JPH0328418B2 - - Google Patents
Info
- Publication number
- JPH0328418B2 JPH0328418B2 JP57022945A JP2294582A JPH0328418B2 JP H0328418 B2 JPH0328418 B2 JP H0328418B2 JP 57022945 A JP57022945 A JP 57022945A JP 2294582 A JP2294582 A JP 2294582A JP H0328418 B2 JPH0328418 B2 JP H0328418B2
- Authority
- JP
- Japan
- Prior art keywords
- lower alkyl
- mmol
- amino
- aralkyl
- proline
- 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
- 125000000217 alkyl group Chemical group 0.000 claims description 54
- -1 alkoxy CHR 4 Chemical compound 0.000 claims description 27
- 239000001257 hydrogen Substances 0.000 claims description 27
- 229910052739 hydrogen Inorganic materials 0.000 claims description 27
- 150000001875 compounds Chemical class 0.000 claims description 24
- 238000000034 method Methods 0.000 claims description 24
- 125000003118 aryl group Chemical group 0.000 claims description 20
- 150000003839 salts Chemical class 0.000 claims description 20
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 18
- 238000004587 chromatography analysis Methods 0.000 claims description 17
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 16
- 125000004432 carbon atom Chemical group C* 0.000 claims description 13
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims description 12
- 125000004475 heteroaralkyl group Chemical group 0.000 claims description 11
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 10
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 9
- 125000001424 substituent group Chemical group 0.000 claims description 8
- 229910052799 carbon Inorganic materials 0.000 claims description 7
- 125000001072 heteroaryl group Chemical group 0.000 claims description 7
- 125000005110 aryl thio group Chemical group 0.000 claims description 6
- 125000003545 alkoxy group Chemical group 0.000 claims description 5
- 125000004104 aryloxy group Chemical group 0.000 claims description 4
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 4
- 125000005368 heteroarylthio group Chemical group 0.000 claims description 4
- 230000002829 reductive effect Effects 0.000 claims description 4
- ONIBWKKTOPOVIA-BYPYZUCNSA-N L-Proline Chemical compound OC(=O)[C@@H]1CCCN1 ONIBWKKTOPOVIA-BYPYZUCNSA-N 0.000 claims description 3
- 125000004442 acylamino group Chemical group 0.000 claims description 3
- 238000009833 condensation Methods 0.000 claims description 3
- 230000005494 condensation Effects 0.000 claims description 3
- 125000005241 heteroarylamino group Chemical group 0.000 claims description 3
- 238000007796 conventional method Methods 0.000 claims description 2
- 238000002425 crystallisation Methods 0.000 claims description 2
- 230000008025 crystallization Effects 0.000 claims description 2
- 150000004715 keto acids Chemical class 0.000 claims description 2
- 125000006239 protecting group Chemical group 0.000 claims description 2
- 125000001475 halogen functional group Chemical group 0.000 claims 4
- 125000005553 heteroaryloxy group Chemical group 0.000 claims 2
- 150000008575 L-amino acids Chemical class 0.000 claims 1
- 229930182821 L-proline Natural products 0.000 claims 1
- LOTBYPQQWICYBB-UHFFFAOYSA-N methyl n-hexyl-n-[2-(hexylamino)ethyl]carbamate Chemical compound CCCCCCNCCN(C(=O)OC)CCCCCC LOTBYPQQWICYBB-UHFFFAOYSA-N 0.000 claims 1
- 229960002429 proline Drugs 0.000 claims 1
- 150000003349 semicarbazides Chemical class 0.000 claims 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 82
- 239000000741 silica gel Substances 0.000 description 82
- 229910002027 silica gel Inorganic materials 0.000 description 82
- 239000000243 solution Substances 0.000 description 79
- XEKOWRVHYACXOJ-UHFFFAOYSA-N ethyl acetate Substances CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 57
- 239000000203 mixture Substances 0.000 description 50
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 43
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical class C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 41
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 39
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 36
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 36
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 34
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 33
- 239000002904 solvent Substances 0.000 description 33
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 31
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 31
- 239000000047 product Substances 0.000 description 26
- 235000019439 ethyl acetate Nutrition 0.000 description 25
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 24
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 24
- WEVKQMBWAPJFSP-UHFFFAOYSA-N ethyl acetate;2-pyridin-2-ylacetic acid;hydrate Chemical compound O.CCOC(C)=O.OC(=O)CC1=CC=CC=N1 WEVKQMBWAPJFSP-UHFFFAOYSA-N 0.000 description 23
- OAYLNYINCPYISS-UHFFFAOYSA-N ethyl acetate;hexane Chemical compound CCCCCC.CCOC(C)=O OAYLNYINCPYISS-UHFFFAOYSA-N 0.000 description 23
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 22
- XEVRDFDBXJMZFG-UHFFFAOYSA-N carbonyl dihydrazine Chemical compound NNC(=O)NN XEVRDFDBXJMZFG-UHFFFAOYSA-N 0.000 description 22
- 229920001467 poly(styrenesulfonates) Polymers 0.000 description 20
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 18
- JUJWROOIHBZHMG-UHFFFAOYSA-N pyridine Substances C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 18
- 239000007787 solid Substances 0.000 description 17
- 239000012230 colorless oil Substances 0.000 description 16
- 238000000921 elemental analysis Methods 0.000 description 15
- 239000006260 foam Substances 0.000 description 14
- BEOOHQFXGBMRKU-UHFFFAOYSA-N sodium cyanoborohydride Chemical compound [Na+].[B-]C#N BEOOHQFXGBMRKU-UHFFFAOYSA-N 0.000 description 13
- WFJFGMLKAISFOZ-UHFFFAOYSA-N 1-amino-3-iminourea Chemical class NN=C(O)N=N WFJFGMLKAISFOZ-UHFFFAOYSA-N 0.000 description 12
- 229960000583 acetic acid Drugs 0.000 description 11
- 239000012043 crude product Substances 0.000 description 11
- OAKJQQAXSVQMHS-UHFFFAOYSA-N hydrazine Substances NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 description 11
- 150000002431 hydrogen Chemical class 0.000 description 11
- 238000000746 purification Methods 0.000 description 11
- 239000011347 resin Substances 0.000 description 11
- 229920005989 resin Polymers 0.000 description 11
- 238000003756 stirring Methods 0.000 description 11
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 10
- 239000000126 substance Substances 0.000 description 10
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 9
- 239000003921 oil Substances 0.000 description 9
- 235000019198 oils Nutrition 0.000 description 9
- 238000010992 reflux Methods 0.000 description 9
- 239000002253 acid Substances 0.000 description 8
- 239000003054 catalyst Substances 0.000 description 8
- 150000002148 esters Chemical group 0.000 description 8
- 238000003818 flash chromatography Methods 0.000 description 8
- 238000002844 melting Methods 0.000 description 8
- 230000008018 melting Effects 0.000 description 8
- 239000003480 eluent Substances 0.000 description 7
- 239000000543 intermediate Substances 0.000 description 7
- VNWKTOKETHGBQD-UHFFFAOYSA-N methane Natural products C VNWKTOKETHGBQD-UHFFFAOYSA-N 0.000 description 7
- CKDWPUIZGOQOOM-UHFFFAOYSA-N Carbamyl chloride Chemical compound NC(Cl)=O CKDWPUIZGOQOOM-UHFFFAOYSA-N 0.000 description 6
- 239000002220 antihypertensive agent Substances 0.000 description 6
- 239000007864 aqueous solution Substances 0.000 description 6
- STPXIOGYOLJXMZ-UHFFFAOYSA-N ethyl 2-oxo-4-phenylbutanoate Chemical compound CCOC(=O)C(=O)CCC1=CC=CC=C1 STPXIOGYOLJXMZ-UHFFFAOYSA-N 0.000 description 6
- 238000004108 freeze drying Methods 0.000 description 6
- 125000005843 halogen group Chemical group 0.000 description 6
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 6
- 239000005541 ACE inhibitor Substances 0.000 description 5
- 206010020772 Hypertension Diseases 0.000 description 5
- 229940030600 antihypertensive agent Drugs 0.000 description 5
- 230000036772 blood pressure Effects 0.000 description 5
- 238000006243 chemical reaction Methods 0.000 description 5
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 5
- 238000001914 filtration Methods 0.000 description 5
- 239000012362 glacial acetic acid Substances 0.000 description 5
- 125000004356 hydroxy functional group Chemical group O* 0.000 description 5
- 239000011541 reaction mixture Substances 0.000 description 5
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 5
- 108010064733 Angiotensins Proteins 0.000 description 4
- 102000015427 Angiotensins Human genes 0.000 description 4
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 4
- YGYAWVDWMABLBF-UHFFFAOYSA-N Phosgene Chemical compound ClC(Cl)=O YGYAWVDWMABLBF-UHFFFAOYSA-N 0.000 description 4
- WGLUMOCWFMKWIL-UHFFFAOYSA-N dichloromethane;methanol Chemical compound OC.ClCCl WGLUMOCWFMKWIL-UHFFFAOYSA-N 0.000 description 4
- 229940079593 drug Drugs 0.000 description 4
- 239000003814 drug Substances 0.000 description 4
- 238000010828 elution Methods 0.000 description 4
- 125000000816 ethylene group Chemical group [H]C([H])([*:1])C([H])([H])[*:2] 0.000 description 4
- 238000005984 hydrogenation reaction Methods 0.000 description 4
- 229920006395 saturated elastomer Polymers 0.000 description 4
- 238000000926 separation method Methods 0.000 description 4
- 238000010898 silica gel chromatography Methods 0.000 description 4
- UIIMBOGNXHQVGW-UHFFFAOYSA-M sodium bicarbonate Substances [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 4
- 239000007858 starting material Substances 0.000 description 4
- 239000006188 syrup Substances 0.000 description 4
- 235000020357 syrup Nutrition 0.000 description 4
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 4
- CUKPBFBSMOVFGY-LYKKTTPLSA-N (2s)-1-[[(1-ethoxy-1-oxo-4-phenylbutan-2-yl)amino]-methylcarbamoyl]pyrrolidine-2-carboxylic acid Chemical class N1([C@@H](CCC1)C(O)=O)C(=O)N(C)NC(C(=O)OCC)CCC1=CC=CC=C1 CUKPBFBSMOVFGY-LYKKTTPLSA-N 0.000 description 3
- WJBSPABOJKBLFK-LOACHALJSA-N (2s)-1-[[(1-ethoxy-1-oxo-4-phenylbutan-2-yl)amino]carbamoyl]pyrrolidine-2-carboxylic acid Chemical compound N1([C@@H](CCC1)C(O)=O)C(=O)NNC(C(=O)OCC)CCC1=CC=CC=C1 WJBSPABOJKBLFK-LOACHALJSA-N 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- JZUFKLXOESDKRF-UHFFFAOYSA-N Chlorothiazide Chemical compound C1=C(Cl)C(S(=O)(=O)N)=CC2=C1NCNS2(=O)=O JZUFKLXOESDKRF-UHFFFAOYSA-N 0.000 description 3
- 108090000790 Enzymes Proteins 0.000 description 3
- 102000004190 Enzymes Human genes 0.000 description 3
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 150000001412 amines Chemical class 0.000 description 3
- 150000001413 amino acids Chemical class 0.000 description 3
- 239000002585 base Substances 0.000 description 3
- PUVAQZVULKCPHQ-UHFFFAOYSA-N benzyl 2-oxo-4-phenylbutanoate Chemical compound C=1C=CC=CC=1COC(=O)C(=O)CCC1=CC=CC=C1 PUVAQZVULKCPHQ-UHFFFAOYSA-N 0.000 description 3
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 3
- 239000002775 capsule Substances 0.000 description 3
- 150000001768 cations Chemical class 0.000 description 3
- 239000003795 chemical substances by application Substances 0.000 description 3
- 238000004440 column chromatography Methods 0.000 description 3
- 238000010586 diagram Methods 0.000 description 3
- 150000005690 diesters Chemical class 0.000 description 3
- 201000010099 disease Diseases 0.000 description 3
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 3
- ZKQFHRVKCYFVCN-UHFFFAOYSA-N ethoxyethane;hexane Chemical compound CCOCC.CCCCCC ZKQFHRVKCYFVCN-UHFFFAOYSA-N 0.000 description 3
- 229960002003 hydrochlorothiazide Drugs 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
- 230000001631 hypertensive effect Effects 0.000 description 3
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 3
- HDZGCSFEDULWCS-UHFFFAOYSA-N monomethylhydrazine Chemical compound CNN HDZGCSFEDULWCS-UHFFFAOYSA-N 0.000 description 3
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
- 239000000546 pharmaceutical excipient Substances 0.000 description 3
- 229910000027 potassium carbonate Inorganic materials 0.000 description 3
- 239000000843 powder Substances 0.000 description 3
- 239000003755 preservative agent Substances 0.000 description 3
- DCKVNWZUADLDEH-UHFFFAOYSA-N sec-butyl acetate Chemical compound CCC(C)OC(C)=O DCKVNWZUADLDEH-UHFFFAOYSA-N 0.000 description 3
- 125000000547 substituted alkyl group Chemical group 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- ZUXFIXBNANZIFH-MLWJPKLSSA-N (2s)-1-[(1-carboxyethylamino)-methylcarbamoyl]pyrrolidine-2-carboxylic acid Chemical compound OC(=O)C(C)NN(C)C(=O)N1CCC[C@H]1C(O)=O ZUXFIXBNANZIFH-MLWJPKLSSA-N 0.000 description 2
- XFBLXJVWZUAPNW-KZUDCZAMSA-N (2s)-1-[[(1-carboxy-3-phenylpropyl)amino]-methylcarbamoyl]pyrrolidine-2-carboxylic acid Chemical compound N1([C@@H](CCC1)C(O)=O)C(=O)N(C)NC(C(O)=O)CCC1=CC=CC=C1 XFBLXJVWZUAPNW-KZUDCZAMSA-N 0.000 description 2
- WDFDESQNUUEKEY-KEKNWZKVSA-N (2s)-1-[benzyl-[(1-ethoxy-1-oxo-4-phenylbutan-2-yl)amino]carbamoyl]pyrrolidine-2-carboxylic acid Chemical compound C=1C=CC=CC=1CN(C(=O)N1[C@@H](CCC1)C(O)=O)NC(C(=O)OCC)CCC1=CC=CC=C1 WDFDESQNUUEKEY-KEKNWZKVSA-N 0.000 description 2
- NWUYHJFMYQTDRP-UHFFFAOYSA-N 1,2-bis(ethenyl)benzene;1-ethenyl-2-ethylbenzene;styrene Chemical compound C=CC1=CC=CC=C1.CCC1=CC=CC=C1C=C.C=CC1=CC=CC=C1C=C NWUYHJFMYQTDRP-UHFFFAOYSA-N 0.000 description 2
- OGYGFUAIIOPWQD-UHFFFAOYSA-N 1,3-thiazolidine Chemical compound C1CSCN1 OGYGFUAIIOPWQD-UHFFFAOYSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- 241000167854 Bourreria succulenta Species 0.000 description 2
- 241001465754 Metazoa Species 0.000 description 2
- DBTDEFJAFBUGPP-UHFFFAOYSA-N Methanethial Chemical compound S=C DBTDEFJAFBUGPP-UHFFFAOYSA-N 0.000 description 2
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 2
- DTQVDTLACAAQTR-UHFFFAOYSA-M Trifluoroacetate Chemical compound [O-]C(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-M 0.000 description 2
- 239000013543 active substance Substances 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- RXUBZLMIGSAPEJ-UHFFFAOYSA-N benzyl n-aminocarbamate Chemical compound NNC(=O)OCC1=CC=CC=C1 RXUBZLMIGSAPEJ-UHFFFAOYSA-N 0.000 description 2
- 239000000969 carrier Substances 0.000 description 2
- 235000019693 cherries Nutrition 0.000 description 2
- 239000012141 concentrate Substances 0.000 description 2
- 235000008504 concentrate Nutrition 0.000 description 2
- 230000018044 dehydration Effects 0.000 description 2
- 238000006297 dehydration reaction Methods 0.000 description 2
- 238000010511 deprotection reaction Methods 0.000 description 2
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N diphenyl Chemical compound C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 description 2
- 238000004821 distillation Methods 0.000 description 2
- 239000002934 diuretic Substances 0.000 description 2
- 229940030606 diuretics Drugs 0.000 description 2
- 239000002552 dosage form Substances 0.000 description 2
- 125000001033 ether group Chemical group 0.000 description 2
- 238000011156 evaluation Methods 0.000 description 2
- 239000000796 flavoring agent Substances 0.000 description 2
- QEWYKACRFQMRMB-UHFFFAOYSA-N fluoroacetic acid Chemical compound OC(=O)CF QEWYKACRFQMRMB-UHFFFAOYSA-N 0.000 description 2
- 235000013355 food flavoring agent Nutrition 0.000 description 2
- 235000003599 food sweetener Nutrition 0.000 description 2
- 238000001640 fractional crystallisation Methods 0.000 description 2
- 239000012458 free base Substances 0.000 description 2
- 125000002883 imidazolyl group Chemical group 0.000 description 2
- 239000004615 ingredient Substances 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- CBEQRNSPHCCXSH-UHFFFAOYSA-N iodine monobromide Chemical compound IBr CBEQRNSPHCCXSH-UHFFFAOYSA-N 0.000 description 2
- 239000003456 ion exchange resin Substances 0.000 description 2
- 229920003303 ion-exchange polymer Polymers 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- 230000003287 optical effect Effects 0.000 description 2
- 229910052763 palladium Inorganic materials 0.000 description 2
- 235000015320 potassium carbonate Nutrition 0.000 description 2
- 239000002244 precipitate Substances 0.000 description 2
- 108090000765 processed proteins & peptides Proteins 0.000 description 2
- QELSKZZBTMNZEB-UHFFFAOYSA-N propylparaben Chemical compound CCCOC(=O)C1=CC=C(O)C=C1 QELSKZZBTMNZEB-UHFFFAOYSA-N 0.000 description 2
- SMQUZDBALVYZAC-UHFFFAOYSA-N salicylaldehyde Chemical compound OC1=CC=CC=C1C=O SMQUZDBALVYZAC-UHFFFAOYSA-N 0.000 description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 2
- DAEPDZWVDSPTHF-UHFFFAOYSA-M sodium pyruvate Chemical compound [Na+].CC(=O)C([O-])=O DAEPDZWVDSPTHF-UHFFFAOYSA-M 0.000 description 2
- 239000011877 solvent mixture Substances 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- 239000003765 sweetening agent Substances 0.000 description 2
- 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 2
- 238000012360 testing method Methods 0.000 description 2
- BRRMHOCHPIHVSK-GKAPJAKFSA-N (2s)-1-[(1-carboxybutylamino)-methylcarbamoyl]pyrrolidine-2-carboxylic acid Chemical compound CCCC(C(O)=O)NN(C)C(=O)N1CCC[C@H]1C(O)=O BRRMHOCHPIHVSK-GKAPJAKFSA-N 0.000 description 1
- VMWQJPKUCVAELD-ABLWVSNPSA-N (2s)-1-[[(1-carboxy-3-phenylpropyl)amino]carbamoyl]pyrrolidine-2-carboxylic acid Chemical compound N1([C@@H](CCC1)C(O)=O)C(=O)NNC(C(=O)O)CCC1=CC=CC=C1 VMWQJPKUCVAELD-ABLWVSNPSA-N 0.000 description 1
- DSKTUOUFEUGXAH-AXDSSHIGSA-N (2s)-1-[[(5-amino-1-carboxypentyl)amino]-methylcarbamoyl]pyrrolidine-2-carboxylic acid Chemical compound NCCCCC(C(O)=O)NN(C)C(=O)N1CCC[C@H]1C(O)=O DSKTUOUFEUGXAH-AXDSSHIGSA-N 0.000 description 1
- RDLUYPXLJXWJST-YFKPBYRVSA-N (2s)-1-[amino(methyl)carbamoyl]pyrrolidine-2-carboxylic acid Chemical compound CN(N)C(=O)N1CCC[C@H]1C(O)=O RDLUYPXLJXWJST-YFKPBYRVSA-N 0.000 description 1
- PDEMESDQITXJHV-ANYOKISRSA-N (2s)-1-[benzyl-[(1-carboxy-3-phenylpropyl)amino]carbamoyl]pyrrolidine-2-carboxylic acid Chemical compound C=1C=CC=CC=1CN(C(=O)N1[C@@H](CCC1)C(O)=O)NC(C(=O)O)CCC1=CC=CC=C1 PDEMESDQITXJHV-ANYOKISRSA-N 0.000 description 1
- RAIVUYZLIKVOPY-LBAQZLPGSA-N (2s)-1-[methyl-[(1-oxo-4-phenyl-1-phenylmethoxybutan-2-yl)amino]carbamoyl]pyrrolidine-2-carboxylic acid Chemical class N1([C@@H](CCC1)C(O)=O)C(=O)N(C)NC(C(=O)OCC=1C=CC=CC=1)CCC1=CC=CC=C1 RAIVUYZLIKVOPY-LBAQZLPGSA-N 0.000 description 1
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- 239000000052 vinegar Substances 0.000 description 1
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- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
- 239000009637 wintergreen oil Substances 0.000 description 1
- 238000010626 work up procedure Methods 0.000 description 1
Landscapes
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Thiazole And Isothizaole Compounds (AREA)
- Pyrrole Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Other In-Based Heterocyclic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US23532181A | 1981-02-17 | 1981-02-17 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPS57176946A JPS57176946A (en) | 1982-10-30 |
| JPH0328418B2 true JPH0328418B2 (fi) | 1991-04-19 |
Family
ID=22885014
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP2294582A Granted JPS57176946A (en) | 1981-02-17 | 1982-02-17 | Antihypertensive aza analogues of amino acid derivatives |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPS57176946A (fi) |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS5832851A (ja) * | 1980-12-18 | 1983-02-25 | シエリング・コ−ポレ−シヨン | 置換ジペプチド類、その製造方法および該ジペプチドを含有する薬剤組成物 |
-
1982
- 1982-02-17 JP JP2294582A patent/JPS57176946A/ja active Granted
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS5832851A (ja) * | 1980-12-18 | 1983-02-25 | シエリング・コ−ポレ−シヨン | 置換ジペプチド類、その製造方法および該ジペプチドを含有する薬剤組成物 |
Also Published As
| Publication number | Publication date |
|---|---|
| JPS57176946A (en) | 1982-10-30 |
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