CA2546264A1 - 4-phenylpiperidine derivatives as renin inhibitors - Google Patents
4-phenylpiperidine derivatives as renin inhibitors Download PDFInfo
- Publication number
- CA2546264A1 CA2546264A1 CA002546264A CA2546264A CA2546264A1 CA 2546264 A1 CA2546264 A1 CA 2546264A1 CA 002546264 A CA002546264 A CA 002546264A CA 2546264 A CA2546264 A CA 2546264A CA 2546264 A1 CA2546264 A1 CA 2546264A1
- Authority
- CA
- Canada
- Prior art keywords
- hydrogen
- lower alkyl
- halogen
- hydroxy
- combined
- 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.)
- Abandoned
Links
- 239000002461 renin inhibitor Substances 0.000 title description 3
- 229940086526 renin-inhibitors Drugs 0.000 title description 3
- UTBULQCHEUWJNV-UHFFFAOYSA-N 4-phenylpiperidine Chemical class C1CNCCC1C1=CC=CC=C1 UTBULQCHEUWJNV-UHFFFAOYSA-N 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims abstract description 307
- 108090000783 Renin Proteins 0.000 claims abstract description 24
- 208000010877 cognitive disease Diseases 0.000 claims abstract description 20
- 208000011580 syndromic disease Diseases 0.000 claims abstract description 20
- 230000004410 intraocular pressure Effects 0.000 claims abstract description 14
- 201000010099 disease Diseases 0.000 claims abstract description 11
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 11
- 208000019901 Anxiety disease Diseases 0.000 claims abstract description 10
- 201000001320 Atherosclerosis Diseases 0.000 claims abstract description 10
- 206010007559 Cardiac failure congestive Diseases 0.000 claims abstract description 10
- 206010007572 Cardiac hypertrophy Diseases 0.000 claims abstract description 10
- 208000006029 Cardiomegaly Diseases 0.000 claims abstract description 10
- 208000031229 Cardiomyopathies Diseases 0.000 claims abstract description 10
- 208000028698 Cognitive impairment Diseases 0.000 claims abstract description 10
- 206010012289 Dementia Diseases 0.000 claims abstract description 10
- 206010052337 Diastolic dysfunction Diseases 0.000 claims abstract description 10
- 208000010412 Glaucoma Diseases 0.000 claims abstract description 10
- 206010019280 Heart failures Diseases 0.000 claims abstract description 10
- 206010019668 Hepatic fibrosis Diseases 0.000 claims abstract description 10
- 206010020571 Hyperaldosteronism Diseases 0.000 claims abstract description 10
- 206010020772 Hypertension Diseases 0.000 claims abstract description 10
- 206010061216 Infarction Diseases 0.000 claims abstract description 10
- 230000002159 abnormal effect Effects 0.000 claims abstract description 10
- 238000002399 angioplasty Methods 0.000 claims abstract description 10
- 230000009787 cardiac fibrosis Effects 0.000 claims abstract description 10
- 208000020832 chronic kidney disease Diseases 0.000 claims abstract description 10
- 210000004351 coronary vessel Anatomy 0.000 claims abstract description 10
- 206010012601 diabetes mellitus Diseases 0.000 claims abstract description 10
- 208000017169 kidney disease Diseases 0.000 claims abstract description 10
- 201000001119 neuropathy Diseases 0.000 claims abstract description 10
- 230000007823 neuropathy Effects 0.000 claims abstract description 10
- 208000033808 peripheral neuropathy Diseases 0.000 claims abstract description 10
- 201000009395 primary hyperaldosteronism Diseases 0.000 claims abstract description 10
- 208000037803 restenosis Diseases 0.000 claims abstract description 10
- 230000006444 vascular growth Effects 0.000 claims abstract description 10
- 239000001257 hydrogen Substances 0.000 claims description 138
- 229910052739 hydrogen Inorganic materials 0.000 claims description 138
- 125000000217 alkyl group Chemical group 0.000 claims description 123
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 80
- 229910052736 halogen Inorganic materials 0.000 claims description 68
- 150000002367 halogens Chemical class 0.000 claims description 68
- 150000003839 salts Chemical class 0.000 claims description 63
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 58
- -1 cyano, hydroxy Chemical group 0.000 claims description 56
- 125000003545 alkoxy group Chemical group 0.000 claims description 54
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 49
- 125000003118 aryl group Chemical group 0.000 claims description 44
- 125000000623 heterocyclic group Chemical group 0.000 claims description 42
- 125000004432 carbon atom Chemical group C* 0.000 claims description 37
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 37
- 238000000034 method Methods 0.000 claims description 29
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 28
- 229910052760 oxygen Inorganic materials 0.000 claims description 27
- 239000008194 pharmaceutical composition Substances 0.000 claims description 23
- 102100028255 Renin Human genes 0.000 claims description 21
- 230000000694 effects Effects 0.000 claims description 21
- 125000002947 alkylene group Chemical group 0.000 claims description 19
- 229910052799 carbon Inorganic materials 0.000 claims description 16
- 125000001072 heteroaryl group Chemical group 0.000 claims description 16
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 16
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 14
- 229910052757 nitrogen Inorganic materials 0.000 claims description 14
- 125000004429 atom Chemical group 0.000 claims description 13
- 239000003814 drug Substances 0.000 claims description 12
- 241000124008 Mammalia Species 0.000 claims description 10
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 10
- 239000003524 antilipemic agent Substances 0.000 claims description 9
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 9
- 239000000883 anti-obesity agent Substances 0.000 claims description 8
- 239000003472 antidiabetic agent Substances 0.000 claims description 8
- 229940030600 antihypertensive agent Drugs 0.000 claims description 8
- 239000002220 antihypertensive agent Substances 0.000 claims description 8
- 229940125710 antiobesity agent Drugs 0.000 claims description 8
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 claims description 8
- 125000003396 thiol group Chemical class [H]S* 0.000 claims description 8
- 125000004423 acyloxy group Chemical group 0.000 claims description 7
- 125000003282 alkyl amino group Chemical group 0.000 claims description 7
- 125000004414 alkyl thio group Chemical group 0.000 claims description 7
- 125000004397 aminosulfonyl group Chemical group NS(=O)(=O)* 0.000 claims description 7
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 7
- 125000002541 furyl group Chemical group 0.000 claims description 7
- 125000001041 indolyl group Chemical group 0.000 claims description 7
- 125000004076 pyridyl group Chemical group 0.000 claims description 7
- 125000000714 pyrimidinyl group Chemical group 0.000 claims description 7
- 125000005420 sulfonamido group Chemical group S(=O)(=O)(N*)* 0.000 claims description 7
- 125000001544 thienyl group Chemical group 0.000 claims description 7
- 125000001589 carboacyl group Chemical group 0.000 claims description 6
- 125000004663 dialkyl amino group Chemical group 0.000 claims description 6
- 125000004442 acylamino group Chemical group 0.000 claims description 5
- 125000003342 alkenyl group Chemical group 0.000 claims description 5
- 229940125708 antidiabetic agent Drugs 0.000 claims description 5
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 5
- 125000004475 heteroaralkyl group Chemical group 0.000 claims description 5
- 125000002883 imidazolyl group Chemical group 0.000 claims description 5
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 5
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 5
- 238000002360 preparation method Methods 0.000 claims description 5
- 125000000335 thiazolyl group Chemical group 0.000 claims description 5
- 125000000304 alkynyl group Chemical group 0.000 claims description 4
- 230000005764 inhibitory process Effects 0.000 claims description 4
- 125000002757 morpholinyl group Chemical group 0.000 claims description 4
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 4
- 125000000168 pyrrolyl group Chemical group 0.000 claims description 4
- 125000005936 piperidyl group Chemical group 0.000 claims description 3
- 230000002265 prevention Effects 0.000 claims description 3
- 239000003937 drug carrier Substances 0.000 claims description 2
- 125000003831 tetrazolyl group Chemical group 0.000 claims description 2
- 150000002431 hydrogen Chemical class 0.000 claims 30
- 230000002401 inhibitory effect Effects 0.000 abstract description 3
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 193
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 174
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 145
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 134
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 113
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 94
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 81
- 238000004128 high performance liquid chromatography Methods 0.000 description 64
- 229910001868 water Inorganic materials 0.000 description 62
- 239000000243 solution Substances 0.000 description 58
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 56
- 239000000203 mixture Substances 0.000 description 51
- 235000019439 ethyl acetate Nutrition 0.000 description 45
- 230000002829 reductive effect Effects 0.000 description 34
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 29
- 239000000284 extract Substances 0.000 description 29
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 28
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 27
- 239000011541 reaction mixture Substances 0.000 description 27
- 239000010410 layer Substances 0.000 description 26
- 239000002904 solvent Substances 0.000 description 26
- 238000003818 flash chromatography Methods 0.000 description 25
- 238000006243 chemical reaction Methods 0.000 description 22
- 238000012360 testing method Methods 0.000 description 22
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 20
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 19
- 239000002253 acid Substances 0.000 description 17
- 239000003112 inhibitor Substances 0.000 description 17
- 230000014759 maintenance of location Effects 0.000 description 15
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 14
- 239000000047 product Substances 0.000 description 14
- 239000011347 resin Substances 0.000 description 14
- 229920005989 resin Polymers 0.000 description 14
- 239000000741 silica gel Substances 0.000 description 14
- 229910002027 silica gel Inorganic materials 0.000 description 14
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 13
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 13
- DCKVNWZUADLDEH-UHFFFAOYSA-N sec-butyl acetate Chemical compound CCC(C)OC(C)=O DCKVNWZUADLDEH-UHFFFAOYSA-N 0.000 description 13
- 229910000029 sodium carbonate Inorganic materials 0.000 description 13
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 12
- 239000007787 solid Substances 0.000 description 12
- HEMHJVSKTPXQMS-UHFFFAOYSA-M sodium hydroxide Inorganic materials [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 11
- 239000000725 suspension Substances 0.000 description 11
- 229910052786 argon Inorganic materials 0.000 description 10
- 125000006239 protecting group Chemical group 0.000 description 10
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 10
- 229910052681 coesite Inorganic materials 0.000 description 9
- 229910052906 cristobalite Inorganic materials 0.000 description 9
- 238000001727 in vivo Methods 0.000 description 9
- 239000003921 oil Substances 0.000 description 9
- 235000019198 oils Nutrition 0.000 description 9
- NFHFRUOZVGFOOS-UHFFFAOYSA-N palladium;triphenylphosphane Chemical compound [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 NFHFRUOZVGFOOS-UHFFFAOYSA-N 0.000 description 9
- 229910052682 stishovite Inorganic materials 0.000 description 9
- 229910052905 tridymite Inorganic materials 0.000 description 9
- 150000007513 acids Chemical class 0.000 description 8
- 239000007864 aqueous solution Substances 0.000 description 8
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 8
- 238000010992 reflux Methods 0.000 description 8
- 239000007858 starting material Substances 0.000 description 8
- 239000012258 stirred mixture Substances 0.000 description 8
- 238000003756 stirring Methods 0.000 description 8
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 7
- 239000002585 base Substances 0.000 description 7
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 7
- 229910000027 potassium carbonate Inorganic materials 0.000 description 7
- 229920006395 saturated elastomer Polymers 0.000 description 7
- 239000011734 sodium Substances 0.000 description 7
- 125000001424 substituent group Chemical group 0.000 description 7
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- 230000009471 action Effects 0.000 description 6
- 230000036772 blood pressure Effects 0.000 description 6
- 150000001721 carbon Chemical group 0.000 description 6
- 150000002148 esters Chemical class 0.000 description 6
- 238000001704 evaporation Methods 0.000 description 6
- 230000008020 evaporation Effects 0.000 description 6
- ZZUFCTLCJUWOSV-UHFFFAOYSA-N furosemide Chemical compound C1=C(Cl)C(S(=O)(=O)N)=CC(C(O)=O)=C1NCC1=CC=CO1 ZZUFCTLCJUWOSV-UHFFFAOYSA-N 0.000 description 6
- 125000005843 halogen group Chemical group 0.000 description 6
- 230000001404 mediated effect Effects 0.000 description 6
- 238000002953 preparative HPLC Methods 0.000 description 6
- 229940002612 prodrug Drugs 0.000 description 6
- 239000000651 prodrug Substances 0.000 description 6
- CDBYLPFSWZWCQE-UHFFFAOYSA-L sodium carbonate Substances [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 6
- 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 6
- 101800000734 Angiotensin-1 Proteins 0.000 description 5
- 102400000344 Angiotensin-1 Human genes 0.000 description 5
- 241000282693 Cercopithecidae Species 0.000 description 5
- 101000579218 Homo sapiens Renin Proteins 0.000 description 5
- 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 5
- 241001465754 Metazoa Species 0.000 description 5
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 5
- 239000004480 active ingredient Substances 0.000 description 5
- 125000002252 acyl group Chemical group 0.000 description 5
- 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 5
- 230000003178 anti-diabetic effect Effects 0.000 description 5
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 5
- 239000012230 colorless oil Substances 0.000 description 5
- 239000000706 filtrate Substances 0.000 description 5
- 125000005842 heteroatom Chemical group 0.000 description 5
- 150000002430 hydrocarbons Chemical group 0.000 description 5
- 238000000338 in vitro Methods 0.000 description 5
- 239000000543 intermediate Substances 0.000 description 5
- 125000002950 monocyclic group Chemical group 0.000 description 5
- 230000009467 reduction Effects 0.000 description 5
- 238000006722 reduction reaction Methods 0.000 description 5
- 235000015424 sodium Nutrition 0.000 description 5
- 229940124597 therapeutic agent Drugs 0.000 description 5
- YILPAIKZHXATHY-UHFFFAOYSA-N 5-bromo-2-methylbenzaldehyde Chemical compound CC1=CC=C(Br)C=C1C=O YILPAIKZHXATHY-UHFFFAOYSA-N 0.000 description 4
- DTHNMHAUYICORS-KTKZVXAJSA-N Glucagon-like peptide 1 Chemical compound C([C@@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](C)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCCCN)C(=O)NCC(=O)N[C@@H](CCCNC(N)=N)C(N)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CCCCN)NC(=O)[C@H](C)NC(=O)[C@H](C)NC(=O)[C@H](CCC(N)=O)NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CO)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@@H](NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C)NC(=O)[C@@H](N)CC=1N=CNC=1)[C@@H](C)O)[C@@H](C)O)C(C)C)C1=CC=CC=C1 DTHNMHAUYICORS-KTKZVXAJSA-N 0.000 description 4
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 4
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 4
- 238000006069 Suzuki reaction reaction Methods 0.000 description 4
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 4
- 125000005907 alkyl ester group Chemical group 0.000 description 4
- 125000002619 bicyclic group Chemical group 0.000 description 4
- 239000003054 catalyst Substances 0.000 description 4
- 229960003883 furosemide Drugs 0.000 description 4
- 239000003446 ligand Substances 0.000 description 4
- KWGKDLIKAYFUFQ-UHFFFAOYSA-M lithium chloride Chemical compound [Li+].[Cl-] KWGKDLIKAYFUFQ-UHFFFAOYSA-M 0.000 description 4
- 230000003287 optical effect Effects 0.000 description 4
- 239000012044 organic layer Substances 0.000 description 4
- 239000002244 precipitate Substances 0.000 description 4
- 229910000033 sodium borohydride Inorganic materials 0.000 description 4
- 239000012279 sodium borohydride Substances 0.000 description 4
- 238000010561 standard procedure Methods 0.000 description 4
- YZOCZRLLXVKGIP-SXOMAYOGSA-N (3r,4r)-3-[(1-benzylcyclopropyl)methoxy]-4-(3-phenylphenyl)piperidine Chemical compound C=1C([C@H]2CCNC[C@@H]2OCC2(CC=3C=CC=CC=3)CC2)=CC=CC=1C1=CC=CC=C1 YZOCZRLLXVKGIP-SXOMAYOGSA-N 0.000 description 3
- DXDIYCATUIDVDL-CNORLSDQSA-N (3r,4r)-3-[[2-(3-methoxypropyl)phenyl]methoxy]-4-(3-phenylphenyl)piperidine;2,2,2-trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F.COCCCC1=CC=CC=C1CO[C@@H]1[C@@H](C=2C=C(C=CC=2)C=2C=CC=CC=2)CCNC1 DXDIYCATUIDVDL-CNORLSDQSA-N 0.000 description 3
- 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
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 3
- XBUMXCATZYHBOC-UHFFFAOYSA-N 1-(bromomethyl)-2-(3-methoxypropoxy)benzene Chemical compound COCCCOC1=CC=CC=C1CBr XBUMXCATZYHBOC-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
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Classifications
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- C07D401/02—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 two hetero rings
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D211/40—Oxygen atoms
- C07D211/42—Oxygen atoms attached in position 3 or 5
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing aromatic rings
Landscapes
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- Gastroenterology & Hepatology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Hydrogenated Pyridines (AREA)
- Plural Heterocyclic Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US52537503P | 2003-11-26 | 2003-11-26 | |
| US60/525,375 | 2003-11-26 | ||
| PCT/EP2004/013410 WO2005051911A1 (en) | 2003-11-26 | 2004-11-25 | 4-phenylpiperidine derivatives as renin inhibitors |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2546264A1 true CA2546264A1 (en) | 2005-06-09 |
Family
ID=34632979
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002546264A Abandoned CA2546264A1 (en) | 2003-11-26 | 2004-11-25 | 4-phenylpiperidine derivatives as renin inhibitors |
Country Status (15)
| Country | Link |
|---|---|
| US (3) | US20070078164A1 (enExample) |
| EP (1) | EP1689712B1 (enExample) |
| JP (1) | JP4750712B2 (enExample) |
| KR (1) | KR20060120146A (enExample) |
| CN (1) | CN1906163A (enExample) |
| AT (1) | ATE440082T1 (enExample) |
| AU (1) | AU2004293177B2 (enExample) |
| BR (1) | BRPI0416976A (enExample) |
| CA (1) | CA2546264A1 (enExample) |
| DE (1) | DE602004022704D1 (enExample) |
| ES (1) | ES2332053T3 (enExample) |
| PL (1) | PL1689712T3 (enExample) |
| PT (1) | PT1689712E (enExample) |
| RU (1) | RU2374228C2 (enExample) |
| WO (1) | WO2005051911A1 (enExample) |
Families Citing this family (16)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| BRPI0416976A (pt) * | 2003-11-26 | 2007-02-21 | Novartis Ag | derivados de 4-fenilpiperidina como inibidores de renina |
| AU2005276624B2 (en) | 2004-08-25 | 2011-09-29 | Actelion Pharmaceuticals Ltd. | Bicyclononene derivatives as renin inhibitors |
| EP2248520A3 (en) * | 2004-10-08 | 2010-11-17 | Novartis AG | Use of renin inhibitors for the prevention or treatment of diastolic dysfunction or diastolic heart failure |
| GB0428526D0 (en) | 2004-12-30 | 2005-02-09 | Novartis Ag | Organic compounds |
| EP1707202A1 (de) * | 2005-03-31 | 2006-10-04 | Speedel Experimenta AG | Organische Verbindungen |
| GB0508992D0 (en) * | 2005-05-03 | 2005-06-08 | Novartis Ag | Organic compounds |
| US7799805B2 (en) | 2005-05-27 | 2010-09-21 | Actelion Pharmaceuticals Ltd. | Piperidine carboxylic acid amide derivatives |
| GB0514203D0 (en) * | 2005-07-11 | 2005-08-17 | Novartis Ag | Organic compounds |
| NZ569135A (en) | 2005-12-30 | 2011-08-26 | Novartis Ag | 3,5-Substituted piperidine compounds as renin inhibitors |
| RU2415840C2 (ru) * | 2005-12-30 | 2011-04-10 | Новартис Аг | 3,5-замещенные пиперидины, как ингибиторы ренина |
| GB0611696D0 (en) * | 2006-06-13 | 2006-07-26 | Novartis Ag | Organic compounds |
| TW200821303A (en) * | 2006-08-08 | 2008-05-16 | Speedel Experimenta Ag | Organic compounds |
| WO2008074450A2 (en) * | 2006-12-20 | 2008-06-26 | Nicox S.A. | Non-peptidic renin inhibitors nitroderivatives |
| EP1987834A3 (en) * | 2007-02-13 | 2008-11-19 | Speedel Experimenta AG | Substituted piperidines as therapeutic compounds |
| EP1958634A3 (en) * | 2007-02-14 | 2008-09-24 | Speedel Experimenta AG | Substituted piperidines as inhibitors of beta-secretase, cathepsin D, plasmepsin II and/or HIV protease |
| WO2009000811A1 (en) | 2007-06-25 | 2008-12-31 | Novartis Ag | N5-(2-ethoxyethyl)-n3-(2-pyridinyl)-3,5-piperidinedicarboxamide derivatives for use as renin inhibitors |
Family Cites Families (12)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4616088A (en) * | 1984-10-29 | 1986-10-07 | E. R. Squibb & Sons, Inc. | Amino acid ester and amide renin inhibitor |
| US5668151A (en) * | 1995-06-07 | 1997-09-16 | Bristol-Myers Squibb Company | Dihydropyridine NPY antagonists: piperidine derivatives |
| PL193686B1 (pl) * | 1995-09-07 | 2007-03-30 | Hoffmann La Roche | Pochodne piperydyny, środki lecznicze zawierającepochodne piperydyny, sposoby wytwarzania tych pochodnych oraz zastosowanie pochodnych |
| AU3818900A (en) | 1999-04-14 | 2000-11-02 | F. Hoffmann-La Roche Ag | Process for the preparation of substituted piperidines |
| US6376672B1 (en) | 1999-04-27 | 2002-04-23 | Hoffmann-La Roche Inc. | Naphthalenylmethoxypiperidines as renin inhibitors |
| US6197959B1 (en) | 1999-04-27 | 2001-03-06 | Hoffmann-La Roche Inc. | Piperidine derivatives |
| US20060079533A1 (en) | 2001-03-23 | 2006-04-13 | Nieman James A | Methods of treating alzheimer's disease |
| AU2002256418A1 (en) | 2001-04-27 | 2002-11-11 | Vertex Pharmaceuticals Incorporated | Inhibitors of bace |
| WO2004002549A1 (en) * | 2002-06-28 | 2004-01-08 | Novartis Ag | Use of organic compounds |
| US20040214832A1 (en) | 2003-04-10 | 2004-10-28 | Cuiman Cai | Piperazine derivative renin inhibitors |
| US20040204455A1 (en) | 2003-04-10 | 2004-10-14 | Cody Wayne Livingston | Piperidine derivative rennin inhibitors |
| BRPI0416976A (pt) * | 2003-11-26 | 2007-02-21 | Novartis Ag | derivados de 4-fenilpiperidina como inibidores de renina |
-
2004
- 2004-11-25 BR BRPI0416976-0A patent/BRPI0416976A/pt not_active IP Right Cessation
- 2004-11-25 KR KR1020067010229A patent/KR20060120146A/ko not_active Ceased
- 2004-11-25 PL PL04798086T patent/PL1689712T3/pl unknown
- 2004-11-25 DE DE602004022704T patent/DE602004022704D1/de not_active Expired - Lifetime
- 2004-11-25 JP JP2006540386A patent/JP4750712B2/ja not_active Expired - Fee Related
- 2004-11-25 AU AU2004293177A patent/AU2004293177B2/en not_active Ceased
- 2004-11-25 EP EP04798086A patent/EP1689712B1/en not_active Expired - Lifetime
- 2004-11-25 WO PCT/EP2004/013410 patent/WO2005051911A1/en not_active Ceased
- 2004-11-25 CN CNA2004800409431A patent/CN1906163A/zh active Pending
- 2004-11-25 US US10/580,296 patent/US20070078164A1/en not_active Abandoned
- 2004-11-25 PT PT04798086T patent/PT1689712E/pt unknown
- 2004-11-25 RU RU2006122637/04A patent/RU2374228C2/ru not_active IP Right Cessation
- 2004-11-25 ES ES04798086T patent/ES2332053T3/es not_active Expired - Lifetime
- 2004-11-25 AT AT04798086T patent/ATE440082T1/de not_active IP Right Cessation
- 2004-11-25 CA CA002546264A patent/CA2546264A1/en not_active Abandoned
-
2008
- 2008-06-27 US US12/163,038 patent/US7754727B2/en not_active Expired - Fee Related
-
2010
- 2010-05-28 US US12/789,892 patent/US8362040B2/en not_active Expired - Fee Related
Also Published As
| Publication number | Publication date |
|---|---|
| EP1689712A1 (en) | 2006-08-16 |
| JP4750712B2 (ja) | 2011-08-17 |
| BRPI0416976A (pt) | 2007-02-21 |
| EP1689712B1 (en) | 2009-08-19 |
| KR20060120146A (ko) | 2006-11-24 |
| RU2006122637A (ru) | 2008-01-27 |
| DE602004022704D1 (de) | 2009-10-01 |
| AU2004293177A1 (en) | 2005-06-09 |
| US20070078164A1 (en) | 2007-04-05 |
| PL1689712T3 (pl) | 2010-01-29 |
| US7754727B2 (en) | 2010-07-13 |
| RU2374228C2 (ru) | 2009-11-27 |
| US20080269255A1 (en) | 2008-10-30 |
| JP2007512282A (ja) | 2007-05-17 |
| ES2332053T3 (es) | 2010-01-25 |
| US20100240679A1 (en) | 2010-09-23 |
| US8362040B2 (en) | 2013-01-29 |
| AU2004293177B2 (en) | 2008-10-23 |
| WO2005051911A1 (en) | 2005-06-09 |
| ATE440082T1 (de) | 2009-09-15 |
| PT1689712E (pt) | 2009-11-25 |
| CN1906163A (zh) | 2007-01-31 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| EEER | Examination request | ||
| FZDE | Discontinued |