JPH056544B2 - - Google Patents
Info
- Publication number
- JPH056544B2 JPH056544B2 JP60049953A JP4995385A JPH056544B2 JP H056544 B2 JPH056544 B2 JP H056544B2 JP 60049953 A JP60049953 A JP 60049953A JP 4995385 A JP4995385 A JP 4995385A JP H056544 B2 JPH056544 B2 JP H056544B2
- Authority
- JP
- Japan
- Prior art keywords
- naphthyl
- tert
- compound
- reaction
- proton
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Fee Related
Links
- 125000001624 naphthyl group Chemical group 0.000 claims description 24
- 125000006239 protecting group Chemical group 0.000 claims description 17
- 125000000217 alkyl group Chemical group 0.000 claims description 11
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 10
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 8
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 8
- 125000002947 alkylene group Chemical group 0.000 claims description 4
- 125000001316 cycloalkyl alkyl group Chemical group 0.000 claims description 3
- YBUWZZKYXPWDGO-UHFFFAOYSA-N 1,4-thiazepan-5-one Chemical class O=C1CCSCCN1 YBUWZZKYXPWDGO-UHFFFAOYSA-N 0.000 claims description 2
- -1 2-cyclopentylethyl Chemical group 0.000 description 109
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 75
- 150000001875 compounds Chemical class 0.000 description 67
- 238000006243 chemical reaction Methods 0.000 description 47
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 36
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 28
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 28
- 239000002904 solvent Substances 0.000 description 23
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 21
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 20
- 239000000243 solution Substances 0.000 description 19
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 18
- 238000000034 method Methods 0.000 description 17
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 16
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 15
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 15
- 238000010511 deprotection reaction Methods 0.000 description 15
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 14
- 239000002585 base Substances 0.000 description 13
- 125000004432 carbon atom Chemical group C* 0.000 description 13
- 150000003839 salts Chemical class 0.000 description 13
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 12
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 12
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 12
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 12
- 239000000203 mixture Substances 0.000 description 12
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 10
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 10
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 10
- 239000002253 acid Substances 0.000 description 10
- 238000002844 melting Methods 0.000 description 10
- 230000008018 melting Effects 0.000 description 10
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 10
- 125000001424 substituent group Chemical group 0.000 description 10
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 9
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 9
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 9
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 9
- 150000002148 esters Chemical group 0.000 description 9
- QIAFMBKCNZACKA-UHFFFAOYSA-N N-benzoylglycine Chemical compound OC(=O)CNC(=O)C1=CC=CC=C1 QIAFMBKCNZACKA-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
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 8
- 102100030988 Angiotensin-converting enzyme Human genes 0.000 description 7
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 7
- 125000003277 amino group Chemical group 0.000 description 7
- 125000006244 carboxylic acid protecting group Chemical group 0.000 description 7
- 125000005982 diphenylmethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])(*)C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 7
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 7
- 125000001557 phthalyl group Chemical group C(=O)(O)C1=C(C(=O)*)C=CC=C1 0.000 description 7
- 235000011121 sodium hydroxide Nutrition 0.000 description 7
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 6
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 6
- RDOXTESZEPMUJZ-UHFFFAOYSA-N anisole Chemical compound COC1=CC=CC=C1 RDOXTESZEPMUJZ-UHFFFAOYSA-N 0.000 description 6
- 230000000694 effects Effects 0.000 description 6
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 6
- 239000000843 powder Substances 0.000 description 6
- 238000006722 reduction reaction Methods 0.000 description 6
- 238000003756 stirring Methods 0.000 description 6
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 5
- 238000004440 column chromatography Methods 0.000 description 5
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 5
- 125000004184 methoxymethyl group Chemical group [H]C([H])([H])OC([H])([H])* 0.000 description 5
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 5
- 239000003960 organic solvent Substances 0.000 description 5
- 238000010898 silica gel chromatography Methods 0.000 description 5
- 125000001981 tert-butyldimethylsilyl group Chemical group [H]C([H])([H])[Si]([H])(C([H])([H])[H])[*]C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 5
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 5
- 125000000453 2,2,2-trichloroethyl group Chemical group [H]C([H])(*)C(Cl)(Cl)Cl 0.000 description 4
- 125000000094 2-phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])* 0.000 description 4
- 108010064733 Angiotensins Proteins 0.000 description 4
- 102000015427 Angiotensins Human genes 0.000 description 4
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 4
- 206010020772 Hypertension Diseases 0.000 description 4
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
- 125000003545 alkoxy group Chemical group 0.000 description 4
- 235000001014 amino acid Nutrition 0.000 description 4
- 229910052799 carbon Inorganic materials 0.000 description 4
- 229910002091 carbon monoxide Inorganic materials 0.000 description 4
- 238000007796 conventional method Methods 0.000 description 4
- 239000003814 drug Substances 0.000 description 4
- 229930195733 hydrocarbon Natural products 0.000 description 4
- 150000002430 hydrocarbons Chemical class 0.000 description 4
- 238000004519 manufacturing process Methods 0.000 description 4
- 229910052757 nitrogen Inorganic materials 0.000 description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 4
- 235000011118 potassium hydroxide Nutrition 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- 239000011541 reaction mixture Substances 0.000 description 4
- 238000001953 recrystallisation Methods 0.000 description 4
- 230000002829 reductive effect Effects 0.000 description 4
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 description 4
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 3
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 3
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 3
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 3
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 3
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 3
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 3
- XAKBSHICSHRJCL-UHFFFAOYSA-N [CH2]C(=O)C1=CC=CC=C1 Chemical group [CH2]C(=O)C1=CC=CC=C1 XAKBSHICSHRJCL-UHFFFAOYSA-N 0.000 description 3
- 229910052783 alkali metal Inorganic materials 0.000 description 3
- 150000008044 alkali metal hydroxides Chemical class 0.000 description 3
- 125000004453 alkoxycarbonyl group Chemical group 0.000 description 3
- 125000004414 alkyl thio group Chemical group 0.000 description 3
- 150000001413 amino acids Chemical class 0.000 description 3
- LOUPRKONTZGTKE-UHFFFAOYSA-N cinchonine Natural products C1C(C(C2)C=C)CCN2C1C(O)C1=CC=NC2=CC=C(OC)C=C21 LOUPRKONTZGTKE-UHFFFAOYSA-N 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- GKIRPKYJQBWNGO-OCEACIFDSA-N clomifene Chemical compound C1=CC(OCCN(CC)CC)=CC=C1C(\C=1C=CC=CC=1)=C(\Cl)C1=CC=CC=C1 GKIRPKYJQBWNGO-OCEACIFDSA-N 0.000 description 3
- 238000001816 cooling Methods 0.000 description 3
- MKRTXPORKIRPDG-UHFFFAOYSA-N diphenylphosphoryl azide Chemical compound C=1C=CC=CC=1P(=O)(N=[N+]=[N-])C1=CC=CC=C1 MKRTXPORKIRPDG-UHFFFAOYSA-N 0.000 description 3
- 238000001035 drying Methods 0.000 description 3
- 150000002170 ethers Chemical class 0.000 description 3
- 229910052736 halogen Inorganic materials 0.000 description 3
- 150000002367 halogens Chemical class 0.000 description 3
- GNOIPBMMFNIUFM-UHFFFAOYSA-N hexamethylphosphoric triamide Chemical compound CN(C)P(=O)(N(C)C)N(C)C GNOIPBMMFNIUFM-UHFFFAOYSA-N 0.000 description 3
- 238000001727 in vivo Methods 0.000 description 3
- 150000002576 ketones Chemical class 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- 239000012280 lithium aluminium hydride Substances 0.000 description 3
- UZKWTJUDCOPSNM-UHFFFAOYSA-N methoxybenzene Substances CCCCOC=C UZKWTJUDCOPSNM-UHFFFAOYSA-N 0.000 description 3
- HDZGCSFEDULWCS-UHFFFAOYSA-N monomethylhydrazine Chemical compound CNN HDZGCSFEDULWCS-UHFFFAOYSA-N 0.000 description 3
- SYSQUGFVNFXIIT-UHFFFAOYSA-N n-[4-(1,3-benzoxazol-2-yl)phenyl]-4-nitrobenzenesulfonamide Chemical class C1=CC([N+](=O)[O-])=CC=C1S(=O)(=O)NC1=CC=C(C=2OC3=CC=CC=C3N=2)C=C1 SYSQUGFVNFXIIT-UHFFFAOYSA-N 0.000 description 3
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 description 3
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 3
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 3
- 230000003287 optical effect Effects 0.000 description 3
- 125000006503 p-nitrobenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1[N+]([O-])=O)C([H])([H])* 0.000 description 3
- UHZYTMXLRWXGPK-UHFFFAOYSA-N phosphorus pentachloride Chemical compound ClP(Cl)(Cl)(Cl)Cl UHZYTMXLRWXGPK-UHFFFAOYSA-N 0.000 description 3
- 125000005633 phthalidyl group Chemical group 0.000 description 3
- 230000035484 reaction time Effects 0.000 description 3
- 125000003808 silyl group Chemical group [H][Si]([H])([H])[*] 0.000 description 3
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 3
- 235000017557 sodium bicarbonate Nutrition 0.000 description 3
- 229910000029 sodium carbonate Inorganic materials 0.000 description 3
- 239000012312 sodium hydride Substances 0.000 description 3
- 229910000104 sodium hydride Inorganic materials 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 3
- 238000005406 washing Methods 0.000 description 3
- 239000011701 zinc Substances 0.000 description 3
- 229910052725 zinc Inorganic materials 0.000 description 3
- ZFPPQCXZXICVQM-WNQIDUERSA-N (2r)-2-amino-3-sulfanylpropanoic acid;4-methylbenzenesulfonic acid Chemical compound SC[C@H](N)C(O)=O.CC1=CC=C(S(O)(=O)=O)C=C1 ZFPPQCXZXICVQM-WNQIDUERSA-N 0.000 description 2
- 125000001637 1-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C(*)=C([H])C([H])=C([H])C2=C1[H] 0.000 description 2
- DCTOHCCUXLBQMS-UHFFFAOYSA-N 1-undecene Chemical compound CCCCCCCCCC=C DCTOHCCUXLBQMS-UHFFFAOYSA-N 0.000 description 2
- YRCQQABRFCQGQB-UHFFFAOYSA-N 2-(2-naphthalen-1-yl-5-oxo-1,4-thiazepan-6-yl)isoindole-1,3-dione Chemical compound O=C1C2=CC=CC=C2C(=O)N1C(C(NC1)=O)CSC1C1=CC=CC2=CC=CC=C12 YRCQQABRFCQGQB-UHFFFAOYSA-N 0.000 description 2
- XNUIMVZFWPXWFQ-UHFFFAOYSA-N 2-(2-naphthalen-2-yl-5-oxo-1,4-thiazepan-6-yl)isoindole-1,3-dione Chemical compound O=C1C2=CC=CC=C2C(=O)N1C(C(NC1)=O)CSC1C1=CC=C(C=CC=C2)C2=C1 XNUIMVZFWPXWFQ-UHFFFAOYSA-N 0.000 description 2
- BSKHPKMHTQYZBB-UHFFFAOYSA-N 2-methylpyridine Chemical compound CC1=CC=CC=N1 BSKHPKMHTQYZBB-UHFFFAOYSA-N 0.000 description 2
- 125000001622 2-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C([H])=C(*)C([H])=C([H])C2=C1[H] 0.000 description 2
- 125000004924 2-naphthylethyl group Chemical group C1=C(C=CC2=CC=CC=C12)CC* 0.000 description 2
- CMNQIVHHHBBVSC-UHFFFAOYSA-N 5-hydroxy-3,4-dihydro-2h-isoquinolin-1-one Chemical compound O=C1NCCC2=C1C=CC=C2O CMNQIVHHHBBVSC-UHFFFAOYSA-N 0.000 description 2
- 239000004475 Arginine Substances 0.000 description 2
- 101800004538 Bradykinin Proteins 0.000 description 2
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 2
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 2
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 2
- QXZGBUJJYSLZLT-UHFFFAOYSA-N H-Arg-Pro-Pro-Gly-Phe-Ser-Pro-Phe-Arg-OH Natural products NC(N)=NCCCC(N)C(=O)N1CCCC1C(=O)N1C(C(=O)NCC(=O)NC(CC=2C=CC=CC=2)C(=O)NC(CO)C(=O)N2C(CCC2)C(=O)NC(CC=2C=CC=CC=2)C(=O)NC(CCCN=C(N)N)C(O)=O)CCC1 QXZGBUJJYSLZLT-UHFFFAOYSA-N 0.000 description 2
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 description 2
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 2
- 102100035792 Kininogen-1 Human genes 0.000 description 2
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 description 2
- 239000004472 Lysine Substances 0.000 description 2
- DBTDEFJAFBUGPP-UHFFFAOYSA-N Methanethial Chemical compound S=C DBTDEFJAFBUGPP-UHFFFAOYSA-N 0.000 description 2
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 2
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- LOUPRKONTZGTKE-WZBLMQSHSA-N Quinine Chemical compound C([C@H]([C@H](C1)C=C)C2)C[N@@]1[C@@H]2[C@H](O)C1=CC=NC2=CC=C(OC)C=C21 LOUPRKONTZGTKE-WZBLMQSHSA-N 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- ITLHXEGAYQFOHJ-UHFFFAOYSA-N [diazo(phenyl)methyl]benzene Chemical compound C=1C=CC=CC=1C(=[N+]=[N-])C1=CC=CC=C1 ITLHXEGAYQFOHJ-UHFFFAOYSA-N 0.000 description 2
- 150000007513 acids Chemical class 0.000 description 2
- 125000004442 acylamino group Chemical group 0.000 description 2
- 125000004423 acyloxy group Chemical group 0.000 description 2
- 150000001298 alcohols Chemical class 0.000 description 2
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 2
- 125000005194 alkoxycarbonyloxy group Chemical group 0.000 description 2
- 125000004390 alkyl sulfonyl group Chemical group 0.000 description 2
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 description 2
- 150000001408 amides Chemical class 0.000 description 2
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 description 2
- 125000003118 aryl group Chemical group 0.000 description 2
- 125000004391 aryl sulfonyl group Chemical group 0.000 description 2
- 125000005110 aryl thio group Chemical group 0.000 description 2
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 description 2
- QXZGBUJJYSLZLT-FDISYFBBSA-N bradykinin Chemical compound NC(=N)NCCC[C@H](N)C(=O)N1CCC[C@H]1C(=O)N1[C@H](C(=O)NCC(=O)N[C@@H](CC=2C=CC=CC=2)C(=O)N[C@@H](CO)C(=O)N2[C@@H](CCC2)C(=O)N[C@@H](CC=2C=CC=CC=2)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O)CCC1 QXZGBUJJYSLZLT-FDISYFBBSA-N 0.000 description 2
- 239000012267 brine Substances 0.000 description 2
- 150000001721 carbon Chemical group 0.000 description 2
- 238000010531 catalytic reduction reaction Methods 0.000 description 2
- 239000007795 chemical reaction product Substances 0.000 description 2
- KMPWYEUPVWOPIM-KODHJQJWSA-N cinchonidine Chemical compound C1=CC=C2C([C@H]([C@H]3[N@]4CC[C@H]([C@H](C4)C=C)C3)O)=CC=NC2=C1 KMPWYEUPVWOPIM-KODHJQJWSA-N 0.000 description 2
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- 125000004043 oxo group Chemical group O=* 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- 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 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- 239000008194 pharmaceutical composition Substances 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 125000000612 phthaloyl group Chemical group C(C=1C(C(=O)*)=CC=CC1)(=O)* 0.000 description 1
- 230000001766 physiological effect Effects 0.000 description 1
- 229910052697 platinum Inorganic materials 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910000343 potassium bisulfate Inorganic materials 0.000 description 1
- NTTOTNSKUYCDAV-UHFFFAOYSA-N potassium hydride Chemical compound [KH] NTTOTNSKUYCDAV-UHFFFAOYSA-N 0.000 description 1
- 229910000105 potassium hydride Inorganic materials 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 230000003449 preventive effect Effects 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 229960001404 quinidine Drugs 0.000 description 1
- 229960000948 quinine Drugs 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 238000012827 research and development Methods 0.000 description 1
- 229910052703 rhodium Inorganic materials 0.000 description 1
- 239000010948 rhodium Substances 0.000 description 1
- MHOVAHRLVXNVSD-UHFFFAOYSA-N rhodium atom Chemical compound [Rh] MHOVAHRLVXNVSD-UHFFFAOYSA-N 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 239000012279 sodium borohydride Substances 0.000 description 1
- 229910000033 sodium borohydride Inorganic materials 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- BEOOHQFXGBMRKU-UHFFFAOYSA-N sodium cyanoborohydride Chemical compound [Na+].[B-]C#N BEOOHQFXGBMRKU-UHFFFAOYSA-N 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- AJDQFVOHOVOKHX-UHFFFAOYSA-N tert-butyl n-(2-chloro-2-naphthalen-1-ylethyl)carbamate Chemical compound C1=CC=C2C(C(Cl)CNC(=O)OC(C)(C)C)=CC=CC2=C1 AJDQFVOHOVOKHX-UHFFFAOYSA-N 0.000 description 1
- ZXXFCLYSEBBPKQ-UHFFFAOYSA-N tert-butyl n-(2-chloro-2-naphthalen-2-ylethyl)carbamate Chemical compound C1=CC=CC2=CC(C(Cl)CNC(=O)OC(C)(C)C)=CC=C21 ZXXFCLYSEBBPKQ-UHFFFAOYSA-N 0.000 description 1
- FICZYIJOWAZXCK-UHFFFAOYSA-N tert-butyl n-(2-hydroxy-2-naphthalen-1-ylethyl)carbamate Chemical compound C1=CC=C2C(C(O)CNC(=O)OC(C)(C)C)=CC=CC2=C1 FICZYIJOWAZXCK-UHFFFAOYSA-N 0.000 description 1
- WCGMORNUMWJZGG-UHFFFAOYSA-N tert-butyl n-(2-hydroxy-2-naphthalen-2-ylethyl)carbamate Chemical compound C1=CC=CC2=CC(C(O)CNC(=O)OC(C)(C)C)=CC=C21 WCGMORNUMWJZGG-UHFFFAOYSA-N 0.000 description 1
- 229940073455 tetraethylammonium hydroxide Drugs 0.000 description 1
- LRGJRHZIDJQFCL-UHFFFAOYSA-M tetraethylazanium;hydroxide Chemical compound [OH-].CC[N+](CC)(CC)CC LRGJRHZIDJQFCL-UHFFFAOYSA-M 0.000 description 1
- JWCVYQRPINPYQJ-UHFFFAOYSA-N thiepane Chemical class C1CCCSCC1 JWCVYQRPINPYQJ-UHFFFAOYSA-N 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- 125000004044 trifluoroacetyl group Chemical group FC(C(=O)*)(F)F 0.000 description 1
- 229940124549 vasodilator Drugs 0.000 description 1
- 239000003071 vasodilator agent Substances 0.000 description 1
Classifications
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Landscapes
- Nitrogen- Or Sulfur-Containing Heterocyclic Ring Compounds With Rings Of Six Or More Members (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
発明の目的
本発明は血圧降下作用を表わす医薬およびその
重要合成中間体として有用な4−アザ−5−オキ
ソ−1−チアシクロヘプタン〔別称、テトラヒド
ロ−1,4−チアデピン−5−(2H)−オン〕誘
導体に関するものである。
さらに詳しくは本発明は一般式
(式中、R1はアルキル基、シクロアルキルアル
キル基またはアラルキル基を示し、R2およびR4
は同一または異なつて水素原子またはカルボキシ
基の保護基を示し、R3はナフチル基を示し、A
は低級アルキレン基を示す。)
で表わされる新規な4−アザ−5−オキソ−1−
チアシクロヘプタン誘導体およびその薬理上許容
される塩に関するものである。
本発明者等は、血圧降下剤の研究開発を目的と
して合成研究を行に、前記一般式〔〕を有する
新規化合物がアンジオテンシン変換酵素に対する
阻害活性を有し、経口投与によつて持続性を表わ
す高血圧症治療剤として有用であることを見出し
て本発明を完成した。
発明の構成
前記一般式〔〕で表わされる化合物は、星印
(*)で表わされる位置(場合によつてはその他
の位置)に不斉炭素原子を含有するので、光学的
に純粋なジアステレオ異性体、ジアステレオ異性
体のラセミ体またはジアステレオ異性体の混合物
が存在し得る。本発明はこれら立体異性体のいず
れも形態も包含することができる。
次に、前記一般式〔〕中の置換基R1、R2、
R3、R4およびAについて具体的に説明する。
R1におけるアルキル基としては、炭素数1乃
至9個のアルキル基であり、例えばメチル、エチ
ル、n−プロピル、イソプロピル、n−ブチル、
イソブチル、tert−ブチル、ペンチル、ネオペン
チル、ヘキシル、オクチル、ノニル等であり、シ
クロアルキルアルキル基としては、炭素数5乃至
7個のシクロアルキル基を有する炭素数1乃至2
個を有するアルキル基であり、例えばシクロペン
チルメチル、2−シクロペンチルエチル、シクロ
ヘキシルメチル、2−シクロヘキシルエチル、シ
クロヘプチルメチル、2−シクロヘプチルエチル
等であり、アラルキル基胃としては例えばベンジ
ル、フエネチル、1−ナフチルメチル、1−ナフ
チルエチル、2−ナフチルメチル、2−ナフチル
エチル、2−インダニル等があげられる。これら
のシクロアルキル基またはアラルキル基は置換基
を有してもよく、そのような置換基としては、炭
素数1乃至4個の低級アルキル基(例えばメチ
ル、エチル、n−プロピル、イソプロピル、n−
ブチル、イソブチル、tert−ブチル等)、炭素数
1乃至4個の低級アルコキシ基(例えばメトキ
シ、エトキシ、n−プロポキシ、イソプポキシ、
n−プトキシ、イソブトキシ等)、ハロゲン(例
えばフツ素、塩素、臭素等)、炭素数1乃至4個
の低級アルキルチオ基(例えばメチルチオ、エチ
ルチオ等)、があげられ、これらの置換基は同一
または組合わされて1乃至3個置換されていても
よい。
R2およびR4におけるカルボン酸の保護基とし
ては、有機合成化学において一般に広く知られて
いる保護基であるかまたは薬理学的に生体内にお
いてカルボキシ基に変換し得るエステル残基のこ
とである。そのような保護基としては炭素数1乃
至6個のアルキル基(例えばメチル、エチル、n
−プロピル、イソプロピル、n−ブチル、イソブ
チル、tert−ブチル、n−ペンチル、n−ヘキシ
ル等)、アラルキル基(例えばベンジル、ジフエ
ニルメチル、1−インダニル、2−インダニル、
1−(1,2,3,4−テトラヒドロナフチル)、
2−(1,2,3,4−テトラヒドロナフチル)、
フタリジル等)、アリール等(例えばフエニル
等)、シリル基(例えばトリメチルシリル、tert
−ブチルジメチルシリル等)があげられる。上記
保護基には、アルキル、ハロゲン、ヒドロキシ、
アルコキシ、アシルオキシ、オキソ、カルボキ
シ、アルコキシカルボニル、アルコキシカルボニ
ルオキシ、アシルアミノ、ニトロ、シアノ、アミ
ノ、モノアルキルアミノ、ジアルキルアミノ、ア
シルアミノ、アルキルチオ、アリールチオ、アル
キルスルホニル、アリールスルホニル、2−オキ
ソ−1,3−ジオキソレン−4−イル基等の置換
基が存在してもよく、これらの置換基は同一また
は組合わされて1乃至3個置換されていてもよ
い。そのような置換基の例としては例えばハロゲ
ンにおいて2,2,2−トリクロルエチル、2−
ヨードエチル等、ヒドロキシにおいて2−ヒドロ
キシエチル、2,3−ジヒドロキシプロピル等、
アルコキシにおいてはメトキシメチル、2−メト
キシエトキシメチル、p−メトキシベンジル等、
アシルオキシにおいてはアセトキシメチル、1−
アセトキシエチル、ピバロイルオキシメチル等、
オキソにおいてはフエナシル等、アルコキシカル
ボニルにおいてはメトキシカルボニルメチル等、
アルコキシカルボニルオキシにおいてはエトキシ
カルボニルオキシメチル、1−(エトキシカルボ
ニルオキシ)エチル等、ニトロにおいてはp−ニ
トロベンジル等、シアノにおいてはシアノエチル
等、アルキルチオにおいてはメチルチオメチル、
エチルチオメチル等、アリールチオにおいてはフ
エニルチオメチル等、アルキルスルホニルにおい
ては2−(メタンスルホニル)エチル等、アリー
ルスルホニルにおいては2−(ベンゼンスルホニ
ル)エチル等、2−オキソ−1,3−ジオキソレ
ン−4−イルにおいては、(5−メチル−2−オ
キソ−1,3−ジオキソレン−4−イル)メチ
ル、(5−フエニル−2−オキソ−1,3−ジオ
キソレン−4−イル)メチル等があげられる。こ
れらカルボン酸の保護基は、保護の目的を達する
限りこの発明の要旨を変更することなく広範な変
化が可能である。
R3は1−ナフチルィまたは2−ナフチル基で
あり、これらナフチル基は置換基を有していても
よく、そのような置換基としては、炭素数1乃至
4個のアルキル基(例えばメチル、エチル、n−
プロピル、イソプロピル、n−ブチル、イソブチ
ル、tert−ブチル等)、炭素数1乃至4個のアル
コキシ基(例えばメトキシ、エトキシ、n−プロ
ポキシ、イソプロポキシ、n−ブトキシ、イソブ
トキシ、tert−ブトキシ等)があげられる。
Aの低級アルキレン基としては、炭素数1乃至
2個のアルキレン基であり、例えばメチレン、エ
チレン、エチリデン等があげられる。
前記一般式〔〕における好適な化合物として
は、R1がn−ブチル、イソブチル、n−ペンチ
ル、イソブンチル、ネオペンチル、n−ヘキシ
ル、イソオクチル、n−オクチル、n−ノニルの
ような炭素数4乃至9個を有する直鎖状若しくは
分枝鎖状のアルキル基、2−シクロペンチルエチ
ル、2−シクロヘキシルエチルのような五員若し
くは六員シクロアルキルエチル基、ベンジル、フ
エネチル、1−ナフチルメチル、2−ナフチルメ
チル、1−ナフチルエチル、2−ナフチルエチ
ル、2−インドリルのような炭素数7乃至12個を
有するアラアルキル基であり、R2が水素原子、
またはメチル、エチル、n−プロピル、イソプロ
ピル、n−ブチル、イソブチル、n−ペンチル、
n−ヘキシルのような炭素数1乃至6個を有する
直鎖状若しくは分枝鎖状のアルキル基、、ベンジ
ルのようなアラルキル基、アセトキシメチル、ピ
バロイルオキシメチル、フタリジル、1−(エト
キシカルボニルオキシ)エチル、(5−メチル−
2−オキソ−1,3−ジオキソレン−4−イル)
メチルのような生体内で容易にカルボキシ基に変
換し得る保護基であり、
R3が1−ナフチル基または2−ナフチル基で
あり、
Aがメチレン基であり、
R4が水素原子、tert−ブチル、メトキシメチ
ル、2,2,2,−トリクロルエチル、アリル、
ベンジル、p−ニトロベンジル、p−メトキシベ
ンジル、ジフエニルメチルのような有機合成化学
において使用するカルボキシ基の保護基またはア
セトキシメチル、ビバロイルオキシメチル、1−
(エトキシカルボニルオキシ)エチル、フタリジ
ル、(5−メチル−2−オキソ−1,3−ジオキ
ソレン−4−イル)メチルのような生体内で容易
にカルボキシ基に変換し得る保護基である化合物
をあげることができる。
このような本発明の新規化合物〔〕は、常法
に従つて酸または塩基で処理することにより、薬
理上許容し得る塩に変えることができる。このよ
うな酸付加塩の例としては、無機酸、例えばハロ
ゲン化水素酸(例えば塩酸、臭化水素酸等)、硫
酸、リン酸および硝酸等の塩、および有機酸(例
えばシユウ酸、マレイン酸、フマル酸、酒石酸、
クエン酸、メタンスルホンおよびベンゼンスルホ
ン酸等)などによる付加塩があげれる。また塩基
による塩としては、アルカリ金属水酸化物(例え
ばカ性ソーダ、水酸化カリウム等)、アルカリ土
類金属酸化物(例えば水酸化カルシウム、水酸化
マグネシウム等)、水酸化アンモニウム、水酸化
アルミニウムおよび有機塩基(例えばトリエチル
アミン、ジシクロヘキシルアミン、ジンコニン、
グアニジン、キニーネ等)、塩基性アミノ酸(例
えばリジン、アルギニン等)などによる塩があげ
られる。
本発明の前記一般式〔〕で表わされる具体的
化合物として、以下に記載する化合物を例示する
ことができる。
Purpose of the Invention The present invention discloses 4-aza-5-oxo-1-thiacycloheptane [also known as tetrahydro-1,4-thiadepine-5-(2H)] which is useful as a medicine exhibiting a blood pressure lowering effect and an important synthetic intermediate thereof. -one] derivative. More specifically, the present invention relates to the general formula (In the formula, R 1 represents an alkyl group, a cycloalkylalkyl group, or an aralkyl group, and R 2 and R 4
are the same or different and represent a hydrogen atom or a protecting group for a carboxy group, R 3 represents a naphthyl group, and A
represents a lower alkylene group. ) Novel 4-aza-5-oxo-1-
This invention relates to thiacycloheptane derivatives and pharmacologically acceptable salts thereof. The present inventors carried out synthetic research for the purpose of research and development of antihypertensive agents, and found that a new compound having the general formula [] has inhibitory activity against angiotensin converting enzyme and exhibits long-lasting activity when administered orally. The present invention was completed based on the discovery that the present invention is useful as a therapeutic agent for hypertension. Structure of the Invention The compound represented by the general formula [] contains an asymmetric carbon atom at the position indicated by an asterisk (*) (or at other positions as the case may be), so it is an optically pure diastereomer. Isomers, racemates of diastereoisomers or mixtures of diastereoisomers may be present. The present invention may encompass any of these stereoisomeric forms. Next, the substituents R 1 , R 2 in the general formula [],
R 3 , R 4 and A will be specifically explained. The alkyl group for R 1 is an alkyl group having 1 to 9 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl,
Isobutyl, tert-butyl, pentyl, neopentyl, hexyl, octyl, nonyl, etc., and the cycloalkylalkyl group has 1 to 2 carbon atoms and has a cycloalkyl group with 5 to 7 carbon atoms.
Examples of aralkyl groups include cyclopentylmethyl, 2-cyclopentylethyl, cyclohexylmethyl, 2-cyclohexylethyl, cycloheptylmethyl, 2-cycloheptylethyl, etc. Aralkyl groups include benzyl, phenethyl, 1- Examples include naphthylmethyl, 1-naphthylethyl, 2-naphthylmethyl, 2-naphthylethyl, 2-indanyl and the like. These cycloalkyl groups or aralkyl groups may have a substituent, and such substituents include lower alkyl groups having 1 to 4 carbon atoms (for example, methyl, ethyl, n-propyl, isopropyl, n-
butyl, isobutyl, tert-butyl, etc.), lower alkoxy groups having 1 to 4 carbon atoms (such as methoxy, ethoxy, n-propoxy, isopropoxy,
(n-ptoxy, isobutoxy, etc.), halogen (e.g., fluorine, chlorine, bromine, etc.), and lower alkylthio groups having 1 to 4 carbon atoms (e.g., methylthio, ethylthio, etc.), and these substituents may be the same or have different groups. A total of 1 to 3 may be substituted. The carboxylic acid protecting groups in R 2 and R 4 are generally widely known protecting groups in organic synthetic chemistry, or are ester residues that can be pharmacologically converted into carboxy groups in vivo. . Such protecting groups include alkyl groups having 1 to 6 carbon atoms (for example, methyl, ethyl, n
-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, n-hexyl, etc.), aralkyl groups (e.g. benzyl, diphenylmethyl, 1-indanyl, 2-indanyl,
1-(1,2,3,4-tetrahydronaphthyl),
2-(1,2,3,4-tetrahydronaphthyl),
phthalidyl, etc.), aryl, etc. (e.g. phenyl, etc.), silyl groups (e.g. trimethylsilyl, tert
-butyldimethylsilyl, etc.). The above protecting groups include alkyl, halogen, hydroxy,
Alkoxy, acyloxy, oxo, carboxy, alkoxycarbonyl, alkoxycarbonyloxy, acylamino, nitro, cyano, amino, monoalkylamino, dialkylamino, acylamino, alkylthio, arylthio, alkylsulfonyl, arylsulfonyl, 2-oxo-1,3- A substituent such as a dioxolen-4-yl group may be present, and 1 to 3 of these substituents may be the same or in combination. Examples of such substituents include 2,2,2-trichloroethyl, 2-
Iodoethyl, etc., hydroxy such as 2-hydroxyethyl, 2,3-dihydroxypropyl, etc.
For alkoxy, methoxymethyl, 2-methoxyethoxymethyl, p-methoxybenzyl, etc.
In acyloxy, acetoxymethyl, 1-
Acetoxyethyl, pivaloyloxymethyl, etc.
For oxo, phenacyl etc. For alkoxycarbonyl, methoxycarbonylmethyl etc.
For alkoxycarbonyloxy, ethoxycarbonyloxymethyl, 1-(ethoxycarbonyloxy)ethyl, etc. For nitro, p-nitrobenzyl, etc. For cyano, cyanoethyl, etc. For alkylthio, methylthiomethyl,
Ethylthiomethyl etc., arylthio such as phenylthiomethyl, alkylsulfonyl such as 2-(methanesulfonyl)ethyl, arylsulfonyl such as 2-(benzenesulfonyl)ethyl, 2-oxo-1,3-dioxolene- Examples of 4-yl include (5-methyl-2-oxo-1,3-dioxolen-4-yl)methyl, (5-phenyl-2-oxo-1,3-dioxolen-4-yl)methyl, etc. It will be done. These carboxylic acid protecting groups can be widely varied without changing the gist of the invention as long as the purpose of protection is achieved. R 3 is a 1-naphthyl or 2-naphthyl group, and these naphthyl groups may have a substituent, such as an alkyl group having 1 to 4 carbon atoms (for example, methyl, ethyl , n-
propyl, isopropyl, n-butyl, isobutyl, tert-butyl, etc.), alkoxy groups having 1 to 4 carbon atoms (e.g. methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, etc.) can give. The lower alkylene group of A is an alkylene group having 1 to 2 carbon atoms, such as methylene, ethylene, ethylidene, and the like. Suitable compounds in the above general formula [] include those in which R 1 has 4 to 9 carbon atoms, such as n-butyl, isobutyl, n-pentyl, isobutyl, neopentyl, n-hexyl, isooctyl, n-octyl, and n-nonyl. linear or branched alkyl groups having 5- or 6-membered cycloalkylethyl groups such as 2-cyclopentylethyl, 2-cyclohexylethyl, benzyl, phenethyl, 1-naphthylmethyl, 2-naphthylmethyl , 1-naphthylethyl, 2-naphthylethyl, 2-indolyl, an aralkyl group having 7 to 12 carbon atoms, and R 2 is a hydrogen atom,
or methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, n-pentyl,
Straight-chain or branched alkyl groups having 1 to 6 carbon atoms such as n-hexyl, aralkyl groups such as benzyl, acetoxymethyl, pivaloyloxymethyl, phthalidyl, 1-(ethoxycarbonyl) oxy)ethyl, (5-methyl-
2-oxo-1,3-dioxolen-4-yl)
It is a protecting group such as methyl that can be easily converted into a carboxy group in vivo, R 3 is a 1-naphthyl group or 2-naphthyl group, A is a methylene group, R 4 is a hydrogen atom, a tert- Butyl, methoxymethyl, 2,2,2,-trichloroethyl, allyl,
Protecting groups for carboxyl groups used in organic synthetic chemistry such as benzyl, p-nitrobenzyl, p-methoxybenzyl, diphenylmethyl, or acetoxymethyl, bivaloyloxymethyl, 1-
Compounds that are protective groups that can be easily converted into carboxyl groups in vivo, such as (ethoxycarbonyloxy)ethyl, phthalidyl, and (5-methyl-2-oxo-1,3-dioxolen-4-yl)methyl, are listed. be able to. Such a novel compound of the present invention [ ] can be converted into a pharmacologically acceptable salt by treatment with an acid or base according to a conventional method. Examples of such acid addition salts include salts of inorganic acids such as hydrohalic acids (e.g. hydrochloric acid, hydrobromic acid, etc.), sulfuric acid, phosphoric acid and nitric acid, and organic acids (e.g. oxalic acid, maleic acid, etc.). , fumaric acid, tartaric acid,
Examples include addition salts with citric acid, methanesulfone, benzenesulfonic acid, etc.). Salts with bases include alkali metal hydroxides (e.g. caustic soda, potassium hydroxide, etc.), alkaline earth metal oxides (e.g. calcium hydroxide, magnesium hydroxide, etc.), ammonium hydroxide, aluminum hydroxide, Organic bases (e.g. triethylamine, dicyclohexylamine, zinconine,
Examples include salts based on basic amino acids (e.g. lysine, arginine, etc.) and basic amino acids (e.g. lysine, arginine, etc.). As specific compounds represented by the above general formula [] of the present invention, the compounds described below can be exemplified.
【表】【table】
【表】【table】
【表】
本発明の化合物〔〕は、一般式
(式中、R3、R4およびAは前述したものと同意
義を示す。)を有する化合物と一般式
(式中、R1およびR2は前述したものと同意義を
示し、Xはハロゲン原子またはスルホニルオキシ
基を示す。)を有する化合物とを縮合させるか、
または前記化合物〔〕と一般式
(式中、R1およびR2は前述したものと同意義を
示す。)を有する化合物とを還元的に縮合させる
ことにより製造することができる。
一般式〔〕におけるXのハロゲン原子として
は塩素、臭素および沃素があげられ、スルホニル
オキシ基としてはメタンスルホニルオキシ、エタ
ンスルホニルオキシ、トフルオロメタンスルホニ
ルオキシ等のような置換されているかまたは置換
されていない低級アルカンスルホニルオキシ基お
よびベンゼンスルホニルオキシ、p−トルエンス
ルホニルオキシ等の置換されているかまたは置換
されていない芳香族スルホニルオキシ基があげら
れる。
化合物〔〕と化合物〔〕との縮合反応は、
本反応を阻害しない適当に溶媒中、塩基の存在下
に行なわれる。溶媒としては、ヘキサン、ベンゼ
ンのような炭化水素類、ジクロルメタン、1,2
−シクロルエタンのようなハロゲン化炭化水素
類、テトラヒドロフラン、ジオキサンのようなエ
ーテル類、酢酸エチルのようなエステル類、アセ
トンのようなケトン類、N,N−ジメチルホルム
アミド、N,N−ジメチルアセトアミド、ヘキサ
メチルホスホルアミドのようなアミド類、ジメチ
ルスルホキシド等があげられる。使用される塩基
としては特に限定はないが、炭酸ナトリウム、炭
酸カリウム、炭酸カルシウム等のアルカリ若しく
はアルカリ土類金属炭酸塩、重層、重炭酸カリウ
ム等のアルカリ金属重炭酸塩、水素化ナトリウ
ム、水素リチウム等の水素化アルカリ金属、トリ
エチルアミン、ピリジン、ピコリン、テトラエチ
ルアンモニウムヒドロキシド等の有機塩基があげ
られる。またテトラn−ブチルアンモニウムプロ
マイド、ベンジルトリエチルアンモニウムヨーダ
イド等のような相間移動触媒を用い、ジクロルメ
タン、クロロホルム等のような水に不溶の溶媒と
水との二層系において本反応を行なう時には、カ
性ソーダ、カ性カリのような水酸化アルカリ金属
を使うこともできる。反応温度は通常0〜120℃
で行なわれ、反応時間は溶媒、塩基の種類等によ
つて異なるが、通常は1時間乃至3日間である。
反応終了後、本反応の目的化合物は常法に従つて
反応混合物より採取することができる。例えば反
応混合物に酢酸エチルのような有機溶媒を加え、
有機溶媒層を水で洗浄し、乾燥後、溶媒を留去す
ることにより得ることができ、必要ならば再結
晶、カラムクロマトグラフイー等で精製できる。
化合物〔〕と化合物〔〕との反応における
還元的条件としては、例えば、白金、パラジウ
ム、ラネーニツケル、ロジウム等の金属やそれら
と任意の担体との混合物を触媒する触媒還元、例
えば水素化リチウムアルミニウム、水素化硼素リ
チウム、水素化シアノ硼素ナトリウム、水素化硼
素ナトリウム、水素化硼素カリウム等の水素化金
属類による還元、金属ナトリウム、金属マグネシ
ウム等とメタノール、エタノール等のアルコール
類による還元、鉄、亜鉛等の金属の塩酸、酢酸等
の酸による還元等の反応条件をあげることができ
る。上記反応は通常水または有機溶媒(例えばメ
タノール、エタノール、テトラヒドロフラン、ジ
エチルエーテル、ジオキサン、ジクロルメタン、
クロロホルム、酢酸エチル、ベンゼン、トルエ
ン、ジメチルホルムアミド、ジメチルアセトアミ
ド、酢酸等)の存在下に行なわれ、反応温度は還
元手段により異なるが、一般には−20〜100℃程
度が好ましい。本反応は常圧で充分目的を達成で
きるが、場合によつては加圧あるいは減圧下に反
応を行なつてもよい。
このようにして製造される化合物〔〕の内、
R2がエステル残基、R4が水素原子または塩で示
されるモノエステルカルボン酸化合物およびR2、
R4が共に水素原子または塩であるジカルボン酸
は医療品上重要な化合物である。上記のモノエス
テルモノカルボン酸化合物はR2およびR4がとも
にエステル残基である一般式〔〕で示されるジ
エステル化合物の選択的なエステル残基R4の脱
保護により製造できるか、または一般式〔〕に
おいてR4が水素原子であるアミノ酸化合物とケ
トエステル〔〕(R2はエステル残基)との還元
的縮合反応により製造できる。
また、上記のR2およびR4が共に水素原子であ
るジカルボン酸化合物は、上記の反応によつて得
られるジエステル化合物またはモノエステル化合
物〔〕を常法に従つて、酸または塩基による加
水分解法またはエステル基の還元的除去法によつ
ても製造することができる。その反応条件は後述
する化合物〔〕におけるカルボン酸の保護基
R7の脱保護の場合と同様である。
一般式〔〕で表わされる原料化合物、すなわ
ち一般式
(式中、R3、R4およびAは前述したものと同意
義を有する。)で表わされる化合物は例えば次に
示す反応式により製造できる。
(式中、R3、R4、AおよびXは前述したものと
同意義を有し、R5、R6、R8およびR9は水素原子
またはアミノ基の保護基を示し、R7はカルボン
酸の保護基を示す。)
上記式中、R7で表わされるカルボン酸の保護
基は有機合成化学で一般によく知られているエス
テル残基のことであり、例えばメチル、アリル、
メトキシメチル、メチルチオメチル、メトキシエ
トキシメチル、ベンジルオキシメチル、フエナシ
ル、p−プロムフエナシル、N−フタルイミドメ
チル等のメチルおよび置換基を有するメチル、エ
チル、2,2,2−トリクロルエチル、2−ヨー
ドエチル、2−トリメチルシリルエチル、2−
(p−トルエンスルホニル)エチル、tert−ブチ
ル等の置換基を有してもよい低級アルキル基、ベ
ンジル、ジフエニルメチル、p−メトキシベンジ
ル、p−ニトロベンジル等の置換基を有してもよ
いベンジル基およびトリメチルシリル、tert−ブ
チルジメチルシリル等のシリル基などがあげられ
る。これらカルボン酸の保護基は、保護の目的を
達成する限り、何ら制限するものではない。
R5、R6、R8およびR9における、アミノ基の保
護基は、有機合成化学で一般によく知られている
保護基であり、例えば2,2,2−トリクロルエ
トキシカルボニル、2−ヨードエトキシカルボニ
ル、トリメチルシリルエトキシカルボニル、2−
(p−トルエンスルホニル)エトキシカルボニル、
tert−ブトキシカルボニル、アリルオキシカルボ
ニル、ベンジルオキシカルボニル、p−メトキシ
ベンジルオキシカルボニル、p−ニトロベンジル
オキシカルボニル等のようなアルコキシカルボニ
ル基、ホルミル、アセチル、ベンゾイル、クロル
アセチル、トリフルオロアセチル等のアシル等、
N−フタロイル、N−2,3−ジフエニルマレイ
ニル等の環式ジアシル基、メトキシメチル、ベン
ジルオキシメチル、ベンジル、3,4−ジメトキ
シベンジル、トリチル等の置換メチル基、イソプ
ロピリデン、ベンジリデン、サリチリデン等のア
ルキリデンまたはアラルキリデン基、1−メチル
−2−アセチルビニル、1−メチル−2−ベンゾ
イルビニル等のアシルビニル基およびトリメチル
シリル、tert−ブチルジメチルシリル等のシリル
基などがあげられるが、これらアミノ基の保護基
は、保護の目的を達する限り何ら制限するもので
はない。
システイン誘導体である化合物〔〕と化合物
〔〕の反応は、本反応を阻害しない適当な溶媒
中、塩基の存在下に行なわれる。使用される溶
媒、塩基の種類、反応温度、反応時間等の反応条
件および反応生成物〔〕の精製、分離等は、す
でに詳しく述べた化合物〔〕と化合物〔〕に
おける反応のものと同様である。
化合物〔〕におけるR7で表わされるカルボ
ン酸の保護基およびR8、R9で表わされるアミノ
基の保護基の脱保護は、有機合成化学でよく知ら
れている方法であるが、本反応の場合にはシステ
イン部分のアミノ基の保護基R5、R6に影響を及
ぼさない方法が必要である。そのような例とし
て、水酸化リチウム、カ性ソーダ、水酸化カリウ
ム等によるアルカリ加水分解による脱保護(例え
ばR7がメチル、エチル等)、塩酸、トリフルオロ
酢酸、塩化アルミニウム酸等、ルイス酸による脱
保護(例えばR7がメトキシメチル、メトキシエ
トキシメチル、tert−ブチル、ジフエニルメチ
ル、p−メトキシベンジル、トリメチルシリル、
tert−ブチルジメチルシリル等、R8がtert−ブト
キシカルボニル、p−メトキシベンジルオキシカ
ルボニル、トリチル、tert−ブチルヂメチルシリ
ル等)、接触還元による脱保護(例えばR7がベン
ジル、p−ニトロベンジル等、R8がベンジルオ
キシカルボニル、p−ニトロベンジルオキシカル
ボニル等)、亜鉛末−酸による還元による脱保護
(例えばR7が2,2,2−トリクロルエチル、2
−ヨードエチル、フエナシル、p−ブロムフエナ
シル等、R8が2,2,2−トリクロルエトキシ
カルボニル、2−ヨードエトキシカルボニル等)、
テトラキス(トリフエニルホスフイン)パラジウ
ム(O)を触媒とする脱保護(例えばR7がアリル等、
R8がアリルオキシカルボニル等)、ヒドラジン、
メチルヒドラジン等のヒドラジン類による脱保護
(例えばR8、R9がフタロイル等)などがあげられ
る。使用される溶媒は脱保護方法により異なる
が、水、酢酸、ギ酸の酸類、メタノール、エタノ
ール等のアルコール類、テトラヒドロフラン、ジ
オキサン、アニソール等のエーテル類、アセトン
等のケトン類、ジクロルメタン、クロロホルム等
のハロゲン化炭化水素類、ベンゼン、トルエン等
の炭化水素類等が用いられる。反応温度および反
応時間は脱保護方法により異なるが、一般に−10
℃乃至100℃、30分乃至一昼夜である。脱保護に
よるアミノ酸〔〕の製造は、二段階、即ち最初
にカルボン酸の保護基R7を脱保護し、次いてア
ミノ基の保護基R8、R9を脱保護するか、最初に
アミノ基の保護基R8、R9を脱保護し、続いてカ
ルボン酸の保護基R7を脱保護する方法があるが、
一挙に2つの保護基R7およびR8、R9を脱保護す
る方法もある。例えばR7がtert−ブチル、R8が
tert−ブトキシカルボニル、R9が水素原子の時は
酸による脱保護方法で化合物〔〕が得られる
し、R7が2,2,2−トリクロルエチル、R8が
2,2,2−トリクロルエトキシカルボニル、
R9が水素原子の時は亜鉛末−酸による還元方法
で化合物〔〕が得られる。化合物〔〕は等電
点沈澱法、再結晶、カラムクロマトグラフイー等
で精製もできるが、粗生成物のまま次の反応に用
いても差し支えない。
次に化合物〔〕を分子内縮合して4−アザ−
5−オキソシクロヘプタン環誘導体〔〕を製造
する方法は、ペプチドの化学で広く知られている
アミノ基とカルボキシル基のアミド結合への縮合
方法である。一般に本反応にN,N′−ジシクロ
ヘキシルカルボジイミド、カルボニルジイミダゾ
ール、ジフエニルホスホリルアジド、シアノリン
酸ジエチル、五塩化リン等の脱水剤の存在下に行
なわれる。カルボジイミド類の脱水剤を使用する
際には1−ヒドロキシベンゾトリアゾール、N−
ヒドロキシサクシイミド等を反応系中に加える反
応は促進させる。また例えばピリジン、ピコリ
ン、トリエチルアミン、N−メチルモルホリン、
炭酸ナトリウム、重層等のような塩基の存在下に
反応をさせることもできる。反応は一般に本反応
に阻害しない限りあらゆる溶媒を使用できる(例
えば、N,N−ジメチルホルムアミド、N,N−
ジメチルアセトアミド、ヘキサメチルホスホルア
ミド、テトラヒドロフラン、ジオキサン、メタノ
ール、エタノール、アセトン、ジクロルメタン、
クロロホルム、酢酸エチル、ベンゼン、トルエン
等)。生成物は反応系中から決小として単離され
ることもあるが、カラムクロマトグラフイー等で
精製して得ることもできる。
化合物〔〕に対する化合物〔〕によるN−
アルキル化による化合物〔XI〕の製造は、適当な
溶媒中、塩基存在下に行なわれる。溶媒として
は、ヘキサン、ベンゼンのような炭化水素類、ジ
クロルメタン、1,2−ジクロルエタンのような
ハロゲン化炭化水素類、テトラヒドロフラン、ジ
オキサンのようなエーテル類、酢酸エチルのよう
なエステル類、アセトンのようなケトン類、N,
N−ジメチルホルムアミド、N,N−ジメチルア
セトアミド、ヘキサメチルホスホルアミドのよう
なアミド類、ジメチルスルホキシド等があげられ
るが、本反応を阻害しない溶媒なら制限はない。
塩基としては、水素化ナトリウム、水素化リチウ
ム、水素化カリウム等の水素化アルカリ金属、n
−ブチルリチウム等のアルキルアルカリ金属、リ
チウムジイソプロピルアミド、リチウムジシクロ
ヘキシルアミド、リチウムビス(トリメチルシリ
ル)アミド等のアルカリ金属アミド類、炭酸ナト
リウム、炭酸カリウム等のアルカリ金属炭酸塩、
トリエチルアミン、トリエチレンジアミン、1,
5−ジアザビシクロ〔4.3.0〕−5−ノネン
(DBN)、1,8−ジアザビシクロ〔5.4.0〕−4−
ウンデセン(DBU)等のアミン類があげられる。
またテトラn−ブチルアンモニウムブロマイド、
ベンジルトリエチルアンモニウムヨーダイド等の
ような相間移動触媒を用い、ジクロルメタン、ク
ロロホルム等のような水に不溶の溶媒と水系の二
相系において本反応を行なう時には、カ性ソー
ダ、カ性カリのような水酸化アルカリ金属を使う
こともできる。反応温度および時間は、溶媒、塩
基の種類により異なるが、通常−2℃乃至100℃、
30分乃至一昼夜である。反応終了後、本反応の目
的化合物は常法に従つて反応混合物より採取でき
る。例えば反応混合物に酢酸エチルのような有機
溶媒を加え、有機溶媒層を水洗後、乾燥し、溶媒
を留去することにより得ることができ、必要なら
再結晶、カラムクロマトグラフイー等で精製でき
る。
化合物〔XI〕から化合物〔〕へのアミノ基の
脱保護の方法はすでに詳述した化合物〔〕から
化合物〔〕へのアミノ保護基の除去と同様の方
法である。反応生成物は例えば再結晶、カラムク
ロマトグラフイー等により精製することができ
る。
このようにして製造される一般式〔〕で表わ
される化合物は、分子内に不斉炭素原子を有する
ため、複数個の光学異性体が存在することをすで
に述べたが、所望によつてはこれらの異性体を別
個に製造することもできる。すなわち予め光学分
割された原料化合物のそれぞれ一方の光学異性体
を用いて上記の反応を行なうことにより反応する
化合物〔〕の光学異性体を得ることができる。
原料化合物の少くとも一方がラセミ体の場合に
は、化合物〔〕は通常異性体の混合物として得
られるが、この異性体混合物を所望により通常の
分離方法、例えば光学活性塩基(例えばシンコニ
ン、シンコニジン、キニーネ、キニジン等)、光
学活性有機酸(例えばl−カーンフアースルホン
酸、d−カンフアースルホン酸等)との塩を生成
させる方法や、各種のクロマトグラフイー、分別
再結晶等を用いて処理することによつてそれぞれ
の異性体を分離することもできる。
発明の効果
本発明の化合物〔〕は、アンジオテンシン
をアンジオテンシンへ変換する酵素(以下、
ACEと略す)の活性が阻害する用を有する。ア
ンジオテンシンな血圧上昇活性物質であり、人
を含む哺乳動物の高血圧の原因になる物質として
関連がある。ACEはこのアンジオテンシンの
産生に関与する他に、血管拡張因子物質ブラジキ
ニンの代謝にも関与しており、ブランジキニンを
不活性物質に変換させる作用を表わす。
本発明の化合物〔〕の生理活性の評価は、生
体外(in、vitro)において、ACE活性を50%抑
制するに必要な化合物〔〕の濃度(IC50)を例
えばD.W.Cushman等〔Biochemical
Pharmacology、20巻、1637頁(1971年)〕の方
法により測定することにより行なわれる。すなわ
ち化合物の種々の濃度の溶液の家兎肺より抽出し
たACEおよび基質としてヒプリルヒスチジルロ
イシンを、食塩を含むPH8.3の硼酸緩衝液とし、
37℃、30分間酵素反応させた後、1N塩酸で反応
を停止させ、生成する馬尿酸(ヒプリツクアシ
ド)を酢酸エチルで抽出し、ついで酢酸エチルを
留去し、残留の馬尿酸を水に溶かし、228mμに
おけるUV吸収率から馬尿酸の量を測定する。こ
の値を化合物〔〕の濃度に対する曲線としてグ
ラフ表示し、化合物〔〕を含まない時に生成す
る馬尿酸の半量を生成させる時の化合物の〔〕
の濃度をグラフから読むことによりIC50が求めら
れた、このようにして求められたIC50を第1表に
示す。[Table] The compound of the present invention [] has the general formula (In the formula, R 3 , R 4 and A have the same meanings as described above.) and a compound having the general formula (In the formula, R 1 and R 2 have the same meanings as described above, and X represents a halogen atom or a sulfonyloxy group.)
or the above compound [] and the general formula (In the formula, R 1 and R 2 have the same meanings as those described above.) Examples of the halogen atom of and substituted or unsubstituted aromatic sulfonyloxy groups such as benzenesulfonyloxy and p-toluenesulfonyloxy. The condensation reaction between compound [] and compound [] is
This reaction is carried out in the presence of a base in an appropriate solvent that does not inhibit the reaction. As a solvent, hydrocarbons such as hexane, benzene, dichloromethane, 1,2
-Halogenated hydrocarbons such as cycloethane, ethers such as tetrahydrofuran and dioxane, esters such as ethyl acetate, ketones such as acetone, N,N-dimethylformamide, N,N-dimethylacetamide, hexa Examples include amides such as methylphosphoramide, dimethyl sulfoxide, and the like. The base used is not particularly limited, but includes alkali or alkaline earth metal carbonates such as sodium carbonate, potassium carbonate, and calcium carbonate, alkali metal bicarbonates such as bicarbonate, sodium hydride, and lithium hydrogen carbonate. and organic bases such as triethylamine, pyridine, picoline, and tetraethylammonium hydroxide. Furthermore, when carrying out this reaction in a two-layer system of water and a water-insoluble solvent such as dichloromethane or chloroform using a phase transfer catalyst such as tetra-n-butylammonium bromide or benzyltriethylammonium iodide, Alkali metal hydroxides such as sodium hydroxide and potassium hydroxide can also be used. Reaction temperature is usually 0-120℃
The reaction time varies depending on the solvent, type of base, etc., but is usually 1 hour to 3 days.
After completion of the reaction, the target compound of this reaction can be collected from the reaction mixture according to a conventional method. For example, adding an organic solvent such as ethyl acetate to the reaction mixture;
It can be obtained by washing the organic solvent layer with water, drying, and then distilling off the solvent, and if necessary, it can be purified by recrystallization, column chromatography, etc. Reductive conditions for the reaction between compound [] and compound [] include, for example, catalytic reduction using a metal such as platinum, palladium, Raney nickel, or rhodium, or a mixture of these and an arbitrary carrier, such as lithium aluminum hydride, Reduction with metal hydrides such as lithium borohydride, sodium cyanoborohydride, sodium borohydride, potassium borohydride, reduction with metallic sodium, metallic magnesium, etc. and alcohols such as methanol and ethanol, iron, zinc, etc. Examples of reaction conditions include reduction of the metal with an acid such as hydrochloric acid or acetic acid. The above reaction is usually carried out in water or in an organic solvent (e.g. methanol, ethanol, tetrahydrofuran, diethyl ether, dioxane, dichloromethane,
(chloroform, ethyl acetate, benzene, toluene, dimethylformamide, dimethylacetamide, acetic acid, etc.), and the reaction temperature varies depending on the reduction method, but is generally preferably about -20 to 100°C. Although the purpose of this reaction can be sufficiently achieved at normal pressure, the reaction may be carried out under increased pressure or reduced pressure depending on the case. Among the compounds [] produced in this way,
A monoester carboxylic acid compound in which R 2 is an ester residue and R 4 is a hydrogen atom or a salt, and R 2 ,
Dicarboxylic acids in which R 4 are both hydrogen atoms or salts are important compounds in medical products. The above monoester monocarboxylic acid compound can be produced by selective deprotection of the ester residue R 4 of a diester compound represented by the general formula [ ] in which R 2 and R 4 are both ester residues, or by selective deprotection of the ester residue R 4 of the diester compound represented by the general formula It can be produced by a reductive condensation reaction between an amino acid compound in which R 4 is a hydrogen atom and a ketoester [ ] (R 2 is an ester residue). In addition, the dicarboxylic acid compound in which R 2 and R 4 are both hydrogen atoms can be obtained by hydrolyzing the diester compound or monoester compound obtained by the above reaction [ ] with an acid or base according to a conventional method. Alternatively, it can also be produced by a reductive removal method of ester groups. The reaction conditions are as follows:
The same is true for the deprotection of R7 . Raw material compound represented by general formula [], i.e. general formula The compound represented by (wherein R 3 , R 4 and A have the same meanings as defined above) can be produced, for example, according to the reaction formula shown below. ( In the formula, R 3 , R 4 , A and In the above formula, the carboxylic acid protecting group represented by R 7 is an ester residue that is generally well known in organic synthetic chemistry, such as methyl, allyl,
Methyl and substituent methyl such as methoxymethyl, methylthiomethyl, methoxyethoxymethyl, benzyloxymethyl, phenacyl, p-promphenacil, N-phthalimidomethyl, ethyl, 2,2,2-trichloroethyl, 2-iodoethyl, 2 -trimethylsilylethyl, 2-
Lower alkyl group which may have a substituent such as (p-toluenesulfonyl)ethyl or tert-butyl; benzyl group which may have a substituent such as benzyl, diphenylmethyl, p-methoxybenzyl, p-nitrobenzyl, etc. and silyl groups such as trimethylsilyl and tert-butyldimethylsilyl. These carboxylic acid protecting groups are not limited in any way as long as the purpose of protection is achieved. The protecting groups for the amino group in R 5 , R 6 , R 8 and R 9 are protecting groups generally well known in organic synthetic chemistry, such as 2,2,2-trichloroethoxycarbonyl, 2-iodoethoxy carbonyl, trimethylsilylethoxycarbonyl, 2-
(p-toluenesulfonyl)ethoxycarbonyl,
Alkoxycarbonyl groups such as tert-butoxycarbonyl, allyloxycarbonyl, benzyloxycarbonyl, p-methoxybenzyloxycarbonyl, p-nitrobenzyloxycarbonyl, acyl such as formyl, acetyl, benzoyl, chloroacetyl, trifluoroacetyl, etc. ,
Cyclic diacyl groups such as N-phthaloyl and N-2,3-diphenylmaleinyl, substituted methyl groups such as methoxymethyl, benzyloxymethyl, benzyl, 3,4-dimethoxybenzyl, and trityl, isopropylidene, benzylidene, and salicylidene Examples include alkylidene or aralkylidene groups such as, acylvinyl groups such as 1-methyl-2-acetylvinyl and 1-methyl-2-benzoylvinyl, and silyl groups such as trimethylsilyl and tert-butyldimethylsilyl. There are no restrictions on the protecting group as long as it achieves the purpose of protection. The reaction between compound [] which is a cysteine derivative and compound [] is carried out in the presence of a base in a suitable solvent that does not inhibit the reaction. The reaction conditions such as the solvent used, the type of base, the reaction temperature, and the reaction time, as well as the purification and separation of the reaction product [], are the same as those for the reaction between compound [] and compound [], which have already been described in detail. . Deprotection of the carboxylic acid protecting group represented by R 7 and the amino group protecting group represented by R 8 and R 9 in compound [] is a well-known method in organic synthetic chemistry, but this reaction In some cases, a method is required that does not affect the protecting groups R 5 and R 6 of the amino group of the cysteine moiety. Examples include deprotection by alkaline hydrolysis with lithium hydroxide, caustic soda, potassium hydroxide, etc. (for example, R 7 is methyl, ethyl, etc.), deprotection with Lewis acids such as hydrochloric acid, trifluoroacetic acid, aluminum chloride, etc. Deprotection (e.g. R 7 is methoxymethyl, methoxyethoxymethyl, tert-butyl, diphenylmethyl, p-methoxybenzyl, trimethylsilyl,
tert-butyldimethylsilyl, etc., R 8 is tert-butoxycarbonyl, p-methoxybenzyloxycarbonyl, trityl, tert-butyldimethylsilyl, etc.), deprotection by catalytic reduction (e.g. R 7 is benzyl, p-nitrobenzyl, etc.) , R 8 is benzyloxycarbonyl, p-nitrobenzyloxycarbonyl, etc.), deprotection by reduction with zinc dust-acid (for example, R 7 is 2,2,2-trichloroethyl, 2
-iodoethyl, phenacyl, p-bromphenacyl, etc., R 8 is 2,2,2-trichloroethoxycarbonyl, 2-iodoethoxycarbonyl, etc.),
Deprotection catalyzed by tetrakis(triphenylphosphine)palladium(O) (for example, R 7 is allyl, etc.)
R 8 is allyloxycarbonyl, etc.), hydrazine,
Examples include deprotection using hydrazines such as methylhydrazine (for example, R 8 and R 9 are phthaloyl, etc.). The solvents used vary depending on the deprotection method, but include water, acids such as acetic acid and formic acid, alcohols such as methanol and ethanol, ethers such as tetrahydrofuran, dioxane and anisole, ketones such as acetone, and halogens such as dichloromethane and chloroform. Hydrocarbons such as carbonized hydrocarbons, benzene, and toluene are used. The reaction temperature and reaction time vary depending on the deprotection method, but generally -10
℃ to 100℃ for 30 minutes to one day and night. The production of amino acids [ ] by deprotection involves two steps: first, the carboxylic acid protecting group R 7 is deprotected, and then the amino group protecting groups R 8 and R 9 are deprotected, or the amino group is first deprotected. There is a method of deprotecting the protecting groups R 8 and R 9 and then deprotecting the carboxylic acid protecting group R 7 .
There is also a method of deprotecting two protecting groups R 7 and R 8 and R 9 at once. For example, R 7 is tert-butyl, R 8 is
When R 9 is a hydrogen atom in tert-butoxycarbonyl, the compound [] can be obtained by deprotection with an acid, and when R 7 is 2,2,2-trichloroethyl and R 8 is 2,2,2-trichloroethoxy carbonyl,
When R 9 is a hydrogen atom, the compound [ ] can be obtained by the zinc dust-acid reduction method. Compound [] can be purified by isoelectric precipitation, recrystallization, column chromatography, etc., but it can also be used as a crude product in the next reaction. Next, compound [] is intramolecularly condensed to form 4-aza-
The method for producing the 5-oxocycloheptane ring derivative [] is a method of condensing an amino group and a carboxyl group into an amide bond, which is widely known in peptide chemistry. This reaction is generally carried out in the presence of a dehydrating agent such as N,N'-dicyclohexylcarbodiimide, carbonyldiimidazole, diphenylphosphoryl azide, diethyl cyanophosphate, or phosphorus pentachloride. When using carbodiimide dehydrating agents, 1-hydroxybenzotriazole, N-
The reaction is accelerated by adding hydroxysuccinimide or the like to the reaction system. Also, for example, pyridine, picoline, triethylamine, N-methylmorpholine,
The reaction can also be carried out in the presence of a base such as sodium carbonate, overlay, etc. In general, any solvent can be used in the reaction as long as it does not interfere with the reaction (e.g., N,N-dimethylformamide, N,N-
Dimethylacetamide, hexamethylphosphoramide, tetrahydrofuran, dioxane, methanol, ethanol, acetone, dichloromethane,
chloroform, ethyl acetate, benzene, toluene, etc.). The product may be isolated as a small sample from the reaction system, but it can also be purified by column chromatography or the like. N- by compound [] for compound []
The production of compound [XI] by alkylation is carried out in a suitable solvent in the presence of a base. Examples of solvents include hydrocarbons such as hexane and benzene, halogenated hydrocarbons such as dichloromethane and 1,2-dichloroethane, ethers such as tetrahydrofuran and dioxane, esters such as ethyl acetate, and acetone. Ketones, N,
Examples include amides such as N-dimethylformamide, N,N-dimethylacetamide, hexamethylphosphoramide, dimethyl sulfoxide, etc., but there are no limitations as long as the solvent does not inhibit this reaction.
As the base, alkali metal hydride such as sodium hydride, lithium hydride, potassium hydride, n
- Alkyl alkali metals such as butyl lithium, alkali metal amides such as lithium diisopropylamide, lithium dicyclohexylamide, lithium bis(trimethylsilyl)amide, alkali metal carbonates such as sodium carbonate and potassium carbonate,
Triethylamine, triethylenediamine, 1,
5-Diazabicyclo[4.3.0]-5-nonene (DBN), 1,8-diazabicyclo[5.4.0]-4-
Examples include amines such as undecene (DBU).
Also, tetra n-butylammonium bromide,
When carrying out this reaction in a two-phase system consisting of a water-insoluble solvent such as dichloromethane, chloroform, etc. and an aqueous phase transfer catalyst such as benzyltriethylammonium iodide, a phase transfer catalyst such as caustic soda or caustic potash is used. Alkali metal hydroxides can also be used. The reaction temperature and time vary depending on the type of solvent and base, but are usually -2°C to 100°C,
It lasts from 30 minutes to a day and night. After completion of the reaction, the target compound of this reaction can be collected from the reaction mixture according to a conventional method. For example, it can be obtained by adding an organic solvent such as ethyl acetate to the reaction mixture, washing the organic solvent layer with water, drying, and distilling off the solvent. If necessary, it can be purified by recrystallization, column chromatography, etc. The method for deprotecting the amino group from compound [XI] to compound [] is the same as the method for removing the amino protecting group from compound [] to compound [], which has already been described in detail. The reaction product can be purified, for example, by recrystallization, column chromatography, etc. As mentioned above, the compound represented by the general formula [] produced in this way has multiple optical isomers because it has an asymmetric carbon atom in the molecule. The isomers of can also be prepared separately. That is, by carrying out the above reaction using each optical isomer of the raw material compound that has been optically resolved in advance, the optical isomer of the reacting compound [ ] can be obtained.
When at least one of the starting compounds is a racemate, the compound [ ] is usually obtained as a mixture of isomers, but this isomer mixture can be separated, if desired, by a conventional separation method, such as an optically active base (such as cinchonine, cinchonidine, etc.). quinine, quinidine, etc.), methods to generate salts with optically active organic acids (e.g. l-carnpharusulfonic acid, d-camphorsulfonic acid, etc.), various chromatography methods, fractional recrystallization, etc. It is also possible to separate each isomer by doing this. Effects of the Invention The compound [] of the present invention is an enzyme that converts angiotensin to angiotensin (hereinafter referred to as
It has the function of inhibiting the activity of ACE (abbreviated as ACE). Angiotensin is an active substance that increases blood pressure and is associated with a substance that causes hypertension in mammals including humans. In addition to being involved in the production of angiotensin, ACE is also involved in the metabolism of bradykinin, a vasodilator, and has the effect of converting bradykinin into an inactive substance. To evaluate the physiological activity of the compound [ ] of the present invention, the concentration (IC 50 ) of the compound [ ] required to inhibit ACE activity by 50% in vitro was determined, for example, by DWCushman et al.
Pharmacology, Vol. 20 , p. 1637 (1971)]. That is, ACE extracted from rabbit lung in various concentrations of the compound and hipryl histidyl leucine as a substrate were used as a borate buffer of PH 8.3 containing salt,
After enzymatic reaction at 37°C for 30 minutes, the reaction was stopped with 1N hydrochloric acid, the generated hippuric acid was extracted with ethyl acetate, the ethyl acetate was distilled off, and the remaining hippuric acid was dissolved in water. The amount of hippuric acid is measured from the UV absorption rate at 228 mμ. This value is graphically displayed as a curve against the concentration of compound [], and the concentration of compound [] when half the amount of hippuric acid produced without compound [] is produced.
The IC 50 was determined by reading the concentration from the graph. The IC 50 thus determined is shown in Table 1.
【表】
従つてACE活性を阻害する本発明化合物〔〕
およびその薬理学的に許容される塩類は、高血圧
症の診断、予防または治療剤として有用である。
化合物〔〕およびその薬理学的に許容される塩
類を上記の医薬として用いる場合、それ自体ある
いは適宜の薬理学的に許容される担体、賦形剤、
希釈剤等と混合し、散剤、顆粒剤、錠剤、カプセ
ル剤、注射剤等の医薬組成物として経口的または
非経口的に投与することができる。投与量は対象
疾患の状態、投与方法により異なるが、例えば高
血圧症の治療の目的で成人患者に投与する場合、
経口投与では通常1回量0.5〜1000mg、とりわけ
約5〜100mg程度が、静脈内投与では1回量約0.5
〜100mg、とりわけ約0.5〜10mg程度が好ましく、
これらの薬用量を症状に応じて1日1回乃至3回
投与するのが望ましい。
以下に実施例を示して本発明をさらに詳細に説
明するが、本発明の範囲はこれらに限定されるも
のではない。
実施例 1
4−アザ−4−tert−ブトキシカルボニルメチ
ル−6−(1−エトキシカルボニル−3−フエ
ニルプロピル)アミノ−5−オキソ−2−(1
−ナフチル)−1−チアシクロヘプタン
工程A
2−tert−ブトキシカルボニルアミノ−1−
(1−ナフチル)エタノール
1−ナフトアルデヒドシアンヒドリン44gを水
素化リチウムアルミニウムで還元して得られる粗
2−アミノ−1−(1−ナフチル)エタノールを、
メタノール200ml中、トリエチルアミン12.8gと
ジ−tert−ブチルジカーボネート20gと室温で1
時間撹拌する。反応液を濃縮し、残留物を酢酸エ
チルと水に溶かし、酢酸エチル層を水洗し、無水
硫酸マグネシウムで乾燥後、溶媒を留去した。結
晶性残留物をジイソプロピルエーテルを用いて
取した。収量14.2g。融点109−110℃。
NMR(CDCl3)δ(ppm):
1.44(9H、s、tert−Bu)、
3.05−3.9(3H、m、−CH2−、OH)、
5.60(1H、d、t、J=4、8Hz、
[Table] Compounds of the present invention that inhibit ACE activity []
and its pharmacologically acceptable salts are useful as diagnostic, preventive or therapeutic agents for hypertension.
When the compound [] and its pharmacologically acceptable salts are used as the above-mentioned medicine, the compound itself or an appropriate pharmacologically acceptable carrier, excipient,
It can be mixed with a diluent and administered orally or parenterally as a pharmaceutical composition such as a powder, granule, tablet, capsule, or injection. The dosage varies depending on the condition of the target disease and the administration method, but for example, when administering to adult patients for the purpose of treating hypertension,
For oral administration, a single dose is usually 0.5 to 1000 mg, especially about 5 to 100 mg, and for intravenous administration, a single dose is about 0.5 mg.
~100mg, especially about 0.5~10mg is preferable,
It is desirable to administer these doses once to three times a day depending on the symptoms. EXAMPLES The present invention will be explained in more detail with reference to Examples below, but the scope of the present invention is not limited thereto. Example 1 4-aza-4-tert-butoxycarbonylmethyl-6-(1-ethoxycarbonyl-3-phenylpropyl)amino-5-oxo-2-(1
-naphthyl)-1-thiacycloheptane Step A 2-tert-butoxycarbonylamino-1-
(1-naphthyl)ethanol Crude 2-amino-1-(1-naphthyl)ethanol obtained by reducing 44 g of 1-naphthaldehyde cyanohydrin with lithium aluminum hydride,
12.8 g of triethylamine and 20 g of di-tert-butyl dicarbonate in 200 ml of methanol at room temperature.
Stir for an hour. The reaction solution was concentrated, the residue was dissolved in ethyl acetate and water, the ethyl acetate layer was washed with water, dried over anhydrous magnesium sulfate, and then the solvent was distilled off. The crystalline residue was taken up with diisopropyl ether. Yield: 14.2g. Melting point 109-110℃. NMR ( CDCl3 ) δ (ppm): 1.44 (9H, s, tert-Bu), 3.05-3.9 (3H, m, -CH2- , OH), 5.60 (1H, d, t, J = 4, 8Hz ,
【式】、
7.25−8.25(7H、m、ナフチルプロトン)。
工程B
2−tert−ブトキシカボニルアミノ−1−クロ
ル−1−(1−ナフチル)エタン
2−tert−ブトキシカルボニルアミノ−1−
(1−ナフチル)エタノール13gの無水ジクロル
メタン200ml溶液に、五塩化リン9.4gの無水ジク
ロルメタン190ml溶液を0〜−5℃滴加した。滴
加後、さらに5分間撹拌し、4Nカ性ソーダ195ml
を一時に加え、氷冷下30分間撹拌した。ジクロル
メタン層を多量の水で洗浄後、無水硫酸マグネシ
ウムで乾燥し、溶媒を留去した。残留物を酢酸エ
チル−シクロヘキサン1:7を溶媒系とするシリ
カゲル・カラムクロマトに付してシロツプ状の目
的化合物9.0gを得た。
NMR(CDCl3)δ(ppm):
1.43(9H、s、tert−Bu)、
3.3−4.2(2H、m、−CH2−)、
5.00(1H、brt、NH)、
5.83(1H、d、d、J=5.5、8Hz、
[Formula], 7.25−8.25 (7H, m, naphthyl proton). Step B 2-tert-butoxycarbonylamino-1-chloro-1-(1-naphthyl)ethane 2-tert-butoxycarbonylamino-1-
A solution of 9.4 g of phosphorus pentachloride in 190 ml of anhydrous dichloromethane was added dropwise to a solution of 13 g of (1-naphthyl)ethanol in 200 ml of anhydrous dichloromethane at 0 to -5°C. After the dropwise addition, stir for another 5 minutes and add 195ml of 4N caustic soda.
was added at once and stirred for 30 minutes under ice cooling. The dichloromethane layer was washed with a large amount of water, dried over anhydrous magnesium sulfate, and the solvent was distilled off. The residue was subjected to silica gel column chromatography using ethyl acetate-cyclohexane 1:7 as a solvent system to obtain 9.0 g of the target compound in the form of syrup. NMR ( CDCl3 ) δ (ppm): 1.43 (9H, s, tert-Bu), 3.3-4.2 (2H, m, -CH2- ), 5.00 (1H, brt, NH), 5.83 (1H, d, d, J=5.5, 8Hz,
【式】)、
7.2−8.3(7H、m、ナフチルプロトン)。
工程C
S−〔2−tert−ブトキシカボニルアミノ−1
−(1−ナフチル)エチル〕−N−フタリルシス
テインジフエニルメチルエステル
L−システインp−トルエンスルホン酸塩10g
とN−カルボエトキシフタルイミド7.5gのジメ
チルホルムアミド68ml溶液に窒素ガス下、重曹
6.2gを加え、90−100℃で3.5時間撹拌した。反
応液を冷却後、酢酸エチルと重硫酸カリウム水溶
液に溶かし、水層を酸性にして酢酸エチル層を分
離した。食塩水で洗浄し、無水硫酸マグネシウム
で乾燥後、ジフエニルジアゾメタン7.4gを加え、
窒素気流中、1時間撹拌した。溶媒を留去後、ジ
メチルホルムアミド60mlに溶かし、これに2−
tert−ブトキシカルボニルアミノ−1−クロル−
1−(1−ナフチル)エタン9.6gを加え、窒素気
流中、70℃で16時間撹拌した。反応液を酢酸エチ
ルと水に溶かし、酢酸エチル層を分離し、食塩水
で洗浄後、無水硫酸マグネシウムで乾燥した。溶
媒を留去し、残留物を酢酸エチル−シクロヘキサ
ン1:4を溶媒系とするシリカゲル・カラムクロ
マトに付して、無定形固形物として目的化合物を
得た。
収量10.4g
NMR(CDCl3)δ(ppm):
1.35(9H、s、tert−Bu)、
3.15−3.8(4H、m、CH2S、C−CH2−N)、
4.5−5.1(3H、m、NH、[Formula]), 7.2−8.3 (7H, m, naphthyl proton). Step C S-[2-tert-butoxycarbonylamino-1
-(1-naphthyl)ethyl]-N-phthalylcysteine diphenyl methyl ester L-cysteine p-toluenesulfonate 10g
Add baking soda to a solution of 7.5 g of N-carboethoxyphthalimide in 68 ml of dimethylformamide under nitrogen gas.
6.2g was added and stirred at 90-100°C for 3.5 hours. After cooling the reaction solution, it was dissolved in ethyl acetate and an aqueous potassium bisulfate solution, the aqueous layer was made acidic, and the ethyl acetate layer was separated. After washing with saline and drying with anhydrous magnesium sulfate, 7.4 g of diphenyldiazomethane was added.
The mixture was stirred for 1 hour in a nitrogen stream. After distilling off the solvent, dissolve in 60 ml of dimethylformamide and add 2-
tert-butoxycarbonylamino-1-chloro-
9.6 g of 1-(1-naphthyl)ethane was added, and the mixture was stirred at 70°C for 16 hours in a nitrogen stream. The reaction solution was dissolved in ethyl acetate and water, and the ethyl acetate layer was separated, washed with brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off, and the residue was subjected to silica gel column chromatography using ethyl acetate-cyclohexane 1:4 as a solvent system to obtain the target compound as an amorphous solid. Yield 10.4g NMR ( CDCl3 ) δ (ppm): 1.35 (9H, s, tert-Bu), 3.15-3.8 (4H, m, CH2S , C- CH2- N), 4.5-5.1 (3H, m, NH,
【式】【formula】
【式】
6.6と6.70(合せて1H、s、CH〜ph2)、
6.75−8.3(21H、m、CH(C6H〜5)2、ナフチルプ
ロトン、フタリルプロトン)。
工程D
S−〔2−アミノ−1−(1−ナフチル)エチ
ル〕−N−フタリルシステイン
S−〔2−tert−ブトキシカルボニルアミノ−
1−(1−ナフチル)エチル〕−N−フタリリシス
テインジフエニルメチルエステル10.4gのアニソ
ール40ml溶液にトリフルオロ酢酸50mlを加え、室
温で2時間撹拌した。反応液を濃縮後、酢酸エチ
ル40ml、水30mlを加え、さらに重曹2.0gを加え
よく撹拌後、3N塩酸でPH5.8に調整した。氷冷
下、撹拌後、析出している目的化合物を取し、
アセトン−ジエチルエーテル1:1で洗浄した。
収量5.6g。融点195−199℃。
工程E
4−アザ−5−オキソ−2−(1−ナフチル)−
6−フタルイミド−1−チアシクロヘプタン
S−〔2−アミノ−1−(1−ナフチル)エチ
ル〕−N−フタリルシステイン5.5gのジメチルホ
ルムアミド110ml溶液に、ジフエニルホスホリル
アジド5.1g、N−メチルモリホリン2.6mlを加
え、室温で15時間撹拌した。反応液に水約200ml
と酢酸エチル約500mlを加え撹拌し、析出してい
る目的化合物を取し、水、酢酸エチルで洗浄し
た。収量3.5g。融点300℃以上。
NMR(DMSO−d6)δ(ppm):
2.7−4.6(4H、m、CH〜−S、N−CH〜−C)、
4.94(1H、brd、J=8Hz、
[Formula] 6.6 and 6.70 (combined 1H, s, CH~ ph2 ), 6.75-8.3 (21H, m, CH( C6H ~ 5 ) 2 , naphthyl proton, phthalyl proton). Step D S-[2-amino-1-(1-naphthyl)ethyl]-N-phthalylcysteine S-[2-tert-butoxycarbonylamino-
50 ml of trifluoroacetic acid was added to a solution of 10.4 g of 1-(1-naphthyl)ethyl]-N-phthalylcysteine diphenylmethyl ester in 40 ml of anisole, and the mixture was stirred at room temperature for 2 hours. After concentrating the reaction solution, 40 ml of ethyl acetate and 30 ml of water were added, followed by 2.0 g of sodium bicarbonate, and after stirring well, the pH was adjusted to 5.8 with 3N hydrochloric acid. After stirring under ice cooling, remove the precipitated target compound,
Washed with acetone-diethyl ether 1:1.
Yield: 5.6g. Melting point 195-199℃. Step E 4-aza-5-oxo-2-(1-naphthyl)-
6-phthalimido-1-thiacycloheptane To a solution of 5.5 g of S-[2-amino-1-(1-naphthyl)ethyl]-N-phthalylcysteine in 110 ml of dimethylformamide were added 5.1 g of diphenylphosphoryl azide and 2.6 ml of N-methylmorpholine, and the mixture was heated at room temperature. Stirred for 15 hours. Approximately 200ml of water to the reaction solution
About 500 ml of ethyl acetate was added and stirred, and the precipitated target compound was collected and washed with water and ethyl acetate. Yield 3.5g. Melting point over 300℃. NMR (DMSO- d6 ) δ (ppm): 2.7-4.6 (4H, m, CH~-S, N-CH~-C), 4.94 (1H, brd, J=8Hz,
【式】
5.47(1H、d、d、J=3、8Hz、
[Formula] 5.47 (1H, d, d, J = 3, 8Hz,
【式】)、
7.4−8.5(11H、ナフチルプロトン、フタリルプ
ロトン)。
工程F
4−アザ−4−tert−ブトキシカルボニルメチ
ル−5−オキソ−2−(1−ナフチル)−6−フ
タルイミド−1−チアシクロヘプタン
4−アザ−5−オキソ−2−(1−ナフチル)−
6−フタルイミド−1−チアシクロヘプタン3.4
gのジメチルホルムアミド34mlとヘキサメチルホ
スホルアミド10mlけん濁液に窒素気流中、内温0
〜5℃でブロム酢酸tert−ブチルィ2.25ml、つい
で55%油性水素化ナトリウム609mgを少しずつ加
えた。添加後、室温で16時間撹拌した。反応溶液
に酢酸エチルと水を加え、酢酸エチル層を分離
し、水洗後、無水硫酸マグネシウムで乾燥し、溶
媒を留去した。残留物をシクロヘキサン−酢酸エ
チル2:1溶媒系とするシリカゲル・カラムに付
し、結晶性の目的化合物2.6gを得た。融点211−
213℃。
NMR(CDCl3)δ(ppm):
1.47(9H、s、tert−Bu)、
3.0−4.9(6H、m、−CH〜2−S、N−CH2〜−
CH〜2−N)、
5.30(1H、d、J=9Hz、[Formula]), 7.4−8.5 (11H, naphthyl proton, phthalyl proton). Step F 4-aza-4-tert-butoxycarbonylmethyl-5-oxo-2-(1-naphthyl)-6-phthalimido-1-thiacycloheptane 4-Aza-5-oxo-2-(1-naphthyl)-
6-phthalimido-1-thiacycloheptane 3.4
34 ml of dimethylformamide and 10 ml of hexamethylphosphoramide were suspended in a nitrogen stream, and the internal temperature was 0.
At ~5°C, 2.25 ml of tert-butyl bromoacetate was added in portions, followed by 609 mg of 55% oily sodium hydride. After addition, it was stirred at room temperature for 16 hours. Ethyl acetate and water were added to the reaction solution, and the ethyl acetate layer was separated, washed with water, dried over anhydrous magnesium sulfate, and the solvent was distilled off. The residue was applied to a silica gel column using a cyclohexane-ethyl acetate 2:1 solvent system to obtain 2.6 g of the crystalline target compound. Melting point 211−
213℃. NMR ( CDCl3 ) δ (ppm): 1.47 (9H, s, tert-Bu), 3.0-4.9 (6H, m, -CH~ 2- S, N- CH2 ~-
CH~ 2 -N), 5.30 (1H, d, J=9Hz,
【式】)、
5.78(1H、brd、J=10Hz、
[Formula]), 5.78 (1H, brd, J=10Hz,
【式】)、
7.3−8.35(11H、ナフチルプロトン、フタリル
プロトン)。
工程G
6−アミノ−4−アザ−4−tert−ブトキシカ
ルボニルメチル−5−オキソ−2−(1−ナフ
チル)−1−チアシクロヘプタン
4−アザ−4−tert−ブトキシカルボニルメチ
ル−5−オキソ−2−(1−ナフチル)−6−フタ
ルイミド−1−チアシクロヘプタン2.5gをジク
ロルメタン20mlとメタノール2mlに溶かし、メチ
ルヒドラジン0.77mlを加え、室温で2日間放置し
た。反応液を濃縮し、残留物にジクロメタン15ml
を加え、よく撹拌後、沈澱物を去した。液を
濃縮し、残留物をメタノール−酢酸エチル1:20
のシリカゲル・カラムクロマトに付して無定形固
形物として目的化合物1.92gを得た。
NMR(CDCl3)δ(ppm):
1.47(9H、s、tert−Bu)、
2.11(2H、brs、NH2)、
2.45−4.8(7H、m、N−CH〜2−CO、
[Formula]), 7.3−8.35 (11H, naphthyl proton, phthalyl proton). Step G 6-amino-4-aza-4-tert-butoxycarbonylmethyl-5-oxo-2-(1-naphthyl)-1-thiacycloheptane Dissolve 2.5 g of 4-aza-4-tert-butoxycarbonylmethyl-5-oxo-2-(1-naphthyl)-6-phthalimido-1-thiacycloheptane in 20 ml of dichloromethane and 2 ml of methanol, and add 0.77 ml of methylhydrazine. , and left at room temperature for 2 days. Concentrate the reaction solution and add 15 ml of dichloromethane to the residue.
was added, and after thorough stirring, the precipitate was removed. Concentrate the liquid and mix the residue with methanol-ethyl acetate 1:20.
The resulting product was subjected to silica gel column chromatography to obtain 1.92 g of the target compound as an amorphous solid. NMR ( CDCl3 ) δ (ppm): 1.47 (9H, s, tert-Bu), 2.11 (2H, brs, NH2 ), 2.45-4.8 (7H, m, N-CH~ 2 -CO,
【式】、N−CH〜2−C)、
5.15(1H、d、J=9.5Hz、
[Formula], N-CH~ 2 -C), 5.15 (1H, d, J=9.5Hz,
【式】)、
7.2−8.3(7H、m、ナフチルプロトン)。
工程H
4−アザ−4−tert王−ブトキシカルボニルメ
チル−6−(1−エトキシカルボニル−3−フ
エニルプロピル)アミノ−5−オキソ−2−
(1−ナフチル)−1−チアシクロヘプタン
6−アミノ−4−アザ−tert−ブトキシカルボ
ニルメチル−5−オキソ−2−(1−ナフチル)−
1−チアシクロヘプタン803mgと2−ブロム−4
−フエニル絡酸エチル1.13gのジメチルホルムア
ミド10ml溶液に炭酸ソーダ0.66gを加え、80℃で
15時間撹拌した。反応液を酢酸エチルと食塩水に
溶かし、酢酸エチル層を分離し、水洗後、無水硫
酸マグネシウムで乾燥した。溶媒を留去し、残留
物を酢酸エチル−ジクロルメタン1:30.のシリ
カゲル・カラムクロマトに付して、フエネチル基
の結合する炭素の不斉性に由来する2種類の異性
体AとBに分離した。最初に溶離する異性体A:
油状物0.49g。
NMR(CDCl3)δ(ppm):
1.24(3H、t、J=7.5Hz、CO2CH2CH〜3)、
1.46(9H、s、tert−Bu)、
1.7−2.2(2H、m、PhCH2CH2)、
2.4−4.7(13H、m、
[Formula]), 7.2−8.3 (7H, m, naphthyl proton). Step H 4-aza-4-tert-butoxycarbonylmethyl-6-(1-ethoxycarbonyl-3-phenylpropyl)amino-5-oxo-2-
(1-naphthyl)-1-thiacycloheptane 6-amino-4-aza-tert-butoxycarbonylmethyl-5-oxo-2-(1-naphthyl)-
1-thiacycloheptane 803mg and 2-bromo-4
- Add 0.66 g of soda carbonate to a solution of 1.13 g of ethyl phenylformamide in 10 ml of dimethylformamide and heat at 80℃.
Stirred for 15 hours. The reaction solution was dissolved in ethyl acetate and brine, and the ethyl acetate layer was separated, washed with water, and dried over anhydrous magnesium sulfate. The solvent was distilled off, and the residue was subjected to silica gel column chromatography using ethyl acetate-dichloromethane (1:30) to separate it into two types of isomers, A and B, which are derived from the chirality of the carbon to which the phenethyl group is bonded. did. Isomer A eluting first:
Oily 0.49g. NMR ( CDCl3 ) δ (ppm): 1.24 (3H, t, J = 7.5Hz, CO2CH2CH ~ 3 ) , 1.46 (9H, s, tert-Bu), 1.7-2.2 (2H, m, PhCH 2 CH 2 ), 2.4−4.7 (13H, m,
【式】、7員環の[Formula], 7-membered ring
【式】、N−CH〜2−
CO、CO2CH〜2CH3)、
5.13(1H、brd、J=9Hz、
[Formula], N-CH~ 2 - CO , CO2CH ~ 2CH3 ), 5.13 (1H, brd, J=9Hz,
【式】)、 7.14(5H、s、フエニルプロトン)、 7.2−8.2(7H、m、ナフチルプロトン)。 次に溶離する異性体B:油状物0.46g。 NMR(CDCl3)δ(ppm): 1.28(3H、t、J=7.5Hz、CO2CH2CH〜3)、 1.48(9H、s、tert−Bu)、 1.8−2.3(2H、m、PhCH2CH〜2)、 2.5−4.8(13H、m、[Formula]), 7.14 (5H, s, phenyl proton), 7.2−8.2 (7H, m, naphthyl proton). Isomer B eluted next: 0.46 g of oil. NMR ( CDCl3 ) δ (ppm): 1.28 (3H, t, J = 7.5Hz, CO2CH2CH ~ 3 ) , 1.48 (9H, s, tert-Bu), 1.8-2.3 (2H, m, PhCH 2 CH~ 2 ), 2.5-4.8 (13H, m,
【式】、 7員環の【formula】, 7-membered ring
【式】、
N−CH〜2−CO、CO2CH〜2CH3)、
5.18(1H、brd、J=9.5Hz、
[Formula], N-CH~ 2 -CO, CO2CH ~ 2CH3 ), 5.18 (1H, brd, J=9.5Hz ,
【式】)、
7.14(5H、s、フエニルプロトン)、
7.21(5H、s、フエニルプロトン)、
7.35−8.3(7H、m、ナフチルプロトン)。
実施例 2
4−アザ−4−カルボキシメチル−6−(1−
エトキシカルボニル−3−フエニルプロピル)
アミノ−5−オシソ−2−(1−ナフチル)−1
−チアシクロヘプタン
実施例1工程Hで製造される4−アザ−4−
tert−ブトキシカルボニルメチル−6−(1−エ
トキシカルボニル−3−フエニルプロピル)アミ
ノ−5−オキソ−2−(1−ナフチル)−1−チア
シクロヘプタンの異性体B455mgをアニソール2
mlとトリフルオロ酢酸2mlに溶かし、室温で4時
間撹拌した。反応溶液を濃縮し、残留物にジイソ
プロピルエーテルを加え撹拌し、結晶体粉末を
取した。収量447mg。これを酢酸エチル2mlと水
2mlに溶かし、重曹0.2gを加え、撹拌後、3N塩
酸を加えPH2.5に調整した。析出する目的化合物
を取した。収量216mg。液中の酢酸エチル層
を分離し、水層を酢酸エチルで抽出後、全酢酸エ
チル層を合せ、無水硫酸マグネシウムで乾燥し、
溶媒を留去すると、目的化合物が結晶として析出
した。ジイソプロビルエーテルを用いて取し
た。収量70mg。
融点201−203℃
NMR(DMSO−d6)δ(ppm):
1.28(3H、t、J=7.5Hz、CO2CH2CH〜3)、
2.0−2.4(2H、m、phCH2CH〜2)、
2.5−5.4(13H、m、[Formula]), 7.14 (5H, s, phenyl proton), 7.21 (5H, s, phenyl proton), 7.35-8.3 (7H, m, naphthyl proton). Example 2 4-aza-4-carboxymethyl-6-(1-
ethoxycarbonyl-3-phenylpropyl)
Amino-5-osiso-2-(1-naphthyl)-1
-thiacycloheptane 4-Aza-4- produced in Example 1 Step H
455 mg of isomer B of tert-butoxycarbonylmethyl-6-(1-ethoxycarbonyl-3-phenylpropyl)amino-5-oxo-2-(1-naphthyl)-1-thiacycloheptane was added to anisole 2
ml and 2 ml of trifluoroacetic acid, and the mixture was stirred at room temperature for 4 hours. The reaction solution was concentrated, diisopropyl ether was added to the residue, and the mixture was stirred to obtain a crystalline powder. Yield 447mg. This was dissolved in 2 ml of ethyl acetate and 2 ml of water, 0.2 g of sodium bicarbonate was added, and after stirring, 3N hydrochloric acid was added to adjust the pH to 2.5. The precipitated target compound was collected. Yield 216mg. After separating the ethyl acetate layer in the liquid and extracting the aqueous layer with ethyl acetate, all the ethyl acetate layers were combined and dried over anhydrous magnesium sulfate.
When the solvent was distilled off, the target compound precipitated as crystals. It was extracted using diisopropyl ether. Yield 70mg. Melting point 201-203℃ NMR (DMSO- d6 ) δ (ppm): 1.28 (3H, t, J=7.5Hz, CO2CH2CH ~ 3 ), 2.0-2.4 (2H, m, phCH2CH ~ 2 ), 2.5−5.4 (13H, m,
【式】、
7員環プロトン、N−CH〜2−CO、CO2CH〜
2CH3)、
7.32(5H、s、フエニルプロトン)、
7.2−8.3(7H、m、ナフチルプロトン)。
実施例 3
4−アザ−4−カルオキウシメチル−6−(1
−カルボキシ−3−フエニルィプロピル)アミ
ノ−5−オキソ−2−(1−ナフチル)−1−チ
アシクロヘプタン
実施例2で製造される4−アザ−4−カルボキ
シメチル−6−(1−エトキシカルボニル−3−
フエニルプロピル)アミノ−5−オキソ−2−
(1−ナフチル)−1−ニアシクロヘプタン216mg
を1Nカ性ソーダ水溶液2mlと混ぜ、室温で16時
間撹拌した。少量の不溶物を去し、液に1N
塩酸を滴加し、PH2.0にして析出する粉末状目的
化合物を取し、少量の水で洗浄した。収量201
mg。
NMR(DMSO−d6)δ(ppm):
1.7−2.1(2H、m、phCH2CH〜2)、
2.5−5.35(11H、m、
[Formula], 7-membered ring proton, N-CH~ 2 -CO, CO 2 CH~
2 CH3 ), 7.32 (5H, s, phenyl proton), 7.2-8.3 (7H, m, naphthyl proton). Example 3 4-aza-4-caloximethyl-6-(1
-carboxy-3-phenylipropyl)amino-5-oxo-2-(1-naphthyl)-1-thiacycloheptane 4-aza-4-carboxymethyl-6-(1-ethoxycarbonyl-3-
phenylpropyl)amino-5-oxo-2-
(1-naphthyl)-1-niacycloheptane 216mg
was mixed with 2 ml of 1N aqueous caustic soda solution and stirred at room temperature for 16 hours. Remove a small amount of insoluble matter and add 1N to the liquid.
Hydrochloric acid was added dropwise to adjust the pH to 2.0, and the precipitated powdery target compound was collected and washed with a small amount of water. Yield 201
mg. NMR (DMSO- d6 ) δ (ppm): 1.7-2.1 (2H, m, phCH2CH ~ 2 ), 2.5-5.35 (11H, m,
【式】、7員環プロトン、
N−CH〜2−CO)、
7.28(5H、s、フエニルプロトン)、
7.1−8.3(7H、ナフチルプロトン)。
実施例 4
4−アザ−4−tert−ブトキシカルボニルメチ
ル−6−(1−エトキシカルボニル−3−フエ
ニルプロピル)アミノ−5−オキソ−2−(2
−ナフチル)−1−チアシクロヘプタン
工程A
2−tert−ブトキシカルボニルアミノ−1−
(2−ナフチル)エタノール
2−ナフトアルデヒドシアンヒドリン26gを水
素化リチウムアルミニウムで還元して得られた粗
2−アミノ−1−(2−ナフチル)エタノールを、
実施例1、工程Aと同様の方法によりtert−ブト
キシカルボニル化して、結晶性の目的化合物16g
を得た。融点99−100.5℃。
NMR(CDCl3)δ(ppm):
1.43(9H、s、tert−Bu)、
3.1−3.75(3H、m、−CH2−、OH)、
4.95(1H、br、NH)、
4.96(1H.d、d、J=4、8Hz、
[Formula], 7-membered ring proton, N-CH~ 2 -CO), 7.28 (5H, s, phenyl proton), 7.1-8.3 (7H, naphthyl proton). Example 4 4-aza-4-tert-butoxycarbonylmethyl-6-(1-ethoxycarbonyl-3-phenylpropyl)amino-5-oxo-2-(2
-naphthyl)-1-thiacycloheptane Step A 2-tert-butoxycarbonylamino-1-
(2-naphthyl)ethanol Crude 2-amino-1-(2-naphthyl)ethanol obtained by reducing 26 g of 2-naphthaldehyde cyanohydrin with lithium aluminum hydride,
Tert-butoxycarbonylation was performed in the same manner as in Example 1, Step A to obtain 16 g of the crystalline target compound.
I got it. Melting point 99-100.5℃. NMR ( CDCl3 ) δ (ppm): 1.43 (9H, s, tert-Bu), 3.1-3.75 (3H, m, -CH2- , OH), 4.95 (1H, br, NH), 4.96 (1H. d, d, J = 4, 8Hz,
【式】)、
7.4−8.0(7H、m、ナフチルプロトン)。
工程B
2−tert−ブトキシカルボニルアミノ−1−ク
ロル−1−(2−ナフチル)エタン
2−tert−ブトキシカルボニルアミノ−1−
(2−ナフチル)エタノール16gを実施例1、工
程Bと同様の方法により、五塩化リンでクロル化
して、結晶性の目的化合物9.1gを得た。
融点97−98℃
NMR(CDCl3)δ(ppm):
1.43(9H、s、tert−Bu)、
3.4−4.0(2H、m、−CH2−)、
4.93(1H、br、NH)、
5.18(1H.d、d、J=6、7Hz、
[Formula]), 7.4−8.0 (7H, m, naphthyl proton). Step B 2-tert-butoxycarbonylamino-1-chloro-1-(2-naphthyl)ethane 2-tert-butoxycarbonylamino-1-
16 g of (2-naphthyl)ethanol was chlorinated with phosphorus pentachloride in the same manner as in Example 1, Step B to obtain 9.1 g of the crystalline target compound. Melting point 97-98℃ NMR ( CDCl3 ) δ (ppm): 1.43 (9H, s, tert-Bu), 3.4-4.0 (2H, m, -CH2- ), 4.93 (1H, br, NH), 5.18 (1H.d, d, J=6,7Hz,
【式】)、
7.45−8.0(7H、m、ナフチルプロトン)。
工程C
S−〔2−tert−ブトキシカルボニルアミノ−
1−(2−ナフチル)エチル〕−N−フタリルシ
ステインジフエニルメチルエステル
実施例1工程Cと同様の操作によりL−システ
インp−トルエンスルホン酸塩10g、N−カルボ
エトキシフタルイミド7.5g、重曹6.2gおよびジ
フエニルジアゾメタン7.4gから製造されるN−
フタリル−L−システインジフエニルメチルエス
テルと2−tert−ブトキシカルボニルアミノ−1
−クロル−1−(2−ナフチル)エタン9.6gのジ
メチルホルムアミド80ml溶液に炭酸ソーダ7.3g
を加え、窒素気流中、80℃で18時間撹拌した。反
応液を実施例1工程Cと同様に処理し、目的化合
物を無定形固体として得た。収量12.3g。
NMR(CDCl3)δ(ppm):
1.37(9H、s、tert−Bu)、
3.2−3.7(4H、m、CH2S、C−CH2−N)、
4.22(1H、t、J=4.5Hz、
[Formula]), 7.45−8.0 (7H, m, naphthyl proton). Step C S-[2-tert-butoxycarbonylamino-
1-(2-naphthyl)ethyl]-N-phthalylcysteine diphenyl methyl ester N- produced from 10 g of L-cysteine p-toluenesulfonate, 7.5 g of N-carboethoxyphthalimide, 6.2 g of sodium bicarbonate and 7.4 g of diphenyldiazomethane in the same manner as in Step C of Example 1.
Phthalyl-L-cysteine diphenyl methyl ester and 2-tert-butoxycarbonylamino-1
-7.3 g of soda carbonate in a solution of 9.6 g of chloro-1-(2-naphthyl)ethane in 80 ml of dimethylformamide
was added, and the mixture was stirred at 80°C for 18 hours in a nitrogen stream. The reaction solution was treated in the same manner as in Step C of Example 1 to obtain the target compound as an amorphous solid. Yield: 12.3g. NMR ( CDCl3 ) δ (ppm): 1.37 (9H, s, tert-Bu), 3.2-3.7 (4H, m, CH2S , C- CH2 -N), 4.22 (1H, t, J=4.5 Hz,
【式】)、 4.67(1H、br、NH)、 5.05(1H、m、【formula】), 4.67 (1H, br, NH), 5.05 (1H, m,
【式】)、
6.79と7.82(合せて1H、s、CH〜ph2)、
7.0−8.0(21H、m、CH(C6H〜5)2、ナフチルプ
ロトン、フタリルプロトン)。
工程D
S−〔2−アミノ−1−(2−ナフチル)エチ
ル〕−N−フタリルシステイン
S−〔2−tert−ブトキシカルボニルアミノ−
1−(2−ナフチル)エチル〕−N−フタリルシス
テインジフエニルメチルエステル12.3gを実施例
1工程Dと同様の操作により、トリフルオロ酢酸
で脱保護して、粉末状の目的化合物6.6gを得た。
融点196−200℃。
工程E
4−アザ−5−オキソ−2−(2−ナフチル)−
6−フタルイミド−1−チアシクロヘプタン
S−〔2−アミノ−1−(2−ナフチル)エチ
ル〕−N−フタリルシステイン6.5gを実施例1工
程Eと同様の操作により、ジフエニルホスホリル
アジド4.7mlを用いて縮合環化して、目的化合物
4.25gを得た。融点270℃から軟化し、283−285
℃で溶融。
NMR(DMSO−d6)δ(ppm):
3.1−4.6(CH〜2−S、
[Formula]), 6.79 and 7.82 (combined 1H, s, CH~ ph2 ), 7.0-8.0 (21H, m, CH( C6H ~ 5 ) 2 , naphthyl proton, phthalyl proton). Step D S-[2-amino-1-(2-naphthyl)ethyl]-N-phthalylcysteine S-[2-tert-butoxycarbonylamino-
12.3 g of 1-(2-naphthyl)ethyl]-N-phthalylcysteine diphenyl methyl ester was deprotected with trifluoroacetic acid in the same manner as in Step D of Example 1 to obtain 6.6 g of the target compound in powder form. Obtained.
Melting point 196-200℃. Step E 4-aza-5-oxo-2-(2-naphthyl)-
6-phthalimido-1-thiacycloheptane 6.5 g of S-[2-amino-1-(2-naphthyl)ethyl]-N-phthalylcysteine was condensed and cyclized using 4.7 ml of diphenylphosphoryl azide in the same manner as in Step E of Example 1. Target compound
4.25g was obtained. Softens from melting point 270℃, 283−285
Melt at °C. NMR (DMSO- d6 ) δ (ppm): 3.1-4.6 (CH~ 2 -S,
【式】、 5.43(1H、m、【formula】, 5.43 (1H, m,
【式】)、
7.5−8.4(11H、m、ナフチルプロトン、フタリ
ルプロトン)。
工程F
4−アザ−4−tert−ブトキシカルボニルメチ
ル−5−オキソ−2−(2−ナフチル)−6−フ
タルイミド−1−チアシクロヘプタン
4−アザ−5−オキソ−2−(2−ナフチル)−
6−フタルイミド−1−チアシクロヘプタン4.15
gを実施例1工程Fと同様の方法によりブロム酢
酸tert−ブチルで処理して、結晶性の目的化合物
3.35gを得た。融点208−209.5℃
NMR(CDCl3)δ(ppm):
1.47(9H、s、tert−Bu)、
2.9−4.85(7H、m、N−CH〜2−CH〜(ナフチ
ル)−S−CH〜2、N−CH〜2−CO)、
5.72(1H、d、d、J=2、10Hz、
[Formula]), 7.5−8.4 (11H, m, naphthyl proton, phthalyl proton). Step F 4-aza-4-tert-butoxycarbonylmethyl-5-oxo-2-(2-naphthyl)-6-phthalimido-1-thiacycloheptane 4-aza-5-oxo-2-(2-naphthyl)-
6-phthalimido-1-thiacycloheptane 4.15
g was treated with tert-butyl bromoacetate in the same manner as in Example 1 Step F to obtain the crystalline target compound.
3.35g was obtained. Melting point 208-209.5℃ NMR ( CDCl3 ) δ (ppm): 1.47 (9H, s, tert-Bu), 2.9-4.85 (7H, m, N-CH~ 2 -CH~ (naphthyl) -S-CH~ 2 , N-CH~ 2 -CO), 5.72 (1H, d, d, J=2, 10Hz,
【式】)、
7.3−8.0(11H、m、ナフチルプロトン、フタリ
ルプロトン)。
工程G
6−アミノ−4−アザ−4−tert−ブトキシカ
ルボニルメチル−5−オキソ−2−(2−ナフ
チル)−1−チアシクロヘプタン
4−アザ−4−tert−ブトキシカルボニルメチ
ル−5−オキソ−2−(2−ナフチル)−6−フタ
ルイミド−1−チアシクロヘプタン3.25gを実施
例1工程Gと同様に処理により、メチルヒドラジ
ンで脱フタリル化して無定形粉末の目的化合物
2.6gを得た。
NMR(CDCl3)δ(ppm):
1.46(9H、s、tert−Bu)、
2.26(2H、s、NH2)、
2.45−4.75(8H、m、7員環プロトン、−N−C
H〜2−CO)、
7.2−7.9(11H、m、ナフチルプロトン、フタリ
ルプロトン)。
工程H
4−アザ−4−tert−ブトキシカルボニルメチ
ル−6−(1−エトキシカルボニル−3−フエ
ニルプロピル)アミノ−5−オキソ−2−(2
−ナフチル)−1−チアシクロヘプタン
6−アミノ−4−アザ−4−tert−ブトキシカ
ルボニルメチル−5−オキソ−2−(2−ナフチ
ル)−1−チアシクロヘプタン0.85gを実施例1
工程Hと同様の方法により、2−ブロム−4−フ
エニル酪酸エチル1.08gでN−アルキル化した。
生成物を酢酸エチル−ジクロルメタン1:30のシ
リカゲル・カラムクロマトに付して、フエネチル
基の結合する炭素に由来する2種類の異性体Aと
Bに分離した。最初に溶離する異性体A:油状物
0.47g
NMR(CDCl3)δ(ppm):
1.25(3H、t、J=7.5Hz、CO2CH2CH〜3)、
1.47(9H、s、tert−Bu)、
1.7−2.2(2H、m、PhCH2CH〜2)、
2.4−4.6(12H、m、
[Formula]), 7.3−8.0 (11H, m, naphthyl proton, phthalyl proton). Step G 6-amino-4-aza-4-tert-butoxycarbonylmethyl-5-oxo-2-(2-naphthyl)-1-thiacycloheptane 3.25 g of 4-aza-4-tert-butoxycarbonylmethyl-5-oxo-2-(2-naphthyl)-6-phthalimido-1-thiacycloheptane was treated with methylhydrazine in the same manner as in Step G of Example 1. Defthalylated target compound into amorphous powder
2.6g was obtained. NMR ( CDCl3 ) δ (ppm): 1.46 (9H, s, tert-Bu), 2.26 (2H, s, NH2 ), 2.45-4.75 (8H, m, 7-membered ring proton, -N-C
H~ 2 -CO), 7.2-7.9 (11H, m, naphthyl proton, phthalyl proton). Step H 4-aza-4-tert-butoxycarbonylmethyl-6-(1-ethoxycarbonyl-3-phenylpropyl)amino-5-oxo-2-(2
-naphthyl)-1-thiacycloheptane Example 1: 0.85 g of 6-amino-4-aza-4-tert-butoxycarbonylmethyl-5-oxo-2-(2-naphthyl)-1-thiacycloheptane
N-alkylation was carried out using 1.08 g of ethyl 2-bromo-4-phenylbutyrate in the same manner as in Step H.
The product was subjected to silica gel column chromatography using ethyl acetate-dichloromethane (1:30) to separate it into two types of isomers A and B derived from the carbon to which the phenethyl group is bonded. Isomer A eluting first: oil
0.47g NMR ( CDCl3 ) δ (ppm): 1.25 (3H, t, J = 7.5Hz, CO2CH2CH ~ 3 ), 1.47 (9H, s, tert-Bu), 1.7-2.2 (2H, m , PhCH2CH ~ 2 ), 2.4−4.6(12H, m,
【式】7員環プロトン、N −CH〜2)、 4.14(2H、q、J=7.5Hz、CO2CH〜2CH3)、 7.20(5H、s、フエニルプロトン)、 7.1−7.9(7H、m、ナフチルプロトン)。 次に溶離する異性体B0.50g。 NMR(CDCl3)δ(ppm): 1.27(3H、t、J=7.5Hz、CO2CH2CH〜3)、 1.47(9H、s、tert−Bu)、 1.8−2.25(2H、m、PhCH2CH〜2)、 2.5−4.6(12H、[Formula] 7-membered ring proton , N -CH~ 2 ), 4.14 (2H, q, J=7.5Hz, CO2CH ~ 2CH3 ), 7.20 (5H, s, phenyl proton), 7.1-7.9 ( 7H, m, naphthyl proton). Next, 0.50 g of isomer B is eluted. NMR ( CDCl3 ) δ (ppm): 1.27 (3H, t, J = 7.5Hz, CO2CH2CH ~ 3 ), 1.47 (9H, s, tert-Bu), 1.8-2.25 (2H, m, PhCH 2 CH~ 2 ), 2.5−4.6 (12H,
【式】7
員環プロトン、N−CH〜2−CO)、
4.16(2H、q、J=7.5Hz、CO2CH〜2CH3)、
7.20(5H、s、フエニルプロトン)、
7.1−7.9(7H、m、ナフチルプロトン)。
実施例 5
4−アザ−4−カルボキシメチル−6−(1−
エトキシカルボニル−3−フエニルプロピル)
アミノ−5−オキソ−2−(2−ナフチル)−1
−チアシクロヘプタン
実施例4工程Hで製造される4−アザ−4−
tert−ブトキシカルボニルメチル−6−(1−エ
トキシカルボニル−3−フエニルプロピル)アミ
ノ−5−オキソ−2−(2−ナフチル)−1−チア
シクロヘプタンの異性体B0.47gを実施例2の方
法により、トリフルオロ酢酸で脱tert−ブチル化
して、結晶性粉末として目的物を得た。収量0.42
g。115℃付近から軟化し、175−180℃で溶融。
NMR(DMSO−d6)δ(ppm):
1.30(3H、t、J=7.5Hz、CO2CH2CH〜3)、
2.0−2.35(2H、m、PhCH2CH〜2)、
2.55−5.2(13H、m、[Formula] 7-membered ring proton, N-CH~ 2 -CO), 4.16 (2H , q, J=7.5Hz, CO2CH~2CH3 ) , 7.20 (5H, s, phenyl proton), 7.1- 7.9 (7H, m, naphthyl proton). Example 5 4-aza-4-carboxymethyl-6-(1-
ethoxycarbonyl-3-phenylpropyl)
Amino-5-oxo-2-(2-naphthyl)-1
-thiacycloheptane 4-Aza-4- produced in Example 4 Step H
0.47 g of tert-butoxycarbonylmethyl-6-(1-ethoxycarbonyl-3-phenylpropyl)amino-5-oxo-2-(2-naphthyl)-1-thiacycloheptane isomer B of Example 2 was added. According to the method, the desired product was obtained as a crystalline powder by detert-butylation with trifluoroacetic acid. Yield 0.42
g. It softens around 115℃ and melts at 175-180℃. NMR (DMSO- d6 ) δ (ppm): 1.30 (3H, t, J=7.5Hz, CO2CH2CH ~ 3 ), 2.0-2.35 (2H , m, PhCH2CH ~ 2 ), 2.55-5.2 (13H, m,
【式】
7員環プロトン、N−CH〜2−CO、CO2CH〜
2CH3)、
7.33(5H、s、フエニルプロトン)、
7.2−8.1(7H、m、ナフチルプロトン)。
実施例 6
4−アザ−4−カルボキシメチル−6−(1−
カルボキシ−3−フエニルプロピル)アミノ−
5−オキソ−2−(2−ナフチル)−1−チアシ
クロヘプタン
実施例5で製造される4−アザ−4−カルボキ
シメチル−6−(1−エトキシカルボニル−3−
フエニルプロピル)アミノ−5−オキソ−2−
(2−ナフチル)−1−チアシクロヘプタン200mg
を実施例3の方法により、カ性ソーダで加水分解
して、粉末状の目的化合物133mgを得た。
NMR(DMSO−d6)δ(ppm):
1.7−2.1(2H、m、PhCH2CH〜2)、
2.5−4.8(11H、m、[Formula] 7-membered ring proton, N-CH~ 2 -CO, CO 2 CH~
2 CH3 ), 7.33 (5H, s, phenyl proton), 7.2-8.1 (7H, m, naphthyl proton). Example 6 4-aza-4-carboxymethyl-6-(1-
carboxy-3-phenylpropyl)amino-
5-oxo-2-(2-naphthyl)-1-thiacycloheptane 4-aza-4-carboxymethyl-6-(1-ethoxycarbonyl-3-
phenylpropyl)amino-5-oxo-2-
(2-naphthyl)-1-thiacycloheptane 200mg
was hydrolyzed with caustic soda according to the method of Example 3 to obtain 133 mg of the target compound in powder form. NMR (DMSO- d6 ) δ (ppm): 1.7-2.1 (2H, m, PhCH2CH ~ 2 ), 2.5-4.8 (11H, m,
【式】 7員環プロトン、N−CH〜2−CO)、 7.30(5H、s、フエニルプロトン)、 7.2−8.1(7H、m、ナフチルプロトン)。[Formula] 7-membered ring proton, N-CH~ 2 -CO), 7.30 (5H, s, phenyl proton), 7.2-8.1 (7H, m, naphthyl proton).
Claims (1)
キル基またはアラルキル基を示し、R2およびR4
は同一または異なつて水素原子またはカルボキシ
基の保護基を示し、R3はナフチル基を示し、A
は低級アルキレン基を示す。) を有する4−アザ−5−オキソ−1−チアシクロ
ヘプタン誘導体。[Claims] 1. General formula (In the formula, R 1 represents an alkyl group, a cycloalkylalkyl group, or an aralkyl group, and R 2 and R 4
are the same or different and represent a hydrogen atom or a protecting group for a carboxy group, R 3 represents a naphthyl group, and A
represents a lower alkylene group. ) A 4-aza-5-oxo-1-thiacycloheptane derivative having the following formula.
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP60049953A JPS61210079A (en) | 1985-03-13 | 1985-03-13 | 4-aza-1-thiacycloheptane derivative |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP60049953A JPS61210079A (en) | 1985-03-13 | 1985-03-13 | 4-aza-1-thiacycloheptane derivative |
Publications (2)
Publication Number | Publication Date |
---|---|
JPS61210079A JPS61210079A (en) | 1986-09-18 |
JPH056544B2 true JPH056544B2 (en) | 1993-01-26 |
Family
ID=12845400
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP60049953A Granted JPS61210079A (en) | 1985-03-13 | 1985-03-13 | 4-aza-1-thiacycloheptane derivative |
Country Status (1)
Country | Link |
---|---|
JP (1) | JPS61210079A (en) |
-
1985
- 1985-03-13 JP JP60049953A patent/JPS61210079A/en active Granted
Also Published As
Publication number | Publication date |
---|---|
JPS61210079A (en) | 1986-09-18 |
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