ES2653215T3 - Inhibidores de neprilisina - Google Patents
Inhibidores de neprilisina Download PDFInfo
- Publication number
- ES2653215T3 ES2653215T3 ES12725202.1T ES12725202T ES2653215T3 ES 2653215 T3 ES2653215 T3 ES 2653215T3 ES 12725202 T ES12725202 T ES 12725202T ES 2653215 T3 ES2653215 T3 ES 2653215T3
- Authority
- ES
- Spain
- Prior art keywords
- alkyl
- compounds
- benzyl
- alkylene
- phenyl
- 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.)
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- 239000002792 enkephalinase inhibitor Substances 0.000 title 1
- 150000001875 compounds Chemical class 0.000 abstract description 93
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 abstract description 44
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 abstract description 43
- -1 -OH Chemical group 0.000 abstract description 31
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 abstract description 24
- 125000002947 alkylene group Chemical group 0.000 abstract description 12
- 125000006272 (C3-C7) cycloalkyl group Chemical group 0.000 abstract description 11
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 abstract description 11
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 abstract description 11
- YLQBMQCUIZJEEH-UHFFFAOYSA-N Furan Chemical compound C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 abstract description 9
- UFWIBTONFRDIAS-UHFFFAOYSA-N Naphthalene Chemical compound C1=CC=CC2=CC=CC=C21 UFWIBTONFRDIAS-UHFFFAOYSA-N 0.000 abstract description 8
- NCTHHJRIJGFPTG-UHFFFAOYSA-N 6,7-bis(aziridin-1-yl)-4-[7-[[6,7-bis(aziridin-1-yl)-5,8-dioxoquinazolin-4-yl]amino]heptylamino]quinazoline-5,8-dione Chemical compound C1CN1C=1C(=O)C2=C(NCCCCCCCNC=3C=4C(=O)C(N5CC5)=C(N5CC5)C(=O)C=4N=CN=3)N=CN=C2C(=O)C=1N1CC1 NCTHHJRIJGFPTG-UHFFFAOYSA-N 0.000 abstract description 6
- KYQCOXFCLRTKLS-UHFFFAOYSA-N Pyrazine Chemical compound C1=CN=CC=N1 KYQCOXFCLRTKLS-UHFFFAOYSA-N 0.000 abstract description 6
- 125000001072 heteroaryl group Chemical group 0.000 abstract description 6
- 229910052801 chlorine Inorganic materials 0.000 abstract description 5
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 abstract description 4
- 229910052739 hydrogen Inorganic materials 0.000 abstract description 4
- PCNDJXKNXGMECE-UHFFFAOYSA-N Phenazine Natural products C1=CC=CC2=NC3=CC=CC=C3N=C21 PCNDJXKNXGMECE-UHFFFAOYSA-N 0.000 abstract description 3
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 abstract description 3
- 101000599004 Homo sapiens Olfactory receptor 3A1 Proteins 0.000 abstract description 2
- 102100037784 Olfactory receptor 3A1 Human genes 0.000 abstract description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 abstract description 2
- 125000001475 halogen functional group Chemical group 0.000 abstract 3
- YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical group C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 abstract 2
- NOIXNOMHHWGUTG-UHFFFAOYSA-N 2-[[4-[4-pyridin-4-yl-1-(2,2,2-trifluoroethyl)pyrazol-3-yl]phenoxy]methyl]quinoline Chemical compound C=1C=C(OCC=2N=C3C=CC=CC3=CC=2)C=CC=1C1=NN(CC(F)(F)F)C=C1C1=CC=NC=C1 NOIXNOMHHWGUTG-UHFFFAOYSA-N 0.000 abstract 1
- 229930192474 thiophene Chemical group 0.000 abstract 1
- 238000012360 testing method Methods 0.000 description 29
- 239000000460 chlorine Substances 0.000 description 23
- 238000000034 method Methods 0.000 description 21
- 206010020772 Hypertension Diseases 0.000 description 19
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 17
- 201000010099 disease Diseases 0.000 description 16
- 230000005764 inhibitory process Effects 0.000 description 16
- 238000006243 chemical reaction Methods 0.000 description 15
- 230000000694 effects Effects 0.000 description 15
- 238000003556 assay Methods 0.000 description 13
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 12
- 125000006239 protecting group Chemical group 0.000 description 12
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 11
- 125000005843 halogen group Chemical group 0.000 description 11
- 229940002612 prodrug Drugs 0.000 description 11
- 239000000651 prodrug Substances 0.000 description 11
- HEMHJVSKTPXQMS-UHFFFAOYSA-M sodium hydroxide Inorganic materials [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 11
- 238000011282 treatment Methods 0.000 description 11
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 10
- 125000000217 alkyl group Chemical group 0.000 description 10
- 239000003153 chemical reaction reagent Substances 0.000 description 10
- 150000003839 salts Chemical class 0.000 description 10
- 239000002253 acid Substances 0.000 description 9
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-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 7
- 125000004432 carbon atom Chemical group C* 0.000 description 7
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 7
- 241000124008 Mammalia Species 0.000 description 6
- 241000700159 Rattus Species 0.000 description 6
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 6
- 150000002148 esters Chemical class 0.000 description 6
- 230000014509 gene expression Effects 0.000 description 6
- 230000002401 inhibitory effect Effects 0.000 description 6
- 238000011160 research Methods 0.000 description 6
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 5
- 230000036772 blood pressure Effects 0.000 description 5
- 238000010511 deprotection reaction Methods 0.000 description 5
- 229940079593 drug Drugs 0.000 description 5
- 239000003814 drug Substances 0.000 description 5
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 5
- 125000000524 functional group Chemical group 0.000 description 5
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 description 5
- 125000006282 2-chlorobenzyl group Chemical group [H]C1=C([H])C(Cl)=C(C([H])=C1[H])C([H])([H])* 0.000 description 4
- KDCGOANMDULRCW-UHFFFAOYSA-N 7H-purine Chemical compound N1=CNC2=NC=NC2=C1 KDCGOANMDULRCW-UHFFFAOYSA-N 0.000 description 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 4
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 4
- 125000002252 acyl group Chemical group 0.000 description 4
- 125000004429 atom Chemical group 0.000 description 4
- 229910052799 carbon Inorganic materials 0.000 description 4
- 235000019439 ethyl acetate Nutrition 0.000 description 4
- 239000002994 raw material Substances 0.000 description 4
- 239000000758 substrate Substances 0.000 description 4
- 208000024891 symptom Diseases 0.000 description 4
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 4
- 230000001225 therapeutic effect Effects 0.000 description 4
- 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
- FERIUCNNQQJTOY-UHFFFAOYSA-N Butyric acid Chemical class CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 description 3
- DCERHCFNWRGHLK-UHFFFAOYSA-N C[Si](C)C Chemical compound C[Si](C)C DCERHCFNWRGHLK-UHFFFAOYSA-N 0.000 description 3
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical class Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 3
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 150000001412 amines Chemical class 0.000 description 3
- 238000010171 animal model Methods 0.000 description 3
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 description 3
- 210000004027 cell Anatomy 0.000 description 3
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 3
- 125000004430 oxygen atom Chemical group O* 0.000 description 3
- 230000002265 prevention Effects 0.000 description 3
- 108090000765 processed proteins & peptides Proteins 0.000 description 3
- 125000004076 pyridyl group Chemical group 0.000 description 3
- 229920006395 saturated elastomer Polymers 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- 125000001424 substituent group Chemical group 0.000 description 3
- 125000001981 tert-butyldimethylsilyl group Chemical group [H]C([H])([H])[Si]([H])(C([H])([H])[H])[*]C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 3
- 238000002560 therapeutic procedure Methods 0.000 description 3
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 3
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 description 3
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 2
- SJJCQDRGABAVBB-UHFFFAOYSA-N 1-hydroxy-2-naphthoic acid Chemical compound C1=CC=CC2=C(O)C(C(=O)O)=CC=C21 SJJCQDRGABAVBB-UHFFFAOYSA-N 0.000 description 2
- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 description 2
- 125000004182 2-chlorophenyl group Chemical group [H]C1=C([H])C(Cl)=C(*)C([H])=C1[H] 0.000 description 2
- ZOOGRGPOEVQQDX-UUOKFMHZSA-N 3',5'-cyclic GMP Chemical compound C([C@H]1O2)OP(O)(=O)O[C@H]1[C@@H](O)[C@@H]2N1C(N=C(NC2=O)N)=C2N=C1 ZOOGRGPOEVQQDX-UUOKFMHZSA-N 0.000 description 2
- 102000001921 Aminopeptidase P Human genes 0.000 description 2
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 2
- 206010019280 Heart failures Diseases 0.000 description 2
- 241000282414 Homo sapiens Species 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
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 2
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 2
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 2
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 2
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 2
- 206010064911 Pulmonary arterial hypertension Diseases 0.000 description 2
- 108010038900 X-Pro aminopeptidase Proteins 0.000 description 2
- 150000007513 acids Chemical class 0.000 description 2
- 125000003118 aryl group Chemical group 0.000 description 2
- RROBIDXNTUAHFW-UHFFFAOYSA-N benzotriazol-1-yloxy-tris(dimethylamino)phosphanium Chemical compound C1=CC=C2N(O[P+](N(C)C)(N(C)C)N(C)C)N=NC2=C1 RROBIDXNTUAHFW-UHFFFAOYSA-N 0.000 description 2
- RYYVLZVUVIJVGH-UHFFFAOYSA-N caffeine Chemical compound CN1C(=O)N(C)C(=O)C2=C1N=CN2C RYYVLZVUVIJVGH-UHFFFAOYSA-N 0.000 description 2
- PFKFTWBEEFSNDU-UHFFFAOYSA-N carbonyldiimidazole Chemical compound C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 description 2
- 239000007795 chemical reaction product Substances 0.000 description 2
- 238000005859 coupling reaction Methods 0.000 description 2
- 238000002425 crystallisation Methods 0.000 description 2
- 230000008025 crystallization Effects 0.000 description 2
- ZOOGRGPOEVQQDX-UHFFFAOYSA-N cyclic GMP Natural products O1C2COP(O)(=O)OC2C(O)C1N1C=NC2=C1NC(N)=NC2=O ZOOGRGPOEVQQDX-UHFFFAOYSA-N 0.000 description 2
- 230000001419 dependent effect Effects 0.000 description 2
- ZZVUWRFHKOJYTH-UHFFFAOYSA-N diphenhydramine Chemical group C=1C=CC=CC=1C(OCCN(C)C)C1=CC=CC=C1 ZZVUWRFHKOJYTH-UHFFFAOYSA-N 0.000 description 2
- 125000005982 diphenylmethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])(*)C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 2
- 230000002255 enzymatic effect Effects 0.000 description 2
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 description 2
- 238000002825 functional assay Methods 0.000 description 2
- 125000000623 heterocyclic group Chemical group 0.000 description 2
- 230000001631 hypertensive effect Effects 0.000 description 2
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Substances C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 2
- 238000001727 in vivo Methods 0.000 description 2
- 238000005462 in vivo assay Methods 0.000 description 2
- 239000003701 inert diluent Substances 0.000 description 2
- 239000000543 intermediate Substances 0.000 description 2
- 238000005259 measurement Methods 0.000 description 2
- 230000001404 mediated effect Effects 0.000 description 2
- 230000004060 metabolic process Effects 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical class CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 2
- 230000004962 physiological condition Effects 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 description 2
- 235000017550 sodium carbonate Nutrition 0.000 description 2
- 239000011780 sodium chloride Substances 0.000 description 2
- 238000003786 synthesis reaction Methods 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
- 238000004809 thin layer chromatography Methods 0.000 description 2
- GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical compound CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- NFJVTGGTJSAPPN-CRAIPNDOSA-N (2R,3R)-4-(2-chlorophenyl)-2-hydroxy-3-[[3-(2-hydroxyphenyl)-1H-pyrazole-5-carbonyl]amino]butanoic acid Chemical compound C([C@H]([C@@H](O)C(O)=O)NC(=O)C1=NNC(=C1)C=1C(=CC=CC=1)O)C1=CC=CC=C1Cl NFJVTGGTJSAPPN-CRAIPNDOSA-N 0.000 description 1
- BWIPIAZEKOXBAU-BXKDBHETSA-N (2r,3r)-2-hydroxy-3-[(3-nitro-1h-pyrazole-5-carbonyl)amino]-4-phenylbutanoic acid Chemical compound C([C@H]([C@@H](O)C(O)=O)NC(=O)C1=NNC(=C1)[N+]([O-])=O)C1=CC=CC=C1 BWIPIAZEKOXBAU-BXKDBHETSA-N 0.000 description 1
- JWZOQMABLZEKKF-IFMALSPDSA-N (2r,3r)-3-[(1-benzyl-5-propylpyrazole-3-carbonyl)amino]-2-hydroxy-4-phenylbutanoic acid Chemical compound CCCC1=CC(C(=O)N[C@H](CC=2C=CC=CC=2)[C@@H](O)C(O)=O)=NN1CC1=CC=CC=C1 JWZOQMABLZEKKF-IFMALSPDSA-N 0.000 description 1
- MABLWHGNBWWQKR-WIYYLYMNSA-N (2r,3r)-3-[[1-[(4-chlorophenyl)methyl]-5-(dimethylcarbamoyl)pyrazole-3-carbonyl]amino]-2-hydroxy-4-phenylbutanoic acid Chemical compound CN(C)C(=O)C1=CC(C(=O)N[C@H](CC=2C=CC=CC=2)[C@@H](O)C(O)=O)=NN1CC1=CC=C(Cl)C=C1 MABLWHGNBWWQKR-WIYYLYMNSA-N 0.000 description 1
- WVSRTDLFFBCOSK-RTBURBONSA-N (2r,3r)-3-[[1-[(4-chlorophenyl)methyl]pyrazole-3-carbonyl]amino]-2-hydroxy-4-phenylbutanoic acid Chemical compound C([C@H]([C@@H](O)C(O)=O)NC(=O)C1=NN(CC=2C=CC(Cl)=CC=2)C=C1)C1=CC=CC=C1 WVSRTDLFFBCOSK-RTBURBONSA-N 0.000 description 1
- LKXLCILSJSEAPT-UYAOXDASSA-N (2r,3r)-3-[[3-(3-acetamidophenyl)-1h-pyrazole-5-carbonyl]amino]-4-(2-chlorophenyl)-2-hydroxybutanoic acid Chemical compound CC(=O)NC1=CC=CC(C=2NN=C(C=2)C(=O)N[C@H](CC=2C(=CC=CC=2)Cl)[C@@H](O)C(O)=O)=C1 LKXLCILSJSEAPT-UYAOXDASSA-N 0.000 description 1
- REDQUAXFKHQTET-NFBKMPQASA-N (2r,3r)-3-[[5-cyclopropyl-1-[(4-methoxyphenyl)methyl]pyrazole-3-carbonyl]amino]-2-hydroxy-4-phenylbutanoic acid Chemical compound C1=CC(OC)=CC=C1CN1C(C2CC2)=CC(C(=O)N[C@H](CC=2C=CC=CC=2)[C@@H](O)C(O)=O)=N1 REDQUAXFKHQTET-NFBKMPQASA-N 0.000 description 1
- QDKKXGQORNWBHO-NFBKMPQASA-N (2r,3r)-3-[[5-cyclopropyl-1-[(4-methylsulfanylphenyl)methyl]pyrazole-3-carbonyl]amino]-2-hydroxy-4-phenylbutanoic acid Chemical compound C1=CC(SC)=CC=C1CN1C(C2CC2)=CC(C(=O)N[C@H](CC=2C=CC=CC=2)[C@@H](O)C(O)=O)=N1 QDKKXGQORNWBHO-NFBKMPQASA-N 0.000 description 1
- XYYYIQCCSKMIMY-ISKFKSNPSA-N (2r,3r)-4-(2-chlorophenyl)-2-hydroxy-3-[[3-(4-phenylphenyl)-1h-pyrazole-5-carbonyl]amino]butanoic acid Chemical compound C([C@H]([C@@H](O)C(O)=O)NC(=O)C1=NNC(=C1)C=1C=CC(=CC=1)C=1C=CC=CC=1)C1=CC=CC=C1Cl XYYYIQCCSKMIMY-ISKFKSNPSA-N 0.000 description 1
- 125000003161 (C1-C6) alkylene group Chemical group 0.000 description 1
- 125000003088 (fluoren-9-ylmethoxy)carbonyl group Chemical group 0.000 description 1
- ASOKPJOREAFHNY-UHFFFAOYSA-N 1-Hydroxybenzotriazole Chemical compound C1=CC=C2N(O)N=NC2=C1 ASOKPJOREAFHNY-UHFFFAOYSA-N 0.000 description 1
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide Chemical compound CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 1
- DCYGAPKNVCQNOE-UHFFFAOYSA-N 2,2,2-triphenylacetic acid Chemical class C=1C=CC=CC=1C(C=1C=CC=CC=1)(C(=O)O)C1=CC=CC=C1 DCYGAPKNVCQNOE-UHFFFAOYSA-N 0.000 description 1
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Classifications
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- 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
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- 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
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Applications Claiming Priority (3)
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| US201161491750P | 2011-05-31 | 2011-05-31 | |
| US201161491750P | 2011-05-31 | ||
| PCT/US2012/038511 WO2012166387A1 (en) | 2011-05-31 | 2012-05-18 | Neprilysin inhibitors |
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| ES2653215T3 true ES2653215T3 (es) | 2018-02-06 |
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| ES12725202.1T Active ES2653215T3 (es) | 2011-05-31 | 2012-05-18 | Inhibidores de neprilisina |
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- 2012-05-18 JP JP2014513547A patent/JP5959074B2/ja not_active Expired - Fee Related
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| US8993752B2 (en) | 2015-03-31 |
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| US20180194757A1 (en) | 2018-07-12 |
| US20120308587A1 (en) | 2012-12-06 |
| JP2014515401A (ja) | 2014-06-30 |
| JP5959074B2 (ja) | 2016-08-02 |
| EP2714662A1 (en) | 2014-04-09 |
| US9828367B2 (en) | 2017-11-28 |
| CA2835216A1 (en) | 2012-12-06 |
| WO2012166387A1 (en) | 2012-12-06 |
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