JPH0569098B2 - - Google Patents
Info
- Publication number
- JPH0569098B2 JPH0569098B2 JP8613908A JP1390886A JPH0569098B2 JP H0569098 B2 JPH0569098 B2 JP H0569098B2 JP 8613908 A JP8613908 A JP 8613908A JP 1390886 A JP1390886 A JP 1390886A JP H0569098 B2 JPH0569098 B2 JP H0569098B2
- Authority
- JP
- Japan
- Prior art keywords
- group
- formula
- amino
- alkyl
- heterocyclyl
- 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
- -1 ethylene, trimethylene Chemical group 0.000 claims description 61
- 125000000217 alkyl group Chemical group 0.000 claims description 49
- 125000003277 amino group Chemical group 0.000 claims description 40
- 125000001424 substituent group Chemical group 0.000 claims description 30
- 125000003545 alkoxy group Chemical group 0.000 claims description 26
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 25
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 24
- 229910052757 nitrogen Inorganic materials 0.000 claims description 23
- 125000000623 heterocyclic group Chemical group 0.000 claims description 21
- 125000005843 halogen group Chemical group 0.000 claims description 15
- 125000001931 aliphatic group Chemical group 0.000 claims description 13
- 125000003118 aryl group Chemical group 0.000 claims description 13
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 13
- 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 claims description 11
- 125000004442 acylamino group Chemical group 0.000 claims description 8
- 125000004076 pyridyl group Chemical group 0.000 claims description 8
- 125000006729 (C2-C5) alkenyl group Chemical group 0.000 claims description 7
- 125000002947 alkylene group Chemical group 0.000 claims description 7
- 125000004104 aryloxy group Chemical group 0.000 claims description 7
- 125000006310 cycloalkyl amino group Chemical group 0.000 claims description 7
- 150000003839 salts Chemical class 0.000 claims description 7
- 125000002252 acyl group Chemical group 0.000 claims description 6
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 6
- 125000003282 alkyl amino group Chemical group 0.000 claims description 5
- 125000004430 oxygen atom Chemical group O* 0.000 claims description 5
- 125000000008 (C1-C10) alkyl group Chemical group 0.000 claims description 4
- 125000006730 (C2-C5) alkynyl group Chemical group 0.000 claims description 4
- 108010016626 Dipeptides Proteins 0.000 claims description 4
- 125000005251 aryl acyl group Chemical group 0.000 claims description 4
- 125000001769 aryl amino group Chemical group 0.000 claims description 4
- 229910052736 halogen Inorganic materials 0.000 claims description 4
- 125000001072 heteroaryl group Chemical group 0.000 claims description 4
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 4
- 229910052717 sulfur Inorganic materials 0.000 claims description 4
- 125000000383 tetramethylene group Chemical group [H]C([H])([*:1])C([H])([H])C([H])([H])C([H])([H])[*:2] 0.000 claims description 4
- 125000003342 alkenyl group Chemical group 0.000 claims description 3
- 125000005110 aryl thio group Chemical group 0.000 claims description 3
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 3
- 125000004434 sulfur atom Chemical group 0.000 claims description 3
- 125000000027 (C1-C10) alkoxy group Chemical group 0.000 claims description 2
- 125000002102 aryl alkyloxo group Chemical group 0.000 claims description 2
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 2
- 125000004423 acyloxy group Chemical group 0.000 claims 1
- 150000001875 compounds Chemical class 0.000 description 40
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 30
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 24
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 18
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 15
- 238000002844 melting Methods 0.000 description 13
- 230000008018 melting Effects 0.000 description 13
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 11
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 10
- 239000000203 mixture Substances 0.000 description 10
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 9
- 239000013078 crystal Substances 0.000 description 9
- 125000001501 propionyl group Chemical group O=C([*])C([H])([H])C([H])([H])[H] 0.000 description 9
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 6
- 230000002401 inhibitory effect Effects 0.000 description 6
- 239000000843 powder Substances 0.000 description 6
- 239000000243 solution Substances 0.000 description 6
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 5
- ZWWWLCMDTZFSOO-UHFFFAOYSA-N diethoxyphosphorylformonitrile Chemical compound CCOP(=O)(C#N)OCC ZWWWLCMDTZFSOO-UHFFFAOYSA-N 0.000 description 5
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 5
- 239000002904 solvent Substances 0.000 description 5
- 238000003756 stirring Methods 0.000 description 5
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 4
- 108090000783 Renin Proteins 0.000 description 4
- 102100028255 Renin Human genes 0.000 description 4
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 4
- 238000001816 cooling Methods 0.000 description 4
- 125000004093 cyano group Chemical group *C#N 0.000 description 4
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 4
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 4
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 3
- 101000579218 Homo sapiens Renin Proteins 0.000 description 3
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 3
- 150000002367 halogens Chemical group 0.000 description 3
- 238000000034 method Methods 0.000 description 3
- RWIVICVCHVMHMU-UHFFFAOYSA-N n-aminoethylmorpholine Chemical compound NCCN1CCOCC1 RWIVICVCHVMHMU-UHFFFAOYSA-N 0.000 description 3
- 239000012044 organic layer Substances 0.000 description 3
- 108090000765 processed proteins & peptides Proteins 0.000 description 3
- 239000000741 silica gel Substances 0.000 description 3
- 229910002027 silica gel Inorganic materials 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- 238000004809 thin layer chromatography Methods 0.000 description 3
- 125000004974 2-butenyl group Chemical group C(C=CC)* 0.000 description 2
- 125000004975 3-butenyl group Chemical group C(CC=C)* 0.000 description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 2
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 2
- 125000004453 alkoxycarbonyl group Chemical group 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 125000003710 aryl alkyl group Chemical group 0.000 description 2
- 125000000043 benzamido group Chemical group [H]N([*])C(=O)C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 2
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 2
- 229910052799 carbon Inorganic materials 0.000 description 2
- 238000006243 chemical reaction Methods 0.000 description 2
- 239000000460 chlorine Substances 0.000 description 2
- 125000000753 cycloalkyl group Chemical group 0.000 description 2
- 238000000921 elemental analysis Methods 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- MNWFXJYAOYHMED-UHFFFAOYSA-N heptanoic acid Chemical compound CCCCCCC(O)=O MNWFXJYAOYHMED-UHFFFAOYSA-N 0.000 description 2
- 125000005253 heteroarylacyl group Chemical group 0.000 description 2
- 239000010410 layer Substances 0.000 description 2
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 2
- 235000019341 magnesium sulphate Nutrition 0.000 description 2
- 239000012299 nitrogen atmosphere Substances 0.000 description 2
- 229910052760 oxygen Inorganic materials 0.000 description 2
- 239000001301 oxygen Substances 0.000 description 2
- 238000010898 silica gel chromatography Methods 0.000 description 2
- 235000017557 sodium bicarbonate Nutrition 0.000 description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 2
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 2
- NWZSZGALRFJKBT-KNIFDHDWSA-N (2s)-2,6-diaminohexanoic acid;(2s)-2-hydroxybutanedioic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O.NCCCC[C@H](N)C(O)=O NWZSZGALRFJKBT-KNIFDHDWSA-N 0.000 description 1
- ADFXKUOMJKEIND-UHFFFAOYSA-N 1,3-dicyclohexylurea Chemical compound C1CCCCC1NC(=O)NC1CCCCC1 ADFXKUOMJKEIND-UHFFFAOYSA-N 0.000 description 1
- WORJRXHJTUTINR-UHFFFAOYSA-N 1,4-dioxane;hydron;chloride Chemical compound Cl.C1COCCO1 WORJRXHJTUTINR-UHFFFAOYSA-N 0.000 description 1
- ASOKPJOREAFHNY-UHFFFAOYSA-N 1-Hydroxybenzotriazole Chemical compound C1=CC=C2N(O)N=NC2=C1 ASOKPJOREAFHNY-UHFFFAOYSA-N 0.000 description 1
- 125000001637 1-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C(*)=C([H])C([H])=C([H])C2=C1[H] 0.000 description 1
- YBYIRNPNPLQARY-UHFFFAOYSA-N 1H-indene Natural products C1=CC=C2CC=CC2=C1 YBYIRNPNPLQARY-UHFFFAOYSA-N 0.000 description 1
- YQTCQNIPQMJNTI-UHFFFAOYSA-N 2,2-dimethylpropan-1-one Chemical group CC(C)(C)[C]=O YQTCQNIPQMJNTI-UHFFFAOYSA-N 0.000 description 1
- AMKHAJIFPHJYMH-UHFFFAOYSA-N 2-[(2-methylpropan-2-yl)oxycarbonylamino]pent-4-ynoic acid Chemical compound CC(C)(C)OC(=O)NC(C(O)=O)CC#C AMKHAJIFPHJYMH-UHFFFAOYSA-N 0.000 description 1
- 125000000069 2-butynyl group Chemical group [H]C([H])([H])C#CC([H])([H])* 0.000 description 1
- 125000006029 2-methyl-2-butenyl group Chemical group 0.000 description 1
- 125000006031 2-methyl-3-butenyl group Chemical group 0.000 description 1
- 125000004493 2-methylbut-1-yl group Chemical group CC(C*)CC 0.000 description 1
- 125000000094 2-phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001494 2-propynyl group Chemical group [H]C#CC([H])([H])* 0.000 description 1
- 125000000474 3-butynyl group Chemical group [H]C#CC([H])([H])C([H])([H])* 0.000 description 1
- 125000003542 3-methylbutan-2-yl group Chemical group [H]C([H])([H])C([H])(*)C([H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- RMTCEQSLPGEKAH-UHFFFAOYSA-N 3-naphthalen-1-yl-2-(naphthalen-1-ylmethyl)propanoic acid Chemical compound C1=CC=C2C(CC(CC=3C4=CC=CC=C4C=CC=3)C(=O)O)=CC=CC2=C1 RMTCEQSLPGEKAH-UHFFFAOYSA-N 0.000 description 1
- 108010072661 Angiotensin Amide Proteins 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- XBPCUCUWBYBCDP-UHFFFAOYSA-N Dicyclohexylamine Chemical class C1CCCCC1NC1CCCCC1 XBPCUCUWBYBCDP-UHFFFAOYSA-N 0.000 description 1
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 1
- MYMOFIZGZYHOMD-UHFFFAOYSA-N Dioxygen Chemical compound O=O MYMOFIZGZYHOMD-UHFFFAOYSA-N 0.000 description 1
- VGGSQFUCUMXWEO-UHFFFAOYSA-N Ethene Chemical compound C=C VGGSQFUCUMXWEO-UHFFFAOYSA-N 0.000 description 1
- 239000005977 Ethylene Substances 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
- 206010020772 Hypertension Diseases 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
- 229910019142 PO4 Inorganic materials 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 1
- 125000006323 alkenyl amino group Chemical group 0.000 description 1
- 125000000304 alkynyl group Chemical group 0.000 description 1
- HSFWRNGVRCDJHI-UHFFFAOYSA-N alpha-acetylene Natural products C#C HSFWRNGVRCDJHI-UHFFFAOYSA-N 0.000 description 1
- 125000000732 arylene group Chemical group 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- SRSXLGNVWSONIS-UHFFFAOYSA-M benzenesulfonate Chemical compound [O-]S(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-M 0.000 description 1
- 229940077388 benzenesulfonate Drugs 0.000 description 1
- 125000003785 benzimidazolyl group Chemical group N1=C(NC2=C1C=CC=C2)* 0.000 description 1
- 125000004618 benzofuryl group Chemical group O1C(=CC2=C1C=CC=C2)* 0.000 description 1
- 125000001164 benzothiazolyl group Chemical group S1C(=NC2=C1C=CC=C2)* 0.000 description 1
- 125000004196 benzothienyl group Chemical group S1C(=CC2=C1C=CC=C2)* 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 159000000007 calcium salts Chemical class 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 150000001860 citric acid derivatives Chemical class 0.000 description 1
- 239000012230 colorless oil Substances 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 125000004122 cyclic group Chemical group 0.000 description 1
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000000582 cycloheptyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 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
- 125000000640 cyclooctyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 1
- 239000000032 diagnostic agent Substances 0.000 description 1
- 229940039227 diagnostic agent Drugs 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 125000002534 ethynyl group Chemical group [H]C#C* 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 description 1
- 125000002541 furyl group Chemical group 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine monohydrate Substances O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 description 1
- 150000003840 hydrochlorides Chemical class 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 125000002883 imidazolyl group Chemical group 0.000 description 1
- 125000003454 indenyl group Chemical group C1(C=CC2=CC=CC=C12)* 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
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000005956 isoquinolyl group Chemical group 0.000 description 1
- 159000000003 magnesium salts Chemical class 0.000 description 1
- 150000002688 maleic acid derivatives Chemical class 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-M methanesulfonate group Chemical class CS(=O)(=O)[O-] AFVFQIVMOAPDHO-UHFFFAOYSA-M 0.000 description 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 1
- 235000010755 mineral Nutrition 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 239000012452 mother liquor Substances 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000003136 n-heptyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 description 1
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 125000004923 naphthylmethyl group Chemical group C1(=CC=CC2=CC=CC=C12)C* 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 150000003891 oxalate salts Chemical class 0.000 description 1
- 125000002971 oxazolyl group Chemical group 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 235000021317 phosphate Nutrition 0.000 description 1
- 150000003013 phosphoric acid derivatives Chemical class 0.000 description 1
- 125000004193 piperazinyl group Chemical group 0.000 description 1
- 125000005936 piperidyl group Chemical group 0.000 description 1
- XAEFZNCEHLXOMS-UHFFFAOYSA-M potassium benzoate Chemical compound [K+].[O-]C(=O)C1=CC=CC=C1 XAEFZNCEHLXOMS-UHFFFAOYSA-M 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 125000001844 prenyl group Chemical group [H]C([*])([H])C([H])=C(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 238000012746 preparative thin layer chromatography Methods 0.000 description 1
- 102000004196 processed proteins & peptides Human genes 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 125000005344 pyridylmethyl group Chemical group [H]C1=C([H])C([H])=C([H])C(=N1)C([H])([H])* 0.000 description 1
- 125000005493 quinolyl group Chemical group 0.000 description 1
- 230000036454 renin-angiotensin system Effects 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 125000003548 sec-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 150000003890 succinate salts Chemical class 0.000 description 1
- 150000003871 sulfonates Chemical class 0.000 description 1
- 239000011593 sulfur Substances 0.000 description 1
- 150000003467 sulfuric acid derivatives Chemical class 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- DYHSDKLCOJIUFX-UHFFFAOYSA-N tert-butoxycarbonyl anhydride Chemical compound CC(C)(C)OC(=O)OC(=O)OC(C)(C)C DYHSDKLCOJIUFX-UHFFFAOYSA-N 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000001973 tert-pentyl group Chemical group [H]C([H])([H])C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 238000010998 test method Methods 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 125000001984 thiazolidinyl group Chemical group 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- 125000005301 thienylmethyl group Chemical group [H]C1=C([H])C([H])=C(S1)C([H])([H])* 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-M toluene-4-sulfonate Chemical compound CC1=CC=C(S([O-])(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-M 0.000 description 1
- 125000003258 trimethylene group Chemical group [H]C([H])([*:2])C([H])([H])C([H])([H])[*:1] 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Description
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(Objective) The present invention relates to novel dipeptides having renin inhibitory activity and pharmacologically acceptable salts thereof. As peptide derivatives having a renin inhibitory effect, tetrapeptides, tripeptide derivatives, and the like are conventionally known (Japanese Patent Application Laid-Open No. 151166/1989, etc.). As a result of many years of intensive research into the synthesis of peptide derivatives and their renin inhibitory activity, the inventors of the present application have discovered that dipeptides with novel structures previously unknown have excellent renin inhibitory activity. The present invention was completed by discovering that the compound can be an important intermediate for synthesizing the compound. (Constitution) The dipeptide derivative according to the present invention has the formula ()
It is a compound with
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[Chemical Formula] In the above formula, R 1 and R 2 are the same or different, and are a group of the formula -B-R 6 (wherein B is a single bond or a straight chain which may have a double bond in the chain) or a branched lower alkylene group, R 6 represents an aryl group or a heteroaryl group), a C 1 -C 10 alkyl group or a group of the formula -E-R 7 (in the formula,
E represents a lower alkylene group which may be interrupted by one oxygen atom, R 7 represents a lower alkoxy group,
It represents an aryloxy group, an arylthio group, an aralkyloxy group, or a heterocyclyl group containing a nitrogen atom. ), R 3 is an optionally substituted ethylene, trimethylene or tetramethylene group (the substituent represents lower alkyl, phenyl or hydroxyl group), formula
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R1ãR2ïŒA group having [Formula] (wherein R 9 and R 10 are the same or different and represent a lower alkyl group;
A C3 - C8 cycloalkyl group may also be formed. )
, R 4 represents an isopropyl group, a C 3 -C 8 cycloalkyl group, or a phenyl group, and R 5 represents a hydroxyl group, a C 1 -C 10 alkoxy group, an aryloxy group, an amino group, a mono- or di-( C 1 â
C 10 alkyl) amino group [The alkyl group may have one or two substituents, which may be the same or different and include a hydroxyl group, a lower alkoxy group, a halogen atom, an optionally substituted phenyl group , a pyridyl group, a C3 - C8 cycloalkyl group, a di-(lower alkyl)amino group, a di-(hydroxy-lower alkyl)amino group, or a heterocyclyl group containing a nitrogen atom. ], mono- or di-( C3 - C4 alkenyl)amino group, C3 - C8 cycloalkylamino group,
arylamino group, heterocyclylamino group containing a nitrogen atom (amino and heterocyclyl in the group are bonded with N-C), heterocyclyl group containing a nitrogen atom (the heterocyclyl group is a carbonyl group at the nitrogen atom contained in the group) or a group having the formula -NHR 11 (wherein R 11 is an amino group,
An optionally substituted C1 - C10 aliphatic acylamino group (the substituents include a halogen atom, a lower alkoxy group, an aryloxy group, an arylacyl group,
Indicates an aryl group or a C3 - C8 cycloalkyl group. ), an arylacylamino group, a cinnamoylamino group, a heteroarylacylamino group, an optionally substituted lower alkylamino group (the substituents include a hydroxyl group, a lower alkoxy group, a C 1 -C 5 aliphatic acyloxy group, represents an arylacyloxy group or an aryl group), an arylamino group or a heterocyclyl group containing a nitrogen atom (the heterocyclyl group is bonded to an -NH- group through a nitrogen atom), R is a hydrogen atom, and C 1 -C5 represents an aliphatic acyl group or an arylacyl group, and A represents a single bond, an oxygen atom, or a sulfur atom. The groups defined in compound () have the following meanings. A straight-chain or branched lower alkylene group which may have a double bond in the chain refers to a C 1 -C 4 alkylene group, such as methylene, ethylene, methylmethylene, trimethylene, propylene, tetra Methylene, n-propylmethylene, 2-ethylethylene, 3-methyltrimethylene, 2-methyltrimethylene, arylene (-CH 2 CH=CH-), 2
-butenylene ( -CH2CH =CH- CH2- ) or 3
-Butenylene (-CH 2 CH 2 CH=CH-) can be mentioned. An aryl group or an aryl moiety such as an aryloxy group or an arylthio group represents optionally substituted phenyl, indenyl or naphthyl, and examples of the substituent include a lower alkyl group,
Halogen atoms such as fluorine, chlorine, bromine, and iodine,
It represents a lower alkoxy group, a lower alkoxycarbonyl group, a trifluoromethyl group, an amino group, a cyano group, or a nitro group. In addition, examples of the lower alkyl group or the lower alkyl moiety of the lower alkoxy group include methyl, ethyl, n-propyl,
Examples include isopropyl, n-butyl, isobutyl, s-butyl and t-butyl (the same applies hereinafter). The heteroaryl group may be fused with a phenyl ring and represents a 5- to 6-membered cyclic aromatic group containing oxygen, sulfur, or/and nitrogen atoms, such as furyl, thienyl, oxazolyl, thiazolyl, imidazolyl, pyridyl, Examples include benzofuryl, benzothiophenyl, isodryl, benzthiazolyl, benzimidazolyl, quinolyl, and isoquinolyl, and the ring may have a substituent, such as a lower alkyl group, a halogen atom, or Examples include lower alkoxy groups. The C 1 -C 10 alkyl group is, for example, the above-mentioned C 1 -
In addition to C4 alkyl groups, n-pentyl, 2-ethylpropyl, 1,2-dimethylpropyl, 1-methylbutyl, 2-methylbutyl, isopentyl,
s-pentyl, t-pentyl, n-hexyl, 1
-Methylpentyl, s-hexyl, 1,3-dimethylbutyl, 3,3-dimethylbutyl, n-heptyl, 1-methylhexyl, n-octyl, 1,
Examples include 5-dimethylhexyl, n-nonyl, and n-decyl. A lower alkylene group optionally interrupted by one oxygen atom represents a C 1 -C 4 alkylene group,
For example, C 1 which does not have a double bond in the above B
-C4 alkylene, formula -CH2 -O- CH2 -,-
CH 2 CH 2 âOâCH 2 â, âCH 2 âOâCH 2 CH 2 â,
-CH2CH2 - O- CH2CH2- group can be mentioned. The aralkyl group is, for example, a benzyl or phenethyl group, and the phenyl moiety may have a substituent, and the substituent is the same as the substituent for the above-mentioned aryl group. A heterocyclyl group containing a nitrogen atom refers to a 5- to 6-membered cyclic group containing one or two nitrogen atoms and optionally containing an oxygen or sulfur atom, such as piperidyl, piperidino, pyrrolidyl, pyrrolidino, morpholinyl, morpholino, oxazolidinyl. , oxazolidino, thiazolidinyl, thiazolidino,
Examples include imidazolidino, piperazinyl, and piperazino, and the ring may have a substituent, such as lower alkyl,
Hydroxy lower alkyl group, lower alkoxy, optionally substituted phenyl (the substituent is the same as the substituent for the above aryl group), heteroaryl group, aralkyl, carboxy, lower alkoxycarbonyl or cinnamoyl (the phenyl The substituent on the ring is the same as the substituent of the aryl group described above. The C5 - C18 alkyl group in R8 is, for example, n-dodecyl, n-hexadecyl, n-octadecyl, in addition to the C5 - C10 alkyl group among the C1 - C10 alkyl groups mentioned above. I can give you, but
Preferably it is a C5 - C10 alkyl group. Optionally substituted with halogen in R 8
Examples of C 2 -C 5 alkenyl groups include vinyl,
Allyl, 2-propenyl, metaallyl, 2-butenyl, 3-butenyl, 2-methyl-2-butenyl, 3-methyl-2-butenyl, 2-methyl-3
-butenyl, 4-pentenyl, 2-chloroallyl, and 2,2-dichlorovinyl. Examples of the C2 - C5 alkynyl group include ethynyl, propargyl, 2-butynyl, 3-butynyl, and 4-pentynyl. C3 - C8 cycloalkyl groups are, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl groups. Examples of the alkenyl moiety of the C3 - C4 alkenylamino group in R5 include allyl, metaallyl, 2-butenyl, and 3-butenyl. Examples of the C 1 -C 10 aliphatic acyl group include formyl, acetyl, propionyl, n-butyryl, isobutyryl, n-valeryl, isovaleryl, pivaloyl, n-hexanoyl, n-heptanoyl, n-octanoyl, n-nonanoyl. I can give it to you. Furthermore, the C 1 -C 5 aliphatic acyl group refers to a C 1 -C 5 group among the above groups. The substituents on the aryl moiety of the arylacylamino group or cinnamoylamino group in R 11 may be the same or different, and 1 to 3 substituents may be present, but preferably a lower alkyl group, a halogen atom, or a lower alkoxy group. , trifluoromethyl group, C 1 â
Mention may be made of a C5 aliphatic acyl group, a nitro group or a cyano group. The heteroarylacyl moiety of the heteroarylacyl amino group of R 11 is preferably a halogen atom,
2- optionally substituted with methyl or methoxy
Alternatively, 3-furoylcarbonyl, 2-thienylcarbonyl, 2-, 3- or 4-pyridinecarbonyl or indolyl-2-carbonyl can be mentioned. Moreover, in the compound (), R 1 , R 2 , R 3 and
Suitable groups for R 5 are, for example, as follows. R1 , R2 :
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ãåŒã CH3âãCH3CH2âã[Formula] CH 3 â, CH 3 CH 2 â,
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CH3OCH2CH2âãCH3CH2OCH2CH2âãCH3O
ïŒâCH2ïŒâ2OïŒâCH2ïŒâ2ãCH3CH2âïŒâCH2ïŒâ2O
ïŒCH2ïŒâ2ã[Formula] CH 3 OCH 2 CH 2 â, CH 3 CH 2 OCH 2 CH 2 â, CH 3 O
(-CH 2 )- 2 O(-CH 2 )- 2 , CH 3 CH 2 -O(-CH 2 )- 2 O
( CH2 ) â2 ,
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ãåã R3ïŒ âCH2CH2âã[C] R 3 : âCH 2 CH 2 â,
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ãåŒã ïŒâCH2ïŒâ3ã[Formula] (-CH 2 )- 3 ,
ãåŒã ïŒâCH2ïŒâ4ã[Formula] (-CH 2 )- 4 ,
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ãåŒã R8ïŒ[Formula] R8 :
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ãåã ïœâC5H11âããCã nâC 5 H 11 â,
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ãåŒã ïœâC6H13âã[Formula] nâC 6 H 13 â,
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ãåŒãïœâC7H15âã[Formula] n-C 7 H 15 â,
ãåŒã ïœâC8H17âã[Formula] nâC 8 H 17 â,
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âã
ïœâC10H21âãïœâC12H25âãïœâC16H33âã
ïœâC18H37âãâCHïŒCH2ã
[Formula]n- C9H19- , n - C10H21- , n- C12H25- , n- C16H33- , n- C18H37- , -CH= CH2 ,
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ãåŒãââ¡CHãâCH2ââ¡ CHã âCH2ââ¡âCH3 ïŒR3ïŒïŒ[Formula] âCâ¡CH, âCH 2 ââ¡ CH, âCH 2 ââ¡âCH 3 (R 3 :)
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ãåŒã R5ïŒ âOCH3ãâOC2H5ã[Formula] R 5 : âOCH 3 , âOC 2 H 5 ,
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âNH2ãâNHCH3ãâNHC2H5ãâNHâïœâ
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âNHâïœâC3H7ãâNHâïœâC4H9ãâNHâïœ
âC4H9ã
âNHâïœâC4H9ãâNHâïœâC5H11ãâNHâ
ïœâC5H11ã[Formula] -NH 2 , -NHCH 3 , -NHC 2 H 5 , -NH-n-
C3H7 , -NH-i- C3H7 , -NH -n- C4H9 , -NH -i
-C4H9 , -NH-s- C4H9 , -NH -n - C5H11 , -NH-
i- C5H11 ,
ãåŒãâNHâïœâC6H13ã[Formula] -NH-n-C 6 H 13 ,
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ãåŒãâNHâïœâC7H15ãâNHâ ïœâC8H17ã[Formula] -NH-n-C 7 H 15 , -NH- n-C 8 H 17 ,
ãåŒãâNHâïœâC9H19ãâ ïŒCH3ïŒ2ã[Formula] -NH-n-C 9 H 19 , -N (CH 3 ) 2 ,
ãåŒã âïŒO2H5ïŒ2ãâïŒïœâC3H7ïŒ2ã âïŒïœâC3H7ïŒ2ãâïŒïœâC4H9ïŒ2ã[Formula] -N(O 2 H 5 ) 2 , -N(n-C 3 H 7 ) 2 , -N(i-C 3 H 7 ) 2 , -N(n-C 4 H 9 ) 2 ,
ãåŒã âïŒïœâC4H9ïŒ2ãâïŒïœâC6H13ïŒ2ã âïŒïœâC8H17ïŒ2ãâïŒïœâC9H19ïŒ2ã[Formula] -N(i-C 4 H 9 ) 2 , -N(n-C 6 H 13 ) 2 , -N(n-C 8 H 17 ) 2 , -N(n-C 9 H 19 ) 2 ,
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ãåŒã âïŒCH2CH2OHïŒ2ã[Formula] âN(CH 2 CH 2 OH) 2 ,
ãåŒã âNHïŒCH2CH2OC2H5ïŒ2ã[Formula] âNH(CH 2 CH 2 OC 2 H 5 ) 2 ,
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ãåã NHR11 R11ïŒâNH2ãâNHCOCH3 âNHCOC2H5ãâNHCOâïœâC3H7 âNHCOâïœâC3H7ãâNHCOâïœâC4H9 [Chemical] NHR 11 R 11 :-NH 2 , -NHCOCH 3 -NHCOC 2 H 5 , -NHCO-n-C 3 H 7 -NHCO-i-C 3 H 7 , -NHCO-n-C 4 H 9
ãåŒãâNHCOâïœâC5H11 [Formula] -NHCO-n-C 5 H 11
ãåŒãâNHCOâïœâC6H13 NHCOâïœâC7H15ã[Formula] -NHCO-n-C 6 H 13 NHCO-n-C 7 H 15 ,
ãåŒã NHCOCH2Clã[Formula] NHCOCH 2 Cl,
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ãåŒã NHCOCH2OC2H5ã[Formula] NHCOCH 2 OC 2 H 5 ,
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ãåã NHCH3ãNHC2C5 [C] NHCH 3 , NHC 2 C 5
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ãäœãå«ããã奜é©ã«ã¯ãåŒ[Chemical formula] In the case where an optical isomer based on an asymmetric carbon exists in the compound (), it includes an optically active form and a racemic form, but it is preferably a compound of the formula
ãåŒãéšåãé äœã§ãããåŒ[Formula] moiety is S-coordinated, and the formula
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[Formula] is a compound in which the moiety is S-coordinated. The compound of the present invention having the general formula () is:
It can be made into a pharmacologically acceptable salt. Such salts include, for example, mineral salts such as hydrochlorides, sulphates, phosphates, organic salts such as oxalates, maleates, succinates, citrates, methanesulfonates, Acid addition salts of sulfonates such as benzenesulfonate and P-toluenesulfonate; alkali metal salts or alkaline earth metal salts such as sodium salt, potassium salt, calcium salt, and magnesium salt; and dicyclohexylamine salt. Organic base salts such as Further, in the compound (), preferably (1) a compound in which at least one of R 1 and R 2 is a formula -B-R 6 group, (2) ethylene even if R 3 is substituted with methyl,
trimethylene or tetramethylene group or formula
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ã¬ã³åºåã¯åŒA group having the formula (wherein R 8 is a methyl group substituted with a heterocyclyl group containing a nitrogen atom,
C5 - C18 alkyl group, C2 - C5 alkenyl group optionally substituted with halogen, or C2 - C5
is an alkynyl group. ), (3) Compounds where R 4 is isopropyl (4) R 5 is an amino group, mono- or di-(C 1 -C 10
alkyl) amino group, mono- or di-(hydroxyC 1 -C 10 alkyl) amino group, mono- or di-(substituted C 1 -C 4 alkyl) amino group [the substituent of the alkyl group is a lower alkoxy group, a substituted optional phenyl group, pyridyl group, di-
(Lower alkyl) An amino group or a heterocyclyl group containing a nitrogen atom. ], a C 3 -C 8 cycloalkylamino group, a heterocyclylamino group or a group having the formula -NHR 11 [wherein R 11 is an amino group, a C 1 -C 10 aliphatic acylamino group, a substituted C 2 - C5 aliphatic acylamino group (the substituent is a halogen atom, lower alkoxy group, optionally substituted phenyl or C3 - C8 cycloalkyl group), benzoylamino group, cinnamoylamino group ( The phenyl moiety of the group may be substituted with a lower alkyl group, a halogen atom, a lower alkoxy group, a trifluoromethyl group, a C1 - C5 aliphatic acyl group, a nitro group, or a cyano group. (The substituent is a hydroxyl group, a lower alkoxy group, or a phenyl group.) ]
(5) A compound where R is a hydrogen atom, (6) A compound where A is a single bond, (7) At least one of R 1 and R 2 has the formula -B-R 6
an ethylene, trimethylene or tetramethylene group in which R 3 may be substituted with methyl, or a group of the formula
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(9) R3ãåŒ A group having the formula or a C2 - C5 aquinyl group), R4 is isobropyl, and R5 is an amino group, a mono- or di-( C1 - C10 alkyl)amino group, a mono- or di-( Hydroxy C 1 -C 10 alkyl) amino group, mono- or di-(substituted C 1 -C 4 alkyl) amino group [the substituent of the alkyl group is a lower alkoxy group, an optionally substituted phenyl group,
It is a pyridyl group, a di-(lower alkyl)amino group, or a heterocyclyl group containing a nitrogen atom. ],
C 3 - C 8 cycloalkylamino group, heterocyclylamino group or group having the formula -NHR 11 [wherein R 11 is an amino group, a C 1 - C 10 aliphatic acylamino group, a substituted C 2 - C 5 aliphatic acylamino group (the substituent is a halogen atom, a lower alkoxy group, an optionally substituted phenyl or
It is a C3 - C8 cycloalkyl group. ), benzoylamino group, cinnamoylamino group (the phenyl part of the group is a lower alkyl group, a halogen atom, a lower alkoxy group, a trifluoromethyl group, a C1 - C5 aliphatic acyl group, a nitro group or a cyano group) ) or an optionally substituted lower alkylamino group (the substituent is a hydroxyl group, a lower alkoxy group, or a phenyl group)], R is a hydrogen atom, and A (8) A compound in which R 1 and R 2 are the same or different and are a group of formula -B-R 6 ; (9) A compound in which R 3 is a formula
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ã§ãããR3ãåŒA group having the formula (wherein R 8 is a C 5 - C 18 alkyl group, a C 2 - C 5 alkenyl group, or
It is a C2 - C5 alkynyl group. ), (10) R 5 is a mono-(C 1 -C 10 alkyl) amino group,
Mono-(hydroxy C 1 -C 10 alkyl) amino group, mono-(substituted C 1 -C 4 alkyl) amino group [the substituent of the alkyl group is a lower alkoxy group, an optionally substituted phenyl group, a pyridyl group,
It is a di-(lower alkyl)amino group or a heterocyclyl group containing a nitrogen atom. ], a C 3 -C 8 cycloalkylamino group, or a group having the formula -NHR 11 [wherein R 11 is an amino group, a C 1 -C 10 aliphatic acylamino group, a substituted C 2 -C 5 aliphatic A lower alkylamino group which may be substituted with a group acylamino group (the substituent is a halogen atom, a lower alkoxy group, phenyl or a C5 - C7 cycloalkyl group) or a hydroxyl group. ]
(11) R 1 and R 2 are the same or different and are -B-R 6 groups, and R 3 is of the formula
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ã R3ãåŒ A group having the formula _ _ _ group, and R 5 is mono-
(C 1 -C 10 alkyl)amino group, mono-(hydroxyC 1 -C 10 alkyl)amino group, mono-(substituted
C1 - C4 alkyl)amino group [The substituent of the alkyl group is a lower alkoxy group, an optionally substituted phenyl group, a pyridyl group, a di-(lower alkyl)amino group, or a nitrogen atom-containing heterocyclyl group. ], a C 3 -C 8 cycloalkylamino group or a group having the formula -NHR 11 [wherein R 11 is an amino group, a C 1 -C 10 aliphatic acylamino group, a substituted C 2 -C 5 aliphatic Acylamino group (the substituent is a halogen atom, lower alkoxy group, phenyl or C5 - C8 cycloalkyl group)
or a lower alkylamino group which may be substituted with a hydroxyl group. ], where R is a hydrogen atom and A is a single bond; (12) a compound where R 1 or R 2 are the same or different and are naphthylmethyl, quinolylmethyl, benzyl, pyridylmethyl or thienylmethyl group; ã R 3 is the formula
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It is a C2 - C5 alkynyl group. ), ã R 5 is a mono-(C 1 -C 10 alkyl) amino group,
Mono-(hydroxy C 1 -C 10 alkyl) amino group, mono-(substituted C 1 -C 4 alkyl) amino group [alkyl group substituents include lower alkoxy group, optionally substituted phenyl group, pyridyl group, â
It is a (lower alkyl) amino group or a heterocyclyl group containing a nitrogen atom. ] or a compound that is a C 3 -C 8 cycloalkylamino group. Furthermore, in the compound (), the compounds illustrated below can be preferably mentioned.
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ãã[C] Furthermore, in the above table, compound numbers 74, 79,
Regarding 179, 183 and 205, compounds in which R is an acetyl group instead of a hydrogen atom can be mentioned. The compound of the present invention having the general formula () is
It can be easily manufactured according to the following method.
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The results of an inhibitory effect test on human renin of the peptides of the present invention having the general formula () are shown below. The test method was carried out according to the method of Kokufu et al. [Hypertensin, 5 , 191-197 (1983)]. Inhibition test compound against human renin Hazard level (%) (1Ã10 -6 M) Compound of Example 1 99 Compound of Example 7 82 Compound of Example 3 99 The target compound of the present invention () is the same as the above test example. As shown above, it exhibits an excellent inhibitory effect on human renin, and is useful as a diagnostic and therapeutic agent for hypertension based on the renin-angiotensin system.
Examples of dosage forms include tablets, capsules,
Examples include oral administration in the form of granules, powders, syrups, etc., and parenteral administration in the form of injections, suppositories, etc. The amount used depends on the purpose of use, symptoms,
It varies depending on age, etc., but for example, about 0.01mg per day.
The dose ranges from 100 mg/Kg body weight, and can be administered once or in divided doses. Next, the present invention will be explained in more detail with reference to Examples. Example 1 (3S,4S)-4-[2(RS)-[2-(1-naphthyl)methyl-3-(1-naphthyl)propionylamino]nonanoylamino-3-hydroxy-6-methylheptanoyl -L-isoleucinol (3S, 4S)-4-t-Butyloxycarbonylamino-3-hydroxy-6-methylheptanoyl-L-isoleucinol 58.6 mg (0.156 mmol) was added with 6N hydrochloric acid/dioxane 3 ml, and the mixture was heated at room temperature. After stirring for 30 minutes, the mixture was concentrated to dryness under reduced pressure. Dissolve the residue in 2 ml of dimethylformamide and add 2
(RS)-[2-(1-naphthyl)methyl-3-(1-
naphthyl)propionylamino]-nonanoic acid 77.5
mg (0.156 mmol) and diethyl cyanophosphate
27.9 mg (0.17 mmol) was added and cooled on ice. Next, 33 mg (0.327 mmol) of triethylamine was added dropwise, stirred at room temperature for 3.5 hours, and then concentrated under reduced pressure. Add 2 ml of water to the residue and extract with ethyl acetate.
The organic layer was dried over magnesium sulfate and then concentrated under reduced pressure. The residue was subjected to preparative silica gel chromatography (developing solvent: chloroform/methanol = 10/1)
21.0 mg of the title compound was obtained in the form of a colorless powder. Melting point 75-78â Example 2 (3S, 4S)-4-[2(RS)-[2-(1-naphthyl)methyl-3-(1-naphthyl)propionylamino]heptanoylamino-3-hydroxy- 6-Methylheptanoyl-L-isoleucinol 2(RS)-[2-(1-naphthyl)methyl-3-
The mixture was reacted and treated in the same manner as in Example 1 using (1-naphthyl)propionylamino]heptanoic acid to obtain 102 mg of the title compound in the form of a colorless powder. Melting point 95-97â Example 3 N-[2-(1-naphthyl)methyl-3-(1-
naphthyl)propionyl]-DL-allylglycyl-(3S,4S)-4-amino-3-hydroxy-6-methylheptanoyl-L-isoleucinol N-[2-(1-naphthyl)methyl-3-(1-
Naphthyl)propionyl]-DL-allylglycyl was reacted and treated in the same manner as in Example 1 to obtain 59 mg of the title compound in the form of a colorless powder. Melting point 93-95â Example 4 N-[2-(1-naphthyl)methyl-3-(1-
naphthyl)propionyl]-DL-propargylglycyl-(3S,4S)-4-amino-3-hydroxy-6-methylheptanoyl-L-isoleucinol (3S,4S)-4-t-butyloxycarbonylamino-3 -Hydroxy-6-methylheptanoyl-L-isoleucinol 749 mg (2 mmol)
Add 10ml of 6N hydrochloric acid/dioxane to
After stirring for a minute, the mixture was concentrated to dryness under reduced pressure. Dissolve the residue in 20 ml of dimethylformamide and add N-
426 mg (2 mmol) of t-butyloxycarbonyl-DL-propargylglycine and 270 mg (2 mmol) of 1-hydroxybenztriazole were added. Dicyclohexylcarbodiimide under ice cooling
After adding 412 mg (2 mmol) and 1 ml of triethylamine and stirring at 40-50°C for 2 hours, the precipitated dicyclohexylurea was filtered off. Ethyl acetate was added to the filtrate and washed with water, 10% citric acid aqueous solution, 5% sodium bicarbonate aqueous solution and saturated saline, and then the organic layer was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, ethyl ether was added to the residue, and the precipitate precipitated was collected by filtration. After the filtrate was distilled off under reduced pressure, 10 ml of 6N hydrochloric acid/dioxane was added, stirred at room temperature for 30 minutes, and then concentrated to dryness under reduced pressure. Dissolve the residue in 20 ml of dimethylformamide and add 2-
680 mg (2 mmol) of (1-naphthyl)methyl-3-(1-naphthyl)propionic acid and 543 mg (3 mmol) of diethyl cyanophosphate were added. Add 1 ml of triethylamine to this solution while stirring,
After stirring at ~50°C for 2 hours, the mixture was poured into ice water and extracted with ethyl acetate. After washing the extracted ethyl acetate with a 10% aqueous citric acid solution, a 5% aqueous sodium bicarbonate solution, and saturated brine, the organic layer was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by preparative thin layer chromatography (developing solution: ethyl acetate) to obtain two isomers based on the asymmetric carbon of the propargylglycyl moiety. Melting point 182-188°C (isomer 1), 92-94°C (isomer 2) Example 5 N-[2-(1-naphthyl)methyl-3-(1-
naphthyl)propionyl]-DL-decylglycyl-(3S,4S)-4-amino-3-hydroxy-6-methylheptanoyl-L-isoleucinol (3S,4S)-4-t-butyloxycarbonylamino-3-hydroxy -6-methylheptanoyl-L-isoleucinol 312 mg (1 mmol)
The title compound was synthesized using the same procedure as in Example 4. Melting point 55-58â (isomer 1), 52-55â (isomer 2) Example 6 (3S,4S)-4-[3(RS)-[2-(1-naphthyl)methyl-3-( 1-naphthyl)propionylamino]butyroylamino-3-hydroxy6-methylheptanoic acid morpholinoethylamide (a) (3S,4S)-4-[3(RS)-t-butyloxycarbonylamino]butyroylamino- 3-
Hydroxy-6-methylheptanoic acid morpholinoethylamide DL-β-amino-n-butanoic acid 2.06 g (20
mmol) in aqueous dioxane (1:1) solution 20
ml and 2.8 ml of triethylamine, under ice cooling,
4.8 g (22 mmol) of di-t-butyl dicarbonate was added, and the mixture was stirred at room temperature for 4 hours. After the reaction is complete, add 20ml of water and add 20ml of ethyl acetate.
Wash once with water, cool the aqueous layer thoroughly,
After adjusting the pH to 2 with an aqueous citric acid solution, the mixture was extracted twice with 20 ml of ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried over magnesium sulfate, and evaporated under reduced pressure to give N-t-butoxycarbonyl-DL-β-amino-n-butanoic acid.
Obtained 3.45 g (85%) as white crystals. This N
-t-butoxycarbonyl-DL-β-amino-n-butanoic acid 1.02 g (5.00 mmol) and
(3S,4S)-4-amino-3-hydroxy-6
- methylheptanoic acid morpholine ethylamide,
1.8 g (5.00 mmol) of dihydrochloride was dissolved in 20 ml of anhydrous tetrahydrofuran, and under nitrogen atmosphere,
While cooling, 0.83 ml (5.47 mmol) of diethyl cyanophosphate and 2.30 ml (16.5 mmol) of triethylamine were added, and the mixture was stirred at room temperature overnight. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (chloroform:methanol=1:1) to obtain 1.36 g (58%) of the title compound as a colorless oil. Silica gel thin layer chromatography (R f
Value): 0.30 (Chloroform: Methanol = 5:
1) (b) (3S,4S)-4-[3(RS)-[2-(1-naphthyl)methyl-3-(1-naphthyl)propionylamino]butyroylamino-3-hydroxy-6-methyl Heptanoic acid morpholinoethylamide (3S,4S)-4-[3 synthesized in Example 6(a)
(R,S)-t-butyloxycarbonylamino]butyroylamino-3-hydroxy-6-
400 mg (0.90 mmol) of a compound obtained by removing the t-butoxycarbonyl group from methylheptanoic acid morpholinoethylamide according to a conventional method, and 2
306 mg (0.90 mmol) of -(1-naphthyl)methyl-3-(1-naphthyl)propionic acid was dissolved in 10 ml of anhydrous tetrahydrofuran, and 0.15 ml of diethyl cyanophosphate was dissolved under ice cooling under a nitrogen atmosphere.
(0.99 mmol) and triethylamine 0.41 ml
(2.94 mmol) was added and stirred overnight at room temperature. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel thin layer chromatography (chloroform:methanol=1:1) to obtain 380 mg (61%) of the title compound as white crystals. Melting point 169-171â Example 7 N-[2-(1-naphthyl)methyl-3-(1-
naphthyl)propionyl]-β-alanyl-
(3S,4S)-4-amino-3-hydroxy-6
-Methylheptanoic acid morpholinoethylamide Reacted and treated in the same manner as in Example 6 to obtain the title compound 56.
mg was obtained as colorless powder crystals. Melting point 108-111â Example 8 N-[2-(1-naphthyl)methyl-3-(1-
naphthyl)propionyl]-cycloleucyl-
(3S,4S)-4-amino-3-hydroxy-6
-Methylheptanoyl-L-isoleucinol The title compound was obtained by reacting and treating in the same manner as in Example 6.
86 mg was obtained as colorless powdery crystals. Melting point 167-170â Example 9 (3S,4S)-4-[2(RS)-[2-(1-naphthyl)methyl-3-(1-naphthyl)propionylamino]heptanoylamino-3-hydroxy- 6-Methylheptanoic acid morpholinoethylamide React and treat in the same manner as in Example 1 to obtain the title compound.
200 mg was obtained as colorless powdery crystals. Melting point 85-88â Example 10 (3S,4S)-4-[2(RS)-[2-(1-naphthyl)methyl-3-(1-naphthyl)propionylamino]heptanoylamino-3-hydroxy- 6-Methylheptanoic acid cyclohexylamide React and treat in the same manner as in Example 1 to obtain the title compound.
150 mg was obtained as colorless powdery crystals. Melting point 78-80â Example 11 (3S,4S)-4-[2(RS)-[2-(1-naphthyl)methyl-3-(1-naphthyl)propionylamino]heptanoylamino-3-hydroxy- 6-Methylheptanoic acid 2(RS)-methylbutyramide React and treat in the same manner as in Example 1 to obtain the title compound.
270 mg was obtained as colorless powdery crystals. Melting point 71-72â Example 12 (3S,4S)-4-[2(RS)-[2-(1-naphthyl)methyl-3-(1-naphthyl)propionylamino]heptanoylamino-3-hydroxy- 6-Methylheptanoic acid hydrazide N[2-(1-naphthyl)methyl-3-1-naphthyl)propionyl]-heptanoylamino(3S,4S)-3-hydroxy-6- in 3 ml of ethanol
Ethyl methylheptanoate 284 mg (0.435 mmol)
and 275 mg (4.35 mmol) of 80% hydrazine hydrate were added, stirred at room temperature for 2 hours, and then left overnight. Then, the precipitated crystals were collected and dried to obtain 45 mg of crystals having a melting point of 176-177°C. The reaction mother liquor was concentrated under reduced pressure, and further 185 mg of the target product was obtained.
(82.8%). Elemental analysis: as C39H52N4O5 ã» H2O Calculated value: C , 71.31; H, 7.98; N, 8.53 Actual value: C, 71.80; H, 7.99; N, 8.60 Example 13 N-[ 2-(1-naphthyl)methyl-3-(1-
naphthyl)propionyl]-RS-allylglycyl-(3S,4S)-4-amino-3-hydroxy-6-methylheptanoic acid morpholinoethylamide (3S,4S)-4-[3(RS)-t-butyloxycarbonyl 3 ml of 6N dioxane hydrochloric acid was added to 387.5 mg (1 mmol) of amino]butyroylamino-3-hydroxy-6-methylheptanoic acid morpholinoethylamide, and the mixture was stirred at room temperature for 30 minutes. Then, dioxane was distilled off under reduced pressure, and 10 ml of methanol was added.
was added and evaporated under reduced pressure (repeated 3 times), the residue was dissolved in 5 ml of dimethylformamide, 101.2 mg (1 mmol) of triethylamine, N-[2-(1-
Naphthyl)methyl-3-(1-naphthyl)propionyl]-(RS)-allylglycine 437.5 mg (1 mmol) and diethyl cyanophosphate 179.4 mg
(1.1 mmol) and 111.1 mg (1.1 mmol) of triethylamine were added thereto, and the mixture was stirred at room temperature for 3 hours. After standing overnight, dimethylformamide was distilled off under reduced pressure.
A small amount of water was added to the residue, extracted with ethyl acetate, washed with water, dried, and ethyl acetate was distilled off. The residue was purified by silica gel thin layer chromatography (chloroform:methanol = 5:1) to obtain 251 mg of white powder.
(35.5%). Melting point 90-93â Elemental analysis: C 43 H 54 N 4 O 5ã»H 2 O Calculated value C, 71.24; H, 7.79; N, 7.73 Actual value C, 71.18; H, 7.81; N, 7.39
Claims (1)
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ãªãŒã«ã¢ã·ã«åºã瀺ãã ã¯åçµåãé žçŽ åååã¯ç¡«é»ååã瀺ãã[Claims] 1 Dipeptides having the formula: and pharmacologically acceptable salts thereof. In the above formula, R 1 and R 2 are the same or different, and are a group of the formula -B-R 6 (wherein B is a single bond or a linear or branched chain which may have a double bond in the chain) R6 represents an aryl group or a heteroaryl group), a C1 - C10 alkyl group, or a lower alkylene group of the formula -E-
R 7 group (wherein E represents a lower alkylene group optionally interrupted by one oxygen atom, R 7 is a lower alkoxy group, an aryloxy group, an arylthio group, an aralkyloxy group, or a heterocyclyl group containing a nitrogen atom) R 3 is an optionally substituted ethylene, trimethylene or tetramethylene group (the substituent represents a lower alkyl, phenyl or hydroxyl group), a group having the formula [formula] (in the formula , R 8 is a heterocyclyl-substituted lower alkyl group containing a nitrogen atom, C 5 -C 18
Alkyl group, may be substituted with halogen
Represents a C2 - C5 alkenyl group or a C2 - C5 alkynyl group. ) or a group having the formula [formula] (wherein R 9 and R 10 are the same or different and represent a lower alkyl group. Also, R 9 and R 10 are
A C3 - C8 cycloalkyl group may also be formed. )
, R 4 represents an isopropyl group, a C 3 -C 8 cycloalkyl group, or a phenyl group, and R 5 represents a hydroxyl group, a C 1 -C 10 alkoxy group, an aryloxy group, an amino group, a mono- or di-(C 1 â
C 10 alkyl) amino group [The alkyl group may have one or two substituents, which may be the same or different and include a hydroxyl group, a lower alkoxy group, a halogen atom, an optionally substituted phenyl group , a pyridyl group, a C3 - C8 cycloalkyl group, a di-(lower alkyl)amino group, a di-(hydroxy-lower alkyl)amino group, or a heterocyclyl group containing a nitrogen atom. ], mono- or di-( C3 - C4 alkenyl)amino group, C3 - C8 cycloalkylamino group,
arylamino group, heterocyclylamino group containing a nitrogen atom (amino and heterocyclyl in the group are bonded with N-C), heterocyclyl group containing a nitrogen atom (the heterocyclyl group is a carbonyl group at the nitrogen atom contained in the group) or a group having the formula -NHR 11 (wherein R 11 is an amino group,
An optionally substituted C1 - C10 aliphatic acylamino group (the substituents include a halogen atom, a lower alkoxy group, an aryloxy group, an arylacyl group,
Indicates an aryl group or a C3 - C8 cycloalkyl group. ) arylacylamino group, cinnamoylamino group, heteroarylacylamino group, optionally substituted lower alkylamino group (the substituents include hydroxyl group, lower alkoxy group, C 1 -C 5 aliphatic acyloxy group, aryl acyloxy group or aryl group), an arylamino group or a heterocyclyl group containing a nitrogen atom (the heterocyclyl group is bonded to an -NH- group through a nitrogen atom), R is a hydrogen atom, and C1- It represents a C5 aliphatic acyl group or an arylacyl group, and A represents a single bond, an oxygen atom, or a sulfur atom.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP1517785 | 1985-01-29 | ||
| JP60-15177 | 1985-01-29 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPS61275258A JPS61275258A (en) | 1986-12-05 |
| JPH0569098B2 true JPH0569098B2 (en) | 1993-09-30 |
Family
ID=11881530
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP61013908A Granted JPS61275258A (en) | 1985-01-29 | 1986-01-27 | Dipeptide or the like |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPS61275258A (en) |
-
1986
- 1986-01-27 JP JP61013908A patent/JPS61275258A/en active Granted
Also Published As
| Publication number | Publication date |
|---|---|
| JPS61275258A (en) | 1986-12-05 |
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