KR20130029116A - 레닌 억제제로서의 3,4-치환된 피페리딘 유도체 - Google Patents
레닌 억제제로서의 3,4-치환된 피페리딘 유도체 Download PDFInfo
- Publication number
- KR20130029116A KR20130029116A KR1020137003332A KR20137003332A KR20130029116A KR 20130029116 A KR20130029116 A KR 20130029116A KR 1020137003332 A KR1020137003332 A KR 1020137003332A KR 20137003332 A KR20137003332 A KR 20137003332A KR 20130029116 A KR20130029116 A KR 20130029116A
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- South Korea
- Prior art keywords
- alkylene
- optionally substituted
- halogens
- alkyl
- methyl
- 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.)
- Withdrawn
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- 239000002461 renin inhibitor Substances 0.000 title abstract description 11
- 229940086526 renin-inhibitors Drugs 0.000 title abstract description 10
- 150000003053 piperidines Chemical class 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims abstract description 315
- 238000011282 treatment Methods 0.000 claims abstract description 11
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 9
- 150000002367 halogens Chemical class 0.000 claims description 197
- 229910052736 halogen Inorganic materials 0.000 claims description 194
- 125000006833 (C1-C5) alkylene group Chemical group 0.000 claims description 156
- -1 C 1 -C 5 alkyl Chemical group 0.000 claims description 128
- 238000000034 method Methods 0.000 claims description 82
- 229910052739 hydrogen Inorganic materials 0.000 claims description 67
- 239000001257 hydrogen Substances 0.000 claims description 65
- 150000003839 salts Chemical class 0.000 claims description 62
- 239000007787 solid Substances 0.000 claims description 56
- 229920006395 saturated elastomer Polymers 0.000 claims description 48
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 44
- 229910052757 nitrogen Inorganic materials 0.000 claims description 33
- 125000000217 alkyl group Chemical group 0.000 claims description 31
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 21
- 125000001424 substituent group Chemical group 0.000 claims description 21
- 125000000623 heterocyclic group Chemical group 0.000 claims description 19
- 229910052717 sulfur Inorganic materials 0.000 claims description 19
- 125000003342 alkenyl group Chemical group 0.000 claims description 17
- 150000002431 hydrogen Chemical class 0.000 claims description 17
- 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 claims description 16
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 16
- 125000001072 heteroaryl group Chemical group 0.000 claims description 16
- 125000003118 aryl group Chemical group 0.000 claims description 15
- 125000005842 heteroatom Chemical group 0.000 claims description 15
- 125000000392 cycloalkenyl group Chemical group 0.000 claims description 14
- 125000002947 alkylene group Chemical group 0.000 claims description 13
- 229910052799 carbon Inorganic materials 0.000 claims description 13
- 239000003814 drug Substances 0.000 claims description 13
- 229910052760 oxygen Inorganic materials 0.000 claims description 13
- 125000006729 (C2-C5) alkenyl group Chemical group 0.000 claims description 12
- 201000010099 disease Diseases 0.000 claims description 12
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 12
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 claims description 12
- SNOOUWRIMMFWNE-UHFFFAOYSA-M sodium;6-[(3,4,5-trimethoxybenzoyl)amino]hexanoate Chemical compound [Na+].COC1=CC(C(=O)NCCCCCC([O-])=O)=CC(OC)=C1OC SNOOUWRIMMFWNE-UHFFFAOYSA-M 0.000 claims description 12
- 239000000126 substance Substances 0.000 claims description 12
- VMJNTFXCTXAXTC-UHFFFAOYSA-N 2,2-difluoro-1,3-benzodioxole-5-carbonitrile Chemical group C1=C(C#N)C=C2OC(F)(F)OC2=C1 VMJNTFXCTXAXTC-UHFFFAOYSA-N 0.000 claims description 10
- 125000002837 carbocyclic group Chemical group 0.000 claims description 10
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 10
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 9
- 125000003601 C2-C6 alkynyl group Chemical group 0.000 claims description 9
- 206010007559 Cardiac failure congestive Diseases 0.000 claims description 9
- 206010019280 Heart failures Diseases 0.000 claims description 9
- 206010020772 Hypertension Diseases 0.000 claims description 9
- 125000003545 alkoxy group Chemical group 0.000 claims description 9
- 239000002904 solvent Substances 0.000 claims description 9
- 125000006730 (C2-C5) alkynyl group Chemical group 0.000 claims description 8
- 208000001647 Renal Insufficiency Diseases 0.000 claims description 8
- 201000006370 kidney failure Diseases 0.000 claims description 8
- 125000002950 monocyclic group Chemical group 0.000 claims description 8
- 230000036454 renin-angiotensin system Effects 0.000 claims description 8
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 6
- 208000031229 Cardiomyopathies Diseases 0.000 claims description 5
- 125000000304 alkynyl group Chemical group 0.000 claims description 5
- 230000008878 coupling Effects 0.000 claims description 5
- 238000010168 coupling process Methods 0.000 claims description 5
- 238000005859 coupling reaction Methods 0.000 claims description 5
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 5
- 206010012601 diabetes mellitus Diseases 0.000 claims description 5
- 239000011737 fluorine Substances 0.000 claims description 5
- 229910052731 fluorine Inorganic materials 0.000 claims description 5
- 201000001320 Atherosclerosis Diseases 0.000 claims description 4
- 206010007572 Cardiac hypertrophy Diseases 0.000 claims description 4
- 208000006029 Cardiomegaly Diseases 0.000 claims description 4
- 206010063897 Renal ischaemia Diseases 0.000 claims description 4
- 239000003937 drug carrier Substances 0.000 claims description 4
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 4
- 238000004519 manufacturing process Methods 0.000 claims description 4
- 208000002815 pulmonary hypertension Diseases 0.000 claims description 4
- 201000002793 renal fibrosis Diseases 0.000 claims description 4
- 208000037803 restenosis Diseases 0.000 claims description 4
- 238000000371 solid-state nuclear magnetic resonance spectroscopy Methods 0.000 claims description 4
- 230000002792 vascular Effects 0.000 claims description 4
- 208000019901 Anxiety disease Diseases 0.000 claims description 3
- 208000010228 Erectile Dysfunction Diseases 0.000 claims description 3
- 208000010412 Glaucoma Diseases 0.000 claims description 3
- 206010018364 Glomerulonephritis Diseases 0.000 claims description 3
- 206010038419 Renal colic Diseases 0.000 claims description 3
- 206010039710 Scleroderma Diseases 0.000 claims description 3
- 238000002441 X-ray diffraction Methods 0.000 claims description 3
- 238000002399 angioplasty Methods 0.000 claims description 3
- 230000036506 anxiety Effects 0.000 claims description 3
- 125000004429 atom Chemical group 0.000 claims description 3
- 238000007675 cardiac surgery Methods 0.000 claims description 3
- 208000010877 cognitive disease Diseases 0.000 claims description 3
- 230000004406 elevated intraocular pressure Effects 0.000 claims description 3
- 239000003018 immunosuppressive agent Substances 0.000 claims description 3
- 201000001881 impotence Diseases 0.000 claims description 3
- 208000017169 kidney disease Diseases 0.000 claims description 3
- 208000031225 myocardial ischemia Diseases 0.000 claims description 3
- 201000001119 neuropathy Diseases 0.000 claims description 3
- 230000007823 neuropathy Effects 0.000 claims description 3
- 208000033808 peripheral neuropathy Diseases 0.000 claims description 3
- 208000005069 pulmonary fibrosis Diseases 0.000 claims description 3
- 238000001757 thermogravimetry curve Methods 0.000 claims description 3
- 238000007631 vascular surgery Methods 0.000 claims description 3
- 125000006726 (C1-C5) alkenyl group Chemical group 0.000 claims description 2
- 125000002373 5 membered heterocyclic group Chemical group 0.000 claims description 2
- 125000004070 6 membered heterocyclic group Chemical group 0.000 claims description 2
- 238000005384 cross polarization magic-angle spinning Methods 0.000 claims description 2
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 claims description 2
- 238000000634 powder X-ray diffraction Methods 0.000 claims description 2
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 claims 3
- 229910052698 phosphorus Inorganic materials 0.000 claims 3
- 239000011574 phosphorus Substances 0.000 claims 3
- 208000028698 Cognitive impairment Diseases 0.000 claims 2
- 230000009787 cardiac fibrosis Effects 0.000 claims 2
- 229940125721 immunosuppressive agent Drugs 0.000 claims 2
- 125000001153 fluoro group Chemical group F* 0.000 claims 1
- 208000028867 ischemia Diseases 0.000 claims 1
- 210000004165 myocardium Anatomy 0.000 claims 1
- 238000011321 prophylaxis Methods 0.000 claims 1
- 208000024172 Cardiovascular disease Diseases 0.000 abstract description 3
- 125000003386 piperidinyl group Chemical class 0.000 abstract description 2
- 230000008085 renal dysfunction Effects 0.000 abstract description 2
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 467
- 239000000243 solution Substances 0.000 description 281
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 271
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 267
- 150000001412 amines Chemical class 0.000 description 249
- 235000019439 ethyl acetate Nutrition 0.000 description 227
- 239000000706 filtrate Substances 0.000 description 202
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 195
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 173
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 159
- 239000011734 sodium Substances 0.000 description 144
- 239000012267 brine Substances 0.000 description 140
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 140
- 239000000284 extract Substances 0.000 description 134
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 121
- 239000000203 mixture Substances 0.000 description 119
- 229910004298 SiO 2 Inorganic materials 0.000 description 116
- 239000000725 suspension Substances 0.000 description 116
- 239000012043 crude product Substances 0.000 description 113
- 238000006243 chemical reaction Methods 0.000 description 108
- 238000003818 flash chromatography Methods 0.000 description 103
- 239000003921 oil Substances 0.000 description 93
- 235000019198 oils Nutrition 0.000 description 92
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 75
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 73
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 71
- 239000012230 colorless oil Substances 0.000 description 69
- 239000010410 layer Substances 0.000 description 69
- 239000011541 reaction mixture Substances 0.000 description 69
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 67
- 239000000460 chlorine Substances 0.000 description 62
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 48
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 45
- 239000003039 volatile agent Substances 0.000 description 43
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 39
- HTJDQJBWANPRPF-UHFFFAOYSA-N Cyclopropylamine Chemical compound NC1CC1 HTJDQJBWANPRPF-UHFFFAOYSA-N 0.000 description 38
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 36
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 36
- 235000002639 sodium chloride Nutrition 0.000 description 36
- SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical compound C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 description 33
- 239000012279 sodium borohydride Substances 0.000 description 32
- 229910000033 sodium borohydride Inorganic materials 0.000 description 32
- 239000002198 insoluble material Substances 0.000 description 31
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 30
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 28
- 238000002360 preparation method Methods 0.000 description 27
- GRVDJDISBSALJP-UHFFFAOYSA-N methyloxidanyl Chemical group [O]C GRVDJDISBSALJP-UHFFFAOYSA-N 0.000 description 25
- 239000002168 alkylating agent Substances 0.000 description 24
- 229940100198 alkylating agent Drugs 0.000 description 24
- 238000003756 stirring Methods 0.000 description 23
- ALKXELCMIXGBSG-UHFFFAOYSA-N CN1C(C=C(C=C1)N1CC(CCC1)C(=O)N)=O Chemical compound CN1C(C=C(C=C1)N1CC(CCC1)C(=O)N)=O ALKXELCMIXGBSG-UHFFFAOYSA-N 0.000 description 22
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 22
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 21
- 238000001914 filtration Methods 0.000 description 21
- 150000002466 imines Chemical class 0.000 description 20
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 18
- 235000017557 sodium bicarbonate Nutrition 0.000 description 18
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 18
- PZOUSPYUWWUPPK-UHFFFAOYSA-N indole Natural products CC1=CC=CC2=C1C=CN2 PZOUSPYUWWUPPK-UHFFFAOYSA-N 0.000 description 17
- LVWZTYCIRDMTEY-UHFFFAOYSA-N metamizole Chemical class O=C1C(N(CS(O)(=O)=O)C)=C(C)N(C)N1C1=CC=CC=C1 LVWZTYCIRDMTEY-UHFFFAOYSA-N 0.000 description 17
- 125000004432 carbon atom Chemical group C* 0.000 description 15
- RKJUIXBNRJVNHR-UHFFFAOYSA-N indolenine Natural products C1=CC=C2CC=NC2=C1 RKJUIXBNRJVNHR-UHFFFAOYSA-N 0.000 description 15
- 230000003287 optical effect Effects 0.000 description 15
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 14
- 239000012298 atmosphere Substances 0.000 description 14
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 13
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 13
- 230000008569 process Effects 0.000 description 13
- GQHTUMJGOHRCHB-UHFFFAOYSA-N 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine Chemical compound C1CCCCN2CCCN=C21 GQHTUMJGOHRCHB-UHFFFAOYSA-N 0.000 description 12
- PAIZBXZLPQCZCY-UHFFFAOYSA-N CN(C=CC=C1N(CCC2)CC2C(N)=O)C1=O Chemical compound CN(C=CC=C1N(CCC2)CC2C(N)=O)C1=O PAIZBXZLPQCZCY-UHFFFAOYSA-N 0.000 description 12
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 12
- 239000002002 slurry Substances 0.000 description 12
- JCMBUJZAIZUVKK-UHFFFAOYSA-N 1-methylpiperidine-3-carboxamide Chemical compound CN1CCCC(C(N)=O)C1 JCMBUJZAIZUVKK-UHFFFAOYSA-N 0.000 description 11
- 229910021605 Palladium(II) bromide Inorganic materials 0.000 description 11
- 239000007864 aqueous solution Substances 0.000 description 11
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 11
- 235000019341 magnesium sulphate Nutrition 0.000 description 11
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 11
- 238000010992 reflux Methods 0.000 description 11
- TVZJDJRECYJFED-UHFFFAOYSA-N CC(C(N(CCC1)CC1C(N)=O)=CN1C)=CC1=O Chemical compound CC(C(N(CCC1)CC1C(N)=O)=CN1C)=CC1=O TVZJDJRECYJFED-UHFFFAOYSA-N 0.000 description 10
- 238000004440 column chromatography Methods 0.000 description 10
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 10
- 239000007858 starting material Substances 0.000 description 10
- AGEZXYOZHKGVCM-UHFFFAOYSA-N benzyl bromide Chemical compound BrCC1=CC=CC=C1 AGEZXYOZHKGVCM-UHFFFAOYSA-N 0.000 description 9
- 150000002148 esters Chemical class 0.000 description 9
- 229910052763 palladium Inorganic materials 0.000 description 9
- 239000000047 product Substances 0.000 description 9
- 235000015041 whisky Nutrition 0.000 description 9
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 8
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 8
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 8
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 8
- OLNJUISKUQQNIM-UHFFFAOYSA-N indole-3-carbaldehyde Chemical compound C1=CC=C2C(C=O)=CNC2=C1 OLNJUISKUQQNIM-UHFFFAOYSA-N 0.000 description 8
- KWGKDLIKAYFUFQ-UHFFFAOYSA-M lithium chloride Chemical compound [Li+].[Cl-] KWGKDLIKAYFUFQ-UHFFFAOYSA-M 0.000 description 8
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 8
- 239000012044 organic layer Substances 0.000 description 8
- INIOZDBICVTGEO-UHFFFAOYSA-L palladium(ii) bromide Chemical compound Br[Pd]Br INIOZDBICVTGEO-UHFFFAOYSA-L 0.000 description 8
- 239000012312 sodium hydride Substances 0.000 description 8
- 229910000104 sodium hydride Inorganic materials 0.000 description 8
- 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 8
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 7
- 239000005541 ACE inhibitor Substances 0.000 description 7
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 7
- 235000011054 acetic acid Nutrition 0.000 description 7
- 230000029936 alkylation Effects 0.000 description 7
- 238000005804 alkylation reaction Methods 0.000 description 7
- 229940044094 angiotensin-converting-enzyme inhibitor Drugs 0.000 description 7
- 229940079593 drug Drugs 0.000 description 7
- WVDDGKGOMKODPV-UHFFFAOYSA-N hydroxymethyl benzene Natural products OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 description 7
- 239000000651 prodrug Substances 0.000 description 7
- 229940002612 prodrug Drugs 0.000 description 7
- 239000000741 silica gel Substances 0.000 description 7
- 229910002027 silica gel Inorganic materials 0.000 description 7
- 229910000029 sodium carbonate Inorganic materials 0.000 description 7
- DPKBAXPHAYBPRL-UHFFFAOYSA-M tetrabutylazanium;iodide Chemical compound [I-].CCCC[N+](CCCC)(CCCC)CCCC DPKBAXPHAYBPRL-UHFFFAOYSA-M 0.000 description 7
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 6
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 6
- 108090000783 Renin Proteins 0.000 description 6
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 6
- OKJPEAGHQZHRQV-UHFFFAOYSA-N Triiodomethane Natural products IC(I)I OKJPEAGHQZHRQV-UHFFFAOYSA-N 0.000 description 6
- 239000008346 aqueous phase Substances 0.000 description 6
- 238000010936 aqueous wash Methods 0.000 description 6
- HUMNYLRZRPPJDN-UHFFFAOYSA-N benzaldehyde Chemical compound O=CC1=CC=CC=C1 HUMNYLRZRPPJDN-UHFFFAOYSA-N 0.000 description 6
- 238000001816 cooling Methods 0.000 description 6
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 6
- 238000000746 purification Methods 0.000 description 6
- FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Chemical compound [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 description 6
- 238000003786 synthesis reaction Methods 0.000 description 6
- FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 description 6
- CSRZQMIRAZTJOY-UHFFFAOYSA-N trimethylsilyl iodide Chemical compound C[Si](C)(C)I CSRZQMIRAZTJOY-UHFFFAOYSA-N 0.000 description 6
- 238000005406 washing Methods 0.000 description 6
- KZPYGQFFRCFCPP-UHFFFAOYSA-N 1,1'-bis(diphenylphosphino)ferrocene Chemical compound [Fe+2].C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1 KZPYGQFFRCFCPP-UHFFFAOYSA-N 0.000 description 5
- CEVMYGZHEJSOHZ-UHFFFAOYSA-N 1-bromo-3-methoxypropane Chemical compound COCCCBr CEVMYGZHEJSOHZ-UHFFFAOYSA-N 0.000 description 5
- BCJVBDBJSMFBRW-UHFFFAOYSA-N 4-diphenylphosphanylbutyl(diphenyl)phosphane Chemical compound C=1C=CC=CC=1P(C=1C=CC=CC=1)CCCCP(C=1C=CC=CC=1)C1=CC=CC=C1 BCJVBDBJSMFBRW-UHFFFAOYSA-N 0.000 description 5
- 102100028255 Renin Human genes 0.000 description 5
- 230000015572 biosynthetic process Effects 0.000 description 5
- UORVGPXVDQYIDP-UHFFFAOYSA-N borane Chemical compound B UORVGPXVDQYIDP-UHFFFAOYSA-N 0.000 description 5
- MCQRPQCQMGVWIQ-UHFFFAOYSA-N boron;methylsulfanylmethane Chemical compound [B].CSC MCQRPQCQMGVWIQ-UHFFFAOYSA-N 0.000 description 5
- 239000003153 chemical reaction reagent Substances 0.000 description 5
- 238000005984 hydrogenation reaction Methods 0.000 description 5
- 229910000027 potassium carbonate Inorganic materials 0.000 description 5
- 239000000843 powder Substances 0.000 description 5
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 5
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- HGPFPIZJIIHKBA-UHFFFAOYSA-N tert-butyl n-cyclopropyl-n-[[2,3-dichloro-5-[2-(methoxycarbonylamino)ethyl]phenyl]methyl]carbamate Chemical compound COC(=O)NCCC1=CC(Cl)=C(Cl)C(CN(C2CC2)C(=O)OC(C)(C)C)=C1 HGPFPIZJIIHKBA-UHFFFAOYSA-N 0.000 description 1
- RNQQYRZDXYSSFT-AATRIKPKSA-N tert-butyl n-cyclopropyl-n-[[3-formyl-5-[(e)-3-methoxyprop-1-enyl]phenyl]methyl]carbamate Chemical compound O=CC1=CC(/C=C/COC)=CC(CN(C2CC2)C(=O)OC(C)(C)C)=C1 RNQQYRZDXYSSFT-AATRIKPKSA-N 0.000 description 1
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Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
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| PCT/CA2009/000611 WO2009135299A1 (en) | 2008-05-05 | 2009-05-04 | 3, 4 - substituted piperidine derivatives as renin inhibitors |
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| US8304413B2 (en) | 2008-06-03 | 2012-11-06 | Intermune, Inc. | Compounds and methods for treating inflammatory and fibrotic disorders |
| JP2012511514A (ja) * | 2008-12-10 | 2012-05-24 | メルク・カナダ・インコーポレイテツド | レニン阻害剤としての3,4−置換ピペリジン誘導体 |
| TWI622573B (zh) * | 2010-11-05 | 2018-05-01 | 拜耳知識產權公司 | 藉由亞胺氫化製備經取代n-(苄基)環丙胺之方法 |
| UA112897C2 (uk) * | 2012-05-09 | 2016-11-10 | Байєр Фарма Акцієнгезелльшафт | Біциклічно заміщені урацили та їх застосування для лікування і/або профілактики захворювань |
| AR092742A1 (es) | 2012-10-02 | 2015-04-29 | Intermune Inc | Piridinonas antifibroticas |
| KR102373700B1 (ko) | 2014-04-02 | 2022-03-11 | 인터뮨, 인크. | 항섬유성 피리디논 |
| CN107602381B (zh) * | 2017-09-11 | 2021-03-16 | 陕西莱特光电材料股份有限公司 | 一种萘甲酸酯类衍生物及其制备方法 |
| CN108033876A (zh) * | 2017-12-20 | 2018-05-15 | 江汉大学 | 一种5-溴-2-氯苯甲醛的制备方法 |
| EP3887357A1 (en) | 2018-11-28 | 2021-10-06 | Basf Se | Pesticidal compounds |
| WO2021219513A1 (en) | 2020-04-28 | 2021-11-04 | Basf Se | Pesticidal compounds |
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