JPH0560466B2 - - Google Patents
Info
- Publication number
- JPH0560466B2 JPH0560466B2 JP60041614A JP4161485A JPH0560466B2 JP H0560466 B2 JPH0560466 B2 JP H0560466B2 JP 60041614 A JP60041614 A JP 60041614A JP 4161485 A JP4161485 A JP 4161485A JP H0560466 B2 JPH0560466 B2 JP H0560466B2
- Authority
- JP
- Japan
- Prior art keywords
- formula
- represented
- group
- general formula
- amino
- 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
- 150000003839 salts Chemical class 0.000 claims description 26
- 239000002253 acid Substances 0.000 claims description 24
- 150000003862 amino acid derivatives Chemical class 0.000 claims description 24
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 6
- 229910052799 carbon Inorganic materials 0.000 claims description 5
- 125000002066 L-histidyl group Chemical group [H]N1C([H])=NC(C([H])([H])[C@](C(=O)[*])([H])N([H])[H])=C1[H] 0.000 claims description 4
- 125000000217 alkyl group Chemical group 0.000 claims description 4
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 2
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 87
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 70
- 239000000243 solution Substances 0.000 description 61
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 48
- 150000001875 compounds Chemical class 0.000 description 48
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 45
- 239000002904 solvent Substances 0.000 description 43
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 34
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical group Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 33
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 32
- 125000001501 propionyl group Chemical group O=C([*])C([H])([H])C([H])([H])[H] 0.000 description 32
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 30
- 239000000203 mixture Substances 0.000 description 24
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 22
- 108090000783 Renin Proteins 0.000 description 20
- 102100028255 Renin Human genes 0.000 description 20
- 238000003756 stirring Methods 0.000 description 20
- -1 10, 11- dihydro-5H-dibenzo[a,d]cycloheptenyl group Chemical group 0.000 description 19
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 19
- 239000000741 silica gel Substances 0.000 description 18
- 229910002027 silica gel Inorganic materials 0.000 description 18
- 238000001914 filtration Methods 0.000 description 17
- 238000002844 melting Methods 0.000 description 17
- 230000008018 melting Effects 0.000 description 17
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 16
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 16
- 230000000694 effects Effects 0.000 description 16
- 230000002401 inhibitory effect Effects 0.000 description 15
- 238000001816 cooling Methods 0.000 description 14
- 239000013078 crystal Substances 0.000 description 13
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- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 13
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 12
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 12
- 235000017557 sodium bicarbonate Nutrition 0.000 description 11
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 11
- 238000000034 method Methods 0.000 description 10
- 239000003921 oil Substances 0.000 description 10
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 9
- 238000005481 NMR spectroscopy Methods 0.000 description 9
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 9
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 9
- 108090000765 processed proteins & peptides Proteins 0.000 description 9
- 238000004809 thin layer chromatography Methods 0.000 description 9
- 229940121710 HMGCoA reductase inhibitor Drugs 0.000 description 8
- OWFXIOWLTKNBAP-UHFFFAOYSA-N isoamyl nitrite Chemical compound CC(C)CCON=O OWFXIOWLTKNBAP-UHFFFAOYSA-N 0.000 description 8
- HIQSHBQGIXVMBC-YFKPBYRVSA-N (2s)-2-amino-3-(1h-imidazol-5-yl)propanehydrazide Chemical compound NNC(=O)[C@@H](N)CC1=CN=CN1 HIQSHBQGIXVMBC-YFKPBYRVSA-N 0.000 description 7
- 108091005804 Peptidases Proteins 0.000 description 7
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- PNEYBMLMFCGWSK-UHFFFAOYSA-N aluminium oxide Inorganic materials [O-2].[O-2].[O-2].[Al+3].[Al+3] PNEYBMLMFCGWSK-UHFFFAOYSA-N 0.000 description 7
- 150000001540 azides Chemical class 0.000 description 7
- 230000008034 disappearance Effects 0.000 description 7
- 239000012156 elution solvent Substances 0.000 description 7
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 6
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N DMSO Substances CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 6
- 125000002252 acyl group Chemical group 0.000 description 6
- 239000003054 catalyst Substances 0.000 description 6
- 238000007796 conventional method Methods 0.000 description 6
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 6
- 229940024999 proteolytic enzymes for treatment of wounds and ulcers Drugs 0.000 description 6
- XTDHJNGGUYRMLH-UHFFFAOYSA-N 2-(naphthalen-1-ylmethyl)-4-oxo-4-(2-phenylethylamino)butanoic acid Chemical compound C=1C=CC2=CC=CC=C2C=1CC(C(=O)O)CC(=O)NCCC1=CC=CC=C1 XTDHJNGGUYRMLH-UHFFFAOYSA-N 0.000 description 5
- 102000004881 Angiotensinogen Human genes 0.000 description 5
- 108010064733 Angiotensins Proteins 0.000 description 5
- 102000015427 Angiotensins Human genes 0.000 description 5
- 125000003277 amino group Chemical group 0.000 description 5
- 125000004432 carbon atom Chemical group C* 0.000 description 5
- 238000003818 flash chromatography Methods 0.000 description 5
- 239000011541 reaction mixture Substances 0.000 description 5
- 108090001067 Angiotensinogen Proteins 0.000 description 4
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 4
- 239000012230 colorless oil Substances 0.000 description 4
- 229960002885 histidine Drugs 0.000 description 4
- 239000007788 liquid Substances 0.000 description 4
- 231100000053 low toxicity Toxicity 0.000 description 4
- 238000004519 manufacturing process Methods 0.000 description 4
- 230000007935 neutral effect Effects 0.000 description 4
- 229920001184 polypeptide Polymers 0.000 description 4
- 102000004196 processed proteins & peptides Human genes 0.000 description 4
- 238000010992 reflux Methods 0.000 description 4
- 239000007858 starting material Substances 0.000 description 4
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 4
- HAMRIBBQVJPIBF-NASUQTAISA-N (2s)-3-(1h-imidazol-5-yl)-2-[[2-(naphthalen-1-ylmethyl)-4-oxo-4-(2-phenylethylamino)butanoyl]amino]propanoyl azide Chemical compound C([C@@H](C(=O)N=[N+]=[N-])NC(=O)C(CC(=O)NCCC=1C=CC=CC=1)CC=1C2=CC=CC=C2C=CC=1)C1=CN=CN1 HAMRIBBQVJPIBF-NASUQTAISA-N 0.000 description 3
- RQEUFEKYXDPUSK-UHFFFAOYSA-N 1-phenylethylamine Chemical compound CC(N)C1=CC=CC=C1 RQEUFEKYXDPUSK-UHFFFAOYSA-N 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 3
- 101800000734 Angiotensin-1 Proteins 0.000 description 3
- 102400000344 Angiotensin-1 Human genes 0.000 description 3
- WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 description 3
- 241000282693 Cercopithecidae Species 0.000 description 3
- 108090000317 Chymotrypsin Proteins 0.000 description 3
- 206010020772 Hypertension Diseases 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- DWAYENIPKPKKMV-ILKKLZGPSA-N [(2s)-3-(1h-imidazol-3-ium-4-yl)-1-methoxy-1-oxopropan-2-yl]azanium;dichloride Chemical compound Cl.Cl.COC(=O)[C@@H](N)CC1=CN=CN1 DWAYENIPKPKKMV-ILKKLZGPSA-N 0.000 description 3
- 150000001412 amines Chemical class 0.000 description 3
- 229940024606 amino acid Drugs 0.000 description 3
- 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 3
- BSMQSOVSXSDDBL-LSLKUGRBSA-N benzyl n-[(1s)-3-methyl-1-(oxiran-2-yl)butyl]carbamate Chemical compound N([C@@H](CC(C)C)C1OC1)C(=O)OCC1=CC=CC=C1 BSMQSOVSXSDDBL-LSLKUGRBSA-N 0.000 description 3
- SEWLQRPKYMZHDM-ZDUSSCGKSA-N benzyl n-[(2s)-4-methyl-1-oxopentan-2-yl]carbamate Chemical compound CC(C)C[C@@H](C=O)NC(=O)OCC1=CC=CC=C1 SEWLQRPKYMZHDM-ZDUSSCGKSA-N 0.000 description 3
- 229960002376 chymotrypsin Drugs 0.000 description 3
- 238000004440 column chromatography Methods 0.000 description 3
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- 150000002170 ethers Chemical class 0.000 description 3
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 3
- 230000005764 inhibitory process Effects 0.000 description 3
- 150000004702 methyl esters Chemical class 0.000 description 3
- 239000008194 pharmaceutical composition Substances 0.000 description 3
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 3
- 239000012279 sodium borohydride Substances 0.000 description 3
- 229910000033 sodium borohydride Inorganic materials 0.000 description 3
- 125000001424 substituent group Chemical group 0.000 description 3
- 239000000758 substrate Substances 0.000 description 3
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 3
- SQAINHDHICKHLX-UHFFFAOYSA-N 1-naphthaldehyde Chemical compound C1=CC=C2C(C=O)=CC=CC2=C1 SQAINHDHICKHLX-UHFFFAOYSA-N 0.000 description 2
- LLJIDEXGXUFMCT-UHFFFAOYSA-N 2-(naphthalen-1-ylmethylidene)-4-oxo-4-(2-phenylethylamino)butanoic acid Chemical compound C=1C=CC2=CC=CC=C2C=1C=C(C(=O)O)CC(=O)NCCC1=CC=CC=C1 LLJIDEXGXUFMCT-UHFFFAOYSA-N 0.000 description 2
- OCEJTXWZGWBSPX-UHFFFAOYSA-N 2-(naphthalen-1-ylmethylidene)butanedioic acid Chemical compound C1=CC=C2C(C=C(CC(=O)O)C(O)=O)=CC=CC2=C1 OCEJTXWZGWBSPX-UHFFFAOYSA-N 0.000 description 2
- GZLMFCWSEKVVGO-UHFFFAOYSA-N 3-azaniumyl-2-hydroxy-5-methylhexanoate Chemical compound CC(C)CC(N)C(O)C(O)=O GZLMFCWSEKVVGO-UHFFFAOYSA-N 0.000 description 2
- NHQDETIJWKXCTC-UHFFFAOYSA-N 3-chloroperbenzoic acid Chemical compound OOC(=O)C1=CC=CC(Cl)=C1 NHQDETIJWKXCTC-UHFFFAOYSA-N 0.000 description 2
- MHPUGCYGQWGLJL-UHFFFAOYSA-N 5-methyl-hexanoic acid Chemical compound CC(C)CCCC(O)=O MHPUGCYGQWGLJL-UHFFFAOYSA-N 0.000 description 2
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 2
- DKMROQRQHGEIOW-UHFFFAOYSA-N Diethyl succinate Chemical compound CCOC(=O)CCC(=O)OCC DKMROQRQHGEIOW-UHFFFAOYSA-N 0.000 description 2
- 101000579218 Homo sapiens Renin Proteins 0.000 description 2
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- 108090000284 Pepsin A Proteins 0.000 description 2
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- BHHGXPLMPWCGHP-UHFFFAOYSA-N Phenethylamine Chemical compound NCCC1=CC=CC=C1 BHHGXPLMPWCGHP-UHFFFAOYSA-N 0.000 description 2
- 150000001413 amino acids Chemical class 0.000 description 2
- 239000002220 antihypertensive agent Substances 0.000 description 2
- 229940030600 antihypertensive agent Drugs 0.000 description 2
- WGQKYBSKWIADBV-UHFFFAOYSA-N benzylamine Chemical compound NCC1=CC=CC=C1 WGQKYBSKWIADBV-UHFFFAOYSA-N 0.000 description 2
- 230000036772 blood pressure Effects 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
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- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 description 2
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- IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine hydrate Chemical compound O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 description 2
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- BMFVGAAISNGQNM-UHFFFAOYSA-N isopentylamine Chemical compound CC(C)CCN BMFVGAAISNGQNM-UHFFFAOYSA-N 0.000 description 2
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- RINCXYDBBGOEEQ-UHFFFAOYSA-N succinic anhydride Chemical class O=C1CCC(=O)O1 RINCXYDBBGOEEQ-UHFFFAOYSA-N 0.000 description 2
- 125000003396 thiol group Chemical group [H]S* 0.000 description 2
- UKUPHXWJZMXUNW-YLIVSKOQSA-N (3S)-3-amino-5-methyl-1-(3-methylbutoxy)hexan-2-ol hydrochloride Chemical compound Cl.CC(C)CCOCC(O)[C@@H](N)CC(C)C UKUPHXWJZMXUNW-YLIVSKOQSA-N 0.000 description 1
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- 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
- 125000000415 L-cysteinyl group Chemical group O=C([*])[C@@](N([H])[H])([H])C([H])([H])S[H] 0.000 description 1
- 125000002061 L-isoleucyl group Chemical group [H]N([H])[C@]([H])(C(=O)[*])[C@](C([H])([H])[H])([H])C(C([H])([H])[H])([H])[H] 0.000 description 1
- 235000019454 L-leucine Nutrition 0.000 description 1
- 239000004395 L-leucine Substances 0.000 description 1
- 125000003440 L-leucyl group Chemical group O=C([*])[C@](N([H])[H])([H])C([H])([H])C(C([H])([H])[H])([H])C([H])([H])[H] 0.000 description 1
- 125000002435 L-phenylalanyl group Chemical group O=C([*])[C@](N([H])[H])([H])C([H])([H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- 125000002707 L-tryptophyl group Chemical group [H]C1=C([H])C([H])=C2C(C([C@](N([H])[H])(C(=O)[*])[H])([H])[H])=C([H])N([H])C2=C1[H] 0.000 description 1
- 125000003798 L-tyrosyl group Chemical group [H]N([H])[C@]([H])(C(=O)[*])C([H])([H])C1=C([H])C([H])=C(O[H])C([H])=C1[H] 0.000 description 1
- 101000579223 Ovis aries Renin Proteins 0.000 description 1
- 102000004270 Peptidyl-Dipeptidase A Human genes 0.000 description 1
- 108090000882 Peptidyl-Dipeptidase A Proteins 0.000 description 1
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 1
- DWAQJAXMDSEUJJ-UHFFFAOYSA-M Sodium bisulfite Chemical compound [Na+].OS([O-])=O DWAQJAXMDSEUJJ-UHFFFAOYSA-M 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 210000004404 adrenal cortex Anatomy 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 229960002478 aldosterone Drugs 0.000 description 1
- 125000003342 alkenyl group Chemical group 0.000 description 1
- 125000003545 alkoxy group Chemical group 0.000 description 1
- 150000003973 alkyl amines Chemical class 0.000 description 1
- 125000003282 alkyl amino group Chemical group 0.000 description 1
- 125000000539 amino acid group Chemical group 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-N ammonia Natural products N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 1
- 235000019270 ammonium chloride Nutrition 0.000 description 1
- 229940044094 angiotensin-converting-enzyme inhibitor Drugs 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- IQGBCOXICGFDMW-OYKVQYDMSA-N benzyl N-[(3S)-2-hydroxy-5-methyl-1-(3-methylbutoxy)hexan-3-yl]carbamate Chemical compound CC(C)CCOCC(O)[C@H](CC(C)C)NC(=O)OCC1=CC=CC=C1 IQGBCOXICGFDMW-OYKVQYDMSA-N 0.000 description 1
- FLPZQTBHQDYDSI-BGERDNNASA-N benzyl N-[(3S)-2-hydroxy-5-methyl-1-phenylmethoxyhexan-3-yl]carbamate Chemical compound N([C@@H](CC(C)C)C(O)COCC=1C=CC=CC=1)C(=O)OCC1=CC=CC=C1 FLPZQTBHQDYDSI-BGERDNNASA-N 0.000 description 1
- 235000019445 benzyl alcohol Nutrition 0.000 description 1
- FHYREDOQUFUFOO-UHFFFAOYSA-N benzyl n-(1-cyano-1-hydroxy-4-methylpentan-2-yl)carbamate Chemical compound CC(C)CC(C(O)C#N)NC(=O)OCC1=CC=CC=C1 FHYREDOQUFUFOO-UHFFFAOYSA-N 0.000 description 1
- AWYQYXFFQDATDI-BGERDNNASA-N benzyl n-[(3s)-1-(benzylamino)-2-hydroxy-5-methylhexan-3-yl]carbamate Chemical compound N([C@@H](CC(C)C)C(O)CNCC=1C=CC=CC=1)C(=O)OCC1=CC=CC=C1 AWYQYXFFQDATDI-BGERDNNASA-N 0.000 description 1
- 238000007664 blowing Methods 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 description 1
- 150000001768 cations Chemical class 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- LDHQCZJRKDOVOX-NSCUHMNNSA-N crotonic acid Chemical class C\C=C\C(O)=O LDHQCZJRKDOVOX-NSCUHMNNSA-N 0.000 description 1
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 239000008367 deionised water Substances 0.000 description 1
- 229910021641 deionized water Inorganic materials 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- XPPKVPWEQAFLFU-UHFFFAOYSA-J diphosphate(4-) Chemical compound [O-]P([O-])(=O)OP([O-])([O-])=O XPPKVPWEQAFLFU-UHFFFAOYSA-J 0.000 description 1
- 235000011180 diphosphates Nutrition 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- LBAQSKZHMLAFHH-UHFFFAOYSA-N ethoxyethane;hydron;chloride Chemical compound Cl.CCOCC LBAQSKZHMLAFHH-UHFFFAOYSA-N 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 125000000623 heterocyclic group Chemical group 0.000 description 1
- FUKUFMFMCZIRNT-UHFFFAOYSA-N hydron;methanol;chloride Chemical compound Cl.OC FUKUFMFMCZIRNT-UHFFFAOYSA-N 0.000 description 1
- 230000001077 hypotensive effect Effects 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- 229960003136 leucine Drugs 0.000 description 1
- 238000001819 mass spectrum Methods 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 230000010534 mechanism of action Effects 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- DNMZJIGSDQVGSA-UHFFFAOYSA-N methoxymethane;hydrochloride Chemical compound Cl.COC DNMZJIGSDQVGSA-UHFFFAOYSA-N 0.000 description 1
- SJBCYUJXLMDZDW-OXIGJRIQSA-N methyl (3s)-3-amino-2-hydroxy-5-methylhexanoate;hydrochloride Chemical compound Cl.COC(=O)C(O)[C@@H](N)CC(C)C SJBCYUJXLMDZDW-OXIGJRIQSA-N 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- LSEFCHWGJNHZNT-UHFFFAOYSA-M methyl(triphenyl)phosphanium;bromide Chemical compound [Br-].C=1C=CC=CC=1[P+](C=1C=CC=CC=1)(C)C1=CC=CC=C1 LSEFCHWGJNHZNT-UHFFFAOYSA-M 0.000 description 1
- XYDYWTJEGDZLTH-UHFFFAOYSA-N methylenetriphenylphosphorane Chemical group C=1C=CC=CC=1P(C=1C=CC=CC=1)(=C)C1=CC=CC=C1 XYDYWTJEGDZLTH-UHFFFAOYSA-N 0.000 description 1
- XJINZNWPEQMMBV-UHFFFAOYSA-N n-methylhexan-1-amine Chemical compound CCCCCCNC XJINZNWPEQMMBV-UHFFFAOYSA-N 0.000 description 1
- 150000002825 nitriles Chemical class 0.000 description 1
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 229940127557 pharmaceutical product Drugs 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 229940117803 phenethylamine Drugs 0.000 description 1
- 125000003884 phenylalkyl group Chemical group 0.000 description 1
- 230000000704 physical effect Effects 0.000 description 1
- NNFCIKHAZHQZJG-UHFFFAOYSA-N potassium cyanide Chemical compound [K+].N#[C-] NNFCIKHAZHQZJG-UHFFFAOYSA-N 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- 125000006239 protecting group Chemical group 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
- 238000003127 radioimmunoassay Methods 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 238000010898 silica gel chromatography Methods 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- 229910000104 sodium hydride Inorganic materials 0.000 description 1
- 235000010267 sodium hydrogen sulphite Nutrition 0.000 description 1
- AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 description 1
- 235000019345 sodium thiosulphate Nutrition 0.000 description 1
- 125000000547 substituted alkyl group Chemical group 0.000 description 1
- 229940014800 succinic anhydride Drugs 0.000 description 1
- BDHFUVZGWQCTTF-UHFFFAOYSA-M sulfonate Chemical compound [O-]S(=O)=O BDHFUVZGWQCTTF-UHFFFAOYSA-M 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 230000003639 vasoconstrictive effect Effects 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
〔産業上の利用分野〕
本発明の目的は医薬品として有用な一般式
〔式中のHisはＬ−ヒスチジル基であり、ｍは
１〜３の整数であり、ｎは１または２であり、Ｘ
は水酸基または式−Ｙ−Ｒ（式中のＹは−０−ま
たは−NH−であり、直鎖状または枝分かれ状の
アルキル基またはアラルキル基である）で表され
る基である〕で表される新規なアミノ酸誘導体お
よびそれらの薬理学的に許容できる酸付加塩を提
供することである。さらに詳しくいえば、ヒトレ
ニン（humanrenin）阻害作用を有し、経口投与
可能な高血圧症の治療剤として有用な前記一般式
（）で表される新規なアミノ酸誘導体およびそ
れらの薬理学的に許容できる酸付加塩を提供する
ことである。
〔従来の技術〕
レニンは腎臓の傍糸球体細胞から遊離する蛋白
分解酵素である。このものは血漿のα2グロブリン
分画中にあるレニン基質と反応し、アンジオテン
シン（angiotensin）を生成させる。生成し
たアンジオテンシンはアンジオテンシン変換酵
素によりアンジオテンシン（angiotensin）
に変換される。このアンジオテンシンは血管収
縮作用を有するとともに、副腎皮質に働き、ナト
リウムや水の代謝に影響するアルドステロン
（aldo−sterone）を分泌させる高血圧症の一つの
因子である。
このような、レニンとレニン基質との反応を阻
害し、アンジオテンシンの生成を抑制する化合
物は新しい作用機作による高血圧治療剤として注
目されており、その開発が強く要望されている。
今迄にレニンとレニン基質との反応を阻害、す
なわち、レニン活性阻害作用を有する化合物とし
て、多くのペプチド誘導体が知られている（日本
特許公告公報昭58−39149号、日本特許公開公報
昭59−110661号、同昭59−155345号、同昭59−
227851号、ヨーロツパ特許公開公報707029号、同
77028号、同81783号）
これらの特許出願の中で、特に日本特許公開公
報昭59−155345号には一般式
（式中のＡは水素原子、フエニル基、10，11−
ジヒドロ−5H−ジベンゾ〔ａ，ｄ〕シクロヘプ
テニル基などであり、Ｂは−０−、−CH＝CH
−、−CH2−などで示される結合のいずれかであ
り、ｐおよびｑは同じでも異なつていてもよくそ
れぞれ０または１〜３の整数であり、Ｄは水素原
子、低級アルキル基、低級アルケニル基、フエニ
ル基、フエニルアルキル基などであり、Ｆはフエ
ニル基、シクロヘキシル基、イソプロプル基など
であり、HisはＬ−ヒスチジル基であり、Ｆはア
ミノ酸残基、例えば Ｌ−ロイシル基、Ｌ−イソ
ロイシル基、Ｌ−ロイシル−Ｌ−フエニルアラニ
ル基、Ｌ−フエニルアラニル−Ｌ−フエニルアラ
ニル基、Ｌ−アラニル−Ｌ−フエニルアラニル基
などであり、Ｇはアミノ酸Ｃ末端の保護基、例え
ばアミノ基、アルキルアミノ基、アリルアルキル
アミノ基、アルコキシ基などである）で表される
ペプチド誘導体を開示している。
また、日本特許公開公報昭59−227851号には、
一般式
（式中のR1CO−はＮ−置換アミノ酸のアシル
基、例えばペンジルオキシカルボニル基、ｔ−ブ
トキシカルボニル基、α−ナフトキシアセチル
基、フエニルブチリル基、３−（３−ニトロ−２
−ピリジンスルフエニル）チオプロピオニル基、
９−フルオレニルメチロキシカルボニル基などで
アミノ基が置換されたアミノ酸、例えばＬ−フエ
ニルアラニル基、Ｌ−トリプトフイル基、Ｌ−チ
ロシル基、Ｌ−システイニル基、３−（１−ナフ
チル）−Ｌ−アラニル基、Ｌ−フエニルグリシル
基、１−アミノ−４−フエニルブチリル基、１，
２，３，４−テトラヒドロ−β−カルボリン−３
−Ｌ−カルボキシル基などであり、HisはＬ−ヒ
スチジル基であり、ＣはＳ配置を示し、Ｚは水酸
基、メルカプト基、またはホルミル基であり、
R2は水素原子、アルキル基、置換基として水酸
基、メルカプト基、アミノ基、カルバモイル基、
ホルミル基、アリール基または異項環基を有して
いる置換アルキル基を示す）で表されるペプチド
誘導体を開示している。
〔発明が解決しようとする問題〕
前記の特許出願等に開示されている化合物群は
ほとんどポリペプチドでその合成が厄介であり、
かつ、体内の蛋白分解酵素、例えば、キモトリプ
チシン（chymotrypsin）で分解され、経口投与
においてはその薬理効果を発揮することが期待で
きない。
前記一般式（）で表されるペプチド誘導体は
トリまたはテトラペプチド誘導体であり、他のポ
リペプチド誘導体に比べ製造が比較的容易ではあ
るが、この化合物も前記の特許出願等に開示され
ているポリペプチド誘導体と同様、蛋白分解酵素
に対し不安定で経口投与によつてその薬効を発揮
することが期待し難い。
また、前記式（）で表される化合物は他のペ
プチド誘導体に比べ製造が容易ではあるが、この
化合物も前記の特許出願等に開示されているポリ
ペプチド誘導体と同様、蛋白分解酵素に対し不安
定で経口投与によつてその薬効を発揮することが
期待し難い。
本発明者らはこのような問題を解決すべく種々
検討した結果、前記一般式（）で表されるアミ
ノ酸誘導体およびそれらの薬理学的に許容できる
酸付加塩が比較的容易に製造することができ、強
いレニン活性阻害作用を示し、かつ低毒性で経口
投与が可能なものであり、前述の問題点を解決し
うるものであることを見出した。
(2) 発明の構成
〔問題点を解決するための手段および作用〕
本発明の前記一般式（）で表されるアミノ酸
誘導体およびそれらの薬理学的に許容できる酸付
加塩はヒトレニン−羊レニン基質系で強いレニン
活性阻害作用を示し、さらにキモトリプシン、ペ
プシンのような蛋白分解酵素に安定である。ま
た、このものはサルにおいて経口または静脈内注
入で明らかな降圧効果を発揮する。
このことは本発明の前記一般式（）で表され
るアミノ酸誘導体およびそれらの薬理学的に許容
できる酸付加塩が強いレニン活性阻害作用を有
し、しかも低毒性で経口投与可能な高血圧症治療
剤として有用であることを示している。
本発明の前記一般式（）で表されるアミノ酸
誘導体でＸが式−Ｙ−Ｒ（式中のＹおよびＲは前
記と同じ意味を持つ）で表される基である化合物
は、式
（式中ＣはＬ−配置を示し、ｍは前記と同じ意
味を持つ）で表される化合物と、一般式
（式中のｎ、ＹおよびＲは前記と同じ意味を持
ち、ａは１または２である）で表される化合物と
を反応させることにより製造することができる。
この反応で出発原料として用いられる前記一般
式（）で表される化合物は、一般式
（式中のｍは前記と同じ意味を持つ）で表され
るカルボン酸の反応性官能的誘導体とＬ−ヒスチ
ジンメチルエステル２塩酸塩とをＮ，Ｎ−ジメチ
ルホルムアミド中で反応させ、一般式
（式中のｍおよびＣは前記と同じ意味を持つ）
で表される化合物を得、次いでこれをメタノール
溶液中でヒドラジン１水和物と反応させることに
より製造することができる。
前記一般式（）で表されるカルボン酸は下記
の方法またはその類似方法によつて製造すること
ができる。すなわち、１−ナフトアルデヒドとコ
ハク酸ジエチルとを反応させて、式
で表される化合物を得、これを水酸化ナトリウム
で加水分解してジカルボン酸とした後、無水酢酸
で閉環させて、式
で表される無水コハク酸誘導体を得る。この式
（）の無水コハク酸誘導体にフエニルアルキル
アミンを反応させて、式
（式中のｍは前記と同じ意味を持つ）で表され
る化合物を得、これをパラジウム炭素の存在下に
水添することにより製造することができる。
上記製造方法でもう一方の出発原料としてもち
いられる一般式（）の化合物は文献記載の方法
またはその類似方法により製造することができ
る。例えば一般式（）の化合物でｎが１である
化合物はメチルトリフエニルホスホニウムブロミ
ドをテトラヒドロフラン中ブチルリチウムで処理
してトリフエニルホスフインメチレンを製し、こ
れにＮ−カルボベンゾキシロイシナールを反応さ
せて、式
で表される化合物を得、次いでこれを３−クロロ
過安息香酸を反応させて、式
で表されるエポキシ体を得る。
これにアルミナまたはシリカゲルの存在下、一
般式
Ｒ−YH （）
（式中のＲおよびＹは前記と同じ意味を持つ）
で表されるアルコールまたはアルキルアミン類を
反応させ、次いでパラジウム炭素の存在下水添す
ることにより製造することができる。
本発明の一般式（）で表される化合物でが
水酸基である化合物は、一般式
（式中のn′は０または１であり、ｍおよびHis
は前記と同じ意味を持つ）で表される化合物を水
素化ホウ素ナトリウム等をもちいて還元すること
により製造することができる。
この一般式（）で表される化合物は前記一
般式（）で表される化合物と、一般式
（式中のn′は前記と同じ意味をもち、HXは塩
酸またはｐ−トルエンスルホン酸を示す）で表さ
れる化合物とを反応させることにより製造するこ
とができる。
上記の製造方法で出発原料として用いられる一
般式（）の化合物は、文献記載の方法または
その類似方法により製造することができる。例え
ば、一般式（）の化合物でn′が０である化合
物は、ザ ジヤーナル オブ オルガニツク ケ
ミストリー〔J.Org.Chem.〕45巻、2288〜2290ペ
ージ（1980年）に記載された方法と同様な方法に
より３−アミノ−２−ヒドロキシ−５−メチルヘ
キサン酸を得、これを常法によりエステル化する
ことにより製造される。また、一般式（）の
化合物でn′が１である化合物はスタチンまたはＮ
−（tert−ブチルオキシカルボニル）スタチンを
常法によりエステル化することにより製造され
る。
本発明の前記式（）で表される化合物と一般
式（）または一般式（）で表される化合物
との反応は常法に従つて行うことができる。本反
応を好適に実施するには式（）で表される化合
物をＮ，Ｎ−ジメチルホルムアミドに懸濁し、こ
れに３〜５倍モルの塩化水素を加え、この溶液に
一般式（）で表される化合物に対して、１〜３
モル量の亜硝酸イソアミルを加え５〜30分間−20
〜−５℃で反応させる。この反応液にトリエチル
アミンを加え、PH８〜９にし、この溶液を式
（）で表される化合物に対して等モル量の前記
一般式（）または一般式（）の化合物およ
びトリエチルアミンのＮ，Ｎ−ジメチルホルムア
ミド溶液に冷却下、好ましくは−20〜０℃で加
え、次いで５〜20時間０℃ないし室温で反応さ
せ、反応物を常法に従い処理し、目的物を得るこ
とができる。
本発明の一般式（）で表されるアミノ酸誘導
体には４個の不斉炭素があり、個々の不斉炭素に
おける置換基の立体配置により種々の異性体が存
在する。これらの不斉炭素における置換基の立体
配置は一般式（）で表される化合物のもつレニ
ン阻害活性に対し大きく影響を与える。
本発明においては、一般式（）または一般式
（）で表される化合物のアミノ基が置換され
ている炭素原子の立体配置はＳ配置であることが
好ましいが、水酸基が置換されている炭素原子の
立体配置は活性に与える影響が比較的小さく、Ｓ
配置、Ｒ配置のいずれでもまたその混合物でもよ
い。
一般式（）で表されるカルボン酸の立体構造
は本発明の一般式（）で表される化合物のもつ
レニン阻害活性に大きく影響を与え、アシル部分
が（＋）体のカルボン酸で形成される化合物はア
シル部分が（−）体のカルボン酸で形成される化
合物に比べ極めて高い活性を示す。
このような光学活性化合物の製造に用いられる
光学活性出発原料は常法により光学分割するか、
または光学活性な化合物を用いることにより製造
される。
例えば前記一般式（）または一般式（）
で表される化合物でアミノ基が置換されている炭
素原子の立体配置がＳ配置である化合物はＬ−ロ
イシンまたはスタチンを用いることにより製造さ
れる。また、前記一般式（）で表されるカルボ
ン酸の光学活性体は光学活性アミン例えば（＋）
−α−メチルベンジルアミンを用いることにより
（＋）体のカルボン酸を分離精製することができ、
（−）−α−メチルベンジルアミンを用いることに
より（−）体のカルボン酸を分離精製することが
できる。
本発明の前記一般式（）で表される化合物の
アシル部分が（＋）体のカルボン酸で形成される
化合物は、カルボン酸（）とＬ−ヒスチジンメ
チルエステル２塩酸塩とを反応させて得られる前
記一般式（）で表される化合物のジアステレオ
マー化合物を再結晶あるいはカラムクロマトグラ
フイーで分離精製してアシル部分が（＋）体のカ
ルボン酸で形成される化合物（）を得、これを
用いることによつて製造することもできる。
本発明の前記一般式（）で表される化合物は
常法に従い、薬理学的に許容できる酸付加塩とす
ることができ、これらの塩としては塩酸塩、スル
ホン酸塩、ｐ−トルエンスルホン酸塩、酢酸塩、
クエン酸塩等をあげることができる。これらの酸
付加塩も強いレニン活性阻害作用を有し、蛋白分
解酵素に安定であり、経口投与によつて高レニン
状態のサルの血圧を明らかに下降させる。
本発明の一般式（）で表されるアミノ酸誘導
体およびその薬理学的に許容できる酸付加塩は常
法に従い医薬品組成物とすることができる。その
ような医薬品組成物として例えば、錠剤、カプセ
ル剤、顆粒剤、注射剤をあげることができる。
前記一般式（）で表されるアミノ酸誘導体お
よび薬理学的に許容できる酸付加塩は強いレニン
活性阻害作用を有し、ヒトレニン−羊レニン基質
系での50％阻害活性値（IC50）は5.9×10-6〜1.5
×10-7モル濃度であり、かつ低毒素である。この
一般式（）で表されるアミノ酸誘導体またはそ
の薬理学的に許容できる酸付加塩を含有する医薬
品組成物を治療に用いる場合、その投与量は疾病
の程度、患者の性、年齢、体重等により調整され
るが、経口投与では概ね成人１日当り５mg〜5000
mg、非経口投与では１日当り１mg〜1000mgの範囲
内で投与することができる。
〔実施例〕
本発明をさらに詳述するために以下に参考例お
よび実施例をあげる。なお、各参考例および実施
例中の化合物の融点は未補正である。また、各化
合物のNMRスペクトルは日本電子JNM−
GX270型高分解能核磁気共鳴装置を用いて測定
した。Massスペクトルは日本電子JMS−DX300
型マススペクトロメーターを用いてFAB法によ
り測定した。薄層クロマトグラフイーはメルク社
のプレコートプレートシリカゲル（precoated
plates silica gel）60F254を、カラムクロマトグ
ラフイーはメルク社のキーゼル・ゲル
（Kieselgel）60（230−400メツシユ）を用いて行
つた。また薄層クロマトグラフイーの展開溶媒は
クロロホルム／メタノール／水＝８／３／１の混
合液の下層およびクロロホルム／メタノール＝
５／１の混合液の２種類を用い、Rf値（Rf1およ
びRf2）を算出した。
参考例 １
（±）−２−（１−ナフチルメチル）−３−（フエ
ネチルカルバモイル）プロピオン酸
コハク酸エチル17.40ｇと１−ナフトアルデヒ
ド15.62ｇを無水エタノール100mlに溶解し、氷冷
下に50％水素化ナトリウム（油性）6.00ｇを加え
たのち、３時間加熱還流する。減圧下に溶媒を留
去し残留物に水を加え、中性部をエーテルで抽出
除去したのち、水層に濃塩酸を加え酸性とし、エ
ーテルで抽出する。エーテル層を飽和食塩水で洗
つたのち無水硫酸マグネシウムで乾燥する。減圧
下に溶媒を留去し、黄色油状の３−エトキシカル
ボニル−４−（１−ナフチル）−３−ブテン酸
23.60ｇを得る。このブテン酸23.50ｇに１規定水
酸化ナトリウム水溶液200mlとエタノール170mlを
加え、50℃で1.5時間加熱する。減圧下に溶媒を
留去し、残留物に水を加え中性部をエーテルで抽
出除去したのち、水層に濃塩酸を加え酸性とし、
エーテルで抽出する。エーテル層を飽和食塩水で
洗つたのち、無水硫酸マグネシウムで乾燥する。
減圧下に溶媒を留去し、黄色結晶の２−（１−ナ
フチルメチレン）コハク酸15.30ｇを得る。
２−（１−ナフチルメチレン）コハク酸15.20ｇ
に無水酢酸260mlを加え、１時間加熱還流する。
減圧下に溶媒を留去し、残留物に乾燥ベンゼン
100mlを加え、折出結晶をろ取し、橙黄色結晶の
２−（１−ナフチルメチレン）無水コハク酸6.80
ｇを得る。この無水コハク酸3.00ｇとフエネチル
アミン1.52ｇを乾燥塩化メチレン60mlに溶解し、
室温で２時間攪拌する。折出結晶をろ取し、無色
結晶の２−（１−ナフチルメチレン）−３−（フエ
ネチルカルバモイル）プロピオン酸4.02ｇを得
る。
融 点：183〜187℃
IR（KBr）：νCO 1670，1640 cm-1
NMR（d6−DMSO）δ：2.69（ｔ，2H，Ｊ＝
7.1Hz），3.15（ｓ，2H），3.26（ｔ，2H，Ｊ＝
7.1Hz），7.1〜8.1（ｍ，13H），8.20（ｓ，1H）
２−（１−ナフチルメチレン）−３−（フエネチ
ルカルバモイル）プロピオン酸4.00ｇを酢酸120
mlに溶解し、10％パラジウム炭素2.0ｇを加えて
常圧で水添する。触媒をろ去後減圧下に溶媒を留
去し、残留物にヘキサンを加え、折出結晶をろ取
し、無色結晶の（±）−２−（１−ナフチルメチ
ル）−３−（フエネチルカルバモイル）プロピオン
酸3.40ｇを得る。
融 点：131〜135℃
IR（KBr）：νCO 1720，1640 cm-1
NMR（d6−DMSO）δ：2.15〜2.55（ｍ，2H），
2.68（ｔ，2H，Ｊ＝7.1Hz），3.0〜3.5（ｍ，
5H），7.1〜8.2（ｍ，13H）
参考例 ２
（±）−２−（１−ナフチルメチル）−３−（フエ
ネチルカルバモイル）プロピオン酸の光学分割
（±）−２−（１−ナフチルメチル）−３−（フエ
ネチルカルバモイル）プロピオン酸1.0ｇをメタ
ノール20mlに溶解し、（＋）−α−メチルベンジル
アミン335mgのメタノール10ml溶液を加え減圧下
に溶媒を留去する。残留物を酢酸エチルより３回
再結晶して330mgの白色結晶を得る。このものに
水、１規定塩酸および酢酸エチルを加え、酢酸エ
チル層を分離し、さらに0.1規定塩酸で洗い、無
水硫酸マグネシウムで乾燥後減圧下に溶媒を留去
する。残留物をシリカゲルカラムクロマトグラフ
イー（溶出溶媒：クロロホルム／エタノール＝
10／１）で精製して、白色粉末状の（＋）−２−
（１−ナフチルメチル）−３−（フエネチルカルバ
モイル）プロピオン酸220mgを得る。
融 点：146〜150℃
IR（KBr）：νCO 1705，1635 cm-1
NMR（CDCI3）δ：2.25〜2.55（ｍ，2H），2.74
（ｔ，2H，Ｊ＝7.1Hz），3.12（dd，1H，Ｊ＝
9.9，13.7Hz），3.20〜3.60（ｍ，3H），3.73
（dd，1H，Ｊ＝5.0，13.7Hz），5.45〜5.60
（ｍ，1H），7.00〜8.15（ｍ，12H）
〔α〕21 D＋7.3°（メタノール ｃ＝1.00）
（−）−α−メチルベンジルアミンを用いる他
は上記と同様に処理して（−）−２−（１−ナフチ
ルメチル）−３−（フエネチルカルバモイル）プロ
ピオン酸を得る。
融 点：147〜151℃
IR（KBr）：νCO 1705，1635 cm-1
NMR（CDCL3）δ：2.30〜2.50（ｍ，2H），2.75
（ｔ，2H，Ｊ＝7.1Hz），3.11（dd，1H，Ｊ＝
10.5，13.8Hz），3.20〜3.60（ｍ，3H），3.75
（dd，1H，Ｊ＝5.0，14.3Hz），5.40〜5.60
（ｍ，1H），7.05〜8.15（ｍ，12H）
〔α〕23 D−6.2°（メタノール ｃ＝1.00）
参考例 ３
Ｎ−〔２−（１−ナフチルメチル）−３−（フエネ
チルカルバモイル）プロピオニル〕−Ｌ−ヒスチ
ジンヒドラジド
（±）−２−（１−ナフチルメチル）−３−（フエ
ネチルカルバモイル）プロピオン酸3.00gとＬ−
ヒスチジンメチルエステル２塩酸塩2.01gをＮ，
Ｎ−ジメチルホルムアミド24mlに懸濁し、氷冷攪
拌下にジフエニルリン酸アジド2.16mlとトリエチ
ルアミン3.81mlを加え、そのまま16時間攪拌す
る。減圧下に冷媒を留去し、残留物に５％炭酸水
素ナトリウム水溶液を加えて、酢酸エチルで抽出
後、水で洗い、無水硫酸マグネシウムで乾燥す
る。減圧下に冷媒を留去し、残留物にエーテルを
加え、析出結晶をろ取し、白色粉末状のＮ−
〔（±）−２−（１−ナフチルメチル）−３−（フエネ
チルカルバモイル）プロピオニル〕−Ｌ−ヒスチ
ジンメチルエステル4.08gを得る。このエステル
4.00gをメタノール25mlに溶解し、ヒトラジン１
水和物2.75ｇを加え、室温で４時間攪拌する。減
圧下に溶媒を留去し、残留物をエーテルで洗浄
後、減圧下に40℃以下で乾燥し、白色粉末状のＮ
−〔（±）−２−（１−ナフチルメチル）−３−（フエ
ネチルカルバモイル）プロピオニル〕−Ｌ−ヒス
チジンヒドラジド3.90gを得る。このヒドラジド
2.20gをメタノール５mlに40℃で加熱溶解し、不
溶物をろ去する。この溶液を一夜室温で放置後、
析出結晶をろ取し、白色粉末状のＮ−〔（＋）−２
−（１−ナフチルメチル）−３−（フエネチルカル
バモイル）プロピオニル〕−Ｌ−ヒスチジンヒド
ラジド0.70gを得る。
〔α〕10 D＋20.6°（メタノール ｃ＝0.19）
融 点：214〜218℃
RF1：0.53
MS：MH+，513
一方、ろ液にエーテル200mlを加え、一夜放置
し、析出結晶をろ去する。ろ液を、減圧下に濃縮
し、残留物にエーテルを加え、析出結晶をろ取す
る。塩化メチレン／メタノール＝10／１で再結晶
し、白色粉末状のＮ−〔（−）−２−（１−ナフチル
メチル）−３−（フエネチルカルバモイル）プロピ
オニル〕−Ｌ−ヒスチジンヒドラジド1.10gを得
る。
〔α〕10 D−47.0°（メタノール ｃ＝0.20）
融 点：145〜148℃
RF1：0.54
MS：MH+，513
なお、上記で得たヒドラジドは、光学分割した
（＋）および（−）−２−（１−ナフチルメチル）−
３−（フエネチルカルバモイル）プロピオン酸か
ら誘導したヒドラジドと物性（NMR，IR，MS，
旋光度）が一致した。
参考例 ４
（2RS，3S）−３−アミノ−２−ヒドロキシ−
５−メチルヘキサン酸
Ｎ−カルボベンゾキシ−Ｌ−ロイシナール
2.81gに亜硫酸水素ナトリウム3.43gの水20ml溶液
を加え、氷冷下に14時間攪拌する。この反応液に
シアン化カリウム1.41gの水50ml溶液と酢酸エチ
ル200mlを加え室温で４時間攪拌する。酢酸エチ
ル層を飽和食塩水で洗つたのち無水硫酸マグネシ
ウムで乾燥する。減圧下に溶媒を留去し、無色油
状の３−カルボベンゾキシアミノ−２−ヒドロキ
シ−５−メチルヘキサンニトリル2.54gを得る。
このニトリル500mgにジオキサン20mlと濃塩酸
20mlの混液を加え、12時間加熱還流する。減圧下
に溶媒を留去し残留結晶を陽イオンカラムクロマ
イトグラフイー（溶出溶媒：２規定アンモニア
水）により精製し、無色結晶の（2RS，3S）−３
−アミノ−２−ヒドロキシ−５−メチルヘキサン
酸254mg（2R：2Sの比が約７：３の混合物）を得
る。
融 点：137〜140℃
IR（KBr）：νCO 1570 cm-1
NMR（D2Ｏ）δ：0.8〜1.0（ｍ，6H），1.2〜1.4
（ｍ，2H），1.55〜1.8（ｍ，1H），3.0〜3.4
（ｍ，1H）3.89（ｄ，0.7H，Ｊ＝3.3Hz），4.00
（ｄ，0.3H，Ｊ＝3.3Hz）
MS：MH+，162
参考例 ５
（3S）−３−カルボベンゾキシアミノ−５−メ
チル−１，２−エポキシヘキサン
メチルトリフエニルホスホニウムブロミド12g
を乾燥テトラヒドロフラン100mlに溶解し、氷冷
下にアルゴン気流中でｎ−ブチルリチウム（1.6
モルヘキサン溶液）19.5mlを滴下したのち、室温
で１時間攪拌する。反応液を５℃以下に冷却し、
Ｎ−カルボベンゾキシ−Ｌ−ロイシナール7.5gの
乾燥テトラヒドロフラン20mlを滴下したのち、室
温で１時間反応させる。反応液に塩化アンモニウ
ム水溶液を加え、酢酸エチルで抽出し、飽和食塩
水で洗つたのち無水硫酸マグネシウムで乾燥す
る。減圧下に溶媒を留去し、残留物をシリカゲル
フラツシユカラムクロマトグラフイー（溶出溶
媒：塩化メチレン）で精製し、無色粘性油状の
（3S）−３−カルボベンゾキシアミノ−５−メチ
ル−１−ヘキセン1.6gを得る。
IR（液膜）：νCO 1690 cm-1
NMR（CDC13）δ：0.85〜0.95（ｍ，6H），1.3
〜1.75（ｍ，3H），4.15〜4.25（ｍ，1H），4.61
（ｓ，1H）5.05〜5.2（ｍ，2H），5.10（ｓ，
2H）5.74（ddd，1H，Ｊ＝6.0，10.0，17.0
Hz），7.35（ｓ，5H）
次いで、３−クロロ過安息香酸600mgを乾燥ク
ロロホルム５mlに溶解し、氷冷下に（3S）−３−
カルボベンゾキシアミノ−５−メチル−１−ヘキ
セン850mgの乾燥クロロホルム５ml溶液を加え、
16時間攪拌する。反応液に塩化メチレンを加え、
チオ硫酸ナトリウム水溶液、５％炭酸水素ナトリ
ウム水溶液および飽和食塩水で洗い、無水硫酸マ
グネシウムで乾燥する。減圧下に溶媒を留去し、
残留物をシリカゲルフラツシユカラムクロマトグ
ラフイー（溶出溶媒：ベンゼン／ヘキサン＝１／
１）で精製し、無色粘性油状の（3S）−３−カル
ボベンゾキシアミノ−５−メチル−１，２エポキ
シヘキサン401mgを得る。
IR（液膜）：νCO 1695 cm-1
NMR（CDC13）δ：0.85〜1.0（ｍ，6H），1.35
〜1.8（ｍ，3H），2.58（ｔ，1H，Ｊ＝4.4Hz），
2.72（ｔ，1H，Ｊ＝4.4Hz），2.99（ｓ，1H），
3.95〜4.1（ｍ，1H），4.45〜4.55（ｍ，1H），
5.09（ｓ，2H），7.34（ｓ，5H）
実施例 １
（2RS，3S）−３−｛Ｎ−〔（＋）−２−（１−ナフ
チルメチル）−３−（フエネチルカルバモイル）プ
ロピオニル〕−Ｌ−ヒスチジル｝アミノ−２−ヒ
ドロキシ−５−メチルヘキシルメチルエーテル
（3S）−３−カルボベンゾキシアミノ−５−メ
チル−１，２−エポキシヘキサン176mgをメタノ
ール10mlに溶解し、乾燥中性アルミナ2gを加え
て、16時間加熱還流する。アルミナをろ去したの
ち、減圧下に溶媒を留去し、残留物をプレパラテ
イブシリカゲル薄層クロマトグラフイー（展開溶
媒：クロロホルム／メタノール／水＝８／３／１
の下層）で精製し、無色粘性油状の（2RS，3S）
−３−カルボベンゾキシアミノ−２−ヒドロキシ
−５−メチルヘキシルメチルエーテル96mgを得
る。このエーテル94mgをメタノール10mlに溶解
し、２規定塩酸0.16mlおよび10％パラジウム炭素
10mgを加え常圧で水添する。触媒をろ去後、減圧
下に溶媒を留去し、無色粘性油状の（2RS，3S）
−３−アミノ−２−ヒドロキシ−５−メチルヘキ
シルメチルエーテル塩酸塩54mgを得る。
一方、Ｎ−〔（＋）−２−（１−ナフチルメチル）
−３−（フエネチルカルバモイル）プロピオニル〕
−Ｌ−ヒスチジンヒドラジド130mgを乾燥Ｎ，Ｎ
−ジメチルホルムアミド６mlに懸濁し、−20℃で
攪拌下に5.1規定乾燥塩化水素／Ｎ，Ｎ−ジメチ
ルホルムアミド0.19ml、続いて亜硝酸イソアミル
0.05mlを加える。ヒドラジドの消失を確認した
後、反応液の温度を−30℃まで下げてトリエチル
アミン0.14mlで中和し、Ｎ−〔（＋）−２−（１−ナ
フチルメチル）−３−（フエネチルカルバモイル）
プロピオニル〕−Ｌ−ヒスチジンアジド溶液を調
整する。別に、（2RS，3S）−３−アミノ−２−ヒ
ドロキシ−５−メチルヘキシルメチルエーテル塩
酸塩52mgと、トリエチルアミン0.05mlの乾燥Ｎ，
Ｎ−ジメチルホルムアミドml溶液に氷冷下、先の
アジド溶液を滴下し、16時間攪拌する。減圧下に
溶媒を留去し、残留物に５％炭酸水素ナトリウム
水溶液を加えて酢酸エチルで抽出し、次いで飽和
食塩水で洗つたのち、無水硫酸マグネシウムで乾
燥する。減圧下に溶媒を留去し、残留物をプレパ
ラテイブシリカゲル薄層クロマトグラフイー）展
開溶媒：クロロホルム／メタノール／水＝８／
３／１の下層）で精製し、白色粉末状の（2RS，
3S）−３−｛Ｎ〔（＋）−２−（１−ナフチルメチル）
−３−（フエネチルカルバモイル）プロピオニル〕
−Ｌ−ヒスチジル｝アミノ−２−ヒドロキシ−５
−メチルヘキシルメチルエーテル55mgを得る。
融 点：91〜95℃
Rf1：0.60
Rf2：0.40
MS：MH+，642
実施例 ２
（2RS，3S）−３−｛Ｎ−〔（＋）−２−（１−ナフ
チルメチル）−３−（フエネチルカルバモイル）プ
ロピオニル〕−Ｌ−ヒスチジル｝アミノ−２−ヒ
ドロキシ−５−メチルヘキシルイソアミルエーテ
ル
（3S）−３−カルボベンゾキシアミノ−５−メ
チル−１，２−エポキシヘキサン100mgと乾燥中
性アルミナ２ｇにイソアミルアルコール２mlを加
え100℃で16時間さらに140℃で90分間加熱攪拌す
る。アルミナをろ去した後、減圧下に濃縮して、
無色油状の（2RS，3S）−３−カルボベンゾキシ
アミノ−２−ヒドロキシ−５−メチルヘキシルイ
ソアミルエーテル97mgを得る。このエーテル95mg
をメタノール２mlに溶解し、１規定塩酸0.27mlお
よび10％パラジウム炭素10mgを加え常圧で水添す
る。触媒をろ去後、減圧下に溶媒を留去して、無
色粘性油状の（2RS，3S）−３−アミノ−２−ヒ
ドロキシ−５−メチルヘキシルイソアミルエーテ
ル塩酸塩65mgを得る。
一方、Ｎ−〔（＋）−２−（１−ナフチルメチル）
−３−（フエネチルカルバモイル）プロピオニル〕
−Ｌ−ヒスチジンヒドラジド115mgをＮ，Ｎ−ジ
メチルホルムアミド２mlに溶かし、−20℃で5.1規
定乾燥塩化水素／Ｎ，Ｎ−ジメチルホルムアミド
0.16ml、続いて亜硝酸イソアミル0.04mlを加えて
攪拌する。ヒドラジドの消失を確認した後、反応
液の温度を−30℃まで下げてトリエチルアミン
0.11mlで中和し、Ｎ−〔（＋）−２−（１−ナフチル
メチル）−３−（フエネチルカルバモイル）プロピ
オニル〕−Ｌ−ヒスチジンアジド溶液を調整する。
別に（2RS，3S）−３−アミノ−２−ヒドロキシ
−５−メチルヘキシルイソアミルエーテル63mgと
トリアチルアミン0.035mlのＮ，Ｎ−ジメチルホ
ルムアミド２ml溶液に氷冷下、先のアジド冷溶液
を滴下し、そのまま16時間攪拌する。反応液に５
％炭酸水素ナトリウム水溶液を加え、酢酸エチル
で抽出し、飽和食塩水で洗い、無水硫酸マグネシ
ウムで乾燥する。減圧下に溶媒を留去し、残留物
をプレパラテイブシリカゲル薄層クロマトグラフ
イー（展開溶媒：クロロホルム／メタノール／水
＝８／３／１の下層）で分離精製し、白色粉末状
の（2RS，3S）−３−｛Ｎ−〔（＋）−２−（１−ナフ
チルメチル）−３−（フエネチルカルバモイル）プ
ロピオニル〕−Ｌ−ヒスチジル｝アミノ−２−ヒ
ドロキシ−５−メチルヘキシルアミルエーテル51
mgを得る。
融 点：73〜76℃
Rf1：0.63
Rf2：0.57
MS：MH+，698
実施例 ３
（2RS，3S）−３−｛Ｎ−〔（＋）−２−（１−ナフ
チルメチル）−３−（フエネチルカルバモイル）プ
ロピオニル〕−Ｌ−ヒスチジル｝アミノ−２−ヒ
ドロキシ−５−メチルヘキシルベンジルエーテル
（3S）−３−カルボベンゾキシアミノ−５−メ
チル−１，２−エポキシヘキサン100mgと乾燥シ
リカゲル２ｇにベンジルアルコール２mlを加え
100℃で16時間加熱攪拌する。シリカゲルをろ去
した後、減圧下に濃縮して、無色油状の（2RS，
3S）−３−カルボベンゾキシアミノ−２−ヒドロ
キシ−５−メチルヘキシルベンジルエーテル105
mgを得る。このエーテル86mgをメタノール10mlに
溶解し、２規定塩酸0.14mlおよび５％パラジウム
炭素17mgを加え常圧で水添する。触媒をろ去後、
減圧下に溶媒を留去し、残留物をプレパラテイブ
シリカゲル薄層クロマトグラフイー（展開溶媒：
クロロホルム／メタノール／水＝８／３／１の下
層）で分離精製し、無色粘性油状の（2RS，3S）
−３−アミノ−２−ヒドロキシ−５−メチルヘキ
シルベンジルエーテル塩酸塩17mgを得る。
一方、Ｎ−〔（＋）−２−（１−ナフチルメチル）
−３−（フエネチルカルバモイル）プロピオニル〕
−Ｌ−ヒスチジンヒドラジド31mgをＮ，Ｎ−ジメ
チルホルムアミド１mlに溶かし、−20℃で5.1規定
乾燥塩化水素／Ｎ，Ｎ−ジメチルホルムアミド
0.044ml、続いて亜硝酸イソアミル0.011mlを加え
て攪拌する。ヒドラジドの消失を確認した後、反
応液の温度を−30℃まで下げてトリエチルアミン
0.031mlで中和し、Ｎ−〔（＋）−２−（１−ナフチ
ルメチル）−３−（フエネチルカルバモイル）プロ
ピオニル〕−Ｌ−ヒスチジンアジド溶液を調整す
る。別に（2RS，3S）−３−アミノ−２−ヒドロ
キシ−５−メチルヘキシルベンジルエーテル塩酸
塩16mgとトリエチルアミン0.011mlのＮ，Ｎ−ジ
メチルホルムアミド１ml溶液に氷冷下、先のアジ
ド冷溶液を滴下し、そのまま16時間攪拌する。反
応液に５％炭酸水素ナトリウム水溶液を加え、酢
酸エチルで抽出し、飽和食塩水で洗い、無水硫酸
マグネシウムで乾燥する。減圧下に溶媒を留去
し、残留物をプレパラテイブシリカゲル薄層クロ
マトグラフイー（展開溶媒：クロロホルム／メタ
ノール／水＝８／３／１の下層）で分離精製し、
白色粉末状の（2RS，3S）−３−｛Ｎ−〔（＋）−２
−（１−ナフチルメチル）−３−（フエネチルカル
バモイル）プロピオニル〕−Ｌ−ヒスチジル｝ア
ミノ−２−ヒドロキシ−５−メチルヘキシルベン
ジルエーテル18mgを得る。
融 点：76〜79℃
Rf1：0.61
Rf2：0.55
MS：MH+，718
実施例 ４
（2RS，3S）−Ｎ−イソアミル−３−｛Ｎ−
〔（＋）−２−（１−ナフチルメチル）−３−（フエネ
チルカルバモイル）プロピオニル〕−Ｌ−ヒスチ
ジル｝アミノ−２−ヒドロキシ−５−メチルヘキ
シルアミン
（3S）−３−カルボベンゾキシアミノ−５−メチ
ル−１，２−エポキシヘキサン50mgと乾燥中性ア
ルミナ0.5ｇにイソアミルアミン１mlを加え室温
で16時間さらに70℃で90分間攪拌する。アルミナ
をろ去したのち、減圧下に濃縮して、無色油状の
（2RS，3S）−Ｎ−イソアミル−３−カルボベンゾ
キシアミノ−２−ヒドロキシ−５−メチルヘキシ
ルアミン71mgを得る。このアミン70mgをメタノー
ル２mlに溶解し、２規定塩酸0.2mlおよび10％パ
ラジウム炭素７mgを加え常圧で水添する。触媒を
ろ去後、減圧下に溶媒を留去して、無色粘性油状
の（2RS，3S）−Ｎ−イソアミル−３−アミノ−
２−ヒドロキシ−５−メチルヘキシルアミン２塩
酸塩42mgを得る。
一方、Ｎ−〔（＋）−２−（１−ナフチルメチル）−
３−（フエネチルカルバモイル）プロピオニル〕−
Ｌ−ヒスチジンヒドラジド64mgをＮ，Ｎ−ジメチ
ルホルムアミド２mlに溶かし、−20℃で5.1規定乾
燥塩化水素／Ｎ，Ｎ−ジメチルホルムアミド0.09
ml、続いて亜硝酸イソアミル0.022mlを加えて攪
拌する。ヒドラジドの消失を確認した後、反応液
の温度を−30℃まで下げてトリエチルアミン
0.063mlで中和し、Ｎ−〔（＋）−２−（１−ナフチ
ルメチル）−３−（フエネチルカルバモイル）プロ
ピオニル〕−Ｌ−ヒスチジンアジド溶液を調整す
る。別に（2RS，3S）−Ｎ−イソアミル−３−ア
ミノ−２−ヒドロキシ−５−メチルヘキシルアミ
ン２塩酸塩40mgとトリエチルアミン0.063mlのＮ，
Ｎ−ジメチルホルムアミド２ml溶液に氷冷下、先
のアジド冷溶液を滴下し、そのまま16時間攪拌す
る。反応液に５％炭酸水素ナトリウム水溶液を加
え、酢酸エチルで抽出し、飽和食塩水で洗い、無
水硫酸マグネシウムで乾燥する。減圧下に溶媒を
留去し、残留物をプレパラテイブシリカゲル薄層
クロマトグラフイー（展開溶媒：クロロホルム／
メタノール／水＝８／３／１の下層）で分離精製
し、白色粉末状の（2RS，3S）−Ｎ−イソアミル
−３−｛Ｎ−〔（＋）−２−（１−ナフチルメチル）−
３−（フエネチルカルバモイル）プロピオニル〕−
Ｌ−ヒスチジル｝アミノ−２−ヒドロキシ−５−
メチルヘキシルアミン８mgを得る。
融 点：92〜97℃
Rf1：0.10
Rf2：0.04
MS：MH+，697
実施例 ５
（2RS，3S）−Ｎ−ベンジル−３−｛Ｎ−〔（＋）
−２−（１−ナフチルメチル）−３−（フエネチル
カルバモイル）プロピオニル〕−Ｌ−ヒスチジル｝
アミノ−２−ヒドロキシ−５−メチルヘキシルア
ミン
（3S）−３−カルボベンゾキシアミノ−５−メ
チル−１，２−エポキシヘキサン100mgをジエチ
ルエータル10mlに溶解し、乾燥シリカゲル２ｇお
よびベンジルアミン0.1mlを加え、室温で16時間
攪拌し、さらに２時間加熱攪拌する。シリカゲル
をろ去したのち、減圧下に溶媒を留去し、残留物
をプレパラテイブシリカゲル薄層クロマトグラフ
イー（展開溶媒：クロロホルム／メタノール／水
＝８／３／１の下層）で精製し、無色粘性油状の
（3S）−Ｎ−ベンジル−３−カルボベンゾキシア
ミノ−２−ヒドロキシ−５−メチルヘキシルアミ
ン56mgを得る。このアミン54mgをメタノール10ml
に溶解し、２規定塩酸0.2mlおよび10％パラジウ
ム炭素10mgを加え常圧で水添する。触媒をろ去
後、減圧下に溶媒を留去して、白色粉末状の
（3S）−Ｎ−ベンジル−３−アミノ−２−ヒドロ
キシ−５−メチルヘキシルアミン２塩酸塩43mgを
得る。
一方、Ｎ−〔（＋）−２−（１−ナフチルメチル）
−３−（フエネチルカルバモイル）プロピオニル〕
−Ｌ−ヒスチジンヒドラジド66mgを乾燥Ｎ，Ｎ−
ジメチルホルムアミド５mlに懸濁し、−20℃で攪
拌下に5.1規定乾燥塩化水素／Ｎ，Ｎ−ジメチル
ホルムアミド0.08ml、続いて亜硝酸イソアミル
0.02mlを加える。ヒドラジドの消失を確認したの
ち、反応液の温度を−30℃まで下げてトリエチル
アミン0.06mlで中和し、Ｎ−〔（＋）−２−（１−ナ
フチルメチル）−３−（フエネチルカルバモイル）
プロピオニル〕−Ｌ−ヒスチジンアジド溶液を調
整する。別に（3S）−Ｎ−ベンジル−３−アミノ
−２−ヒドロキシ−５−メチルヘキシルアミン２
塩酸塩40mgとトリエチルアミン0.018mlの乾燥Ｎ，
Ｎ−ジメチルホルムアミド２ml溶液に氷冷下、先
のアジド冷溶液を滴下し、16時間攪拌する。減圧
下に溶媒を留去し、残留物に５％炭酸水素ナトリ
ウム水溶液を加えて酢酸エチルで抽出し、次いで
飽和食塩水で洗つたのち、無水硫酸マグネシウム
で乾燥する。減圧下に溶媒を留去し、残留物をシ
リカゲルフラツシユカラムクロマトグラフイー
（溶出溶媒：クロロホルム／メタノール／＝15／
１）で精製し、白色粉末状の（2RS，3S）−Ｎ−
ベンジル−３−｛Ｎ−〔（＋）−２−（１−ナフチル
メチル）−３−（フエネチルカルバモイル）プロピ
オニル〕−Ｌ−ヒスチジル｝アミノ−２−ヒドロ
キシ−５−メチルヘキシルアミン33mgを得る。
融 点：108〜113℃
Rf1：0.44
Rf2：0.14
MS：MH+，717
実施例 ６
（2RS，3S）−３−｛Ｎ−〔（＋）−２−（１−ナフ
チルメチル）−３−（フエネチルカルバモイル）プ
ロピオニル〕−Ｌ−ヒスチジル｝アミノ−２−ヒ
ドロキシ−５−メチルヘキサノール
（2RS，3S）−３−アミノ−２−ヒドロキシ−
５−メチル−ヘキサン酸110mgをメタノール10ml
に溶解し、氷冷攪拌下に塩化水素ガスを吹き込み
一夜攪拌する。反応液を減圧下に濃縮乾固し、白
色粉末状の（2RS，3S）−３−アミノ−２−ヒド
ロキシ−５−メチルヘキサン酸メチル塩酸塩150
mgを得る。〔IR（KBr）：νCO1740 cm-1〕
一方、Ｎ−〔（＋）−２−（１−ナフチルメチル）
−３−（フエネチルカルバモイル）プロピオニル〕
−Ｌ−ヒスチジンヒドラジド154mgをＮ，Ｎ−ジ
メチルホルムアミド４mlに溶かし、−20℃で攪拌
下に5.1規定乾燥塩化水素／Ｎ，Ｎ−ジメチルホ
ルムアミド0.19ml、続いて亜硝酸イソアミル0.05
mlを加えて攪拌する。ヒドラジドの消失を確認し
た後、反応液の温度を−30℃まで下げてトリエチ
ルアミン0.14mlで中和し、Ｎ−〔（＋）−２−（１−
ナフチルメチル）−３−（フエネチルカルバモイ
ル）プロピオニル〕−Ｌ−ヒスチジンアジド溶液
を調整する。別に（2RS，3S）−３−アミノ−２
−ヒドロキシ−５−メチルヘキサン酸メチル塩酸
塩64mgとトリエチルアミン0.09mlのＮ，Ｎ−ジメ
チルホルムアミド２ml溶液に氷冷下、先のアジド
冷溶液を滴下し、そのまま16時間攪拌する。反応
液に５％炭酸水素ナトリウム水溶液を加え、酢酸
エチルで抽出し、飽和食塩水で洗い、無水硫酸マ
グネシウムで乾燥する。減圧下に溶媒を留去し、
残留物をシリカゲルフラツシユカラムクロマトグ
ラフイー（溶出溶媒：クロロホルム／メタノール
＝10／１）で分離精製し、白色粉末状の（2RS，
3S）−３−｛Ｎ−〔（＋）−２−（１−ナフチルメチ
ル）−３−（フエネチルカルバモイル）プロピオニ
ル〕−Ｌ−ヒスチジル｝アミノ−２−ヒドロキシ
−５−メチルヘキサン酸メチル120mgを得る。
融 点：82〜87℃
Rf1：0.58
MS：MH+，656
次いで、上記のメチルエステル37mgをエタノー
ル８mlと水２mlの混液に溶解し、氷冷下に水素化
ホウ素ナトリウム22mgを加え、室温にもどし16時
間攪拌する。減圧下に溶媒を留去し、残留物に酢
酸エチルを加え５％炭酸水素ナトリウム水溶液お
よび飽和食塩水で洗い、無水硫酸マグネシウムで
乾燥する。減圧下に溶媒を留去し、白色粉末状の
（2RS，3S）−３−｛Ｎ−〔（＋）−２−（１−ナフチ
ルメチル）−３−（フエネチルカルバモイル）プロ
ピオニル〕−Ｌ−ヒスチジル｝アミノ−２−ヒド
ロキシ−５−メチルヘキサノール25mgを得る。
融 点：101〜107℃
Rf1：0.44
Rf2：0.15
MS：MH+，536
実施例 ７
（3S，4S）−４−｛Ｎ−〔（＋）−２−（１−ナフ
チルメチル）−３−（フエネチルカルバモイル）プ
ロピオニル〕−Ｌ−ヒスチジル｝アミノ−３−ヒ
ドロキシ−６−メチルヘプタノール
Ｎ−（tert−ブチルオキシカルボニル）スタチ
ン（市販）100mgを乾燥メタノール20mlに溶解し、
氷冷攪拌下に塩化水素ガスを吹き込んだ後、室温
にもどし一夜反応させる。減圧下に溶媒を留去
し、無色粘性油状のスタチンメチルエステル塩酸
塩81mgを加える。〔IR（液膜）：νCO 1725 cm-1〕
一方、Ｎ−〔（＋）−２−（１−ナフチルメチル）
−３−（フエネチルカルバモイル）プロピオニル〕
−Ｌ−ヒスチジンヒドラジド180mgを乾燥Ｎ，Ｎ
−ジメチルホルムアミド10mlに懸濁し、−20℃で
攪拌下に5.1規定乾燥塩化水素／Ｎ，Ｎ−ジメチ
ルホルムアミド0.24ml、続いて亜硝酸イソアミル
0.06mlを加える。ヒドラジドの消失を確認した
後、反応液の温度を−30℃まで下げてトリエチル
アミン0.16mlで中和し、Ｎ−〔（＋）−２−（１−ナ
フチルメチル）−３−（フエネチルカルバモイル）
プロピオニル〕−Ｌ−ヒスチジンアジド溶液を調
整する。別にスタチンメチルエステル塩酸塩80mg
とトリエチルアミン0.06mlの乾燥Ｎ，Ｎ−ジメチ
ルホルムアミド２ml溶液に氷冷下、先のアジド冷
溶液を滴下し、16時間攪拌する。減圧下に溶媒を
留去し、残留物に５％炭酸水素ナトリウム水溶液
を加えて酢酸エチルで抽出し、次いで飽和食塩水
で洗つたのち、無水硫酸マグネシウムで乾燥す
る。減圧下に溶媒を留去し、残留物をシリカゲル
フラツシユカラムクロマトグラフイー（溶出溶
媒：クロロホルム／メタノール＝15／１）で精製
し、白色粉末状のＮ−〔（＋）−２−（１−ナフチル
メチル）−３−（フエネチルカルバモイル）プロピ
オニル〕−Ｌ−ヒスチジル−スタチンメチルエス
テル35mgを得る。
融 点：90〜94℃
Rf1：0.67
Rf2：0.65
MS：MH+，670
次いで、このスタチンメチルエステル25mgをエ
タノール８mlと水２mlの混液に溶解し、氷冷下に
水素化ホウ素ナトリウム14mgを加え、室温にもど
し16時間攪拌する。減圧下に溶媒を留去し、残留
物に酢酸エチルを加え５％炭酸水素ナトリウム水
溶液および飽和食塩水で洗い、無水硫酸マグネシ
ウムで乾燥する。減圧下に溶媒を留去し、白色粉
末状の（3S，4S）−４−｛Ｎ−〔（＋）−２−（１−
ナフチルメチル）−３−（フエネチルカルバモイ
ル）プロピオニル〕−Ｌ−ヒスチジル｝アミノ−
３−ヒドロキシ−６−メチルヘプタノール７mgを
得る。
融 点：87〜92℃
Rf1：0.53
Rf2：0.25
MS：MH+，642
実施例 ８
ヒトレニン−羊レニン基質でのレニン活性阻害
作用
125mMのピロフオスフエート緩衝液
（pyrophosphate buffer）（PH7.4）200μとアン
ジオテンシン変換酵素阻害剤として20mMのＬ−
フエニルアラニル−Ｌ−アラニル−Ｌ−プロリン
の水溶液25μ、2000ngアンジオテンシンＩ当
量／mlの部分精製羊レニン基質50μ、脱イオン
水150μと本発明の化合物のジメチルスルホキ
シド溶液50μまたはコントロール群としてジメ
チルスルホキシド50μの溶液中に20〜30ngアン
ジオテンシンＩ／時間の精製ヒトレニン25μを
加え、37℃の水浴中で15分間インキユベート
（incubate）したのち、この反応液を100℃の水浴
中に５分間入れ、反応を停止する。冷却後200μ
を分取し、レニン添加によつて生成されたアン
ジオテンシンＩの量をラジオイムノアツセイ
（radioimmunoassay）法で定量し、下式により
阻害活性を求めた。
阻害活性（％）＝コントロール値−本発明の化合物存
在下の値／コントロール値×100
上式により求められた阻害活性から50％阻害活
性モル濃度（IC50）を求め、その結果を以下に示
す。
[Industrial Application Field] The purpose of the present invention is to obtain a general formula useful as a pharmaceutical product. [His in the formula is an L-histidyl group, m is an integer of 1 to 3, n is 1 or 2,
is a hydroxyl group or a group represented by the formula -Y-R (wherein Y is -0- or -NH- and is a linear or branched alkyl group or an aralkyl group)] An object of the present invention is to provide novel amino acid derivatives and pharmacologically acceptable acid addition salts thereof. More specifically, novel amino acid derivatives represented by the above general formula () and their pharmacologically acceptable acids, which have humanrenin inhibitory action and are useful as orally administrable therapeutic agents for hypertension. It is to provide an addition salt. [Prior Art] Renin is a proteolytic enzyme released from juxtaglomerular cells of the kidney. This reacts with the renin substrate present in the alpha 2 globulin fraction of plasma to produce angiotensin. The generated angiotensin is converted into angiotensin by angiotensin converting enzyme.
is converted to Angiotensin has a vasoconstrictive effect and is a factor in hypertension that acts on the adrenal cortex to secrete aldosterone, which affects sodium and water metabolism. Compounds that inhibit the reaction between renin and renin substrates and suppress the production of angiotensin are attracting attention as antihypertensive agents with a new mechanism of action, and their development is strongly desired. Until now, many peptide derivatives have been known as compounds that inhibit the reaction between renin and renin substrates, that is, have the effect of inhibiting renin activity (Japanese Patent Publication No. 58-39149, Japanese Patent Publication No. 1983 -No. 110661, No. 155345, No. 155345, No. 59-
No. 227851, European Patent Publication No. 707029,
(No. 77028, No. 81783) Among these patent applications, in particular, Japanese Patent Publication No. 155345 (1983) contains the general formula (A in the formula is a hydrogen atom, a phenyl group, 10, 11-
dihydro-5H-dibenzo[a,d]cycloheptenyl group, etc., and B is -0-, -CH=CH
-, -CH 2 -, etc., p and q may be the same or different and each is an integer of 0 or 1 to 3, and D is a hydrogen atom, a lower alkyl group, a lower Alkenyl group, phenyl group, phenylalkyl group, etc., F is phenyl group, cyclohexyl group, isopropyl group, etc., His is L-histidyl group, F is an amino acid residue, such as L-leucyl group, L - isoleucyl group, L-leucyl-L-phenylalanyl group, L-phenylalanyl-L-phenylalanyl group, L-alanyl-L-phenylalanyl group, etc., and G is a protecting group at the C-terminus of the amino acid, such as an amino group or an alkylamino group. , allylalkylamino group, alkoxy group, etc.) are disclosed. Also, in Japanese Patent Publication No. 1982-227851, the general formula (In the formula, R 1 CO- is an acyl group of an N-substituted amino acid, such as penzyloxycarbonyl group, t-butoxycarbonyl group, α-naphthoxyacetyl group, phenylbutyryl group, 3-(3-nitro-2
-pyridine sulfenyl)thiopropionyl group,
Amino acids whose amino groups are substituted with 9-fluorenylmethyloxycarbonyl groups, such as L-phenylalanyl groups, L-tryptophyl groups, L-tyrosyl groups, L-cysteinyl groups, 3-(1-naphthyl)-L- Alanyl group, L-phenylglycyl group, 1-amino-4-phenylbutyryl group, 1,
2,3,4-tetrahydro-β-carboline-3
-L-carboxyl group, etc., His is an L-histidyl group, C indicates an S configuration, Z is a hydroxyl group, a mercapto group, or a formyl group,
R2 is a hydrogen atom, an alkyl group, a hydroxyl group, a mercapto group, an amino group, a carbamoyl group as a substituent,
Discloses a peptide derivative represented by a formyl group, an aryl group, or a substituted alkyl group having a heterocyclic group. [Problem to be solved by the invention] Most of the compounds disclosed in the above-mentioned patent applications are polypeptides, which are difficult to synthesize.
Moreover, it is degraded by proteolytic enzymes in the body, such as chymotrypsin, and cannot be expected to exert its pharmacological effects when administered orally. The peptide derivative represented by the above general formula () is a tri- or tetra-peptide derivative, and although it is relatively easy to produce compared to other polypeptide derivatives, this compound is also a polypeptide derivative as disclosed in the above-mentioned patent application. Like peptide derivatives, it is unstable to proteolytic enzymes, and it is difficult to expect that it will exhibit its medicinal efficacy when administered orally. Furthermore, although the compound represented by the above formula () is easier to produce than other peptide derivatives, this compound is also resistant to proteolytic enzymes, similar to the polypeptide derivatives disclosed in the above-mentioned patent applications. It is stable and it is difficult to expect that it will exhibit its medicinal efficacy through oral administration. As a result of various studies to solve these problems, the present inventors found that the amino acid derivatives represented by the above general formula () and their pharmacologically acceptable acid addition salts can be produced relatively easily. The inventors have discovered that the drug has a strong renin activity inhibiting effect, has low toxicity, can be administered orally, and can solve the above-mentioned problems. (2) Structure of the invention [Means and effects for solving the problems] The amino acid derivatives of the present invention represented by the general formula () and their pharmacologically acceptable acid addition salts are human renin-sheep renin substrates. It exhibits a strong renin activity inhibitory effect in the system, and is stable against proteolytic enzymes such as chymotrypsin and pepsin. Additionally, this product exhibits a clear hypotensive effect in monkeys when injected orally or intravenously. This indicates that the amino acid derivatives of the present invention represented by the general formula () and their pharmacologically acceptable acid addition salts have a strong renin activity inhibiting effect, and can be orally administered with low toxicity for the treatment of hypertension. This indicates that it is useful as a drug. The amino acid derivative of the present invention represented by the general formula () in which X is a group represented by the formula -Y-R (in which Y and R have the same meanings as above) is a compound represented by the formula (In the formula, C represents L-configuration and m has the same meaning as above) and a compound represented by the general formula (in the formula, n, Y and R have the same meanings as above, and a is 1 or 2). The compound represented by the general formula () used as a starting material in this reaction has the general formula A reactive functional derivative of carboxylic acid represented by (m in the formula has the same meaning as above) and L-histidine methyl ester dihydrochloride are reacted in N,N-dimethylformamide, and the general formula (m and C in the formula have the same meanings as above)
It can be produced by obtaining a compound represented by and then reacting this with hydrazine monohydrate in a methanol solution. The carboxylic acid represented by the general formula () can be produced by the following method or a method similar thereto. That is, by reacting 1-naphthaldehyde and diethyl succinate, the formula A compound represented by the formula A succinic anhydride derivative represented by is obtained. By reacting the succinic anhydride derivative of this formula () with phenylalkylamine, the formula It can be produced by obtaining a compound represented by (m in the formula has the same meaning as above) and hydrogenating this in the presence of palladium on carbon. The compound of general formula () used as the other starting material in the above production method can be produced by a method described in the literature or a method similar thereto. For example, a compound of the general formula () where n is 1 is obtained by treating methyltriphenylphosphonium bromide with butyllithium in tetrahydrofuran to produce triphenylphosphine methylene, and reacting this with N-carbobenzoxyleucinal. The expression A compound represented by the formula is obtained, which is then reacted with 3-chloroperbenzoic acid to form An epoxy body represented by is obtained. In the presence of alumina or silica gel, the general formula R-YH () (R and Y in the formula have the same meanings as above)
It can be produced by reacting alcohols or alkylamines represented by and then hydrogenating in the presence of palladium on carbon. The compound represented by the general formula () of the present invention has a hydroxyl group, the compound represented by the general formula (n' in the formula is 0 or 1, m and His
It can be produced by reducing a compound represented by (has the same meaning as above) using sodium borohydride or the like. The compound represented by this general formula () is the compound represented by the above general formula () and the general formula (In the formula, n' has the same meaning as above, and HX represents hydrochloric acid or p-toluenesulfonic acid.) The compound of general formula () used as a starting material in the above production method can be produced by a method described in the literature or a method similar thereto. For example, a compound of general formula () where n' is 0 can be prepared using a method similar to that described in The Journal of Organic Chemistry [J.Org.Chem.] Vol. 45, pp. 2288-2290 (1980). It is produced by obtaining 3-amino-2-hydroxy-5-methylhexanoic acid by a method and esterifying it by a conventional method. In addition, the compound of general formula () where n' is 1 is statin or N
It is produced by esterifying -(tert-butyloxycarbonyl)statin by a conventional method. The reaction between the compound represented by the above formula () of the present invention and the compound represented by the general formula () or the general formula () can be carried out according to a conventional method. To suitably carry out this reaction, the compound represented by the formula () is suspended in N,N-dimethylformamide, 3 to 5 times the mole of hydrogen chloride is added to this solution, and the compound represented by the general formula () is suspended in N,N-dimethylformamide. 1 to 3 for the compound
Add molar amount of isoamyl nitrite for 5 to 30 minutes -20
React at ~-5°C. Triethylamine is added to this reaction solution to adjust the pH to 8 to 9, and this solution is mixed with the above general formula () or the compound of general formula () in an equimolar amount to the compound represented by formula () and the N,N- The reaction mixture is added to a dimethylformamide solution under cooling, preferably at -20 to 0°C, and then reacted for 5 to 20 hours at 0°C to room temperature, and the reaction product is treated in a conventional manner to obtain the desired product. The amino acid derivative represented by the general formula () of the present invention has four asymmetric carbon atoms, and various isomers exist depending on the configuration of substituents at each asymmetric carbon. The configuration of substituents on these asymmetric carbon atoms greatly influences the renin inhibitory activity of the compound represented by the general formula (). In the present invention, the configuration of the carbon atom substituted with the amino group of the compound represented by general formula () or general formula () is preferably S configuration, but the carbon atom substituted with the hydroxyl group The configuration of S has a relatively small effect on activity;
configuration, R configuration, or a mixture thereof. The steric structure of the carboxylic acid represented by the general formula () greatly influences the renin inhibitory activity of the compound represented by the general formula () of the present invention, and the acyl moiety is formed from the (+) form of the carboxylic acid. Compounds in which the acyl moiety is formed from a (-) carboxylic acid exhibit extremely high activity compared to compounds in which the acyl moiety is formed from a (-) carboxylic acid. The optically active starting materials used in the production of such optically active compounds are optically resolved by conventional methods, or
Alternatively, it is produced using an optically active compound. For example, the general formula () or the general formula ()
A compound represented by the formula in which the carbon atom substituted with an amino group has an S configuration is produced by using L-leucine or statin. Furthermore, the optically active form of the carboxylic acid represented by the general formula () is an optically active amine such as (+)
By using -α-methylbenzylamine, the (+) carboxylic acid can be separated and purified,
By using (-)-α-methylbenzylamine, the (-) carboxylic acid can be separated and purified. A compound of the present invention in which the acyl moiety of the compound represented by the general formula () is formed from a (+) carboxylic acid can be obtained by reacting the carboxylic acid () with L-histidine methyl ester dihydrochloride. The diastereomer compound of the compound represented by the general formula () is separated and purified by recrystallization or column chromatography to obtain a compound () in which the acyl moiety is formed from a (+) carboxylic acid, and this It can also be manufactured by using. The compound represented by the general formula () of the present invention can be converted into a pharmacologically acceptable acid addition salt according to a conventional method, and examples of these salts include hydrochloride, sulfonate, and p-toluenesulfonic acid. salt, acetate,
Examples include citrate. These acid addition salts also have a strong renin activity inhibiting effect, are stable to proteolytic enzymes, and clearly lower blood pressure in monkeys with high renin status when orally administered. The amino acid derivative represented by the general formula () and its pharmacologically acceptable acid addition salt of the present invention can be made into a pharmaceutical composition according to a conventional method. Examples of such pharmaceutical compositions include tablets, capsules, granules, and injections. The amino acid derivatives and pharmacologically acceptable acid addition salts represented by the general formula () have a strong renin activity inhibitory effect, and the 50% inhibitory activity value (IC 50 ) in the human renin-sheep renin substrate system is 5.9. ×10 -6 ~1.5
×10 -7 molar concentration and low toxicity. When a pharmaceutical composition containing an amino acid derivative represented by the general formula () or a pharmacologically acceptable acid addition salt thereof is used for treatment, the dosage is determined based on the severity of the disease, the sex, age, and weight of the patient. However, when administered orally, the dose is generally 5mg to 5000 per day for adults
mg, and parenteral administration can be administered within the range of 1 mg to 1000 mg per day. [Example] In order to further explain the present invention in detail, reference examples and examples are given below. Note that the melting points of the compounds in each Reference Example and Examples are uncorrected. In addition, the NMR spectra of each compound are JEOL JNM-
Measurements were made using a GX270 high-resolution nuclear magnetic resonance apparatus. Mass spectrum is JEOL JMS-DX300
It was measured by the FAB method using a model mass spectrometer. Thin layer chromatography is performed using Merck's precoated plate silica gel.
Column chromatography was performed using Merck's Kieselgel 60 (230-400 mesh). In addition, the developing solvent for thin layer chromatography is the lower layer of a mixture of chloroform/methanol/water = 8/3/1 and the lower layer of a mixture of chloroform/methanol/water = 8/3/1.
Rf values (Rf 1 and Rf 2 ) were calculated using two types of 5/1 mixed liquids. Reference example 1 (±)-2-(1-naphthylmethyl)-3-(phenethylcarbamoyl)propionic acid 17.40 g of ethyl succinate and 15.62 g of 1-naphthaldehyde were dissolved in 100 ml of absolute ethanol, and cooled on ice for 50 min. After adding 6.00 g of % sodium hydride (oil-based), the mixture was heated under reflux for 3 hours. The solvent is distilled off under reduced pressure, water is added to the residue, the neutral part is extracted and removed with ether, the aqueous layer is acidified with concentrated hydrochloric acid, and extracted with ether. The ether layer was washed with saturated brine and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain 3-ethoxycarbonyl-4-(1-naphthyl)-3-butenoic acid as a yellow oil.
Obtain 23.60g. Add 200 ml of 1N aqueous sodium hydroxide solution and 170 ml of ethanol to 23.50 g of this butenoic acid, and heat at 50°C for 1.5 hours. The solvent was distilled off under reduced pressure, water was added to the residue, the neutral part was extracted and removed with ether, and concentrated hydrochloric acid was added to the aqueous layer to make it acidic.
Extract with ether. After washing the ether layer with saturated brine, it is dried over anhydrous magnesium sulfate.
The solvent was distilled off under reduced pressure to obtain 15.30 g of 2-(1-naphthylmethylene)succinic acid as yellow crystals. 2-(1-naphthylmethylene)succinic acid 15.20g
Add 260 ml of acetic anhydride to the mixture and heat under reflux for 1 hour.
The solvent was distilled off under reduced pressure and the residue was dissolved in dry benzene.
Add 100ml of 2-(1-naphthylmethylene)succinic anhydride and collect the precipitated crystals by filtration.
get g. Dissolve 3.00 g of this succinic anhydride and 1.52 g of phenethylamine in 60 ml of dry methylene chloride,
Stir at room temperature for 2 hours. The precipitated crystals were collected by filtration to obtain 4.02 g of 2-(1-naphthylmethylene)-3-(phenethylcarbamoyl)propionic acid as colorless crystals. Melting point: 183-187℃ IR (KBr): νCO 1670, 1640 cm -1 NMR (d 6 -DMSO) δ: 2.69 (t, 2H, J=
7.1Hz), 3.15 (s, 2H), 3.26 (t, 2H, J=
7.1Hz), 7.1 to 8.1 (m, 13H), 8.20 (s, 1H) 4.00g of 2-(1-naphthylmethylene)-3-(phenethylcarbamoyl)propionic acid to 120g of acetic acid
ml, add 2.0 g of 10% palladium on carbon, and hydrogenate at normal pressure. After removing the catalyst by filtration, the solvent was distilled off under reduced pressure, hexane was added to the residue, and the precipitated crystals were collected by filtration to give colorless crystals of (±)-2-(1-naphthylmethyl)-3-(phenethyl). 3.40 g of (carbamoyl)propionic acid are obtained. Melting point: 131-135℃ IR (KBr): νCO 1720, 1640 cm -1 NMR (d 6 -DMSO) δ: 2.15-2.55 (m, 2H),
2.68 (t, 2H, J=7.1Hz), 3.0~3.5 (m,
5H), 7.1-8.2 (m, 13H) Reference example 2 Optical resolution of (±)-2-(1-naphthylmethyl)-3-(phenethylcarbamoyl)propionic acid (±)-2-(1-naphthylmethyl 1.0 g of )-3-(phenethylcarbamoyl)propionic acid is dissolved in 20 ml of methanol, a solution of 335 mg of (+)-α-methylbenzylamine in 10 ml of methanol is added, and the solvent is distilled off under reduced pressure. The residue was recrystallized three times from ethyl acetate to obtain 330 mg of white crystals. Water, 1N hydrochloric acid and ethyl acetate are added to this, and the ethyl acetate layer is separated, further washed with 0.1N hydrochloric acid, dried over anhydrous magnesium sulfate, and the solvent is distilled off under reduced pressure. The residue was subjected to silica gel column chromatography (elution solvent: chloroform/ethanol =
10/1) to produce white powder (+)-2-
220 mg of (1-naphthylmethyl)-3-(phenethylcarbamoyl)propionic acid are obtained. Melting point: 146-150℃ IR (KBr): νCO 1705, 1635 cm -1 NMR (CDCI 3 ) δ: 2.25-2.55 (m, 2H), 2.74
(t, 2H, J=7.1Hz), 3.12(dd, 1H, J=
9.9, 13.7Hz), 3.20-3.60 (m, 3H), 3.73
(dd, 1H, J=5.0, 13.7Hz), 5.45~5.60
(m, 1H), 7.00-8.15 (m, 12H) [α] 21 D +7.3° (methanol c=1.00) (-)-α-Methylbenzylamine was used in the same manner as above ( -)-2-(1-naphthylmethyl)-3-(phenethylcarbamoyl)propionic acid is obtained. Melting point: 147-151℃ IR (KBr): νCO 1705, 1635 cm -1 NMR (CDCL 3 ) δ: 2.30-2.50 (m, 2H), 2.75
(t, 2H, J=7.1Hz), 3.11(dd, 1H, J=
10.5, 13.8Hz), 3.20-3.60 (m, 3H), 3.75
(dd, 1H, J=5.0, 14.3Hz), 5.40~5.60
(m, 1H), 7.05-8.15 (m, 12H) [α] 23 D -6.2° (methanol c=1.00) Reference example 3 N-[2-(1-naphthylmethyl)-3-(phenethylcarbamoyl) propionyl]-L-histidine hydrazide (±)-2-(1-naphthylmethyl)-3-(phenethylcarbamoyl)propionic acid 3.00 g and L-
Histidine methyl ester dihydrochloride 2.01g N,
Suspend in 24 ml of N-dimethylformamide, add 2.16 ml of diphenylphosphoric acid azide and 3.81 ml of triethylamine while stirring under ice cooling, and stir for 16 hours. The refrigerant is distilled off under reduced pressure, a 5% aqueous sodium bicarbonate solution is added to the residue, extracted with ethyl acetate, washed with water, and dried over anhydrous magnesium sulfate. The refrigerant was distilled off under reduced pressure, ether was added to the residue, the precipitated crystals were collected by filtration, and a white powder of N-
4.08 g of [(±)-2-(1-naphthylmethyl)-3-(phenethylcarbamoyl)propionyl]-L-histidine methyl ester is obtained. This ester
Dissolve 4.00g in 25ml of methanol and add 1
Add 2.75 g of hydrate and stir at room temperature for 4 hours. The solvent was distilled off under reduced pressure, the residue was washed with ether, and dried under reduced pressure at below 40°C to form a white powder of N.
3.90 g of -[(±)-2-(1-naphthylmethyl)-3-(phenethylcarbamoyl)propionyl]-L-histidine hydrazide is obtained. This hydrazide
Dissolve 2.20 g in 5 ml of methanol by heating at 40°C, and filter off insoluble matter. After leaving this solution overnight at room temperature,
The precipitated crystals were collected by filtration, and white powdery N-[(+)-2
0.70 g of -(1-naphthylmethyl)-3-(phenethylcarbamoyl)propionyl]-L-histidine hydrazide is obtained. [α] 10 D +20.6° (methanol c=0.19) Melting point: 214-218°C RF 1 : 0.53 MS: MH + , 513 Meanwhile, add 200 ml of ether to the filtrate, leave it overnight, and filter out the precipitated crystals. leave The filtrate is concentrated under reduced pressure, ether is added to the residue, and the precipitated crystals are collected by filtration. Recrystallize with methylene chloride/methanol = 10/1 to obtain 1.10 g of white powdery N-[(-)-2-(1-naphthylmethyl)-3-(phenethylcarbamoyl)propionyl]-L-histidine hydrazide. obtain. [α] 10 D −47.0° (methanol c=0.20) Melting point: 145-148°C RF 1 : 0.54 MS: MH + , 513 The hydrazide obtained above was optically resolved (+) and (-) -2-(1-naphthylmethyl)-
Hydrazide derived from 3-(phenethylcarbamoyl)propionic acid and its physical properties (NMR, IR, MS,
(optical rotation) were matched. Reference example 4 (2RS,3S)-3-amino-2-hydroxy-
5-Methylhexanoic acid N-carbobenzoxy-L-leucinal
Add a solution of 3.43 g of sodium bisulfite in 20 ml of water to 2.81 g, and stir under ice cooling for 14 hours. A solution of 1.41 g of potassium cyanide in 50 ml of water and 200 ml of ethyl acetate were added to this reaction solution and stirred at room temperature for 4 hours. The ethyl acetate layer was washed with saturated brine and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain 2.54 g of 3-carbobenzoxyamino-2-hydroxy-5-methylhexanenitrile as a colorless oil. 500mg of this nitrile, 20ml of dioxane and concentrated hydrochloric acid.
Add 20 ml of the mixture and heat under reflux for 12 hours. The solvent was distilled off under reduced pressure, and the remaining crystals were purified by cation column chromatography (elution solvent: 2N aqueous ammonia) to obtain colorless crystals of (2RS,3S)-3.
254 mg of -amino-2-hydroxy-5-methylhexanoic acid (a mixture with a ratio of 2R:2S of approximately 7:3) are obtained. Melting point: 137-140℃ IR (KBr): νCO 1570 cm -1 NMR (D 2 O) δ: 0.8-1.0 (m, 6H), 1.2-1.4
(m, 2H), 1.55-1.8 (m, 1H), 3.0-3.4
(m, 1H) 3.89 (d, 0.7H, J=3.3Hz), 4.00
(d, 0.3H, J=3.3Hz) MS: MH + , 162 Reference example 5 (3S)-3-carbobenzoxyamino-5-methyl-1,2-epoxyhexane Methyltriphenylphosphonium bromide 12g
was dissolved in 100 ml of dry tetrahydrofuran, and n-butyllithium (1.6
After dropping 19.5 ml of molhexane solution, the mixture was stirred at room temperature for 1 hour. Cool the reaction solution to below 5°C,
After dropping 7.5 g of N-carbobenzoxy-L-leucinal in 20 ml of dry tetrahydrofuran, the mixture was allowed to react at room temperature for 1 hour. An aqueous ammonium chloride solution is added to the reaction mixture, extracted with ethyl acetate, washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel flash column chromatography (elution solvent: methylene chloride) to obtain (3S)-3-carbobenzoxyamino-5-methyl-1 as a colorless viscous oil. - Obtain 1.6 g of hexene. IR (liquid film): νCO 1690 cm -1 NMR (CDC1 3 ) δ: 0.85 to 0.95 (m, 6H), 1.3
~1.75 (m, 3H), 4.15 ~ 4.25 (m, 1H), 4.61
(s, 1H) 5.05~5.2 (m, 2H), 5.10 (s,
2H) 5.74 (ddd, 1H, J = 6.0, 10.0, 17.0
Hz), 7.35 (s, 5H) Next, 600 mg of 3-chloroperbenzoic acid was dissolved in 5 ml of dry chloroform, and (3S)-3-
Add a solution of 850 mg of carbobenzoxyamino-5-methyl-1-hexene in 5 ml of dry chloroform,
Stir for 16 hours. Add methylene chloride to the reaction solution,
Wash with aqueous sodium thiosulfate solution, 5% aqueous sodium bicarbonate solution and saturated saline, and dry over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure,
The residue was subjected to silica gel flash column chromatography (elution solvent: benzene/hexane = 1/
1) to obtain 401 mg of (3S)-3-carbobenzoxyamino-5-methyl-1,2 epoxyhexane as a colorless viscous oil. IR (liquid film): νCO 1695 cm -1 NMR (CDC1 3 ) δ: 0.85 to 1.0 (m, 6H), 1.35
~1.8 (m, 3H), 2.58 (t, 1H, J=4.4Hz),
2.72 (t, 1H, J=4.4Hz), 2.99 (s, 1H),
3.95~4.1 (m, 1H), 4.45~4.55 (m, 1H),
5.09 (s, 2H), 7.34 (s, 5H) Example 1 (2RS, 3S)-3-{N-[(+)-2-(1-naphthylmethyl)-3-(phenethylcarbamoyl)propionyl] -L-histidyl}amino-2-hydroxy-5-methylhexyl methyl ether (3S)-3-Carbobenzoxyamino-5-methyl-1,2-epoxyhexane (176 mg) was dissolved in methanol (10 ml), and dried neutral alumina was dissolved. Add 2g and heat under reflux for 16 hours. After filtering off the alumina, the solvent was distilled off under reduced pressure, and the residue was subjected to preparative silica gel thin layer chromatography (developing solvent: chloroform/methanol/water = 8/3/1
The lower layer of
96 mg of -3-carbobenzoxyamino-2-hydroxy-5-methylhexyl methyl ether are obtained. Dissolve 94 mg of this ether in 10 ml of methanol, add 0.16 ml of 2N hydrochloric acid and 10% palladium on carbon.
Add 10mg and hydrogenate at normal pressure. After removing the catalyst by filtration, the solvent was distilled off under reduced pressure to obtain a colorless viscous oil (2RS, 3S).
54 mg of -3-amino-2-hydroxy-5-methylhexyl methyl ether hydrochloride are obtained. On the other hand, N-[(+)-2-(1-naphthylmethyl)
-3-(phenethylcarbamoyl)propionyl]
-130 mg of L-histidine hydrazide was dried N,N
- Suspended in 6 ml of dimethylformamide and added with stirring at -20°C to 0.19 ml of 5.1 N dry hydrogen chloride/N,N-dimethylformamide, followed by isoamyl nitrite.
Add 0.05ml. After confirming the disappearance of hydrazide, the temperature of the reaction solution was lowered to -30℃ and neutralized with 0.14 ml of triethylamine.
[Propionyl]-L-histidine azide solution is prepared. Separately, 52 mg of (2RS,3S)-3-amino-2-hydroxy-5-methylhexyl methyl ether hydrochloride and 0.05 ml of triethylamine in dry N,
The above azide solution was added dropwise to a ml solution of N-dimethylformamide under ice cooling, and the mixture was stirred for 16 hours. The solvent was distilled off under reduced pressure, 5% aqueous sodium hydrogen carbonate solution was added to the residue, extracted with ethyl acetate, washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was subjected to preparative silica gel thin layer chromatography (Developing solvent: chloroform/methanol/water = 8/
(lower layer of 3/1) and white powder (2RS,
3S)-3-{N[(+)-2-(1-naphthylmethyl)
-3-(phenethylcarbamoyl)propionyl]
-L-histidyl}amino-2-hydroxy-5
-55 mg of methylhexyl methyl ether are obtained. Melting point: 91-95℃ Rf 1 : 0.60 Rf 2 : 0.40 MS: MH + , 642 Example 2 (2RS, 3S)-3-{N-[(+)-2-(1-naphthylmethyl)-3 -(Phenethylcarbamoyl)propionyl]-L-histidyl}amino-2-hydroxy-5-methylhexylisoamyl ether (3S)-3-carbobenzoxyamino-5-methyl-1,2-epoxyhexane 100mg and during drying Add 2 ml of isoamyl alcohol to 2 g of alumina and heat and stir at 100°C for 16 hours, and then at 140°C for 90 minutes. After filtering off the alumina, it was concentrated under reduced pressure.
97 mg of (2RS,3S)-3-carbobenzoxyamino-2-hydroxy-5-methylhexylisoamyl ether is obtained as a colorless oil. This ether 95mg
Dissolve in 2 ml of methanol, add 0.27 ml of 1N hydrochloric acid and 10 mg of 10% palladium on carbon, and hydrogenate at normal pressure. After filtering off the catalyst, the solvent was distilled off under reduced pressure to obtain 65 mg of (2RS,3S)-3-amino-2-hydroxy-5-methylhexylisoamyl ether hydrochloride as a colorless viscous oil. On the other hand, N-[(+)-2-(1-naphthylmethyl)
-3-(phenethylcarbamoyl)propionyl]
-Dissolve 115 mg of L-histidine hydrazide in 2 ml of N,N-dimethylformamide, and prepare 5.1N dry hydrogen chloride/N,N-dimethylformamide at -20℃.
Add 0.16 ml followed by 0.04 ml of isoamyl nitrite and stir. After confirming the disappearance of hydrazide, the temperature of the reaction solution was lowered to -30℃ and triethylamine was added.
Neutralize with 0.11 ml to prepare an N-[(+)-2-(1-naphthylmethyl)-3-(phenethylcarbamoyl)propionyl]-L-histidine azide solution.
Separately, the above cold azide solution was added dropwise to a solution of 63 mg of (2RS,3S)-3-amino-2-hydroxy-5-methylhexylisoamyl ether and 0.035 ml of triatylamine in 2 ml of N,N-dimethylformamide under ice cooling. , and continue to stir for 16 hours. 5 to the reaction solution
% aqueous sodium bicarbonate solution, extracted with ethyl acetate, washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was separated and purified by preparative silica gel thin layer chromatography (developing solvent: chloroform/methanol/water = 8/3/1 lower layer) to obtain a white powder (2RS ,3S)-3-{N-[(+)-2-(1-naphthylmethyl)-3-(phenethylcarbamoyl)propionyl]-L-histidyl}amino-2-hydroxy-5-methylhexyl amyl ether 51
Get mg. Melting point: 73-76℃ Rf 1 : 0.63 Rf 2 : 0.57 MS: MH + , 698 Example 3 (2RS, 3S)-3-{N-[(+)-2-(1-naphthylmethyl)-3 -(phenethylcarbamoyl)propionyl]-L-histidyl}amino-2-hydroxy-5-methylhexylbenzyl ether (3S)-3-carbobenzoxyamino-5-methyl-1,2-epoxyhexane 100 mg and dry silica gel Add 2ml of benzyl alcohol to 2g
Heat and stir at 100°C for 16 hours. After filtering off the silica gel, it was concentrated under reduced pressure to form a colorless oil (2RS,
3S)-3-Carbobenzoxyamino-2-hydroxy-5-methylhexylbenzyl ether 105
Get mg. 86 mg of this ether was dissolved in 10 ml of methanol, 0.14 ml of 2N hydrochloric acid and 17 mg of 5% palladium on carbon were added, and the mixture was hydrogenated at normal pressure. After filtering off the catalyst,
The solvent was distilled off under reduced pressure, and the residue was subjected to preparative silica gel thin layer chromatography (developing solvent:
Separation and purification (lower layer of chloroform/methanol/water = 8/3/1) yields a colorless viscous oil (2RS, 3S).
17 mg of -3-amino-2-hydroxy-5-methylhexylbenzyl ether hydrochloride are obtained. On the other hand, N-[(+)-2-(1-naphthylmethyl)
-3-(phenethylcarbamoyl)propionyl]
-Dissolve 31 mg of L-histidine hydrazide in 1 ml of N,N-dimethylformamide, and prepare 5.1N dry hydrogen chloride/N,N-dimethylformamide at -20℃.
Add 0.044 ml followed by 0.011 ml of isoamyl nitrite and stir. After confirming the disappearance of hydrazide, the temperature of the reaction solution was lowered to -30℃ and triethylamine was added.
Neutralize with 0.031 ml to prepare an N-[(+)-2-(1-naphthylmethyl)-3-(phenethylcarbamoyl)propionyl]-L-histidine azide solution. Separately, the above cold azide solution was added dropwise to a solution of 16 mg of (2RS,3S)-3-amino-2-hydroxy-5-methylhexylbenzyl ether hydrochloride and 0.011 ml of triethylamine in 1 ml of N,N-dimethylformamide under ice cooling. , and continue to stir for 16 hours. A 5% aqueous sodium bicarbonate solution is added to the reaction mixture, extracted with ethyl acetate, washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was separated and purified by preparative silica gel thin layer chromatography (developing solvent: chloroform/methanol/water = 8/3/1 lower layer).
White powder (2RS, 3S)-3-{N-[(+)-2
18 mg of -(1-naphthylmethyl)-3-(phenethylcarbamoyl)propionyl]-L-histidyl}amino-2-hydroxy-5-methylhexylbenzyl ether is obtained. Melting point: 76-79℃ Rf 1 : 0.61 Rf 2 : 0.55 MS: MH + , 718 Example 4 (2RS, 3S)-N-isoamyl-3-{N-
[(+)-2-(1-naphthylmethyl)-3-(phenethylcarbamoyl)propionyl]-L-histidyl}amino-2-hydroxy-5-methylhexylamine(3S)-3-carbobenzoxyamino- 1 ml of isoamylamine was added to 50 mg of 5-methyl-1,2-epoxyhexane and 0.5 g of dry neutral alumina, and the mixture was stirred at room temperature for 16 hours and further at 70°C for 90 minutes. After filtering off the alumina, the mixture was concentrated under reduced pressure to obtain 71 mg of (2RS,3S)-N-isoamyl-3-carbobenzoxyamino-2-hydroxy-5-methylhexylamine as a colorless oil. Dissolve 70 mg of this amine in 2 ml of methanol, add 0.2 ml of 2N hydrochloric acid and 7 mg of 10% palladium on carbon, and hydrogenate at normal pressure. After removing the catalyst by filtration, the solvent was distilled off under reduced pressure to obtain (2RS,3S)-N-isoamyl-3-amino- as a colorless viscous oil.
42 mg of 2-hydroxy-5-methylhexylamine dihydrochloride are obtained. On the other hand, N-[(+)-2-(1-naphthylmethyl)-
3-(phenethylcarbamoyl)propionyl]-
Dissolve 64 mg of L-histidine hydrazide in 2 ml of N,N-dimethylformamide and prepare 5.1N dry hydrogen chloride/N,N-dimethylformamide 0.09 at -20℃.
ml, followed by 0.022 ml of isoamyl nitrite and stir. After confirming the disappearance of hydrazide, the temperature of the reaction solution was lowered to -30℃ and triethylamine was added.
Neutralize with 0.063 ml to prepare a N-[(+)-2-(1-naphthylmethyl)-3-(phenethylcarbamoyl)propionyl]-L-histidine azide solution. Separately, (2RS,3S)-N-isoamyl-3-amino-2-hydroxy-5-methylhexylamine dihydrochloride 40 mg and triethylamine 0.063 ml N,
The cold azide solution was added dropwise to 2 ml of N-dimethylformamide solution under ice cooling, and the mixture was stirred for 16 hours. A 5% aqueous sodium bicarbonate solution is added to the reaction mixture, extracted with ethyl acetate, washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was subjected to preparative silica gel thin layer chromatography (developing solvent: chloroform/
(lower layer of methanol/water = 8/3/1) was separated and purified to give a white powder (2RS,3S)-N-isoamyl-3-{N-[(+)-2-(1-naphthylmethyl)-
3-(phenethylcarbamoyl)propionyl]-
L-histidyl}amino-2-hydroxy-5-
8 mg of methylhexylamine is obtained. Melting point: 92-97℃ Rf 1 : 0.10 Rf 2 : 0.04 MS: MH + , 697 Example 5 (2RS, 3S)-N-benzyl-3-{N-[(+)
-2-(1-naphthylmethyl)-3-(phenethylcarbamoyl)propionyl]-L-histidyl}
Dissolve 100 mg of amino-2-hydroxy-5-methylhexylamine (3S)-3-carbobenzoxyamino-5-methyl-1,2-epoxyhexane in 10 ml of diethyl ether, 2 g of dry silica gel and 0.1 ml of benzylamine. was added, stirred at room temperature for 16 hours, and further heated and stirred for 2 hours. After filtering off the silica gel, the solvent was distilled off under reduced pressure, and the residue was purified by preparative silica gel thin layer chromatography (developing solvent: chloroform/methanol/water = 8/3/1 lower layer), 56 mg of (3S)-N-benzyl-3-carbobenzoxyamino-2-hydroxy-5-methylhexylamine is obtained as a colorless viscous oil. 54mg of this amine and 10ml of methanol
Add 0.2 ml of 2N hydrochloric acid and 10 mg of 10% palladium on carbon, and hydrogenate at normal pressure. After filtering off the catalyst, the solvent was distilled off under reduced pressure to obtain 43 mg of (3S)-N-benzyl-3-amino-2-hydroxy-5-methylhexylamine dihydrochloride as a white powder. On the other hand, N-[(+)-2-(1-naphthylmethyl)
-3-(phenethylcarbamoyl)propionyl]
-66 mg of L-histidine hydrazide was dried N,N-
Suspended in 5 ml of dimethylformamide, stirred at -20°C with 5.1 N dry hydrogen chloride/N,N-dimethylformamide 0.08 ml, followed by isoamyl nitrite.
Add 0.02ml. After confirming the disappearance of hydrazide, the temperature of the reaction solution was lowered to -30℃ and neutralized with 0.06 ml of triethylamine.
[Propionyl]-L-histidine azide solution is prepared. Separately (3S)-N-benzyl-3-amino-2-hydroxy-5-methylhexylamine 2
40 mg of hydrochloride and 0.018 ml of triethylamine in dry N,
The cold azide solution was added dropwise to 2 ml of N-dimethylformamide solution under ice cooling, and the mixture was stirred for 16 hours. The solvent was distilled off under reduced pressure, 5% aqueous sodium hydrogen carbonate solution was added to the residue, extracted with ethyl acetate, washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was subjected to silica gel flash column chromatography (elution solvent: chloroform/methanol/=15/
1), white powdered (2RS,3S)-N-
33 mg of benzyl-3-{N-[(+)-2-(1-naphthylmethyl)-3-(phenethylcarbamoyl)propionyl]-L-histidyl}amino-2-hydroxy-5-methylhexylamine is obtained. Melting point: 108-113℃ Rf 1 : 0.44 Rf 2 : 0.14 MS: MH + , 717 Example 6 (2RS, 3S)-3-{N-[(+)-2-(1-naphthylmethyl)-3 -(phenethylcarbamoyl)propionyl]-L-histidyl}amino-2-hydroxy-5-methylhexanol (2RS,3S)-3-amino-2-hydroxy-
110 mg of 5-methyl-hexanoic acid in 10 ml of methanol
Hydrogen chloride gas was blown into the mixture under ice-cooling, and the mixture was stirred overnight. The reaction solution was concentrated to dryness under reduced pressure to obtain 150 ml of methyl (2RS,3S)-3-amino-2-hydroxy-5-methylhexanoate hydrochloride in the form of a white powder.
Get mg. [IR (KBr): νCO1740 cm -1 ] On the other hand, N-[(+)-2-(1-naphthylmethyl)
-3-(phenethylcarbamoyl)propionyl]
- Dissolve 154 mg of L-histidine hydrazide in 4 ml of N,N-dimethylformamide, add 0.19 ml of 5.1N dry hydrogen chloride/N,N-dimethylformamide, and then 0.05 ml of isoamyl nitrite under stirring at -20°C.
Add ml and stir. After confirming the disappearance of hydrazide, the temperature of the reaction solution was lowered to -30℃, neutralized with 0.14 ml of triethylamine, and N-[(+)-2-(1-
A solution of naphthylmethyl)-3-(phenethylcarbamoyl)propionyl]-L-histidine azide is prepared. Separately (2RS,3S)-3-amino-2
The cold azide solution was added dropwise to a solution of 64 mg of methyl -hydroxy-5-methylhexanoate hydrochloride and 0.09 ml of triethylamine in 2 ml of N,N-dimethylformamide under ice cooling, and the mixture was stirred for 16 hours. A 5% aqueous sodium hydrogen carbonate solution is added to the reaction mixture, extracted with ethyl acetate, washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure,
The residue was separated and purified by silica gel flash column chromatography (elution solvent: chloroform/methanol = 10/1) to obtain a white powder (2RS,
120 mg of methyl 3S)-3-{N-[(+)-2-(1-naphthylmethyl)-3-(phenethylcarbamoyl)propionyl]-L-histidyl}amino-2-hydroxy-5-methylhexanoate. obtain. Melting point: 82-87°C Rf 1 : 0.58 MS: MH + , 656 Next, 37 mg of the above methyl ester was dissolved in a mixture of 8 ml of ethanol and 2 ml of water, 22 mg of sodium borohydride was added under ice cooling, and the mixture was heated to room temperature. Reconstitute and stir for 16 hours. The solvent was distilled off under reduced pressure, and ethyl acetate was added to the residue, which was washed with a 5% aqueous sodium bicarbonate solution and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain a white powder of (2RS,3S)-3-{N-[(+)-2-(1-naphthylmethyl)-3-(phenethylcarbamoyl)propionyl]-L- 25 mg of }amino-2-hydroxy-5-methylhexanol are obtained. Melting point: 101-107℃ Rf 1 : 0.44 Rf 2 : 0.15 MS: MH + , 536 Example 7 (3S, 4S)-4-{N-[(+)-2-(1-naphthylmethyl)-3 -(Phenethylcarbamoyl)propionyl]-L-histidyl}amino-3-hydroxy-6-methylheptanol Dissolve 100 mg of N-(tert-butyloxycarbonyl)statin (commercially available) in 20 ml of dry methanol,
After blowing hydrogen chloride gas into the mixture while stirring on ice, the mixture was returned to room temperature and allowed to react overnight. The solvent is distilled off under reduced pressure, and 81 mg of statin methyl ester hydrochloride as a colorless viscous oil is added. [IR (liquid film): νCO 1725 cm -1 ] On the other hand, N-[(+)-2-(1-naphthylmethyl)
-3-(phenethylcarbamoyl)propionyl]
- Dry 180 mg of L-histidine hydrazide with N,N
- Suspended in 10 ml of dimethylformamide and added with stirring at -20°C to 0.24 ml of 5.1 N dry hydrogen chloride/N,N-dimethylformamide, followed by isoamyl nitrite.
Add 0.06ml. After confirming the disappearance of hydrazide, the temperature of the reaction solution was lowered to -30°C and neutralized with 0.16 ml of triethylamine.
[Propionyl]-L-histidine azide solution is prepared. Separately statin methyl ester hydrochloride 80mg
The cold azide solution was added dropwise to a solution of 0.06 ml of triethylamine and 2 ml of dry N,N-dimethylformamide under ice cooling, and the mixture was stirred for 16 hours. The solvent was distilled off under reduced pressure, 5% aqueous sodium hydrogen carbonate solution was added to the residue, extracted with ethyl acetate, washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel flash column chromatography (elution solvent: chloroform/methanol = 15/1) to obtain a white powder of N-[(+)-2-(1 35 mg of -naphthylmethyl)-3-(phenethylcarbamoyl)propionyl]-L-histidyl-statin methyl ester are obtained. Melting point: 90-94℃ Rf 1 : 0.67 Rf 2 : 0.65 MS: MH + , 670 Next, 25 mg of this statin methyl ester was dissolved in a mixture of 8 ml of ethanol and 2 ml of water, and 14 mg of sodium borohydride was added under ice cooling. Add, return to room temperature, and stir for 16 hours. The solvent was distilled off under reduced pressure, and ethyl acetate was added to the residue, which was washed with a 5% aqueous sodium bicarbonate solution and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain a white powder of (3S,4S)-4-{N-[(+)-2-(1-
naphthylmethyl)-3-(phenethylcarbamoyl)propionyl]-L-histidyl}amino-
7 mg of 3-hydroxy-6-methylheptanol are obtained. Melting point: 87-92℃ Rf 1 : 0.53 Rf 2 : 0.25 MS: MH + , 642 Example 8 Inhibition of renin activity with human renin-sheep renin substrate 125mM pyrophosphate buffer (PH7. 4) 200μ and 20mM L- as angiotensin converting enzyme inhibitor
25μ of an aqueous solution of phenylalanyl-L-alanyl-L-proline, 50μ of partially purified sheep renin substrate with 2000 ng angiotensin I equivalents/ml, 150μ of deionized water and 50μ of a solution of the compound of the invention in dimethyl sulfoxide or as a control group a solution of 50μ of dimethylsulfoxide. 25μ of purified human renin containing 20 to 30 ng angiotensin I/hour is added thereto and incubated in a 37°C water bath for 15 minutes, followed by placing the reaction solution in a 100°C water bath for 5 minutes to stop the reaction. 200μ after cooling
was fractionated, and the amount of angiotensin I produced by addition of renin was determined by radioimmunoassay method, and the inhibitory activity was determined by the following formula. Inhibitory activity (%) = control value - value in the presence of the compound of the present invention / control value x 100 The 50% inhibitory activity molar concentration (IC 50 ) was determined from the inhibitory activity determined by the above formula, and the results are shown below. .
【表】
ル
[Table] Le
本発明の一般式（）で表されるアミノ酸誘導
体およびそれらの薬理学的に許容できる酸付加塩
はヒトレニン−羊レニン基質系でのレニン活性阻
害試験において50％阻害活性値（IC50）が5.9×
10-6〜1.5×10-7モル濃度という強いレニン活性
阻害作用を示し、かつ低毒性である。また、本発
明の一般式（）で表されるアミノ酸誘導体およ
びそれらの薬理学的に許容できる酸付加塩は、蛋
白分解酵素、例えばキモトリプシン、ペプシンの
ような酵素に対し安定であり、経口投与により高
レニン状態のサルの血圧を下降させることができ
る。
したがつて、本発明の一般式（）で表される
アミノ酸誘導体およびそれらの薬理学的に許容で
きる酸付加塩は経口投与可能な高血圧症治療剤と
して有用である。
The amino acid derivatives represented by the general formula () and their pharmacologically acceptable acid addition salts of the present invention have a 50% inhibitory activity value (IC 50 ) of 5.9 in a renin activity inhibition test using a human renin-sheep renin substrate system. ×
It exhibits a strong renin activity inhibition effect at a molar concentration of 10 -6 to 1.5 x 10 -7 and has low toxicity. Furthermore, the amino acid derivatives represented by the general formula () and their pharmacologically acceptable acid addition salts of the present invention are stable against proteolytic enzymes such as chymotrypsin and pepsin, and can be administered orally. It can lower blood pressure in monkeys with high renin status. Therefore, the amino acid derivatives represented by the general formula () and their pharmacologically acceptable acid addition salts of the present invention are useful as orally administrable antihypertensive agents.
Claims (1)
１〜３の整数であり、ｎは１または２であり、Ｘ
は水酸基または式−Ｙ−Ｒ（式中のＹは−０−ま
たは−NH−であり、Ｒは直鎖状または枝分かれ
状のアルキル基またはアラルキル基である）で表
される基である〕で表されるアミノ酸誘導体およ
びそれらの薬理学的に許容できる酸付加塩。 ２ 一般式 （式中のＣは（＋）体を示し、ＣはＳ配置を示
し、His、Ｘ、ｍおよびｎは前記と同じ意味を持
つ）で表される特許請求の範囲第１項記載のアミ
ノ酸誘導体およびその薬理学的に許容できる酸付
加塩。 ３ 一般式 （式中のＣ、His、Ｃ、Ｘおよびｍは前記と同
じ意味を持つ）で表される特許請求の範囲第２項
記載のアミノ酸誘導体およびその薬理学的に許容
できる酸付加塩。 ４ 一般式 （式中のＣ、His、Ｃ、Ｙ、Ｒおよびｍは前記と
同じ意味を持つ）で表される特許請求の範囲第３
項記載のアミノ酸誘導体およびその薬理学的に許
容できる酸付加塩。 ５ 式 （式中のＣ、HisおよびＣは前記と同じ意味を持
つ）で表される特許請求の範囲第４項記載のアミ
ノ酸誘導体およびその薬理学的に許容できる酸付
加塩。 ６ 式 （式中のＣ、HisおよびＣは前記と同じ意味を
持つ）で表される特許請求の範囲第４項記載のア
ミノ酸誘導体およびその薬理学的に許容できる酸
付加塩。 ７ 式 （式中のＣ、HisおよびＣは前記と同じ意味を
持つ）で表される特許請求の範囲第４項記載のア
ミノ酸誘導体およびその薬理学的に許容できる酸
付加塩。 ８ 式 （式中のＣ、HisおよびＣは前記と同じ意味を
持つ）で表される特許請求の範囲第４項記載のア
ミノ酸誘導体およびその薬理学的に許容できる酸
付加塩。 ９ 式 （式中のＣ、HisおよびＣは前記と同じ意味を
持つ）で表される特許請求の範囲第４項記載のア
ミノ酸誘導体およびその薬理学的に許容できる酸
付加塩。 １０ 式 （式中のＣ、HisおよびＣは前記と同じ意味を
持つ）で表される特許請求の範囲第３項記載のア
ミノ酸誘導体およびその薬理学的に許容できる酸
付加塩。 １１ 式 （式中のＣ、HisおよびＣは前記と同じ意味を
持つ）で表される特許請求の範囲第２項記載のア
ミノ酸誘導体およびその薬理学的に許容できる酸
付加塩。[Claims] 1. General formula [His in the formula is an L-histidyl group, m is an integer of 1 to 3, n is 1 or 2,
is a hydroxyl group or a group represented by the formula -Y-R (in the formula, Y is -0- or -NH-, and R is a linear or branched alkyl group or an aralkyl group)] The represented amino acid derivatives and their pharmacologically acceptable acid addition salts. 2 General formula (In the formula, C represents the (+) form, C represents the S configuration, and His, X, m, and n have the same meanings as above.) Amino acid derivative according to claim 1 and pharmacologically acceptable acid addition salts thereof. 3 General formula The amino acid derivative and its pharmacologically acceptable acid addition salt according to claim 2, represented by the formula (C, His, C, X and m have the same meanings as above). 4 General formula (C, His, C, Y, R and m in the formula have the same meanings as above) Claim 3
Amino acid derivatives and pharmacologically acceptable acid addition salts thereof as described in 1. 5 formula The amino acid derivative according to claim 4, represented by the formula (C, His, and C have the same meanings as above) and a pharmacologically acceptable acid addition salt thereof. 6 formula The amino acid derivative according to claim 4, represented by the formula (C, His, and C have the same meanings as above) and a pharmacologically acceptable acid addition salt thereof. 7 formula The amino acid derivative according to claim 4, represented by the formula (C, His, and C have the same meanings as above) and a pharmacologically acceptable acid addition salt thereof. 8 formula The amino acid derivative according to claim 4, represented by the formula (C, His, and C have the same meanings as above) and a pharmacologically acceptable acid addition salt thereof. 9 formula The amino acid derivative according to claim 4, represented by the formula (C, His, and C have the same meanings as above) and a pharmacologically acceptable acid addition salt thereof. 10 formula The amino acid derivative according to claim 3, represented by the formula (C, His, and C have the same meanings as above) and a pharmacologically acceptable acid addition salt thereof. 11 formula The amino acid derivative according to claim 2, represented by the formula (C, His, and C have the same meanings as above) and a pharmacologically acceptable acid addition salt thereof.
Priority Applications (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP60041614A JPS61200970A (en) | 1985-03-01 | 1985-03-01 | Novel aminoacid derivative |
| EP86300666A EP0190891A3 (en) | 1985-01-31 | 1986-01-31 | Novel amino acid derivatives |
| US07/233,962 US4841067A (en) | 1985-01-31 | 1988-08-19 | Novel amino acid derivatives |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP60041614A JPS61200970A (en) | 1985-03-01 | 1985-03-01 | Novel aminoacid derivative |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPS61200970A JPS61200970A (en) | 1986-09-05 |
| JPH0560466B2 true JPH0560466B2 (en) | 1993-09-02 |
Family
ID=12613211
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP60041614A Granted JPS61200970A (en) | 1985-01-31 | 1985-03-01 | Novel aminoacid derivative |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPS61200970A (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6313094B1 (en) | 1990-12-11 | 2001-11-06 | Japan Energy Corporation | β-amino-α-hydroxycarboxylic acid derivatives and HIV protease inhibitors |
-
1985
- 1985-03-01 JP JP60041614A patent/JPS61200970A/en active Granted
Also Published As
| Publication number | Publication date |
|---|---|
| JPS61200970A (en) | 1986-09-05 |
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