JPS61100595A - Novel dipeptide derivative - Google Patents
Novel dipeptide derivativeInfo
- Publication number
- JPS61100595A JPS61100595A JP59221853A JP22185384A JPS61100595A JP S61100595 A JPS61100595 A JP S61100595A JP 59221853 A JP59221853 A JP 59221853A JP 22185384 A JP22185384 A JP 22185384A JP S61100595 A JPS61100595 A JP S61100595A
- Authority
- JP
- Japan
- Prior art keywords
- formula
- represented
- general formula
- pharmacologically acceptable
- acid addition
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- 108010016626 Dipeptides Proteins 0.000 title claims description 25
- 239000002253 acid Substances 0.000 claims abstract description 30
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 6
- 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 abstract description 4
- 125000001624 naphthyl group Chemical group 0.000 claims abstract description 4
- 150000003839 salts Chemical class 0.000 claims description 26
- 239000000126 substance Substances 0.000 claims description 14
- 150000001875 compounds Chemical class 0.000 abstract description 45
- 238000006243 chemical reaction Methods 0.000 abstract description 18
- 150000001732 carboxylic acid derivatives Chemical class 0.000 abstract description 9
- 206010020772 Hypertension Diseases 0.000 abstract description 7
- 101000579218 Homo sapiens Renin Proteins 0.000 abstract description 3
- 125000006243 carbonyl protecting group Chemical group 0.000 abstract 1
- 239000000463 material Substances 0.000 abstract 1
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 abstract 1
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 60
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 39
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 38
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 31
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 30
- 239000000243 solution Substances 0.000 description 29
- 239000002904 solvent Substances 0.000 description 27
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 25
- 238000002844 melting Methods 0.000 description 22
- 230000008018 melting Effects 0.000 description 22
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 21
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 17
- 239000000843 powder Substances 0.000 description 17
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 16
- 108090000783 Renin Proteins 0.000 description 16
- 102100028255 Renin Human genes 0.000 description 16
- 239000000203 mixture Substances 0.000 description 16
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 15
- 238000001816 cooling Methods 0.000 description 14
- 230000000694 effects Effects 0.000 description 14
- 230000002401 inhibitory effect Effects 0.000 description 14
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 12
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 12
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 12
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 11
- -1 L-histidyl-prolyl-phenylalanyl group Chemical group 0.000 description 11
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 11
- 239000012156 elution solvent Substances 0.000 description 10
- 239000003921 oil Substances 0.000 description 10
- 239000000741 silica gel Substances 0.000 description 10
- 229910002027 silica gel Inorganic materials 0.000 description 10
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 10
- 239000013078 crystal Substances 0.000 description 9
- 238000003818 flash chromatography Methods 0.000 description 9
- 238000000034 method Methods 0.000 description 7
- 238000003756 stirring Methods 0.000 description 7
- PPXCXZRXDMMPNB-UHFFFAOYSA-N 2-(naphthalen-1-ylmethyl)-6-phenylhexanoic acid Chemical compound C=1C=CC2=CC=CC=C2C=1CC(C(=O)O)CCCCC1=CC=CC=C1 PPXCXZRXDMMPNB-UHFFFAOYSA-N 0.000 description 6
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 6
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 6
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 6
- 238000005481 NMR spectroscopy Methods 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 229910052786 argon Inorganic materials 0.000 description 6
- 238000007796 conventional method Methods 0.000 description 6
- KWGKDLIKAYFUFQ-UHFFFAOYSA-M lithium chloride Chemical compound [Li+].[Cl-] KWGKDLIKAYFUFQ-UHFFFAOYSA-M 0.000 description 6
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 6
- 238000010992 reflux Methods 0.000 description 6
- 235000017557 sodium bicarbonate Nutrition 0.000 description 6
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 6
- 102000004881 Angiotensinogen Human genes 0.000 description 5
- 101150041968 CDC13 gene Proteins 0.000 description 5
- 108091005804 Peptidases Proteins 0.000 description 5
- 102000035195 Peptidases Human genes 0.000 description 5
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 5
- 239000007864 aqueous solution Substances 0.000 description 5
- 150000001735 carboxylic acids Chemical class 0.000 description 5
- 239000007788 liquid Substances 0.000 description 5
- 108090000765 processed proteins & peptides Proteins 0.000 description 5
- 150000007659 semicarbazones Chemical class 0.000 description 5
- 108090001067 Angiotensinogen Proteins 0.000 description 4
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 4
- IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine hydrate Chemical compound O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 description 4
- 125000006239 protecting group Chemical group 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- 101800000734 Angiotensin-1 Proteins 0.000 description 3
- 102400000344 Angiotensin-1 Human genes 0.000 description 3
- 108010064733 Angiotensins Proteins 0.000 description 3
- 102000015427 Angiotensins Human genes 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- 108090000317 Chymotrypsin Proteins 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- 241000700159 Rattus Species 0.000 description 3
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 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
- 229910052799 carbon Inorganic materials 0.000 description 3
- 229960002376 chymotrypsin Drugs 0.000 description 3
- 239000012230 colorless oil Substances 0.000 description 3
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 3
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 3
- OWFXIOWLTKNBAP-UHFFFAOYSA-N isoamyl nitrite Chemical compound CC(C)CCON=O OWFXIOWLTKNBAP-UHFFFAOYSA-N 0.000 description 3
- 230000007935 neutral effect Effects 0.000 description 3
- 239000008194 pharmaceutical composition Substances 0.000 description 3
- 229940024999 proteolytic enzymes for treatment of wounds and ulcers Drugs 0.000 description 3
- 239000012312 sodium hydride Substances 0.000 description 3
- 229910000104 sodium hydride Inorganic materials 0.000 description 3
- DLNKOYKMWOXYQA-CBAPKCEASA-N (-)-norephedrine Chemical compound C[C@H](N)[C@H](O)C1=CC=CC=C1 DLNKOYKMWOXYQA-CBAPKCEASA-N 0.000 description 2
- 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 2
- ZOFRRNUENOHELM-LURJTMIESA-N (2s)-2-amino-4-methylpentanal Chemical compound CC(C)C[C@H](N)C=O ZOFRRNUENOHELM-LURJTMIESA-N 0.000 description 2
- UNNVAEPRUIWKPG-UHFFFAOYSA-N 2-(naphthalen-1-ylmethyl)-8-phenyloctanoic acid Chemical compound C=1C=CC2=CC=CC=C2C=1CC(C(=O)O)CCCCCCC1=CC=CC=C1 UNNVAEPRUIWKPG-UHFFFAOYSA-N 0.000 description 2
- RBLAOGBEJPHFHW-UHFFFAOYSA-N 2-benzyl-3-phenylpropanoic acid Chemical compound C=1C=CC=CC=1CC(C(=O)O)CC1=CC=CC=C1 RBLAOGBEJPHFHW-UHFFFAOYSA-N 0.000 description 2
- XJGZAEOOWPXFAS-UHFFFAOYSA-N 2-benzyl-5-phenylpentanoic acid Chemical compound C=1C=CC=CC=1CC(C(=O)O)CCCC1=CC=CC=C1 XJGZAEOOWPXFAS-UHFFFAOYSA-N 0.000 description 2
- TWPKEZACBDVQNY-UHFFFAOYSA-N 3-(6-phenoxypyridin-3-yl)prop-2-enoic acid Chemical compound N1=CC(C=CC(=O)O)=CC=C1OC1=CC=CC=C1 TWPKEZACBDVQNY-UHFFFAOYSA-N 0.000 description 2
- IKHGUXGNUITLKF-UHFFFAOYSA-N Acetaldehyde Chemical compound CC=O IKHGUXGNUITLKF-UHFFFAOYSA-N 0.000 description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 2
- BVKZGUZCCUSVTD-UHFFFAOYSA-M Bicarbonate Chemical compound OC([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-M 0.000 description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- 102000006395 Globulins Human genes 0.000 description 2
- 108010044091 Globulins Proteins 0.000 description 2
- BXRMEWOQUXOLDH-LURJTMIESA-N L-Histidine methyl ester Chemical compound COC(=O)[C@@H](N)CC1=CN=CN1 BXRMEWOQUXOLDH-LURJTMIESA-N 0.000 description 2
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 2
- 108090000284 Pepsin A Proteins 0.000 description 2
- 102000057297 Pepsin A Human genes 0.000 description 2
- 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 2
- 239000002220 antihypertensive agent Substances 0.000 description 2
- 229940030600 antihypertensive agent Drugs 0.000 description 2
- 150000001540 azides Chemical class 0.000 description 2
- 125000000051 benzyloxy group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])O* 0.000 description 2
- 239000007795 chemical reaction product Substances 0.000 description 2
- 238000004440 column chromatography Methods 0.000 description 2
- 239000012141 concentrate Substances 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- AIGHFRSPAYFRBL-UHFFFAOYSA-N ethyl 2-benzyl-3-phenylpropanoate Chemical compound C=1C=CC=CC=1CC(C(=O)OCC)CC1=CC=CC=C1 AIGHFRSPAYFRBL-UHFFFAOYSA-N 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 230000001631 hypertensive effect Effects 0.000 description 2
- PHTQWCKDNZKARW-UHFFFAOYSA-N isoamylol Chemical compound CC(C)CCO PHTQWCKDNZKARW-UHFFFAOYSA-N 0.000 description 2
- 239000011259 mixed solution Substances 0.000 description 2
- 229940111202 pepsin Drugs 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 239000000758 substrate Substances 0.000 description 2
- 208000024891 symptom Diseases 0.000 description 2
- 229940124597 therapeutic agent Drugs 0.000 description 2
- 238000004809 thin layer chromatography Methods 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- KRMJFEUBTGNKFL-YFKPBYRVSA-N (2S)-2-amino-3-(1H-imidazol-5-yl)propanoyl azide Chemical compound N[C@@H](Cc1c[nH]cn1)C(=O)N=[N+]=[N-] KRMJFEUBTGNKFL-YFKPBYRVSA-N 0.000 description 1
- QMMRHASQEVCJGR-FPMFFAJLSA-N (2r)-1-[(2s)-2-[[(2s)-2-amino-3-phenylpropanoyl]amino]propanoyl]pyrrolidine-2-carboxylic acid Chemical compound C([C@H](N)C(=O)N[C@@H](C)C(=O)N1[C@H](CCC1)C(O)=O)C1=CC=CC=C1 QMMRHASQEVCJGR-FPMFFAJLSA-N 0.000 description 1
- UUUHXMGGBIUAPW-UHFFFAOYSA-N 1-[1-[2-[[5-amino-2-[[1-[5-(diaminomethylideneamino)-2-[[1-[3-(1h-indol-3-yl)-2-[(5-oxopyrrolidine-2-carbonyl)amino]propanoyl]pyrrolidine-2-carbonyl]amino]pentanoyl]pyrrolidine-2-carbonyl]amino]-5-oxopentanoyl]amino]-3-methylpentanoyl]pyrrolidine-2-carbon Chemical compound C1CCC(C(=O)N2C(CCC2)C(O)=O)N1C(=O)C(C(C)CC)NC(=O)C(CCC(N)=O)NC(=O)C1CCCN1C(=O)C(CCCN=C(N)N)NC(=O)C1CCCN1C(=O)C(CC=1C2=CC=CC=C2NC=1)NC(=O)C1CCC(=O)N1 UUUHXMGGBIUAPW-UHFFFAOYSA-N 0.000 description 1
- LKYFYQXPFFFDCD-UHFFFAOYSA-N 2,2-bis(2-phenylethyl)propanedioic acid Chemical compound C=1C=CC=CC=1CCC(C(O)=O)(C(=O)O)CCC1=CC=CC=C1 LKYFYQXPFFFDCD-UHFFFAOYSA-N 0.000 description 1
- LTMRRSWNXVJMBA-UHFFFAOYSA-L 2,2-diethylpropanedioate Chemical compound CCC(CC)(C([O-])=O)C([O-])=O LTMRRSWNXVJMBA-UHFFFAOYSA-L 0.000 description 1
- UDUSBAGVXBMXHE-UHFFFAOYSA-N 2-benzyl-6-naphthalen-2-ylhexanoic acid Chemical compound C=1C=C2C=CC=CC2=CC=1CCCCC(C(=O)O)CC1=CC=CC=C1 UDUSBAGVXBMXHE-UHFFFAOYSA-N 0.000 description 1
- WMPPDTMATNBGJN-UHFFFAOYSA-N 2-phenylethylbromide Chemical compound BrCCC1=CC=CC=C1 WMPPDTMATNBGJN-UHFFFAOYSA-N 0.000 description 1
- XMIIGOLPHOKFCH-UHFFFAOYSA-N 3-phenylpropionic acid Chemical compound OC(=O)CCC1=CC=CC=C1 XMIIGOLPHOKFCH-UHFFFAOYSA-N 0.000 description 1
- XPBQQAHIVODAIC-UHFFFAOYSA-N 4-bromobutylbenzene Chemical compound BrCCCCC1=CC=CC=C1 XPBQQAHIVODAIC-UHFFFAOYSA-N 0.000 description 1
- ZSDJHOFUWZAZOJ-UHFFFAOYSA-N 4-phenyl-2-(2-phenylethyl)butanoic acid Chemical compound C=1C=CC=CC=1CCC(C(=O)O)CCC1=CC=CC=C1 ZSDJHOFUWZAZOJ-UHFFFAOYSA-N 0.000 description 1
- 239000005541 ACE inhibitor Substances 0.000 description 1
- 102000005862 Angiotensin II Human genes 0.000 description 1
- 101800000733 Angiotensin-2 Proteins 0.000 description 1
- 101710129690 Angiotensin-converting enzyme inhibitor Proteins 0.000 description 1
- SJUXYGVRSGTPMC-IMJSIDKUSA-N Asn-Ala Chemical class OC(=O)[C@H](C)NC(=O)[C@@H](N)CC(N)=O SJUXYGVRSGTPMC-IMJSIDKUSA-N 0.000 description 1
- 101710086378 Bradykinin-potentiating and C-type natriuretic peptides Proteins 0.000 description 1
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 1
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 1
- ASMQGLCHMVWBQR-UHFFFAOYSA-N Diphenyl phosphate Chemical compound C=1C=CC=CC=1OP(=O)(O)OC1=CC=CC=C1 ASMQGLCHMVWBQR-UHFFFAOYSA-N 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- CZGUSIXMZVURDU-JZXHSEFVSA-N Ile(5)-angiotensin II Chemical compound C([C@@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC=1NC=NC=1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CC=1C=CC=CC=1)C([O-])=O)NC(=O)[C@@H](NC(=O)[C@H](CCCNC(N)=[NH2+])NC(=O)[C@@H]([NH3+])CC([O-])=O)C(C)C)C1=CC=C(O)C=C1 CZGUSIXMZVURDU-JZXHSEFVSA-N 0.000 description 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
- 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
- OFOBLEOULBTSOW-UHFFFAOYSA-L Malonate Chemical compound [O-]C(=O)CC([O-])=O OFOBLEOULBTSOW-UHFFFAOYSA-L 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
- 239000004365 Protease Substances 0.000 description 1
- 229920005654 Sephadex Polymers 0.000 description 1
- 239000012507 Sephadex™ Substances 0.000 description 1
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- ICNDIUHGRAMXAQ-RGMNGODLSA-N acetic acid [[(2S)-2-amino-4-methylpentylidene]amino]urea Chemical compound CC(O)=O.CC(C)C[C@H](N)C=NNC(N)=O ICNDIUHGRAMXAQ-RGMNGODLSA-N 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 125000005073 adamantyl group Chemical group C12(CC3CC(CC(C1)C3)C2)* 0.000 description 1
- 210000004404 adrenal cortex Anatomy 0.000 description 1
- 229950006323 angiotensin ii Drugs 0.000 description 1
- 229940044094 angiotensin-converting-enzyme inhibitor Drugs 0.000 description 1
- 150000008064 anhydrides Chemical class 0.000 description 1
- YNAZZKCLDDTEPY-LBPRGKRZSA-N benzyl N-amino-N-[(2S)-2-amino-3-(1H-imidazol-5-yl)propanoyl]carbamate Chemical compound N[C@@H](Cc1cnc[nH]1)C(=O)N(N)C(=O)OCc1ccccc1 YNAZZKCLDDTEPY-LBPRGKRZSA-N 0.000 description 1
- AGEZXYOZHKGVCM-UHFFFAOYSA-N benzyl bromide Chemical compound BrCC1=CC=CC=C1 AGEZXYOZHKGVCM-UHFFFAOYSA-N 0.000 description 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
- CQHWVCAKPRTJLY-LBPRGKRZSA-N benzyl n-[(2s)-1-azido-3-(1h-imidazol-5-yl)-1-oxopropan-2-yl]carbamate Chemical compound C([C@@H](C(=O)N=[N+]=[N-])NC(=O)OCC=1C=CC=CC=1)C1=CN=CN1 CQHWVCAKPRTJLY-LBPRGKRZSA-N 0.000 description 1
- PFYXSUNOLOJMDX-UHFFFAOYSA-N bis(2,5-dioxopyrrolidin-1-yl) carbonate Chemical compound O=C1CCC(=O)N1OC(=O)ON1C(=O)CCC1=O PFYXSUNOLOJMDX-UHFFFAOYSA-N 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 238000000354 decomposition reaction Methods 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
- MZMPXSNDGZIHLU-UHFFFAOYSA-N diethyl 2-(naphthalen-1-ylmethyl)-2-(4-phenylbutyl)propanedioate Chemical compound C=1C=CC2=CC=CC=C2C=1CC(C(=O)OCC)(C(=O)OCC)CCCCC1=CC=CC=C1 MZMPXSNDGZIHLU-UHFFFAOYSA-N 0.000 description 1
- 125000004177 diethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- DLNKOYKMWOXYQA-UHFFFAOYSA-N dl-pseudophenylpropanolamine Natural products CC(N)C(O)C1=CC=CC=C1 DLNKOYKMWOXYQA-UHFFFAOYSA-N 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 229940088598 enzyme Drugs 0.000 description 1
- ZLGQOFNUQJNLQH-UHFFFAOYSA-N ethyl 2-(naphthalen-1-ylmethyl)-6-phenylhexanoate Chemical compound C=1C=CC2=CC=CC=C2C=1CC(C(=O)OCC)CCCCC1=CC=CC=C1 ZLGQOFNUQJNLQH-UHFFFAOYSA-N 0.000 description 1
- SKCHNHKFQWMLLJ-UHFFFAOYSA-N ethyl 6-phenylhexanoate Chemical compound CCOC(=O)CCCCCC1=CC=CC=C1 SKCHNHKFQWMLLJ-UHFFFAOYSA-N 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 239000000499 gel Substances 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 125000005843 halogen group Chemical group 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 230000001077 hypotensive effect Effects 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 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
- 238000004519 manufacturing process Methods 0.000 description 1
- 238000001819 mass spectrum Methods 0.000 description 1
- 230000010534 mechanism of action Effects 0.000 description 1
- 230000007721 medicinal effect Effects 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 235000010755 mineral Nutrition 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 150000002923 oximes Chemical class 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 238000010647 peptide synthesis reaction Methods 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- DLNKOYKMWOXYQA-APPZFPTMSA-N phenylpropanolamine Chemical class C[C@@H](N)[C@H](O)C1=CC=CC=C1 DLNKOYKMWOXYQA-APPZFPTMSA-N 0.000 description 1
- 229920001184 polypeptide Polymers 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 102000004196 processed proteins & peptides Human genes 0.000 description 1
- 230000017854 proteolysis Effects 0.000 description 1
- 238000003127 radioimmunoassay Methods 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 230000028327 secretion Effects 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- BDHFUVZGWQCTTF-UHFFFAOYSA-M sulfonate Chemical compound [O-]S(=O)=O BDHFUVZGWQCTTF-UHFFFAOYSA-M 0.000 description 1
- 230000003639 vasoconstrictive effect Effects 0.000 description 1
Classifications
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Peptides Or Proteins (AREA)
Abstract
Description
【発明の詳細な説明】
（１）発明の目的
、 〔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Ａｒ
はフェニル基またはナフチル基であり、ｍは１〜６の整
数であり、ｎは１〜４の整数であり、Ｈｉｓ はＬ−ヒ
スチジル基であり、ＣはＬ−配ｍ＞で表される新規なジ
ペプチド誘導体およびそ ′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（ｈｕ−ｍａｎ ｒｅｎｉｎ）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ジペプチド誘導体およびそ
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。DETAILED DESCRIPTION OF THE INVENTION (1) Object of the invention, [Field of industrial application]
is a phenyl group or a naphthyl group, m is an integer of 1 to 6, n is an integer of 1 to 4, His is an L-histidyl group, and C is a novel An object of the present invention is to provide dipeptide derivatives and pharmacologically acceptable acid addition salts thereof. More specifically, novel dipeptide derivatives represented by the above general formula which have human renin inhibitory action and are useful as orally administrable therapeutic agents for hypertension, and their pharmacologically acceptable To provide acid addition salts.
レニンは腎臓の傍系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、アンジオテア シフ Ｉ （ａｎ
ｇｉｏｔｅｎｓｉｎ Ｉ ） を生成させる。生成し
たアンジオテンシンＩはアンジオテンシン変換酵素によ
りアンジオテンシンＩＩ （ａｎｇｉｏｔｅｎｓｉｎ
ＩＩ） 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。Renin is a proteolytic enzyme released from paraglobular cells of the kidney. This substance reacts with the renin substrate present in the α2 globulin fraction of plasma, and it reacts with the renin substrate present in the α2 globulin fraction of plasma.
giotensin I). The generated angiotensin I is converted to angiotensin II by angiotensin converting enzyme.
II) is converted into This angiotensin ■ has a vasoconstrictive effect, and also acts on the adrenal cortex and affects sodium and water metabolism.
It is a factor in hypertension that causes the secretion of sterone.
従って、新しい作用機作による高血圧治療剤として、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
■の生成を抑制する高血圧症治療剤の開発が強く要望さ
れている。Therefore, there is a strong demand for the development of a hypertension therapeutic agent with a new mechanism of action, which inhibits the reaction between renin and renin substrates and suppresses the production of angiotensin (2).
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、日本特許公告公報昭５９−１１０６６１
号、ヨーロッパ特許公開公報７０７０２９号、同７７０
２８号、同８１７８３号、バイオケミカル アンドバイ
オフィジカル リサーチ コミュニケーションズ（Ｂｉ
ｏｃｈｅｍｉｃａｌ ａｎｄ Ｂｉｏｐｈｙｓｉｃａｌ
Ｒｅ５ｅａｒｃｈ［：ｏｍｍｕｎｉｃａｔｉｏｎｓ］
１１８巻、９２９〜９３３ ページ、１９８４年）。Until now, the reaction between renin and renin substrate has been inhibited, i.e.
Many peptide derivatives are known as compounds that inhibit renin activity (Japanese Patent Publication No. 1983-
No. 39149, Japanese Patent Publication No. 59-110661
European Patent Publication No. 707029, European Patent Publication No. 770
No. 28, No. 81783, Biochemical and Biophysical Research Communications (Bi
chemical and biophysical
Re5search[:communications]
118, pages 929-933, 1984).
これらの特許出願の中で、特に日本特許公告公報昭５８
−３９１４９号は一般式
（式中のＲ１はメチル基、エチル基、ベンジル基、アダ
マンチル基またはベンジルオキシ基を示し、ＸはＬ−フ
ェニルアラニル基、Ｌ−７’ロリル−Ｌ−フェニルアラ
ニル基マたはＬ−ヒスチジル−し−プロリル−し−フェ
ニルアラニル基を示し、Ｌ −Ｈｌｓ はＬ−ヒスチジ
ル基を示し、Ｒ２はイソプロピル基、フェニル基または
３−インドリル基を示す。ＣはＬ−配置を示す）で表さ
れるペプチド誘導体を開示している。Among these patent applications, especially the Japanese Patent Publication No. 1983
-39149 is a general formula (in the formula, R1 represents a methyl group, an ethyl group, a benzyl group, an adamantyl group, or a benzyloxy group, and X represents an L-phenylalanyl group, L-7'loryl-L-phenylalanyl group or L-histidyl-prolyl-phenylalanyl group, L-Hls represents L-histidyl group, R2 represents isopropyl group, phenyl group or 3-indolyl group.C is L A peptide derivative represented by -indicating the configuration is disclosed.
上記一般式（Ｉ［）で表されるペプチド誘導体は強いレ
ニン活性阻害作用を有するが、体内の蛋白分解酵素、例
えば、キモトリプシン（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。The peptide derivative represented by the above general formula (I[) has a strong renin activity inhibiting effect, but it is degraded by proteases in the body, such as chymotrypsin, and exerts its pharmacological effects when administered orally. I can't expect that.
また、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、かつ前記
日本特許公告公報に開示されている一般式（ｎ）のペプ
チド誘導体と同様、蛋白分解酵素に対し不安定で経口投
与によってその薬効を発揮させることが期待し難い。In addition, most of the compound groups disclosed in the above-mentioned patent applications are polypeptides, which are difficult to synthesize, and similar to the peptide derivatives of general formula (n) disclosed in the above-mentioned Japanese Patent Publication, they undergo proteolysis. It is unstable to enzymes and it is difficult to expect its medicinal effects to be exerted by oral administration.
さらに、前記のバイオケミカル アンド バイオフィジ
カル リサーチ コミュニケーションズには、式
（Ｒ１゛はベンジルオキシ基であり、Ｌ ＨＩＳ Ｎ
ＣおよびＲ２は前記と同じ意味をもつ）で表されるジ
ペプチド誘導体が開示されているが、このものはレニン
活性阻害作用がきわめて弱いものである。Furthermore, the above-mentioned Biochemical and Biophysical Research Communications has the formula (R1 is a benzyloxy group, L HIS N
A dipeptide derivative represented by (C and R2 have the same meanings as above) has been disclosed, but this dipeptide derivative has an extremely weak renin activity inhibitory effect.
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（Ｉ）で表されるジペプチド誘導体お
よびそれらの薬理学的に許容できる酸付加塩が簡易に製
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。As a result of various studies to solve these problems, the present inventors have found that the dipeptide derivatives represented by the general formula (I) and their pharmacologically acceptable acid addition salts can be easily produced. It has been found that this compound exhibits a strong renin activity inhibiting effect, can be administered orally, and can solve the above-mentioned problems.
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（Ｉ）で表されるジペプチド誘導体およびそれ
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５ＨＲ−３Ｐラツトのもつ高血
圧症に対して、経口投与によって有意に改善効果すなわ
ち降圧効果を発揮する。2. Structure of the invention [Means and effects for solving the problems] The dipeptide derivatives represented by the general formula (I) of the present invention 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. Furthermore, this product exhibits a significant improving effect, ie, a hypotensive effect, on the hypertension of 5HR-3P rats when administered orally.
このことは本発明の前記一般式（Ｉ）で表されるジペプ
チド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
。This indicates that the dipeptide derivatives represented by the general formula (I) of the present invention and their pharmacologically acceptable acid addition salts have a strong renin activity inhibiting effect and can be used as an orally administrable antihypertensive agent. It has been shown to be useful.
本発明の前記一般式（Ｉ）で表されるジペプチド誘導体
は、一般式
（式中のＡｒＳｍおよびｎ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、一般式
じ意味を持つ）で表される化合物と反応させるかまたは
、一般式
（式中のＡｒ、ｍＳｎおよびＣ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ＣおよびＺは前記と同じ意味を持つ）で表され
る化合物とを反応させたのち、カルボニル基の保護基を
除去させることにより製造することができる。The dipeptide derivative represented by the general formula (I) of the present invention comprises a reactive functional derivative of a carboxylic acid represented by the general formula (ArSm and n in the formula have the same meanings as above), and a dipeptide derivative represented by the general formula or react with a compound represented by the general formula (in which Ar, mSn and C have the same meanings as above) and a compound represented by the general formula (in which C and C have the same meanings as above). It can be produced by reacting a compound represented by (Z has the same meaning as above) and then removing the protecting group of the carbonyl group.
前記一般式（ＩＩＩ）で表されるカルボン酸は公知化合
物または新規化合物で、文献記載の方法またはその類似
方法によって製造することができる。The carboxylic acid represented by the general formula (III) is a known compound or a new compound, and can be produced by a method described in literature or a method similar thereto.
すなわち、一般式（Ｉ）で表されるカルボン酸のうち、
Ａｒがフェニル基で、ｍおよびｎが同じであるカルボン
酸は、一般式
（式中のＸはハロゲン原子であり、ｍは前記と同じ意味
をもつ）で表される化合物または一般式（式中のｎおよ
びＸは前記と同じ意味を持つ）で表される化合物をナト
リウムエトキサイドの存在下にマロン酸ジエチルと反応
させ、生成物を含水ジメチルスルホキシド中塩化リチウ
ムで処理し、次いで生成物を加水分解することにより製
造することができる。また、Ａｒがナフチル基であるカ
ルボン酸またはＡｒがフェニル基でｍおよびｎが異なる
カルボン酸は、一般式
（式中のｍは前記と同じ意味を持つ）で表される化合物
または一般式
（式中のＡｒおよびｎは前記と同じ意味を持つ）で表さ
れる化合物をマロン酸ジエチルと反応させ、次いでパラ
ジウム炭素の存在下に水添し、一般式（式中のｍは前記
と同じ意味を持つ）で表される化合物または一般式
（式のＡｒおよびｎは前記と同じ意味を持つ）で表され
る化合物を得たのち、これに一般式（式中のＡｒ、ｎお
よびＸは前記と同じ意味を持つ）で表される化合物また
は一般式（■）で表される化合物をエタノール中ナトリ
ウムエトキサイドまたは１．２−ジメトキシエタン中、
水素化ナトリウムの存在下に反応させ、生成物を含水ジ
メチルスルホキシド中塩化リチウムで処理し、次いで、
加水分解することにより製造することができる。That is, among the carboxylic acids represented by general formula (I),
A carboxylic acid in which Ar is a phenyl group and m and n are the same is a compound represented by the general formula (in the formula, X is a halogen atom, and m has the same meaning as above) or a general formula (in the formula, n and It can be produced by decomposition. In addition, carboxylic acids in which Ar is a naphthyl group or carboxylic acids in which Ar is a phenyl group and m and n are different are compounds represented by the general formula (m in the formula has the same meaning as above) or compounds represented by the general formula (formula A compound represented by the general formula (Ar and n have the same meaning as above) is reacted with diethyl malonate, and then hydrogenated in the presence of palladium carbon to form a compound represented by the general formula (m in the formula has the same meaning as above). After obtaining a compound represented by the general formula (Ar and n in the formula have the same meanings as above), a compound represented by the general formula (Ar, n and X in the formula have the same meanings as above) is obtained. ) or a compound represented by the general formula (■) in sodium ethoxide in ethanol or in 1,2-dimethoxyethane,
Reacted in the presence of sodium hydride and treated the product with lithium chloride in aqueous dimethyl sulfoxide, then
It can be produced by hydrolysis.
これらの反応により得られる前記一般式（Ｉ）のカルボ
ン酸としては、２−ベンジル−３−フェニルプロピオン
酸、４−フェニル−２−（２−フェニルエチル）酪酸、
２−ベンジル−５−フェニルペンタン酸、２−ベンジル
−７−フェニルへブタン酸、２−（１−ナフチルメチル
）−６−フェニルヘキサン酸、２−ベンジル−６−（２
−ナフチル）ヘキサン酸、２−（１−ナフチルメチル）
−８−フェニルオクタン酸等をあげることができる。こ
れらのカルボン酸の中には不斉炭素原子を有するものも
あるが、それらは通常の光学分割方法により分割するこ
とができる。本発明においては光学活性体（Ｒまたは８
体）およびラセミ体（Ｒ３体）のいずれをも使用するこ
とができる。The carboxylic acids of general formula (I) obtained by these reactions include 2-benzyl-3-phenylpropionic acid, 4-phenyl-2-(2-phenylethyl)butyric acid,
2-benzyl-5-phenylpentanoic acid, 2-benzyl-7-phenylhebutanoic acid, 2-(1-naphthylmethyl)-6-phenylhexanoic acid, 2-benzyl-6-(2
-naphthyl)hexanoic acid, 2-(1-naphthylmethyl)
-8-phenyloctanoic acid and the like can be mentioned. Although some of these carboxylic acids have asymmetric carbon atoms, they can be resolved by conventional optical resolution methods. In the present invention, the optically active form (R or 8
Both the R3 form) and the racemic form (R3 form) can be used.
前記一般式（ＩＶ）で表される化合物はカルボニル基を
保護したし一ロイシナールとアミノ基を保護したし一ヒ
スチジンとを用い、通常用いられるペプチド合成の方法
に従い反応させることにより製造することができる。The compound represented by the general formula (IV) can be produced by reacting a carbonyl group-protected monoleucinal and an amino group-protected monohistidine according to a commonly used peptide synthesis method. .
前記一般式（Ｖ）で表される化合物は前記一般式（Ｉ［
Ｉ）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ｌ、 Ｎ−ジメ
チルホルムアミド中で反応させ、一般式
（式中のＡｒＳｍ、ｎ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たのち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。The compound represented by the general formula (V) is the compound represented by the general formula (I[
A reactive functional derivative of the carboxylic acid represented by I) and L-
After reacting with histidine methyl ester dihydrochloride in l,N-dimethylformamide to obtain a compound represented by the general formula (ArSm, n and C in the formula have the same meanings as above), this was mixed with methanol. It can be produced by reacting with hydrazine monohydrate in a solution.
また、前記一般式（ＶＩ）で表される化合物はＬ−ロイ
シナールから容易に製造することができる。Moreover, the compound represented by the general formula (VI) can be easily produced from L-leucinal.
一般式（ｒＶ）および（ＶＩ）で表される化合物のカル
ボニル基の保護基（Ｚ）としてはセミカルバゾン、オキ
シム等をあげることができ、セミカルバゾンが好適であ
る。As the protective group (Z) for the carbonyl group of the compounds represented by the general formulas (rV) and (VI), semicarbazone, oxime, etc. can be mentioned, and semicarbazone is preferable.
前記一般式（ＩＩ［）で表されるカルボン酸と一般式（
ＴＶ）で表される化合物との反応は常法に従って行うこ
とができる。本反応を好適に実施するには一般式（ＩＩ
Ｉ）で表されるカルボン酸を不活性有機溶媒中例えば、
クロロホルム、塩化メチレン、Ｎ、Ｎ−ジメチルホルム
アミド、アセトニトリル等に溶解し、一般式（Ｉ［Ｉ）
で表されるカルボン酸に対して等モルないしやや過剰モ
ル量の１．１°−カルボニルジイミダゾール、Ｎ、Ｎ”
−ジスクシンイミジルカルボナートまたはジフェニルリ
ン酸アジドを加え室温または冷却下で０．５〜３時間反
応させたのち、一般式（ＩＩ［）で表されるカルボン酸
に対して等モル量の一般式（ＴＶ）で表される化合物を
加え、０〜５０℃で１〜２０時間反応させる。反応生成
物を常法に従って処理し、得られた化合物をさらに、メ
チルアルコール中塩酸のような鉱酸または酢酸、ハロゲ
ン酢酸などの有機酸の存在下、ホルムアルデヒド、アセ
トアルデヒド等のアルデヒド化合物で処理すること等に
よりカルボニル基の保護基を除去し、前記一般式（１）
で表される化合物をＢ ｉる。The carboxylic acid represented by the general formula (II[) and the general formula (
The reaction with the compound represented by TV) can be carried out according to a conventional method. To carry out this reaction suitably, the general formula (II
For example, the carboxylic acid represented by I) in an inert organic solvent,
Dissolved in chloroform, methylene chloride, N,N-dimethylformamide, acetonitrile, etc., the general formula (I[I)
1.1°-carbonyldiimidazole, N, N'' in an equimolar to slightly excess molar amount relative to the carboxylic acid represented by
- After adding disuccinimidyl carbonate or diphenyl phosphoric acid azide and reacting at room temperature or under cooling for 0.5 to 3 hours, an equimolar amount of the A compound represented by formula (TV) is added and reacted at 0 to 50°C for 1 to 20 hours. The reaction product is treated according to a conventional method, and the resulting compound is further treated with an aldehyde compound such as formaldehyde or acetaldehyde in the presence of a mineral acid such as hydrochloric acid or an organic acid such as acetic acid or halogenacetic acid in methyl alcohol. The protecting group of the carbonyl group is removed by etc., and the above general formula (1)
B i is a compound represented by
また、前記一般式（Ｖ）で表される化合物と一般式（Ｖ
Ｉ）で表される化合物との反応は常法に従って行うこと
ができる。すなわち、前記一般式（Ｖ）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（Ｖ）
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、この溶液を一般式（Ｖ）で表される化合物に対して
等モル量の前記一般式（ＶＩ）の化合物のＮ、Ｎ−ジメ
チルホルムアミド溶液に冷却下、好ましくは一２０〜０
℃で加え、次いで５〜２０時間０℃ないし室温で反応さ
せる。反応物を常法に従い処理し得られる化合物をメチ
ルアルコール中塩酸の存在下にホルムアルデヒドと反応
させること等により保護基を除去し、目的物を得ること
ができる。Furthermore, the compound represented by the general formula (V) and the general formula (V
The reaction with the compound represented by I) can be carried out according to a conventional method. That is, the compound represented by the general formula (V) is suspended in N,N-dimethylformamide, and 3
~5 times the mole of hydrogen chloride is added to this solution, and the general formula (V) is added.
A 1 to 3 mole amount of isoamyl nitrite is added to the compound represented by the above formula, and the mixture is reacted at -20 to -5°C for 5 to 30 minutes. Triethylamine is added to this reaction solution to adjust the pH to 8 to 9, and this solution is added to an N,N-dimethylformamide solution of the compound represented by the general formula (VI) in an equimolar amount to the compound represented by the general formula (V). Under cooling, preferably -20-0
C. and then reacted for 5-20 hours at 0.degree. C. to room temperature. The target compound can be obtained by treating the reaction product according to a conventional method and reacting the resulting compound with formaldehyde in the presence of hydrochloric acid in methyl alcohol to remove the protecting group.
本発明の前記一般式（１）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六ができ、
これらの塩としては塩酸塩、スルホン酸塩、ｐ−）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、経口投与によって５
ＨＲ−８Ｐラツトのもつ高血圧症状を有意に改善する。The compound represented by the general formula (1) of the present invention can be converted into a pharmacologically acceptable acid addition salt according to a conventional method,
Examples of these salts include hydrochloride, sulfonate, p-)luenesulfonate, acetate, and citrate. These acid addition salts also have a strong renin activity inhibitory effect, are stable to proteolytic enzymes, and when administered orally,
Significantly improves hypertensive symptoms in HR-8P rats.
本発明の一般式（Ｉ）で表されるジペプチド誘導体およ
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、そのような医薬品組成物と
しては例えば、錠剤、カプセル剤、顆粒剤、注射剤をあ
げることができる。The dipeptide derivative represented by general formula (I) of the present invention and its pharmacologically acceptable acid addition salt can be made into a pharmaceutical composition according to a conventional method, and such pharmaceutical compositions include, for example, tablets, Examples include capsules, granules, and injections.
前記一般式（Ｉ）で表されるジペプチド誘導体および薬
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、（Ｉ Ｃｓａ ）値は１０−６〜１０−８モル濃度
である。この一般式（、Ｉ）で表されるジペプチド誘導
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５ ｍｇ〜５０００■、非
経口投与では１日当り１■〜１０００ｍｇ程度、と思わ
れる。The dipeptide derivative and pharmacologically acceptable acid addition salt represented by the general formula (I) have a strong renin activity inhibitory effect, and have a 50% inhibitory activity (I Csa ) value in the human renin-sheep renin substrate system. is a 10-6 to 10-8 molar concentration. When a pharmaceutical composition containing the dipeptide derivative represented by the general formula (I) or a pharmacologically acceptable acid addition salt thereof is used for treatment, the dosage is determined depending on the degree of the disease, the sex and age of the patient, It is adjusted depending on body weight, etc., but it is estimated that oral administration is approximately 5 mg to 5,000 mg per day for adults, and parenteral administration is approximately 1 to 1,000 mg per day.
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−ロｘ３００型マススペクトロメーターを用いて
ＦＡＤ法により測定した。薄層クロマトグラフィーはメ
ルク社のプレコートプレートシリカゲル（ｐｒｅｃｏａ
ｔｅｄ ｐｌａｔｅｓ ５ｉｌｉｃａ ｇｅｌ ）６０
Ｆａｓ＜ を、カラムクロマトグラフィーはメルク社
のキーゼ）Ｌｔ−ゲル（Ｋｉｅｓｅｌｇｅｌ） ６０
（２３０−４００メッシ、） を用いて行った。また
薄層クロマトグラフィーの展開溶媒はクロロホルム／メ
タノール／水＝８／３／１の混合液の下層を用い、Ｒｆ
値を算出した。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 were measured using a JEOL JNM-GX270 high-resolution nuclear magnetic resonance apparatus. The mass spectrum was measured by the FAD method using a JEOL JMS-ROX300 mass spectrometer. Thin layer chromatography was performed using Merck's precoated plate silica gel (precoa).
ted plates 5ilica gel)60
Column chromatography was performed using Merck's Kieselgel 60.
(230-400 Messi,). In addition, the developing solvent for thin layer chromatography is the lower layer of a mixture of chloroform/methanol/water = 8/3/1, and Rf
The value was calculated.
参考例 １
２−（１−ナフチルメチル）−６−フェニルヘキサン酸
２−（１−ナフチルメチル）マロン酸ジエチル２．６２
ｇを乾燥１．２−ジメトキシエタン４０ｍ１ に溶解
し、冷却下に５０％水素化ナトリウム（油性）０．４６
ｇを加えたのち、４−フェニルブチルプロミド２．０５
ｇを滴下し、１９時間加熱還流する。冷、後含水エーテ
ルを加え、エーテルで抽出し飽和食塩水で洗ったのち、
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ッシュカラムクロマトグラ
フィー（溶出溶媒：ベンゼン／ヘキサン＝ １ ／ １
） で精製し、無色油状の２−（１−ナフチルメチル
）−２−（４−７エニルブチル）マロン酸ジエチル２．
７７ｇを得る。Reference example 1 Diethyl 2-(1-naphthylmethyl)-6-phenylhexanoate 2-(1-naphthylmethyl)malonate 2.62
Dissolve g in 40 ml of dry 1,2-dimethoxyethane and add 0.46 ml of 50% sodium hydride (oil) while cooling.
After adding 2.05 g of 4-phenylbutyl bromide
g was added dropwise, and the mixture was heated under reflux for 19 hours. After cooling, add aqueous ether, extract with ether, wash with saturated saline,
Dry with anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was subjected to silica gel flash column chromatography (elution solvent: benzene/hexane = 1/1
) to give diethyl 2-(1-naphthylmethyl)-2-(4-7enylbutyl)malonate as a colorless oil.
Obtain 77g.
２−（１−ナフチルメチル）−２−（４−フェニルブチ
ル）マロン酸ジエチル２．７６ｇをジメチルスルホキシ
ド２０ｍ１．水０．５ｍｌに溶解し、塩化リチウム１．
２７ｇを加え１８０〜１９０ ℃で８時間加熱する。冷
浸、水を加え酢酸エチルで抽出し、飽和食塩水で洗った
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、淡かっ色油状の２−（１−ナフチルメチル）−
６−フェニルヘキサン酸エチル２．０６ｇを得る。 。2.76 g of diethyl 2-(1-naphthylmethyl)-2-(4-phenylbutyl)malonate was added to 20 ml of dimethyl sulfoxide. Dissolved in 0.5 ml of water, 1.5 ml of lithium chloride.
Add 27g and heat at 180-190°C for 8 hours. Cool, add water, extract with ethyl acetate, wash with saturated brine, and dry over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain a light brown oily 2-(1-naphthylmethyl)-
2.06 g of ethyl 6-phenylhexanoate is obtained. .
２−（１−ナフチルメチル）−６−フェニルヘキサン酸
エチル２．０５ｇをエタノール３０ｍ１ に溶解し、２
規定水酸化ナトリウム水溶液１０ｍ１ を加え、１．５
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
を飽和食塩水で洗っ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２−（１−ナ
フチルメチル）−６−フェニルヘキサン酸１．８５ｇを
得る。Dissolve 2.05 g of ethyl 2-(1-naphthylmethyl)-6-phenylhexanoate in 30 ml of ethanol,
Add 10ml of normal sodium hydroxide aqueous solution and
Heat to reflux for an hour. 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 1.85 g of 2-(1-naphthylmethyl)-6-phenylhexanoic acid as a colorless oil.
ＩＲ（液膜）： νｃｏ １６９０ ｃｍ−’ＮＭＲ
（ＣＤＣ１，） δ： １．２５〜１．９ （ｍ、
６）１） 、 ２．５６ （ｔ。IR (liquid film): νco 1690 cm-'NMR
(CDC1,) δ: 1.25 to 1.9 (m,
6) 1) , 2.56 (t.
２Ｈ） 、 ２．８〜３．０ （ｍ、 ＬＨ）、 ３．
１７（ｄｄ、 ｌｔｌ、 Ｊ＝７．２．１４Ｊ Ｈｚ）
。2H), 2.8-3.0 (m, LH), 3.
17 (dd, ltl, J=7.2.14J Hz)
.
３．４８（ｄｄ、 ＩＬ Ｊ＝７．７． １４．３ Ｈ
ｚ）。3.48 (dd, IL J=7.7. 14.3 H
z).
７、０５〜８．１ （ｍ、 １２Ｈ）参考例 ２
参考例１と同様の方法によって下記のカルボン酸を合成
した。7,05-8.1 (m, 12H) Reference Example 2 The following carboxylic acid was synthesized in the same manner as in Reference Example 1.
無色結−晶
融 点： ８６〜８８℃
ＩＲ（ＫＢｒ）： νｃ０１６８５ ｃｍ−’ＮＭ
Ｒ（ＣＤＣｌ２） δ： ＩＪ 〜１．８（ｍ、 ６
Ｈ）、 ２．６〜２．８５ （ｍ、 ４Ｈ） 、 ２．
９〜３．０５（ｍ、 ＩＨ）、 ７．１〜７．８５（
ｍ。Colorless crystal Melting point: 86-88°C IR (KBr): νc01685 cm-'NM
R(CDCl2) δ: IJ ~1.8(m, 6
H), 2.6-2.85 (m, 4H), 2.
9-3.05 (m, IH), 7.1-7.85 (
m.
１２Ｈ）
２−（１−ナフチルメチル）−８−フェニルオクタン酸
無色粘性油状物
ＩＲ（液膜）： ！／Ｃｏ １７００ ｃｍ−’ＮＭ
Ｒ（ＣＤＣ１３） δ： １．１〜１．９（ｍ、 ｌ
０Ｈ）、 ２．５６（ｔ、 ２Ｈ，Ｊ＝７．１Ｈｚ）、
２．８〜２．９５（ｍ、 ＩＨ）、 ３．１９（ｄｄ
。12H) 2-(1-naphthylmethyl)-8-phenyloctanoic acid colorless viscous oil IR (liquid film): ! /Co 1700 cm-'NM
R (CDC13) δ: 1.1 to 1.9 (m, l
0H), 2.56 (t, 2H, J=7.1Hz),
2.8-2.95 (m, IH), 3.19 (dd
.
ＬＨ，Ｊ＝７．１．１４Ｊｌ（ｚ）、 ３．４６（ｄｄ
、 ＬＨ，Ｊ＝７．７．１４．３Ｈｚ）。LH, J=7.1.14Jl(z), 3.46(dd
, LH, J = 7.7.14.3Hz).
７、１〜８．０５ （ｍ、 １２！（）２−ベンジル−
７−フェニルへブタン酸無色粘性油状物
ＩＲ（液膜）： νｃ０１７００ ｃｍ−’ＮＭＲ（
ＣＤＣ１３） δ： １，２〜１．８（ｍ、 ８Ｈ）
、 ２．５７（ｔ、 ２）１． Ｊ＝７．ＩＨｚ）
、 ２．６ 〜２、８ （ｍ、 ２Ｈ） 、 ２
．９６ （ｄｄ、 ＬＨ。7, 1-8.05 (m, 12!()2-benzyl-
7-phenylhebutanoic acid colorless viscous oil IR (liquid film): νc01700 cm-'NMR (
CDC13) δ: 1,2-1.8 (m, 8H)
, 2.57(t, 2)1. J=7. IHz)
, 2.6 ~ 2, 8 (m, 2H) , 2
．． 96 (dd, LH.
Ｊ＝１．７． １３．２Ｈｚ） 、 ７．１ 〜７、
３ （ｍ、 ｌ０Ｈ）
２−ベンジル−５−フェニルペンタン酸無色粘性油状物
ＩＲ（液膜）： νｃ０１７００ ｃｍ−’ＮＭＲ（
ＣＤＣ１３） δ： １．６〜１．７（ｍ、 ４Ｈ）
、 ２．５５〜３、０（ｍ、 ５Ｈ）、 ７．１〜７．
３（ｍ、 ｌ０Ｈ）
参考例 ３
４−フェニル−２−（２−フェニルエチル）酪酸マロン
酸ジエチル３．２ｇを乾燥１，２−ジメトキシエタン２
０ ｍｌ に溶解し、冷却下に５０％水素化ナトリウ
ム（油性）２．４ｇを加えたのち、２−フェニルエチル
プロミド９．２５ｇを加え１６時間加熱還流する。J=1.7. 13.2Hz), 7.1 ~7,
3 (m, 10H) 2-benzyl-5-phenylpentanoic acid colorless viscous oil IR (liquid film): νc01700 cm-'NMR(
CDC13) δ: 1.6-1.7 (m, 4H)
, 2.55-3, 0 (m, 5H), 7.1-7.
3(m, l0H) Reference Example 3 3.2 g of diethyl malonate 4-phenyl-2-(2-phenylethyl)butyrate was dried in 1,2-dimethoxyethane 2
After 2.4 g of 50% sodium hydride (oil-based) was added while cooling, 9.25 g of 2-phenylethyl bromide was added and heated under reflux for 16 hours.
冷機、含水エーテルを加え、エーテルで抽出し、飽和食
塩水で洗ったのち、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て、淡黄色油状物５．５５ｇを
得る。この油状物５．５２ｇに水酸化カリウム１７ｇ１
水６０ｍ１、イソアミルアルコール１００ ｍｌを加え
１６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っ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たのち、残留物にヘキサ
ンを加え析出結晶をろ取し、無色結晶の２．２−ビス（
２−フェニルエチル）マロン酸３．１０８’１６゜融
点： １６８〜１７２ ℃ＩＲ（にＯｒ） ：
！／ＣＯ１６８０ｃｍ−’ＮＭＲ（ｄ６−ＤＭＳ
Ｏ） δ： １．９５〜２．２（ｍ、 ４Ｈ）、 ２
．３〜２、６ （ｍ、 ４Ｈ） 、 ７．０５〜７．４
５（ｍ、 ｌ０Ｈ） 、 １２．５〜１３．３ （ｂｒ
。Cool the mixture, add aqueous ether, extract with ether, wash with saturated brine, and dry over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain 5.55 g of a pale yellow oil. Potassium hydroxide 17g1 to 5.52g of this oily substance
Add 60 ml of water and 100 ml of isoamyl alcohol, and heat under reflux for 16 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 the aqueous layer was made acidic by adding concentrated hydrochloric acid and extracted with ether. The ether layer was washed with saturated brine and then dried over anhydrous magnesium sulfate. After distilling off the solvent under reduced pressure, hexane was added to the residue and the precipitated crystals were collected by filtration to give colorless crystals of 2,2-bis(
2-phenylethyl) malonic acid 3.108'16° melting
Point: 168-172℃ IR (in Or):
! /CO1680cm-'NMR(d6-DMS
O) δ: 1.95-2.2 (m, 4H), 2
．． 3-2, 6 (m, 4H), 7.05-7.4
5 (m, 10H), 12.5~13.3 (br
.
２Ｈ）
２．２−ビス（２−フェニルエチル）マロン酸２．９５
ｇを１９０〜１９５℃で１時間加熱する。冷機、シリカ
ゲルフラッシュカラムクロマトグラフィー（溶出溶媒：
クロロホルム）で精製し、淡黄色油状の４−フェニル−
２−（２−フェニルエチル＞ＲＡＭ、２．２７ ｇ ヲ
得る。2H) 2.2-bis(2-phenylethyl)malonic acid 2.95
Heat g at 190-195°C for 1 hour. Refrigerator, silica gel flash column chromatography (elution solvent:
chloroform) to produce 4-phenyl- as a pale yellow oil.
2.27 g of 2-(2-phenylethyl>RAM) is obtained.
ＩＲ（液膜）： Ｌ／Ｃｏ １６９０ ａｍ−１
ＨＭＲ（ＣＤＣ１３） δ： １．７５〜２．１５
（ｍ、 ４Ｈ）、 ２．４〜２゜５５ （ｍ、
１）１）、 ２．５５ 〜２．８（ｍ、 ４Ｈ）
、 ７．０５ 〜７．４ （ｍ。IR (liquid film): L/Co 1690 am-1
HMR (CDC13) δ: 1.75-2.15
(m, 4H), 2.4~2゜55 (m,
1) 1), 2.55 to 2.8 (m, 4H)
, 7.05 ~ 7.4 (m.
１０Ｈ）
参考例 ４
２−ベンジル−３−フェニルプロピオン酸マロン酸ジエ
チル３．２ ｇヲ乾燥エタノール１００ ｍｌに溶解し
、ナトリウムエトキサイド３．０ｇを加え、室温で３０
分攪拌する。さらに、ベンジルブロマイド６．８ｇを加
え、３０分攪拌したのち、４時間加熱還流する。減圧下
に溶媒を留去し、希塩酸を加えて酸性とし、酢酸エチル
で抽出する。抽出液を５％炭酸水素ナトリウム水溶液お
よび飽和食塩水で洗ったのち、無水硫酸マグネシウムで
乾燥する。10H) Reference Example 4 3.2 g of diethyl 2-benzyl-3-phenylpropionate malonate was dissolved in 100 ml of dry ethanol, 3.0 g of sodium ethoxide was added, and the mixture was heated at room temperature for 30 g.
Stir for a minute. Further, 6.8 g of benzyl bromide was added, and the mixture was stirred for 30 minutes, and then heated under reflux for 4 hours. The solvent is distilled off under reduced pressure, acidified with dilute hydrochloric acid, and extracted with ethyl acetate. The extract is washed with a 5% aqueous sodium bicarbonate solution and saturated brine, and then dried over anhydrous magnesium sulfate.
減圧下に溶媒を留去し、残留物をシリカゲルフラッシュ
カラムクロマトグラフィー（溶出溶媒：塩化メチレン）
で精製し、無色油状のジベンジルマロン酸ジエチル６．
０ｇを得る。The solvent was distilled off under reduced pressure, and the residue was subjected to silica gel flash column chromatography (elution solvent: methylene chloride).
6. Purify diethyl dibenzylmalonate as a colorless oil.
Obtain 0g.
ジベンジルマロン酸ジエチル６．０ｇをジメチルスルホ
キシド４０ｍ１．水１．２ｍｌに溶解し、塩化リチウム
３．７ｇを加え、１８０〜１９０℃で６時間加熱する。6.0 g of diethyl dibenzylmalonate was added to 40 ml of dimethyl sulfoxide. Dissolve in 1.2 ml of water, add 3.7 g of lithium chloride, and heat at 180-190°C for 6 hours.
冷機、水を加え、酢酸エチルで抽出し、飽和食塩水で洗
ったのち、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ッシュカラムク
ロマトグラフィー（溶出溶媒：塩化メチレン）で精製し
、淡かっ色油状の２−ベンジル−３−フェニルプロピオ
ン酸エチル４６２ｇを得る。Cool the mixture, add water, extract with ethyl acetate, wash with saturated brine, and dry 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 462 g of ethyl 2-benzyl-3-phenylpropionate as a pale brown oil.
２−ベンジル−３−フェニルプロピオン酸エチル３．４
ｇをエタノール１７０ ｍｌに溶解し、２規定水酸化ナ
トリウム水溶液３４ ｍｌを加え、１．５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
塩水で洗ったのち、無水硫酸マグネシウムで乾燥する。Ethyl 2-benzyl-3-phenylpropionate 3.4
Dissolve g in 170 ml of ethanol, add 34 ml of 2N aqueous sodium hydroxide solution, and heat under reflux for 1.5 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. After washing the ether layer with saturated brine, it is dried over anhydrous magnesium sulfate.
減圧下に溶媒を留去し、無色結晶の２−ベンジル−３−
フェニルプロピオン酸２．８ｇを得る。The solvent was distilled off under reduced pressure to obtain colorless crystals of 2-benzyl-3-
2.8 g of phenylpropionic acid are obtained.
無色結晶
融 点二 ８７〜８９℃
ＩＲ（ＫＢｒ） ： ｖ ＣＯ１７００ｃｍ−’ＮＭ
Ｒ（ＣＤＣ１３） δ： ２．７〜２．８５（ｍ、
２Ｈ）、 ２．９〜３．０５（ｍ、 ３Ｈ）、 ７．１
〜７Ｊ（ｍ。Colorless crystal Melting point 2 87-89℃ IR (KBr): v CO1700cm-'NM
R (CDC13) δ: 2.7 to 2.85 (m,
2H), 2.9-3.05 (m, 3H), 7.1
~7J (m.
１０Ｈ）
参考例 ５
（±）−２−（１−ナフチルメチル）−６−フェニルヘ
キサン酸５．０８ と（−）−ノルエフェドリン２．２
７ｇをメタノール５０ ｍｌに溶解し、減圧下に濃縮す
る。残留物に酢酸エチル６０ ｍｌを加えて４０℃で加
熱溶解後室撫で一夜放置する。析出した結晶をろ取し、
その結晶を同様に３回再結晶してノルエフェドリン塩１
．５ｇ（融点＝１２８〜１３１ ℃）を得る。この塩を
メタノール３０ｍ１に溶かし、１規定塩酸５ ｍｌを加
えてエーテル抽出し、エーテル層を水洗したのち無水硫
酸マグネシウムで乾燥する。減圧下にエーテルを留去し
、無色粘性油状の（＋）−２−（１−ナフチルメチル）
−６−フェニルヘキサン酸０．９５ｇを得る。10H) Reference example 5 (±)-2-(1-naphthylmethyl)-6-phenylhexanoic acid 5.08 and (-)-norephedrine 2.2
Dissolve 7 g in 50 ml of methanol and concentrate under reduced pressure. Add 60 ml of ethyl acetate to the residue, heat and dissolve at 40°C, and then leave overnight in a room. Filter the precipitated crystals,
Recrystallize the crystals three times in the same way to obtain 1 norephedrine salt.
．． 5 g (melting point = 128-131 °C) are obtained. Dissolve this salt in 30 ml of methanol, add 5 ml of 1N hydrochloric acid, extract with ether, wash the ether layer with water, and then dry over anhydrous magnesium sulfate. Ether was distilled off under reduced pressure to obtain (+)-2-(1-naphthylmethyl) as a colorless viscous oil.
0.95 g of -6-phenylhexanoic acid is obtained.
Ｃα〕＋ ２．５４ （ＭｅＯＨ）
一方、１回目に結晶化したろ液を濃縮し、残留物を上記
同様に３回結晶化して、その結晶をろ去したろ液を減圧
下に濃縮して２．２ｇの固体を得る。Cα] + 2.54 (MeOH) On the other hand, the filtrate that was crystallized the first time was concentrated, the residue was crystallized three times in the same manner as above, and the filtrate from which the crystals were filtered off was concentrated under reduced pressure to give 2. Obtain .2 g of solid.
この固体をイソプロピルエーテルより再結晶してノルエ
フェドリン塩１．１ｇ（融点＝９４〜９７℃）を得る。This solid is recrystallized from isopropyl ether to obtain 1.1 g of norephedrine salt (melting point = 94-97°C).
この結晶をメタノール１５ ｍｌに溶解し、１規定塩酸
３ ｍｌを加えて中和し、エーテルで抽出する。エーテ
ル層を水洗したのち無水硫酸マグネシウムで乾燥する。The crystals are dissolved in 15 ml of methanol, neutralized by adding 3 ml of 1N hydrochloric acid, and extracted with ether. After washing the ether layer with water, it is dried over anhydrous magnesium sulfate.
減圧下に溶媒を留去し、無色粘性油状の（−） −２−
（１−ナフチルメチル）−６−フェニルヘキサン酸０．
６９ｇを得る。The solvent was distilled off under reduced pressure to form a colorless viscous oil (-) -2-
(1-naphthylmethyl)-6-phenylhexanoic acid 0.
Obtain 69g.
〔ｃｔ） −２，５０（ＭｅＯＨ）
参考例 ６
Ｌ−ヒスチジル−し−ロイシナールセミカルバゾン−２
−トルエンスルホン酸塩
Ｎ−ベンジルオキシカルボニル−し−ヒスチジンヒドラ
ジド２．０ｇをＮ、Ｎ−ジメチルホルムアミド２５ｍ１
に懸濁し、−２０℃で５．１規定乾燥塩化水素／Ｎ、Ｎ
−ジメチルホルムアミド４．３ｍｌを加え、続いて亜硝
酸イソアミル１．１ｍｌを加えて攪拌する。ヒドラジド
の消失したことを確認した後混合物の温度を一３０℃ま
で下げてトリエチルアミン３．１ｍｌを加えて中和し、
Ｎ−ベンジルオキシカルボニル−し−ヒスチジンアジド
溶液を調整する。別にし一ロイシナールセミカルバゾン
酢酸塩１．５１ｇをＮ、Ｎ−ジメチルホルムアミド３０
ｍ１に溶かし、水冷下にトリエチルアミン２．８ｍｌを
加えた溶液に先のアジド***液を加え、水冷下に一夜攪
拌する。反応液を減圧下に濃縮し、５％炭酸水素ナトリ
ウム水溶液を加え酢酸エチルで抽出する。抽出液を飽和
食塩水で洗い、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フラッシニ力ラ
ムクロマトグラフィー（溶出溶媒：クロロホルム／メタ
ノール＝１０／１）で精製し、１．８１ｇの白色粉末を
得る。[ct) -2,50(MeOH) Reference Example 6 L-Histidyl-Sy-Leucinal Semicarbazone-2
-Toluenesulfonate N-benzyloxycarbonyl-histidine hydrazide 2.0g in N,N-dimethylformamide 25ml
Suspended in 5.1N dry hydrogen chloride/N, N at -20℃
- Add 4.3 ml of dimethylformamide, followed by 1.1 ml of isoamyl nitrite, and stir. After confirming that the hydrazide had disappeared, the temperature of the mixture was lowered to -30°C, and 3.1 ml of triethylamine was added to neutralize it.
Prepare an N-benzyloxycarbonyl-histidine azide solution. Separately, add 1.51 g of leucinal semicarbazone acetate to 30 g of N,N-dimethylformamide.
To a solution prepared by adding 2.8 ml of triethylamine under water cooling, the cold azide solution was added, and the mixture was stirred overnight under water cooling. The reaction solution was concentrated under reduced pressure, a 5% aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel flash column chromatography (elution solvent: chloroform/methanol = 10/1) to obtain 1.81 g of white powder.
融点：１０５〜１１１ ℃
Ｒｆ値： ０．３７
上記粉末１゜ＯｇとＩ）−）ルエンスルホン酸（無水）
０．７８ｇをメタノール２５ｍ１に溶解し、１０％パラ
ジウム炭素１００ ｍｇと活性炭３００ ｍｇを加えて
常圧で水添する。触媒をろ失投溶媒を減圧下に濃縮し、
残留物をエーテルで洗い、白色粉末のし一ヒスチジルー
し一ロイシナールセミカルバゾン・２ｐ−トルエンスル
ホン酸塩１．２５ｇを得る。Melting point: 105-111°C Rf value: 0.37 1°Og of the above powder and I)-) Luenesulfonic acid (anhydride)
Dissolve 0.78 g in 25 ml of methanol, add 100 mg of 10% palladium on carbon and 300 mg of activated carbon, and hydrogenate at normal pressure. Filter the catalyst, concentrate the solvent under reduced pressure,
The residue was washed with ether, and 1.25 g of histidyl monoleucinal semicarbazone 2p-toluenesulfonate was obtained as a white powder.
融 点＝ １２６〜１３０ ℃
ＮＭＲ（ｄ、−ＤＭＳＯ） δ： ０．８８（ｄ、
６Ｈ，Ｊ＝６．０Ｈｚ）。Melting point = 126-130°C NMR (d, -DMSO) δ: 0.88 (d,
6H, J=6.0Hz).
１、２５〜１．７ （ｍ、 ３１（） 、 ２．３０
（ｓ。1, 25-1.7 (m, 31(), 2.30
(s.
６Ｈ） 、 ３．０５〜３．３ （ｍ、 ２Ｈ） 。6H), 3.05-3.3 (m, 2H).
４．１〜４Ｊ（ｍ、 ＬＨ）、 ４Ｊ５〜４、５５
（ｍ、 ＬＨ） 、 ６．０〜６．４ （ｂｒ。4.1~4J (m, LH), 4J5~4, 55
(m, LH), 6.0-6.4 (br.
２８） 、 ７．０６ （ｄ、 ＬＨ，Ｊ＝３．９Ｈ
ｚ） 。28), 7.06 (d, LH, J=3.9H
z).
７、１４（ｄ、 ４Ｈ，Ｊ＝７．７Ｈｚ）、 ７．４３
ｓ、 ＬＨ）、 ？、５２（ｄ、 ４）１．Ｊ＝７．
７Ｈｚ）、 ８．１〜８．５ （ｂｒ、 ３Ｈ） 。7, 14 (d, 4H, J=7.7Hz), 7.43
s, LH), ? , 52(d, 4)1. J=7.
7Hz), 8.1-8.5 (br, 3H).
８．５３（ｄ、 ＬＨ，Ｊ＝８．２Ｈｚ）。8.53 (d, LH, J=8.2Hz).
９．０１（ｓ、 １）１）、 ９．９６（ｓ、
ＬＨ）参考例 ７
Ｎ−［”２−（１−ナフチルメチル）−６−フェニルヘ
キサノイルシーシー ヒスチジンヒドラジド
２−（１−ナフチルメチル）−６−フェニルヘキサン酸
３．３２ｇを乾燥アセトニトリル５０ｍ１ に溶解し
、室温攪拌下にＮ、Ｎ−ジスクシンイミジルカルボナー
Ｂ、７０ｇとトリエチルアミン２．０ｍｌを加え室温で
１時間攪拌する。し−ヒスチジンメチルエステル２塩酸
塩２゜４２ｇ、Ｎ−メチルモルホリン６ ｍ １ ％
乾４゜Ｎ−ジメチルホルムアミド１２０ｍ１．乾燥クロ
ロホルム３００ ［１１１の混液に先の反応液を滴下し
、５０℃で２４時間攪拌する。減圧下に溶媒を留去し、
残留物に５％炭酸水素す） ＩＪウム水溶液を加え、酢
酸エチルで抽出し、飽和食塩水で洗ったのち、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ッシュカラムクロマトグラフィー（
溶出溶媒：クロロホルム／メタノール＝３０／ １ ”
）で精製し、白色粉末のＮ−［２−（１−ナフチルメチ
ル）−６−フェニルヘキサノイルシーシー ヒスチジン
メチルエステル３．０６ｇを得る。9.01(s, 1)1), 9.96(s,
LH) Reference Example 7 N-["2-(1-Naphthylmethyl)-6-phenylhexanoylc Histidine hydrazide 3.32 g of 2-(1-naphthylmethyl)-6-phenylhexanoic acid was dissolved in 50 ml of dry acetonitrile. 70 g of N,N-disuccinimidyl carboner B and 2.0 ml of triethylamine were added to the mixture under stirring at room temperature. The mixture was stirred at room temperature for 1 hour. Histidine methyl ester dihydrochloride 2.42 g, N-methylmorpholine 6 m 1 %
Dry 4°N-dimethylformamide 120 ml. The above reaction solution was added dropwise to a mixed solution of 300 [111] of dry chloroform, and the mixture was stirred at 50°C for 24 hours. The solvent was distilled off under reduced pressure,
Add a 5% aqueous solution of hydrogen carbonate to the residue, extract with ethyl acetate, wash with saturated brine, and dry 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 = 30/1''
) to obtain 3.06 g of N-[2-(1-naphthylmethyl)-6-phenylhexanoyl C histidine methyl ester as a white powder.
融 点： ４５〜４７℃
Ｎ−（２−（１−ナフチルメチル）−６−フェニルヘキ
サノイルシーシー ヒスチジンメチルエステル３．０５
ｇをメタノール３０ ｍｌ に溶解し、ヒドラジン１水
和物１．６ｇを加え室温で４時間攪拌する。減圧下に溶
媒を留去したのち、残留物に水を加え、酢酸エチルで抽
出し、水で洗ったのち、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、白色粉末のＮ−［：２−（
１−ナフチルメチル）−６−フェニルヘキサノイル、ｌ
−Ｌ−ヒスチジンヒドラジド２．９２ｇを得る。Melting point: 45-47°C N-(2-(1-naphthylmethyl)-6-phenylhexanoylcss Histidine methyl ester 3.05
g was dissolved in 30 ml of methanol, 1.6 g of hydrazine monohydrate was added, and the mixture was stirred at room temperature for 4 hours. After evaporating the solvent under reduced pressure, water was added to the residue, extracted with ethyl acetate, washed with water, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain a white powder of N-[:2-(
1-naphthylmethyl)-6-phenylhexanoyl, l
-2.92 g of L-histidine hydrazide are obtained.
融 点 ＝ ７４〜７５℃
実施例 １
２−ベンジル−３−フェニルプロピオン酸２４０ｍｇト
１．１°−カルボニルジイミダゾール１７０ ｍｇを乾
燥塩化メチレン１０ｍ１に加え３０分攪拌する。この溶
液をし−ヒスチジルーし−ロイシナールセミカルバゾン
２ｐ−トルエンスルホン酸塩６５０ ｍｇおよびＮ−メ
チルモルホリン２００ ｍｇの乾Ｇ−Ｎ、Ｎ−ジメチル
ホルムアミド１０ ｍｌの溶液に加え室温で一夜攪拌す
る。反応液を減圧下に濃縮し、残留物に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、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
をシリカゲルフラッシニ力ラムクロマトグラフィー（溶
出溶媒：塩化メチレン／メタノール＝ １０／１）
で精製し、Ｎ−（２−ベンジル−３−フェニルプロピオ
ニル）−Ｌ−ヒスチジル−し−ロイシナールセミカルバ
ゾンの白色粉末１６２ ｍｇを得る。Melting point = 74-75°C Example 1 240 mg of 2-benzyl-3-phenylpropionic acid and 170 mg of 1.1°-carbonyldiimidazole were added to 10 ml of dry methylene chloride and stirred for 30 minutes. This solution was added to a solution of 650 mg of histidyl-leucinal semicarbazone 2p-toluenesulfonate and 200 mg of N-methylmorpholine in 10 ml of dry G-N, N-dimethylformamide and stirred overnight at room temperature. The reaction solution was concentrated under reduced pressure, 5% aqueous sodium hydrogen carbonate solution was added to the residue, extracted with ethyl acetate, 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: methylene chloride/methanol = 10/1).
to obtain 162 mg of white powder of N-(2-benzyl-3-phenylpropionyl)-L-histidyl-dis-leucinal semicarbazone.
融点＝１１１〜１１４ ℃
Ｒｆ値： ０．５４
Ｍ５ ： Ｍ）Ｉ” 、 ５３２
上記セミカルバゾン１６０ ｍｇをメタノール５ ｍｌ
に溶かし、水冷下にアルゴン気流中で、１規定塩酸０．
５ｍｌ、 ３７％ホルマリン０．５ｍｌを加え室温で
１時間攪拌する。反応後、反応液に５％炭酸水素ナトリ
ウム水溶液を加えて中和し、酢酸エチルで抽出し、水洗
、乾燥後、減圧下に溶媒を留去する。残留物をセファデ
ックスＬｌ１２０カラムクロマトグラフィー（溶出溶媒
：メタノール）で精製し、白色粉末のＮ−（２−ベンジ
ル−３−フェニルプロピオニル）−Ｌ−ヒスチジル−し
−ロイシナール１００ｍｇヲ得る。Melting point = 111-114 °C Rf value: 0.54 M5: M)I”, 532 160 mg of the above semicarbazone was added to 5 ml of methanol.
of 1N hydrochloric acid in an argon stream while cooling with water.
Add 5 ml and 0.5 ml of 37% formalin, and stir at room temperature for 1 hour. After the reaction, the reaction solution is neutralized by adding 5% aqueous sodium hydrogen carbonate solution, extracted with ethyl acetate, washed with water, dried, and then the solvent is distilled off under reduced pressure. The residue was purified by Sephadex L1120 column chromatography (elution solvent: methanol) to obtain 100 mg of N-(2-benzyl-3-phenylpropionyl)-L-histidyl-leucinal as a white powder.
融点：１０３〜１０５ ℃
Ｒｆ値： ０．６５
Ｍ５ ： Ｍｌ” 、 ４７５
実施例 ２
Ｎ−（２−（１−ナフチルメチル）−６−フェニルヘキ
サノイル） −Ｌ−ヒスチジンヒドラジド２．９０ｇを
乾燥Ｎ、Ｎ−ジメチルホルムアミド７０ｍ１に懸濁し、
−２０℃で５．１規定塩化水素／Ｎ、Ｎ−ジメチルホル
ムアミド３．６５ｍ１を加え溶解し、ついで亜硝酸イソ
アミルＬ３３ｍｌを加え２０分間攪拌する。ヒドラジド
の消失したことを確認したのち反応液を一３０℃まで冷
却してトリエチルアミン２．７３ｍ１を加えＮ−Ｃ２−
（１−ナフチルメチル）−６−フェニルヘキサノイル〕
−し一ヒスチジンアジド溶液を調整する。一方、Ｌ−ロ
イシナールセミカルバゾン酢酸塩１．４０ ｇ、 ト
リエチルアミン１．８０ｍ１、乾燥Ｎ、 Ｎ−ジメチル
ホルムアミド５０ ｍｌの混液に水冷下、先のアジド溶
液を滴下し１４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、ついで水で洗ったのち、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
リカゲルフラッシュカラムクロマトグラフィー（溶出溶
媒：クロロホルム／メタノール＝２０／１） で精製し
、白色粉末のＮ−［：２−（１−ナフチルメチル）−６
−フェニルヘキサノイル］−Ｌ−ヒスチジル−し−ロイ
シナールセミカルバゾン１．８３ｇを得る。Melting point: 103-105°C Rf value: 0.65 M5: Ml”, 475 Example 2 2.90 g of N-(2-(1-naphthylmethyl)-6-phenylhexanoyl)-L-histidine hydrazide was dried with N , suspended in 70 ml of N-dimethylformamide,
Add and dissolve 3.65 ml of 5.1N hydrogen chloride/N,N-dimethylformamide at -20°C, then add 33 ml of isoamyl nitrite L and stir for 20 minutes. After confirming that hydrazide had disappeared, the reaction solution was cooled to -30°C, 2.73 ml of triethylamine was added, and N-C2-
(1-naphthylmethyl)-6-phenylhexanoyl]
- Prepare a histidine azide solution. On the other hand, the above azide solution was added dropwise to a mixed solution of 1.40 g of L-leucinal semicarbazone acetate, 1.80 ml of triethylamine, and 50 ml of dry N,N-dimethylformamide under water cooling, and the mixture was stirred for 14 hours. The solvent was distilled off under reduced pressure,
A 5% aqueous sodium bicarbonate solution was added to the residue, extracted with ethyl acetate, washed with water, 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 = 20/1) to obtain a white powder of N-[:2-(1-naphthylmethyl)-6].
1.83 g of -phenylhexanoyl]-L-histidyl-d-leucinal semicarbazone are obtained.
融点＝１０８〜１１４ ℃
Ｒｆ値： ０．５１
Ｎ−［２−（１−ナフチルメチル）−６−フェニルヘキ
サノイル〕−し−ヒスチジル−し−ロイシナールセミカ
ルバゾン１．８２ｇをメタノール８０ ｍｌに溶解し、
これに水冷下、アルゴン気流中で１規定塩酸２９ｍ１゜
３７％ホルマリン７．６ｍｌを加えたのち、室温で１．
５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
、白色粉末のＮ−Ｃ２−（１−ナフチルメチル）−６−
フェニルヘキサノイル］−Ｌ−ヒスチジ°ルーＬ−ロイ
シナール１．５５ｇを得る。Melting point = 108-114 °C Rf value: 0.51 N-[2-(1-naphthylmethyl)-6-phenylhexanoyl]-histidyl-leucinal semicarbazone (1.82 g) in 80 ml of methanol dissolve,
To this was added 29 ml of 1N hydrochloric acid and 7.6 ml of 37% formalin in an argon stream under water cooling, and 1.
Stir for 5 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 to obtain a white powder of N-C2-(1-naphthylmethyl)-6-.
1.55 g of L-phenylhexanoyl-L-histidine-L-leucinal are obtained.
融点：８７〜９２℃
Ｒｆ値： ０．５９
Ｍ５ ： ＭＨ” 、 ５６７
実施例 ３
実施例２と同様の方法によって以下の化合物を合成した
。Melting point: 87-92°C Rf value: 0.59 M5: MH'', 567 Example 3 The following compound was synthesized by the same method as Example 2.
白色粉末
融点二８８〜９２℃
Ｒｆ値： ０．５５
Ｍ５ ： ＭＨ” 、 ５０３
白色粉末
融点＝８２〜８８℃
Ｒｆ値： ０．５５
Ｍ５ ： ＭＨ” 、 ５６７
白色粉末
融点：８６〜９２℃
Ｒｆ値： ０．５９
Ｍ５ ： ＭＨ” 、 ５９５
白色粉末
融点ニア４〜７８℃
Ｒｆ 値 二 〇、６７
Ｍ５ ： Ｍｌｌ” 、 ５３１
白色粉末
融点＝８８〜９２℃
Ｒｆ値： ０．５６
Ｍ５ ： ＭＨ” 、 ５０３実施例 ４
（＋）−２−（１−ナフチルメチル）−６−フェニルヘ
キサン酸２０９ ｍｇと Ｌ−ヒスチジル−し−ロイシ
ナールセミカルバゾン・２ｐ’−）レニンスルホン酸塩
４１１ ｍｇをＮ、Ｎ−ジメチルホルムアミド３ ｍｌ
に溶かしたのち、水冷攪拌下にジフェニルリン酸アジド
０．１６３ ｍｌ、続いてトリエチルアミン０．２９
ｍｌ を加え、水冷下で一夜攪拌する。反応溶液に５％
炭酸水素ナト’Ｊウム水溶液を加え、酢酸エチルで抽出
し、水洗後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ッシニ力ラムク
ロマトグラフィ−（溶出溶媒：クロロホルム／メタノー
ル＝１５／１）で精製し、白色粉末のＮ−（（＋）−２
−（１−ナフチルメチル）−４−フェニルヘキサノイル
） −Ｌ−ヒスチジル−し−ロイシナールセミカルバゾ
ン２２２ ｍｇを得る。White powder melting point: 288-92℃ Rf value: 0.55 M5: MH'', 503 White powder melting point: 82-88℃ Rf value: 0.55 M5: MH'', 567 White powder melting point: 86-92℃ Rf value : 0.59 M5: MH", 595 White powder melting point near 4-78°C Rf value 20, 67 M5: Mll", 531 White powder melting point = 88-92°C Rf value: 0.56 M5: MH", 503 Example 4 209 mg of (+)-2-(1-naphthylmethyl)-6-phenylhexanoic acid and 411 mg of L-histidyl-cy-leucinal semicarbazone 2p'-)reninsulfonate were mixed with N,N -3 ml of dimethylformamide
After dissolving in water, add 0.163 ml of diphenylphosphoric acid azide, followed by 0.29 ml of triethylamine while cooling with water and stirring.
ml and stirred overnight under water cooling. 5% in reaction solution
Add an aqueous solution of sodium bicarbonate, extract with ethyl acetate, wash with water, and dry 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
222 mg of -(1-naphthylmethyl)-4-phenylhexanoyl)-L-histidyl-d-leucinal semicarbazone is obtained.
融点＝１０５〜１０９ ℃
Ｒｆ値： ０．５１
上記のセミカルバゾン１６０ ｍｇをメタノール５ ｍ
ｌに溶かし、これにアルゴン気流下で、氷冷しながら２
規定塩酸１．４ｍｌと３７％ホルマリン０．７ｍｌを加
えたのち、室温で１時間攪拌する。反応液を５％炭酸水
素す） ＩＪウム水溶液で中和した後、酢酸エチイレで
抽出し、減圧下に溶媒を留去し、白色粉末のＮ−Ｃ（＋
） −２−（１−ナフチルメチル）−６−フェニルヘキ
サノイル〕−Ｌ−ヒスチジル−し−ロイシナール１４５
ｍｇを得る。Melting point = 105-109 °C Rf value: 0.51 160 mg of the above semicarbazone was added to 5 m of methanol.
Dissolve the solution in 1 liter of water and add to it under an argon stream while cooling on ice.
After adding 1.4 ml of normal hydrochloric acid and 0.7 ml of 37% formalin, the mixture was stirred at room temperature for 1 hour. The reaction solution was neutralized with an aqueous solution of 5% hydrogen carbonate, extracted with ethyl acetate, and the solvent was distilled off under reduced pressure to give a white powder of N-C(+
) -2-(1-naphthylmethyl)-6-phenylhexanoyl]-L-histidyl-shi-leucinal 145
Get mg.
融点＝８７〜９１℃ Ｒｆ値： ０．５９ Ｍ５ ： ＭＨ” 、 ５６７ 実施例 ５ 実施例４と同様の方法によって次の化合物を合成した。Melting point = 87-91℃ Rf value: 0.59 M5: MH", 567 Example 5 The following compound was synthesized by the same method as in Example 4.
白色粉末
融点＝８６〜９２℃
Ｒｆ値： ０．５９
Ｍ５ ： Ｍｌｌ” 、 ５６７実施例 ６
ヒトレニンー羊しニン基質系でのレニン活性１ 害作用
１２５ ｍＭのピロフォスフェート緩衝液（ｐｙｒｏｐ
ｈｏｓ−ｐｈａｔｅ ｂｕｆｆｅｒ）（ｐＨ７，４）
２００ μｌ とアンジオテンシン変換酵素阻害剤と
して２０ミリモルのし一フェニルアラニルーし−アラニ
ルーし一プロリンの水溶液２５μｌ 、 ４４００ ｎ
ｇ アンジオテンシンＩ当量／ｍｌの部分精製羊レニン
基質５０μ１１脱イオン水１５０ μｌと本発明の化合
物のジメチルスルホキシド溶液５０μＩまたはコントロ
ール群としてジメチルスルホキシド５０μｍの溶液中に
２０〜３０ ｎｇアンジオテンシン■／時間の精製ヒト
レニン２５μｌを加、ｔ、３７℃の水浴中で１５分間イ
ンキニベート（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２００Ａ１１ を分取し、レニン添加によって
生成されたアンジオテンシンＩの量をラジオイムノアッ
セイ（ｒａｄ ｉｏ ｉｍｍｕｎｏ−ａｓｓａｙ）法で
定量し、下式により阻害活性を求めた。White powder melting point = 86-92°C Rf value: 0.59
hos-phate buffer) (pH 7,4)
200 μl and 25 μl of an aqueous solution of 20 mmol of phenylalanyl-alanyl-proline as an angiotensin-converting enzyme inhibitor, 4400 n
g Angiotensin I equivalents/ml of partially purified sheep renin substrate 50 μl 150 μl of deionized water and 50 μl of a compound of the invention in dimethyl sulfoxide or as a control group 20-30 ng angiotensin/h purified human renin in a solution of 50 μm of dimethyl sulfoxide. After adding 25 μl and incubating for 15 minutes in a 37° C. water bath, the reaction solution was placed in a 100° C. water bath for 5 minutes to stop the reaction. After cooling, 200A11 was collected, and the amount of angiotensin I produced by the addition of renin was determined by radioimmunoassay, and the inhibitory activity was determined using the following formula.
阻害活性（％）＝
コントロール 本発明の化合物
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（ＩＣ５゜値）を求め、その結果を以下に示す。Inhibitory activity (%) = Control The 50% inhibitory activity molar concentration (IC5° value) was determined from the inhibitory activity of the compound of the present invention determined by the above formula, and the results are shown below.
化合物名 ＩＣ５ｏ値（モル）化合物名
ＩＣ５ｏ値（モル）〔発明の効果〕
本発明の一般式（Ｉ）で表されるジペプチド誘導体およ
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
−羊しニン基貿系でのレニン活性阻害試験において５０
％阻害活性モル濃度（ＩＣｓｏ）が３．５Ｘ１０−’〜
８．８Ｘ１０〜８という強いレニン活性阻害作用を示す
。また、本発明の一般式（Ｉ）で表されるジペプチド誘
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、たと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５ＨＲ−３
Ｐラツトのもつ高血圧症状を低減させることができる。Compound name IC5o value (mol) Compound name
IC5o value (mol) [Effect of the invention] The dipeptide derivatives represented by the general formula (I) of the present invention and their pharmacologically acceptable acid addition salts inhibit renin activity in the human renin-sheep nin base trade system. 50 in the exam
% inhibitory activity molar concentration (ICso) is 3.5X10-' ~
It shows a strong renin activity inhibition effect of 8.8×10-8. Furthermore, the dipeptide derivatives represented by the general formula (I) of the present invention and their pharmacologically acceptable acid addition salts include:
It is stable against proteolytic enzymes such as chymotrypsin and pepsin, and 5HR-3
Hypertensive symptoms in P rats can be reduced.
したがって、本発明の一般式（Ｉ）で表されるジペプチ
ド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。Therefore, the dipeptide derivatives represented by general formula (I) of the present invention and their pharmacologically acceptable acid addition salts are useful as orally administrable antihypertensive agents.
特 許 出 願 人 キッセイ薬品工業株式会社Patent applicant Kissei Pharmaceutical Co., Ltd.
Claims (1)
は１〜６の整数であり、ｎは１〜４の整数であり、Ｈｉ
ｓはＬ−ヒスチジル基であり、ＣはＬ−配置を示す）で
表されるジペプチド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 ▲数式、化学式、表等があります▼ （式中のｍ、ｎ、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１項記載のジペプチド
誘導体およびそれらの薬理学的に許容できる酸付加塩。 ３）一般式 ▲数式、化学式、表等があります▼ （式中のｍ、ｎ、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１項記載のジペプチド
誘導体およびそれらの薬理学的に許容できる酸付加塩。 ４）式 ▲数式、化学式、表等があります▼ （式中のｍ、ｎ、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項記載のジペプチド
誘導体およびそれらの薬理学的に許容できる酸付加塩。 ５）式 ▲数式、化学式、表等があります▼ （式中の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項記載のジペプチド誘導体お
よびその薬理学的に許容できる酸付加塩。 ６）式 ▲数式、化学式、表等があります▼ （式中の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項記載のジペプチド誘導体お
よびその薬理学的に許容できる酸付加塩。 ７）式 ▲数式、化学式、表等があります▼ （式中の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項記載のジペプチド誘導体お
よびその薬理学的に許容できる酸付加塩。 ８）式 ▲数式、化学式、表等があります▼ （式中の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項記載のジペプチド誘導体お
よびその薬理学的に許容できる酸付加塩。 ９）式 ▲数式、化学式、表等があります▼ （式中の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項記載のジペプチド誘導体お
よびその薬理学的に許容できる酸付加塩。 １０）式 ▲数式、化学式、表等があります▼ （式中の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項記載のジペプチド誘導体お
よびその薬理学的に許容できる酸付加塩。 １１）式 ▲数式、化学式、表等があります▼ （式中の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項記載のジペプチド誘導体お
よびその薬理学的に許容できる酸付加塩。[Claims] 1) General formula ▲ Numerical formula, chemical formula, table, etc. ▼ (Ar in the formula is a phenyl group or naphthyl group, m
is an integer from 1 to 6, n is an integer from 1 to 4, and Hi
s is an L-histidyl group and C indicates an L-configuration) and pharmacologically acceptable acid addition salts thereof. 2) Dipeptide derivatives according to claim 1 represented by the general formula ▲ There are mathematical formulas, chemical formulas, tables, etc. Pharmacologically acceptable acid addition salts of. 3) Dipeptide derivatives according to claim 1 represented by the general formula ▲ There are mathematical formulas, chemical formulas, tables, etc. Pharmacologically acceptable acid addition salts of. 4) Dipeptide derivatives according to claim 3 represented by the formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (m, n, His and C in the formula have the same meanings as above) and their Pharmacologically acceptable acid addition salts. 5) The dipeptide derivative according to claim 2 represented by the formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (His and C in the formula have the same meanings as above) and their pharmacologically acceptable Acid addition salts that can be formed. 6) The dipeptide derivative according to claim 2 represented by the formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (His and C in the formula have the same meanings as above) and their pharmacologically acceptable Acid addition salts that can be formed. 7) The dipeptide derivative according to claim 2, represented by the formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (His and C in the formula have the same meanings as above) and their pharmacologically acceptable Acid addition salts that can be formed. 8) The dipeptide derivative according to claim 2 represented by the formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (His and C in the formula have the same meanings as above) and their pharmacologically acceptable Acid addition salts that can be formed. 9) The dipeptide derivative according to claim 3 represented by the formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (His and C in the formula have the same meanings as above) and their pharmacologically acceptable Acid addition salts that can be formed. 10) The dipeptide derivative according to claim 4 represented by the formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (His and C in the formula have the same meanings as above) and their pharmacologically acceptable Acid addition salts that can be formed. 11) The dipeptide derivative according to claim 4 represented by the formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (His and C in the formula have the same meanings as above) and their pharmacologically acceptable Acid addition salts that can be formed.
Priority Applications (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP59221853A JPS61100595A (en) | 1984-10-22 | 1984-10-22 | Novel dipeptide derivative |
| EP85307555A EP0181110A3 (en) | 1984-10-22 | 1985-10-18 | Histidine derivatives as renin inhibitors |
| US06/789,597 US4863904A (en) | 1984-10-22 | 1985-10-21 | Dipeptides as renin inhibitors |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP59221853A JPS61100595A (en) | 1984-10-22 | 1984-10-22 | Novel dipeptide derivative |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| JPS61100595A true JPS61100595A (en) | 1986-05-19 |
Family
ID=16773210
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP59221853A Pending JPS61100595A (en) | 1984-10-22 | 1984-10-22 | Novel dipeptide derivative |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPS61100595A (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4870183A (en) * | 1986-07-11 | 1989-09-26 | Kissei Pharmaceutical Co., Ltd. | Novel amino acid derivatives |
-
1984
- 1984-10-22 JP JP59221853A patent/JPS61100595A/en active Pending
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4870183A (en) * | 1986-07-11 | 1989-09-26 | Kissei Pharmaceutical Co., Ltd. | Novel amino acid derivatives |
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