CA1310792C - Inhibiteurs de la renine de type alcool n-heterocyclique - Google Patents

Inhibiteurs de la renine de type alcool n-heterocyclique

Info

Publication number: CA1310792C
Authority: CA; Canada
Prior art keywords: methyl; compound; ha375a; mmole; hydroxy
Prior art date: 1986-02-03
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

Application number

CA000528852A

Other languages

English (en)

Inventor

Denis E. Ryono

Harold N. Weller, Iii

Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)

ER Squibb and Sons LLC

Original Assignee

ER Squibb and Sons LLC

Priority date (The priority date 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 date listed.)

1986-02-03

Filing date

1987-02-03

Publication date

1992-11-24

1987-02-03 Application filed by ER Squibb and Sons LLC filed Critical ER Squibb and Sons LLC

1992-11-24 Application granted granted Critical

1992-11-24 Publication of CA1310792C publication Critical patent/CA1310792C/fr

2009-11-24 Anticipated expiration legal-status Critical

Status Expired - Lifetime legal-status Critical Current

Links

LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 title abstract description 40
239000002461 renin inhibitor Substances 0.000 title abstract description 4
229940086526 renin-inhibitors Drugs 0.000 title abstract description 4
150000001875 compounds Chemical class 0.000 claims abstract description 72
-1 hydroxy, amino Chemical group 0.000 claims description 178
QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 171
125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 158
VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 104
125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 104
125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 60
125000000217 alkyl group Chemical group 0.000 claims description 52
239000001257 hydrogen Substances 0.000 claims description 34
229910052739 hydrogen Inorganic materials 0.000 claims description 34
229920006395 saturated elastomer Polymers 0.000 claims description 33
150000003839 salts Chemical class 0.000 claims description 24
125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 22
UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 17
159000000021 acetate salts Chemical class 0.000 claims description 17
229910052799 carbon Inorganic materials 0.000 claims description 13
125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 13
QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical class CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 claims description 11
125000004435 hydrogen atom Chemical class [H]* 0.000 claims description 10
125000004433 nitrogen atom Chemical group N* 0.000 claims description 10
125000001622 2-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C([H])=C(*)C([H])=C([H])C2=C1[H] 0.000 claims description 9
125000005843 halogen group Chemical group 0.000 claims description 9
125000003118 aryl group Chemical group 0.000 claims description 8
125000004432 carbon atom Chemical group C* 0.000 claims description 8
229910052760 oxygen Inorganic materials 0.000 claims description 7
125000002619 bicyclic group Chemical group 0.000 claims description 6
125000000753 cycloalkyl group Chemical group 0.000 claims description 6
125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 6
239000012453 solvate Substances 0.000 claims description 6
125000001917 2,4-dinitrophenyl group Chemical group [H]C1=C([H])C(=C([H])C(=C1*)[N+]([O-])=O)[N+]([O-])=O 0.000 claims description 5
206010020772 Hypertension Diseases 0.000 claims description 5
125000003545 alkoxy group Chemical group 0.000 claims description 5
125000004414 alkyl thio group Chemical group 0.000 claims description 5
125000004429 atom Chemical group 0.000 claims description 5
VFRSADQPWYCXDG-LEUCUCNGSA-N ethyl (2s,5s)-5-methylpyrrolidine-2-carboxylate;2,2,2-trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F.CCOC(=O)[C@@H]1CC[C@H](C)N1 VFRSADQPWYCXDG-LEUCUCNGSA-N 0.000 claims description 5
125000005842 heteroatom Chemical group 0.000 claims description 5
125000003037 imidazol-2-yl group Chemical group [H]N1C([*])=NC([H])=C1[H] 0.000 claims description 5
125000001424 substituent group Chemical group 0.000 claims description 5
229910052717 sulfur Inorganic materials 0.000 claims description 5
125000004434 sulfur atom Chemical group 0.000 claims description 5
125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 4
125000001309 chloro group Chemical group Cl* 0.000 claims description 4
229910052736 halogen Inorganic materials 0.000 claims description 4
150000002367 halogens Chemical class 0.000 claims description 4
125000000623 heterocyclic group Chemical group 0.000 claims description 4
125000002950 monocyclic group Chemical group 0.000 claims description 4
125000004430 oxygen atom Chemical group O* 0.000 claims description 4
125000002435 L-phenylalanyl group Chemical group O=C([*])[C@](N([H])[H])([H])C([H])([H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims description 3
125000001246 bromo group Chemical group Br* 0.000 claims description 3
125000001153 fluoro group Chemical group F* 0.000 claims description 3
125000004356 hydroxy functional group Chemical group O* 0.000 claims description 3
125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 3
125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 3
125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 3
229910052801 chlorine Inorganic materials 0.000 claims description 2
125000001637 1-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C(*)=C([H])C([H])=C([H])C2=C1[H] 0.000 claims 4
239000003937 drug carrier Substances 0.000 claims 2
239000008194 pharmaceutical composition Substances 0.000 claims 2
102100034535 Histone H3.1 Human genes 0.000 claims 1
101001067844 Homo sapiens Histone H3.1 Proteins 0.000 claims 1
229910052794 bromium Inorganic materials 0.000 claims 1
229910052731 fluorine Inorganic materials 0.000 claims 1
125000002816 methylsulfanyl group Chemical group [H]C([H])([H])S[*] 0.000 claims 1
238000006243 chemical reaction Methods 0.000 abstract description 27
108090000783 Renin Proteins 0.000 abstract description 7
102100028255 Renin Human genes 0.000 abstract description 6
230000002401 inhibitory effect Effects 0.000 abstract description 5
102000005862 Angiotensin II Human genes 0.000 abstract description 3
101800000733 Angiotensin-2 Proteins 0.000 abstract description 3
102000015427 Angiotensins Human genes 0.000 abstract description 3
108010064733 Angiotensins Proteins 0.000 abstract description 3
229950006323 angiotensin ii Drugs 0.000 abstract description 3
229940030600 antihypertensive agent Drugs 0.000 abstract description 3
239000002220 antihypertensive agent Substances 0.000 abstract description 3
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 abstract 1
OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 458
XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 294
239000000243 solution Substances 0.000 description 143
239000000203 mixture Substances 0.000 description 118
XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 115
229910001868 water Inorganic materials 0.000 description 115
HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 114
VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 113
239000000047 product Substances 0.000 description 96
239000000741 silica gel Substances 0.000 description 93
229910002027 silica gel Inorganic materials 0.000 description 93
WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 90
RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 88
VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 83
XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 58
CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 58
235000011054 acetic acid Nutrition 0.000 description 56
229960000583 acetic acid Drugs 0.000 description 56
YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 45
UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 44
HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 42
ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 42
SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 40
JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 38
229910052943 magnesium sulfate Inorganic materials 0.000 description 38
YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 36
235000011167 hydrochloric acid Nutrition 0.000 description 36
229960000443 hydrochloric acid Drugs 0.000 description 36
ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 35
239000011541 reaction mixture Substances 0.000 description 34
CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 33
239000012043 crude product Substances 0.000 description 33
QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 32
239000012267 brine Substances 0.000 description 30
HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 30
229910052786 argon Inorganic materials 0.000 description 29
235000019341 magnesium sulphate Nutrition 0.000 description 29
239000007787 solid Substances 0.000 description 27
125000000325 methylidene group Chemical group [H]C([H])=* 0.000 description 25
IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 23
229910000041 hydrogen chloride Inorganic materials 0.000 description 23
239000003054 catalyst Substances 0.000 description 21
239000000284 extract Substances 0.000 description 21
239000000706 filtrate Substances 0.000 description 21
238000003818 flash chromatography Methods 0.000 description 20
125000002887 hydroxy group Chemical group [H]O* 0.000 description 20
UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 19
239000005457 ice water Substances 0.000 description 18
NXJCBFBQEVOTOW-UHFFFAOYSA-L palladium(2+);dihydroxide Chemical compound O[Pd]O NXJCBFBQEVOTOW-UHFFFAOYSA-L 0.000 description 18
UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 17
FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 17
239000002253 acid Substances 0.000 description 17
QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 16
MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 16
239000002904 solvent Substances 0.000 description 16
ASOKPJOREAFHNY-UHFFFAOYSA-N 1-Hydroxybenzotriazole Chemical compound C1=CC=C2N(O)N=NC2=C1 ASOKPJOREAFHNY-UHFFFAOYSA-N 0.000 description 15
JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 14
229940024606 amino acid Drugs 0.000 description 14
229960002885 histidine Drugs 0.000 description 14
229910000030 sodium bicarbonate Inorganic materials 0.000 description 14
235000017557 sodium bicarbonate Nutrition 0.000 description 14
229960001407 sodium bicarbonate Drugs 0.000 description 14
150000001412 amines Chemical class 0.000 description 13
235000001014 amino acid Nutrition 0.000 description 13
150000001413 amino acids Chemical class 0.000 description 13
150000002148 esters Chemical class 0.000 description 13
150000004702 methyl esters Chemical class 0.000 description 13
239000003208 petroleum Substances 0.000 description 13
229960005190 phenylalanine Drugs 0.000 description 13
WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 12
YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 12
238000003756 stirring Methods 0.000 description 11
KXDHJXZQYSOELW-UHFFFAOYSA-N carbonic acid monoamide Natural products NC(O)=O KXDHJXZQYSOELW-UHFFFAOYSA-N 0.000 description 10
238000000034 method Methods 0.000 description 10
KJAMZCVTJDTESW-UHFFFAOYSA-N tiracizine Chemical compound C1CC2=CC=CC=C2N(C(=O)CN(C)C)C2=CC(NC(=O)OCC)=CC=C21 KJAMZCVTJDTESW-UHFFFAOYSA-N 0.000 description 10
OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 9
DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 9
230000008878 coupling Effects 0.000 description 9
238000010168 coupling process Methods 0.000 description 9
238000005859 coupling reaction Methods 0.000 description 9
150000002431 hydrogen Chemical class 0.000 description 9
238000010992 reflux Methods 0.000 description 9
UMMQVDUMUMBTAV-YFKPBYRVSA-N (2s)-2-amino-3-(1h-imidazol-5-yl)propanamide Chemical compound NC(=O)[C@@H](N)CC1=CN=CN1 UMMQVDUMUMBTAV-YFKPBYRVSA-N 0.000 description 8
NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical class [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 8
229910021529 ammonia Inorganic materials 0.000 description 8
239000007789 gas Substances 0.000 description 8
239000003921 oil Substances 0.000 description 8
239000011780 sodium chloride Substances 0.000 description 8
PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 7
UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical class [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 7
239000007822 coupling agent Substances 0.000 description 7
239000000463 material Substances 0.000 description 7
239000000843 powder Substances 0.000 description 7
239000002244 precipitate Substances 0.000 description 7
239000000377 silicon dioxide Substances 0.000 description 7
229910052938 sodium sulfate Inorganic materials 0.000 description 7
235000011152 sodium sulphate Nutrition 0.000 description 7
NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical compound CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 description 6
QCQCHGYLTSGIGX-GHXANHINSA-N 4-[[(3ar,5ar,5br,7ar,9s,11ar,11br,13as)-5a,5b,8,8,11a-pentamethyl-3a-[(5-methylpyridine-3-carbonyl)amino]-2-oxo-1-propan-2-yl-4,5,6,7,7a,9,10,11,11b,12,13,13a-dodecahydro-3h-cyclopenta[a]chrysen-9-yl]oxy]-2,2-dimethyl-4-oxobutanoic acid Chemical compound N([C@@]12CC[C@@]3(C)[C@]4(C)CC[C@H]5C(C)(C)[C@@H](OC(=O)CC(C)(C)C(O)=O)CC[C@]5(C)[C@H]4CC[C@@H]3C1=C(C(C2)=O)C(C)C)C(=O)C1=CN=CC(C)=C1 QCQCHGYLTSGIGX-GHXANHINSA-N 0.000 description 6
VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 6
LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 6
KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 6
238000001816 cooling Methods 0.000 description 6
BEBCJVAWIBVWNZ-UHFFFAOYSA-N glycinamide Chemical compound NCC(N)=O BEBCJVAWIBVWNZ-UHFFFAOYSA-N 0.000 description 6
239000012044 organic layer Substances 0.000 description 6
108090000765 processed proteins & peptides Proteins 0.000 description 6
239000000725 suspension Substances 0.000 description 6
239000000908 ammonium hydroxide Substances 0.000 description 5
NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 5
RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Substances C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 5
239000000543 intermediate Substances 0.000 description 5
239000010410 layer Substances 0.000 description 5
229960003136 leucine Drugs 0.000 description 5
PJUPKRYGDFTMTM-UHFFFAOYSA-N 1-hydroxybenzotriazole;hydrate Chemical compound O.C1=CC=C2N(O)N=NC2=C1 PJUPKRYGDFTMTM-UHFFFAOYSA-N 0.000 description 4
101800000734 Angiotensin-1 Proteins 0.000 description 4
102400000344 Angiotensin-1 Human genes 0.000 description 4
229910014033 C-OH Inorganic materials 0.000 description 4
229910014570 C—OH Inorganic materials 0.000 description 4
IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 4
DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 4
HNDVDQJCIGZPNO-YFKPBYRVSA-N L-histidine Chemical compound OC(=O)[C@@H](N)CC1=CN=CN1 HNDVDQJCIGZPNO-YFKPBYRVSA-N 0.000 description 4
239000004395 L-leucine Substances 0.000 description 4
YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 4
125000001980 alanyl group Chemical group 0.000 description 4
ORWYRWWVDCYOMK-HBZPZAIKSA-N angiotensin I Chemical compound C([C@@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC=1NC=NC=1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CC=1NC=NC=1)C(=O)N[C@@H](CC(C)C)C(O)=O)NC(=O)[C@@H](NC(=O)[C@H](CCCN=C(N)N)NC(=O)[C@@H](N)CC(O)=O)C(C)C)C1=CC=C(O)C=C1 ORWYRWWVDCYOMK-HBZPZAIKSA-N 0.000 description 4
125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 4
238000004587 chromatography analysis Methods 0.000 description 4
239000013078 crystal Substances 0.000 description 4
239000002934 diuretic Substances 0.000 description 4
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 4
LFKDJXLFVYVEFG-UHFFFAOYSA-N tert-butyl carbamate Chemical compound CC(C)(C)OC(N)=O LFKDJXLFVYVEFG-UHFFFAOYSA-N 0.000 description 4
FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 4
CUKWUWBLQQDQAC-VEQWQPCFSA-N (3s)-3-amino-4-[[(2s)-1-[[(2s)-1-[[(2s)-1-[[(2s,3s)-1-[[(2s)-1-[(2s)-2-[[(1s)-1-carboxyethyl]carbamoyl]pyrrolidin-1-yl]-3-(1h-imidazol-5-yl)-1-oxopropan-2-yl]amino]-3-methyl-1-oxopentan-2-yl]amino]-3-(4-hydroxyphenyl)-1-oxopropan-2-yl]amino]-3-methyl-1-ox 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](C)C(O)=O)NC(=O)[C@@H](NC(=O)[C@H](CCCN=C(N)N)NC(=O)[C@@H](N)CC(O)=O)C(C)C)C1=CC=C(O)C=C1 CUKWUWBLQQDQAC-VEQWQPCFSA-N 0.000 description 3
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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
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YXZISSQOFIZLNX-JTQLQIEISA-N tert-butyl n-[(2s)-1-oxo-1-phenylpropan-2-yl]carbamate Chemical compound CC(C)(C)OC(=O)N[C@@H](C)C(=O)C1=CC=CC=C1 YXZISSQOFIZLNX-JTQLQIEISA-N 0.000 description 1
RQSBRFZHUKLKNO-VIFPVBQESA-N tert-butyl n-[(2s)-4-methyl-1-oxopentan-2-yl]carbamate Chemical compound CC(C)C[C@@H](C=O)NC(=O)OC(C)(C)C RQSBRFZHUKLKNO-VIFPVBQESA-N 0.000 description 1
239000003451 thiazide diuretic agent Substances 0.000 description 1
AGHANLSBXUWXTB-UHFFFAOYSA-N tienilic acid Chemical compound ClC1=C(Cl)C(OCC(=O)O)=CC=C1C(=O)C1=CC=CS1 AGHANLSBXUWXTB-UHFFFAOYSA-N 0.000 description 1
229960000356 tienilic acid Drugs 0.000 description 1
VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
230000007704 transition Effects 0.000 description 1
229960001288 triamterene 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
229960004813 trichlormethiazide Drugs 0.000 description 1
125000002221 trityl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C([*])(C1=C(C(=C(C(=C1[H])[H])[H])[H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
239000008215 water for injection Substances 0.000 description 1

Landscapes

Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

CA000528852A 1986-02-03 1987-02-03 Inhibiteurs de la renine de type alcool n-heterocyclique Expired - Lifetime CA1310792C (fr)

Applications Claiming Priority (4)

Application Number	Priority Date	Filing Date
US82572486A	1986-02-03	1986-02-03
US825,724		1986-02-03
US344687A	1987-01-15	1987-01-15
US3,446		1987-01-15

Publications (1)

Publication Number	Publication Date
CA1310792C true CA1310792C (fr)	1992-11-24

Family

ID=26671757

Family Applications (1)

Application Number	Title	Priority Date	Filing Date
CA000528852A Expired - Lifetime CA1310792C (fr)	1986-02-03	1987-02-03	Inhibiteurs de la renine de type alcool n-heterocyclique

Country Status (1)

Country	Link
CA (1)	CA1310792C (fr)

1987
- 1987-02-03 CA CA000528852A patent/CA1310792C/fr not_active Expired - Lifetime

Legal Events

Date	Code	Title	Description
1995-05-24	MKLA	Lapsed
2023-05-26	MKLA	Lapsed	Effective date: 19950524

Publication	Publication Date	Title
EP0231919B1 (fr)	1993-01-20	Inhibiteurs de la rénine alcool-hétérocycliques
CA1258948A (fr)	1989-08-29	Derives de substitution hydroxyles de peptides
CA1282549C (fr)	1991-04-02	Inhibiteurs de l'aminocarbonyl resine
US4885292A (en)	1989-12-05	N-heterocyclic alcohol renin inhibitors
CA1269497A (fr)	1990-05-22	Ester et amide d'acides amines inhibiteurs de la renine
CA1297631C (fr)	1992-03-17	Inhibiteurs de la renine a groupement ureido
CA1274346A (fr)	1990-09-18	Derives amides et esters d'acides amines inhibant la resine
US4757050A (en)	1988-07-12	Ureido renin inhibitors
CA1293589C (fr)	1991-12-24	Derives acide amine carboxyalkylique de diverses prolines substituees
EP0601459A2 (fr)	1994-06-15	Inhibiteurs hétérocycliques de thrombine contenant un groupe sulfonamid
EP0189203A2 (fr)	1986-07-30	Peptidylaminodioles
BG63876B1 (bg)	2003-04-30	Инхибитори на клетъчна адхезия
HUT59087A (en)	1992-04-28	Process for producing sulfinic and sulfonamidic derivatives of dioles and pharmaceutical preparatives containing these compounds
EP0155809A2 (fr)	1985-09-25	Inhibiteurs de larénine contenant de la rénine ou ses dérivés
CA1261332A (fr)	1989-09-26	Derives de substitution esterifies d'aminoalcanoylureidoamino- et imino-acides et -esters
CA1269496A (fr)	1990-05-22	Mercaptocycloalcoylcarbonyl- et mercaptoarylcarbonyldipeptides
NZ211600A (en)	1988-03-30	Substituted ureido-amino and -imino acid derivatives and pharmaceutical compositions
CA2012901A1 (fr)	1990-10-05	Derives d'acides amines
CA1244006A (fr)	1988-11-01	Composes de peptides substitues
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EP0380805A1 (fr)	1990-08-08	Inhibiteurs de rénine contenant des dihydroxy-amides à C terminal
US4749781A (en)	1988-06-07	Aminocarbonyl renin inhibitors