JPH0745453B2 - Acylaminohydroxyalkanoylamino and imino acids and esters - Google Patents
Acylaminohydroxyalkanoylamino and imino acids and estersInfo
- Publication number
- JPH0745453B2 JPH0745453B2 JP60263593A JP26359385A JPH0745453B2 JP H0745453 B2 JPH0745453 B2 JP H0745453B2 JP 60263593 A JP60263593 A JP 60263593A JP 26359385 A JP26359385 A JP 26359385A JP H0745453 B2 JPH0745453 B2 JP H0745453B2
- Authority
- JP
- Japan
- Prior art keywords
- item
- lower alkyl
- hydrogen
- compound according
- methyl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Lifetime
Links
- 150000002148 esters Chemical class 0.000 title description 14
- 125000001841 imino group Chemical group [H]N=* 0.000 title description 8
- 125000000217 alkyl group Chemical group 0.000 claims description 60
- 150000001875 compounds Chemical class 0.000 claims description 51
- 239000001257 hydrogen Substances 0.000 claims description 42
- 229910052739 hydrogen Inorganic materials 0.000 claims description 42
- -1 2-naphthylthio Chemical group 0.000 claims description 28
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 23
- 125000004432 carbon atom Chemical group C* 0.000 claims description 22
- 150000002431 hydrogen Chemical class 0.000 claims description 19
- 229960002429 proline Drugs 0.000 claims description 17
- 125000000043 benzamido group Chemical group [H]N([*])C(=O)C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims description 16
- 150000003839 salts Chemical class 0.000 claims description 14
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 12
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 12
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 11
- 125000003545 alkoxy group Chemical group 0.000 claims description 10
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 10
- 125000001153 fluoro group Chemical group F* 0.000 claims description 10
- 125000005978 1-naphthyloxy group Chemical group 0.000 claims description 8
- 125000005979 2-naphthyloxy group Chemical group 0.000 claims description 8
- 125000001246 bromo group Chemical group Br* 0.000 claims description 8
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 8
- 229910052736 halogen Inorganic materials 0.000 claims description 6
- 150000002367 halogens Chemical class 0.000 claims description 6
- 125000004122 cyclic group Chemical group 0.000 claims description 5
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 5
- 125000001424 substituent group Chemical group 0.000 claims description 5
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 5
- 125000001637 1-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C(*)=C([H])C([H])=C([H])C2=C1[H] 0.000 claims description 4
- 125000001622 2-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C([H])=C(*)C([H])=C([H])C2=C1[H] 0.000 claims 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 claims description 4
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 4
- 229910052794 bromium Inorganic materials 0.000 claims description 4
- 229910052801 chlorine Inorganic materials 0.000 claims description 4
- ZZVUWRFHKOJYTH-UHFFFAOYSA-N diphenhydramine Chemical group C=1C=CC=CC=1C(OCCN(C)C)C1=CC=CC=C1 ZZVUWRFHKOJYTH-UHFFFAOYSA-N 0.000 claims description 4
- 239000001301 oxygen Substances 0.000 claims description 4
- 229910052760 oxygen Inorganic materials 0.000 claims description 4
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 3
- 229910001413 alkali metal ion Inorganic materials 0.000 claims description 3
- 125000004414 alkyl thio group Chemical group 0.000 claims description 3
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 3
- 150000002500 ions Chemical class 0.000 claims description 3
- 229910052717 sulfur Chemical group 0.000 claims description 3
- 239000011593 sulfur Chemical group 0.000 claims description 3
- 229910052731 fluorine Inorganic materials 0.000 claims description 2
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 2
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 36
- 239000000203 mixture Substances 0.000 description 35
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 24
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 18
- 239000000243 solution Substances 0.000 description 15
- 239000000047 product Substances 0.000 description 14
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 12
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 12
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 12
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 11
- 239000000741 silica gel Substances 0.000 description 11
- 229910002027 silica gel Inorganic materials 0.000 description 11
- UIIMBOGNXHQVGW-UHFFFAOYSA-M sodium bicarbonate Substances [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 11
- 239000002904 solvent Substances 0.000 description 11
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 10
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 10
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 9
- 239000012267 brine Substances 0.000 description 9
- 238000001035 drying Methods 0.000 description 9
- VEXZGXHMUGYJMC-UHFFFAOYSA-N hydrochloric acid Substances Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 9
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 9
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 8
- 239000007787 solid Substances 0.000 description 8
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 7
- 239000002253 acid Substances 0.000 description 7
- 238000006243 chemical reaction Methods 0.000 description 7
- 238000000034 method Methods 0.000 description 7
- 125000006239 protecting group Chemical group 0.000 description 7
- 238000003756 stirring Methods 0.000 description 7
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 6
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 6
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 6
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 6
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 6
- 102000005862 Angiotensin II Human genes 0.000 description 5
- 101800000733 Angiotensin-2 Proteins 0.000 description 5
- 206010020772 Hypertension Diseases 0.000 description 5
- CZGUSIXMZVURDU-JZXHSEFVSA-N Ile(5)-angiotensin II Chemical compound C([C@@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC=1NC=NC=1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CC=1C=CC=CC=1)C([O-])=O)NC(=O)[C@@H](NC(=O)[C@H](CCCNC(N)=[NH2+])NC(=O)[C@@H]([NH3+])CC([O-])=O)C(C)C)C1=CC=C(O)C=C1 CZGUSIXMZVURDU-JZXHSEFVSA-N 0.000 description 5
- 239000013543 active substance Substances 0.000 description 5
- 229950006323 angiotensin ii Drugs 0.000 description 5
- 229910052786 argon Inorganic materials 0.000 description 5
- 239000003921 oil Substances 0.000 description 5
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 5
- UUUHXMGGBIUAPW-UHFFFAOYSA-N 1-[1-[2-[[5-amino-2-[[1-[5-(diaminomethylideneamino)-2-[[1-[3-(1h-indol-3-yl)-2-[(5-oxopyrrolidine-2-carbonyl)amino]propanoyl]pyrrolidine-2-carbonyl]amino]pentanoyl]pyrrolidine-2-carbonyl]amino]-5-oxopentanoyl]amino]-3-methylpentanoyl]pyrrolidine-2-carbon Chemical compound C1CCC(C(=O)N2C(CCC2)C(O)=O)N1C(=O)C(C(C)CC)NC(=O)C(CCC(N)=O)NC(=O)C1CCCN1C(=O)C(CCCN=C(N)N)NC(=O)C1CCCN1C(=O)C(CC=1C2=CC=CC=C2NC=1)NC(=O)C1CCC(=O)N1 UUUHXMGGBIUAPW-UHFFFAOYSA-N 0.000 description 4
- 101800000734 Angiotensin-1 Proteins 0.000 description 4
- 102400000344 Angiotensin-1 Human genes 0.000 description 4
- JZUFKLXOESDKRF-UHFFFAOYSA-N Chlorothiazide Chemical compound C1=C(Cl)C(S(=O)(=O)N)=CC2=C1NCNS2(=O)=O JZUFKLXOESDKRF-UHFFFAOYSA-N 0.000 description 4
- 229920002261 Corn starch Polymers 0.000 description 4
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 4
- 241000124008 Mammalia Species 0.000 description 4
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 4
- OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 description 4
- 102000004270 Peptidyl-Dipeptidase A Human genes 0.000 description 4
- 108090000882 Peptidyl-Dipeptidase A Proteins 0.000 description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 4
- WGLPBDUCMAPZCE-UHFFFAOYSA-N Trioxochromium Chemical compound O=[Cr](=O)=O WGLPBDUCMAPZCE-UHFFFAOYSA-N 0.000 description 4
- 239000004480 active ingredient Substances 0.000 description 4
- ORWYRWWVDCYOMK-HBZPZAIKSA-N angiotensin I Chemical compound C([C@@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC=1NC=NC=1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CC=1NC=NC=1)C(=O)N[C@@H](CC(C)C)C(O)=O)NC(=O)[C@@H](NC(=O)[C@H](CCCN=C(N)N)NC(=O)[C@@H](N)CC(O)=O)C(C)C)C1=CC=C(O)C=C1 ORWYRWWVDCYOMK-HBZPZAIKSA-N 0.000 description 4
- 239000000460 chlorine Substances 0.000 description 4
- 239000008120 corn starch Substances 0.000 description 4
- 239000002934 diuretic Substances 0.000 description 4
- 239000004615 ingredient Substances 0.000 description 4
- 239000000463 material Substances 0.000 description 4
- UBQKCCHYAOITMY-UHFFFAOYSA-N pyridin-2-ol Chemical compound OC1=CC=CC=N1 UBQKCCHYAOITMY-UHFFFAOYSA-N 0.000 description 4
- 239000013076 target substance Substances 0.000 description 4
- ZYJPUMXJBDHSIF-NSHDSACASA-N (2s)-2-[(2-methylpropan-2-yl)oxycarbonylamino]-3-phenylpropanoic acid Chemical compound CC(C)(C)OC(=O)N[C@H](C(O)=O)CC1=CC=CC=C1 ZYJPUMXJBDHSIF-NSHDSACASA-N 0.000 description 3
- ADFXKUOMJKEIND-UHFFFAOYSA-N 1,3-dicyclohexylurea Chemical compound C1CCCCC1NC(=O)NC1CCCCC1 ADFXKUOMJKEIND-UHFFFAOYSA-N 0.000 description 3
- NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical compound CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 description 3
- 108010064733 Angiotensins Proteins 0.000 description 3
- 102000015427 Angiotensins Human genes 0.000 description 3
- QMMFVYPAHWMCMS-UHFFFAOYSA-N Dimethyl sulfide Chemical compound CSC QMMFVYPAHWMCMS-UHFFFAOYSA-N 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- 239000007818 Grignard reagent Substances 0.000 description 3
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 3
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 3
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- 235000021355 Stearic acid Nutrition 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 239000008280 blood Substances 0.000 description 3
- 210000004369 blood Anatomy 0.000 description 3
- 230000036772 blood pressure Effects 0.000 description 3
- 239000002775 capsule Substances 0.000 description 3
- 239000007822 coupling agent Substances 0.000 description 3
- 238000005859 coupling reaction Methods 0.000 description 3
- 230000001882 diuretic effect Effects 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 239000000284 extract Substances 0.000 description 3
- 238000003818 flash chromatography Methods 0.000 description 3
- 150000004795 grignard reagents Chemical class 0.000 description 3
- 229960002003 hydrochlorothiazide Drugs 0.000 description 3
- 230000002401 inhibitory effect Effects 0.000 description 3
- 239000008101 lactose Substances 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- 239000011777 magnesium Substances 0.000 description 3
- 229910052749 magnesium Inorganic materials 0.000 description 3
- 235000019359 magnesium stearate Nutrition 0.000 description 3
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 3
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 3
- 235000017557 sodium bicarbonate Nutrition 0.000 description 3
- 239000012279 sodium borohydride Substances 0.000 description 3
- 229910000033 sodium borohydride Inorganic materials 0.000 description 3
- 239000008117 stearic acid Substances 0.000 description 3
- IIRUREIGPQBHMF-UHFFFAOYSA-N 4-bromo-3-methylbut-1-ene Chemical compound BrCC(C)C=C IIRUREIGPQBHMF-UHFFFAOYSA-N 0.000 description 2
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- 108010010803 Gelatin Proteins 0.000 description 2
- 239000003810 Jones reagent Substances 0.000 description 2
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- 102000003729 Neprilysin Human genes 0.000 description 2
- 108090000028 Neprilysin Proteins 0.000 description 2
- CBENFWSGALASAD-UHFFFAOYSA-N Ozone Chemical compound [O-][O+]=O CBENFWSGALASAD-UHFFFAOYSA-N 0.000 description 2
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 2
- 108090000783 Renin Proteins 0.000 description 2
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 2
- 238000010306 acid treatment Methods 0.000 description 2
- 229940024606 amino acid Drugs 0.000 description 2
- 150000001413 amino acids Chemical class 0.000 description 2
- 230000000202 analgesic effect Effects 0.000 description 2
- 150000008064 anhydrides Chemical class 0.000 description 2
- 239000012223 aqueous fraction Substances 0.000 description 2
- 125000003118 aryl group Chemical group 0.000 description 2
- 239000002585 base Substances 0.000 description 2
- LDECUSDQMXVUMP-UHFFFAOYSA-N benzyl 3-[6-[[2-(butylamino)-1-[3-methoxycarbonyl-4-(2-methoxy-2-oxoethoxy)phenyl]-2-oxoethyl]-hexylamino]-6-oxohexyl]-4-methyl-2-oxo-6-(4-phenylphenyl)-1,6-dihydropyrimidine-5-carboxylate Chemical compound O=C1NC(C=2C=CC(=CC=2)C=2C=CC=CC=2)C(C(=O)OCC=2C=CC=CC=2)=C(C)N1CCCCCC(=O)N(CCCCCC)C(C(=O)NCCCC)C1=CC=C(OCC(=O)OC)C(C(=O)OC)=C1 LDECUSDQMXVUMP-UHFFFAOYSA-N 0.000 description 2
- 230000037396 body weight Effects 0.000 description 2
- 239000003054 catalyst Substances 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 239000003638 chemical reducing agent Substances 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 230000008878 coupling Effects 0.000 description 2
- 238000010168 coupling process Methods 0.000 description 2
- 238000000921 elemental analysis Methods 0.000 description 2
- 239000008273 gelatin Substances 0.000 description 2
- 229920000159 gelatin Polymers 0.000 description 2
- 235000019322 gelatine Nutrition 0.000 description 2
- 235000011852 gelatine desserts Nutrition 0.000 description 2
- 238000005984 hydrogenation reaction Methods 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- 125000000468 ketone group Chemical group 0.000 description 2
- 229910052744 lithium Inorganic materials 0.000 description 2
- AMXOYNBUYSYVKV-UHFFFAOYSA-M lithium bromide Chemical compound [Li+].[Br-] AMXOYNBUYSYVKV-UHFFFAOYSA-M 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 239000002609 medium Substances 0.000 description 2
- LXCFILQKKLGQFO-UHFFFAOYSA-N methylparaben Chemical compound COC(=O)C1=CC=C(O)C=C1 LXCFILQKKLGQFO-UHFFFAOYSA-N 0.000 description 2
- 239000003755 preservative agent Substances 0.000 description 2
- 230000002335 preservative effect Effects 0.000 description 2
- QELSKZZBTMNZEB-UHFFFAOYSA-N propylparaben Chemical compound CCCOC(=O)C1=CC=C(O)C=C1 QELSKZZBTMNZEB-UHFFFAOYSA-N 0.000 description 2
- 239000011780 sodium chloride Substances 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- HOPAEWRWVNCCKU-WMCAAGNKSA-N tert-butyl N-[(2S)-5-methyl-3-oxo-1-phenylhept-6-en-2-yl]carbamate Chemical compound CC(C)(OC(=O)N[C@H](C(CC(C=C)C)=O)CC1=CC=CC=C1)C HOPAEWRWVNCCKU-WMCAAGNKSA-N 0.000 description 2
- 239000008215 water for injection Substances 0.000 description 2
- PJUPKRYGDFTMTM-UHFFFAOYSA-N 1-hydroxybenzotriazole;hydrate Chemical compound O.C1=CC=C2N(O)N=NC2=C1 PJUPKRYGDFTMTM-UHFFFAOYSA-N 0.000 description 1
- JIVPVXMEBJLZRO-CQSZACIVSA-N 2-chloro-5-[(1r)-1-hydroxy-3-oxo-2h-isoindol-1-yl]benzenesulfonamide Chemical compound C1=C(Cl)C(S(=O)(=O)N)=CC([C@@]2(O)C3=CC=CC=C3C(=O)N2)=C1 JIVPVXMEBJLZRO-CQSZACIVSA-N 0.000 description 1
- XVMSFILGAMDHEY-UHFFFAOYSA-N 6-(4-aminophenyl)sulfonylpyridin-3-amine Chemical compound C1=CC(N)=CC=C1S(=O)(=O)C1=CC=C(N)C=N1 XVMSFILGAMDHEY-UHFFFAOYSA-N 0.000 description 1
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- 102000004881 Angiotensinogen Human genes 0.000 description 1
- 108090001067 Angiotensinogen Proteins 0.000 description 1
- 239000004475 Arginine Substances 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- 102000006395 Globulins Human genes 0.000 description 1
- 108010044091 Globulins Proteins 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- 229930194542 Keto Natural products 0.000 description 1
- 229930182821 L-proline Natural products 0.000 description 1
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 description 1
- 239000004472 Lysine Substances 0.000 description 1
- 239000012359 Methanesulfonyl chloride Substances 0.000 description 1
- LSDPWZHWYPCBBB-UHFFFAOYSA-N Methanethiol Chemical compound SC LSDPWZHWYPCBBB-UHFFFAOYSA-N 0.000 description 1
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 1
- CRLOTIRONDSKSS-CVMIBEPCSA-N N-[(2S)-5-methyl-3-oxo-1-phenylhept-6-en-2-yl]benzamide Chemical compound C(C1=CC=CC=C1)(=O)N[C@H](C(CC(C=C)C)=O)CC1=CC=CC=C1 CRLOTIRONDSKSS-CVMIBEPCSA-N 0.000 description 1
- CYLWJCABXYDINA-UHFFFAOYSA-N Polythiazide Polymers ClC1=C(S(N)(=O)=O)C=C2S(=O)(=O)N(C)C(CSCC(F)(F)F)NC2=C1 CYLWJCABXYDINA-UHFFFAOYSA-N 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- 102100028255 Renin Human genes 0.000 description 1
- FNYLWPVRPXGIIP-UHFFFAOYSA-N Triamterene Chemical compound NC1=NC2=NC(N)=NC(N)=C2N=C1C1=CC=CC=C1 FNYLWPVRPXGIIP-UHFFFAOYSA-N 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 150000001340 alkali metals Chemical class 0.000 description 1
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 1
- 150000001342 alkaline earth metals Chemical class 0.000 description 1
- XSDQTOBWRPYKKA-UHFFFAOYSA-N amiloride Chemical compound NC(=N)NC(=O)C1=NC(Cl)=C(N)N=C1N XSDQTOBWRPYKKA-UHFFFAOYSA-N 0.000 description 1
- 229960002576 amiloride Drugs 0.000 description 1
- 235000019270 ammonium chloride Nutrition 0.000 description 1
- 229940035676 analgesics Drugs 0.000 description 1
- 239000000730 antalgic agent Substances 0.000 description 1
- 229940030600 antihypertensive agent Drugs 0.000 description 1
- 239000002220 antihypertensive agent Substances 0.000 description 1
- 239000012736 aqueous medium Substances 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 description 1
- 150000001540 azides Chemical class 0.000 description 1
- 229960003515 bendroflumethiazide Drugs 0.000 description 1
- HDWIHXWEUNVBIY-UHFFFAOYSA-N bendroflumethiazidum Chemical compound C1=C(C(F)(F)F)C(S(=O)(=O)N)=CC(S(N2)(=O)=O)=C1NC2CC1=CC=CC=C1 HDWIHXWEUNVBIY-UHFFFAOYSA-N 0.000 description 1
- PASDCCFISLVPSO-UHFFFAOYSA-N benzoyl chloride Chemical compound ClC(=O)C1=CC=CC=C1 PASDCCFISLVPSO-UHFFFAOYSA-N 0.000 description 1
- 229960001541 benzthiazide Drugs 0.000 description 1
- NDTSRXAMMQDVSW-UHFFFAOYSA-N benzthiazide Chemical compound C1=C(Cl)C(S(=O)(=O)N)=CC(S(N2)(=O)=O)=C1N=C2CSCC1=CC=CC=C1 NDTSRXAMMQDVSW-UHFFFAOYSA-N 0.000 description 1
- NEDMOHHWRPHBAL-MERQFXBCSA-N benzyl (2s)-pyrrolidin-1-ium-2-carboxylate;chloride Chemical compound Cl.O=C([C@H]1NCCC1)OCC1=CC=CC=C1 NEDMOHHWRPHBAL-MERQFXBCSA-N 0.000 description 1
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- SIPUZPBQZHNSDW-UHFFFAOYSA-N bis(2-methylpropyl)aluminum Chemical compound CC(C)C[Al]CC(C)C SIPUZPBQZHNSDW-UHFFFAOYSA-N 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 125000005997 bromomethyl group Chemical group 0.000 description 1
- MAEIEVLCKWDQJH-UHFFFAOYSA-N bumetanide Chemical compound CCCCNC1=CC(C(O)=O)=CC(S(N)(=O)=O)=C1OC1=CC=CC=C1 MAEIEVLCKWDQJH-UHFFFAOYSA-N 0.000 description 1
- 229960004064 bumetanide Drugs 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 125000004218 chloromethyl group Chemical group [H]C([H])(Cl)* 0.000 description 1
- 229960002155 chlorothiazide Drugs 0.000 description 1
- 229960001523 chlortalidone Drugs 0.000 description 1
- 239000012230 colorless oil Substances 0.000 description 1
- 229940125904 compound 1 Drugs 0.000 description 1
- 239000013058 crude material Substances 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 238000007865 diluting Methods 0.000 description 1
- 231100000676 disease causative agent Toxicity 0.000 description 1
- ODCCJTMPMUFERV-UHFFFAOYSA-N ditert-butyl carbonate Chemical compound CC(C)(C)OC(=O)OC(C)(C)C ODCCJTMPMUFERV-UHFFFAOYSA-N 0.000 description 1
- 229940030606 diuretics Drugs 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 229920001971 elastomer Polymers 0.000 description 1
- 125000004185 ester group Chemical group 0.000 description 1
- AVOLMBLBETYQHX-UHFFFAOYSA-N etacrynic acid Chemical compound CCC(=C)C(=O)C1=CC=C(OCC(O)=O)C(Cl)=C1Cl AVOLMBLBETYQHX-UHFFFAOYSA-N 0.000 description 1
- 229960003199 etacrynic acid Drugs 0.000 description 1
- 239000012259 ether extract Substances 0.000 description 1
- 239000002038 ethyl acetate fraction Substances 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 229960003028 flumethiazide Drugs 0.000 description 1
- RGUQWGXAYZNLMI-UHFFFAOYSA-N flumethiazide Chemical compound C1=C(C(F)(F)F)C(S(=O)(=O)N)=CC2=C1NC=NS2(=O)=O RGUQWGXAYZNLMI-UHFFFAOYSA-N 0.000 description 1
- 235000013355 food flavoring agent Nutrition 0.000 description 1
- 238000001640 fractional crystallisation Methods 0.000 description 1
- 238000004108 freeze drying Methods 0.000 description 1
- ZZUFCTLCJUWOSV-UHFFFAOYSA-N furosemide Chemical compound C1=C(Cl)C(S(=O)(=O)N)=CC(C(O)=O)=C1NCC1=CC=CO1 ZZUFCTLCJUWOSV-UHFFFAOYSA-N 0.000 description 1
- 229960003883 furosemide Drugs 0.000 description 1
- 239000007903 gelatin capsule Substances 0.000 description 1
- 238000005469 granulation Methods 0.000 description 1
- 230000003179 granulation Effects 0.000 description 1
- 125000005843 halogen group Chemical group 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
- 229960003313 hydroflumethiazide Drugs 0.000 description 1
- DMDGGSIALPNSEE-UHFFFAOYSA-N hydroflumethiazide Chemical compound C1=C(C(F)(F)F)C(S(=O)(=O)N)=CC2=C1NCNS2(=O)=O DMDGGSIALPNSEE-UHFFFAOYSA-N 0.000 description 1
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 1
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 1
- 230000001631 hypertensive effect Effects 0.000 description 1
- 229940102223 injectable solution Drugs 0.000 description 1
- 150000007529 inorganic bases Chemical class 0.000 description 1
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 1
- 239000004292 methyl p-hydroxybenzoate Substances 0.000 description 1
- 235000010270 methyl p-hydroxybenzoate Nutrition 0.000 description 1
- 229960002216 methylparaben Drugs 0.000 description 1
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 1
- 239000008108 microcrystalline cellulose Substances 0.000 description 1
- 229940016286 microcrystalline cellulose Drugs 0.000 description 1
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 125000004433 nitrogen atom Chemical group N* 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 125000006340 pentafluoro ethyl group Chemical group FC(F)(F)C(F)(F)* 0.000 description 1
- YWAKXRMUMFPDSH-UHFFFAOYSA-N pentene Chemical compound CCCC=C YWAKXRMUMFPDSH-UHFFFAOYSA-N 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Natural products O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 description 1
- 229960005483 polythiazide Drugs 0.000 description 1
- 229920000046 polythiazide Polymers 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 239000004405 propyl p-hydroxybenzoate Substances 0.000 description 1
- 235000010232 propyl p-hydroxybenzoate Nutrition 0.000 description 1
- 229960003415 propylparaben Drugs 0.000 description 1
- 238000010791 quenching Methods 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 239000002893 slag Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- BEOOHQFXGBMRKU-UHFFFAOYSA-N sodium cyanoborohydride Chemical compound [Na+].[B-]C#N BEOOHQFXGBMRKU-UHFFFAOYSA-N 0.000 description 1
- 241000894007 species Species 0.000 description 1
- LXMSZDCAJNLERA-ZHYRCANASA-N spironolactone Chemical compound C([C@@H]1[C@]2(C)CC[C@@H]3[C@@]4(C)CCC(=O)C=C4C[C@H]([C@@H]13)SC(=O)C)C[C@@]21CCC(=O)O1 LXMSZDCAJNLERA-ZHYRCANASA-N 0.000 description 1
- 229960002256 spironolactone Drugs 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 239000008174 sterile solution Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 239000003451 thiazide diuretic agent Substances 0.000 description 1
- 229960001288 triamterene Drugs 0.000 description 1
- 229960004813 trichlormethiazide Drugs 0.000 description 1
- LMJSLTNSBFUCMU-UHFFFAOYSA-N trichlormethiazide Chemical compound C1=C(Cl)C(S(=O)(=O)N)=CC2=C1NC(C(Cl)Cl)NS2(=O)=O LMJSLTNSBFUCMU-UHFFFAOYSA-N 0.000 description 1
- 125000006000 trichloroethyl group Chemical group 0.000 description 1
- 125000002221 trityl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C([*])(C1=C(C(=C(C(=C1[H])[H])[H])[H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D207/16—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/04—Centrally acting analgesics, e.g. opioids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/12—Antihypertensives
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (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)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Engineering & Computer Science (AREA)
- Cardiology (AREA)
- Heart & Thoracic Surgery (AREA)
- Pain & Pain Management (AREA)
- Biomedical Technology (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Thiazole And Isothizaole Compounds (AREA)
- Pyridine Compounds (AREA)
- Indole Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Other In-Based Heterocyclic Compounds (AREA)
- Pyrrole Compounds (AREA)
Description
【発明の詳細な説明】 産業上の利用分野 本発明はアシルアミノヒドロキシアルカノイルアミノお
よびイミノ酸並びにエステル類、更に詳しくは、そのア
ンギオテンシン変換酵素抑制活性に基づき血圧降下剤と
して有用であり、また後述の定義においてＸが である場合にエンケフアリナーゼ（enkephalinase）抑
制活性に基づき鎮痛剤としても有用である新規なアミノ
酸およびイミノ酸化合物およびこれらの塩類に関する。TECHNICAL FIELD OF THE INVENTION The present invention relates to acylaminohydroxyalkanoylamino and imino acids and esters, more specifically, as an antihypertensive agent on the basis of their angiotensin converting enzyme inhibitory activity, and further described below. X is by definition , A novel amino acid and imino acid compound and salts thereof which are also useful as analgesics based on the enkephalinase inhibitory activity.
発明の構成と効果 本発明に係る新規化合物は、下記式〔Ｉ〕で示され、そ
の薬理学的に許容しうる塩類も包含される。Structure and Effect of the Invention The novel compound according to the present invention is represented by the following formula [I] and includes its pharmacologically acceptable salts.
〔式中、Ｘは ｎは０、１または2; Ｒ25は炭素数１〜４の低級アルキルまたは Ｒ7水素、低級アルキル、ハロゲン、ヒドロキシ、 で示される１−もしくは２−ナフチル、 で示される置換１−もしくは２−ナフチル、 で示される１−もしくは２−ナフチルオキシ、 で示される置換１−もしくは２−ナフチルオキシ、−Ｓ
−低級アルキル、 で示される１−もしくは２−ナフチルチオ、または で示される置換１−もしくは２−ナフチルチオ； Ｒ8はハロゲン、 で示される１−もしくは２−ナフチルオキシ、 で示される置換１−もしくは２−ナフチルオキシ、−Ｓ
−低級アルキル、 で示される１−もしくは２−ナフチルチオ、または で示される置換１−もしくは２−ナフチルチオ； Ｒ9はケト、 Ｒ10はハロゲンまたは−Ｙ−Ｒ16； Ｒ11,R′11,R12およびＲ′12はそれぞれ個別に水素また
は低級アルキル、もしくはＲ′11,R12およびＲ′12が水
素でＲ11が Ｒ13は炭素数１〜４の低級アルキル、炭素数１〜４の低
級アルコキシ、炭素数１〜４の低級アルキルチオ、クロ
ロ、ブロモ、フルオロ、トリフルオロメチル、ヒドロキ
シ、フエニル、フエノキシ、フエニルチオまたはフエニ
ルメチル； Ｒ14は炭素数１〜４の低級アルキル、炭素数１〜４の低
級アルコキシ、炭素数１〜４の低級アルキルチオ、クロ
ロ、ブロモ、フルオロ、トリフルオロメチルまたはヒド
ロキシ； ｍは0,1,2,3または4; ｐは1,2または３（但しＲ13とＲ14のいずれかがメチ
ル、メトキシ、クロロまたはフルオロである場合、ｐは
１より大）； Ｒ15は水素または炭素数１〜４の低級アルキル； Ｙは酸素または硫黄； Ｒ16は炭素数１〜４の低級アルキル、 もしくは２個のＲ16が合して構成される非置換５〜６員
環式基、あるいは１個ないしそれ以上の環形成炭素原子
が低級アルキル（炭素数１〜４）置換基またはジ低級ア
ルキル（炭素数１〜４）置換基を有する置換５〜６員環
式基； Ｒ4は水素、低級アルキル、 −（CH2）m−シクロアルキル、 Ｒ5は水素、低級アルキル、 −（CH2）r−OH、−（CH2）r−NH2、 −（CH2）r−SH、−（CH2）r−Ｓ−低級アルキル、 ｒは１〜４の整数； Ｒ19は低級アルキル、ベンジルまたはフエネチル； Ｒ20は水素、低級アルキル、ベンジルまたはフエネチ
ル； Ｒ1は低級アルキル、ハロ置換低級アルキル、 Ｒ6は水素、低級アルキル、ベンジル、ベンズヒドリ
ル、薬理学的に許容しうる塩形成イオン、 Ｒ17は水素、低級アルキル、シクロアルキルまたはフエ
ニル； Ｒ18は水素、低級アルキル、低級アルコキシまたはフエ
ニル、 Ｒ24は水素、低級アルキル、 Ｒ21およびＲ22はそれぞれ別個に水素または低級アルキ
ル；および Ｒ23は低級アルキルを表わす〕 式〔Ｉ〕中、種々の記号の定義に用いた用語はそれぞれ
次の意義を有する。 [Where X is n is 0, 1 or 2; R 25 is lower alkyl having 1 to 4 carbon atoms or R 7 hydrogen, lower alkyl, halogen, hydroxy, 1- or 2-naphthyl represented by A substituted 1- or 2-naphthyl represented by 1- or 2-naphthyloxy represented by A substituted 1- or 2-naphthyloxy represented by
-Lower alkyl, 1- or 2-naphthylthio represented by, or A substituted 1- or 2-naphthylthio represented by: R 8 is halogen; 1- or 2-naphthyloxy represented by A substituted 1- or 2-naphthyloxy represented by
-Lower alkyl, 1- or 2-naphthylthio represented by, or A substituted 1- or 2-naphthylthio represented by: R 9 is keto, R 10 is halogen or -Y-R 16; is R 11 with R 11, R '11, R 12 and R' 12 are each independently hydrogen or lower alkyl or R '11, R 12 and R' 12, hydrogen R 13 is lower alkyl having 1 to 4 carbons, lower alkoxy having 1 to 4 carbons, lower alkylthio having 1 to 4 carbons, chloro, bromo, fluoro, trifluoromethyl, hydroxy, phenyl, phenoxy, phenylthio or phenylmethyl; R 14 is lower alkyl having 1 to 4 carbons, lower alkoxy having 1 to 4 carbons, lower alkyl having 1 to 4 carbons, chloro, bromo, fluoro, trifluoromethyl or hydroxy; m is 0, 1, 2, 3 or 4; p is 1, 2 or 3 (provided that either R 13 or R 14 is methyl, methoxy, chloro or fluoro, p is greater than 1); R 15 is hydrogen or 1 to 4 carbon atoms Lower alkyl; Y is oxygen or sulfur; R 16 is lower alkyl having 1 to 4 carbon atoms; Alternatively, an unsubstituted 5- or 6-membered cyclic group formed by combining two R 16 's, or a substituent in which one or more ring-forming carbon atoms is a lower alkyl (1 to 4 carbon atoms) or di-lower alkyl. substituted 5 to 6 membered cyclic group having a (1 to 4 carbon atoms) substituent; R 4 is hydrogen, lower alkyl, - (CH 2) m - cycloalkyl, R 5 is hydrogen, lower alkyl, - (CH 2) r -OH, - (CH 2) r -NH 2, - (CH 2) r -SH, - (CH 2) r -S- lower alkyl, r is an integer of 1 to 4; R 19 is lower alkyl, benzyl or phenethyl; R 20 is hydrogen, lower alkyl, benzyl or phenethyl; R 1 is lower alkyl, halo-substituted lower alkyl, R 6 is hydrogen, lower alkyl, benzyl, benzhydryl, a pharmacologically acceptable salt-forming ion, R 17 is hydrogen, lower alkyl, cycloalkyl or phenyl; R 18 is hydrogen, lower alkyl, lower alkoxy or phenyl, R 24 is hydrogen, lower alkyl, R 21 and R 22 each independently represent hydrogen or lower alkyl; and R 23 represents lower alkyl.] In the formula [I], the terms used in the definition of various symbols have the following meanings.
低級アルキルは炭素数７を越えない直鎖もしくは分枝基
を包含し、特に炭素数４を越えない低級アルキルが好ま
しく、メチルおよびエチルが最も好ましい。同様に、低
級アルコキシおよび低級アルキルチオは酸素または硫黄
に結合した前記のような低級アルキルを包含する。Lower alkyl includes a straight chain or branched group having not more than 7 carbon atoms, particularly lower alkyl having not more than 4 carbon atoms is preferable, and methyl and ethyl are most preferable. Similarly, lower alkoxy and lower alkylthio include lower alkyl as described above attached to oxygen or sulfur.
シクロアルキルは炭素数４〜７の飽和環式基を包含し、
このうちシクロペンチルおよびシクロヘキシルが最も好
ましい。Cycloalkyl includes a saturated cyclic group having 4 to 7 carbon atoms,
Of these, cyclopentyl and cyclohexyl are most preferred.
ハロゲンはクロロ、ブロモおよびフルオロを包含する。Halogen includes chloro, bromo and fluoro.
ハロ置換（低級）アルキルは、１個ないしそれ以上の水
素がクロロ、ブロモまたはフルオロで置換された前記の
ような低級アルキル基、たとえばトリフルオロメチル
（これが好ましい）、ペンタフルオロエチル、2,2,2−
トリクロロエチル、クロロメチル、ブロモメチルなどを
包含する。Halo-substituted (lower) alkyl means a lower alkyl group as defined above in which one or more hydrogen has been replaced by chloro, bromo or fluoro, such as trifluoromethyl (which is preferred), pentafluoroethyl, 2,2, 2-
Includes trichloroethyl, chloromethyl, bromomethyl and the like.
は、それぞれのアルキレン橋が結合し得るすべての環形
成炭素原子に結合し得ることを表す。 Represents that each alkylene bridge can be bonded to all ring-forming carbon atoms to which it can be bonded.
アルモキストらの米国特許第4329473号に、式： 〔式中、Ｒ1はアリール;R2はアリール、アルキルまたは
アルコキシ;R3は水素または低級アルキル;R4は水素また
はヒドロキシ；およびＲ5は水素または低級アルキルで
ある〕 のアンギオテンシン変換酵素抑制剤が開示されている。U.S. Pat. No. 4,329,473 to Almoquist et al. Has the formula: [Wherein R 1 is aryl; R 2 is aryl, alkyl or alkoxy; R 3 is hydrogen or lower alkyl; R 4 is hydrogen or hydroxy; and R 5 is hydrogen or lower alkyl]. Is disclosed.
本発明は、その最も広い観点において、前記置換アミノ
およびイミノ酸類並びにエステル類〔Ｉ〕、かかる化合
物を含む組成物、かかる化合物を薬剤として使用する方
法に関連する。The invention in its broadest aspect relates to said substituted amino and imino acids and esters [I], compositions containing such compounds and methods of using such compounds as medicaments.
本発明化合物〔Ｉ〕は、式： の化合物を通常の還元剤（たとえばホウ水素化ナトリウ
ム、シアノホウ水素化ナトリウム、水素化ジイソブチル
アルミニウム、水素化トリｔ−ブトキシアルミニウム・
リチウムなど）で処理することにより得られる。The compound [I] of the present invention has the formula: To a conventional reducing agent (eg sodium borohydride, sodium cyanoborohydride, diisobutylaluminum hydride, tri-t-butoxyaluminum hydride.
It is obtained by treating with lithium).
上記化合物〔II〕は各種の方法で製造することができ
る。たとえば、式： のケトカルボン酸を、式： Ｈ−Ｘ 〔IV〕 〔式中、Ｘの定義中のＲ6は容易に脱離しうる保護基
（たとえばベンジル、ベンズヒドリル、ｔ−ブチルな
ど）である〕 のアミノまたはイミノ酸エステルとカツプリングさせる
ことができる。このカツプリング反応は、ジシクロヘキ
シルカルボジイミドなどの触媒の存在下で行うのが好ま
しい。また上記酸〔III〕を酸クロリド、混合無水物、
対称無水物などの活性体に変換することも可能である。The above compound [II] can be produced by various methods. For example, the expression: An amino or imino of the formula: H-X [IV], wherein R 6 in the definition of X is a protecting group which can be easily removed (eg benzyl, benzhydryl, t-butyl, etc.). Can be coupled with acid esters. This coupling reaction is preferably carried out in the presence of a catalyst such as dicyclohexylcarbodiimide. Further, the above acid [III] is acid chloride, mixed anhydride,
It is also possible to convert it into an active form such as a symmetrical anhydride.
酸〔III〕は以下の手順で製造することができる。式： 〔式中、Protはｔ−ブトキシカルボニルなどの保護基で
ある〕 のアミノ酸を、ジシクロヘキシルカルボジイミドの存在
下２−ヒドロキシピリジン／乾燥ピリジンで処理するこ
とにより、式： のエステルに変換する。式： 〔式中、ハロはClまたはBrである〕 のハライドをマグネシウムで処理し、得られるグリニヤ
ル試薬を上記エステル〔VI〕と反応させて、式： の化合物を得る。The acid [III] can be produced by the following procedure. formula: [Wherein Prot is a protecting group such as t-butoxycarbonyl] by treatment with 2-hydroxypyridine / dry pyridine in the presence of dicyclohexylcarbodiimide to give the formula: Converted to the ester of. formula: [Wherein halo is Cl or Br] is treated with magnesium and the resulting Grignard reagent is reacted with the ester [VI] to give the formula: To obtain the compound of
保護基を脱離した後、式： の酸クロリドと反応させて、式： の中間体を得る。After removal of the protecting group, the formula: By reacting with the acid chloride of the formula: To obtain the intermediate.
中間体〔Ｘ〕を酸化し、ジヨーンズ（Jones）試薬（無
水クロム酸／希硫酸）で処理して、カルボン酸〔III〕
を得る。The intermediate [X] is oxidized and treated with a Jones reagent (chromic anhydride / dilute sulfuric acid) to give a carboxylic acid [III].
To get
ケト化合物〔II〕を製造する他の操作法については、ア
ルムキストらの米国特許第4329473号に開示されてい
る。Other procedures for making keto compounds [II] are disclosed in U.S. Pat. No. 4,329,473 to Almquist et al.
上述の反応において、Ｒ1、Ｒ3およびＲ5のいずれかま
たはそのすべてが である場合、反応の間にこれらの基中のヒドロキシル、
アミノ、イミダゾリル、メルカプタンまたはグアニジル
基を保護すべきである。好適な保護基としては、ベンジ
ルオキシカルボニル、ｔ−ブトキシカルボニル、ベンジ
ル、ベンズヒドリル、トリチル等およびニトロ（グアニ
ジルの場合）が包含される。水素添化、酸処理または他
の公知方法で保護基を脱離してから、反応を完了する。In the above reaction, any or all of R 1 , R 3 and R 5 The hydroxyls in these groups during the reaction,
The amino, imidazolyl, mercaptan or guanidyl groups should be protected. Suitable protecting groups include benzyloxycarbonyl, t-butoxycarbonyl, benzyl, benzhydryl, trityl and the like and nitro (in the case of guanidyl). The protecting group is removed by hydrogenation, acid treatment or other known method, and then the reaction is completed.
Ｒ6が である式〔Ｉ〕のエステル生成物は、上述の既存エステ
ル基との反応において式〔IV〕のアミノまたはイミノ酸
を用いることにより得ることができる。かかるエステル
反応体は、Ｒ6が水素である式〔IV〕のアミノまたはイ
ミノ酸を などの酸クロリドまたはジ−ｔ−ブチルカーボネートで
処理してＮ原子を保護することにより製造することがで
きる。次いで、保護された化合物を塩基の存在下、式： （Ｌは塩素、臭素、トリルスルホニルなどの脱離可能
基） の化合物と反応させた後、例えば酸処理または水素添化
でＮ−保護基を脱離する。R 6 is The ester product of the formula [I] which is can be obtained by using the amino or imino acid of the formula [IV] in the reaction with the above existing ester group. Such ester reactants include amino or imino acids of formula [IV] where R 6 is hydrogen. Can be prepared by treatment with acid chloride or di-t-butyl carbonate to protect the N atom. The protected compound is then treated in the presence of a base with the formula: (L is a removable group such as chlorine, bromine or tolylsulfonyl) and then the N-protecting group is removed by, for example, acid treatment or hydrogenation.
またＲ6が である式〔Ｉ〕のエステル生成物は、Ｒ6が水素である
式〔Ｉ〕の生成物をモル過剰の式〔XI〕の化合物で処理
することによつても得ることができる。R 6 is The ester product of formula [I] which is: can also be obtained by treating a product of formula [I] in which R 6 is hydrogen with a molar excess of a compound of formula [XI].
である式〔Ｉ〕のエステル生成物は、Ｒ6が水素である
式〔Ｉ〕の生成物をモル過剰の式： の化合物で処理することにより製造することができる。 The ester product of formula [I] which is: is a molar excess of the product of formula [I] in which R 6 is hydrogen: It can be produced by treating the compound with.
Ｒ6が−CH−（CH2−OH）2または である式〔Ｉ〕のエステル生成物は、Ｒ6が水素である
式〔Ｉ〕の生成物をカツプリング剤（例えばジシクロヘ
キシルカルボジイミド）の存在下、モル過剰の式： の化合物とカツプリングした後ヒドロキシル保護基を脱
離することにより製造することができる。同様に、Ｒ6
が−（CH2）2−Ｎ（CH3）2 または である式〔Ｉ〕のエステル生成物は、Ｒ6が水素である
式〔Ｉ〕の生成物をジシクロヘキシルカルボジイミドな
どのカツプリング剤の存在下、モル過剰の式： の化合物とカツプリングすることにより製造することが
できる。R 6 is -CH- (CH 2 -OH) 2 or An ester product of formula [I] wherein R 6 is hydrogen in the presence of a coupling agent (eg dicyclohexylcarbodiimide) in a molar excess of formula: The compound can be prepared by coupling with the compound of 1 and then removing the hydroxyl protecting group. Similarly, R 6
There - (CH 2) 2 -N ( CH 3) 2 or The ester product of formula [I] is a compound of formula [I] in which R 6 is hydrogen in the presence of a coupling agent such as dicyclohexylcarbodiimide in a molar excess of formula: It can be produced by coupling with the compound of
Ｒ7がアミノである式〔Ｉ〕の生成物は、Ｒ7がアジドで
ある式〔Ｉ〕の対応生成物を還元することによつて得ら
れてよい。The product of formula [I] in which R 7 is amino may be obtained by reducing the corresponding product of formula [I] in which R 7 is azide.
本発明において、好ましい化合物〔Ｉ〕を以下に列挙す
る。In the present invention, preferable compounds [I] are listed below.
Ｒ1が炭素数１〜４の直鎖または分枝状（低級）アルキ
ルまたは−（CH2）１〜４−NH2； Ｒ6が水素、炭素数１〜４の直鎖もしくは分枝状（低
級）アルキルまたはアルカリ金属イオン； Ｒ4がシクロヘキシルまたはフエニルでＲ5が水素； Ｒ4が水素でＲ5がメチル、−CH2−CH（CH3）2、 Ｒ7が水素、シクロヘキシル、炭素数１〜４の低級アル
コキシ、 （ｍは0,1または２、Ｒ13はメチル、メトキシ、メチル
チオ、クロロ、ブロモ、フルオロまたはヒドロキシ）； ｔが２または3; Ｒ2が Ｒ3が炭素数１〜４の直鎖または分枝状（低級）アルキ
ル、 Ｒ14がメチル、メトキシ、メチルチオ、Cl、Br、Ｆまた
はヒドロキシ である化合物〔Ｉ〕。 R 1 is linear or branched (lower) alkyl having 1 to 4 carbon atoms or — (CH 2 ) 1 to 4 —NH 2 ; R 6 is hydrogen, linear or branched having 1 to 4 carbon atoms ( Lower) alkyl or alkali metal ion; R 4 is cyclohexyl or phenyl, R 5 is hydrogen; R 4 is hydrogen and R 5 is methyl, —CH 2 —CH (CH 3 ) 2 , R 7 is hydrogen, cyclohexyl, lower alkoxy having 1 to 4 carbon atoms, (M is 0, 1 or 2, R 13 is methyl, methoxy, methylthio, chloro, bromo, fluoro or hydroxy); t is 2 or 3; R 2 is R 3 is a linear or branched (lower) alkyl having 1 to 4 carbon atoms, A compound [I] in which R 14 is methyl, methoxy, methylthio, Cl, Br, F or hydroxy.
本発明において、最も好ましい化合物〔Ｉ〕を以下に列
挙する。In the present invention, the most preferable compound [I] is listed below.
Ｘが Ｒ1がメチル； Ｒ6が水素またはアルカリ金属イオン； Ｒ2がベンジル； Ｒ3がフエニル である化合物〔Ｉ〕。X is A compound [I] in which R 1 is methyl; R 6 is hydrogen or an alkali metal ion; R 2 is benzyl; and R 3 is phenyl.
Ｒ6が水素である本発明化合物〔Ｉ〕は種々の無機また
は有機塩基との塩を形成する。非毒性であつて薬理学的
に許容される塩が好ましいが、その他の塩も生成物を単
離または精製するのに有用である。このような薬理学的
に許容される塩類は、ナトリウム、カリウムまたはリチ
ウムのようなアルカリ金属の塩類、カルシウムまたはマ
グネシウムのようなアルカリ土類金属の塩類、アルギニ
ン、リシンなどのようなアミノ酸から誘導される塩類を
包含する。かかる塩は、本発明の酸型化合物と所望のイ
オンの供給塩基当量を、塩沈澱性媒体中で反応させる
か、または水性媒体中で反応させて凍結乾燥することに
より、得ることができる。The compound [I] of the present invention in which R 6 is hydrogen forms a salt with various inorganic or organic bases. Non-toxic and pharmaceutically acceptable salts are preferred, although other salts are useful in isolating or purifying the product. Such pharmacologically acceptable salts are derived from salts of alkali metals such as sodium, potassium or lithium, salts of alkaline earth metals such as calcium or magnesium, amino acids such as arginine, lysine and the like. Including salts. Such a salt can be obtained by reacting the acid type compound of the present invention with a supply base equivalent of a desired ion in a salt-precipitating medium or in an aqueous medium and freeze-drying.
式〔Ｉ〕中＊で表されるように、数個の不斉中心が存在
する。勿論、Ｒ3が水素の場合は存在する不斉中心は１
個少ない。このように本発明化合物〔Ｉ〕はジアステレ
オ異性体形状またはその混合物として存在することがで
きる。前記製造法において出発物質としてラセミ化合
物、エナンチオマーまたはジアステレオマーを使用する
ことができる。ジアステレオマー化合物を製造すると
き、この生成物を常套のクロマトグラフイーまたは分別
結晶法により分離することができる。As represented by * in formula [I], there are several asymmetric centers. Of course, when R 3 is hydrogen, the existing asymmetric center is 1
There are few. As described above, the compound [I] of the present invention can exist in a diastereoisomeric form or a mixture thereof. A racemate, an enantiomer or a diastereomer can be used as a starting material in the above-mentioned production method. When producing diastereomeric compounds, the products may be separated by conventional chromatographic or fractional crystallization methods.
イミノ酸環がモノ置換されている本発明化合物〔Ｉ〕は
シス−トランス異性を現わす。最終生成物の配置は出発
物質〔IV〕中のＲ7,R8およびＲ9置換基の配置に依存す
る。The compound [I] of the present invention in which the imino acid ring is mono-substituted exhibits cis-trans isomerism. The configuration of the final product depends on the configuration of the R 7 , R 8 and R 9 substituents in the starting material [IV].
本発明化合物〔Ｉ〕およびその薬理学的に許容される塩
類は、血圧降下剤である。これらの化合物はデカペプチ
ドであるアンギオテンシンＩのアンギオテンシンIIへの
変換を抑制し、それ故アンギオテンシン関連性高血圧症
を軽減または緩和させるのに有用である。アンギオテン
シノーゲン、血中シユードグロブリンに対する酵素レニ
ンの作用によりアンギオテンシンＩを産生する。アンギ
オテンシンＩはアンギオテンシン変換酵素（ACE）によ
りアンギオテンシンIIに変換する。アンギオテンシンII
は血圧上昇活性物質であつて、種々の哺乳類（たとえば
ヒト）の種々の類型の高血圧の原因となる物質として関
連性がある。本発明化合物は、アンギオテンシン変換酵
素を抑制し、血圧上昇活性物質アンギオテンシンIIの生
成を減退または阻止することにより、アンギオテンシン
ノーゲン→（レニン）→アンギオテンシンＩ→アンギオ
テンシンII系に介在する。このように、本発明化合物１
種（または混合物）を含む組成物を投与することによ
り、高血圧症の哺乳類（たとえばヒト）のアンギオテン
シン依存性高血圧を軽減させることができる。血圧を降
下させるため、約0.1〜100mg（好ましくは約１〜50mg）
/kg（体重）／日の投与量を基準としこれを１日当たり
１回好ましくは２〜４回に分けて投与するのが適当であ
る。活性物質は経口的に投与するのが好ましいが、皮
下、筋肉内、静脈内または腹腔内のような非経口的に投
与してもよい。The compound [I] of the present invention and pharmaceutically acceptable salts thereof are blood pressure lowering agents. These compounds inhibit the conversion of the decapeptide angiotensin I to angiotensin II and are therefore useful in reducing or ameliorating angiotensin-related hypertension. Angiotensin I is produced by the action of the enzyme renin on angiotensinogen and blood shroud globulin. Angiotensin I is converted to angiotensin II by angiotensin converting enzyme (ACE). Angiotensin II
Is a blood pressure-increasing active substance and is relevant as a causative agent of various types of hypertension in various mammals (eg, humans). The compound of the present invention inhibits angiotensin-converting enzyme and reduces or blocks the production of angiotensin II, which is a blood pressure-increasing active substance, and thereby mediates angiotensin nogen → (renin) → angiotensin I → angiotensin II system. Thus, the compound 1 of the present invention
Angiotensin-dependent hypertension in hypertensive mammals (eg, humans) can be reduced by administering a composition comprising the species (or mixture). About 0.1 to 100 mg (preferably about 1 to 50 mg) to lower blood pressure
It is appropriate to administer this dose once a day, preferably 2 to 4 times a day, based on the dose of / kg (body weight) / day. The active substance is preferably administered orally, but it may also be administered parenterally, such as subcutaneously, intramuscularly, intravenously or intraperitoneally.
また本発明化合物はこれを高血圧症治療のための利尿剤
と組み合わせて製剤することができる。本発明化合物と
利尿剤を組み合わせて成る薬剤は、これを必要とする哺
乳類に、１日当たり本発明化合物約30〜600mg、好まし
くは約30〜330mgと利尿剤約15〜300mg、好ましくは約15
〜200mgから成る有効量で投与することができる。本発
明化合物と組み合わせて使用するために計画される利尿
剤の例として、チアジド利尿剤たとえばクロロチアジ
ド、ヒドロクロロチアジド、フルメチアジド、ヒドロフ
ルメチアジド、ベンドロフルメチアジド、メチクロチア
ジド、トリクロロメチアジド、ポリチアジドまたはベン
ズチアジド、およびエタクリン酸、チクリナフエン、ク
ロルタリドン、フロセミド、ムソリミン、ブメタニド、
トリアムテレン、アミロリド、スピロノラクトンおよび
これらの化合物の塩類があげられる。Further, the compound of the present invention can be formulated in combination with a diuretic for treating hypertension. A drug comprising the compound of the present invention and a diuretic in combination is administered to a mammal in need thereof in an amount of about 30 to 600 mg, preferably about 30 to 330 mg, and about 15 to 300 mg, preferably about 15 of the diuretic compound of the present invention per day.
It can be administered in an effective amount consisting of ~ 200 mg. Examples of diuretics contemplated for use in combination with the compounds of the present invention include thiazide diuretics such as chlorothiazide, hydrochlorothiazide, flumethiazide, hydroflumethiazide, bendroflumethiazide, methiclotiazide, trichloromethiazide, polythiazide or benzthiazide. , And ethacrynic acid, ticrinafuene, chlorthalidone, furosemide, mussolimine, bumetanide,
Examples include triamterene, amiloride, spironolactone and salts of these compounds.
血圧を降下させるのに使用するため、本発明化合物を経
口投与用錠剤、カプセル剤まはたエリキシル剤のような
組成物、あるいは非経口投与用滅菌液もしくは懸濁液と
して製剤することができる。許容される薬理学的慣行に
適合する単位投与剤型中に本発明化合物〔Ｉ〕約10〜50
0mgを、生理学的に許容される媒体、担体、賦形剤、結
合剤、保存剤、安定剤、香味剤などに配合する。これら
の組成物または薬剤中の活性物質の量は前記のような必
要な投与量が投与されるような量とすべきである。For use in lowering blood pressure, the compounds of the present invention can be formulated as compositions such as tablets for oral administration, capsules or elixirs, or sterile solutions or suspensions for parenteral administration. About 10-50 of the compound [I] of the present invention in unit dosage form compatible with acceptable pharmacological practice.
0 mg is mixed with a physiologically acceptable medium, carrier, excipient, binder, preservative, stabilizer, flavoring agent and the like. The amount of active substance in these compositions or medicaments should be such that the required dosages as indicated above are administered.
また本発明のＸが である化合物〔Ｉ〕はエンケフアリナーゼ抑制活性を有
し、鎮痛剤としても有用である。それ故このような化合
物〔Ｉ〕またはその薬理学的に許容される塩類の１種な
いし混合物を含有する組成物を投与することにより、哺
乳類の苦痛を軽減することができる。活性化合物約0.1
〜100mg（好ましくは約１〜50mg）/kg（体重）／日の投
与量を基準としてこれを１日当たり１回、好ましくは２
〜４回に分けて投与することにより所望の沈痛活性を現
わす。組成物は経口的に投与するのが好ましいが、皮下
投与のような非経口的方法で投与してもよい。In addition, X of the present invention is The compound [I] having the formula (1) has an enkephalinase inhibitory activity and is also useful as an analgesic. Therefore, the pain of mammals can be reduced by administering a composition containing one or a mixture of the compound [I] or a pharmaceutically acceptable salt thereof. Active compound about 0.1
~ 100 mg (preferably about 1-50 mg) / kg (body weight) / day based on the dose once a day, preferably 2
The desired analgesic activity is exhibited by the administration in 4 divided doses. The composition is preferably administered orally, but may be administered parenterally, such as subcutaneously.
次に実施例をあげて本発明化合物を具体的に説明する。
実施例中、温度単位は℃である。Next, the compounds of the present invention will be specifically described with reference to examples.
In the examples, the temperature unit is ° C.
実施例１ （2R,5S）−１−［５−（ベンゾイルアミノ）−４−ヒ
ドロキシ−２−メチル−１−オキソ−６−フェニルヘキ
シル］−Ｌ−プロリンの製造：− ａ）１−ブロモ−２−メチル−３−ブテン 乾燥ジクロロメタン中の２−メチル−３−ブテン−１−
オール（15.0g、0.174モル）およびジイソプロピルエチ
ルアミン（45.5ml、1.5当量）の溶液にアルゴン下−10
°で、メタンスルホニルクロリド（15ml、1.1当量）を1
5分にわたって滴下する。−10°〜０°で１時間撹拌
後、得られる混合物を水、1N−塩酸（２回）、1N−重炭
酸ナトリウムおよび塩水で洗う。MgSO4上で乾燥後、溶
媒を減圧除去してメシレートを黄色油状物で得る。TLC
（シリカゲル、エーテル）,Rf＝0.54。Example 1 Preparation of (2R, 5S) -1- [5- (benzoylamino) -4-hydroxy-2-methyl-1-oxo-6-phenylhexyl] -L-proline: -a) 1-Bromo- 2-Methyl-3-butene 2-Methyl-3-butene-1-in dry dichloromethane
A solution of all (15.0 g, 0.174 mol) and diisopropylethylamine (45.5 ml, 1.5 eq) under argon-10
At 1 °, add methanesulfonyl chloride (15 ml, 1.1 eq) to 1
Add dropwise over 5 minutes. After stirring for 1 hour at -10 ° to 0 °, the resulting mixture is washed with water, 1N-hydrochloric acid (twice), 1N-sodium bicarbonate and brine. After drying over MgSO 4 , the solvent was removed under reduced pressure to give the mesylate as a yellow oil. TLC
(Silica gel, ether), Rf = 0.54.
乾燥ジメチルホルムアミド（80ml）中の上記粗メシレー
ト（約0.174モル）および臭化リチウム（30.22g、２当
量）の混合物をアルゴン下、100°で1.5時間加熱する。
冷却後混合物を水（100ml）で希釈し、ペンタン（150ml
×２）で抽出する。ペンタン抽出物をコンバインし、
水、1N−重炭酸ナトリウムおよび塩水で洗う。無水MgSO
4上で乾燥後、溶媒を大気圧で留去する。残渣を蒸発し
て16.49gの１−ブロモ−２−メチル−３−ブテンを無色
液体で得る。b.p.111°〜115°。A mixture of the above crude mesylate (about 0.174 mol) and lithium bromide (30.22 g, 2 eq) in dry dimethylformamide (80 ml) is heated at 100 ° under argon for 1.5 hours.
After cooling the mixture was diluted with water (100ml) and then pentane (150ml).
Extract with × 2). Combine the pentane extract,
Wash with water, 1N-sodium bicarbonate and brine. Anhydrous MgSO
After drying on 4 , the solvent is distilled off at atmospheric pressure. The residue is evaporated to give 16.49 g of 1-bromo-2-methyl-3-butene as a colorless liquid. bp111 ° ~ 115 °.
ｂ）Ｎ−［（1,1−ジメチルエトキシ）カルボニル］−
Ｌ−フェニルアラニン・２−ピリジルエステル 乾燥ピリジン（130ml）中のＮ−［（1,1−ジメチルエト
キシ）カルボニル］−Ｌ−フェニルアラニン（18.1g、6
8.2ミリモル）および新しく昇華した２−ヒドロキシピ
リジン（7.13g、1.1当量）の０°溶液にアルゴン下、ジ
シクロヘキシルカルボジイミド（15.5g、1.1当量）を加
える。０°で２時間撹拌後、反応混合物を０°で２日間
保持する。次いでこれを過してジシクロヘキシルウレ
アを除去し、ピリジンを室温で減圧（約0.1mmHg）除去
する。残渣を酢酸エチルに溶解し、再過して更にジシ
クロヘキシルウレアを除去する。液を氷冷水（２
回）、氷冷1N−重炭酸ナトリウムおよび塩水で洗う。無
水MgSO4上で乾燥後、溶媒を減圧除去する。残渣をシク
ロヘキサンで２回追い出し（chase）、残りのピリジン
を除去する。過およびシクロヘキサンで洗浄後、18.9
5gのＮ−［（1,1−ジメチルエトキシ）カルボニル］−
Ｌ−フェニルアラニン・２−ピリジルエステルを無色固
体で得る。b) N-[(1,1-dimethylethoxy) carbonyl]-
L-phenylalanine 2-pyridyl ester N-[(1,1-dimethylethoxy) carbonyl] -L-phenylalanine (18.1 g, 6 in dry pyridine (130 ml)
To a 0 ° solution of 8.2 mmol) and freshly sublimed 2-hydroxypyridine (7.13 g, 1.1 eq) under argon was added dicyclohexylcarbodiimide (15.5 g, 1.1 eq). After stirring for 2 hours at 0 °, the reaction mixture is kept at 0 ° for 2 days. It is then passed over to remove dicyclohexylurea and the pyridine is removed at room temperature under reduced pressure (about 0.1 mmHg). The residue is dissolved in ethyl acetate and filtered again to remove further dicyclohexylurea. Liquid is ice-cold water (2
Times), wash with ice cold 1N sodium bicarbonate and brine. After drying over anhydrous MgSO 4 , the solvent is removed under reduced pressure. The residue is chase twice with cyclohexane to remove residual pyridine. After washing with excess and cyclohexane, 18.9
5 g of N-[(1,1-dimethylethoxy) carbonyl]-
L-Phenylalanine 2-pyridyl ester is obtained as a colorless solid.
ｃ）（6S）−６−［［（1,1−ジメチルエトキシ）カル
ボニル］アミノ］−３−メチル−５−オキソ−７−フェ
ニル−１−ヘプテン 無水テトラヒドロフラン（30ml）中の１−ブロモ−２−
メチル−３−ブテン（3.8g、25.7ミリモル）およびマグ
ネシウム削り屑（0.94g、38.6ミリモル）の混合物をア
ルゴン下、室温にて超音波クリーナーで２時間照射し
て、対応するグリニヤル試薬を得る。c) (6S) -6-[[(1,1-Dimethylethoxy) carbonyl] amino] -3-methyl-5-oxo-7-phenyl-1-heptene 1-Bromo-2 in anhydrous tetrahydrofuran (30 ml). −
A mixture of methyl-3-butene (3.8 g, 25.7 mmol) and magnesium shavings (0.94 g, 38.6 mmol) was irradiated with an ultrasonic cleaner at room temperature under argon for 2 hours to give the corresponding Grignard reagent.
無水テトラヒドロフラン（25ml）中のＮ−［（1,1−ジ
メチルエトキシ）カルボニル］−Ｌ−フェニルアラニン
・２−ピリジルエステル（4.0g、11.7ミリモル）の−５
°溶液にアルゴン下、上記グリニヤル試薬を15分にわた
って滴下する。得られる混合物を−５°〜０°で2.5時
間撹拌し、次いで10％塩化アンモニウムで反応を抑え
る。混合物をエーテルで抽出し、エーテル抽出物を水、
1N−塩酸（２回）、1N−重炭酸ナトリウムおよび塩水で
連続して洗う。無水MgSO4上で乾燥後、溶媒を減圧除去
して淡黄色油状物を得る。この物質を同実験で得たもの
とコンバインし、シリカゲルLPS−１にてヘキサン／ア
セトン（96:4）で溶離するフラッシュクロマトグラフィ
ーに付し、3.13g（42％）の（6S）−６−［［（1,1−ジ
メチルエトキシ）カルボニル］アミノ］−３−メチル−
５−オキソ−７−フェニル−１−ヘプテンを無色固体で
得る。TLC（シリカゲル、ヘキサン／アセトン4:1）,Rf
＝0.36。-5 of N-[(1,1-dimethylethoxy) carbonyl] -L-phenylalanine 2-pyridyl ester (4.0 g, 11.7 mmol) in anhydrous tetrahydrofuran (25 ml).
° The above Grignard reagent is added dropwise to the solution under argon over 15 minutes. The resulting mixture is stirred at -5 ° to 0 ° for 2.5 hours and then quenched with 10% ammonium chloride. The mixture is extracted with ether and the ether extract is extracted with water,
Wash successively with 1N-hydrochloric acid (twice), 1N-sodium bicarbonate and brine. After drying over anhydrous MgSO 4 , the solvent was removed under reduced pressure to give a pale yellow oil. This material was combined with that obtained in the same experiment and subjected to flash chromatography on silica gel LPS-1 eluting with hexane / acetone (96: 4) to give 3.13 g (42%) of (6S) -6- [[(1,1-Dimethylethoxy) carbonyl] amino] -3-methyl-
5-Oxo-7-phenyl-1-heptene is obtained as a colorless solid. TLC (silica gel, hexane / acetone 4: 1), Rf
= 0.36.
ｄ）（6S）−６−ベンゾイルアミノ−３−メチル−５−
オキソ−７−フェニル−１−ヘプテン トリフルオロ酢酸（50ml）中の（6S）−６−［［（1,1
−ジメチルエトキシ）カルボニル］アミノ］−３−メチ
ル−５−オキソ−７−フェニル−１−ヘプテン（3.13
g、9.86ミリモル）の溶液を０°で30分、室温で２時間
撹拌する。トリフルオロ酢酸を減圧除去し、トルエンで
２回追い出して黄褐色油状物を得る。次いでこの物質を
無水テトラヒドロフラン（60ml）に溶解し、得られる溶
液を重炭酸ナトリウム（6.0g、7.14ミリモル）および塩
化ベンゾイル（4.0ml、34.5ミリモル）で処理する。24
時間撹拌後、混合物を酢酸エチルで希釈し、得られる溶
液を水、1N−塩酸（２回）、1N−重炭酸ナトリウムおよ
び塩水で洗う、無水MgSO4上で乾燥後、溶媒を減圧除去
して淡黄色固体を得る。ヘキサン／酢酸エチルより再結
晶して、1.56gの（6S）−６−ベンゾイルアミノ−３−
メチル−５−オキソ−７−フェニル−１−ヘプテンを無
色固体で得る。TLC（シリカゲル、ヘキサン／酢酸エチ
ル）,Rf＝0.39。d) (6S) -6-benzoylamino-3-methyl-5-
Oxo-7-phenyl-1-heptene (6S) -6-[[(1,1
-Dimethylethoxy) carbonyl] amino] -3-methyl-5-oxo-7-phenyl-1-heptene (3.13
g, 9.86 mmol) at 0 ° for 30 minutes and at room temperature for 2 hours. Trifluoroacetic acid was removed under reduced pressure and chased with toluene twice to give a tan oil. This material is then dissolved in anhydrous tetrahydrofuran (60ml) and the resulting solution treated with sodium bicarbonate (6.0g, 7.14mmol) and benzoyl chloride (4.0ml, 34.5mmol). twenty four
After stirring for an hour, the mixture was diluted with ethyl acetate and the resulting solution was washed with water, 1N-hydrochloric acid (twice), 1N-sodium bicarbonate and brine, dried over anhydrous MgSO 4 and the solvent removed under reduced pressure. A light yellow solid is obtained. Recrystallize from hexane / ethyl acetate to give 1.56 g of (6S) -6-benzoylamino-3-
Methyl-5-oxo-7-phenyl-1-heptene is obtained as a colorless solid. TLC (silica gel, hexane / ethyl acetate), Rf = 0.39.
ｅ）（5S）−ベンゾイルアミノ−２−メチル−４−オキ
ソ−６−フェニルヘキサン酸 メタノール／ジクロロメタン（1:1、50ml）中の（6S）
−６−ベンゾイルアミノ−３−メチル−５−オキソ−７
−フェニル−１−ヘプテン（970mg、3.02ミリモル）の
溶液を−78°で、青色が持続するまでオゾン／酸素流で
処理する。混合物を更に30分撹拌し、次いで窒素流で過
剰のオゾンを除去する。ジメチルスルフィド１（4ml）
を加え、混合物を室温まで温める。５時間後溶媒を減圧
除去し、アセトンで３回追い出し、次いで残渣をアセト
ン（35ml）に溶解する。０°で冷却後、溶液に10mlのジ
ョーンズ試薬（無水クロム酸／希硫酸）を滴下して処理
する。15分撹拌後、混合物を室温まで温める。30分撹拌
後、混合物を再度０°に冷却し、過剰のイソプロピルア
ルコールで反応を抑える。酢酸エチルで希釈後、得られ
る溶液を水（３回）および塩水で洗う。無水MgSO4上で
乾燥後、溶媒を減圧除去して粗生成物をほぼ無色固体で
得る。この物質をエーテルと1N−重炭酸ナトリウム間に
分配する。水性画分をエーテルで洗い、エーテル画分を
廃棄する。水性画分を10％塩酸を酸性化し、酢酸エチル
（200ml×２）で抽出する。抽出物をコンバインし、水
および塩水で洗う。無水MgSO4上で乾燥後、溶媒を減圧
除去して0.9gの（5S）−ベンゾイルアミノ−２−メチル
−４−オキソ−６−フェニルヘキサン酸を無色固体で得
る。TLC（シリカゲル、酢酸エチル／ピリジン／酢酸／
水＝350:20:6:11）,Rf＝0.51。e) (5S) -Benzoylamino-2-methyl-4-oxo-6-phenylhexanoic acid (6S) in methanol / dichloromethane (1: 1, 50 ml).
-6-benzoylamino-3-methyl-5-oxo-7
A solution of -phenyl-1-heptene (970 mg, 3.02 mmol) is treated at -78 ° with a stream of ozone / oxygen until the blue color persists. The mixture is stirred for a further 30 minutes and then a stream of nitrogen is used to remove excess ozone. Dimethyl sulfide 1 (4 ml)
Is added and the mixture is warmed to room temperature. After 5 hours the solvent was removed under reduced pressure, chased with acetone three times, then the residue was dissolved in acetone (35 ml). After cooling at 0 °, the solution is treated dropwise with 10 ml Jones reagent (chromic anhydride / dilute sulfuric acid). After stirring for 15 minutes, the mixture is warmed to room temperature. After stirring for 30 minutes, the mixture is cooled again to 0 ° and quenched with excess isopropyl alcohol. After diluting with ethyl acetate, the resulting solution is washed with water (3 times) and brine. After drying over anhydrous MgSO 4 , the solvent was removed under reduced pressure to obtain a crude product as an almost colorless solid. This material is partitioned between ether and 1N sodium bicarbonate. Wash the aqueous fraction with ether and discard the ether fraction. The aqueous fraction is acidified with 10% hydrochloric acid and extracted with ethyl acetate (200 ml x 2). Combine the extracts and wash with water and brine. After drying over anhydrous MgSO 4 , the solvent was removed under reduced pressure to give 0.9 g of (5S) -benzoylamino-2-methyl-4-oxo-6-phenylhexanoic acid as a colorless solid. TLC (silica gel, ethyl acetate / pyridine / acetic acid /
Water = 350: 20: 6: 11), Rf = 0.51.
ｆ）（2R,5S）−１−［５−（ベンゾイルアミノ）−２
−メチル−1,4−ジオキソ−６−フェニルヘキシル］−
Ｌ−プロリン・フェニルメチルエステル 無水テトラヒドロフラン中の（5S）−ベンゾイルアミノ
−２−メチル−４−オキソ−６−フェニルヘキサン酸
（0.98g、2.88ミリモル）、Ｌ−プロリン・フェニルメ
チルエステル・塩酸塩（0.767g、1.1当量）、１−ヒド
ロキシベンゾトリアゾール水和物（398ミリグラム、1.0
2当量）の０°溶液にアルゴン下、ジイソプロピルエチ
ルアミン（0.53ml、1.05当量）を加える。得られる混合
物に、テトラヒドロフラン（3ml）中のジシクロヘキシ
ルカルボジイミド（0.60g、1.0当量）の溶液を加える。
０°で１時間撹拌後、混合物を室温まで温め、22時間撹
拌する。得られる混合物を過してジシクロヘキシルウ
レアを除去し、液を酢酸エチルで希釈し、水、1N−塩
酸（２回）、1N−重炭酸ナトリウムおよび塩水で洗う。
無水MgSO4上で乾燥後、溶媒を減圧除去して黄色油状物
を得る。この物質を小規模工程の粗物質とコンバイン
し、シリカゲルLPS−１にてシクロヘキサン／アセトン
（3:1）で溶離するフラッシュクロマトグラフィーに付
し、1.6gの（2R,2S），（5S）−１−［５−（ベンゾイ
ルアミノ）−２−メチル−1,4−ジオキソ−６−フェニ
ルヘキシル］−Ｌ−プロリン・フェニルメチルエステル
（ジアステレオマー混合物）を淡黄色油状物で得る。TL
C（シリカゲル、シクロヘキサン／アセトン＝3:1）,Rf
＝0.18。f) (2R, 5S) -1- [5- (benzoylamino) -2
-Methyl-1,4-dioxo-6-phenylhexyl]-
L-proline phenylmethyl ester (5S) -benzoylamino-2-methyl-4-oxo-6-phenylhexanoic acid (0.98 g, 2.88 mmol) in anhydrous tetrahydrofuran, L-proline phenylmethyl ester hydrochloride ( 0.767 g, 1.1 eq), 1-hydroxybenzotriazole hydrate (398 mg, 1.0
To a 0 ° solution of 2 eq) under argon was added diisopropylethylamine (0.53 ml, 1.05 eq). To the resulting mixture is added a solution of dicyclohexylcarbodiimide (0.60 g, 1.0 eq) in tetrahydrofuran (3 ml).
After stirring for 1 hour at 0 °, the mixture is warmed to room temperature and stirred for 22 hours. The resulting mixture is passed to remove dicyclohexylurea, the solution is diluted with ethyl acetate and washed with water, 1N-hydrochloric acid (twice), 1N-sodium bicarbonate and brine.
After drying over anhydrous MgSO 4 , the solvent was removed under reduced pressure to give a yellow oil. This material was combined with the crude material from a small scale step and subjected to flash chromatography on silica gel LPS-1 eluting with cyclohexane / acetone (3: 1) to give 1.6 g of (2R, 2S), (5S)- 1- [5- (Benzoylamino) -2-methyl-1,4-dioxo-6-phenylhexyl] -L-proline phenylmethyl ester (mixture of diastereomers) is obtained as a pale yellow oil. TL
C (silica gel, cyclohexane / acetone = 3: 1), Rf
= 0.18.
このエステルのジアステレオマー混合物を等量部に分
け、それぞれの部分を同カラムにてフラッシュクロマト
グラフィー（シリカゲルLPS−１、ベンゼン／アセトン
＝4:1で溶離）に付す。所望ジアステレオマーを含む画
分をコンバインし、混合画分を上記分離に用いた同じカ
ラムにて、再度クロマトグラフィーに付す。所望ジアス
テレオマーを含む画分をコンバインし、溶媒を減圧除去
して0.60gの（2R,5S）−１−［５−（ベンゾイルアミ
ノ）−２−メチル−1,4−ジオキソ−６−フェニルヘキ
シル］−Ｌ−プロリン・フェニルメチルエステルを無色
油状物で得る。TLC（シリカゲル、ベンゼン／アセトン
＝4:1）,Rf＝0.33。The diastereomeric mixture of this ester is divided into equal parts and each part is subjected to flash chromatography on the same column (silica gel LPS-1, eluting with benzene / acetone = 4: 1). Fractions containing the desired diastereomer are combined and the mixed fractions are rechromatographed on the same column used for the above separations. Fractions containing the desired diastereomer were combined and the solvent removed under reduced pressure to give 0.60 g of (2R, 5S) -1- [5- (benzoylamino) -2-methyl-1,4-dioxo-6-phenyl. Hexyl] -L-proline phenylmethyl ester is obtained as a colorless oil. TLC (silica gel, benzene / acetone = 4: 1), Rf = 0.33.
ｇ）（2R,5S）−１−［５−（ベンゾイルアミノ）−２
−メチル−1,4−ジオキソ−６−フェニルヘキシル］−
Ｌ−プロリン 酢酸エチル（35ml）中の上記（ｆ）のエステル生成物
（0.57g、1.08ミリモル）および10％パラジウム／炭素
触媒（106mg）の混合物を水素（バルーン）下で６時間
撹拌する。得られる混合物をミリポア過し、液を減
圧濃縮する。減圧乾燥後、430mgの（2R,5S）−１−［５
−（ベンゾイルアミノ）−２−メチル−1,4−ジオキソ
−６−フェニルヘキシル］−Ｌ−プロリンをガラス状固
体で得る。▲［α］20 D▼＝−95.7°（Ｃ＝1.14、95％
エタノール）。TLC（シリカゲル、酢酸エチル／ピリジ
ン／酢酸／水＝180:20:6:11）,Rf＝0.27。g) (2R, 5S) -1- [5- (benzoylamino) -2
-Methyl-1,4-dioxo-6-phenylhexyl]-
L-Proline A mixture of the ester product of (f) above (0.57 g, 1.08 mmol) and 10% palladium on carbon catalyst (106 mg) in ethyl acetate (35 ml) is stirred under hydrogen (balloon) for 6 hours. The resulting mixture is passed through a millipore and the liquid is concentrated under reduced pressure. After drying under reduced pressure, 430 mg of (2R, 5S) -1- [5
-(Benzoylamino) -2-methyl-1,4-dioxo-6-phenylhexyl] -L-proline is obtained as a glassy solid. ▲ [α] 20 D ▼ = -95.7 ° (C = 1.14, 95%
ethanol). TLC (silica gel, ethyl acetate / pyridine / acetic acid / water = 180: 20: 6: 11), Rf = 0.27.
元素分析（C25H28N2O5・0.25CH3COOC2H5として） 計算値:C68.10、H6.64、N6.11 実測値:C68.08、H6.62、N5.95 ｈ）（2R,5S）−１−［５−（ベンゾイルアミノ）−４
−ヒドロキシ−２−メチル−１−オキソ−６−フェニル
ヘキシル］−Ｌ−プロリン テトラヒドロフラン（4ml）および水（1ml）中の（2R,5
S）−１−［５−（ベンゾイルアミノ）−２−メチル−
1,4−ジオキソ−６−フェニルヘキシル］−Ｌ−プロリ
ン（110mg、0.252ミリモル）の溶液に０°で、ホウ水素
化ナトリウム（50mg、5.2当量）を加える。０°で15分
撹拌後、混合物を室温まで温める。2.5時間後、混合物
に1N−塩酸を加えて反応を抑え、酢酸エチルで抽出す
る。酢酸エチル画分を水、1N−塩酸（２回）、水および
塩水で洗う。無水MgSO4で乾燥後、溶媒を減圧除去して9
4mgの（2R,5S）−１−［５−（ベンゾイルアミノ）−４
−ヒドロキシ−２−メチル−１−オキソ−６−フェニル
ヘキシル］−Ｌ−プロリンを無色固体で得る。m.p.146
〜152°。▲［α］20 D▼＝−89.5°。TLC（シリカゲ
ル、酢酸エチル／ピリジン／酢酸／水＝100:20:6:11）,
Rf＝0.27。Elemental analysis (C 25 H 28 N 2 O 5 · 0.25CH 3 COOC 2 as H 5) Calculated: C68.10, H6.64, N6.11 Found: C68.08, H6.62, N5.95 h ) (2R, 5S) -1- [5- (benzoylamino) -4
-Hydroxy-2-methyl-1-oxo-6-phenylhexyl] -L-proline in tetrahydrofuran (4 ml) and water (1 ml) (2R, 5
S) -1- [5- (benzoylamino) -2-methyl-
To a solution of 1,4-dioxo-6-phenylhexyl] -L-proline (110 mg, 0.252 mmol) at 0 ° was added sodium borohydride (50 mg, 5.2 eq). After stirring for 15 minutes at 0 °, the mixture is warmed to room temperature. After 2.5 hours, 1N-hydrochloric acid was added to the mixture to quench the reaction, and the mixture was extracted with ethyl acetate. The ethyl acetate fraction is washed with water, 1N hydrochloric acid (twice), water and brine. After drying over anhydrous MgSO 4 , the solvent was removed under reduced pressure to
4 mg of (2R, 5S) -1- [5- (benzoylamino) -4
-Hydroxy-2-methyl-1-oxo-6-phenylhexyl] -L-proline is obtained as a colorless solid. mp146
~ 152 °. ▲ [α] 20 D ▼ = -89.5 °. TLC (silica gel, ethyl acetate / pyridine / acetic acid / water = 100: 20: 6: 11),
Rf = 0.27.
元素分析（C25H30N2O5として） 計算値:C68.47、H6.89、N6.39 実測値:C68.15、H6.99、N6.14 実施例２〜27 実施例１と同様に、下記欄Ｉに示すジケト化合物を還元
剤（好ましくはホウ水素化ナトリウム）で処理して、欄
IIに示すヒドロキシ生成物を得る。Elemental analysis (as C 25 H 30 N 2 O 5 ) Calculated value: C68.47, H6.89, N6.39 Measured value: C68.15, H6.99, N6.14 Examples 2 to 27 Example 1 and Similarly, treating the diketo compound shown in column I below with a reducing agent (preferably sodium borohydride),
The hydroxy product shown in II is obtained.
実施例16〜19のＲ1保護基および実施例25および26のＲ5
保護基を、合成の最終工程で除去する。 The R 1 protecting group of Examples 16-19 and R 5 of Examples 25 and 26.
The protecting group is removed in the final step of the synthesis.
実施例28〜40 （2R,5S）−１−［５−（ベンゾイルアミノ）−４−ヒ
ドロキシ−２−メチル−１−オキソ−６−フェニルヘキ
シル］−Ｌ−プロリンを下記欄Ｉの試薬で処理して、欄
IIの生成物を得る。Examples 28-40 Treating (2R, 5S) -1- [5- (benzoylamino) -4-hydroxy-2-methyl-1-oxo-6-phenylhexyl] -L-proline with the reagents in column I below. And then the column
The product of II is obtained.
実施例35〜40の場合、欄Ｉの試薬との反応はジシクロヘ
キシルカルボジイミドなどのカップリング剤の存在下で
行う。 For Examples 35-40, the reaction with the reagents in Column I is carried out in the presence of a coupling agent such as dicyclohexylcarbodiimide.
実施例41成分 mg （2R,5S）−１−［５−（ベンゾイルアミノ）−４−ヒ
ドロキシ−２−メチル−１−オキソ−６−フェニルヘキ
シル］−Ｌ−プロリン ……100 コーンスターチ …… 50 ゼラチン …… 7.5 アビセル（微結晶セルロース） …… 25 ステアリン酸マグネシウム …… 2.5 計 185 上記成分をそれぞれ含む1000個の錠剤を十分なバルク量
から調製する。すなわち、（2R,5S）−１−［５−（ベ
ンゾイルアミノ）−４−ヒドロキシ−２−メチル−１−
オキソ−６−フェニルヘキシル］−Ｌ−プロリンとコー
ンスターチを、ゼラチンの水溶液と混合し、混和物を乾
燥し、粉砕して微粉末とする。アゼビル、次いでステア
リン酸マグネシウムを粗砕しながら混合する。次いでこ
の混合物をタブレット成形機に打錠し、それぞれ100mg
の活性成分を含有する1000個の錠剤を形成する。Example 41 Component mg (2R, 5S) -1- [5- (benzoylamino) -4-hydroxy-2-methyl-1-oxo-6-phenylhexyl] -L-proline ...... 100 Corn starch ...... 50 Gelatin …… 7.5 Avicel (microcrystalline cellulose) …… 25 Magnesium stearate …… 2.5 Total 185 Prepare 1000 tablets each containing the above ingredients from a sufficient bulk quantity. That is, (2R, 5S) -1- [5- (benzoylamino) -4-hydroxy-2-methyl-1-
Oxo-6-phenylhexyl] -L-proline and corn starch are mixed with an aqueous solution of gelatin, the mixture is dried and ground to a fine powder. Azevir and then magnesium stearate are mixed with the granulation. The mixture is then tabletted on a tablet machine, 100 mg each.
1000 tablets containing 100 mg of the active ingredient are formed.
実施例２〜40の目的物質100mgを含有する錠剤について
も、同様に製剤することができる。また同様にして、50
mgの活性成分を含有する錠剤を作ることもできる。Tablets containing 100 mg of the target substance of Examples 2 to 40 can be similarly formulated. Similarly, 50
Tablets containing mg of active ingredient can also be made.
実施例42 50mgの（2R,5S）−１−［５−（ベンゾイルアミノ）−
４−ヒドロキシ−２−メチル−１−オキソ−６−フェニ
ルヘキシル］−Ｌ−プロリンをそれぞれ含有するツーピ
ース＃１ゼラチンカプセル剤に、下記成分混合物を充填
する。成分 mg （2R,5S）−１−［５−（ベンゾイルアミノ）−４−ヒ
ドロキシ−２−メチル−１−オキソ−６−フェニルヘキ
シル］−Ｌ−プロリン …… 50 ステアリン酸マグネシウム …… ７ ラクトース ……193 計 250 実施例２〜40の目的物質50mgを含有するカプセル剤につ
いても、同様に製剤することができる。Example 42 50 mg of (2R, 5S) -1- [5- (benzoylamino)-
Two-piece # 1 gelatin capsules, each containing 4-hydroxy-2-methyl-1-oxo-6-phenylhexyl] -L-proline, are filled with the following mixture of ingredients. Ingredient mg (2R, 5S) -1- [5- (Benzoylamino) -4-hydroxy-2-methyl-1-oxo-6-phenylhexyl] -L-proline ...... 50 Magnesium stearate …… 7 Lactose …… 193 Total 250 Capsules containing 50 mg of the target substance of Examples 2 to 40 can be similarly formulated.
実施例43 以下の手順に従って、注射液を調製する。成分 g （2R,5S）−１−［５−（ベンゾイルアミノ）−４−ヒ
ドロキシ−２−メチル−１−オキソ−６−フェニルヘキ
シル］−Ｌ−プロリン ……500 メチルパラベン …… ５ プロピルパラベン …… １ 塩化ナトリウム …… 25 注射用水 …… 5l 上記活性物質、保存剤および塩化ナトリウムを3lの注射
用水に溶解し、容量を5lとする。溶液を殺菌フィルター
で過し、これを殺菌バイアルに無菌的に充填し、殺菌
ゴム栓で閉鎖する。各バイアルは、活性成分100mg/mlの
濃度の注射液5mlを含有する。Example 43 An injection solution is prepared according to the following procedure. Component g (2R, 5S) -1- [5- (benzoylamino) -4-hydroxy-2-methyl-1-oxo-6-phenylhexyl] -L-proline ...... 500 methylparaben ...... 5 propylparaben ...... 1 Sodium chloride ...... 25 Water for injection ・ ・ ・ 5l Dissolve the above active substance, preservative and sodium chloride in 3l water for injection to make a volume of 5l. The solution is passed through a sterile filter, which is aseptically filled into sterile vials and closed with sterile rubber stoppers. Each vial contains 5 ml of injectable solution at a concentration of 100 mg / ml of active ingredient.
実施例２〜40の目的物質についても活性成分100mg/mlの
注射液を同様に調製することができる。For the target substances of Examples 2 to 40, injection solutions containing 100 mg / ml of active ingredient can be similarly prepared.
実施例44成分 mg （2R,5S）−１−［５−（ベンゾイルアミノ）−４−ヒ
ドロキシ−２−メチル−１−オキソ−６−フェニルヘキ
シル］−Ｌ−プロリン …… 100 アビセル ……100 ヒドロクロロチアジド …… 12.5 ラクトース ……113 コーンスターチ …… 17.5 ステアリン酸 …… 7 計 350 上記成分をそれぞれ含有する1000個の錠剤を十分なバル
ク量から調製する。すなわち、（2R,5S）−１−［５−
（ベンゾイルアミノ）−４−ヒドロキシ−２−メチル−
１−オキソ−６−フェニルヘキシル］−Ｌ−プロリン、
アビセルおよび一部のステアリン酸をスラッグし、該ス
ラッグを粉砕し、＃２スクリーンに通し、次いでヒドロ
クロロチアジド、ラクトース、コーンスターチ、および
残りのステアリン酸と混合する。混合物をタブレット成
形機にて350mgのカプセル型錠剤に打錠する。錠剤に半
分分割の刻み目を入れる。Example 4 4 component mg (2R, 5S) -1- [5- (benzoylamino) -4-hydroxy-2-methyl-1-oxo-6-phenylhexyl] -L-proline ...... 100 Avicel ...... 100 hydrochlorothiazide …… 12.5 Lactose …… 113 Corn starch …… 17.5 Stearic acid …… 7 Total 350 1000 tablets each containing the above ingredients are prepared from a sufficient bulk quantity. That is, (2R, 5S) -1- [5-
(Benzoylamino) -4-hydroxy-2-methyl-
1-oxo-6-phenylhexyl] -L-proline,
Slag Avicel and some stearic acid, grind the slug, pass through a # 2 screen, then mix with hydrochlorothiazide, lactose, corn starch, and rest of stearic acid. The mixture is tabletted on a tablet press into 350 mg capsule shaped tablets. Make a half-division score on the tablet.
実施例２〜40の目的物質100mgを含有する錠剤も、同様
にして製剤することができる。Tablets containing 100 mg of the target substance of Examples 2 to 40 can be similarly prepared.
───────────────────────────────────────────────────── フロントページの続き (51)Int.Cl.6 識別記号 庁内整理番号 ＦＩ 技術表示箇所 Ｃ０７Ｃ 323/59 7419−4Ｈ 323/60 7419−4Ｈ Ｃ０７Ｄ 205/04 7019−4Ｃ 207/16 207/20 209/42 8217−4Ｃ 209/52 8217−4Ｃ 213/64 217/26 231/06 233/64 １０５ 233/90 277/06 // Ａ６１Ｋ 31/215 9454−4Ｃ 31/22 9454−4Ｃ 31/40 ＡＢＵ 9454−4Ｃ 31/415 ＡＥＱ 9454−4Ｃ 31/425 ＡＥＤ 9454−4Ｃ 31/47 ＡＡＨ 9454−4Ｃ ─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. 6 Identification code Internal reference number FI Technical display location C07C 323/59 7419-4H 323/60 7419-4H C07D 205/04 7019-4C 207/16 207 / 20 209/42 8217-4C 209/52 8217-4C 213/64 217/26 231/06 233/64 105 233/90 277/06 // A61K 31/215 9454-4C 31/22 9454-4C 31/40 ABU 9454-4C 31/415 AEQ 9454-4C 31/425 AED 9454-4C 31/47 AAH 9454-4C
Claims (14)
シクロアルキル、 −Ｏ−低級アルキル、 で示される１−もしくは２−ナフチルオキシ、 で示される置換１−もしくは２−ナフチルオキシ、−Ｓ
−低級アルキル、 で示される１−もしくは２−ナフチルチオ、または で示される置換１−もしくは２−ナフチルチオ； で示される１−もしくは２−ナフチルオキシ、 で示される置換１−もしくは２−ナフチルオキシ、−Ｓ
−低級アルキル、 で示される１−もしくは２−ナフチルチオ、または で示される置換１−もしくは２−ナフチルチオ； Ｒ10はハロゲンまたは−Ｙ−Ｒ16； Ｒ11,R′11,R12およびＲ′12はそれぞれ個別に水素また
は低級アルキル、もしくはＲ′11,R12およびＲ′12が水
素でＲ11が Ｒ13は炭素数１〜４の低級アルキル、炭素数１〜４の低
級アルコキシ、炭素数１〜４の低級アルキルチオ、クロ
ロ、ブロモ、フルオロ、トリフルオロメチル、ヒドロキ
シ、フエニル、フエノキシ、フエニルチオまたはフエニ
ルメチル； Ｒ14は炭素数１〜４の低級アルキル、炭素数１〜４の低
級アルコキシ、炭素数１〜４の低級アルキルチオ、クロ
ロ、ブロモ、フルオロ、トリフルオロメチルまたはヒド
ロキシ； ｍは0,1,2,3または4; ｐは1,2または３（但しＲ13とＲ14のいずれかがメチ
ル、メトキシ、クロロまたはフルオロである場合、ｐは
１より大）； Ｒ15は水素または炭素数１〜４の低級アルキル； Ｙは酸素または硫黄； Ｒ16は炭素数１〜４の低級アルキル、 もしくは２個のＲ16が合して構成される非置換５〜６員
環式基、あるいは１個ないしそれ以上の環形成炭素原子
が低級アルキル（炭素数１〜４）置換基またはジ低級ア
ルキル（炭素数１〜４）置換基を有する置換５〜６員環
式基； ｒは１〜４の整数； Ｒ19は低級アルキル、ベンジルまたはフエネチル； Ｒ20は水素、低級アルキル、ベンジルまたはフエネチ
ル； Ｒ1は低級アルキル、ハロ置換低級アルキル、 Ｒ6は水素、低級アルキル、ベンジル、ベンズヒドリ
ル、薬理学的に許容しうる塩形成イオン、 Ｒ17は水素、低級アルキル、シクロアルキルまたはフエ
ニル； Ｒ18は水素、低級アルキル、低級アルコキシまたはフエ
ニル、 Ｒ21およびＲ22はそれぞれ別個に水素または低級アルキ
ル；および Ｒ23は低級アルキルを表わす〕 で示される化合物またはその薬理学的に許容しうる塩。1. A formula: [Where X is n is 0, 1 or 2: R 25 is lower alkyl having 1 to 4 carbon atoms or R 7 is hydrogen, lower alkyl, halogen, hydroxy, 1- or 2-naphthyl represented by In shown are substituted 1- or 2-naphthyl, - (CH 2) m -
Cycloalkyl, -O-lower alkyl, 1- or 2-naphthyloxy represented by A substituted 1- or 2-naphthyloxy represented by
-Lower alkyl, 1- or 2-naphthylthio represented by, or A substituted 1- or 2-naphthylthio represented by: 1- or 2-naphthyloxy represented by A substituted 1- or 2-naphthyloxy represented by
-Lower alkyl, 1- or 2-naphthylthio represented by, or A substituted 1- or 2-naphthylthio represented by: R 10 is halogen or -Y-R 16; is R 11 with R 11, R '11, R 12 and R' 12 are each independently hydrogen or lower alkyl or R '11, R 12 and R' 12, hydrogen R 13 is lower alkyl having 1 to 4 carbons, lower alkoxy having 1 to 4 carbons, lower alkylthio having 1 to 4 carbons, chloro, bromo, fluoro, trifluoromethyl, hydroxy, phenyl, phenoxy, phenylthio or phenylmethyl; R 14 is lower alkyl having 1 to 4 carbons, lower alkoxy having 1 to 4 carbons, lower alkyl having 1 to 4 carbons, chloro, bromo, fluoro, trifluoromethyl or hydroxy; m is 0, 1, 2, 3 or 4; p is 1, 2 or 3 (provided that either R 13 or R 14 is methyl, methoxy, chloro or fluoro, p is greater than 1); R 15 is hydrogen or 1 to 4 carbon atoms Lower alkyl; Y is oxygen or sulfur; R 16 is lower alkyl having 1 to 4 carbon atoms; Alternatively, an unsubstituted 5- or 6-membered cyclic group formed by combining two R 16 's, or a substituent in which one or more ring-forming carbon atoms is a lower alkyl (1 to 4 carbon atoms) or di-lower alkyl. A substituted 5- or 6-membered cyclic group having a (C1-4) substituent; r is an integer of 1 to 4; R 19 is lower alkyl, benzyl or phenethyl; R 20 is hydrogen, lower alkyl, benzyl or phenethyl; R 1 is lower alkyl, halo-substituted lower alkyl, R 6 is hydrogen, lower alkyl, benzyl, benzhydryl, a pharmacologically acceptable salt-forming ion, R 17 is hydrogen, lower alkyl, cycloalkyl or phenyl; R 18 is hydrogen, lower alkyl, lower alkoxy or phenyl, R 21 and R 22 each independently represent hydrogen or lower alkyl; and R 23 represents lower alkyl] or a pharmaceutically acceptable salt thereof.
はＲ4が水素でＲ5がメチル、 Ｒ7が水素、シクロヘキシル、炭素数１〜４の低級アル
コキシ、 ｍが0,1または2; Ｒ13がメチル、メトキシ、メチルチオ、クロロ、ブロ
モ、フルオロまたはヒドロキシ；および ｔが２または３である前記第１項記載の化合物。2. R 6 is hydrogen or an alkali metal ion; R 4 is cyclohexyl or phenyl and R 5 is hydrogen, or R 4 is hydrogen and R 5 is methyl, R 7 is hydrogen, cyclohexyl, lower alkoxy having 1 to 4 carbon atoms, The compound according to claim 1, wherein m is 0, 1 or 2; R 13 is methyl, methoxy, methylthio, chloro, bromo, fluoro or hydroxy; and t is 2 or 3.
（低級）アルキルまたは-(CH2)r-NH2； Ｒ2が Ｒ3が炭素数１〜４の直鎖もしくは分枝状（低級）アル
キル、 ｒが１〜４の整数； ｍが0,1または2;および Ｒ14がメチル、メトキシ、メチルチオ、Cl、Br、Ｆまた
はヒドロキシである前記第１項または第２項記載の化合
物。Wherein R 1 is a 1 to 4 carbon atoms straight-chain or branched (lower) alkyl or - (CH 2) r -NH 2 ; is R 2 R 3 is a linear or branched (lower) alkyl having 1 to 4 carbon atoms, The compound according to the above 1 or 2, wherein r is an integer of 1 to 4; m is 0, 1 or 2; and R 14 is methyl, methoxy, methylthio, Cl, Br, F or hydroxy.
たは第３項記載の化合物。4. The compound according to claim 1, 2 or 3 wherein R 1 is methyl.
化合物。5. X is The compound according to the above-mentioned item 1, item 2, item 3, or item 4, which is
が水素である前記第１項、第２項、第３項、第４項また
は第５項記載の化合物。6. R 3 is benzyl; R 2 is phenyl; and R 7
The compound according to the above 1, 2, 3, 4, or 5, wherein is hydrogen.
ノ）−４−ヒドロキシ−２−メチル−１−オキソ−６−
フエニルヘキシル〕−Ｌ−プロリンである前記第１項記
載の化合物。7. (2R, 5S) -1- [5- (benzoylamino) -4-hydroxy-2-methyl-1-oxo-6-
The compound according to claim 1, which is phenylhexyl] -L-proline.
化合物。8. X is The compound according to the above-mentioned item 1, item 2, item 3, or item 4, which is
化合物。9. X is The compound according to the above-mentioned item 1, item 2, item 3, or item 4, which is
化合物。10. X is The compound according to the above-mentioned item 1, item 2, item 3, or item 4, which is
化合物。11. X is The compound according to the above-mentioned item 1, item 2, item 3, or item 4, which is
化合物。12. X is The compound according to the above-mentioned item 1, item 2, item 3, or item 4, which is
化合物。13. X is The compound according to the above-mentioned item 1, item 2, item 3, or item 4, which is
化合物。14. X is The compound according to the above-mentioned item 1, item 2, item 3, or item 4, which is
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US67444584A | 1984-11-23 | 1984-11-23 | |
| US674445 | 1984-11-23 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPS61143348A JPS61143348A (en) | 1986-07-01 |
| JPH0745453B2 true JPH0745453B2 (en) | 1995-05-17 |
Family
ID=24706630
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP60263593A Expired - Lifetime JPH0745453B2 (en) | 1984-11-23 | 1985-11-22 | Acylaminohydroxyalkanoylamino and imino acids and esters |
Country Status (5)
| Country | Link |
|---|---|
| JP (1) | JPH0745453B2 (en) |
| DE (1) | DE3541346A1 (en) |
| FR (1) | FR2573761B1 (en) |
| GB (1) | GB2167748A (en) |
| IT (1) | IT1186768B (en) |
Families Citing this family (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4749688A (en) * | 1986-06-20 | 1988-06-07 | Schering Corporation | Use of neutral metalloendopeptidase inhibitors in the treatment of hypertension |
| US5192800A (en) * | 1986-12-11 | 1993-03-09 | Pfizer Inc. | Glutaramide diuretic agents |
| KR880007441A (en) * | 1986-12-11 | 1988-08-27 | 알렌 제이.스피겔 | Spiro-Substituted Glutaramide Diuretics |
| JPS6452744A (en) * | 1987-08-24 | 1989-02-28 | Nippon Zoki Pharmaceutical Co | Novel peptide compound and production thereof |
Family Cites Families (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| IE51409B1 (en) * | 1980-07-24 | 1986-12-24 | Ici Ltd | Amide derivatives |
| ZA826022B (en) * | 1981-08-21 | 1983-08-31 | Univ Miami | Novel complex amido and imido derivatives of carboxyalkyl peptides and thioethers and ethers of peptides |
| US4623729A (en) * | 1982-07-22 | 1986-11-18 | E. R. Squibb & Sons, Inc. | Acylalkylaminocarbonyl substituted amino and imino acid compounds |
| US4604402A (en) * | 1984-03-30 | 1986-08-05 | E. R. Squibb & Sons, Inc. | Hydroxy substituted ureido amino and imino acids |
-
1985
- 1985-11-14 GB GB08528122A patent/GB2167748A/en not_active Withdrawn
- 1985-11-22 IT IT22969/85A patent/IT1186768B/en active
- 1985-11-22 FR FR8517326A patent/FR2573761B1/en not_active Expired
- 1985-11-22 DE DE19853541346 patent/DE3541346A1/en not_active Ceased
- 1985-11-22 JP JP60263593A patent/JPH0745453B2/en not_active Expired - Lifetime
Also Published As
| Publication number | Publication date |
|---|---|
| FR2573761A1 (en) | 1986-05-30 |
| DE3541346A1 (en) | 1986-05-28 |
| IT1186768B (en) | 1987-12-16 |
| FR2573761B1 (en) | 1987-11-27 |
| JPS61143348A (en) | 1986-07-01 |
| GB2167748A (en) | 1986-06-04 |
| IT8522969A0 (en) | 1985-11-22 |
| GB8528122D0 (en) | 1985-12-18 |
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