ES2587447T3 - Método de tratamiento de nefropatía inducida por medio de contraste - Google Patents
Método de tratamiento de nefropatía inducida por medio de contraste Download PDFInfo
- Publication number
- ES2587447T3 ES2587447T3 ES11784638.6T ES11784638T ES2587447T3 ES 2587447 T3 ES2587447 T3 ES 2587447T3 ES 11784638 T ES11784638 T ES 11784638T ES 2587447 T3 ES2587447 T3 ES 2587447T3
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- Prior art keywords
- alkyl
- halo
- heteroaryl
- formula
- hydroxy
- Prior art date
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- 208000017169 kidney disease Diseases 0.000 title abstract description 11
- 238000000034 method Methods 0.000 title description 11
- 150000001875 compounds Chemical class 0.000 claims abstract description 43
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 24
- 150000003839 salts Chemical class 0.000 claims abstract description 16
- 125000003545 alkoxy group Chemical group 0.000 claims abstract description 14
- 229910052717 sulfur Inorganic materials 0.000 claims abstract description 5
- 125000006272 (C3-C7) cycloalkyl group Chemical group 0.000 claims abstract 9
- 229910052757 nitrogen Inorganic materials 0.000 claims abstract 5
- 229910052760 oxygen Inorganic materials 0.000 claims abstract 4
- 125000006413 ring segment Chemical group 0.000 claims abstract 4
- 125000001475 halogen functional group Chemical group 0.000 claims 2
- 125000006163 5-membered heteroaryl group Chemical group 0.000 claims 1
- 229940124143 Endopeptidase inhibitor Drugs 0.000 claims 1
- 125000004356 hydroxy functional group Chemical group O* 0.000 claims 1
- 230000007935 neutral effect Effects 0.000 claims 1
- -1 C1-7alkoxy Chemical group 0.000 abstract description 40
- 125000005843 halogen group Chemical group 0.000 abstract description 26
- 125000001072 heteroaryl group Chemical group 0.000 abstract description 22
- 125000002887 hydroxy group Chemical group [H]O* 0.000 abstract description 20
- 125000001424 substituent group Chemical group 0.000 abstract description 17
- 239000003814 drug Substances 0.000 abstract description 13
- 125000000623 heterocyclic group Chemical group 0.000 abstract description 12
- 125000000041 C6-C10 aryl group Chemical group 0.000 abstract description 10
- 238000004519 manufacturing process Methods 0.000 abstract description 10
- 230000002265 prevention Effects 0.000 abstract description 10
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 abstract description 9
- 125000002947 alkylene group Chemical group 0.000 abstract description 8
- 125000003118 aryl group Chemical group 0.000 abstract description 8
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 abstract description 6
- 229920006395 saturated elastomer Polymers 0.000 abstract description 6
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 abstract description 2
- 125000005842 heteroatom Chemical group 0.000 abstract 8
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 abstract 7
- 125000004432 carbon atom Chemical group C* 0.000 abstract 6
- 125000006701 (C1-C7) alkyl group Chemical group 0.000 abstract 4
- 125000002619 bicyclic group Chemical group 0.000 abstract 4
- 125000002950 monocyclic group Chemical group 0.000 abstract 4
- 125000006570 (C5-C6) heteroaryl group Chemical group 0.000 abstract 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 abstract 2
- 125000004429 atom Chemical group 0.000 abstract 2
- 125000000753 cycloalkyl group Chemical group 0.000 abstract 2
- 239000002792 enkephalinase inhibitor Substances 0.000 abstract 2
- 125000002768 hydroxyalkyl group Chemical group 0.000 abstract 2
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 abstract 2
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 abstract 1
- 125000000171 (C1-C6) haloalkyl group Chemical group 0.000 abstract 1
- 125000006590 (C2-C6) alkenylene group Chemical group 0.000 abstract 1
- 125000006719 (C6-C10) aryl (C1-C6) alkyl group Chemical group 0.000 abstract 1
- JCXJVPUVTGWSNB-UHFFFAOYSA-N Nitrogen dioxide Chemical compound O=[N]=O JCXJVPUVTGWSNB-UHFFFAOYSA-N 0.000 abstract 1
- 125000005236 alkanoylamino group Chemical group 0.000 abstract 1
- 125000004450 alkenylene group Chemical group 0.000 abstract 1
- 229910052799 carbon Inorganic materials 0.000 abstract 1
- 229940125898 compound 5 Drugs 0.000 abstract 1
- 125000004093 cyano group Chemical group *C#N 0.000 abstract 1
- 229910052736 halogen Inorganic materials 0.000 abstract 1
- 150000002367 halogens Chemical class 0.000 abstract 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 abstract 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 abstract 1
- 239000000543 intermediate Substances 0.000 description 50
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 42
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 36
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 28
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 27
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 23
- 239000000047 product Substances 0.000 description 20
- 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 17
- 238000005160 1H NMR spectroscopy Methods 0.000 description 16
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 16
- 235000019439 ethyl acetate Nutrition 0.000 description 16
- 239000000203 mixture Substances 0.000 description 15
- KDLHZDBZIXYQEI-UHFFFAOYSA-N palladium Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 15
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 14
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 13
- 238000004128 high performance liquid chromatography Methods 0.000 description 11
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 10
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 10
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 10
- 125000004800 4-bromophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Br 0.000 description 9
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 9
- 238000005481 NMR spectroscopy Methods 0.000 description 9
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 9
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 9
- OBNCKNCVKJNDBV-UHFFFAOYSA-N butanoic acid ethyl ester Natural products CCCC(=O)OCC OBNCKNCVKJNDBV-UHFFFAOYSA-N 0.000 description 9
- 239000003153 chemical reaction reagent Substances 0.000 description 9
- 230000014759 maintenance of location Effects 0.000 description 9
- 238000003756 stirring Methods 0.000 description 9
- ULRPISSMEBPJLN-UHFFFAOYSA-N 2h-tetrazol-5-amine Chemical compound NC1=NN=NN1 ULRPISSMEBPJLN-UHFFFAOYSA-N 0.000 description 8
- 101100030361 Neurospora crassa (strain ATCC 24698 / 74-OR23-1A / CBS 708.71 / DSM 1257 / FGSC 987) pph-3 gene Proteins 0.000 description 8
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 8
- 235000017550 sodium carbonate Nutrition 0.000 description 8
- 229910000029 sodium carbonate Inorganic materials 0.000 description 8
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 7
- 239000012074 organic phase Substances 0.000 description 7
- DTQVDTLACAAQTR-UHFFFAOYSA-N trifluoroacetic acid Substances OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 7
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 6
- 239000002253 acid Substances 0.000 description 6
- 230000015572 biosynthetic process Effects 0.000 description 6
- PFKFTWBEEFSNDU-UHFFFAOYSA-N carbonyldiimidazole Chemical compound C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 description 6
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 6
- 239000000243 solution Substances 0.000 description 6
- 239000000725 suspension Substances 0.000 description 6
- 238000003786 synthesis reaction Methods 0.000 description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 6
- SDEAGACSNFSZCU-UHFFFAOYSA-N (3-chlorophenyl)boronic acid Chemical compound OB(O)C1=CC=CC(Cl)=C1 SDEAGACSNFSZCU-UHFFFAOYSA-N 0.000 description 5
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 description 5
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 5
- 238000006243 chemical reaction Methods 0.000 description 5
- 239000003480 eluent Substances 0.000 description 5
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 5
- 235000019341 magnesium sulphate Nutrition 0.000 description 5
- 239000012071 phase Substances 0.000 description 5
- 239000011541 reaction mixture 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
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide Substances CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 4
- 239000007832 Na2SO4 Substances 0.000 description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 4
- 239000012043 crude product Substances 0.000 description 4
- 238000001514 detection method Methods 0.000 description 4
- 125000004494 ethyl ester group Chemical group 0.000 description 4
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 4
- 238000006460 hydrolysis reaction Methods 0.000 description 4
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 4
- ZCSHNCUQKCANBX-UHFFFAOYSA-N lithium diisopropylamide Chemical compound [Li+].CC(C)[N-]C(C)C ZCSHNCUQKCANBX-UHFFFAOYSA-N 0.000 description 4
- 229910052938 sodium sulfate Inorganic materials 0.000 description 4
- 235000011152 sodium sulphate Nutrition 0.000 description 4
- FPIRBHDGWMWJEP-UHFFFAOYSA-N 1-hydroxy-7-azabenzotriazole Chemical compound C1=CN=C2N(O)N=NC2=C1 FPIRBHDGWMWJEP-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-MZCSYVLQSA-N Deuterated methanol Chemical compound [2H]OC([2H])([2H])[2H] OKKJLVBELUTLKV-MZCSYVLQSA-N 0.000 description 3
- 125000005518 carboxamido group Chemical group 0.000 description 3
- 230000007062 hydrolysis Effects 0.000 description 3
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 3
- 239000012299 nitrogen atmosphere Substances 0.000 description 3
- 235000015320 potassium carbonate Nutrition 0.000 description 3
- 229910000027 potassium carbonate Inorganic materials 0.000 description 3
- 235000017557 sodium bicarbonate Nutrition 0.000 description 3
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 3
- 239000007858 starting material Substances 0.000 description 3
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 description 3
- 229910000404 tripotassium phosphate Inorganic materials 0.000 description 3
- 235000019798 tripotassium phosphate Nutrition 0.000 description 3
- KIWMOCOARQFIAU-KSSFIOAISA-N (2s)-2-[[(2s)-1-ethoxy-1-oxopropan-2-yl]amino]-3-(4-phenylphenyl)propanoic acid Chemical compound C1=CC(C[C@H](N[C@@H](C)C(=O)OCC)C(O)=O)=CC=C1C1=CC=CC=C1 KIWMOCOARQFIAU-KSSFIOAISA-N 0.000 description 2
- WKTDFRMFHHRJPT-PMACEKPBSA-N (2s)-3-[4-(3-chlorophenyl)phenyl]-2-[[(2s)-1-[(2-methylpropan-2-yl)oxy]-1-oxobutan-2-yl]amino]propanoic acid Chemical compound C1=CC(C[C@H](N[C@@H](CC)C(=O)OC(C)(C)C)C(O)=O)=CC=C1C1=CC=CC(Cl)=C1 WKTDFRMFHHRJPT-PMACEKPBSA-N 0.000 description 2
- JDZXXTWEUKWRNA-DQEYMECFSA-N (2s)-3-[4-(3-chlorophenyl)phenyl]-2-[[(2s)-1-ethoxy-1-oxo-4-phenylbutan-2-yl]amino]propanoic acid Chemical compound C([C@@H](C(=O)OCC)N[C@@H](CC=1C=CC(=CC=1)C=1C=C(Cl)C=CC=1)C(O)=O)CC1=CC=CC=C1 JDZXXTWEUKWRNA-DQEYMECFSA-N 0.000 description 2
- XIEAPPZAQSRCSI-OALUTQOASA-N (2s)-3-[4-(3-chlorophenyl)phenyl]-2-[[(2s)-1-ethoxy-3-methoxy-1-oxopropan-2-yl]amino]propanoic acid Chemical compound C1=CC(C[C@H](N[C@@H](COC)C(=O)OCC)C(O)=O)=CC=C1C1=CC=CC(Cl)=C1 XIEAPPZAQSRCSI-OALUTQOASA-N 0.000 description 2
- SJHPCNCNNSSLPL-CSKARUKUSA-N (4e)-4-(ethoxymethylidene)-2-phenyl-1,3-oxazol-5-one Chemical compound O1C(=O)C(=C/OCC)\N=C1C1=CC=CC=C1 SJHPCNCNNSSLPL-CSKARUKUSA-N 0.000 description 2
- PEZNEXFPRSOYPL-UHFFFAOYSA-N (bis(trifluoroacetoxy)iodo)benzene Chemical compound FC(F)(F)C(=O)OI(OC(=O)C(F)(F)F)C1=CC=CC=C1 PEZNEXFPRSOYPL-UHFFFAOYSA-N 0.000 description 2
- QFMZQPDHXULLKC-UHFFFAOYSA-N 1,2-bis(diphenylphosphino)ethane Chemical compound C=1C=CC=CC=1P(C=1C=CC=CC=1)CCP(C=1C=CC=CC=1)C1=CC=CC=C1 QFMZQPDHXULLKC-UHFFFAOYSA-N 0.000 description 2
- 239000004912 1,5-cyclooctadiene Substances 0.000 description 2
- OHVLMTFVQDZYHP-UHFFFAOYSA-N 1-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)-2-[4-[2-[[3-(trifluoromethoxy)phenyl]methylamino]pyrimidin-5-yl]piperazin-1-yl]ethanone Chemical compound N1N=NC=2CN(CCC=21)C(CN1CCN(CC1)C=1C=NC(=NC=1)NCC1=CC(=CC=C1)OC(F)(F)F)=O OHVLMTFVQDZYHP-UHFFFAOYSA-N 0.000 description 2
- YIWGJFPJRAEKMK-UHFFFAOYSA-N 1-(2H-benzotriazol-5-yl)-3-methyl-8-[2-[[3-(trifluoromethoxy)phenyl]methylamino]pyrimidine-5-carbonyl]-1,3,8-triazaspiro[4.5]decane-2,4-dione Chemical compound CN1C(=O)N(c2ccc3n[nH]nc3c2)C2(CCN(CC2)C(=O)c2cnc(NCc3cccc(OC(F)(F)F)c3)nc2)C1=O YIWGJFPJRAEKMK-UHFFFAOYSA-N 0.000 description 2
- JPQXSDYUHBETMN-UHFFFAOYSA-N 1-[(4-methoxyphenyl)methyl]-n-methyltetrazol-5-amine Chemical compound CNC1=NN=NN1CC1=CC=C(OC)C=C1 JPQXSDYUHBETMN-UHFFFAOYSA-N 0.000 description 2
- PGOYNEAPOIJUIS-UHFFFAOYSA-N 1-[(4-methoxyphenyl)methyl]tetrazol-5-amine Chemical compound C1=CC(OC)=CC=C1CN1C(N)=NN=N1 PGOYNEAPOIJUIS-UHFFFAOYSA-N 0.000 description 2
- QKNYBSVHEMOAJP-UHFFFAOYSA-N 2-amino-2-(hydroxymethyl)propane-1,3-diol;hydron;chloride Chemical compound Cl.OCC(N)(CO)CO QKNYBSVHEMOAJP-UHFFFAOYSA-N 0.000 description 2
- ZPSJGADGUYYRKE-UHFFFAOYSA-N 2H-pyran-2-one Chemical compound O=C1C=CC=CO1 ZPSJGADGUYYRKE-UHFFFAOYSA-N 0.000 description 2
- YLZOPXRUQYQQID-UHFFFAOYSA-N 3-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)-1-[4-[2-[[3-(trifluoromethoxy)phenyl]methylamino]pyrimidin-5-yl]piperazin-1-yl]propan-1-one Chemical compound N1N=NC=2CN(CCC=21)CCC(=O)N1CCN(CC1)C=1C=NC(=NC=1)NCC1=CC(=CC=C1)OC(F)(F)F YLZOPXRUQYQQID-UHFFFAOYSA-N 0.000 description 2
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 2
- DEXFNLNNUZKHNO-UHFFFAOYSA-N 6-[3-[4-[2-(2,3-dihydro-1H-inden-2-ylamino)pyrimidin-5-yl]piperidin-1-yl]-3-oxopropyl]-3H-1,3-benzoxazol-2-one Chemical compound C1C(CC2=CC=CC=C12)NC1=NC=C(C=N1)C1CCN(CC1)C(CCC1=CC2=C(NC(O2)=O)C=C1)=O DEXFNLNNUZKHNO-UHFFFAOYSA-N 0.000 description 2
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 2
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 2
- 239000007821 HATU Substances 0.000 description 2
- 108090000028 Neprilysin Proteins 0.000 description 2
- KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical group C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 2
- YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical compound C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 description 2
- JAWMENYCRQKKJY-UHFFFAOYSA-N [3-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-ylmethyl)-1-oxa-2,8-diazaspiro[4.5]dec-2-en-8-yl]-[2-[[3-(trifluoromethoxy)phenyl]methylamino]pyrimidin-5-yl]methanone Chemical compound N1N=NC=2CN(CCC=21)CC1=NOC2(C1)CCN(CC2)C(=O)C=1C=NC(=NC=1)NCC1=CC(=CC=C1)OC(F)(F)F JAWMENYCRQKKJY-UHFFFAOYSA-N 0.000 description 2
- VZTDIZULWFCMLS-UHFFFAOYSA-N ammonium formate Chemical compound [NH4+].[O-]C=O VZTDIZULWFCMLS-UHFFFAOYSA-N 0.000 description 2
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 description 2
- 125000000319 biphenyl-4-yl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 description 2
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 2
- 238000004296 chiral HPLC Methods 0.000 description 2
- LZCLXQDLBQLTDK-SCSAIBSYSA-N ethyl (2R)-lactate Chemical compound CCOC(=O)[C@@H](C)O LZCLXQDLBQLTDK-SCSAIBSYSA-N 0.000 description 2
- FKRCODPIKNYEAC-UHFFFAOYSA-N ethyl propionate Chemical compound CCOC(=O)CC FKRCODPIKNYEAC-UHFFFAOYSA-N 0.000 description 2
- MHMNJMPURVTYEJ-UHFFFAOYSA-N fluorescein-5-isothiocyanate Chemical compound O1C(=O)C2=CC(N=C=S)=CC=C2C21C1=CC=C(O)C=C1OC1=CC(O)=CC=C21 MHMNJMPURVTYEJ-UHFFFAOYSA-N 0.000 description 2
- YNESATAKKCNGOF-UHFFFAOYSA-N lithium bis(trimethylsilyl)amide Chemical compound [Li+].C[Si](C)(C)[N-][Si](C)(C)C YNESATAKKCNGOF-UHFFFAOYSA-N 0.000 description 2
- 238000004949 mass spectrometry Methods 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- 239000008194 pharmaceutical composition Substances 0.000 description 2
- HXITXNWTGFUOAU-UHFFFAOYSA-N phenylboronic acid Chemical compound OB(O)C1=CC=CC=C1 HXITXNWTGFUOAU-UHFFFAOYSA-N 0.000 description 2
- IUBQJLUDMLPAGT-UHFFFAOYSA-N potassium bis(trimethylsilyl)amide Chemical compound C[Si](C)(C)N([K])[Si](C)(C)C IUBQJLUDMLPAGT-UHFFFAOYSA-N 0.000 description 2
- 238000002953 preparative HPLC Methods 0.000 description 2
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 2
- 238000004007 reversed phase HPLC Methods 0.000 description 2
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- WRIKHQLVHPKCJU-UHFFFAOYSA-N sodium bis(trimethylsilyl)amide Chemical compound C[Si](C)(C)N([Na])[Si](C)(C)C WRIKHQLVHPKCJU-UHFFFAOYSA-N 0.000 description 1
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- JBZSEEYKQRWFMS-DJJJIMSYSA-N tert-butyl (2s)-2-[[(2s)-3-[4-(2,5-dichlorophenyl)phenyl]-1-oxo-1-(2h-tetrazol-5-ylamino)propan-2-yl]amino]propanoate Chemical compound C([C@H](N[C@@H](C)C(=O)OC(C)(C)C)C(=O)NC=1NN=NN=1)C(C=C1)=CC=C1C1=CC(Cl)=CC=C1Cl JBZSEEYKQRWFMS-DJJJIMSYSA-N 0.000 description 1
- LUWNNCOLFZMLRL-YWZLYKJASA-N tert-butyl (2s)-2-[[(2s)-3-[4-(3-chlorophenyl)phenyl]-1-oxo-1-[(3-oxo-1,2-oxazol-5-yl)amino]propan-2-yl]amino]propanoate Chemical compound C([C@H](N[C@@H](C)C(=O)OC(C)(C)C)C(=O)NC=1ON=C(O)C=1)C(C=C1)=CC=C1C1=CC=CC(Cl)=C1 LUWNNCOLFZMLRL-YWZLYKJASA-N 0.000 description 1
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Classifications
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- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
- Furan Compounds (AREA)
- Epoxy Compounds (AREA)
Abstract
Uso de un inhibidor de endopeptidasa neutra EC. 3.4. 24.11. en la fabricación de un medicamento para el tratamiento, mejora o prevención de nefropatía inducida por medio de contraste en un sujeto con necesidad de tal tratamiento, en el que el inhibidor de endopeptidasa neutra es: a) un compuesto 5 de Fórmula II:**Fórmula** o una sal farmacéuticamente aceptable del mismo, en la que: R1 es alquilo C1-7; para cada aparición, R2 es independientemente alquilo C1-7, NO2, CN, halo, cicloalquilo C3-7, hidroxi, alcoxi C1-7, halo-alquilo C1-7, NRbRc, arilo C6-10, heteroarilo o heterociclilo; en la que Rb y Rc para cada aparición, son independientemente H o alquilo C1-7; R3 es A1C(O)X1 o A2-R4; R4 es arilo C6-10 o un heteroarilo, que puede ser monocíclico o bicíclico y que puede estar opcionalmente sustituido con uno o más sustituyentes seleccionados independientemente entre hidroxi, hidroxi-alquilo C1-7, NRbRc, nitro, alcoxi C1-7, halo, alquilo C1-7, halo-alquilo C1-7, alquenilo C2-7, arilo C6-10, heteroarilo, -C(O)alquilo C1-7, -NHS(O)2-alquilo C1-7, -SO2alquilo C1-7 y bencilo; R5 es H, halo, hidroxi, alcoxi C1-7, halo, alquilo C1-7 o halo-alquilo C1-7; y X y X1 son independientemente OH, -O-alquilo C1-7, -NRbRc, -NHS(O)2-alquilo C1-7, -NHS(O)2-bencilo u -O-arilo C6-10; en la que alquilo está opcionalmente sustituido con uno o más sustituyentes seleccionados independientemente entre el grupo que consiste en arilo, heteroarilo, heterociclilo, -C(O)NH2, -C(O)NH-alquilo C1-6, y -C(O)N(alquilo C1-6)2; A1 es un enlace ; o A1 es un alquenileno C2-6 lineal o ramificado; o A1 es un alquileno C1-4 lineal en el que uno o más átomo o átomos de carbono está/están reemplazados con un heteroátomo seleccionado entre O, NRa; y A1 está opcionalmente sustituido con uno o más sustituyentes seleccionados independientemente entre el grupo que consiste en halo y alquilo C1-7; en la que Ra para cada aparición, es independientemente H, alquilo C1-7 o CH2C(O)OH; o A1 es un cicloalquilo C3-7, un heterociclilo, un fenilo o un heteroarilo en la que fenilo y heteroarilo están opcionalmente sustituidos con uno o más sustituyentes seleccionados independientemente entre el grupo que consiste en alquilo C1-7, cicloalquilo C3-7, halo-alquilo C1-7, hidroxi, alcoxi C1-7, halo, NRbRc, OCH2CO2H, y OCH2C(O)NH2; o A1 es -alquileno C1-4-aril C6-10-, -alquileno C1-4-heteroaril- o -alquileno C1-4-heterociclil-, en la que A1 puede estar en cualquier dirección; y A2 es un enlace o un alquileno C1-7 lineal o ramificado que está opcionalmente sustituido con uno o más sustituyentes seleccionados independientemente entre el grupo que consiste en halo, alcoxi C1-7, hidroxi, O-Acetato y cicloalquilo C3-7; n es 0, 1, 2, 3, 4 o 5; en la que cada heteroarilo es un anillo aromático monocíclico o bicíclico que comprende 5-10 átomos de anillo seleccionados entre átomos de carbono y de 1 a 5 heteroátomos, y cada heterociclilo es un resto monocíclico saturado o parcialmente saturado pero no aromático que comprende 4-7 átomos de anillo seleccionados entre átomos de carbono y 1-5 heteroátomos, en la que cada heteroátomo de un heteroarilo o un heterociclilo se selecciona independientemente entre O, N y S; o b) un compuesto de Fórmula III:**Fórmula** o una sal farmacéuticamente aceptable del mismo, en la que: R1 es H, alquilo C1-7, hidroxi, alcoxi C1-7, halógeno, -SH, -S-alquilo C1-7 o NRbRc; R2 para cada aparición, es independientemente alquilo C1-7, halo, NO2, CN, alcanoilamino C1-7, cicloalquilo C3-7, hidroxi, alcoxi C1-7, haloalquilo C1-7, -NRbRc, arilo C6-10, heteroarilo o heterociclilo; en la que Rb y Rc para cada aparición son independientemente H o alquilo C1-7; R3 es A1-C(O)X1 o A2-R4; R4 es arilo C6-10 o un heteroarilo, que puede ser monocíclico o bicíclico, y que puede estar opcionalmente sustituido con uno o más sustituyentes seleccionados independientemente entre el grupo que consiste en hidroxi, hidroxialquilo C1-7, nitro, -NRbRc, -C(O)alquilo C1-7, C(O)-O-alquilo C1-7, alcoxi C1-7, halo, alquilo C1-7, halO-alquilo C1-7, alquenilo C2-7, arilo C6-10, heteroarilo, -NHSO2-alquilo C1-7 y bencilo; o R4 es un heterociclilo que puede estar opcionalmente sustituido con uno o más sustituyentes seleccionados independientemente entre el grupo que consiste en oxo, hidroxi, hidroxialquilo C1-7, amino, C(O)-O-alquilo C1-7, alcoxi C1-7, halo, alquilo C1-7, halo-alquilo C1-7, arilo C6-10, heteroarilo, -NHSO2-alquilo C1-7 y bencilo; R5 es H, halo, hidroxi, alcoxi C1-7, halo, alquilo C1-7 o halo-alquilo C1-7; y X y X1 son independientemente OH, -O-alquilo C1-7, -NRbRc, -NHS(O)2-alquilo C1-7, -NHS(O)2-bencilo u -O- arilo C6-10; en la que alquilo está opcionalmente sustituido con uno o más sustituyentes seleccionados independientemente entre el grupo que consiste en arilo C6-10, heteroarilo, heterociclilo, C(O)NH2, C(O)NHalquilo C1-6, y C(O)N(alquilo C1-6)2; B1 es -C(O)NH- o -NHC(O)-; A1 es un enlace o un alquileno C1-7 lineal o ramificado; que está opcionalmente sustituido con uno o más sustituyentes seleccionados independientemente entre el grupo que consiste en halo, cicloalquilo C3-7, alcoxi C1-7, hidroxi y O-acetato; en la que dos alquilos geminales se pueden combinar opcionalmente para formar un cicloalquilo C3-7; o A1 es un alquenileno C1-7 lineal o ramificado; o A1 es un alquileno C1-4 lineal en el que uno o más átomo o átomos de carbono está/están reemplazados con un heteroátomo seleccionado entre O, NRa; y A1 está opcionalmente sustituido con uno o más sustituyentes seleccionados independientemente entre el grupo que consiste en halo y alquilo C1-7; en la que Ra para cada aparición, es independientemente H, alquilo C1-7, -C(O)-O-alquilo C1-7 o -CH2C(O)OH; o A1 es un fenilo o un heteroarilo; cada uno de los cuales está opcionalmente sustituido con uno o más sustituyentes seleccionados independientemente entre el grupo que consiste en alquilo C1-7, cicloalquilo C1-7, halo-alquilo C1-7, hidroxi, alcoxi C1-7, halo, -NRbRc, -OCH2CO2H, y -OCH2C(O)NH2; o A1 es un cicloalquilo C1-7; A1 es -alquileno C1-4-aril C6-10-, -alquileno C1-4-heteroaril- o -alquileno C1-4-heterociclil-, en la que A1 puede estar en cualquier dirección; y A2 es un enlace o un alquileno C1-7 lineal o ramificado; que está opcionalmente sustituido con uno o más sustituyentes seleccionados independientemente entre el grupo que consiste en halo, alcoxi C1-7, hidroxi, O-Acetato y cicloalquilo C en la que cada heteroarilo es un anillo aromático monocíclico o bicíclico que comprende 5-10 átomos de anillo seleccionados entre átomos de carbono y de 1 a 5 heteroátomos, y cada heterociclilo es un resto monocíclico saturado o parcialmente saturado pero no aromático que comprende 4-7 átomos de anillo seleccionados entre átomos de carbono y 1-5 heteroátomos, en la que cada heteroátomo de un heteroarilo o un heterociclilo se selecciona independientemente entre O, N y S; o c) un compuesto de Fórmula IVC:3-7;**Fórmula** n es 0, 1, 2, 3, 4 o 5; en la que: X1 representa OH u O-alquilo C1-6; R1 es H, alquilo C1-6 o aril C6-10-alquilo C1-6; para cada aparición, R2 es independientemente alcoxi C1-6, hidroxi, halo, alquilo C1-6, ciano o trifluorometilo; R2a es halo; Rd y Re son independientemente H o alquilo C1-6; A2 es un enlace o una cadena de alquileno C1-3; R4 es un heteroarilo de 5 o 6 miembros, arilo C6-10 o cicloalquilo C3-7, en la que cada heteroarilo, arilo o cicloalquilo está opcionalmente sustituido con uno o más grupos seleccionados independientemente entre el grupo que consiste en alquilo C1-6, halo, halo-alquilo C1-6, alcoxi C1-6, hidroxi, CO2H y CO2alquilo C1-6; R5 para cada aparición es independientemente halo, hidroxi, alcoxi C1-7, halo, alquilo C1-7 o halo-alquilo C1-7; o Rd, A2-R4, junto con el nitrógeno al que Rd y A2-R4 están unidos, forman un heterociclilo de 4 a 7 miembros o un heteroarilo de 5 a 6 miembros, cada uno de los cuales está opcionalmente sustituido con uno o más grupos seleccionados independientemente entre el grupo que consiste en alquilo C1-6, halo, haloalquilo C1-6, alcoxi C1-6, hidroxi, CO2H y CO2alquilo C1-6; y p es 0, 1, 2, 3 o 4; y s es 0 o un número entero de 1 a 4; una sal farmacéuticamente aceptable del mismo.
Description
hidroxi, CO2H y CO2alquilo C1-6; y p es 0, 1,2, 3o 4;y s es 0 o un número entero de 1 a 4;
En otra realización, la invención se refiere un método de la invención que usa los compuestos de acuerdo con las 5 Fórmulas IV-C y IV-D, o cualquiera de cualquier otra clase y subclase descrita anteriormente, o una sal farmacéuticamente aceptable de los mismos, en las que Re es H.
En otra realización, la invención se refiere al uso de un compuesto de acuerdo con las Fórmulas IV-C y IV-D, o cualquiera de cualquier otra clase y subclase descrita anteriormente, o una sal farmacéuticamente aceptable del mismo, en la fabricación de un medicamento, para el tratamiento, la mejora y/o la prevención de nefropatía inducida
10 por medio de contraste, en un sujeto con necesidad de tal tratamiento, en las que Re es H.
En otra realización, la invención se refiere al uso de un compuesto de acuerdo con las Fórmulas IV-C y IV-D o cualquiera de cualquier otra clase y subclase descrita anteriormente, o una sal farmacéuticamente aceptable del mismo, en la fabricación de un medicamento, para el tratamiento, la mejora y/o la prevención de nefropatía inducida por medio de contraste, en un sujeto con necesidad de tal tratamiento, en las que s es 0.
15 Las siguientes realizaciones se pueden usar independientemente, colectivamente o en cualquier combinación o subcombinación:
En una realización, la invención incluye el uso de un compuesto de acuerdo con una cualquiera de las Fórmulas II, II-N a II-Q, III, III-P a III-R, IV-C y IV-D, o una sal farmacéuticamente aceptable del mismo, en las que A2 es (CH2)p y p es 0, 1, 2 o 3, en la fabricación de un medicamento, para el tratamiento, la mejora y/o la prevención de nefropatía inducida
20 por medio de contraste, en un sujeto con necesidad de tal tratamiento.
En un aspecto de esta realización, p es 0, y por lo tanto A2 es un enlace. En otro aspecto de esta realización, A2 es CH2
o CH2-CH2.
En otro aspecto de esta realización, la invención proporciona el uso de un compuesto de acuerdo con una cualquiera de las Fórmulas II, II-N a II-Q, III, III-P a III-R, IV-C y IV-D, o una sal farmacéuticamente aceptable del mismo, en la
25 fabricación de un medicamento, para el tratamiento, la mejora y/o la prevención de nefropatía inducida por medio de contraste, en un sujeto con necesidad de tal tratamiento, en las que R4 es un arilo C6-10 opcionalmente sustituido; en las que los sustituyentes son como se han definido anteriormente en la Fórmula II, III o IV-C.
Algunos ejemplos representativos de arilo son benzoimidazolona, benzoisotiazolona o fenilo. En un aspecto adicional de esta realización, R4 es fenilo. Los sustituyentes en el anillo de fenilo incluyen por ejemplo, halo (por ejemplo F, Cl),
30 hidroxi, halo-alquilo C1-7 (por ejemplo CF3), alcoxi C1-7 o alquilo C1-7.
En otro aspecto más de esta realización, la invención proporciona el uso de un compuesto de acuerdo con una cualquiera de las Fórmulas II, II-N a II-Q, III, III-P a III-R, IV-C y IV-D o una sal farmacéuticamente aceptable del mismo, en la fabricación de un medicamento, para el tratamiento, la mejora y/o la prevención de nefropatía inducida por medio de contraste, en un sujeto con necesidad de tal tratamiento, en las que R4 es un heteroarilo bicíclico opcionalmente
35 sustituido; en las que los sustituyentes son como se han definido anteriormente en la Fórmula II, III o IV-C.
En otro aspecto más de esta realización, la invención proporciona el uso de un compuesto de acuerdo con una cualquiera de las Fórmulas II, II-N a II-Q, III, III-P a III-R, IV-C y IV-D, o una sal farmacéuticamente aceptable del mismo, en la fabricación de un medicamento, para el tratamiento, la mejora y/o la prevención de nefropatía inducida por medio de contraste, en un sujeto con necesidad de tal tratamiento, en las que R4 es un heteroarilo de 5 o 6
40 miembros opcionalmente sustituido; en las que los sustituyentes son como se han definido anteriormente en la Fórmula II, III o IV-C.
En un aspecto de esta realización, R4 es un heteroarilo de anillo de 6 miembros seleccionado entre el grupo que consiste en pirazinilo, piridinilo, pirimidinilo, oxo-piranilo (por ejemplo piranona, piran-4-ona opcionalmente sustituida, piran-2-ona tal como 3-hidroxi-piran-4-ona, 3-hidroxi-piran-2-ona), y oxo-piridinilo (por ejemplo piridinona, piridin-4-ona 45 opcionalmente sustituido o piridin-2-ona tal como por ejemplo 3-hidroxi-1-metil-piridin-4-ona o 1-bencil-piridin-2-ona); o pirimidinona (es decir, oxo-pirimidinilo). En otro aspecto de esta realización R4 es un heteroarilo de anillo de 5 miembros seleccionado entre el grupo que consiste en oxazol, pirrol, pirazol, isooxazol, triazol, tetrazol, oxadiazol (por ejemplo 1-oxa-3,4-diazol, 1-oxa-2,4-diazol), oxadiazolona (por ejemplo oxadiazol-2-ona), tiazol, isotiazol, tiofeno, imidazol y tiadiazol. En un aspecto particular de esta realización, R4 es tetrazol. Otros ejemplos representativos de R4
50 son oxazolona, tiazolona, oxadiazolona triazolona, oxazolona, imidazolona, pirazolona. En una realización adicional, los sustituyentes opcionales en arilo C6-10 y heteroarilo se seleccionan entre hidroxi, alquilo C1-7, alcoxi C1-7, halo, halo-alquilo C1-7 o bencilo.
18
En un aspecto de esta realización, la invención se refiere al uso de un compuesto de una cualquiera de las Fórmulas II, II-A a II-G, III y III-D a III-K, o una sal farmacéuticamente aceptable del mismo, en la fabricación de un medicamento, 5 para el tratamiento, la mejora y/o la prevención de nefropatía inducida por medio de contraste, en un sujeto con necesidad de tal tratamiento, en las que A1 es fenilo, piridina o pirimidina.
Una realización adicional incluye el uso de un compuesto de acuerdo con una cualquiera de las Fórmulas II, II-A a II-G, II-L, II-M, III, III-D a III-K, III-N y III-O o una sal farmacéuticamente aceptable del mismo, en la fabricación de un medicamento, para el tratamiento, la mejora y/o la prevención de nefropatía inducida por medio de contraste, en un
10 sujeto con necesidad de tal tratamiento, en las que A1 es uno de los siguientes:
En una realización adicional, la invención se refiere al uso de un compuesto de acuerdo con una cualquiera de las
15 Fórmulas II, II-A a II-G, III y III-D a III-K, o una sal farmacéuticamente aceptable del mismo, en la fabricación de un medicamento, para el tratamiento, la mejora y/o la prevención de nefropatía inducida por medio de contraste, en un sujeto con necesidad de tal tratamiento, en las que A1 es -alquileno C1-4-aril C6-10-, -alquileno C1-4-heteroaril-o -alquileno C1-4-heterociclil-, -aril C6-10-alquileno C1-4-, -heteroaril-alquileno C1-4 o -heterociclil-alquileno C1-4-. En un aspecto de esta realización, A1 es -alquileno C1-4-aril C6-10-, -alquileno C1-4-heteroaril-o -alquileno C1-4-heterociclil-, en
20 las que la parte alquileno está unida al grupo C(O)NH y los restos arilo, heteroarilo o heterociclilo están unidos a C(O)X1. En otro aspecto de esta realización, A1 es -CH2-fenil-o -fenil-CH2-. En otro aspecto de esta realización, A1 es -CH2-heteroarilo o -heteroaril-CH2-. En una realización adicional, A1 es -CH2-heterociclilo o -heterociclil-CH2-. Algunos ejemplos representativos de A1 son los siguientes:
21
- Ejemplo n.º
- CI50 de NEP Humana (nM)
- Ejemplo 9-6
- 0,5
- Ejemplo 9-5
- 0,07
- Ejemplo 9-7
- 0,4
- Ejemplo 10-1
- 0,2
- Ejemplo 11-1
- 0,8
- Ejemplo 12-1
- 1,2
- Ejemplo 14-1
- 283
- Ejemplo de Referencia 15-1
- 267
- Ejemplo 16-3
- 250
- Ejemplo 16-5
- 1
- Ejemplo 16-8
- 7,3
- Ejemplo 17
- 350
- Ejemplo 18-1
- 450
- Ejemplo 19
- 93
- Ejemplo 20
- 142
- Ejemplo 23
- 14
- Ejemplo 29
- 0,04
- Ejemplo 29-1
- 0,03
- Ejemplo 29-2
- 0,3
- Ejemplo 32-1
- 0,09
- Ejemplo 32-2
- 0,3
- Ejemplo 32-3
- 11
- Ejemplo 32-4
- 2,4
- Ejemplo 32-5
- 91
- Ejemplo 32-6
- 0,2
- Ejemplo 32-7
- 0,2
- Ejemplo de Referencia 36
- 0,3
Se ha encontrado que los compuestos de la invención tienen valores de CI50 en el intervalo de aproximadamente 0,01 nM a aproximadamente 10.000 nM para NEP. Preferentemente, los compuestos para su uso en la invención tienen una CI50 igual o inferior a 5000 nM. Más preferentemente los compuestos para su uso en la invención tienen una
5 CI50 igual o inferior a 1000 nM.
El compuesto de la presente invención se puede administrar de forma simultánea con, o antes o después, uno u otros agentes terapéuticos más. El compuesto de la presente invención se puede administrar por separado, por la misma o diferente vía de administración, o en conjunto en la misma composición farmacéutica que los otros agentes.
Los productos proporcionados como una preparación combinada para su uso en el método de la invención, incluyen
10 una composición que comprende el compuesto de acuerdo con una cualquiera de las fórmulas II, II-A a II-S, III, III-A a III-T, IV-C y IV-D, o una sal farmacéuticamente aceptable del mismo, y el otro agente(s) terapéutico en conjunto en la misma composición farmacéutica, o el compuesto de acuerdo con una cualquiera de las fórmulas II, II-A a II-S, III, III-A a III-T, IV-C IV-D, o una sal farmacéuticamente aceptable del mismo, y el otro agente(s) terapéutico en forma separada, por ejemplo en forma de un kit.
15 En una realización, la invención proporciona un kit para su uso en el método de la invención, que comprende dos o
52
Los siguientes ejemplos pretenden ilustrar la invención y no se deben interpretar como limitaciones de los mismos. Las temperaturas se proporcionan en grados centígrados. Si no se menciona de otro modo, todas las evaporaciones se realizan a presión reducida, preferentemente entre aproximadamente 15 mm de Hg y 100 mm de Hg (= 2-13 kPa). La estructura de los productos finales, compuestos intermedios y materiales de partida se confirma mediante métodos analíticos convencionales, por ejemplo, microanálisis y características espectroscópicas, por ejemplo, EM, IR, RMN. Las abreviaturas usadas son las convencionales en la técnica. Se ha encontrado que los compuestos en el ejemplo 5-1 a 15-2 tienen valores de CI50 en el intervalo de aproximadamente 0,01 nM a aproximadamente 10.000 nM para NEP.
Abreviaturas:
- ATP: 5’-trifosfato de adenosina
- AS: Aldosterona Sintasa
- Alloc: aliloxicarbonilo
- BOC: terc-butil carboxi
- BOP: hexafluorofosfato de benzotriazol-1iloxi)tris(dimetilamino) fosfonio
- BINAP: 2,2’-bis(difenil fosfino)-1,1’-binaftilo racémico
- BOPCI: Cloruro bis(2-oxo-3-oxazolidinil)-fosfónico
- HBTU: hexafluorofosfato de 2-(1 H-benzotriazol-1-il)-1,1,3,3-tetrametiluronio
- a: ancho
- s a: singlete ancho
- Ac: Acetilo
- Atm: atmósfera
- Ac.: acuoso
- calcd: calculado
- Bn: bencilo
- Cbz: benciloxicarbonilo
- Bu, i-bu y t-Bu: butilo, isobutilo y t-butilo
- Pr e i-Pr: propilo e isopropilo
- CDI: 1, 1’-carbonildiimidazol
- COD: 1,5-ciclooctadieno
- DBU: 1,8-diazabiciclo[5.4.0]undec-7-eno
- DCC: 1,3-diciclohexilcarbodiimida
- DIAD: azodicarboxilato de diisopropilo
- DAST: trifluoruro de (dietilamino)azufre
- d: duplete dd: duplete de dupletes
- DCM: diclorometano
- DIEA: dietilisopropilamina
- DME: 1,4-dimetoxietano
- DMF: N,N-dimetilformamida
- DMSO: dimetilsulfóxido
- DIPEA: N,N-diisopropiletilamina
- DMAP: N,N-dimetilaminopiridina
- Dppb: 1,2-bis(difenilfosfino)butano
- Dppe: 1,2-bis(difenilfosfino) etano
- DAD: detector de matriz de diodo
- DTT: ditiotreitol
- DPPA: difenilfosforilazida
- EDCI, EDIC: Clorhidrato de N-etil-N’-(3dimetilaminopropil)carbodiimida
- EDTA: ácido etilendiaminatetraacético
- ESI: ionización por electronebulización
- Et y EtOAc: etilo y acetato de etilo
- EDC: Clorhidrato de N-etil-N’-(3dimetilaminopropil)carbodiimida
- FITC: isotiocianato de fluoresceína
- HPLC-RT: Tiempo de retención
- HATU: hexafluorofosfato de O-(7-azobenzotriazol-1-il)1,1,3,3-tetrametiluronio
- HOBt: 1-hidroxi-7-azabenzotriazol
- HPLC: cromatografía líquida a alta presión
- LC y LCMS: cromatografía líquida y cromatografía líquida y espectrometría de masas
- H: Hora(s)
- HOAt: 1-hidroxi-7-azabenzotriazol
- IR: infrarrojos
- LDA: diisopropilamida de litio
- KHMDS: bis(trimetilsilil)amida de potasio
- LHMDS: bis(trimetilsilil)amida de litio
- LTA: tetraacetato de plomo
- NHMDS: bis(trimetilsilil)amida de sodio
- MeOD: metanol-d4
- MeOH: metanol
- EM: espectrometría de masas
- m: multiplete
- min: minutos
- m/z: proporción de masa con respecto a carga
55
- Ms: mesilo
- Me: metilo
- M y mM: Molar y milimolar
- mg: miligramo
- MC: metilcelulosa
- n.d.: no determinado
- Ph: fenilo
- RMN: resonancia magnética nuclear
- ppm: partes por millón
- Pr e iPr: propilo e isopropilo
- PyBOP: Hexafluorofosfato de benzotriazol-1-iloxi tripirrolidinofosfonio
- Pd/C: Paladio sobre Carbono
- PS: soportado sobre polímero
- TA: temperatura ambiente
- PIDA: bis(trifluoroacetato) de yodobenceno
- PIFA: diacetato de yodobenceno
- RP: fase inversa
- ETM: error típico de la media
- s: singlete y t: triplete c: cuadruplete
- Ts tosilo
- TFA: ácido trifluoroacético
- THF: tetrahidrofurano
- TEA: trietilamina
- PMBCI: cloruro de para-metoxibencilo
- Tf: triflato
- tBu: terc-butilo
- TLC: cromatografía en capa fina
- Tris.HCl: clorhidrato de aminotris(hidroximetil) metano
- µl, ml y l: microlitro, mililitro y litro
- TMS: Trimetilsililo TMSCI: cloruro de trimetilsililo
- WSC: carbodiimida soluble en agua (N-Etil-N’-(3dimetilaminopropil)carbodiimida
- UV: ultravioleta
- p: peso
Las condiciones para medir los tiempos de retención son las que siguen a continuación:
Condiciones A para HPLC: Columna: INERTSIL C8-3, 3 µm x33 mm x3,0 mm a40 ºC
5 Caudal: 2 ml/min Fase móvil: A) HCOONH4 acuoso 5 mM, B) MeOH / CH3CN (1 / 1, v / v) Gradiente: gradiente lineal de un 5 % de A a un 95 % de B en 2 min Detección: DAD-UV a 200-400 nm
Condiciones B para HPLC:
10 Columna: INERTSIL C8-3, 3 µm x33 mm x3,0 mm a40 ºC Caudal: 2 ml/min Fase móvil: A) HCOONH4 acuoso 5 mM, B) MeOH / CH3CN (1 / 1, v / v) Gradiente: gradiente lineal de un 40 % de A a un 95 % de B en 2 min Detección: DAD-UV a 200-400 nm
15 Condiciones C para HPLC:
Columna: INERTSIL C8-3, 3 µm x33 mm x3,0 mm a40 ºC Caudal: 2 ml/min Fase móvil: A) (NH4+HCOO -5 mM)/agua, B) MeOH / CH3CN (1 / 1, v / v) Gradiente: gradiente lineal de un 5 a un 95 % de B en 2 min
20 Detección: DAD-UV a 200-400 nm
Condiciones D para HPLC:
Columna: INERTSIL C8-3, 3 µm x33 mm x3,0 mm a40 ºC Caudal: 2 ml/min Fase móvil: A) Ácido fórmico acuoso al 0,1 %, B) MeOH / CH3CN (1 / 1, v / v)
25 Gradiente: gradiente lineal de un 5 % de B a un 95 % de B en 2 min Detección: DAD-UV a 200-400 nm
56
- Ejemplo
- Producto Material de Partida HPLC-RT (condiciones) EM (M+1)
- Ejemplo 1-8
- Éster de dimetilcarbamoilmetilo del ácido (R)-3-(3-carboxi-propionilamino)-4-(3’-clorobifenil-4-il)-butírico Compuesto intermedio 9-4 0,89 min. (B) 475,3
- Ejemplo 1-9
- Éster de 2-morfolin-4-il-etilo del ácido (R)-3-(3-carboxi-propionilamino)-4-(3’-clorobifenil-4-il)-butírico Compuesto intermedio 9-5 0,99 min. (B) 503,5
Ejemplo de Referencia 1-7: RMN 1H (400 MHz, CLOROFORMO-d) δ ppm 2,17 (s, 3 H), 2,44 (t, J = 6,2 Hz, 2 H), 2,48 2,57 (m, 1 H), 2,57 -2,73 (m, 3 H), 2,87 (dd, J = 13,6, 7,6 Hz, 1 H), 2,98 (dd, J = 13,9, 7,1 Hz, 1 H), 4,47 -4,58 (m, 1 H), 4,84 (s, 2 H), 6,32 (d, J = 8,6 Hz, 1 H), 7,23 (d, J = 8,1 Hz, 2 H), 7,30 (d, 1 H), 7,35 (t, J = 7,7 Hz, 1 H), 7,44 (d,
5 J=7,3Hz,1H),7,49(d,J=8,1Hz,2H),7,54(s,1H).
Ejemplo 1-8: RMN 1H (400 MHz, CLOROFORMO-d) δ ppm 2,48 -2,59 (m, 3 H), 2,61 -2,71 (m, 3 H), 2,91 -3,06 (m, 8 H), 4,53 -4,63 (m, 1 H), 4,67 (d, J = 14,7 Hz, 1 H), 5,03 (d, J = 14,7 Hz, 1 H), 7,30 (dt, J = 7,8, 1,8 Hz, 1 H), 7,32 -7,38 (m, 3 H),7,45 (dt,J =7,6,1,5Hz, 1 H), 7,50 (d,J = 8,1 Hz, 2H), 7,55(t,J = 1,8 Hz, 1 H), 8,08 (d,J =9,3 Hz, 1 H).
Ejemplo 1-9: RMN 1H (400 MHz, DMSO-d6) δ ppm 2,20 -2,32 (m, 2 H), 2,32 -2,41 (m, 2 H), 2,42 -2,50 (m, 1 H), 2,57
10 (dd, J = 15,4, 5,6 Hz, 1 H), 2,80 (d, J = 36,1 Hz, 2 H), 3,15 (s a., 2 H), 3,31 -3,50 (m, 4 H), 3,52 -4,05 (m, 4 H), 4,25 4,40 (m, 3 H), 7,31 (d, J = 8,3 Hz, 2 H), 7,39 -7,43 (m, 1 H), 7,48 (t, J = 7,8 Hz, 1 H), 7,60 -7,67 (m, 3 H), 7,70 (t, J = 1,8 Hz, 1 H), 8,02 (d, J = 8,6 Hz, 1 H), 10,06 (s a., 1 H), 12,17 (s a., 1 H).
Ejemplo 1-10: Síntesis de ácido (R)-4-(1-(5’-cloro-2’-fluorobifenil-4-il)-4-etoxi-4-oxobutan-2-ilamino)-4-oxobutanoico
La agitación de una solución de clorhidrato de (R)-3-amino-4-(5’-cloro-2’-fluorobifenil-4-il)butanoato de etilo (Compuesto intermedio 8-5: 293 mg, 0,777 mmol), anhídrido succínico (93 mg, 0,932 mmol) y DIPEA (0,204 ml, 1,165 mmol) en diclorometano (4 ml) se permite durante 1,5 horas. La reacción se interrumpe con HCl acuoso 1 M y se extrae con diclorometano. La fase orgánica se separa y se concentra a presión reducida. El residuo resultante es
20 política mediante HPLC preparativa usando un gradiente de un 20 % de MeCN/agua (0,1 % de TFA) a un 100 % de MeCN para dar ácido (R)-4-(1-(5’-cloro-2’-fluorobifenil-4-il)-4-etoxi-4-oxobutan-2-ilamino)-4-oxobutanoico (294 mg). 1H
Tiempo de retención por HPLC = 1,03 minutos (condiciones B); EM (m + 1) = 436,2; RMN (400 MHz,
61
Ejemplo 2-1: Síntesis de éster de etilo del ácido (R)-3-(3-carboxi-propionilamino)-4-(4’-fluoro-bifenil-4-il)-butírico
La agitación de una mezcla de ácido (R)-4-(1-(4-bromofenil)-4-etoxi-4-oxobutan-2-ilamino)-4-oxobutanoico
5 (Compuesto intermedio 3-1: 50 mg, 0,129 mmol), ácido 4-fluorofenilborónico (27,2 mg, 0,194 mmol), Pd(Ph3P)4 (14,96 mg, 0,013 mmol) y Na2CO3 acuoso (0,129 ml, 0,259 mmol) en tolueno (1 ml) a 95 ºC se permite en atmósfera de nitrógeno. Después de agitar durante 13 horas, la solución se enfría a temperatura ambiente y a continuación se inactiva con HCl acuoso 1 M. Los productos se extraen con acetato de etilo, se lavan con solución salina saturada, se secan sobre MgSO4, se filtran, y se concentran a presión reducida. El residuo obtenido se purifica por RP-HPLC
10 (SunFire C18, H2O (0,1 % de TFA)/CH3CN), y a continuación se liofiliza para dar éster de etilo del ácido (R)-3-(3-carboxi-propionilamino)-4-(4’-fluoro-bifenil-4-il)-butírico (29,2 mg). Tiempo de retención por HPLC = 1,26 minutos (condiciones B); EM (m + 1) = 402,2; RMN 1H (400 MHz, CLOROFORMO-d) δ ppm 1,29 (t, J = 7 Hz, 3 H) 2,47 -2,67 (m, 6 H) 2,87 (A de ABX, Jab = 13,7 Hz, Jax = 7,9 Hz, 1 H) 2,99 (B de ABX, Jab = 13,7 Hz, Jbx = 6,6 Hz, 1 H) 4,12 -4,23 (m, 2 H) 4,47 -4,55 (m, 1 H) 6,52 (d a, J = 8,6 Hz, 1 H) 7,08 -7,14 (m, 2 H) 7,24 (d,
15 J=8,4Hz,2H)7,46-7,55(m,4H).
Los siguientes compuestos se preparan usando un procedimiento similar al que se describe en el ejemplo 2-1:
- Ejemplo
- Producto Reactivos HPLC-RT (condiciones) EM (M+1)
- Ejemplo 2-2
-
imagen65 Pd(PPh3)4, ácido m-fluorofenilborónico, Na2CO3 2 M ac., (R)-4-(4-bromofenil)-3-(4metoxi-4-oxobutanamido)butanoato de etilo. 1,24 min. (B) 416,1
- Ejemplo 2-3
- Pd(PPh3)4, ácido o-metoxifenilborónico, Na2CO3 2 M ac., (R)-4-(4-bromofenil)-3-(4metoxi-4-oxobutanamido)butanoato de etilo. 1,22 min. (B) 428,2
- Ejemplo 2-4
- Pd(PPh3)4, ácido 3-nitrofenilborónico, Na2CO3 2 M ac., (R)-4-(4-bromofenil)3-(4-metoxi-4-oxobutanamido)butanoato de etilo. 1,16 min. (B) 443,2
67
- Ejemplo
- Producto Reactivos HPLC-RT (condiciones) EM (M+1)
- Ejemplo 2-5
-
imagen66 Pd(PPh3)4, ácido 3(trifluorometil)fenilborónico, Na2CO3 2 M ac., (R)-4-(4-bromofenil)-3-(4-metoxi-4oxobutanamido)butanoato de etilo. 1,39 min. (G) 466,1
- Ejemplo 2-6
- Pd(PPh3)4, ácido 3-metoxifenilborónico, Na2CO3 2 M ac., (R)-4-(4-bromofenil)-3-(4metoxi-4-oxobutanamido)butanoato de etilo. 1,19 min. (G) 428,2
- Ejemplo 2-7
- Complejo de PdCl2(dppf).CH2Cl2, ácido fenil-d5-borónico, Na2CO3 2 M ac., (R)-4(1-(4-bromofenil)-4-etoxi-4-oxobutan-2ilamino)-4-oxobutanoato de terc-butilo 1,42 min. (B) 445,2
Ejemplo 2-2: RMN 1H (400 MHz, CLOROFORMO-d) δ ppm1,29(t,J =7 Hz,3H)2,43-2,65(m,6H)2,84-3,02(m,2 H)3,67(s,3H)4,12-4,23(m,2H)4,47-4,55(m,1H)6,30(da,J = 8,6 Hz,1H)7,00-7,05(m,1H)7,26-7,29(m, 3 H) 7,34 -7,41 (m, 2 H) 7,51 (d, J = 8,3 Hz, 2H).
5 Ejemplo 2-3: RMN 1H (400 MHz, CLOROFORMO-d) δ ppm1,28(t,J =7 Hz,3H)2,44-2,66(m,6H)2,84-3,01(m,2 H)3,68(s,3H)3,81(s,3H)4,11-4,23(m,2H)4,48-4,56(m,1H)6,26(da,J =8,8 Hz,1H)6,97-7,04(m,2H)7,22 (d, J =8,1Hz, 2 H) 7,29 -7,33(m, 2 H)7,46 -7,48 (m, 2 H).
Ejemplo 2-4: RMN 1H (400 MHz, CLOROFORMO-d) δ ppm 1,30 (t, J = 7,1 Hz, 3 H) 2,41 -2,65 (m, 6 H) 2,67 -2,92 (m, 1 H) 3,00 -3,05 (m, 1 H) 3,68 (s, 3 H) 4,14 -4,22 (m, 2 H) 4,48 -4,56 (m, 1 H) 6,33 (d a, J = 8,6 Hz, 1 H) 7,32 (d,
10 J = 8,3 Hz, 2 H) 7,56 -7,62 (m, 3 H) 7,89 -7,91 (m, 1 H) 8,18 -8,20 (m, 1 H) 8,44 (t, J = 8,0 Hz, 1 H).
Ejemplo 2-5: RMN 1H (400 MHz, CLOROFORMO-d) δ ppm 1,29 (t, J = 7,2 Hz, 3 H) 2,44 -2,65 (m, 6 H) 2,86 -2,91 (m, 1 H) 2,98 -3,03 (m, 1 H) 3,67 (s, 3 H) 4,13 -4,22 (m, 2 H) 4,47 -4,56 (m, 1 H) 6,33 (d a, J = 8,8 Hz, 1 H) 7,29 (d, J = 8,2 Hz, 2 H) 7,53 (d, J = 8,2 Hz, 2 H) 7,56 -7,60 (m, 2 H) 7,75 (d, J = 7,6 Hz, 1 H) 7,81 (s, 1 H).
Ejemplo 2-6: RMN 1H (400 MHz, CLOROFORMO-d) δ ppm 1,28 (t, J = 7,2 Hz, 3 H) 2,43 -2,65 (m, 6 H) 2,84 -2,89 (m,
15 1H)2,96-3,01(m,1H)3,67(s,3H)3,86(s,3H)4,11-4,23(m,2H)4,47-4,55(m,1H)6,30(da, J = 8,8 Hz, 1 H) 6,87 -6,90 (m, 1 H) 7,10 -7,11 (m, 1 H) 7,15 -7,17 (m, 1 H) 7,24 -7,26 (m, 2 H) 7,34 (t, J = 7,8 Hz, 2H) -7,51 -7,53 (m, 2 H).
Ejemplo 2-7: RMN 1H (400 MHz, CLOROFORMO-d) δ ppm 1,28 (t, J = 7,2 Hz, 3 H) 1,43 (s, 9 H) 2,36 -2,56 (m, 6 H) 2,84 -3,01 (m, 4 H) 4,11 -4,22 (m, 2 H) 4,47 -4,56 (m, 1 H) 6,30 -6,35 (m, 1 H) 7,25 -7,27 (m, 2 H) 7,51 -7,54 (m, 2
Ejemplo 2-8: Síntesis de ácido (R)-4-(4-etoxi-1-(5’-fluoro-2’-metoxibifenil-4-il)-4-oxobutan-2-ilamino)-4-oxobutanoico
68
J = 6,7 Hz, 2 H) 4,49 -4,57 (m, 1 H) 6,31 (d a, J = 8,6 Hz, 1 H) 7,26 -7,37 (m, 4 H) 7,43 -7,46 (m, 1 H) 7,49 -7,52 (m, 2 H) 7,55 (t a, J = 1,8 Hz, 1 H).
Tiempo de retención por HPLC quiral = 4,33 min. Columna: Daicel CHIRALPAK IA (4,6 x 100 mm); caudal = 1 ml/min.; eluyente: EtOH (que contiene un 0,1 % de TFA)/heptano = 10/90 a 70/30 en 10 min. (gradiente lineal).
Los siguientes compuestos se preparan usando un procedimiento similar al que se describe en el ejemplo 3-11:
- Ejemplo n.º
- Producto Condiciones HPLC-RT (condiciones) EM (M+1)
- Ejemplo 3-13
- ácido (R)-4-(3’-clorobifenil-4-il)-3-(5-etoxi-5oxopentanamido)butanoico Pd/C, H2, EtOAc, TA Ejemplo 3-7 1,08 min. (B) 432,4
- Ejemplo 3-14
- ácido (R)-4-(3’-clorobifenil-4-il)-3-(4-(2,3-dihidro-1Hinden-5-iloxi)-4-oxobutanamido)butanoico Pd/C, H2, EtOAc, acetona, TA Ejemplo 3-10 1,36 min. (B) 506,4
Ejemplo 3-13: RMN 1H (400 MHz, CLOROFORMO-d) δ ppm 1,23 (t, J = 7,1 Hz, 3 H) 1,86 -1,93 (m, 2 H) 2,57 (A de ABX, Jab = 16,3 Hz, Jax = 5,7 Hz,1H)2,64(B deABX, Jab = 16,3 Hz, Jbx = 5,2 Hz,1H)2,94(A deABX, Jab = 13,7 Hz, Jax = 7,6 Hz,1 H)2,99 (BdeABX, Jab = 13,7 Hz, Jbx = 7,2 Hz, 1H) 4,10 (c, J = 7,1 Hz, 2H) 4,51 -4,60 (m, 1 H) 6,17 (d
10 a, J = 8,6 Hz, 1 H) 7,26 -7,37 (m, 4 H) 7,43 -7,45 (m, 1 H) 7,49 -7,52 (m, 2 H) 7,55 (t a, J = 1,8 Hz, 1 H).
Ejemplo 3-14: RMN 1H (400 MHz, CLOROFORMO-d) δ ppm 2,07 (quint, J = 7,4 Hz, 2 H) 2,51 -2,63 (m, 4 H) 2,82 3,02 (m, 8 H) 4,50 -4,59 (m, 1 H) 6,28 (d, J = 8,6 Hz, 1 H) 6,78 -6,81 (m, 1 H) 6,91 (d, J = 1,8 Hz, 1 H) 7,26 -7,36 (m, 6 H) 7,41 -7,44 (m, 1 H) 7,47 -7,50 (m, 2 H) 7,53 -7,54 (m, 1 H).
Ejemplo 3-15: Síntesis de 15 (R)-4-(3’-clorobifenil-4-il)-3-(5-oxo-4,5-dihidro-1,3,4-oxadiazol-2-carboxamido)butanoato de etilo
A una solución de (R)-4-(3’-clorobifenil-4-il)-3-(2-hidrazinil-2-oxoacetamido)butanoato de etilo, (compuesto intermedio
15: 289 mg, 0,72 mmol) en THF (8,5 ml) se añade CDI (139 mg, 0,86 mmol) a temperatura ambiente. Después de
agitar durante 18 horas a temperatura ambiente, la reacción se interrumpe con H2O y HCl 1 M, y el producto en bruto 20 se diluye con EtOAc. La fase orgánica se lava con solución salina saturada, se seca sobre Na2SO4, se filtra y se
76
Ejemplo 4-2: Síntesis de (R)-4-(bifenil-4-il)-3-(6-(metilsulfonamido)nicotinamido)butanoato de etilo
A una solución de clorhidrato de (R)-3-amino-4-(3’-clorobifenil-4-il)butanoato de etilo (Compuesto intermedio 8-1: 103 mg, 0,32 mmol) y ácido 6-(metilsulfonamido)nicotínico, compuesto intermedio 16, (84 mg, 0,39 mmol) en CH2Cl2 5 (2 ml) y DMF (2 ml) se añade TEA (0,18 ml, 1,29 mmol) y HATU (159 mg, 0,42 mmol) a temperatura ambiente. El producto en bruto se agita a temperatura ambiente durante 2 hrs. El producto en bruto se interrumpe con NaHCO3 saturado, diluido en EtOAc. La fase orgánica se lava seis veces con agua, solución salina saturada, se seca sobre MgSO4, se filtra, y se concentra. El producto en bruto se purifica a través de RP-HPLC (SunFire C18, H2O (0,1 % de TFA)/CH3CN) para dar (R)-4-(bifenil-4-il)-3-(6-(metilsulfonamido)nicotinamido)butanoato de etilo en forma de un sólido
10 de color blanco (4,1 mg). Tiempo de retención por HPLC = 1,61 minutos (condiciones A); EM (m + 1) = 482,3. RMN 1H (400 MHz, CLOROFORMO-d) δ ppm 1,22 (t, J = 7,2 Hz, 3 H), 2,56 (t, J = 4,8 Hz, 2 H), 2,84 -2,92 (m, 1 H), 3,05 (dd, J = 13,6, 6,1 Hz, 1 H), 3,16 (s, 3 H), 4,08 -4,18 (m, 2 H), 4,57 -4,71 (m, 1 H), 7,03 (d, J = 8,3 Hz, 1 H), 7,10 (d, J = 8,3 Hz, 1 H), 7,22 (d, J = 8,3 Hz, 2 H), 7,26 -7,31 (m, 1 H), 7,33 -7,40 (m, 2 H), 7,44 -7,54 (m, 5 H), 7,98 (dd, J = 8,8, 2,3 Hz, 1 H), 8,52 (s, 1 H).
15 Los siguientes compuestos se preparan usando un procedimiento similar al que se describe en el ejemplo 4-2:
- Ejemplo n.º
- Producto Reactivos LCMS-RT (condiciones) EM (M+1)
- Ejemplo 4-3
- (R)-4-(3’-clorobifenil-4-il)-3-(2-etiloxazol-5carboxamido)butanoato de etilo compuesto intermedio 18 1,60 min (A) 441,3
- Ejemplo 4-4
-
(R)-4-(3’-clorobifenil-4-il)-3-(3-hidroxi-1H-pirazol-5carboxamido)butanoato de etilo
imagen77 1,82 min (A) 428,2
78
- Ejemplo n.º
- Producto Material de Partida Condiciones de hidrólisis LCMS-RT (condiciones) EM (M+1)
- 2-ilamino)-4-oxobutanoico
- Ejemplo 5-9
-
imagen88 NaOH ac., MeOH, ta 1,53 min. (D) 402,2
- Ácido R-4-(3’-clorobifenil-4-il)
-
imagen89
- 3-(5-oxo-4,5-dihidro-1,3,4oxadiazol-2-
- Ejemplo 3-15
- carboxamido)butanoico
- Ejemplo 5-10
-
imagen90 NaOH ac., MeOH, ta 1,60 min. (D) 413,3
- Ácido R-4-(3’-clorobifenil-4-il)
- 3-(2-etiloxazol-5-
- Ejemplo 4-3
- carboxamido)butanoico
- Ejemplo 5-11
- NaOH ac., MeOH, ta 1,37 min. (D) 415,1
- Ácido R-4-(5’-fluoro-2’
- metoxibifenil-4-il)-3-(3hidroxiisoxazol-5-
- Ejemplo 4-7
- carboxamido)butanoico
- Ejemplo de Referencia 5-12
- NaOH ac., MeOH, ta 1,43 min. (D) 356,2
- Ácido R-4-(1-carboxi-3-(4
- piridin-2-il)fenil)propan-2
- ilamino)-4-oxobutanoico
Ejemplo 5-8: RMN 1H (400 MHz, CD3OD) δ ppm 2,36 -2,60 (m, 6 H) 2,84 (dd, J = 13,4, 6,1 Hz, 1 H) 2,91 (dd, J = 13,4, 6,1 Hz, 1 H) 3,77 (s, 3 H)4,34-4,58 (m,1 H) 7,03 (d,J =8,6Hz, 1 H) 7,18 -7,31 (m, 4 H)7,39 (d, J = 8,1 Hz, 2 H).
89
- Ejemplo n.º
- Producto Reactivos Condiciones de hidrólisis HPLC-RT (condiciones) EM (M+1)
- Ejemplo 18-2
- Ácido (2R,4S)-5-bifenil-4-il-4-(3carboximetil-3-metil-ureido)-2metil-pentanoico Trietilamina en lugar de diisopropiletil amina NaOH ac., EtOH, TA 0,94 min. (F) 399,3
- Ejemplo 18-3
-
Ácido 1-((1S,3R)-1-bifenil-4-ilmetil-3carboxi-butilcarbamoil)-piperidin-3carboxílico
imagen108 NaOH ac., EtOH, TA 1,15 min. (F) 439,3
Ejemplo 18-2: RMN 1H (400 MHz, DMSO-d6) δ ppm 1,02 (d, J = 6,95 Hz, 3H), 1,43 (m, 1H), 1,70 (m, 1 H), 2,45 (m, 1 H), 2,66 (m, 1 H), 2,78 (m, 2H), 2,79 (s, 2H), 3,81 (m, 3H), 7,26 (d, J = 8,08 Hz, 2H), 7,34 (t, 1 H), 7,45 (t, 2H), 7,56 (d, J = 8,21 Hz, 2H), 7,65 (d, J = 7,20 Hz, 2H). Ejemplo 18-3: RMN 1H (400 MHz, DMSO-d6) δ ppm 1,05 (d, J = 7,07 Hz, 3H), 1,22 (m, 1 H), 1,39-1,58 (m, 3H), 1,74 (m, 1H), 1,89 (m, 1H), 2,18 (m, 1H), 2,43 (m, 1H), 2,62-2,77 (m, 4H), 3,79 (t, 1 H), 3,89 (m, 1 H), 4,01 (m, 1 H), 6,28 (d, J = 8,34 Hz, 1 H), 7,25 (d, J = 7,83 Hz, 2H), 7,34 (t, 1 H), 7,44 (t, 2H), 7,56 (d, J = 8,34 Hz, 2H), 7,64 (d, J = 7,20 Hz, 2H).
A una mezcla de clorhidrato de éster de etilo del ácido (2R,4S)-4-amino-5-bifenil-4-il-2-metil-pentanoico (Compuesto intermedio 29: 50 mg, 0,161 mmol) e éster de etilo del ácido isocianato-acético (0,161 mmol) en DMF (8 ml) se añade piridina (0,161 mmol) y la mezcla se agita a temperatura ambiente durante 18 horas. Se añade agua y la mezcla se extrae con acetato de etilo (3x). Las fases orgánicas combinadas se lavan con agua y solución salina saturada y a
15 continuación se secan sobre sulfato de magnesio. El disolvente se retira a presión reducida para proporcionar el producto de éster. Este se usa en la siguiente reacción de hidrólisis.
A continuación, a una solución del residuo obtenido (0,287 mmol) en etanol (10 ml) se añade NaOH 1 M acuoso (2 ml, 6,97 mmol) y la mezcla se agita a temperatura ambiente durante 18 horas. La mezcla se vierte en acetato de etilo y se lava con HCl acuoso 1 M, la fase orgánica se seca sobre sulfato de magnesio y el disolvente se retira a presión 20 reducida. El residuo se purifica mediante HPLC preparativa usando un gradiente de MeCN/agua (0,1 % de TFA). Las fracciones apropiadas se liofilizan para proporcionar ácido (S)-1-((1S,3R)-1-bifenil-4-ilmetil-3-carboxi-butilcarbamoil)-pirrolidin-2-carboxílico. Tiempo de retención por HPLC = 0,91 minutos (condiciones F); EM 385,4 (M+1); RMN 1H (400 MHz, MeOD-d4) δ ppm 1,15 (d, J = 7,20 Hz, 3H), 1,40 (m, 1 H), 1,91 (m, 1 H), 2,60 (m, 1 H), 2,81 (d, J = 6,32 Hz, 2H), 3,85 (d, J = 1,89 Hz, 2H), 4,00 (m, 1 H), 7,32 (m,
25 3H), 7,42 (m, 2H), 7,53 (m, 2H), 7,59 (m, 2H).
107
- Ejemplo n.º
- Producto Reactivos Condiciones de hidrólisis HPLC-RT (condiciones) EM (M+1)
- Ejemplo 30-1
-
Ácido 5-[(1S,3R)-3-carboxi-1-(3’-clorobifenil-4-ilmetil)-butilcarbamoil]1H-pirazol-3-carboxílico
imagen116 NaOH ac., EtOH, TA 1,13 min. (C) 456,3
- Ejemplo 30-2
-
Ácido 5-[(1S,3R)-3-Carboxi-1-(3’-clorobifenil-4ilmetil)-butilcarbamoil]-furano-2carboxílico
imagen117 NaOH ac., EtOH, TA 1,00 min. (C) 456,1
Ejemplo 31: Síntesis de éster de etilo del ácido (S)-2-[(S)-2-(3’-cloro-bifenil-4-il)-1-(1H-tetrazol-5-ilcarbamoil)-etilamino]-propiónico
A una suspensión de ácido (S)-3-(3’-cloro-bifenil-4-il)-2-((S)-1-etoxicarbonil-etilamino)-propiónico (Compuesto intermedio 42: 4,0 g, 10,84 mmol) en diclorometano (60 ml) y NaHCO3 acuoso saturado (10 ml) se añadió trifosgeno (1,90 g, 6,39 mmol). Después de agitar vigorosamente durante 0,5 horas, la mezcla de reacción se diluyó con EtOAc y se concentró parcialmente a presión reducida. El exceso de trifosgeno se inactivó mediante la adición de NaHCO3 10 acuoso saturado y se agitó durante 0,5 horas. La mezcla se extrajo con EtOAc y se lavo con solución salina saturada. La fase orgánica se secó sobre Na2SO4 y se concentró a presión reducida. El residuo obtenido se disolvió en diclorometano (50 ml). A la mezcla se añadió trietilamina (1,93 ml, 13,8 mmol) y 5-amino-1H-tetrazol (1,18 g, 13,84 mmol) a 0 ºC, y la mezcla de reacción se calentó gradualmente a temperatura ambiente. Después de agitar durante 2 horas, la mezcla de reacción se concentró y se purificó mediante cromatografía en columna sobre gel de 15 sílice (eluyente: 10 % de MeOH en diclorometano) para dar una mezcla del producto de isómero trans deseado y el isómero cis. El material obtenido se recristalizó a partir de CH3CN tres veces para dar éster de etilo del ácido (S)-2-[(S)-2-(3’-cloro-bifenil-4-il)-1-(1H-tetrazol-5-ilcarbamoil)-etilamino]-propiónico. RMN 1H (400 MHz, DMSO-d6) δ 1,11 (t, 3H, J = 7,1 Hz), 1,15 (d, 3H, J = 6,8 Hz), 2,89 (dd, 1H, J = 8,1, 13,7 Hz), 3,02 (dd, 1H, J = 5,8, 14,0 Hz), 3,27-3,36 (m, 1H), 3,75-3,83 (m, 1H), 4,01 (dd, 2H, J = 7,1, 14,1 Hz), 7,34 (d, 2H, J = 8,3 Hz), 7,38-7,42 (m, 1 H), 7,47
20 (dd,1H, J = 7,8, 7,8 Hz), 7,60-7,65 (m, 3H), 7,69 (dd, 1 H, J = 1,8, 1,8 Hz); EM: m/z (MH+) 443; HRMS: calculado para C22H23ClN6O3 (M)+ 442,1, encontrado 442,1; EA: calculado para C21H23CIN6O3: C, 56,95; H, 5,23; N, 18,97. Encontrado: C, 56,88; H, 5,07; N, 19,1.
114
Tiempo de retención por HPLC quiral = 9,26 min. [condiciones: Daicel CHIRALCEL OJ-H 4,6 x 100 mm); caudal = 1 ml/min.; eluyente: 20 % de EtOH (con un 0,1 % de TFA) en heptano].
Los siguientes compuestos se prepararon usando un procedimiento similar al del ejemplo 31 con los compuestos intermedios apropiados:
- Ejemplo n.º
- Producto Compuestos intermedios HPLC-RT (condiciones) EM (M+1)
- Ejemplo 31-1
- Éster de terc-butilo del ácido (S)-2[(S)-2-(2’,5’-dicloro-bifenil-4-il)-1-(1Htetrazol-5-ilcarbamoil)-etilamino]propiónico Ácido (S)-2-((S)-1-terc-butoxicarboniletilamino)-3-(2’,5’-dicloro-bifenil4-il)-propiónico Compuesto intermedio 43 Y 5-amino-1H-tetrazol 1,38 min (C) 505
- Ejemplo 31-2
- Éster de etilo del ácido (S)-2-[(S)-2bifenil-4-il-1-(1H-tetrazol-5ilcarbamoil)-etilamino]-propiónico Ácido (S)-3-bifenil-4-il-2-((S)-1-etoxi carbonil-etilamino)-propiónico Compuesto intermedio 43-1 Y 5-amino-1H-tetrazol 1,55 min (I) 409
- Ejemplo 31-3
- Éster de terc-butilo del ácido (S)-2[(S)-2-(3'-clorobifenil-4-il)1-(3-hidroxi-isoxazol-5-ilcarbamoil)etilamino]-propiónico Ácido (S)-2-((S)-1-terc-butoxicarboniletilamino)-3-(3'-cloro-bifenil-4-il)propiónico Y 1,48 min (J) 486
115 116
- Ejemplo n.º
- Producto Compuestos intermedios HPLC-RT (condiciones) EM (M+1)
- 5-amino-isoxazol-3-ol
- Ejemplo 31-4
- Éster de etilo del ácido (S)-2-[(S)-2-(3'clorobifenil-4-il)-1-(1-metil-1H-tetrazol5-ilcarbamoil)-etilamino]-propiónico Ácido (S)-3-(3'-clorobifenil-4-il)-2-((S)1-etoxicarboniletilamino)-propiónico Compuesto intermedio 42 Y 1,12 min (J) 457
- 1-metil-1H-tetrazol-5-ilamina
- Ejemplo 31-5
- Éster de etilo del ácido (S)-2-[(S)-2-(3’cloro-bifenil-4-il)-1-(1H-tetrazol-5ilcarbamoil)-etilamino]-4-fenil-butírico Éster de etilo del ácido (S)-2-[(S)-1carboxi-2-(3’-cloro-bifenil-4-il)etilamino]-4-fenil-butírico Compuesto intermedio 43-2 Y 5-amino-1H-tetrazol 1,47 min. (J) 533,4
- Ejemplo 31-6
- Éster de terc-butilo del ácido (S)-2[(S)-2-(3’-clorobifenil-4-il)1-(1H-tetrazol-5ilcarbamoil)-etilamino]-butírico Éster de terc-butilo del ácido (S)-2[(S)-1-carboxi-2-(3’-clorobifenil-4-il)-etilamino]-butírico Compuesto intermedio 43-3 Y 1,27 (J) 485
- 5-amino-1H-tetrazol
- Ejemplo n.º
- Producto Compuestos intermedios HPLC-RT (condiciones) EM (M+1)
- Ejemplo de Referencia 31-8
- Éster de etilo del ácido (S)-3-benciloxi-2-[(S)-2-(3’-cloro-bifenil-4-il)-1-(1Htetrazol-5-ilcarbamoil)-etilamino]propiónico Compuesto intermedio 44-1 Ácido (S)-2-((S)-2-benciloxi-1etoxicarbonil-etilamino)-3-(3’cloro-bifenil-4-il)-propiónico Y 5-amino-1H-tetrazol 1,31 min (J) 549
- Ejemplo de Referencia 31-9
-
imagen120 Compuesto intermedio 44-2 Ácido (S)-3-(3’-cloro-bifenil-4-il)-2((S)-1-etoxicarbonil-2-metoxietilamino)-propiónico 1,29 min (I) 471
- Éster de etilo del ácido (S)-2-[(S)-2-(3’cloro-bifenil-4-il)-1-(1H-tetrazol-5ilcarbamoil)-etilamino]-3-metoxipropiónico
- Y 5-amino-1H-tetrazol
Ejemplo 31-10: Éster de etilo del ácido (S)-2-[(S)-2-(3’-cloro-bifenil-4-il)-1-(1H-tetrazol-5-ilcarbamoil)-etoxi]-propiónico
Referencia
118
A una suspensión de ácido (R)-4-(4-bromofenil)-3-(terc-butoxicarbonilamino)butanoico (9,98 g, 27,9 mmol) y NaHCO3 (4,68 g, 55,7 mmol) en DMF (45 ml) se añade yoduro de etilo (6,75 ml, 84 mmol) a temperatura ambiente en atmósfera de nitrógeno. Después de agitar durante 71 horas, la reacción se interrumpe con H2O (300 ml), y a continuación el 5 sólido precipitado se recoge y se lava con H2O (500 ml) para dar (R)-4-(4-bromofenil)-3-(terc-butoxicarbonilamino)butanoato de etilo (10,25 g, 94 %). Tiempo de retención por HPLC = 1,48 minutos (condiciones B); EM (ES+) = 329,9 (m-tBu+2); 286,0 (m-Boc+2; 100 %); RMN 1H (400 MHz, CLOROFORMO-d) δ ppm 1,27 (t, J = 7,2 Hz, 3 H) 1,40 (s, 9 H), 2,43 (A de ABX, Jab = 15,8 Hz, Jax = 5,7 Hz,1H)2,50 (B de ABX, Jab = 15,8 Hz, Jbx = 5,4 Hz, 1 H) 2,74 -2,90 (m, 2 H) 4,11 (s a.) 4,15 (c, J = 7,1 Hz, 2H) 5,04 (d a) 7,07 (d,
10 J = 8,3 Hz, 2 H) 7,40-7,43 (m, 2 H).
Los siguientes compuestos intermedios se preparan usando un procedimiento similar al descrito para el compuesto intermedio 4:
- Compuesto intermedio n.º
- Producto Condiciones HPLC-RT (condiciones) EM (ES+; 100 %)
- Compuesto intermedio 4-1
- Éster de 5-metil-2-oxo-[1,3]dioxol-4-ilmetilo del ácido (R)-4-(4-bromo-fenil)-3-tercbutoxicarbonilamino-butírico K2CO3, DMF, TA 1,28 min. (B) 470 (m + 1)
- Compuesto intermedio 4-2
- Éster de dimetilcarbamoil metilo del ácido (R)-4-(4-Bromofenil)-3-terc-butoxicarbonila mino-butírico K2CO3, DMF, TA 1,65 min. (B) 444 (m + 1)
- Compuesto intermedio 4-3
- Éster de 2-morfolin-4-il-etilo del ácido (R)4-(4-bromofenil)-3-terc-butoxicarbonilaminobutírico K2CO3, DMF, TA 1,19 min. (B) 471 (m + 1)
130
- Compuesto intermedio n.º
- Producto Condiciones HPLC-RT (condiciones) EM (ES+; 100 %)
- Compuesto intermedio 9-3
- Éster de 5-metil-2-oxo-[1,3]dioxol4-ilmetilo del ácido (R)-3-tercbutoxicarbonilamino-4-(3’clorobifenil-4-il)-butírico Pd(OAc)2, ácido diciclohexil(2’,6’-dimetoxi-bifenil-2-il)fosfano,3clorofenilborónico, K3PO4, tolueno, 95 ºC 1,53 min. (B) 502 (m + 1)
- Compuesto intermedio 9-4
- Éster de dimetilcarbamoilmetilo del ácido (R)-3-tercbutoxicarbonilamino-4-(3’clorobifenil-4-il)-butírico Pd(PPh3)4, ácido 3-clorofenilborónico, K3PO4, DMF, 95 ºC 1,51 min. (B) 475 (m + 1)
- Compuesto intermedio 9-5
- Éster de 2-morfolin-4-il-etilo del ácido (R)-3-tercbutoxicarbonilamino-4-(3’clorobifenil-4-il)-butírico Pd(PPh3)4, ácido 3-clorofenilborónico, K3PO4, DMF, 95 ºC 1,51 min. (B) 503 (m + 1)
Compuesto intermedio 9-2: (R)-3-(terc-butoxicarbonilamino)-4-(3’-clorobifenil-4-il)butanoato de bencilo
Se permite la agitación de una suspensión del (R)-4-(4-bromofenil)-3-(terc-butoxicarbonilamino)butanoato de bencilo
5 dado (2,00 g, 4,46 mmol), ácido 3-clorofenilborónico (1,046 g, 6,69 mmol), Pd(PPh3)4 (0,515 g, 0,446 mmol) y Na2CO3 ac. (4,46 ml, 8,92 mmol) en tolueno (30 ml) en atmósfera de nitrógeno a 95 ºC durante 19 h. La mezcla de reacción se enfría a temperatura ambiente, y se diluye con solución salina saturada y EtOAc. Los productos se extraen dos veces con EtOAc, se lavan con solución salina saturada, se secan sobre MgSO4, se filtran, y se concentran. El residuo se purifica mediante cromatografía en columna ultrarrápida sobre 90 g de gel de sílice (eluyente: heptano/EtOAc = 100:0
10 a 65:35) para dar (R)-3-(terc-butoxicarbonilamino)-4-(3’-clorobifenil-4-il)butanoato de bencilo (1,03 g); Tiempo de
136
Los siguientes compuestos intermedios se prepararon usando un procedimiento similar al del compuesto intermedio 42 o el compuesto intermedio 43 con reactivos apropiados:
- Compuesto intermedio n.º
- Compuesto intermedio Reactivos HPLC-RT (condiciones) EM (M+1)
- Compuesto intermedio 43-1
- Ácido (S)-3-bifenil-4-il-2-((S)-1etoxi carboniletilamino)-propiónico En la etapa 1 se usó ácido fenilborónico en lugar de ácido 3-clorofenilborónico 0,71 min (J) 342
- Compuesto intermedio 43-2
- Éster de etilo del ácido (S)-2-[(S)1-carboxi-2-(3’-cloro-bifenil-4-il)etilamino]-4-fenil-butírico El éster de etilo del ácido (R)-2-hidroxi-4-fenil-butírico se usó en lugar de ácido éster de terc-butilo del ácido (R)-2-hidroxi-propiónico en la Etapa 3’ 1,39 min (J) 466
- Compuesto intermedio 43-3
- Éster de terc-butilo del ácido (S)-2[(S)-1-Carboxi-2-(3’-cloro-bifenil-4il)-etilamino]-butírico El éster de terc-butilo del ácido (R)-2hidroxi-butírico se usó en lugar del éster de terc-butilo del ácido (R)-2hidroxi-propiónico en la Etapa 3’ 1,15 min (J) 418
Compuesto intermedio 44: [1-(4-Metoxi-bencil)-1 H-tetrazol-5-il]-metil-amina
A una suspensión de 5-amino-1H-tetrazol (1,50 g, 17,6 mmol) en DMF (30 ml) se añadieron Cs2CO3 (8,62 g, 26,4 mmol) y PMBCI (2,90 g, 18,5 mmol). Después de agitar a 60 ºC durante 3 horas, la mezcla de reacción se enfrió a temperatura ambiente y se diluyó con EtOAc. La mezcla se lavó con H2O y solución salina saturada, se secó sobre Na2SO4, y se concentró a presión reducida. El residuo se diluyó con DCM y el producto precipitado resultante se
10 recogió por filtración para dar 1-(4-metoxi-bencil)-1H-tetrazol-5-ilamina. RMN 1H (400 MHz, DMSO-d6) δ 3,73 (s, 3H), 5,27 (s, 2H), 6,78 (s, 2H), 6,92 (d, 2H, J = 8,8 Hz), 7,21 (d, 2H, J = 8,8 Hz).
A continuación, a una suspensión de 1-(4-metoxi-bencil)-1H-tetrazol-5-ilamina (600 mg, 2,92 mmol) en MeOH (10 ml) se añadieron paraformaldehído (132 mg, 4,39 mmol) y metóxido sódico(632 mg, 25 % en peso en MeOH). La mezcla se calentó reflujo durante 30 min hasta que la suspensión se convirtió en una solución transparente. La mezcla se 15 enfrió a temperatura ambiente y se añadió borohidruro sódico (332 mg, 8,77 mmol) en porciones. La mezcla de
152
reacción se calentó a reflujo de nuevo durante 15 min. Después de enfriar a temperatura ambiente, la reacción se interrumpió con H2O. La mezcla se diluyó con EtOAc, se concentró parcialmente, y se lavó con solución salina saturada. La fase orgánica se secó sobre Na2SO4 y se concentró a presión reducida. El residuo se purificó mediante cromatografía en columna sobre gel de sílice (eluyente: 10 % de MeOH en DCM) para dar [1-(4-metoxi-bencil)-1H-tetrazol-5-il]-metil-amina. RMN 1H (400 MHz, CDCl3) δ 3,00 (d, 3H, J = 5,3 Hz), 3,61 (s a, 1H), 3,82 (s, 3H), 5,25 (s, 2H), 6,91 (d, 2H, J = 8,8 Hz), 7,16 (d, 2H, J = 8,8 Hz); EM: m/z (MH+) 220.
Los siguientes compuestos intermedios se prepararon usando un procedimiento similar al del compuesto intermedio 42 o el compuesto intermedio 43 con reactivos apropiados:
- Compuesto intermedio n.º
- Compuesto intermedio Reactivos HPLC-RT (condiciones ) EM (M+1)
- Compuesto intermedio 44-1
- Ácido (S)-2-((S)-2-benciloxi-1etoxicarbonil-etilamino)-3-(3’cloro-bifenil-4-il)-propiónico El éster de etilo del ácido (R)-3benciloxi-2-hidroxi-propiónico se usó en lugar del éster de etilo del ácido (R)-2-hidroxipropiónico en la Etapa 3 1,41 min (J) 482
- Compuesto intermedio 44-2
- Ácido (S)-3-(3’-clorobifenil-4-il)2-((S)-1 -etoxicarbonil-2-metoxietilamino)-propiónico El éster de etilo del ácido (R)-2-hidroxi3-metoxi-propiónico se usó en lugar del éster de etilo del ácido (R)-2-hidroxipropiónico en la Etapa 3 0,56 min (J) 496
10 Compuesto intermedio 45: Ácido (S)-3-(3’-cloro-bifenil-4-il)-2-((S)-1-etoxicarbonil-etoxi)-propiónico
153
Claims (2)
-
imagen1 imagen2 imagen3 imagen4 imagen5 imagen6 Fórmula II-O Fórmula ll-Pimagen7 Fórmula ll-Q Fórmula ll-Rimagen8 Fórmula ll-So una sal farmacéuticamente aceptable del mismo, en las que p es 0, 1, 2, 3 o 4; R2a es halo; W1, W2, W3 y W4 son independientemente N o CRf, en las que cada Rf se selecciona independientemente entre H, alquilo C1-7, cicloalquilo C3-7, halo-alquilo C1-7, hidroxi, alcoxi C1-7, halo, NRbRc, OCH2CO2H y OCH2C(O)NH2; Rb y Rc para cada aparición, son independientemente H o alquilo C1-7; e Y1, Y2 e Y3 son independientemente N, NH, S, O o CH y forman junto con los átomos de anillo a los que están unidos un anillo de heteroarilo de 5 miembros, y cada Y4 es independientemente N, S, O o CH.172 - 3. Uso de un inhibidor de endopeptidasa neutra EC. 3.4. 24.11., de acuerdo con la reivindicación 1, en el que el compuesto es de las siguientes Fórmulas:
imagen9 Fórmula lll-A Fórmula lll-Bimagen10 Fórmula lll-C Fórmula lll-Dimagen11 Fórmula lll-E Fórmula lll-F173imagen12 imagen13 imagen14 imagen15 imagen16 imagen17 imagen18 Fórmula ll-C Fórmula ll-Dimagen19 Fórmula ll-E Fórmula ll-Fimagen20 Fórmula ll-G Fórmula ll-H180imagen21 imagen22 imagen23 imagen24 Fórmula lll-G Fórmula lll-Himagen25 Fórmula lll-I Fórmula lll-Jimagen26 Fórmula lll-K Fórmula lll-L184imagen27 imagen28 imagen29
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2011
- 2011-11-11 US US13/294,295 patent/US8993631B2/en not_active Expired - Fee Related
- 2011-11-14 WO PCT/EP2011/070084 patent/WO2012065958A1/en active Application Filing
- 2011-11-14 KR KR1020137015363A patent/KR101886894B1/ko active IP Right Grant
- 2011-11-14 ES ES11784638.6T patent/ES2587447T3/es active Active
- 2011-11-14 CN CN201410468788.9A patent/CN104306974B/zh not_active Expired - Fee Related
- 2011-11-14 SG SG2013035886A patent/SG190229A1/en unknown
- 2011-11-14 PL PL11784638T patent/PL2640375T3/pl unknown
- 2011-11-14 EA EA201390707A patent/EA029672B1/ru not_active IP Right Cessation
- 2011-11-14 BR BR112013011876A patent/BR112013011876A2/pt not_active Application Discontinuation
- 2011-11-14 PT PT117846386T patent/PT2640375T/pt unknown
- 2011-11-14 CN CN201180065284.7A patent/CN103313708B/zh not_active Expired - Fee Related
- 2011-11-14 CA CA2817784A patent/CA2817784C/en not_active Expired - Fee Related
- 2011-11-14 EP EP11784638.6A patent/EP2640375B1/en not_active Not-in-force
- 2011-11-14 JP JP2013539220A patent/JP5950926B2/ja not_active Expired - Fee Related
- 2011-11-14 AU AU2011331296A patent/AU2011331296C1/en not_active Ceased
- 2011-11-14 MX MX2013005543A patent/MX2013005543A/es not_active Application Discontinuation
- 2011-11-15 TW TW100141713A patent/TWI576331B/zh not_active IP Right Cessation
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- 2013-05-15 CL CL2013001383A patent/CL2013001383A1/es unknown
- 2013-06-05 MA MA35961A patent/MA35085B1/fr unknown
- 2013-12-18 HK HK13114013.9A patent/HK1186411A1/zh not_active IP Right Cessation
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2014
- 2014-07-28 US US14/341,977 patent/US20140336194A1/en not_active Abandoned
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