS):δ=4.8
5 (2H,s)、 7.32 (1H,dd,J=
2.6,8.9Hz)、 7.39 (1H,d,J=
2.3Hz)、 7.81 (1H,dd,J=2.
0,8.9Hz)、7.94−7.98 (2H,
m)、 8.34 (1H,s)、 13.04(1
H,br)。 FABMS(m/z):285 (M−1)−。Example 12 6- (5-Hydroxy-1,2,4-oxadiazol-3-yl) -2-naphthyloxyacetic acid (Compound 12)
Preparation of Methyl 6- (5-hydroxy-1,2,4-oxadiazol-3-yl) -2-naphthyloxyacetate (190 mg) in methanol (5 ml) was dissolved in 1N aqueous sodium hydroxide ( 1.6 ml) and stirred at room temperature for 1.5 hours. The reaction solution was neutralized with citric acid, and the precipitated solid was collected by filtration to obtain Compound 12. 1H-NMR (DMSO-d6 / TMS): δ = 4.8
5 (2H, s), 7.32 (1H, dd, J =
2.6, 8.9 Hz), 7.39 (1H, d, J =
2.3 Hz), 7.81 (1H, dd, J = 2.
0, 8.9 Hz), 7.94-7.98 (2H,
m), 8.34 (1H, s), 13.04 (1
H, br). FABMS (m / z): 285 (M-1)-.
【0044】実施例13 4−[6−(5−ヒドロキシ−1,2,4−オキサジア
ゾール−3−イル)−2−ナフチルオキシメチルカルボ
ニルアミノ]メチル安息香酸(化合物13)の製造 6−(5−ヒドロキシ−1,2,4−オキサジアゾール
−3−イル)−2−ナフチルオキシ酢酸(80mg)お
よび4−アミノメチル安息香酸メチル(79mg)のD
MF(2ml)溶液に、N−ヒドロキシベンゾトリアゾ
ール一水和物(43mg)、トリエチルアミン(0.0
4ml)、および1−(3−ジメチルアミノプロピル)
−3−エチルカルボジイミド・塩酸塩(54mg)を加
え、室温で一晩攪拌した。反応液を減圧下で濃縮し、残
留物を酢酸エチル−5%クエン酸水溶液で分配した。酢
酸エチル層を飽和炭酸水素ナトイウム水溶液および飽和
食塩水で洗浄したのち、無水硫酸マグネシウムで乾燥
し、減圧下で濃縮して白色固体を得た。得られた白色固
体をメタノール(2ml)に溶解し、4規定水酸化ナト
リウム水溶液(2ml)を加え、室温で1時間攪拌し
た。反応液を減圧下で濃縮したのち、希塩酸で中和し、
析出した固体をろ取して、化合物13を得た。 1H−NMR(DMSO−d6/TMS):δ=4.4
4 (2H,d,J=6.0Hz)、 4.76 (2
H,s)、 7.31−7.42 (4H,m)、
7.81−7.86 (3H,m)、 7.91−8.
00 (2H,m)、 8.35 (1H,s)、
8.84 (1H,t,J=6.0Hz)、12.88
(1H,br)。 FABMS(m/z):420 (M+1)+。Example 13 Preparation of 4- [6- (5-hydroxy-1,2,4-oxadiazol-3-yl) -2-naphthyloxymethylcarbonylamino] methylbenzoic acid (Compound 13) D of (5-hydroxy-1,2,4-oxadiazol-3-yl) -2-naphthyloxyacetic acid (80 mg) and methyl 4-aminomethylbenzoate (79 mg)
In a MF (2 ml) solution, N-hydroxybenzotriazole monohydrate (43 mg), triethylamine (0.0
4 ml), and 1- (3-dimethylaminopropyl)
-3-Ethylcarbodiimide hydrochloride (54 mg) was added, and the mixture was stirred at room temperature overnight. The reaction solution was concentrated under reduced pressure, and the residue was partitioned with ethyl acetate-5% aqueous citric acid solution. The ethyl acetate layer was washed with a saturated aqueous sodium hydrogen carbonate solution and saturated saline, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain a white solid. The obtained white solid was dissolved in methanol (2 ml), 4N aqueous sodium hydroxide solution (2 ml) was added, and the mixture was stirred at room temperature for 1 hour. After concentrating the reaction solution under reduced pressure, neutralize with dilute hydrochloric acid,
The precipitated solid was collected by filtration to obtain Compound 13. 1H-NMR (DMSO-d6 / TMS): δ = 4.4
4 (2H, d, J = 6.0 Hz), 4.76 (2
H, s), 7.31-7.42 (4H, m),
7.81-7.86 (3H, m), 7.91-8.
00 (2H, m), 8.35 (1H, s),
8.84 (1H, t, J = 6.0 Hz), 12.88
(1H, br). FABMS (m / z): 420 (M + 1) +.
【0045】実施例14 N−2−N’,N’−ジメチルアミノエチル−[6−
(5−ヒドロキシ−1,2,4−オキサジアゾール−3
−イル)−2−ナフチルオキシ]アセトアミド(化合物
14)の製造 6−(5−ヒドロキシ−1,2,4−オキサジアゾール
−3−イル)−2−ナフチルオキシ酢酸(80mg)お
よび1−アミノ−2−ジメチルアミノエタン(28m
g)をDMF(1.5ml)に溶解し、N−ヒドロキシ
ベンゾトリアゾール一水和物(43mg)および1−
(3−ジメチルアミノプロピル)−3−エチルカルボジ
イミド・塩酸塩(54mg)を加え、室温で一晩攪拌し
た。反応液を減圧下で濃縮したのち、逆相カラムクロマ
トグラフィー(C−18,水−アセトニトリル)で精製
して、化合物14を固体として得た。 1H−NMR(DMSO−d6/TMS):δ=3.0
5 (6H,s)、 3.08−3.17 (2H,
m)、 3.58−3.62 (2H,m)、 4.9
5 (2Hs)、 7.22 (1H,dd,J=2.
3,8.9Hz)、7.33 (1H,d,J=2.3
Hz)、 7.75−7.91 (3H,m)、 8.
25 (1H,s)。 FABMS(m/z):357 (M+1)+。Example 14 N-2-N ', N'-dimethylaminoethyl- [6-
(5-Hydroxy-1,2,4-oxadiazole-3
Preparation of -yl) -2-naphthyloxy] acetamide (Compound 14) 6- (5-Hydroxy-1,2,4-oxadiazol-3-yl) -2-naphthyloxyacetic acid (80 mg) and 1-amino -2-dimethylaminoethane (28m
g) was dissolved in DMF (1.5 ml), N-hydroxybenzotriazole monohydrate (43 mg) and 1-
(3-Dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (54 mg) was added, and the mixture was stirred at room temperature overnight. After the reaction solution was concentrated under reduced pressure, the residue was purified by reverse phase column chromatography (C-18, water-acetonitrile) to obtain Compound 14 as a solid. 1H-NMR (DMSO-d6 / TMS): δ = 3.0
5 (6H, s), 3.08-3.17 (2H,
m), 3.58-3.62 (2H, m), 4.9
5 (2Hs), 7.22 (1H, dd, J = 2.
3,8.9 Hz), 7.33 (1H, d, J = 2.3)
Hz), 7.75-7.91 (3H, m), 8.
25 (1H, s). FABMS (m / z): 357 (M + 1) +.
【0046】実施例15 6−(1,3,5−トリアジン−2−イル)−2−ナフ
チルオキシ酢酸(化合物15)の製造 アセトアミド(236mg)および1,1−ジメトキシ
トリメチルアミン(0.64ml)を80℃で1時間攪
拌したのち、減圧下で濃縮し、乾燥して反応試薬を調製
した。2−アミジノ−6−ナフトール・メタンスルホン
酸塩(282mg)およびカリウムt−ブトキシド(1
12mg)をジオキサン(5ml)に溶解し、先に調製
した試薬を加えて2時間加熱還流した。反応液を酢酸エ
チル−精製水で分配して、酢酸エチル層を無水硫酸マグ
ネシウムで乾燥し、減圧下で濃縮したのち、シリカゲル
カラム(クロロホルム−エタノール)で精製して、6−
(1,3,5−トリアジン−2−イル)−2−ナフトー
ルを得た。得られた、6−(1,3,5−トリアジン−
2−イル)−2−ナフトール(25mg)および無水炭
酸カリウム(46mg)をDMF(2ml)に懸濁し、
臭化酢酸メチル(0.01ml)を加えて1時間攪拌し
た。反応液を酢酸エチル−飽和炭酸水素ナトリウム水溶
液で分配したのち、酢酸エチル層を無水硫酸マグネシウ
ムで乾燥し、減圧下で濃縮し、残留物をヘキサンおよび
エタノールで洗浄した。得られたメチル 6−(1,
3,5−トリアジン−2−イル)−2−ナフチルオキシ
セタート(23mg)をエタノール(5ml)に懸濁
し、2規定水酸化ナトリウム水溶液(0.2ml)を加
えて20分間攪拌した。反応液を希塩酸で中和後、減圧
下で濃縮した。残留物に精製水を加えて析出した固体を
ろ取して、化合物15を得た。 1H−NMR(DMSO−d6/TMS):δ=4.8
7 (2H,s)、 7.31 (1H,dd,J=2.
3,8.9Hz)、 7.39 (1H,d,J=2.3
Hz)、 7.97 (1H,d,J=8.9Hz)、
8.13 (1H,d,J=9.2Hz)、 8.45
(1H,dd,J=1.7,8.6Hz)、9.06
(1H,s)、 9.38 (2H,s)。 FABMS(m/z):282 (M+1)+。Example 15 Preparation of 6- (1,3,5-triazin-2-yl) -2-naphthyloxyacetic acid (compound 15) Acetamide (236 mg) and 1,1-dimethoxytrimethylamine (0.64 ml) were obtained. After stirring at 80 ° C. for 1 hour, the mixture was concentrated under reduced pressure and dried to prepare a reaction reagent. 2-amidino-6-naphthol methanesulfonate (282 mg) and potassium t-butoxide (1
12 mg) was dissolved in dioxane (5 ml), the reagent prepared above was added, and the mixture was heated under reflux for 2 hours. The reaction solution was partitioned between ethyl acetate and purified water, the ethyl acetate layer was dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and then purified on a silica gel column (chloroform-ethanol) to give 6-
(1,3,5-Triazin-2-yl) -2-naphthol was obtained. The obtained 6- (1,3,5-triazine-
2-yl) -2-naphthol (25 mg) and anhydrous potassium carbonate (46 mg) were suspended in DMF (2 ml),
Methyl bromide acetate (0.01 ml) was added and stirred for 1 hour. After partitioning the reaction solution with ethyl acetate-saturated aqueous sodium hydrogen carbonate solution, the ethyl acetate layer was dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and the residue was washed with hexane and ethanol. The resulting methyl 6- (1,
3,5-Triazin-2-yl) -2-naphthyloxycetate (23 mg) was suspended in ethanol (5 ml), 2N aqueous sodium hydroxide solution (0.2 ml) was added, and the mixture was stirred for 20 minutes. After the reaction solution was neutralized with dilute hydrochloric acid, it was concentrated under reduced pressure. Purified water was added to the residue, and the precipitated solid was collected by filtration to obtain Compound 15. 1H-NMR (DMSO-d6 / TMS): δ = 4.8
7 (2H, s), 7.31 (1H, dd, J = 2.
3,8.9 Hz), 7.39 (1H, d, J = 2.3)
Hz), 7.97 (1H, d, J = 8.9 Hz),
8.13 (1H, d, J = 9.2 Hz), 8.45
(1H, dd, J = 1.7, 8.6 Hz), 9.06
(1H, s), 9.38 (2H, s). FABMS (m / z): 282 (M + 1) +.
【0047】実施例16 6−(1−メチルテトラゾール−5−イル)−2−ナフ
チルオキシ酢酸(化合物16)の製造 6−アセトキシ−2−ナフトエ酸(2.3g)をDMF
(20ml)に溶解し、メチルアミン・塩酸塩(743
mg)、1−(3−ジメチルアミノプロピル)−3−エ
チルカルボジイミド・塩酸塩(2.1g)、N−ヒドロ
キシベンゾトリアゾール一水和物(1.5g)、および
トリエチルアミン(1.5ml)を加え、室温で一晩攪
拌した。反応液を酢酸エチル−飽和塩化アンモニウム水
溶液で分配し、酢酸エチル層を無水硫酸マグネシウムで
乾燥し、減圧下で濃縮した。得られた6−N−メチルカ
ルバモイル−2−ナフチル アセタート(730mg)
をメタノール(10ml)に溶解し、無水炭酸カリウム
(415mg)を加え、室温で30分間攪拌した。反応
液を希塩酸で中和したのち、精製水を加えて析出した固
体をろ取して、N−メチル−6−ヒドロキシナフトエ酸
アミドを得た。得られたN−メチル−6−ヒドロキシナ
フトエ酸アミド(201mg)をDMF(4ml)に溶
解し、t−ブチルクロロジメチルシラン(196mg)
およびイミダゾール(204mg)を加えて、室温で一
晩攪拌した。反応液を減圧下で濃縮したのち、残留物に
精製水を加えて析出した固体をろ取して、N−メチル−
6−(t−ブチルジメチルシリル)オキシ−2−ナフト
エ酸アミドを得た。得られたN−メチル−6−(t−ブ
チルジメチルシリル)オキシ−2−ナフトエ酸アミド
(145mg)およびアジ化ナトリウム(90mg)を
アセトニトリル(5ml)に溶解し、トリフルオロメタ
ンスルホン酸無水物(0.23ml)およびモレキュラ
ーシーブ4A(200mg)を加え、室温で1時間攪拌
した。反応液を酢酸エチル−飽和炭酸水素ナトリウム水
溶液で分配して、酢酸エチル層を無水硫酸マグネシウム
で乾燥し、減圧下で濃縮したのち、シリカゲルカラム
(クロロホルム−エタノール)で精製して、6−(1−
メチルテトラゾール−5−イル)−2−ナフトールを得
た。得られた6−(1−メチルテトラゾール−5−イ
ル)−2−ナフトール(25mg)および無水炭酸カリ
ウム(46mg)をDMF(2ml)に懸濁し、臭化酢
酸メチル(0.02ml)を加えて1時間攪拌した。反
応液を酢酸エチル−飽和炭酸水素ナトリウム水溶液で分
配し、酢酸エチル層を無水硫酸マグネシウムで乾燥後、
減圧下で濃縮し、残留物をヘキサンおよびエタノールで
洗浄して、メチル 6−(1−メチルテトラゾール−5
−イル)−2−ナフチルオキシアセタートを得た。得ら
れた、メチル 6−(1−メチルテトラゾール−5−イ
ル)−2−ナフチルオキシアセタートをエタノール(5
ml)に懸濁し、2規定水酸化ナトリウム水溶液(0.
2ml)を加えて20分間攪拌した。反応液を希塩酸で
中和したのち、減圧下で濃縮し、残留物に精製水を加え
て析出した固体をろ取し、化合物16を得た。 1H−NMR(DMSO−d6/TMS):δ=4.2
6 (3H,s)、 4.87 (2H,s)、 7.35
(1H,dd,J=2.6,8.9Hz)、 7.42
(1H,d,J=2.6Hz)、 7.90 (1H,
dd,J=2.0,8.6Hz)、 8.01−8.0
4 (2H,m)、 8.43 (1H,d,J=1.3
Hz)、 13.11 (1H,br)。 FABMS(m/z):285 (M+1)+。Example 16 Preparation of 6- (1-methyltetrazol-5-yl) -2-naphthyloxyacetic acid (compound 16) 6-acetoxy-2-naphthoic acid (2.3 g) was added to DMF.
(20 ml) and dissolved in methylamine hydrochloride (743).
mg), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (2.1 g), N-hydroxybenzotriazole monohydrate (1.5 g), and triethylamine (1.5 ml). And stirred at room temperature overnight. The reaction solution was partitioned with ethyl acetate-saturated aqueous ammonium chloride solution, and the ethyl acetate layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained 6-N-methylcarbamoyl-2-naphthyl acetate (730 mg)
Was dissolved in methanol (10 ml), anhydrous potassium carbonate (415 mg) was added, and the mixture was stirred at room temperature for 30 minutes. After the reaction solution was neutralized with dilute hydrochloric acid, purified water was added and the precipitated solid was collected by filtration to obtain N-methyl-6-hydroxynaphthoic acid amide. The obtained N-methyl-6-hydroxynaphthoic acid amide (201 mg) was dissolved in DMF (4 ml), and t-butylchlorodimethylsilane (196 mg) was dissolved.
And imidazole (204 mg) were added, and the mixture was stirred at room temperature overnight. After the reaction solution was concentrated under reduced pressure, purified water was added to the residue, and the precipitated solid was collected by filtration to give N-methyl-
6- (t-Butyldimethylsilyl) oxy-2-naphthoic acid amide was obtained. The obtained N-methyl-6- (t-butyldimethylsilyl) oxy-2-naphthoic acid amide (145 mg) and sodium azide (90 mg) were dissolved in acetonitrile (5 ml), and trifluoromethanesulfonic anhydride (0 ml) was dissolved. .23 ml) and Molecular Sieve 4A (200 mg) were added and stirred at room temperature for 1 hour. The reaction solution was partitioned with ethyl acetate-saturated aqueous sodium hydrogen carbonate solution, the ethyl acetate layer was dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and then purified on a silica gel column (chloroform-ethanol) to give 6- (1 −
Methyltetrazol-5-yl) -2-naphthol was obtained. The obtained 6- (1-methyltetrazol-5-yl) -2-naphthol (25 mg) and anhydrous potassium carbonate (46 mg) were suspended in DMF (2 ml), and methyl bromide acetate (0.02 ml) was added. Stir for 1 hour. The reaction solution was partitioned with ethyl acetate-saturated aqueous sodium hydrogen carbonate solution, and the ethyl acetate layer was dried over anhydrous magnesium sulfate.
Concentrate under reduced pressure and wash the residue with hexane and ethanol to give methyl 6- (1-methyltetrazole-5
-Yl) -2-naphthyloxyacetate was obtained. The obtained methyl 6- (1-methyltetrazol-5-yl) -2-naphthyloxyacetate was added to ethanol (5
ml) and suspended in 2N aqueous sodium hydroxide solution (0.
2 ml) and stirred for 20 minutes. The reaction solution was neutralized with dilute hydrochloric acid, concentrated under reduced pressure, purified water was added to the residue, and the precipitated solid was collected by filtration to obtain Compound 16. 1H-NMR (DMSO-d6 / TMS): δ = 4.2
6 (3H, s), 4.87 (2H, s), 7.35
(1H, dd, J = 2.6, 8.9 Hz), 7.42
(1H, d, J = 2.6 Hz), 7.90 (1H, d, J = 2.6 Hz)
dd, J = 2.0, 8.6 Hz), 8.01-8.0
4 (2H, m), 8.43 (1H, d, J = 1.3)
Hz), 13.11 (1H, br). FABMS (m / z): 285 (M + 1) +.
【0048】実施例17 6−(2−イミダゾリニル)−2−ナフチルオキシ酢酸
(化合物17)の製造T.Nakayamaら[Che
m.Pharm.Bull., 41, 117 (1
993).]の方法に従い合成した、6−(2−イミダ
ゾリニル)−2−ナフトール・メタンスルホン酸塩
(1.1g)をDMF(5ml)に溶解し、トリエチル
アミン(1.0ml)および二炭酸ジ−t−ブチル
(0.86ml)を加え、一昼夜攪拌した。反応液を減
圧下で濃縮したのち、シリカゲルカラム(クロロホルム
−メタノール)で精製して、6−(1−t−ブトキシカ
ルボニル−2−イミダゾリニル)−2−ナフトール(3
00mg)を淡褐色固体として得た。得られた6−(1
−t−ブトキシカルボニル−2−イミダゾリニル)−2
−ナフトール(260mg)および無水炭酸カリウム
(115mg)をアセトン(4ml)に懸濁し、臭化酢
酸t−ブチル(0.12ml)を加え、室温で4時間攪
拌した。反応液をろ過し、ろ液を減圧下で濃縮したの
ち、シリカゲルカラム(ヘキサン−酢酸エチル)で精製
して、白色固体を得た。得られた白色固体を4規定塩酸
−ジオキサン溶液(3.3ml)に溶解し、室温で5時
間攪拌した。反応液にエーテルを加え、析出した固体を
ろ取して、化合物17を得た。 1H−NMR(DMSO−d6/TMS):δ=4.0
4 (4H,s)、 4.88 (2H,s)、 7.3
7−7.45 (2H,m)、 7.97−8.01
(3H,m)、 8.69 (1H,s)、 10.8
0 (2H,s)。 FABMS(m/z):271 (M+1)+。Example 17 Preparation of 6- (2-imidazolinyl) -2-naphthyloxyacetic acid (compound 17) Nakayama et al. [Che
m. Pharm. Bull. , 41, 117 (1
993). 6- (2-Imidazolinyl) -2-naphthol methanesulfonate (1.1 g), which was synthesized according to the method described above, was dissolved in DMF (5 ml), and triethylamine (1.0 ml) and di-t-dicarbonate were dissolved. Butyl (0.86 ml) was added, and the mixture was stirred overnight. After the reaction solution was concentrated under reduced pressure, it was purified on a silica gel column (chloroform-methanol) to give 6- (1-t-butoxycarbonyl-2-imidazolinyl) -2-naphthol (3
00 mg) as a light brown solid. The obtained 6- (1
-T-butoxycarbonyl-2-imidazolinyl) -2
-Naphthol (260 mg) and anhydrous potassium carbonate (115 mg) were suspended in acetone (4 ml), t-butyl acetate (0.12 ml) was added, and the mixture was stirred at room temperature for 4 hours. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure, and then purified by a silica gel column (hexane-ethyl acetate) to obtain a white solid. The obtained white solid was dissolved in a 4N hydrochloric acid-dioxane solution (3.3 ml) and stirred at room temperature for 5 hours. Ether was added to the reaction solution, and the precipitated solid was collected by filtration to obtain Compound 17. 1H-NMR (DMSO-d6 / TMS): δ = 4.0
4 (4H, s), 4.88 (2H, s), 7.3
7-7.45 (2H, m), 7.97-8.01
(3H, m), 8.69 (1H, s), 10.8
0 (2H, s). FABMS (m / z): 271 (M + 1) +.
【0049】実施例18 2−(6−ヒドロキシナフチル)−1,2,4−オキサ
ジアゾール−5−オール(化合物18)の製造 6−シアノ−2−(2−メトキシエトキシメチル)ナフ
トール(3.5g)をエタノール(120ml)に溶解
し、ヒドロキシルアミン・塩酸塩(2.8g)および炭
酸ナトリウム(4.3g)の水(80ml)溶液を加
え、5時間加熱還流した。反応液を減圧下で濃縮したの
ち、クロロホルムで抽出した。クロロホルム抽出液を無
水硫酸マグネシウムで乾燥し、減圧下で濃縮したのち、
シリカゲルカラム(ヘキサン−酢酸エチル)で精製し、
6−(2−メトキシエトキシメトキシ)ナフタレン−2
−カルボキシアミドオキシムを得た。得られた6−(2
−メトキシエトキシメトキシ)ナフタレン−2−カルボ
キシアミドオキシム(1.5g)をピリジン(10m
l)に溶解し、塩化ギ酸エチル(0.74ml)を加
え、8時間加熱還流した。反応液を減圧下で濃縮し、シ
リカゲルカラム(クロロホルム−メタノール)で精製し
て、3−(2−メトキシエトキシメトキシ−6−ナフチ
ル)−1,2,4−オキサジアゾール−5−オールを得
た。得られた3−(2−メトキシエトキシメトキシ−6
−ナフチル)−1,2,4−オキサジアゾール−5−オ
ール(1.0g)に4規定塩酸−ジオキサン溶液(9.
5ml)を加え、室温で2時間攪拌した。反応液に精製
水(500ml)を加え、30分間攪拌後、析出した固
体をろ取して、化合物18を得た。 1H−NMR(DMSO−d6/TMS):δ=7.1
7−7.21 (2H,m)、 7.74 (1H,d
d,J=1.7,8.6Hz)、 7.80−7.89
(2H,m)、 8.27 (1H,d,J=1.3
Hz)、 10.16 (1H,br)、 12.93
(1H,br)。 FABMS(m/z):229 (M+1)+。Example 18 Preparation of 2- (6-hydroxynaphthyl) -1,2,4-oxadiazol-5-ol (compound 18) 6-cyano-2- (2-methoxyethoxymethyl) naphthol (3 0.5 g) was dissolved in ethanol (120 ml), a solution of hydroxylamine hydrochloride (2.8 g) and sodium carbonate (4.3 g) in water (80 ml) was added, and the mixture was heated under reflux for 5 hours. After the reaction solution was concentrated under reduced pressure, it was extracted with chloroform. After the chloroform extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure,
Purify on silica gel column (hexane-ethyl acetate),
6- (2-methoxyethoxymethoxy) naphthalene-2
-Carboxamide oxime was obtained. The obtained 6- (2
-Methoxyethoxymethoxy) naphthalene-2-carboxamido oxime (1.5 g) in pyridine (10 m
l), ethyl formate (0.74 ml) was added, and the mixture was refluxed for 8 hours. The reaction solution is concentrated under reduced pressure and purified by a silica gel column (chloroform-methanol) to obtain 3- (2-methoxyethoxymethoxy-6-naphthyl) -1,2,4-oxadiazol-5-ol. Was. The obtained 3- (2-methoxyethoxymethoxy-6)
-Naphthyl) -1,2,4-oxadiazol-5-ol (1.0 g) in 4N hydrochloric acid-dioxane solution (9.
5 ml) and stirred at room temperature for 2 hours. Purified water (500 ml) was added to the reaction solution, and after stirring for 30 minutes, the precipitated solid was collected by filtration to obtain Compound 18. 1H-NMR (DMSO-d6 / TMS): δ = 7.1
7-7.21 (2H, m), 7.74 (1H, d
d, J = 1.7, 8.6 Hz), 7.80-7.89
(2H, m), 8.27 (1H, d, J = 1.3
Hz), 10.16 (1H, br), 12.93
(1H, br). FABMS (m / z): 229 (M + 1) +.
【0050】実施例19 6−(5−クロロ−1,2,4−オキサジアゾール−3
−イル)−2−ナフチルアセタート(化合物19)の製
造 2−(6−ヒドロキシナフチル)−1,2,4−オキサ
ジアゾール−5−オール(260mg)をピリジン(2
ml)に溶解し、室温下で無水酢酸(0.13ml)を
加え、1時間攪拌した。反応液に精製水を加え、析出し
た固体をろ取し、6−(5−ヒドロキシ−1,2,4−
オキサジアゾ−ル−3−イル)−2−ナフチル アセタ
ートを得た。得られた6−(5−ヒドロキシ−1,2,
4−オキサジアゾ−ル−3−イル)−2−ナフチル ア
セタート(250mg)に、オキシ塩化リン(1ml)
およびピリジン(0.2ml)を加え、80℃で12時
間攪拌した。反応液に氷を加え、氷冷下で2時間攪拌
し、析出した固体をろ取して、化合物19を得た。 1H−NMR(DMSO−d6/TMS):δ=2.3
6 (3H,s)、 7.44 (1H,dd,J=
2.3,8.9Hz )、 7.79 (1H,d,J
=2.0Hz)、 8.02−8.11 (2H,
m)、 8.20 (1H,d,J=8.9Hz)、
8.66 (1H,s)。 FABMS(m/z):289 (M+1)+。Example 19 6- (5-Chloro-1,2,4-oxadiazole-3
Preparation of 2- (6-hydroxynaphthyl) -1,2,4-oxadiazol-5-ol (260 mg) in pyridine (2
acetic anhydride (0.13 ml) was added at room temperature and the mixture was stirred for 1 hour. Purified water was added to the reaction solution, the precipitated solid was collected by filtration, and 6- (5-hydroxy-1,2,4-
Oxadiazol-3-yl) -2-naphthyl acetate was obtained. The obtained 6- (5-hydroxy-1,2,2,
To 4-oxadiazol-3-yl) -2-naphthyl acetate (250 mg), phosphorus oxychloride (1 ml)
And pyridine (0.2 ml) were added, and the mixture was stirred at 80 ° C. for 12 hours. Ice was added to the reaction solution, the mixture was stirred under ice cooling for 2 hours, and the precipitated solid was collected by filtration to obtain Compound 19. 1H-NMR (DMSO-d6 / TMS): δ = 2.3
6 (3H, s), 7.44 (1H, dd, J =
2.3, 8.9 Hz), 7.79 (1H, d, J
= 2.0 Hz), 8.02-8.11 (2H,
m), 8.20 (1H, d, J = 8.9 Hz),
8.66 (1H, s). FABMS (m / z): 289 (M + 1) +.
【0051】実施例20 6−(5−チオキソ−1,2,4−オキサジアゾール−
3−イル)−2−ナフトール(化合物20)の製造 6−(5−クロロ−1,2,4−オキサジアゾール−3
−イル)−2−ナフチル アセタート(200mg)を
エタノール(20ml)に溶解し、チオ尿素(126m
g)を加えて6時間加熱還流した。反応液に1規定水酸
化ナトリウム水溶液(4.8ml)を加え、室温で1時
間攪拌した。反応液に精製水(100ml)を加え、1
規定塩酸水溶液で中和したのち、析出した固体をろ取し
て、化合物20を得た。 1H−NMR(DMSO−d6/TMS):δ=7.1
9−7.22 (2H,m)、 7.78−7.90
(3H,m )、 8.40 (1H,s)、10.1
9 (1H,br)。 FABMS(m/z):245 (M+1)+。Example 20 6- (5-Thioxo-1,2,4-oxadiazole-
Preparation of 3-yl) -2-naphthol (compound 20) 6- (5-chloro-1,2,4-oxadiazole-3
-Yl) -2-naphthyl acetate (200 mg) was dissolved in ethanol (20 ml).
g) was added and the mixture was heated under reflux for 6 hours. A 1N aqueous sodium hydroxide solution (4.8 ml) was added to the reaction solution, and the mixture was stirred at room temperature for 1 hour. Purified water (100 ml) was added to the reaction solution, and 1
After neutralization with a normal aqueous hydrochloric acid solution, the precipitated solid was collected by filtration to obtain Compound 20. 1H-NMR (DMSO-d6 / TMS): δ = 7.1
9-7.22 (2H, m), 7.78-7.90
(3H, m), 8.40 (1H, s), 10.1
9 (1H, br). FABMS (m / z): 245 (M + 1) +.
【0052】実施例21 6−(5−カルボキシメチルチオ−1,2,4−オキサ
ジアゾール−3−イル)−2−ナフチルオキシ酢酸(化
合物21)の製造 6−(5−チオキソ−1,2,4−オキサジアゾール−
3−イル)−2−ナフトール(100mg)および無水
炭酸カリウム(141mg)をDMF(3ml)に懸濁
し、室温下で臭化酢酸t−ブチル(0.12ml)を加
えて一晩攪拌した。反応液を酢酸エチル−精製水で分配
した。酢酸エチル層を無水硫酸マグネシウムで乾燥し、
減圧下で濃縮したのち、シリカゲルカラム(ヘキサン−
酢酸エチル)で精製し、t−ブチル 6−(5−t−ブ
トキシカルボニルメチルチオ−1,2,4−オキサジア
ゾール−3−イル−2−ナフチルオキシアセタートを黄
色油状物質として得た。得られたt−ブチル 6−(5
−t−ブトキシカルボニルメチルチオ−1,2,4−オ
キサジアゾール−3−イル)−2−ナフチルオキシアセ
タート(140mg)を4規定塩酸−ジオキサン溶液
(3.9ml)に溶解し、室温で4時間攪拌した。反応
液にエーテル−ヘキサン(1:1)の混合溶液(200
ml)を加え、析出した固体をろ取して、化合物21を
得た。 1H−NMR(DMSO−d6/TMS):δ=4.3
2 (2H,s)、 4.83 (2H,s)、 7.
27−7.36 (2H,m)、 7.95 (2H,
s)、 8.04 (1H,d,J=8.9Hz)、
8.51 (1H,s)、 13.15 (2H,b
r)。 FABMS(m/z):365 (M+1)+。Example 21 Preparation of 6- (5-carboxymethylthio-1,2,4-oxadiazol-3-yl) -2-naphthyloxyacetic acid (compound 21) , 4-oxadiazole-
3-yl) -2-naphthol (100 mg) and anhydrous potassium carbonate (141 mg) were suspended in DMF (3 ml), t-butyl acetate bromide (0.12 ml) was added at room temperature, and the mixture was stirred overnight. The reaction was partitioned between ethyl acetate and purified water. The ethyl acetate layer was dried over anhydrous magnesium sulfate,
After concentration under reduced pressure, a silica gel column (hexane-
The residue was purified by ethyl acetate to give t-butyl 6- (5-t-butoxycarbonylmethylthio-1,2,4-oxadiazol-3-yl-2-naphthyloxyacetate as a yellow oily substance. T-butyl 6- (5
-T-Butoxycarbonylmethylthio-1,2,4-oxadiazol-3-yl) -2-naphthyloxyacetate (140 mg) was dissolved in a 4N hydrochloric acid-dioxane solution (3.9 ml), and dissolved at room temperature. Stirred for hours. A mixed solution of ether-hexane (1: 1) (200
ml) was added, and the precipitated solid was collected by filtration to obtain Compound 21. 1H-NMR (DMSO-d6 / TMS): δ = 4.3
6. (2H, s), 4.83 (2H, s),
27-7.36 (2H, m), 7.95 (2H,
s), 8.04 (1H, d, J = 8.9 Hz),
8.51 (1H, s), 13.15 (2H, b
r). FABMS (m / z): 365 (M + 1) +.
【0053】実施例22 N,N−ジメチル−2−[6−(5−ヒドロキシ−1,
2,4−オキサジアゾール−3−イル)−2−ナフチル
オキシ]エチルアミン(化合物22)の製造 2−(6−ヒドロキシナフチル)−1,2,4−オキサ
ジアゾール−5−オール(150mg)および無水炭酸
カリウム(228mg)をDMF(4ml)に懸濁し、
室温下で2−クロロ−N,N−ジメチルアミン・塩酸塩
(95mg)を加え、80℃で16時間攪拌した。反応
液を減圧下で濃縮したのち、逆相カラムクロマトグラフ
ィー(C−18,水−メタノール)で精製した。得られ
た生成物を少量のメタノールに溶解し、希塩酸で酸性と
したのち、エーテルを加えて、析出した褐色固体をろ取
して、化合物22を得た。 1H−NMR(DMSO−d6/TMS):δ=2.8
6 (6H,s)、 3.57 (2H,t,J=5.
0Hz)、 4.51 (2H,t,J=5.0H
z)、 7.34 (1H,dd,J=2.3,8.9
Hz)、 7.52(1H,d,J=2.3Hz)、
7.85 (1H,dd,J=1.6,8.9Hz)、
7.97−8.01 (2H,m)、 8.38
(1H,s)。 FABMS(m/z):300 (M+1)+。Example 22 N, N-dimethyl-2- [6- (5-hydroxy-1,
Preparation of 2,4-oxadiazol-3-yl) -2-naphthyloxy] ethylamine (compound 22) 2- (6-hydroxynaphthyl) -1,2,4-oxadiazol-5-ol (150 mg) And anhydrous potassium carbonate (228 mg) were suspended in DMF (4 ml),
At room temperature, 2-chloro-N, N-dimethylamine hydrochloride (95 mg) was added, and the mixture was stirred at 80 ° C for 16 hours. After the reaction solution was concentrated under reduced pressure, it was purified by reverse phase column chromatography (C-18, water-methanol). The obtained product was dissolved in a small amount of methanol, acidified with dilute hydrochloric acid, ether was added, and the precipitated brown solid was collected by filtration to obtain Compound 22. 1H-NMR (DMSO-d6 / TMS): δ = 2.8
6 (6H, s), 3.57 (2H, t, J = 5.
0 Hz), 4.51 (2H, t, J = 5.0H)
z), 7.34 (1H, dd, J = 2.3, 8.9)
Hz), 7.52 (1H, d, J = 2.3 Hz),
7.85 (1H, dd, J = 1.6, 8.9 Hz),
7.97-8.01 (2H, m), 8.38
(1H, s). FABMS (m / z): 300 (M + 1) +.
【0054】実施例23 4−[6−(5−ヒドロキシ−1,2,4−オキサジア
ゾール−3−イル)−2−ナフチルオキシ]ブタン酸
(化合物23)の製造 2−(6−ヒドロキシナフチル)−1,2,4−オキサ
ジアゾール−5−オール(200mg)および無水炭酸
カリウム(182mg)をDMF(4ml)に懸濁し、
室温下で4−臭化ブタン酸エチル(0.13ml)を加
え、80℃で8時間攪拌した。反応液を減圧下で濃縮
し、残留物を酢酸エチル−5%クエン酸水溶液で分配し
た。酢酸エチル層を精製水で洗浄したのち、無水硫酸マ
グネシウムで乾燥し、減圧下で濃縮したのち、シリカゲ
ルカラム(クロロホルム−メタノール)で精製し、無色
油状物質を得た。得られた無色油状物質をメタノール
(1ml)に溶解し、4規定水酸化ナトリウム水溶液
(1.5ml)を加えて、室温で1時間攪拌した。反応
液を希塩酸で中和し、減圧下で濃縮したのち、シリカゲ
ルカラム(クロロホルム−メタノール−酢酸)で精製し
て、化合物23を固体として得た。 1H−NMR(DMSO−d6/TMS):δ=1.9
8−2.13 (2H,m)、 2.44 (2H,
t,J=7.3Hz)、 4.15 (2H,t,J=
6.6Hz)、 7.28 (1H,dd,J=2.
3,8.9Hz)、7.43 (1H,d,J=2.3
Hz)、 7.81 (1H,d,J=8.6Hz)、
7.91−7.98 (2H,m)、 8.32
(1H,s)、12.14 (1H,br)、 12.
97 (1H,br)。 FABMS(m/z):315 (M+1)+。Example 23 Preparation of 4- [6- (5-hydroxy-1,2,4-oxadiazol-3-yl) -2-naphthyloxy] butanoic acid (compound 23) Naphthyl) -1,2,4-oxadiazol-5-ol (200 mg) and anhydrous potassium carbonate (182 mg) were suspended in DMF (4 ml),
Ethyl 4-bromobutanoate (0.13 ml) was added at room temperature, and the mixture was stirred at 80 ° C for 8 hours. The reaction solution was concentrated under reduced pressure, and the residue was partitioned with ethyl acetate-5% aqueous citric acid solution. The ethyl acetate layer was washed with purified water, dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and then purified on a silica gel column (chloroform-methanol) to obtain a colorless oil. The obtained colorless oil was dissolved in methanol (1 ml), 4N aqueous sodium hydroxide solution (1.5 ml) was added, and the mixture was stirred at room temperature for 1 hour. The reaction solution was neutralized with dilute hydrochloric acid, concentrated under reduced pressure, and then purified by a silica gel column (chloroform-methanol-acetic acid) to obtain Compound 23 as a solid. 1H-NMR (DMSO-d6 / TMS): δ = 1.9
8-2.13 (2H, m), 2.44 (2H,
t, J = 7.3 Hz), 4.15 (2H, t, J =
6.6 Hz), 7.28 (1H, dd, J = 2.
3,8.9 Hz), 7.43 (1H, d, J = 2.3)
Hz), 7.81 (1H, d, J = 8.6 Hz),
7.91-7.98 (2H, m), 8.32
(1H, s), 12.14 (1H, br), 12.
97 (1H, br). FABMS (m / z): 315 (M + 1) +.
【0055】実施例24 5−(6−ヒドロキシ−2−ナフチル)−2−オキソ−
1,3,4−オキサチアゾール(化合物24)の製造 6−ヒドロキシ−2−ナフトアミド(300mg)をト
ルエン−テトラヒドロフラン(2:1)の混合溶媒(3
0ml)に懸濁し、クロロカルボニルスルホニルクロリ
ド(0.27ml)を加えて4時間加熱還流した。反応
液を減圧下で濃縮したのち、残留物をメタノール(10
ml)に懸濁して不溶物をろ去した。ろ液を減圧下で濃
縮したのち、シリカゲルカラム(クロロホルム−メタノ
ール)で精製して、化合物24を固体として得た。 1H−NMR(DMSO−d6、D2O/TMS):δ
=7.20−7.29(2H,m)、 7.80−8.
01 (3H,m)、 8.37 (1H,s)。 FABMS(m/z):246 (M+1)+。Example 24 5- (6-hydroxy-2-naphthyl) -2-oxo-
Production of 1,3,4-oxathiazole (Compound 24) A mixed solvent of 6-hydroxy-2-naphthamide (300 mg) in toluene-tetrahydrofuran (2: 1) (3
0 ml), chlorocarbonylsulfonyl chloride (0.27 ml) was added, and the mixture was heated under reflux for 4 hours. After the reaction solution was concentrated under reduced pressure, the residue was treated with methanol (10%).
ml), and insolubles were removed by filtration. After the filtrate was concentrated under reduced pressure, the residue was purified by a silica gel column (chloroform-methanol) to obtain Compound 24 as a solid. 1H-NMR (DMSO-d6, D2O / TMS): δ
= 7.20-7.29 (2H, m), 7.80-8.
01 (3H, m), 8.37 (1H, s). FABMS (m / z): 246 (M + 1) +.
【0056】実施例25 6−(2−オキソ−1,3,4−オキサチアゾール−5
−イル)−2−ナフチルオキシ酢酸(化合物25)の製
造 5−(6−ヒドロキシ−2−ナフチル)−2−オキソ−
1,3,4−オキサチアゾール(175mg)およびト
リエチルアミン(0.59ml)のDMF(3ml)溶
液に臭化酢酸t−ブチル(0.63ml)を加え、室温
で6時間攪拌した。反応液を減圧下で濃縮したのち、シ
リカゲルカラム(ヘキサン−酢酸エチル)で精製し、t
−ブチル 6−(2−オキソ−1,3,4,−オキサチ
アゾール−5−イル)−2−ナフチルオキシアセタート
を淡黄色固体として得た。得られたt−ブチル 6−
(2−オキソ−1,3,4,−オキサチアゾール−5−
イル)−2−ナフチルオキシアセタート(50mg)を
4規定塩酸−ジオキサン溶液(4.2ml)に溶解し、
室温で一晩攪拌した。反応液にエーテル−ヘキサン
(1:1)の混合溶液(100ml)を加えて1時間攪
拌し、析出した固体をろ取して、化合物25を得た。 1H−NMR(DMSO−d6/TMS):δ=4.8
6 (2H,s)、 7.32 (1H,dd,J=
2.3,8.9Hz)、 7.39 (1H,d,J=
2.3Hz)、 7.95 (2H,s)、 8.10
(1H,d,J=8.9Hz)、 8.49 (1
H,s)、 13.09 (1H,br)。 FABMS(m/z):302 (M−1)−。Example 25 6- (2-oxo-1,3,4-oxathiazole-5
Preparation of -yl) -2-naphthyloxyacetic acid (compound 25) 5- (6-hydroxy-2-naphthyl) -2-oxo-
To a solution of 1,3,4-oxathiazole (175 mg) and triethylamine (0.59 ml) in DMF (3 ml) was added t-butyl acetate bromide (0.63 ml), and the mixture was stirred at room temperature for 6 hours. After the reaction solution was concentrated under reduced pressure, it was purified by a silica gel column (hexane-ethyl acetate), and t
-Butyl 6- (2-oxo-1,3,4, -oxathiazol-5-yl) -2-naphthyloxyacetate was obtained as a pale yellow solid. The resulting t-butyl 6-
(2-oxo-1,3,4, -oxathiazole-5-
Yl) -2-naphthyloxyacetate (50 mg) was dissolved in 4N hydrochloric acid-dioxane solution (4.2 ml),
Stirred overnight at room temperature. A mixed solution (100 ml) of ether-hexane (1: 1) was added to the reaction solution, the mixture was stirred for 1 hour, and the precipitated solid was collected by filtration to obtain Compound 25. 1H-NMR (DMSO-d6 / TMS): δ = 4.8
6 (2H, s), 7.32 (1H, dd, J =
2.3, 8.9 Hz), 7.39 (1H, d, J =
2.3 Hz), 7.95 (2H, s), 8.10
(1H, d, J = 8.9 Hz), 8.49 (1
H, s), 13.09 (1H, br). FABMS (m / z): 302 (M-1)-.
【0057】実施例26 6−(4,5−ジヒドロ−1,3−チアゾール−2−イ
ル)−2−ナフトール(化合物26)の製造 6−ヒドロキシ−2−ナフトエ酸(1.9g)をエタノ
ール(20ml)に溶解し、炭酸セシウム(2.4g)
の水(5ml)溶液を加え、室温で30分間攪拌した。
反応液を減圧下で濃縮し、乾燥したのち、残留物をDM
F(30ml)に懸濁し、ヨウ化エチル(1.0ml)
を加えて、60℃で2時間攪拌した。反応液を減圧下で
濃縮したのち、シリカゲルカラム(クロロホルム)で精
製し、エチル 6−ヒドロキシ−2−ナフタートを得
た。得られたエチル 6−ヒドロキシ−2−ナフタート
(700mg)および無水炭酸カリウム(1.3g)を
DMF(4ml)に懸濁し、臭化ベンジル(0.77m
l)を加え、室温で2時間攪拌した。反応液を酢酸エチ
ル−精製水で分配し、酢酸エチル層を無水硫酸マグネシ
ウムで乾燥ののち、減圧下で濃縮して、エチル 6−ベ
ンジルオキシ−2−ナフタートを白色固体として得た。
2−アミノエタンチオール・塩酸塩(168mg)をト
ルエン(14ml)に溶解し、窒素気流下で15%トリ
イソブチルアルミニウム−ヘキサン溶液(7.4ml)
を滴下し、30分間加熱還流したのち、先に得たエチル
6−ベンジルオキシ−2−ナフタート(500mg)
のトルエン(15ml)溶液を滴下した。反応液を2時
間加熱還流したのち、酢酸エチル−飽和炭酸水素ナトリ
ウム水溶液で分配した。酢酸エチル層を飽和食塩水で洗
浄し、無水硫酸マグネシウムで乾燥したのち、減圧下で
濃縮した。残留物をシリカゲルカラム(ヘキサン−酢酸
エチル)で精製して、6−(4,5−ジヒドロ−1,3
−チアゾール−2−イル)−2−ベンジルオキシナフタ
レンを白色固体として得た。得られた6−(4,5−ジ
ヒドロ−1,3−チアゾール−2−イル)−2−ベンジ
ルオキシナフタレン(180mg)にトリフルオロメタ
ンスルホン酸−チオアニソール−トリフルオロ酢酸
(1:12:40)の混合溶液(13.3ml)を氷冷
下で加え、50分間攪拌した。反応液を減圧下で濃縮
し、残留物にエーテルを加えて析出した固体をろ取し
て、化合物26を得た。 1H−NMR(Acetone−d6/TMS):δ=
3.51 (2H,t,J=8.6Hz)、 4.41
(2H,t,J=8.6Hz)、 7.10−7.1
5 (2H,m)、 7.64 (1H,d,J=8.
6Hz)、 7.80−7.84 (2H,m)、
8.20 (1H,d,J=1.7Hz)。 FABMS(m/z):230 (M+1)+。Example 26 Preparation of 6- (4,5-dihydro-1,3-thiazol-2-yl) -2-naphthol (Compound 26) 6-Hydroxy-2-naphthoic acid (1.9 g) was dissolved in ethanol. (20 ml) and dissolved in cesium carbonate (2.4 g).
Of water (5 ml) was added and stirred at room temperature for 30 minutes.
After the reaction solution was concentrated under reduced pressure and dried, the residue was
F (30 ml) and suspended in ethyl iodide (1.0 ml)
Was added and stirred at 60 ° C. for 2 hours. After concentrating the reaction solution under reduced pressure, the residue was purified by a silica gel column (chloroform) to obtain ethyl 6-hydroxy-2-naphthalate. The obtained ethyl 6-hydroxy-2-naphthalate (700 mg) and anhydrous potassium carbonate (1.3 g) were suspended in DMF (4 ml), and benzyl bromide (0.77 m
l) was added and the mixture was stirred at room temperature for 2 hours. The reaction solution was partitioned between ethyl acetate and purified water, and the ethyl acetate layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure to obtain ethyl 6-benzyloxy-2-naphthalate as a white solid.
2-aminoethanethiol hydrochloride (168 mg) was dissolved in toluene (14 ml), and a 15% triisobutylaluminum-hexane solution (7.4 ml) was added under a nitrogen stream.
Was added dropwise, and the mixture was heated under reflux for 30 minutes, and then the previously obtained ethyl 6-benzyloxy-2-naphthalate (500 mg) was added.
Was added dropwise to a toluene (15 ml) solution. After the reaction solution was heated under reflux for 2 hours, it was partitioned with ethyl acetate-saturated aqueous sodium hydrogen carbonate solution. The ethyl acetate layer was washed with brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified on a silica gel column (hexane-ethyl acetate) to give 6- (4,5-dihydro-1,3.
-Thiazol-2-yl) -2-benzyloxynaphthalene was obtained as a white solid. To the obtained 6- (4,5-dihydro-1,3-thiazol-2-yl) -2-benzyloxynaphthalene (180 mg), trifluoromethanesulfonic acid-thioanisole-trifluoroacetic acid (1:12:40). (13.3 ml) was added under ice-cooling, and the mixture was stirred for 50 minutes. The reaction solution was concentrated under reduced pressure, ether was added to the residue, and the precipitated solid was collected by filtration to obtain Compound 26. 1H-NMR (acetone-d6 / TMS): δ =
3.51 (2H, t, J = 8.6 Hz), 4.41
(2H, t, J = 8.6 Hz), 7.10-7.1
5 (2H, m), 7.64 (1H, d, J = 8.
6Hz), 7.80-7.84 (2H, m),
8.20 (1H, d, J = 1.7 Hz). FABMS (m / z): 230 (M + 1) +.
【0058】実施例27 6−(4,5−ジヒドロ−1,3−チアゾール−2−イ
ル)−2−ナフチルオキシ酢酸(化合物27)の製造 6−(4,5−ジヒドロ−1,3−チアゾール−2−イ
ル)−2−ナフトール(120mg)および無水炭酸カ
リウム(199mg)をDMF(4ml)に懸濁し、室
温下で臭化酢酸メチル(0.09ml)を加えて一晩攪
拌した。反応液を減圧下で濃縮し、残留物を酢酸エチル
−5%クエン酸水溶液で分配した。酢酸エチル層を無水
硫酸マグネシウムで乾燥後、減圧下で溶媒を留去し、メ
チル 6−(4,5−ジヒドロ−1,3−チアゾール−
2−イル)−2−ナフチルオキシアセタート(116m
g)を黄色固体として得た。得られた、メチル 6−
(4,5−ジヒドロ−1,3−チアゾール−2−イル)
−2−ナフチルオキシアセタート(100mg)をメタ
ノール(2ml)に溶解し、4規定水酸化ナトリウム水
溶液(1.7ml)を加え、室温で30分間攪拌した。
反応液を減圧下で濃縮したのち、希塩酸で中和し、析出
した固体をろ取して、化合物27を得た。 1H−NMR(DMSO−d6/TMS):δ=3.4
6 (2H,t,J=8.3Hz)、 4.27 (2
H,s)、 4.42 (2H,t,J=8.3H
z)、 7.15 (1H,s)、 7.18−7.2
3 (2H,m)、7.75 (1H,d,J=8.9
Hz)、 7.84−7.94 (2H,m)、 8.
14 (1H,s)。 FABMS(m/z):288 (M+1)+。Example 27 Preparation of 6- (4,5-dihydro-1,3-thiazol-2-yl) -2-naphthyloxyacetic acid (compound 27) Thiazol-2-yl) -2-naphthol (120 mg) and anhydrous potassium carbonate (199 mg) were suspended in DMF (4 ml), and methyl bromide acetate (0.09 ml) was added at room temperature, followed by stirring overnight. The reaction solution was concentrated under reduced pressure, and the residue was partitioned with ethyl acetate-5% aqueous citric acid solution. After the ethyl acetate layer was dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure to give methyl 6- (4,5-dihydro-1,3-thiazole-).
2-yl) -2-naphthyloxyacetate (116 m
g) was obtained as a yellow solid. The resulting methyl 6-
(4,5-dihydro-1,3-thiazol-2-yl)
2-Naphthyloxyacetate (100 mg) was dissolved in methanol (2 ml), a 4 N aqueous sodium hydroxide solution (1.7 ml) was added, and the mixture was stirred at room temperature for 30 minutes.
The reaction solution was concentrated under reduced pressure, neutralized with dilute hydrochloric acid, and the precipitated solid was collected by filtration to obtain Compound 27. 1H-NMR (DMSO-d6 / TMS): δ = 3.4
6 (2H, t, J = 8.3 Hz), 4.27 (2
H, s), 4.42 (2H, t, J = 8.3H)
z), 7.15 (1H, s), 7.18-7.2
3 (2H, m), 7.75 (1H, d, J = 8.9)
Hz), 7.84-7.94 (2H, m), 8.
14 (1H, s). FABMS (m / z): 288 (M + 1) +.
【0059】実施例28 6−(5,6−ジヒドロ−4H−1,3−オキサジン−
2−イル)−2−ナフトール・塩酸塩(化合物28)の
製造 実施例26で合成したエチル 6−ヒドロキシ−2−ナ
フタート(1.0g)に3−アミノ−1−プロパノール
(695mg)を加え、120℃で6時間攪拌した。反
応液をシリカゲルカラム(クロロホルム−メタノール)
で精製して、6−ヒドロキシ−N−(3−ヒドロキシプ
ロピル)ナフトアミドを淡赤色固体として得た。得られ
た6−ヒドロキシ−N−(3−ヒドロキシプロピル)ナ
フトアミド(300mg)を酢酸イソプロピル(10m
l)に溶解し、塩化チオニル(0.34ml)を滴下
し、室温で6時間攪拌した。反応液を減圧下で濃縮し、
残留物を酢酸エチルで洗浄して、化合物28を固体とし
て得た。 1H−NMR(DMSO−d6/TMS):δ=2.2
6 (2H,t,J=5.0Hz)、 3.68 (2
H,t,J=5.6Hz)、 4.82 (2H,t,
J=5.0Hz)、 7.23−7.26 (2H,
m)、 7.90(2H,s)、 7.99 (1H,
m)、 8.57 (1H,s)、 10.49 (1
H,s)、 12.43 (1H,br)。 FABMS(m/z):228 (M+1)+。Example 28 6- (5,6-Dihydro-4H-1,3-oxazine-
Production of 2-yl) -2-naphthol.hydrochloride (Compound 28) To the ethyl 6-hydroxy-2-naphthalate (1.0 g) synthesized in Example 26, 3-amino-1-propanol (695 mg) was added. Stirred at 120 ° C. for 6 hours. The reaction solution is applied to a silica gel column (chloroform-methanol)
To give 6-hydroxy-N- (3-hydroxypropyl) naphthamide as a pale red solid. The obtained 6-hydroxy-N- (3-hydroxypropyl) naphthamide (300 mg) was treated with isopropyl acetate (10 m
l), thionyl chloride (0.34 ml) was added dropwise, and the mixture was stirred at room temperature for 6 hours. The reaction is concentrated under reduced pressure,
The residue was washed with ethyl acetate to give compound 28 as a solid. 1H-NMR (DMSO-d6 / TMS): δ = 2.2
6 (2H, t, J = 5.0 Hz), 3.68 (2
H, t, J = 5.6 Hz), 4.82 (2H, t,
J = 5.0 Hz), 7.23-7.26 (2H,
m), 7.90 (2H, s), 7.99 (1H,
m), 8.57 (1H, s), 10.49 (1
H, s), 12.43 (1H, br). FABMS (m / z): 228 (M + 1) +.
【0060】実施例29 6−(5,6−ジヒドロ−4H−1,3−オキサジン−
2−イル)−2−ナフチルオキシ酢酸・塩酸塩(化合物
29)の製造 6−(5,6−ジヒドロ−4H−1,3−オキサジン−
2−イル)−2−ナフトール・塩酸塩(150mg)お
よび無水炭酸カリウム(235mg)をDMF(3m
l)に懸濁し、室温下で臭化酢酸メチル(0.11m
l)を加えて一晩攪拌した。反応液を減圧下で濃縮した
のち、残留物を酢酸エチル−5%クエン酸水溶液で分配
し、酢酸エチル層を無水硫酸マグネシウムで乾燥したの
ち、減圧下で濃縮した。残留物をメタノール(2ml)
に溶解し、4規定水酸化ナトリウム水溶液(1.7m
l)を加え、室温で3時間攪拌した。反応液に1規定塩
酸水溶液を滴下して酸性とし、減圧下で濃縮したのち、
シリカゲルカラム(クロロホルム−メタノール−酢酸)
で精製して、化合物29を固体として得た。 1H−NMR(DMSO−d6/TMS):δ=2.2
4 (2H,t,J=5.0Hz)、 3.67 (2
H,t,J=5.9Hz)、 4.80 (2H,t,
J=5.0Hz)、 4.88 (2H,s)、 7.
36 (1H,dd,J=2.0,8.9Hz)、
7.42 (1H,s)、 8.00 (2H,s)、
8.07 (1H,d,J=8.9Hz)、 8.6
4 (1H,s)。 FABMS(m/z):286 (M+1)+。Example 29 6- (5,6-Dihydro-4H-1,3-oxazine-
Preparation of 2-yl) -2-naphthyloxyacetic acid hydrochloride (compound 29) 6- (5,6-dihydro-4H-1,3-oxazine-
2-yl) -2-naphthol hydrochloride (150 mg) and anhydrous potassium carbonate (235 mg) were added to DMF (3 m
l) and methyl bromide acetate (0.11 m
l) was added and stirred overnight. After the reaction solution was concentrated under reduced pressure, the residue was partitioned with ethyl acetate-5% aqueous citric acid solution, the ethyl acetate layer was dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. Residue in methanol (2 ml)
And a 4N aqueous sodium hydroxide solution (1.7 m
l) was added and the mixture was stirred at room temperature for 3 hours. The reaction solution was acidified by dropwise addition of a 1N aqueous hydrochloric acid solution, and concentrated under reduced pressure.
Silica gel column (chloroform-methanol-acetic acid)
To give Compound 29 as a solid. 1H-NMR (DMSO-d6 / TMS): δ = 2.2
4 (2H, t, J = 5.0 Hz), 3.67 (2
H, t, J = 5.9 Hz), 4.80 (2H, t,
J = 5.0 Hz), 4.88 (2H, s), 7.
36 (1H, dd, J = 2.0, 8.9 Hz),
7.42 (1H, s), 8.00 (2H, s),
8.07 (1H, d, J = 8.9 Hz), 8.6
4 (1H, s). FABMS (m / z): 286 (M + 1) +.
【0061】実施例30 6−(4,5−ジヒドロ−1,3−オキサゾール−2−
イル)−2−ナフチルオキシ酢酸・塩酸塩(化合物3
0)の製造 エチル 6−ヒドロキシナフトエート(216mg)、
2−アミノエタノール(122mg)、および塩化チオ
ニル(0.19ml)を用いて、実施例29と同様にし
て、6−(4,5−ジヒドロ−1,3−オキサゾール−
3−イル)−2−ナフトールを白色固体として得た。得
られた6−(4,5−ジヒドロ−1,3−オキサゾール
−3−イル)−2−ナフトール(45mg)および無水
炭酸カリウム(116mg)をDMF(2ml)に懸濁
し、室温下で臭化酢酸メチル(0.06ml)を加えて
一晩攪拌した。反応液を減圧下で濃縮したのち、残留物
を酢酸エチル−5%クエン酸水溶液で分配し、酢酸エチ
ル層を無水硫酸マグネシウムで乾燥したのち、減圧下で
濃縮した。残留物をメタノール(2ml)に溶解し、4
規定水酸化ナトリウム水溶液(2.1ml)を加え、室
温で2時間攪拌した。反応液に1規定塩酸水溶液を滴下
し酸性とし、析出した固体をろ取して、化合物30を得
た。 1H−NMR(DMSO−d6/TMS):δ=3.9
9 (2H,t,J=9.6Hz)、 4.44 (2
H,t,J=9.6Hz)、 4.82 (2H,
s)、 7.26 (1H,dd,J=2.3,8.9
Hz)、 7.33(1H,d,J=2.3Hz)、
7.83−8.01 (3H,m)、 8.35 (1
H,s)、 13.03 (1H,br)。 FABMS(m/z):272 (M+1)+。Example 30 6- (4,5-Dihydro-1,3-oxazole-2-
Yl) -2-naphthyloxyacetic acid hydrochloride (compound 3
Preparation of 0) Ethyl 6-hydroxynaphthoate (216 mg),
Using 2-aminoethanol (122 mg) and thionyl chloride (0.19 ml) in the same manner as in Example 29, 6- (4,5-dihydro-1,3-oxazole-
3-yl) -2-naphthol was obtained as a white solid. The obtained 6- (4,5-dihydro-1,3-oxazol-3-yl) -2-naphthol (45 mg) and anhydrous potassium carbonate (116 mg) were suspended in DMF (2 ml) and brominated at room temperature. Methyl acetate (0.06 ml) was added and stirred overnight. After the reaction solution was concentrated under reduced pressure, the residue was partitioned with ethyl acetate-5% aqueous citric acid solution, the ethyl acetate layer was dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was dissolved in methanol (2 ml) and 4
A normal aqueous sodium hydroxide solution (2.1 ml) was added, and the mixture was stirred at room temperature for 2 hours. A 1N aqueous hydrochloric acid solution was added dropwise to the reaction solution to make it acidic, and the precipitated solid was collected by filtration to obtain Compound 30. 1H-NMR (DMSO-d6 / TMS): δ = 3.9
9 (2H, t, J = 9.6 Hz), 4.44 (2
H, t, J = 9.6 Hz), 4.82 (2H,
s), 7.26 (1H, dd, J = 2.3, 8.9)
Hz), 7.33 (1H, d, J = 2.3 Hz),
7.83-8.01 (3H, m), 8.35 (1
H, s), 13.03 (1H, br). FABMS (m / z): 272 (M + 1) +.
【0062】実施例31 メチル 6−(2−オキソ−3H−1,2,3,5−オ
キサチアジアゾール−4−イル)−2−ナフチルオキシ
アセタート(化合物31)の製造 メチル 6−ヒドロキシアミジノ−2−ナフチルオキシ
アセタート(274mg)およびピリジン(0.32m
l)のテトラヒドロフラン(5ml)溶液を、塩化チオ
ニル(0.29ml)の塩化メチレン(3ml)溶液に
氷冷下で滴下した。反応液を0℃で30分間攪拌したの
ち、酢酸エチル−飽和炭酸水素ナトリウム水溶液で分配
し、酢酸エチル層を無水硫酸マグネシウムで乾燥し、減
圧下で濃縮したのち、シリカゲルカラム(酢酸エチル)
で精製して、化合物31を固体として得た。 1H−NMR(DMSO−d6/TMS):δ=3.7
4 (3H,s)、 4.97 (2H,s)、 7.
31−7.42 (2H,m)、 7.84−8.00
(3H,m)、 8.38 (1H,s)、 12.
22 (1H,br)。 FABMS(m/z):321 (M+1)+。Example 31 Preparation of methyl 6- (2-oxo-3H-1,2,3,5-oxathiadiazol-4-yl) -2-naphthyloxyacetate (Compound 31) Methyl 6-hydroxyamidino- 2-naphthyloxyacetate (274 mg) and pyridine (0.32 m
A solution of l) in tetrahydrofuran (5 ml) was added dropwise to a solution of thionyl chloride (0.29 ml) in methylene chloride (3 ml) under ice-cooling. After the reaction solution was stirred at 0 ° C. for 30 minutes, it was partitioned with ethyl acetate-saturated aqueous sodium hydrogen carbonate solution. The ethyl acetate layer was dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and then silica gel column (ethyl acetate).
The compound 31 was obtained as a solid. 1H-NMR (DMSO-d6 / TMS): δ = 3.7
4. (3H, s), 4.97 (2H, s), 7.
31-7.42 (2H, m), 7.84-8.00
(3H, m), 8.38 (1H, s), 12.
22 (1H, br). FABMS (m / z): 321 (M + 1) +.
【0063】実施例32 6−(2−イミダゾリル)−2−ナフチルオキシ酢酸
(化合物32)の製造 N−ベンジルオキシカルボニル−6−ヒドロキシナフタ
レン−2−カルボキシアミジン(2.7g)および無水
炭酸カリウム(3.5g)をDMF(40ml)に懸濁
し、臭化酢酸エチル(1.2ml)を加えて室温で一晩
攪拌した。反応液を酢酸エチル−飽和炭酸水素ナトリウ
ム水溶液で分配し、酢酸エチル層を無水硫酸マグネシウ
ムで乾燥し、減圧下で濃縮したのち、残留物をエタノー
ル−クロロホルムから固化させて、エチル 6−(N−
ベンジルオキシカルボニルアミジノ)−2−ナフチルオ
キシアセタートを得た。得られた6−(N−ベンジルオ
キシカルボニルアミジノ)−2−ナフチルオキシアセタ
ート(1.5g)をエタノール(30ml)に溶解し、
10%パラジウム活性炭(300mg)および酢酸
(0.21ml)を加えて、水素気流下で2時間攪拌し
た。反応液をろ過したのち、ろ液を減圧下で濃縮して析
出した固体をろ取して、エチル 6−アミジノ−2−ナ
フチルオキシアセタート・酢酸塩を得た。得られたエチ
ル 6−アミジノ−2−ナフチルオキシアセタート・酢
酸塩(400mg)をジオキサン(10ml)に溶解
し、臭化アセトアルデヒド ジエチルアセタール(3.
6ml)およびトリエチルアミン(0.33ml)を加
えて、1時間加熱還流した。反応液を減圧下で濃縮し、
シリカゲルカラム(クロロホルム−エタノール)で精製
して、エチル 6−(2−イミダゾリル)−2−ナフチ
ルオキシアセタートを得た。得られたエチル 6−(2
−イミダゾリル)−2−ナフチルオキシアセタート(1
00mg)をエタノール(9ml)に懸濁し、2規定水
酸化ナトリウム水溶液(1.0ml)を加えて20分間
攪拌した。希塩酸で中和後、反応液にエタノールを加
え、析出した固体をろ取して、化合物32を得た。 1H−NMR(DMSO−d6/TMS):δ=4.6
4 (2H,s)、 7.18−7.22 (4H,
m)、 7.80−7.85 (2H,m)、 8.04
(1H,dd,J=1.7,8.6Hz)、 8.36
(1H,d,J=1.0Hz)。 FABMS(m/z):267 (M−1)−。Example 32 Preparation of 6- (2-imidazolyl) -2-naphthyloxyacetic acid (Compound 32) N-benzyloxycarbonyl-6-hydroxynaphthalene-2-carboxyamidine (2.7 g) and anhydrous potassium carbonate (2.7 g) 3.5 g) was suspended in DMF (40 ml), ethyl bromide acetate (1.2 ml) was added, and the mixture was stirred at room temperature overnight. The reaction solution was partitioned with ethyl acetate-saturated aqueous sodium hydrogen carbonate solution, and the ethyl acetate layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was solidified from ethanol-chloroform to give ethyl 6- (N-
(Benzyloxycarbonylamidino) -2-naphthyloxy acetate was obtained. The obtained 6- (N-benzyloxycarbonylamidino) -2-naphthyloxyacetate (1.5 g) was dissolved in ethanol (30 ml),
10% palladium activated carbon (300 mg) and acetic acid (0.21 ml) were added, and the mixture was stirred under a hydrogen stream for 2 hours. After filtering the reaction solution, the filtrate was concentrated under reduced pressure, and the precipitated solid was collected by filtration to obtain ethyl 6-amidino-2-naphthyloxyacetate / acetate. The obtained ethyl 6-amidino-2-naphthyloxyacetate / acetate (400 mg) was dissolved in dioxane (10 ml), and acetaldehyde bromide diethylacetal (3.
6 ml) and triethylamine (0.33 ml) were added, and the mixture was heated under reflux for 1 hour. The reaction is concentrated under reduced pressure,
Purification with a silica gel column (chloroform-ethanol) gave ethyl 6- (2-imidazolyl) -2-naphthyloxyacetate. The obtained ethyl 6- (2
-Imidazolyl) -2-naphthyloxyacetate (1
00 mg) was suspended in ethanol (9 ml), 2N aqueous sodium hydroxide solution (1.0 ml) was added, and the mixture was stirred for 20 minutes. After neutralization with dilute hydrochloric acid, ethanol was added to the reaction solution, and the precipitated solid was collected by filtration to obtain Compound 32. 1H-NMR (DMSO-d6 / TMS): δ = 4.6
4 (2H, s), 7.18-7.22 (4H,
m), 7.80-7.85 (2H, m), 8.04
(1H, dd, J = 1.7, 8.6 Hz), 8.36
(1H, d, J = 1.0 Hz). FABMS (m / z): 267 (M-1)-.
【0064】実施例33 6−(1,2,3−トリアゾール−4−イル)−2−ナ
フチルオキシ酢酸(化合物33)の製造 6−ヒドロキシ−2−ナフトアルデヒド(172mg)
および無水炭酸カリウム(415mg)をDMF(10
ml)に懸濁し、臭化酢酸t−ブチル(0.19ml)
を加えて室温で2時間攪拌した。反応液を減圧下で濃縮
ののち、酢酸エチル−精製水で分配し、酢酸エチル層を
無水硫酸マグネシウムで乾燥し、減圧下で濃縮した。残
留物をシリカゲルカラム(へキサン−酢酸エチル)で精
製し、t−ブチル 6−ホルミル−2−ナフチルオキシ
アセタートを得た。得られたt−ブチル 6−ホルミル
−2−ナフチルオキシアセタート(100mg)をメタ
ノール(5ml)に溶解し、ニトロメタン(5ml)お
よび酢酸アンモニウム(270mg)を加えて室温で3
時間攪拌した。反応液を酢酸エチル−飽和炭酸水素ナト
リウム水溶液で分配したのち、酢酸エチル層を無水硫酸
マグネシウムで乾燥し、減圧下で濃縮したのち、シリカ
ゲルカラム(へキサン−酢酸エチル)で精製した。得ら
れた生成物を乾燥したのち、DMF(5ml)に溶解
し、アジ化ナトリウム(22mg)を加えて室温で6時
間攪拌した。反応液を酢酸エチル−飽和炭酸水素ナトリ
ウム水溶液で分配し、酢酸エチル層を無水硫酸マグネシ
ウムで乾燥したのち減圧下で濃縮し、シリカゲルカラム
(へキサン−酢酸エチル)で精製して、t−ブチル 6
−(1,2,3−トリアゾール−4−イル)−2−ナフ
チルオキシアセタートを得た。得られた、t−ブチル
6−(1,2,3−トリアゾール−4−イル)−2−ナ
フチルオキシアセタート(22mg)をエタノール(2
ml)に溶解し、4規定塩酸−ジオキサン溶液(0.1
7ml)を加えて一晩攪拌した。反応液を減圧下で濃縮
し、析出した固体をろ取したのち、エタノールで洗浄し
て、化合物33を得た。 1H−NMR(DMSO−d6/TMS):δ=4.8
2(2H,s)、7.24(1H,dd,J=2.6,
8.9Hz)、7.30(1H,d,J=3.3H
z)、7.79−7.98(4H,m)、8.35(1
H,s)、13.08(1H,br)。 FABMS(m/z):270 (M+1)+。Example 33 Preparation of 6- (1,2,3-triazol-4-yl) -2-naphthyloxyacetic acid (compound 33) 6-hydroxy-2-naphthaldehyde (172 mg)
And anhydrous potassium carbonate (415 mg) in DMF (10
ml) and t-butyl acetate bromide (0.19 ml)
Was added and stirred at room temperature for 2 hours. After the reaction solution was concentrated under reduced pressure, it was partitioned between ethyl acetate and purified water, and the ethyl acetate layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by a silica gel column (hexane-ethyl acetate) to obtain t-butyl 6-formyl-2-naphthyloxyacetate. The obtained t-butyl 6-formyl-2-naphthyloxyacetate (100 mg) was dissolved in methanol (5 ml), and nitromethane (5 ml) and ammonium acetate (270 mg) were added.
Stirred for hours. After partitioning the reaction solution with ethyl acetate-saturated aqueous sodium hydrogen carbonate solution, the ethyl acetate layer was dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and then purified by a silica gel column (hexane-ethyl acetate). After drying the obtained product, it was dissolved in DMF (5 ml), sodium azide (22 mg) was added, and the mixture was stirred at room temperature for 6 hours. The reaction solution was partitioned with ethyl acetate-saturated aqueous sodium hydrogen carbonate solution, and the ethyl acetate layer was dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and purified on a silica gel column (hexane-ethyl acetate) to give t-butyl 6
-(1,2,3-Triazol-4-yl) -2-naphthyloxy acetate was obtained. The obtained t-butyl
6- (1,2,3-Triazol-4-yl) -2-naphthyloxyacetate (22 mg) was added to ethanol (2
ml of a 4N hydrochloric acid-dioxane solution (0.1 ml).
7 ml) and stirred overnight. The reaction solution was concentrated under reduced pressure, and the precipitated solid was collected by filtration and washed with ethanol to obtain Compound 33. 1H-NMR (DMSO-d6 / TMS): δ = 4.8
2 (2H, s), 7.24 (1H, dd, J = 2.6,
8.9 Hz), 7.30 (1H, d, J = 3.3H)
z), 7.79-7.98 (4H, m), 8.35 (1
H, s), 13.08 (1H, br). FABMS (m / z): 270 (M + 1) +.
【0065】以上の実施例で得られた化合物を表1に示
す。The compounds obtained in the above examples are shown in Table 1.
【表1】 [Table 1]
【表2】 [Table 2]
【表3】 [Table 3]
【表4】 [Table 4]
【0066】製剤処方例 1(錠剤) 本発明化合物 10.0g 乳糖 9.0g ヒドロキシプロピルセルロース 2.0g 結晶セルロース 7.7g ステアリン酸マグネシウム 0.3g タルク 1.0g 以上を常法により、本発明化合物100mgを含有する
錠剤とする。Formulation Example 1 (Tablets) Compound of the present invention 10.0 g Lactose 9.0 g Hydroxypropylcellulose 2.0 g Crystalline cellulose 7.7 g Magnesium stearate 0.3 g Talc 1.0 g Tablets containing 100 mg.
【0067】製剤処方例 2(注射剤) 本発明化合物 1mg 5%ブドウ糖注射液 2ml 以上を常法により注射剤とする。Formulation Example 2 (Injection) 1 mg of the compound of the present invention, 5 ml of a 5% glucose injection 2 ml or more is used as an injection by a conventional method.
【0068】製剤処方例 3(坐剤) 本発明化合物 10mg カカオ脂 適量 以上を常法により坐剤とする。Formulation Example 3 (Suppository) Compound of the present invention 10 mg Cacao butter Fat Appropriate The above is used as a suppository by a conventional method.
【0069】試験例1 プラスミン形成促進活性 本
発明化合物を、1×10−2Mになるようにジメチルス
ルホキシド(DMSO)に溶解し、この調製液を0.1
5M塩化ナトリウムを含む20mMリン酸緩衝液 (pH
7.4)で1.2×10−3Mに希釈し、本発明化合
物溶液を調製する。グルタミン酸タイプ−ヒトプラスミ
ノーゲン(終濃度0.1μM)、ヒト組換えt−PA
(終濃度50μM)および本発明化合物溶液(終濃度3
00μM)をそれぞれ96穴マイクロ・タイタープレー
トに50μlずつ添加し、37℃で1時間インキュベー
トする。その後、プラスミンの基質である合成基質溶液
(S−2251,2mM)をそれぞれの穴に50μlず
つ添加し、添加直後に405nmの吸光度(A1)を測
定する。その後、37℃で再び15分間インキュベート
し、405nmの吸光度(A2)を測定する。得られる
吸光度(A1およびA2)の差を求め、コントロール
(対照)に対する比を求めることによりプラスミン形成
促進活性を求めることができる。その結果、本発明化合
物が優れたプラスミン形成促進作用を有することが明ら
かとなった。結果を表2に示す。Test Example 1 Plasmin Formation-Promoting Activity The compound of the present invention was dissolved in dimethyl sulfoxide (DMSO) to a concentration of 1 × 10 −2 M, and the resulting solution was dissolved in 0.1%.
20 mM phosphate buffer containing 5 M sodium chloride (pH
The solution is diluted to 1.2 × 10 −3 M in 7.4) to prepare a solution of the compound of the present invention. Glutamate type-human plasminogen (final concentration 0.1 μM), human recombinant t-PA
(Final concentration 50 μM) and the compound solution of the present invention (final concentration 3
(00 μM) is added to each 96-well microtiter plate in an amount of 50 μl and incubated at 37 ° C. for 1 hour. Then, 50 μl of a synthetic substrate solution (S-2251, mM), which is a plasmin substrate, is added to each well, and immediately after the addition, the absorbance at 405 nm (A1) is measured. Thereafter, the mixture is again incubated at 37 ° C. for 15 minutes, and the absorbance at 405 nm (A2) is measured. The plasmin formation promoting activity can be determined by determining the difference between the obtained absorbances (A1 and A2) and determining the ratio to the control. As a result, it was revealed that the compound of the present invention has an excellent plasmin formation promoting action. Table 2 shows the results.
【0070】[0070]
【表5】 [Table 5]
【0071】試験例2 経口投与によるマウス肺血栓致死モデルに対する致死改
善効果 実験にはddY系雄性マウス6週齡を1群15〜20匹用いて
行った。本発明化合物を1mg/kg(10ml)にな
るように蒸留水に懸濁し、4時間絶食させたマウスに経
口投与した。病態対照群には、蒸留水を経口投与した。
投与6時間後にトロンビン(10U/ml)を尾静脈よ
り1ml投与して血栓を誘発し、翌日生死を確認し、生
存率を求めた。結果を表3に示す。Test Example 2 Effect of Oral Administration on the Improvement of Lethality in a Mouse Pulmonary Thrombus Lethality Model An experiment was performed using 15 to 20 ddY male mice, 6 weeks old, per group. The compound of the present invention was suspended in distilled water at a concentration of 1 mg / kg (10 ml) and orally administered to a mouse fasted for 4 hours. Distilled water was orally administered to the disease state control group.
Six hours after the administration, 1 ml of thrombin (10 U / ml) was administered from the tail vein to induce thrombus, the survival was confirmed the next day, and the survival rate was determined. Table 3 shows the results.
【表6】 [Table 6]
【0072】試験例3 静脈内投与によるマウス肺血栓致死モデルに対する致死
改善効果 実験にはddY系雄性マウス6週齡を1群15〜
20匹用いて行った。本発明化合物を0.1mg/kg
(10ml)になるように5%グルコース溶液に溶解
し、4時間絶食させたマウスの左尾静脈より投与した。
病態対照群には、5%グルコース溶液を同様に投与し
た。投与15分後にトロンビン(10U/ml)を右尾
静脈より1ml投与して血栓を誘発し、翌日生死を確認
し、生存率を求めた。結果を表4に示す。Test Example 3 Effect of Intravenous Administration on Improving Lethality in a Murine Model of Lethal Thrombus Thrombosis In a test, ddY male mice 6 weeks old were grouped at 15-
This was performed using 20 animals. 0.1 mg / kg of the compound of the present invention
(10 ml) was dissolved in a 5% glucose solution and administered via the left tail vein of a mouse fasted for 4 hours.
A 5% glucose solution was similarly administered to the disease control group. Fifteen minutes after the administration, 1 ml of thrombin (10 U / ml) was administered from the right tail vein to induce thrombus, the next day was confirmed for survival, and the survival rate was determined. Table 4 shows the results.
【表7】 [Table 7]
【0073】[0073]
【発明の効果】本発明化合物は線溶促進作用を有し、優
れた血栓溶解作用を発現するため、血栓に関連して起こ
る疾患に有効である。すなわち、静脈血栓症、心筋梗塞
症、肺塞栓症、脳梗塞症、緩徐に進行する脳血栓症、血
管手術および血液体外循環に伴う血栓・塞栓の治療並び
に血流障害の改善、慢性動脈閉塞症に伴う諸症状の改
善、虚血性脳血管障害に伴う血栓・塞栓の治療等、血栓
・塞栓症全般の治療薬として、単独で血栓溶解剤、抗血
栓剤として、あるいは他の血栓溶解剤等の血栓症治療剤
と併用することができる。The compound of the present invention has a fibrinolytic-promoting action and exhibits an excellent thrombolytic action, and is therefore effective for diseases caused by thrombus. In other words, venous thrombosis, myocardial infarction, pulmonary embolism, cerebral infarction, slowly progressing cerebral thrombosis, treatment of thrombosis and embolism associated with vascular surgery and extracorporeal blood circulation, improvement of impaired blood flow, chronic arterial occlusion As a therapeutic agent for thrombolysis / embolism in general, such as the treatment of thrombosis / embolism associated with ischemic cerebrovascular disorders, thrombus such as thrombolytic agents, antithrombotic agents, or other thrombolytic agents, etc. It can be used in combination with an agent for treating symptom.
フロントページの続き (51)Int.Cl.7 識別記号 FI テーマコート゛(参考) A61K 31/4192 A61K 31/41 601 4C056 31/4245 603 4C086 31/415 31/415 601 31/4152 602 31/4164 606 31/421 31/42 601 31/426 31/425 601 31/435 31/435 31/44 31/44 31/47 31/47 31/505 31/505 31/53 31/53 31/535 31/535 C07D 215/14 C07D 215/14 217/16 217/16 231/12 231/12 B 231/22 231/22 Z 233/22 233/22 233/64 101 233/64 101 239/26 239/26 249/04 503 249/04 503 251/24 251/24 257/04 257/04 E 263/14 263/14 265/08 265/08 271/06 271/06 277/10 277/10 291/04 291/04 307/42 307/42 333/16 333/16 (72)発明者 綿貫 達彦 千葉県千葉市緑区大野台1−2−1 鳥居 薬品株式会社研究所内 (72)発明者 緑川 淳 千葉県千葉市緑区大野台1−2−1 鳥居 薬品株式会社研究所内 (72)発明者 池田 滋 千葉県千葉市緑区大野台1−2−1 鳥居 薬品株式会社研究所内 Fターム(参考) 4C023 BA05 4C031 BA05 4C034 AH03 4C037 HA08 4C055 BA16 BB11 FA01 4C056 AA01 AB02 AC07 AD01 AE03 AF05 FA04 FA11 FA17 FB01 FC01 4C086 AA01 AA02 AA03 BA03 BB02 BC17 BC28 BC30 BC36 BC38 BC42 BC62 BC63 BC64 BC66 BC69 BC72 BC82 BC86 BC94 MA03 MA04 MA11 MA52 MA60 MA66 NA14 ZA54 Continued on the front page (51) Int.Cl. 7 Identification code FI Theme coat II (Reference) A61K 31/4192 A61K 31/41 601 4C056 31/4245 603 4C086 31/415 31/415 601 31/4152 602 31/4164 606 31/421 31/42 601 31/426 31/425 601 31/435 31/435 31/44 31/44 31/47 31/47 31/505 31/505 31/53 31/53 31/535 31/535 C07D 215/14 C07D 215/14 217/16 217/16 231/12 231/12 B 231/22 231/22 Z 233/22 233/22 233/64 101 233/64 101 239/26 239/26 249 / 04 503 249/04 503 251/24 251/24 257/04 257/04 E 263/14 263/14 265/08 265/08 271/06 271/06 277/10 277/10 291/04 291/04 307 / 42 307/42 333/16 333/16 (72) Inventor Tatsuhiko Watanuki 1-2-1 Onodai, Midori-ku, Chiba City, Chiba Prefecture Inside Torii Pharmaceutical Co., Ltd. (72) Inventor Jun Midorikawa Onodai, Midori-ku, Chiba City, Chiba 1-2-1 Torii Pharmaceutical Co., Ltd. (72) Inventor Shigeru Ikeda 1-2-1 Onodai, Midori-ku, Chiba-shi, Chiba I Pharmaceutical Co., Ltd. F-term (reference) 4C023 BA05 4C031 BA05 4C034 AH03 4C037 HA08 4C055 BA16 BB11 FA01 4C056 AA01 AB02 AC07 AD01 AE03 AF05 FA04 FA11 FA17 FB01 FC01 4C086 AA01 AA02 AA03 BC03 BC02 BC02 BC30 BC66 BC69 BC72 BC82 BC86 BC94 MA03 MA04 MA11 MA52 MA60 MA66 NA14 ZA54
Claims (5)
ル基またはR3−低級アルキル基を表わし、R2は水酸
基、低級アルコキシ基、置換基を有する低級アルキルア
ミノ基、低級アルキル基を表わし、R3は置換基を有す
るフェニル基、置換基を有するアミノ基または水酸基を
表わし、 Aは 【化2】 を表わし、 R4は水素原子または低級アシル基を表わし、 Xは酸素原子または硫黄原子を表わし、 R5はハロゲン、水酸基、メルカプト基、−OR6また
は−SR6を表わし、 R6は低級アルキル基またはR7−カルボニル低級アル
キル基を表わし、 R7は水酸基または低級アルコキシ基を表わし、 R8は水素原子または低級アルキル基を表わし、 Yは−(CH2)n−(n=2または3)または−CH
=CH−を表わし、 Pは−NH−、酸素原子または硫黄原子を表わす。) (ただし、R1が水素原子を表わすとき、Aが 【化3】 (Yが−(CH2)n−、n=2でPが酸素原子または
−NH−)を表わす場合を除く。)で表わされる化合物
およびそれらの塩化合物並びに溶媒和物。1. A compound of the formula (I) (Wherein, R1 represents a hydrogen atom, an R2-carbonyl lower alkyl group or an R3-lower alkyl group, R2 represents a hydroxyl group, a lower alkoxy group, a lower alkylamino group having a substituent or a lower alkyl group, and R3 represents a substituent. A represents a phenyl group having a group, an amino group having a substituent or a hydroxyl group, and A represents R4 represents a hydrogen atom or a lower acyl group, X represents an oxygen atom or a sulfur atom, R5 represents a halogen, a hydroxyl group, a mercapto group, -OR6 or -SR6, and R6 represents a lower alkyl group or R7-carbonyl. R7 represents a hydroxyl group or a lower alkoxy group; R8 represents a hydrogen atom or a lower alkyl group; Y represents-(CH2) n- (n = 2 or 3) or -CH
= CH-, and P represents -NH-, an oxygen atom or a sulfur atom. (Provided that when R1 represents a hydrogen atom, A is (Y is-(CH2) n-, n = 2 and P represents an oxygen atom or -NH-). And the salt compounds and solvates thereof.
キシ酢酸(化合物2)、6−(2−ピリジル)−2−ナ
フチルオキシ酢酸(化合物3)、6−(5−ピリミジニ
ル)−2−ナフチルオキシ酢酸(化合物5)、6−(3
−キノリル)−2−ナフチルオキシ酢酸(化合物6)、
6−(4−イソキノリル)−2−ナフチルオキシ酢酸
(化合物7)、6−(2,3−ジメチル−1−フェニル
−3−ピラゾリン−5−オン−4−イル)−2−ナフチ
ルオキシ酢酸(化合物8)、6−(4−ピラゾリル)−
2−ナフチルオキシ酢酸(化合物9)、メチル 6−
(5−テトラゾリル)−2−ナフチルオキシアセタート
(化合物10)、メチル 6−(5−ヒドロキシ−1,
2,4−オキサジアゾール−3−イル)−2−ナフチル
オキシアセタート(化合物11)、6−(5−ヒドロキ
シ−1,2,4−オキサジアゾール−3−イル)−2−
ナフチルオキシ酢酸(化合物12)、4−[6−(5−
ヒドロキシ−1,2,4−オキサジアゾール−3−イ
ル)−2−ナフチルオキシメチルカルボニルアミノ]メ
チル安息香酸(化合物13)、N−2−N’,N’−ジ
メチルアミノエチル−[6−(5−ヒドロキシ−1,
2,4−オキサジアゾール−3−イル)−2−ナフチル
オキシ]アセトアミド(化合物14)、6−(1,3,
5−トリアジン−2−イル)−2−ナフチルオキシ酢酸
(化合物15)、6−(1−メチルテトラゾール−5−
イル)−2−ナフチルオキシ酢酸(化合物16)、6−
(2−イミダゾリニル)−2−ナフチルオキシ酢酸(化
合物17)、2−(6−ヒドロキシナフチル)−1,
2,4−オキサジアゾール−5−オール(化合物1
8)、6−(5−クロロ−1,2,4−オキサジアゾー
ル−3−イル)−2−ナフチル アセタート(化合物1
9)、6−(5−チオキソ−1,2,4−オキサジアゾ
ール−3−イル)−2−ナフトール(化合物20)、6
−(5−カルボキシメチルチオ−1,2,4−オキサジ
アゾール−3−イル)−2−ナフチルオキシ酢酸(化合
物21)、N,N−ジメチル−2−[6−(5−ヒドロ
キシ−1,2,4−オキサジアゾール−3−イル)−2
−ナフチルオキシ]エチルアミン(化合物22)、4−
[6−(5−ヒドロキシ−1,2,4−オキサジアゾー
ル−3−イル)−2−ナフチルオキシ]ブタン酸(化合
物23)、6−(4,5−ジヒドロ−1,3−チアゾー
ル−2−イル)−2−ナフトール(化合物26)、6−
(4,5−ジヒドロ−1,3−チアゾール−2−イル)
−2−ナフチルオキシ酢酸(化合物27)、6−(5,
6−ジヒドロ−4H−1,3−オキサジン−2−イル)
−2−ナフチルオキシ酢酸・塩酸塩(化合物29)、6
−(4,5−ジヒドロ−1,3−オキサゾール−2−イ
ル)−2−ナフチルオキシ酢酸・塩酸塩(化合物3
0)、メチル 6−(2−オキソ−3H−1,2,3,
5−オキサチアジアゾール−4−イル)−2−ナフチル
オキシアセタート(化合物31)、6−(2−イミダゾ
リル)−2−ナフチルオキシ酢酸(化合物32)、6−
(1,2,3−トリアゾール−4−イル)−2−ナフチ
ルオキシ酢酸(化合物33)。2. 6- (2-thienyl) -2-naphthyloxyacetic acid (compound 2), 6- (2-pyridyl) -2-naphthyloxyacetic acid (compound 3), 6- (5-pyrimidinyl) -2 -Naphthyloxyacetic acid (compound 5), 6- (3
-Quinolyl) -2-naphthyloxyacetic acid (compound 6),
6- (4-isoquinolyl) -2-naphthyloxyacetic acid (compound 7), 6- (2,3-dimethyl-1-phenyl-3-pyrazolin-5-one-4-yl) -2-naphthyloxyacetic acid ( Compound 8), 6- (4-pyrazolyl)-
2-naphthyloxyacetic acid (compound 9), methyl 6-
(5-tetrazolyl) -2-naphthyloxyacetate (compound 10), methyl 6- (5-hydroxy-1,
2,4-oxadiazol-3-yl) -2-naphthyloxyacetate (compound 11), 6- (5-hydroxy-1,2,4-oxadiazol-3-yl) -2-
Naphthyloxyacetic acid (compound 12), 4- [6- (5-
(Hydroxy-1,2,4-oxadiazol-3-yl) -2-naphthyloxymethylcarbonylamino] methylbenzoic acid (compound 13), N-2-N ′, N′-dimethylaminoethyl- [6- (5-hydroxy-1,
2,4-oxadiazol-3-yl) -2-naphthyloxy] acetamide (compound 14), 6- (1,3
5-triazin-2-yl) -2-naphthyloxyacetic acid (compound 15), 6- (1-methyltetrazole-5-
Yl) -2-naphthyloxyacetic acid (compound 16), 6-
(2-imidazolinyl) -2-naphthyloxyacetic acid (compound 17), 2- (6-hydroxynaphthyl) -1,
2,4-oxadiazol-5-ol (compound 1
8), 6- (5-chloro-1,2,4-oxadiazol-3-yl) -2-naphthyl acetate (compound 1
9), 6- (5-thioxo-1,2,4-oxadiazol-3-yl) -2-naphthol (compound 20), 6
-(5-carboxymethylthio-1,2,4-oxadiazol-3-yl) -2-naphthyloxyacetic acid (compound 21), N, N-dimethyl-2- [6- (5-hydroxy-1, 2,4-oxadiazol-3-yl) -2
-Naphthyloxy] ethylamine (compound 22), 4-
[6- (5-hydroxy-1,2,4-oxadiazol-3-yl) -2-naphthyloxy] butanoic acid (compound 23), 6- (4,5-dihydro-1,3-thiazole- 2-yl) -2-naphthol (compound 26), 6-
(4,5-dihydro-1,3-thiazol-2-yl)
-2-naphthyloxyacetic acid (compound 27), 6- (5,
6-dihydro-4H-1,3-oxazin-2-yl)
-2-naphthyloxyacetic acid hydrochloride (compound 29), 6
-(4,5-dihydro-1,3-oxazol-2-yl) -2-naphthyloxyacetic acid hydrochloride (compound 3
0), methyl 6- (2-oxo-3H-1,2,3,
5-oxathiadiazol-4-yl) -2-naphthyloxyacetate (compound 31), 6- (2-imidazolyl) -2-naphthyloxyacetic acid (compound 32), 6-
(1,2,3-Triazol-4-yl) -2-naphthyloxyacetic acid (Compound 33).
の化合物を含む医薬組成物。A pharmaceutical composition comprising the compound according to any one of claims 1 or 2.
Priority Applications (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP33174798A JP2002275157A (en) | 1998-11-20 | 1998-11-20 | New naphthalene derivative |
AU40584/99A AU4058499A (en) | 1998-11-20 | 1999-06-02 | Novel naphthalene derivatives |
PCT/JP1999/002939 WO2000031036A1 (en) | 1998-11-20 | 1999-06-02 | Novel naphthalene derivatives |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP33174798A JP2002275157A (en) | 1998-11-20 | 1998-11-20 | New naphthalene derivative |
Publications (1)
Publication Number | Publication Date |
---|---|
JP2002275157A true JP2002275157A (en) | 2002-09-25 |
Family
ID=18247171
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP33174798A Pending JP2002275157A (en) | 1998-11-20 | 1998-11-20 | New naphthalene derivative |
Country Status (3)
Country | Link |
---|---|
JP (1) | JP2002275157A (en) |
AU (1) | AU4058499A (en) |
WO (1) | WO2000031036A1 (en) |
Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2004250401A (en) * | 2003-02-21 | 2004-09-09 | Shizuoka Coffein Co Ltd | Oxazole derivative |
JP2006514926A (en) * | 2002-11-12 | 2006-05-18 | アボット・ラボラトリーズ | Bicyclic substituted amines as histamine-3 receptor ligands |
US7186749B2 (en) | 2004-08-23 | 2007-03-06 | Wyeth | Pyrrolo-naphthyl acids and methods for using them |
Families Citing this family (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2001077076A1 (en) * | 1999-06-02 | 2001-10-18 | Torii Pharmaceutical Co., Ltd. | Novel naphthalene derivatives |
JP2003530438A (en) * | 2000-04-12 | 2003-10-14 | スミスクライン・ビーチャム・コーポレイション | Compounds and methods |
US7754747B2 (en) | 2004-08-23 | 2010-07-13 | Wyeth Llc | Oxazolo-naphthyl acids |
US9271963B2 (en) | 2005-03-03 | 2016-03-01 | Universitat Des Saarlandes | Selective inhibitors of human corticosteroid synthases |
Family Cites Families (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0802179B1 (en) * | 1995-01-05 | 2002-08-21 | Torii Pharmaceutical Co., Ltd. | Substituted amidinonaphthyl ester derivatives |
JPH1017549A (en) * | 1996-07-02 | 1998-01-20 | Banyu Pharmaceut Co Ltd | Bicyclic aromatic amidine derivative |
-
1998
- 1998-11-20 JP JP33174798A patent/JP2002275157A/en active Pending
-
1999
- 1999-06-02 WO PCT/JP1999/002939 patent/WO2000031036A1/en active Application Filing
- 1999-06-02 AU AU40584/99A patent/AU4058499A/en not_active Abandoned
Cited By (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2006514926A (en) * | 2002-11-12 | 2006-05-18 | アボット・ラボラトリーズ | Bicyclic substituted amines as histamine-3 receptor ligands |
JP4820094B2 (en) * | 2002-11-12 | 2011-11-24 | アボット・ラボラトリーズ | Bicyclic substituted amines as histamine-3 receptor ligands |
JP2004250401A (en) * | 2003-02-21 | 2004-09-09 | Shizuoka Coffein Co Ltd | Oxazole derivative |
US7186749B2 (en) | 2004-08-23 | 2007-03-06 | Wyeth | Pyrrolo-naphthyl acids and methods for using them |
Also Published As
Publication number | Publication date |
---|---|
WO2000031036A1 (en) | 2000-06-02 |
AU4058499A (en) | 2000-06-13 |
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