JPH0154346B2

JPH0154346B2 -

Info

Publication number: JPH0154346B2
Authority: JP; Japan
Prior art keywords: amino; phenylpropyl; perhydroazocin; ethoxycarbonyl; carboxymethyl
Prior art date: 1980-08-18
Legal status : Expired

Application number

JP12829281A

Other languages

English (en)

Japanese (ja)

Other versions

JPS57112374A (en

Inventor

Ii Harisu Erubaato

Ee Pachetsuto Aasaa

Dee Soosetsuto Yuujin

Current Assignee

Merck and Co Inc

Original Assignee

Merck and Co Inc

Priority date

1980-08-18

Filing date

1981-08-18

Publication date

1989-11-17

1981-08-18 Application filed by Merck and Co Inc filed Critical Merck and Co Inc

1982-07-13 Publication of JPS57112374A publication Critical patent/JPS57112374A/ja

1989-11-17 Publication of JPH0154346B2 publication Critical patent/JPH0154346B2/ja

Status Granted legal-status Critical Current

Links

-1 1-carboxy-3-phenylpropyl Chemical group 0.000 claims description 34
150000001875 compounds Chemical class 0.000 claims description 27
150000003839 salts Chemical class 0.000 claims description 22
125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 16
UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 15
239000001257 hydrogen Substances 0.000 claims description 15
229910052739 hydrogen Inorganic materials 0.000 claims description 15
238000004587 chromatography analysis Methods 0.000 claims description 12
VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 11
239000002253 acid Substances 0.000 claims description 10
125000003545 alkoxy group Chemical group 0.000 claims description 8
CJYXCQLOZNIMFP-UHFFFAOYSA-N azocan-2-one Chemical compound O=C1CCCCCCN1 CJYXCQLOZNIMFP-UHFFFAOYSA-N 0.000 claims description 8
125000000217 alkyl group Chemical group 0.000 claims description 6
238000001640 fractional crystallisation Methods 0.000 claims description 3
125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 3
125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 3
125000003884 phenylalkyl group Chemical group 0.000 claims description 3
SLHZGQUSIZGOKT-HOTGVXAUSA-N (2s)-2-[[(3s)-1-(carboxymethyl)-2-oxoazocan-3-yl]amino]-4-phenylbutanoic acid Chemical compound O=C1N(CC(=O)O)CCCCC[C@@H]1N[C@H](C(O)=O)CCC1=CC=CC=C1 SLHZGQUSIZGOKT-HOTGVXAUSA-N 0.000 claims 1
IRHPAHDKVRJTSO-UHFFFAOYSA-N 2-[3-[(1-ethoxy-1-oxo-4-phenylbutan-2-yl)amino]-8-methyl-2-oxoazocan-1-yl]acetic acid Chemical compound C1CCCC(C)N(CC(O)=O)C(=O)C1NC(C(=O)OCC)CCC1=CC=CC=C1 IRHPAHDKVRJTSO-UHFFFAOYSA-N 0.000 claims 1
STNRYBPBHMQHEA-UHFFFAOYSA-N 2-[[2-oxo-1-(2-oxo-2-phenylmethoxyethyl)azocan-3-yl]amino]-4-phenylbutanoic acid Chemical compound C1CCCCN(CC(=O)OCC=2C=CC=CC=2)C(=O)C1NC(C(=O)O)CCC1=CC=CC=C1 STNRYBPBHMQHEA-UHFFFAOYSA-N 0.000 claims 1
INTZKFZZTMQRBM-PMACEKPBSA-N ethyl (2s)-2-[[(3s)-1-(2-ethoxy-2-oxoethyl)-2-oxoazocan-3-yl]amino]-4-phenylbutanoate Chemical compound O=C1N(CC(=O)OCC)CCCCC[C@@H]1N[C@H](C(=O)OCC)CCC1=CC=CC=C1 INTZKFZZTMQRBM-PMACEKPBSA-N 0.000 claims 1
INTZKFZZTMQRBM-UHFFFAOYSA-N ethyl 2-[[1-(2-ethoxy-2-oxoethyl)-2-oxoazocan-3-yl]amino]-4-phenylbutanoate Chemical compound O=C1N(CC(=O)OCC)CCCCCC1NC(C(=O)OCC)CCC1=CC=CC=C1 INTZKFZZTMQRBM-UHFFFAOYSA-N 0.000 claims 1
238000004519 manufacturing process Methods 0.000 claims 1
125000006239 protecting group Chemical group 0.000 claims 1
LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 47
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 27
239000000243 solution Substances 0.000 description 27
KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 22
WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 21
238000004458 analytical method Methods 0.000 description 21
238000006243 chemical reaction Methods 0.000 description 19
239000000203 mixture Substances 0.000 description 16
HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 15
VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 14
239000000741 silica gel Substances 0.000 description 14
229910002027 silica gel Inorganic materials 0.000 description 14
XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 14
ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 13
238000002844 melting Methods 0.000 description 13
230000008018 melting Effects 0.000 description 13
238000000034 method Methods 0.000 description 13
QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 12
GKIRPKYJQBWNGO-OCEACIFDSA-N clomifene Chemical compound C1=CC(OCCN(CC)CC)=CC=C1C(\C=1C=CC=CC=1)=C(\Cl)C1=CC=CC=C1 GKIRPKYJQBWNGO-OCEACIFDSA-N 0.000 description 12
239000000047 product Substances 0.000 description 12
DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 11
239000012141 concentrate Substances 0.000 description 9
235000008504 concentrate Nutrition 0.000 description 9
VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 9
239000011541 reaction mixture Substances 0.000 description 9
239000002904 solvent Substances 0.000 description 9
WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 8
150000001412 amines Chemical class 0.000 description 8
150000005690 diesters Chemical class 0.000 description 8
HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 8
229910000104 sodium hydride Inorganic materials 0.000 description 8
KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 7
150000001540 azides Chemical class 0.000 description 7
239000002585 base Substances 0.000 description 7
239000002775 capsule Substances 0.000 description 7
239000003054 catalyst Substances 0.000 description 7
239000012312 sodium hydride Substances 0.000 description 7
PXIPVTKHYLBLMZ-UHFFFAOYSA-N Sodium azide Chemical compound [Na+].[N-]=[N+]=[N-] PXIPVTKHYLBLMZ-UHFFFAOYSA-N 0.000 description 6
150000002148 esters Chemical class 0.000 description 6
230000002829 reductive effect Effects 0.000 description 6
239000011734 sodium Substances 0.000 description 6
FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Chemical compound [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 description 6
QCHBORIQPQSOCO-UHFFFAOYSA-N tert-butyl 2-(3-amino-2-oxoazocan-1-yl)acetate Chemical compound CC(C)(C)OC(=O)CN1CCCCCC(N)C1=O QCHBORIQPQSOCO-UHFFFAOYSA-N 0.000 description 6
108010064733 Angiotensins Proteins 0.000 description 5
102000015427 Angiotensins Human genes 0.000 description 5
OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 5
JZUFKLXOESDKRF-UHFFFAOYSA-N Chlorothiazide Chemical compound C1=C(Cl)C(S(=O)(=O)N)=CC2=C1NCNS2(=O)=O JZUFKLXOESDKRF-UHFFFAOYSA-N 0.000 description 5
238000004440 column chromatography Methods 0.000 description 5
STPXIOGYOLJXMZ-UHFFFAOYSA-N ethyl 2-oxo-4-phenylbutanoate Chemical compound CCOC(=O)C(=O)CCC1=CC=CC=C1 STPXIOGYOLJXMZ-UHFFFAOYSA-N 0.000 description 5
239000012044 organic layer Substances 0.000 description 5
BEOOHQFXGBMRKU-UHFFFAOYSA-N sodium cyanoborohydride Chemical compound [Na+].[B-]C#N BEOOHQFXGBMRKU-UHFFFAOYSA-N 0.000 description 5
235000011121 sodium hydroxide Nutrition 0.000 description 5
239000007787 solid Substances 0.000 description 5
QYPDJIDQEZDFLS-UHFFFAOYSA-N tert-butyl 2-iodoacetate Chemical compound CC(C)(C)OC(=O)CI QYPDJIDQEZDFLS-UHFFFAOYSA-N 0.000 description 5
YKFCISHFRZHKHY-NGQGLHOPSA-N (2s)-2-amino-3-(3,4-dihydroxyphenyl)-2-methylpropanoic acid;trihydrate Chemical compound O.O.O.OC(=O)[C@](N)(C)CC1=CC=C(O)C(O)=C1.OC(=O)[C@](N)(C)CC1=CC=C(O)C(O)=C1 YKFCISHFRZHKHY-NGQGLHOPSA-N 0.000 description 4
RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 4
HEHMBIWRMNTGRJ-UHFFFAOYSA-N 2-(3-azido-2-oxoazocan-1-yl)propanoic acid Chemical compound OC(=O)C(C)N1CCCCCC(N=[N+]=[N-])C1=O HEHMBIWRMNTGRJ-UHFFFAOYSA-N 0.000 description 4
239000005541 ACE inhibitor Substances 0.000 description 4
IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
206010020772 Hypertension Diseases 0.000 description 4
239000004480 active ingredient Substances 0.000 description 4
229940030600 antihypertensive agent Drugs 0.000 description 4
239000002220 antihypertensive agent Substances 0.000 description 4
239000012267 brine Substances 0.000 description 4
238000009472 formulation Methods 0.000 description 4
229960002003 hydrochlorothiazide Drugs 0.000 description 4
235000019359 magnesium stearate Nutrition 0.000 description 4
239000000463 material Substances 0.000 description 4
BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 4
238000000746 purification Methods 0.000 description 4
HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 4
TWBNMYSKRDRHAT-RCWTXCDDSA-N (S)-timolol hemihydrate Chemical compound O.CC(C)(C)NC[C@H](O)COC1=NSN=C1N1CCOCC1.CC(C)(C)NC[C@H](O)COC1=NSN=C1N1CCOCC1 TWBNMYSKRDRHAT-RCWTXCDDSA-N 0.000 description 3
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 3
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 3
HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 3
CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 description 3
229920002261 Corn starch Polymers 0.000 description 3
YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 3
102000004270 Peptidyl-Dipeptidase A Human genes 0.000 description 3
108090000882 Peptidyl-Dipeptidase A Proteins 0.000 description 3
ODHCTXKNWHHXJC-GSVOUGTGSA-N Pyroglutamic acid Natural products OC(=O)[C@H]1CCC(=O)N1 ODHCTXKNWHHXJC-GSVOUGTGSA-N 0.000 description 3
YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
150000001413 amino acids Chemical class 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
230000036772 blood pressure Effects 0.000 description 3
229910052794 bromium Inorganic materials 0.000 description 3
229910052799 carbon Inorganic materials 0.000 description 3
229940083181 centrally acting adntiadrenergic agent methyldopa Drugs 0.000 description 3
238000009833 condensation Methods 0.000 description 3
230000005494 condensation Effects 0.000 description 3
239000008120 corn starch Substances 0.000 description 3
239000012043 crude product Substances 0.000 description 3
201000010099 disease Diseases 0.000 description 3
208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 3
229940079593 drug Drugs 0.000 description 3
239000003814 drug Substances 0.000 description 3
238000001035 drying Methods 0.000 description 3
OAYLNYINCPYISS-UHFFFAOYSA-N ethyl acetate;hexane Chemical compound CCCCCC.CCOC(C)=O OAYLNYINCPYISS-UHFFFAOYSA-N 0.000 description 3
125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 3
239000012458 free base Substances 0.000 description 3
239000003456 ion exchange resin Substances 0.000 description 3
229920003303 ion-exchange polymer Polymers 0.000 description 3
239000008101 lactose Substances 0.000 description 3
239000010410 layer Substances 0.000 description 3
239000007788 liquid Substances 0.000 description 3
GUWHRJQTTVADPB-UHFFFAOYSA-N lithium azide Chemical compound [Li+].[N-]=[N+]=[N-] GUWHRJQTTVADPB-UHFFFAOYSA-N 0.000 description 3
125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 3
239000003921 oil Substances 0.000 description 3
235000019198 oils Nutrition 0.000 description 3
150000007524 organic acids Chemical class 0.000 description 3
229920001467 poly(styrenesulfonates) Polymers 0.000 description 3
239000003755 preservative agent Substances 0.000 description 3
239000007858 starting material Substances 0.000 description 3
238000003756 stirring Methods 0.000 description 3
239000000725 suspension Substances 0.000 description 3
229960004605 timolol Drugs 0.000 description 3
METKIMKYRPQLGS-GFCCVEGCSA-N (R)-atenolol Chemical compound CC(C)NC[C@@H](O)COC1=CC=C(CC(N)=O)C=C1 METKIMKYRPQLGS-GFCCVEGCSA-N 0.000 description 2
PRKWVSHZYDOZLP-UHFFFAOYSA-N 2-[(6,7-dichloro-2-methyl-1-oxo-2-phenyl-3h-inden-5-yl)oxy]acetic acid Chemical compound C1C2=CC(OCC(O)=O)=C(Cl)C(Cl)=C2C(=O)C1(C)C1=CC=CC=C1 PRKWVSHZYDOZLP-UHFFFAOYSA-N 0.000 description 2
XAJUMZWRGXACJP-UHFFFAOYSA-N 3-azidoazocan-2-one Chemical compound [N-]=[N+]=NC1CCCCCNC1=O XAJUMZWRGXACJP-UHFFFAOYSA-N 0.000 description 2
XWFHRFPXRGEOGA-UHFFFAOYSA-N 3-bromoazocan-2-one Chemical compound BrC1CCCCCNC1=O XWFHRFPXRGEOGA-UHFFFAOYSA-N 0.000 description 2
VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 2
101800004538 Bradykinin Proteins 0.000 description 2
HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
XBPCUCUWBYBCDP-UHFFFAOYSA-N Dicyclohexylamine Chemical class C1CCCCC1NC1CCCCC1 XBPCUCUWBYBCDP-UHFFFAOYSA-N 0.000 description 2
102000004190 Enzymes Human genes 0.000 description 2
108090000790 Enzymes Proteins 0.000 description 2
VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 2
QXZGBUJJYSLZLT-UHFFFAOYSA-N H-Arg-Pro-Pro-Gly-Phe-Ser-Pro-Phe-Arg-OH Natural products NC(N)=NCCCC(N)C(=O)N1CCCC1C(=O)N1C(C(=O)NCC(=O)NC(CC=2C=CC=CC=2)C(=O)NC(CO)C(=O)N2C(CCC2)C(=O)NC(CC=2C=CC=CC=2)C(=O)NC(CCCN=C(N)N)C(O)=O)CCC1 QXZGBUJJYSLZLT-UHFFFAOYSA-N 0.000 description 2
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 2
244000017020 Ipomoea batatas Species 0.000 description 2
235000002678 Ipomoea batatas Nutrition 0.000 description 2
102100035792 Kininogen-1 Human genes 0.000 description 2
CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 2
AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
HEMHJVSKTPXQMS-DYCDLGHISA-M Sodium hydroxide-d Chemical compound [Na+].[2H][O-] HEMHJVSKTPXQMS-DYCDLGHISA-M 0.000 description 2
DTQVDTLACAAQTR-UHFFFAOYSA-M Trifluoroacetate Chemical compound [O-]C(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-M 0.000 description 2
230000029936 alkylation Effects 0.000 description 2
238000005804 alkylation reaction Methods 0.000 description 2
XSDQTOBWRPYKKA-UHFFFAOYSA-N amiloride Chemical compound NC(=N)NC(=O)C1=NC(Cl)=C(N)N=C1N XSDQTOBWRPYKKA-UHFFFAOYSA-N 0.000 description 2
229960002576 amiloride Drugs 0.000 description 2
239000000538 analytical sample Substances 0.000 description 2
229960002274 atenolol Drugs 0.000 description 2
239000011230 binding agent Substances 0.000 description 2
230000015572 biosynthetic process Effects 0.000 description 2
QXZGBUJJYSLZLT-FDISYFBBSA-N bradykinin Chemical compound NC(=N)NCCC[C@H](N)C(=O)N1CCC[C@H]1C(=O)N1[C@H](C(=O)NCC(=O)N[C@@H](CC=2C=CC=CC=2)C(=O)N[C@@H](CO)C(=O)N2[C@@H](CCC2)C(=O)N[C@@H](CC=2C=CC=CC=2)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O)CCC1 QXZGBUJJYSLZLT-FDISYFBBSA-N 0.000 description 2
239000000872 buffer Substances 0.000 description 2
150000001721 carbon Chemical group 0.000 description 2
125000004432 carbon atom Chemical group C* 0.000 description 2
229940009995 cryptenamine Drugs 0.000 description 2
235000005911 diet Nutrition 0.000 description 2
230000037213 diet Effects 0.000 description 2
239000002552 dosage form Substances 0.000 description 2
239000003480 eluent Substances 0.000 description 2
238000010828 elution Methods 0.000 description 2
239000000796 flavoring agent Substances 0.000 description 2
235000013355 food flavoring agent Nutrition 0.000 description 2
235000003599 food sweetener Nutrition 0.000 description 2
238000004108 freeze drying Methods 0.000 description 2
XLYOFNOQVPJJNP-ZSJDYOACSA-N heavy water Substances [2H]O[2H] XLYOFNOQVPJJNP-ZSJDYOACSA-N 0.000 description 2
230000007062 hydrolysis Effects 0.000 description 2
238000006460 hydrolysis reaction Methods 0.000 description 2
229950009607 indacrinone Drugs 0.000 description 2
239000003112 inhibitor Substances 0.000 description 2
230000005764 inhibitory process Effects 0.000 description 2
238000002955 isolation Methods 0.000 description 2
150000007522 mineralic acids Chemical class 0.000 description 2
239000012452 mother liquor Substances 0.000 description 2
229910052757 nitrogen Inorganic materials 0.000 description 2
235000005985 organic acids Nutrition 0.000 description 2
238000005192 partition Methods 0.000 description 2
239000008194 pharmaceutical composition Substances 0.000 description 2
239000000546 pharmaceutical excipient Substances 0.000 description 2
229910000027 potassium carbonate Inorganic materials 0.000 description 2
239000000843 powder Substances 0.000 description 2
238000002360 preparation method Methods 0.000 description 2
230000002335 preservative effect Effects 0.000 description 2
AQHHHDLHHXJYJD-UHFFFAOYSA-N propranolol Chemical compound C1=CC=C2C(OCC(O)CNC(C)C)=CC=CC2=C1 AQHHHDLHHXJYJD-UHFFFAOYSA-N 0.000 description 2
125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
OENLEHTYJXMVBG-UHFFFAOYSA-N pyridine;hydrate Chemical compound [OH-].C1=CC=[NH+]C=C1 OENLEHTYJXMVBG-UHFFFAOYSA-N 0.000 description 2
238000001953 recrystallisation Methods 0.000 description 2
238000010898 silica gel chromatography Methods 0.000 description 2
229910052708 sodium Inorganic materials 0.000 description 2
235000009518 sodium iodide Nutrition 0.000 description 2
239000003765 sweetening agent Substances 0.000 description 2
239000006188 syrup Substances 0.000 description 2
235000020357 syrup Nutrition 0.000 description 2
XMOJMZGLUFUQAX-UHFFFAOYSA-N tert-butyl 2-(3-azido-2-oxoazocan-1-yl)acetate Chemical compound CC(C)(C)OC(=O)CN1CCCCCC(N=[N+]=[N-])C1=O XMOJMZGLUFUQAX-UHFFFAOYSA-N 0.000 description 2
SSNXHHIKGMYSIV-UHFFFAOYSA-N tert-butyl 2-oxo-4-phenylbutanoate Chemical compound CC(C)(C)OC(=O)C(=O)CCC1=CC=CC=C1 SSNXHHIKGMYSIV-UHFFFAOYSA-N 0.000 description 2
125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 2
YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 2
FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 2
VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
239000003981 vehicle Substances 0.000 description 2
JWZZKOKVBUJMES-UHFFFAOYSA-N (+-)-Isoprenaline Chemical compound CC(C)NCC(O)C1=CC=C(O)C(O)=C1 JWZZKOKVBUJMES-UHFFFAOYSA-N 0.000 description 1
JBDXSZMCXYWGMN-IBGZPJMESA-N (2s)-1-[2-(3,4-dimethoxyphenyl)ethylamino]-3-[2-(5-thiophen-2-yl-1h-imidazol-2-yl)phenoxy]propan-2-ol Chemical compound C1=C(OC)C(OC)=CC=C1CCNC[C@H](O)COC1=CC=CC=C1C1=NC(C=2SC=CC=2)=CN1 JBDXSZMCXYWGMN-IBGZPJMESA-N 0.000 description 1
NLRUDGHSXOEXCE-PPHPATTJSA-N (2s)-2-amino-3-(3,4-dihydroxyphenyl)-2-methylpropanoic acid;hydrochloride Chemical compound Cl.OC(=O)[C@](N)(C)CC1=CC=C(O)C(O)=C1 NLRUDGHSXOEXCE-PPHPATTJSA-N 0.000 description 1
DNXIKVLOVZVMQF-UHFFFAOYSA-N (3beta,16beta,17alpha,18beta,20alpha)-17-hydroxy-11-methoxy-18-[(3,4,5-trimethoxybenzoyl)oxy]-yohimban-16-carboxylic acid, methyl ester Natural products C1C2CN3CCC(C4=CC=C(OC)C=C4N4)=C4C3CC2C(C(=O)OC)C(O)C1OC(=O)C1=CC(OC)=C(OC)C(OC)=C1 DNXIKVLOVZVMQF-UHFFFAOYSA-N 0.000 description 1
MIOPJNTWMNEORI-GMSGAONNSA-N (S)-camphorsulfonic acid Chemical compound C1C[C@@]2(CS(O)(=O)=O)C(=O)C[C@@H]1C2(C)C MIOPJNTWMNEORI-GMSGAONNSA-N 0.000 description 1
IJRHFDHZRCNEJZ-UHFFFAOYSA-N 1-methylazocan-2-one Chemical compound CN1CCCCCCC1=O IJRHFDHZRCNEJZ-UHFFFAOYSA-N 0.000 description 1
SZLZWPPUNLXJEA-UHFFFAOYSA-N 11,17-dimethoxy-18-[3-(3,4,5-trimethoxy-phenyl)-acryloyloxy]-yohimbane-16-carboxylic acid methyl ester Natural products C1C2CN3CCC(C4=CC=C(OC)C=C4N4)=C4C3CC2C(C(=O)OC)C(OC)C1OC(=O)C=CC1=CC(OC)=C(OC)C(OC)=C1 SZLZWPPUNLXJEA-UHFFFAOYSA-N 0.000 description 1
SGTNSNPWRIOYBX-UHFFFAOYSA-N 2-(3,4-dimethoxyphenyl)-5-{[2-(3,4-dimethoxyphenyl)ethyl](methyl)amino}-2-(propan-2-yl)pentanenitrile Chemical compound C1=C(OC)C(OC)=CC=C1CCN(C)CCCC(C#N)(C(C)C)C1=CC=C(OC)C(OC)=C1 SGTNSNPWRIOYBX-UHFFFAOYSA-N 0.000 description 1
LBLYYCQCTBFVLH-UHFFFAOYSA-N 2-Methylbenzenesulfonic acid Chemical compound CC1=CC=CC=C1S(O)(=O)=O LBLYYCQCTBFVLH-UHFFFAOYSA-N 0.000 description 1
SNDCYKVBQOSWHI-UHFFFAOYSA-N 2-[3-[(1-ethoxy-1-oxo-4-phenylbutan-2-yl)amino]-2-oxoazocan-1-yl]propanoic acid Chemical compound C1CCCCN(C(C)C(O)=O)C(=O)C1NC(C(=O)OCC)CCC1=CC=CC=C1 SNDCYKVBQOSWHI-UHFFFAOYSA-N 0.000 description 1
BDKALUDULQZIQS-UHFFFAOYSA-N 2-[3-[(1-ethoxy-1-oxo-4-phenylbutan-2-yl)amino]-8-methyl-2-oxoazocan-1-yl]propanoic acid;2,2,2-trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F.C1CCCC(C)N(C(C)C(O)=O)C(=O)C1NC(C(=O)OCC)CCC1=CC=CC=C1 BDKALUDULQZIQS-UHFFFAOYSA-N 0.000 description 1
LZJDUDUNBFLNGV-UHFFFAOYSA-N 2-[[1-(1-carboxyethyl)-2-oxoazocan-3-yl]amino]-4-phenylbutanoic acid Chemical compound O=C1N(C(C)C(O)=O)CCCCCC1NC(C(O)=O)CCC1=CC=CC=C1 LZJDUDUNBFLNGV-UHFFFAOYSA-N 0.000 description 1
DZDCNPUCPATOIL-UHFFFAOYSA-N 2-[[1-(carboxymethyl)-8-methyl-2-oxoazocan-3-yl]amino]-4-phenylbutanoic acid Chemical compound O=C1N(CC(O)=O)C(C)CCCCC1NC(C(O)=O)CCC1=CC=CC=C1 DZDCNPUCPATOIL-UHFFFAOYSA-N 0.000 description 1
BYHPWVOAXXIYSQ-UHFFFAOYSA-N 2-[[2-oxo-1-(1-oxo-1-phenylmethoxypropan-2-yl)azocan-3-yl]amino]-4-phenylbutanoic acid Chemical compound C=1C=CC=CC=1COC(=O)C(C)N(C1=O)CCCCCC1NC(C(O)=O)CCC1=CC=CC=C1 BYHPWVOAXXIYSQ-UHFFFAOYSA-N 0.000 description 1
FDMAFOTXGNYBFG-UHFFFAOYSA-N 2-methylcycloheptan-1-one Chemical compound CC1CCCCCC1=O FDMAFOTXGNYBFG-UHFFFAOYSA-N 0.000 description 1
125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 1
BOXXLIUQRAXHDO-UHFFFAOYSA-N 3,3-dichloroazocan-2-one Chemical compound ClC1(Cl)CCCCCNC1=O BOXXLIUQRAXHDO-UHFFFAOYSA-N 0.000 description 1
RYIYULASJDAAPM-UHFFFAOYSA-N 3-(3-azido-2-oxoazocan-1-yl)propanoic acid Chemical compound OC(=O)CCN1CCCCCC(N=[N+]=[N-])C1=O RYIYULASJDAAPM-UHFFFAOYSA-N 0.000 description 1
LOSWDTIJHBEXRQ-UHFFFAOYSA-N 3-aminoazocan-2-one Chemical compound NC1CCCCCNC1=O LOSWDTIJHBEXRQ-UHFFFAOYSA-N 0.000 description 1
AYSPLCIFBLSIHV-UHFFFAOYSA-N 3-azido-8-methylazocan-2-one Chemical compound CC1CCCCC(N=[N+]=[N-])C(=O)N1 AYSPLCIFBLSIHV-UHFFFAOYSA-N 0.000 description 1
NTFPITURSPJYPB-UHFFFAOYSA-N 3-bromo-8-methylazocan-2-one Chemical compound CC1CCCCC(Br)C(=O)N1 NTFPITURSPJYPB-UHFFFAOYSA-N 0.000 description 1
NSVJOSYXAQESLB-UHFFFAOYSA-N 4-[3-[2-[2-(1-hydroxycyclohexyl)ethyl]-4-oxo-1,3-thiazolidin-2-yl]propyl]benzoic acid Chemical compound C1=CC(C(=O)O)=CC=C1CCCC1(CCC2(O)CCCCC2)SCC(=O)N1 NSVJOSYXAQESLB-UHFFFAOYSA-N 0.000 description 1
OBKXEAXTFZPCHS-UHFFFAOYSA-N 4-phenylbutyric acid Chemical compound OC(=O)CCCC1=CC=CC=C1 OBKXEAXTFZPCHS-UHFFFAOYSA-N 0.000 description 1
ODHCTXKNWHHXJC-VKHMYHEASA-N 5-oxo-L-proline Chemical compound OC(=O)[C@@H]1CCC(=O)N1 ODHCTXKNWHHXJC-VKHMYHEASA-N 0.000 description 1
244000215068 Acacia senegal Species 0.000 description 1
QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
239000004254 Ammonium phosphate Substances 0.000 description 1
239000004475 Arginine Substances 0.000 description 1
241000416162 Astragalus gummifer Species 0.000 description 1
239000005711 Benzoic acid Substances 0.000 description 1
WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
239000004215 Carbon black (E152) Substances 0.000 description 1
GJSURZIOUXUGAL-UHFFFAOYSA-N Clonidine Chemical compound ClC1=CC=CC(Cl)=C1NC1=NCCN1 GJSURZIOUXUGAL-UHFFFAOYSA-N 0.000 description 1
CVBMAZKKCSYWQR-BPJCFPRXSA-N Deserpidine Natural products O=C(OC)[C@@H]1[C@H](OC)[C@H](OC(=O)c2cc(OC)c(OC)c(OC)c2)C[C@H]2[C@@H]1C[C@H]1N(C2)CCc2c3c([nH]c12)cccc3 CVBMAZKKCSYWQR-BPJCFPRXSA-N 0.000 description 1
FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
235000019739 Dicalciumphosphate Nutrition 0.000 description 1
LVGKNOAMLMIIKO-UHFFFAOYSA-N Elaidinsaeure-aethylester Natural products CCCCCCCCC=CCCCCCCCC(=O)OCC LVGKNOAMLMIIKO-UHFFFAOYSA-N 0.000 description 1
208000007530 Essential hypertension Diseases 0.000 description 1
239000001856 Ethyl cellulose Substances 0.000 description 1
ZZSNKZQZMQGXPY-UHFFFAOYSA-N Ethyl cellulose Chemical compound CCOCC1OC(OC)C(OCC)C(OCC)C1OC1C(O)C(O)C(OC)C(CO)O1 ZZSNKZQZMQGXPY-UHFFFAOYSA-N 0.000 description 1
208000004248 Familial Primary Pulmonary Hypertension Diseases 0.000 description 1
108010010803 Gelatin Proteins 0.000 description 1
229920000084 Gum arabic Polymers 0.000 description 1
206010020571 Hyperaldosteronism Diseases 0.000 description 1
KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 description 1
239000004472 Lysine Substances 0.000 description 1
241001465754 Metazoa Species 0.000 description 1
CESYKOGBSMNBPD-UHFFFAOYSA-N Methyclothiazide Chemical compound ClC1=C(S(N)(=O)=O)C=C2S(=O)(=O)N(C)C(CCl)NC2=C1 CESYKOGBSMNBPD-UHFFFAOYSA-N 0.000 description 1
229920000168 Microcrystalline cellulose Polymers 0.000 description 1
208000019695 Migraine disease Diseases 0.000 description 1
ZFMITUMMTDLWHR-UHFFFAOYSA-N Minoxidil Chemical compound NC1=[N+]([O-])C(N)=CC(N2CCCCC2)=N1 ZFMITUMMTDLWHR-UHFFFAOYSA-N 0.000 description 1
229920000881 Modified starch Polymers 0.000 description 1
MBBZMMPHUWSWHV-BDVNFPICSA-N N-methylglucamine Chemical compound CNC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO MBBZMMPHUWSWHV-BDVNFPICSA-N 0.000 description 1
235000019483 Peanut oil Nutrition 0.000 description 1
CYLWJCABXYDINA-UHFFFAOYSA-N Polythiazide Polymers ClC1=C(S(N)(=O)=O)C=C2S(=O)(=O)N(C)C(CSCC(F)(F)F)NC2=C1 CYLWJCABXYDINA-UHFFFAOYSA-N 0.000 description 1
OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 1
244000007021 Prunus avium Species 0.000 description 1
235000010401 Prunus avium Nutrition 0.000 description 1
241001290151 Prunus avium subsp. avium Species 0.000 description 1
206010064911 Pulmonary arterial hypertension Diseases 0.000 description 1
241000700159 Rattus Species 0.000 description 1
244000061121 Rauvolfia serpentina Species 0.000 description 1
208000001647 Renal Insufficiency Diseases 0.000 description 1
201000003099 Renovascular Hypertension Diseases 0.000 description 1
SZLZWPPUNLXJEA-FMCDHCOASA-N Rescinnamine Natural products O=C(O[C@H]1[C@@H](OC)[C@@H](C(=O)OC)[C@@H]2[C@H](C1)CN1[C@@H](c3[nH]c4c(c3CC1)ccc(OC)c4)C2)/C=C/c1cc(OC)c(OC)c(OC)c1 SZLZWPPUNLXJEA-FMCDHCOASA-N 0.000 description 1
LCQMZZCPPSWADO-UHFFFAOYSA-N Reserpilin Natural products COC(=O)C1COCC2CN3CCc4c([nH]c5cc(OC)c(OC)cc45)C3CC12 LCQMZZCPPSWADO-UHFFFAOYSA-N 0.000 description 1
QEVHRUUCFGRFIF-SFWBKIHZSA-N Reserpine Natural products O=C(OC)[C@@H]1[C@H](OC)[C@H](OC(=O)c2cc(OC)c(OC)c(OC)c2)C[C@H]2[C@@H]1C[C@H]1N(C2)CCc2c3c([nH]c12)cc(OC)cc3 QEVHRUUCFGRFIF-SFWBKIHZSA-N 0.000 description 1
VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 1
DWAQJAXMDSEUJJ-UHFFFAOYSA-M Sodium bisulfite Chemical compound [Na+].OS([O-])=O DWAQJAXMDSEUJJ-UHFFFAOYSA-M 0.000 description 1
QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
229920002253 Tannate Polymers 0.000 description 1
229920001615 Tragacanth Polymers 0.000 description 1
FNYLWPVRPXGIIP-UHFFFAOYSA-N Triamterene Chemical compound NC1=NC2=NC(N)=NC(N)=C2N=C1C1=CC=CC=C1 FNYLWPVRPXGIIP-UHFFFAOYSA-N 0.000 description 1
239000000205 acacia gum Substances 0.000 description 1
235000010489 acacia gum Nutrition 0.000 description 1
ODHCTXKNWHHXJC-UHFFFAOYSA-N acide pyroglutamique Natural products OC(=O)C1CCC(=O)N1 ODHCTXKNWHHXJC-UHFFFAOYSA-N 0.000 description 1
230000002378 acidificating effect Effects 0.000 description 1
150000007513 acids Chemical class 0.000 description 1
230000003213 activating effect Effects 0.000 description 1
239000013543 active substance Substances 0.000 description 1
230000001154 acute effect Effects 0.000 description 1
239000000783 alginic acid Substances 0.000 description 1
235000010443 alginic acid Nutrition 0.000 description 1
229920000615 alginic acid Polymers 0.000 description 1
229960001126 alginic acid Drugs 0.000 description 1
150000004781 alginic acids Chemical class 0.000 description 1
229910052783 alkali metal Inorganic materials 0.000 description 1
229910052784 alkaline earth metal Inorganic materials 0.000 description 1
230000002152 alkylating effect Effects 0.000 description 1
229960003556 aminophylline Drugs 0.000 description 1
FQPFAHBPWDRTLU-UHFFFAOYSA-N aminophylline Chemical compound NCCN.O=C1N(C)C(=O)N(C)C2=C1NC=N2.O=C1N(C)C(=O)N(C)C2=C1NC=N2 FQPFAHBPWDRTLU-UHFFFAOYSA-N 0.000 description 1
QGZKDVFQNNGYKY-UHFFFAOYSA-N ammonia Natural products N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 1
239000000908 ammonium hydroxide Substances 0.000 description 1
229910000148 ammonium phosphate Inorganic materials 0.000 description 1
235000019289 ammonium phosphates Nutrition 0.000 description 1
150000003863 ammonium salts Chemical class 0.000 description 1
229940044094 angiotensin-converting-enzyme inhibitor Drugs 0.000 description 1
238000010171 animal model Methods 0.000 description 1
239000007864 aqueous solution Substances 0.000 description 1
ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 description 1
238000003556 assay Methods 0.000 description 1
229960003515 bendroflumethiazide Drugs 0.000 description 1
HDWIHXWEUNVBIY-UHFFFAOYSA-N bendroflumethiazidum Chemical compound C1=C(C(F)(F)F)C(S(=O)(=O)N)=CC(S(N2)(=O)=O)=C1NC2CC1=CC=CC=C1 HDWIHXWEUNVBIY-UHFFFAOYSA-N 0.000 description 1
NDTSRXAMMQDVSW-UHFFFAOYSA-N benzthiazide Chemical compound C1=C(Cl)C(S(=O)(=O)N)=CC(S(N2)(=O)=O)=C1N=C2CSCC1=CC=CC=C1 NDTSRXAMMQDVSW-UHFFFAOYSA-N 0.000 description 1
229960001541 benzthiazide Drugs 0.000 description 1
235000019445 benzyl alcohol Nutrition 0.000 description 1
GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
MAEIEVLCKWDQJH-UHFFFAOYSA-N bumetanide Chemical compound CCCCNC1=CC(C(O)=O)=CC(S(N)(=O)=O)=C1OC1=CC=CC=C1 MAEIEVLCKWDQJH-UHFFFAOYSA-N 0.000 description 1
229960004064 bumetanide Drugs 0.000 description 1
125000004369 butenyl group Chemical group C(=CCC)* 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
229910052791 calcium Inorganic materials 0.000 description 1
239000011575 calcium Substances 0.000 description 1
239000001506 calcium phosphate Substances 0.000 description 1
235000019693 cherries Nutrition 0.000 description 1
239000007958 cherry flavor Substances 0.000 description 1
229960002155 chlorothiazide Drugs 0.000 description 1
230000001684 chronic effect Effects 0.000 description 1
229960002896 clonidine Drugs 0.000 description 1
239000003240 coconut oil Substances 0.000 description 1
235000019864 coconut oil Nutrition 0.000 description 1
238000001816 cooling Methods 0.000 description 1
235000012343 cottonseed oil Nutrition 0.000 description 1
239000002385 cottonseed oil Substances 0.000 description 1
238000002425 crystallisation Methods 0.000 description 1
230000008025 crystallization Effects 0.000 description 1
229960003176 cyclothiazide Drugs 0.000 description 1
BOCUKUHCLICSIY-QJWLJZLASA-N cyclothiazide Chemical compound C1=C(Cl)C(S(=O)(=O)N)=CC(S(N2)(=O)=O)=C1NC2C1[C@H](C=C2)C[C@H]2C1 BOCUKUHCLICSIY-QJWLJZLASA-N 0.000 description 1
238000000354 decomposition reaction Methods 0.000 description 1
CVBMAZKKCSYWQR-WCGOZPBSSA-N deserpidine Chemical compound O([C@H]1[C@@H]([C@H]([C@H]2C[C@@H]3C4=C(C5=CC=CC=C5N4)CCN3C[C@H]2C1)C(=O)OC)OC)C(=O)C1=CC(OC)=C(OC)C(OC)=C1 CVBMAZKKCSYWQR-WCGOZPBSSA-N 0.000 description 1
229960001993 deserpidine Drugs 0.000 description 1
MNNHAPBLZZVQHP-UHFFFAOYSA-N diammonium hydrogen phosphate Chemical compound [NH4+].[NH4+].OP([O-])([O-])=O MNNHAPBLZZVQHP-UHFFFAOYSA-N 0.000 description 1
229960004042 diazoxide Drugs 0.000 description 1
NEFBYIFKOOEVPA-UHFFFAOYSA-K dicalcium phosphate Chemical compound [Ca+2].[Ca+2].[O-]P([O-])([O-])=O NEFBYIFKOOEVPA-UHFFFAOYSA-K 0.000 description 1
229940038472 dicalcium phosphate Drugs 0.000 description 1
229910000390 dicalcium phosphate Inorganic materials 0.000 description 1
239000002270 dispersing agent Substances 0.000 description 1
239000002934 diuretic Substances 0.000 description 1
229940030606 diuretics Drugs 0.000 description 1
239000000890 drug combination Substances 0.000 description 1
239000013583 drug formulation Substances 0.000 description 1
239000000975 dye Substances 0.000 description 1
125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 description 1
ZKQFHRVKCYFVCN-UHFFFAOYSA-N ethoxyethane;hexane Chemical compound CCOCC.CCCCCC ZKQFHRVKCYFVCN-UHFFFAOYSA-N 0.000 description 1
RBUSQEDXOORFBU-UHFFFAOYSA-N ethyl 2-[(2-oxoazocan-3-yl)amino]-4-phenylbutanoate Chemical compound C1CCCCNC(=O)C1NC(C(=O)OCC)CCC1=CC=CC=C1 RBUSQEDXOORFBU-UHFFFAOYSA-N 0.000 description 1
BETVIXATJAPXEB-BGERDNNASA-N ethyl 2-[[(3s)-1-[2-[(2-methylpropan-2-yl)oxy]-2-oxoethyl]-2-oxoazocan-3-yl]amino]-4-phenylbutanoate Chemical compound N([C@@H]1C(N(CC(=O)OC(C)(C)C)CCCCC1)=O)C(C(=O)OCC)CCC1=CC=CC=C1 BETVIXATJAPXEB-BGERDNNASA-N 0.000 description 1
BETVIXATJAPXEB-UHFFFAOYSA-N ethyl 2-[[1-[2-[(2-methylpropan-2-yl)oxy]-2-oxoethyl]-2-oxoazocan-3-yl]amino]-4-phenylbutanoate Chemical compound C1CCCCN(CC(=O)OC(C)(C)C)C(=O)C1NC(C(=O)OCC)CCC1=CC=CC=C1 BETVIXATJAPXEB-UHFFFAOYSA-N 0.000 description 1
BFDDWTZZQMPMRD-UHFFFAOYSA-N ethyl 2-[[8-methyl-1-[2-[(2-methylpropan-2-yl)oxy]-2-oxoethyl]-2-oxoazocan-3-yl]amino]-4-phenylbutanoate Chemical compound C1CCCC(C)N(CC(=O)OC(C)(C)C)C(=O)C1NC(C(=O)OCC)CCC1=CC=CC=C1 BFDDWTZZQMPMRD-UHFFFAOYSA-N 0.000 description 1
MJCZYRJTANZIEI-UHFFFAOYSA-N ethyl 2-oxo-5-phenylpentanoate Chemical compound CCOC(=O)C(=O)CCCC1=CC=CC=C1 MJCZYRJTANZIEI-UHFFFAOYSA-N 0.000 description 1
235000019325 ethyl cellulose Nutrition 0.000 description 1
229920001249 ethyl cellulose Polymers 0.000 description 1
LVGKNOAMLMIIKO-QXMHVHEDSA-N ethyl oleate Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OCC LVGKNOAMLMIIKO-QXMHVHEDSA-N 0.000 description 1
229940093471 ethyl oleate Drugs 0.000 description 1
238000011156 evaluation Methods 0.000 description 1
238000000605 extraction Methods 0.000 description 1
235000019197 fats Nutrition 0.000 description 1
239000000706 filtrate Substances 0.000 description 1
238000001914 filtration Methods 0.000 description 1
239000001530 fumaric acid Substances 0.000 description 1
239000008273 gelatin Substances 0.000 description 1
229920000159 gelatin Polymers 0.000 description 1
235000019322 gelatine Nutrition 0.000 description 1
235000011852 gelatine desserts Nutrition 0.000 description 1
239000008187 granular material Substances 0.000 description 1
150000004820 halides Chemical class 0.000 description 1
208000019622 heart disease Diseases 0.000 description 1
125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
ZUXNZUWOTSUBMN-UHFFFAOYSA-N hydralazine hydrochloride Chemical compound Cl.C1=CC=C2C(NN)=NN=CC2=C1 ZUXNZUWOTSUBMN-UHFFFAOYSA-N 0.000 description 1
229960005384 hydralazine hydrochloride Drugs 0.000 description 1
229930195733 hydrocarbon Natural products 0.000 description 1
150000002430 hydrocarbons Chemical class 0.000 description 1
150000003840 hydrochlorides Chemical class 0.000 description 1
DMDGGSIALPNSEE-UHFFFAOYSA-N hydroflumethiazide Chemical compound C1=C(C(F)(F)F)C(S(=O)(=O)N)=CC2=C1NCNS2(=O)=O DMDGGSIALPNSEE-UHFFFAOYSA-N 0.000 description 1
229960003313 hydroflumethiazide Drugs 0.000 description 1
238000005984 hydrogenation reaction Methods 0.000 description 1
230000001631 hypertensive effect Effects 0.000 description 1
239000005457 ice water Substances 0.000 description 1
238000000338 in vitro Methods 0.000 description 1
238000001727 in vivo Methods 0.000 description 1
239000004615 ingredient Substances 0.000 description 1
239000007924 injection Substances 0.000 description 1
238000002347 injection Methods 0.000 description 1
238000007918 intramuscular administration Methods 0.000 description 1
150000002500 ions Chemical class 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
125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
150000004715 keto acids Chemical class 0.000 description 1
201000006370 kidney failure Diseases 0.000 description 1
150000003951 lactams Chemical class 0.000 description 1
XMGQYMWWDOXHJM-UHFFFAOYSA-N limonene Chemical compound CC(=C)C1CCC(C)=CC1 XMGQYMWWDOXHJM-UHFFFAOYSA-N 0.000 description 1
150000002632 lipids Chemical class 0.000 description 1
239000000314 lubricant Substances 0.000 description 1
159000000003 magnesium salts Chemical class 0.000 description 1
229910052943 magnesium sulfate Inorganic materials 0.000 description 1
235000019341 magnesium sulphate Nutrition 0.000 description 1
VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
239000011976 maleic acid Substances 0.000 description 1
230000003211 malignant effect Effects 0.000 description 1
201000005857 malignant hypertension Diseases 0.000 description 1
230000007246 mechanism Effects 0.000 description 1
229940098779 methanesulfonic acid Drugs 0.000 description 1
229960003739 methyclothiazide Drugs 0.000 description 1
BMIVDTKSHPDYPG-UHFFFAOYSA-N methyl 2-(3-azido-2-oxoazocan-1-yl)propanoate Chemical compound COC(=O)C(C)N1CCCCCC(N=[N+]=[N-])C1=O BMIVDTKSHPDYPG-UHFFFAOYSA-N 0.000 description 1
BALADIHEPAEKQJ-UHFFFAOYSA-N methyl 2-iodopropanoate Chemical compound COC(=O)C(C)I BALADIHEPAEKQJ-UHFFFAOYSA-N 0.000 description 1
150000004702 methyl esters Chemical class 0.000 description 1
235000010270 methyl p-hydroxybenzoate Nutrition 0.000 description 1
AQCHWTWZEMGIFD-UHFFFAOYSA-N metolazone Chemical compound CC1NC2=CC(Cl)=C(S(N)(=O)=O)C=C2C(=O)N1C1=CC=CC=C1C AQCHWTWZEMGIFD-UHFFFAOYSA-N 0.000 description 1
229960002817 metolazone Drugs 0.000 description 1
235000019813 microcrystalline cellulose Nutrition 0.000 description 1
239000008108 microcrystalline cellulose Substances 0.000 description 1
229940016286 microcrystalline cellulose Drugs 0.000 description 1
229960003632 minoxidil Drugs 0.000 description 1
239000011812 mixed powder Substances 0.000 description 1
230000004048 modification Effects 0.000 description 1
238000012986 modification Methods 0.000 description 1
IGGMKEYOISAENY-UHFFFAOYSA-N n-tert-butylcyclopropanecarboxamide Chemical compound CC(C)(C)NC(=O)C1CC1 IGGMKEYOISAENY-UHFFFAOYSA-N 0.000 description 1
HYIMSNHJOBLJNT-UHFFFAOYSA-N nifedipine Chemical compound COC(=O)C1=C(C)NC(C)=C(C(=O)OC)C1C1=CC=CC=C1[N+]([O-])=O HYIMSNHJOBLJNT-UHFFFAOYSA-N 0.000 description 1
229960001597 nifedipine Drugs 0.000 description 1
231100000252 nontoxic Toxicity 0.000 description 1
230000003000 nontoxic effect Effects 0.000 description 1
239000007968 orange flavor Substances 0.000 description 1
239000003960 organic solvent Substances 0.000 description 1
239000007800 oxidant agent Substances 0.000 description 1
238000007911 parenteral administration Methods 0.000 description 1
239000000312 peanut oil Substances 0.000 description 1
125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
239000003208 petroleum Substances 0.000 description 1
229950009215 phenylbutanoic acid Drugs 0.000 description 1
229960005483 polythiazide Drugs 0.000 description 1
229920000046 polythiazide Polymers 0.000 description 1
159000000001 potassium salts Chemical class 0.000 description 1
IENZQIKPVFGBNW-UHFFFAOYSA-N prazosin Chemical compound N=1C(N)=C2C=C(OC)C(OC)=CC2=NC=1N(CC1)CCN1C(=O)C1=CC=CO1 IENZQIKPVFGBNW-UHFFFAOYSA-N 0.000 description 1
229960001289 prazosin Drugs 0.000 description 1
239000002243 precursor Substances 0.000 description 1
201000009395 primary hyperaldosteronism Diseases 0.000 description 1
201000008312 primary pulmonary hypertension Diseases 0.000 description 1
MFDFERRIHVXMIY-UHFFFAOYSA-N procaine Chemical compound CCN(CC)CCOC(=O)C1=CC=C(N)C=C1 MFDFERRIHVXMIY-UHFFFAOYSA-N 0.000 description 1
229960004919 procaine Drugs 0.000 description 1
238000003672 processing method Methods 0.000 description 1
229960003712 propranolol Drugs 0.000 description 1
235000010232 propyl p-hydroxybenzoate Nutrition 0.000 description 1
UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
239000002516 radical scavenger Substances 0.000 description 1
SZLZWPPUNLXJEA-QEGASFHISA-N rescinnamine Chemical compound O([C@H]1[C@@H]([C@H]([C@H]2C[C@@H]3C4=C(C5=CC=C(OC)C=C5N4)CCN3C[C@H]2C1)C(=O)OC)OC)C(=O)\C=C\C1=CC(OC)=C(OC)C(OC)=C1 SZLZWPPUNLXJEA-QEGASFHISA-N 0.000 description 1
229960001965 rescinnamine Drugs 0.000 description 1
QEVHRUUCFGRFIF-MDEJGZGSSA-N reserpine Chemical compound O([C@H]1[C@@H]([C@H]([C@H]2C[C@@H]3C4=C(C5=CC=C(OC)C=C5N4)CCN3C[C@H]2C1)C(=O)OC)OC)C(=O)C1=CC(OC)=C(OC)C(OC)=C1 QEVHRUUCFGRFIF-MDEJGZGSSA-N 0.000 description 1
229960003147 reserpine Drugs 0.000 description 1
239000011347 resin Substances 0.000 description 1
229920005989 resin Polymers 0.000 description 1
238000004366 reverse phase liquid chromatography Methods 0.000 description 1
MDMGHDFNKNZPAU-UHFFFAOYSA-N roserpine Natural products C1C2CN3CCC(C4=CC=C(OC)C=C4N4)=C4C3CC2C(OC(C)=O)C(OC)C1OC(=O)C1=CC(OC)=C(OC)C(OC)=C1 MDMGHDFNKNZPAU-UHFFFAOYSA-N 0.000 description 1
CVHZOJJKTDOEJC-UHFFFAOYSA-N saccharin Chemical compound C1=CC=C2C(=O)NS(=O)(=O)C2=C1 CVHZOJJKTDOEJC-UHFFFAOYSA-N 0.000 description 1
229940081974 saccharin Drugs 0.000 description 1
235000019204 saccharin Nutrition 0.000 description 1
239000000901 saccharin and its Na,K and Ca salt Substances 0.000 description 1
239000000523 sample Substances 0.000 description 1
229920006395 saturated elastomer Polymers 0.000 description 1
DCKVNWZUADLDEH-UHFFFAOYSA-N sec-butyl acetate Chemical compound CCC(C)OC(C)=O DCKVNWZUADLDEH-UHFFFAOYSA-N 0.000 description 1
208000037812 secondary pulmonary hypertension Diseases 0.000 description 1
239000008159 sesame oil Substances 0.000 description 1
235000011803 sesame oil Nutrition 0.000 description 1
239000001632 sodium acetate Substances 0.000 description 1
235000017281 sodium acetate Nutrition 0.000 description 1
235000017557 sodium bicarbonate Nutrition 0.000 description 1
229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
235000010267 sodium hydrogen sulphite Nutrition 0.000 description 1
LXMSZDCAJNLERA-ZHYRCANASA-N spironolactone Chemical compound C([C@@H]1[C@]2(C)CC[C@@H]3[C@@]4(C)CCC(=O)C=C4C[C@H]([C@@H]13)SC(=O)C)C[C@@]21CCC(=O)O1 LXMSZDCAJNLERA-ZHYRCANASA-N 0.000 description 1
229960002256 spironolactone Drugs 0.000 description 1
239000003381 stabilizer Substances 0.000 description 1
239000008174 sterile solution Substances 0.000 description 1
239000000829 suppository Substances 0.000 description 1
238000003786 synthesis reaction Methods 0.000 description 1
238000010189 synthetic method Methods 0.000 description 1
229940095064 tartrate Drugs 0.000 description 1
VCHDVASVJOSHFS-UHFFFAOYSA-N tert-butyl 2-(3,3-dichloro-2-oxoazocan-1-yl)acetate Chemical compound CC(C)(C)OC(=O)CN1CCCCCC(Cl)(Cl)C1=O VCHDVASVJOSHFS-UHFFFAOYSA-N 0.000 description 1
KAGBTJWBWJNJDU-UHFFFAOYSA-N tert-butyl 2-(3-chloro-2-oxoazocan-1-yl)acetate Chemical compound CC(C)(C)OC(=O)CN1CCCCCC(Cl)C1=O KAGBTJWBWJNJDU-UHFFFAOYSA-N 0.000 description 1
QCHBORIQPQSOCO-SNVBAGLBSA-N tert-butyl 2-[(3r)-3-amino-2-oxoazocan-1-yl]acetate Chemical compound CC(C)(C)OC(=O)CN1CCCCC[C@@H](N)C1=O QCHBORIQPQSOCO-SNVBAGLBSA-N 0.000 description 1
RTMIHIBHGLPUGR-ARCXQOPISA-N tert-butyl 2-[(3r)-3-amino-2-oxoazocan-1-yl]acetate;(2s)-5-oxopyrrolidine-2-carboxylic acid Chemical compound OC(=O)[C@@H]1CCC(=O)N1.CC(C)(C)OC(=O)CN1CCCCC[C@@H](N)C1=O RTMIHIBHGLPUGR-ARCXQOPISA-N 0.000 description 1
QCHBORIQPQSOCO-JTQLQIEISA-N tert-butyl 2-[(3s)-3-amino-2-oxoazocan-1-yl]acetate Chemical compound CC(C)(C)OC(=O)CN1CCCCC[C@H](N)C1=O QCHBORIQPQSOCO-JTQLQIEISA-N 0.000 description 1
LFTIIOJYLKCWEZ-UHFFFAOYSA-N tert-butyl 2-[[2-oxo-1-(2-oxo-2-phenylmethoxyethyl)azocan-3-yl]amino]-4-phenylbutanoate Chemical compound C1CCCCN(CC(=O)OCC=2C=CC=CC=2)C(=O)C1NC(C(=O)OC(C)(C)C)CCC1=CC=CC=C1 LFTIIOJYLKCWEZ-UHFFFAOYSA-N 0.000 description 1
229960001288 triamterene Drugs 0.000 description 1
229960004813 trichlormethiazide Drugs 0.000 description 1
LMJSLTNSBFUCMU-UHFFFAOYSA-N trichlormethiazide Chemical compound C1=C(Cl)C(S(=O)(=O)N)=CC2=C1NC(C(Cl)Cl)NS2(=O)=O LMJSLTNSBFUCMU-UHFFFAOYSA-N 0.000 description 1
230000002792 vascular Effects 0.000 description 1
208000019553 vascular disease Diseases 0.000 description 1
239000003071 vasodilator agent Substances 0.000 description 1
235000015112 vegetable and seed oil Nutrition 0.000 description 1
239000008158 vegetable oil Substances 0.000 description 1
229960001722 verapamil Drugs 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
239000008215 water for injection Substances 0.000 description 1