TWI445530B - 作為奈溶酶抑制劑之經取代胺基丙酸衍生物 - Google Patents
作為奈溶酶抑制劑之經取代胺基丙酸衍生物 Download PDFInfo
- Publication number
- TWI445530B TWI445530B TW099117081A TW99117081A TWI445530B TW I445530 B TWI445530 B TW I445530B TW 099117081 A TW099117081 A TW 099117081A TW 99117081 A TW99117081 A TW 99117081A TW I445530 B TWI445530 B TW I445530B
- Authority
- TW
- Taiwan
- Prior art keywords
- alkyl
- group
- halo
- pharmaceutically acceptable
- compound
- Prior art date
Links
- 239000002792 enkephalinase inhibitor Substances 0.000 title description 2
- 150000001875 compounds Chemical class 0.000 claims description 279
- 125000000217 alkyl group Chemical group 0.000 claims description 172
- 150000003839 salts Chemical class 0.000 claims description 152
- -1 hydroxy, hydroxy Chemical group 0.000 claims description 134
- 125000005843 halogen group Chemical group 0.000 claims description 85
- 125000003118 aryl group Chemical group 0.000 claims description 76
- 125000001072 heteroaryl group Chemical group 0.000 claims description 65
- 125000003545 alkoxy group Chemical group 0.000 claims description 57
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 55
- 125000001424 substituent group Chemical group 0.000 claims description 47
- 108090000028 Neprilysin Proteins 0.000 claims description 46
- 102000003729 Neprilysin Human genes 0.000 claims description 46
- 125000000623 heterocyclic group Chemical group 0.000 claims description 46
- 229910052799 carbon Inorganic materials 0.000 claims description 45
- 125000006272 (C3-C7) cycloalkyl group Chemical group 0.000 claims description 42
- 229910052757 nitrogen Inorganic materials 0.000 claims description 41
- 206010020772 Hypertension Diseases 0.000 claims description 38
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 38
- 239000003814 drug Substances 0.000 claims description 35
- 201000010099 disease Diseases 0.000 claims description 32
- 229910052739 hydrogen Inorganic materials 0.000 claims description 31
- 125000005842 heteroatom Chemical group 0.000 claims description 30
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 30
- 239000003795 chemical substances by application Substances 0.000 claims description 29
- 239000003112 inhibitor Substances 0.000 claims description 27
- 229920006395 saturated elastomer Polymers 0.000 claims description 25
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 24
- 125000004432 carbon atom Chemical group C* 0.000 claims description 24
- 206010019280 Heart failures Diseases 0.000 claims description 23
- 239000008194 pharmaceutical composition Substances 0.000 claims description 22
- 125000002619 bicyclic group Chemical group 0.000 claims description 21
- 230000000694 effects Effects 0.000 claims description 18
- 125000002950 monocyclic group Chemical group 0.000 claims description 18
- 229910052760 oxygen Inorganic materials 0.000 claims description 18
- 229910052717 sulfur Inorganic materials 0.000 claims description 18
- 125000002947 alkylene group Chemical group 0.000 claims description 17
- 229940123338 Aldosterone synthase inhibitor Drugs 0.000 claims description 15
- 125000006413 ring segment Chemical group 0.000 claims description 15
- 208000002815 pulmonary hypertension Diseases 0.000 claims description 14
- 206010007559 Cardiac failure congestive Diseases 0.000 claims description 13
- 125000003342 alkenyl group Chemical group 0.000 claims description 12
- 150000001412 amines Chemical class 0.000 claims description 12
- 125000006701 (C1-C7) alkyl group Chemical group 0.000 claims description 11
- 125000004429 atom Chemical group 0.000 claims description 11
- 239000002934 diuretic Substances 0.000 claims description 11
- 229940127291 Calcium channel antagonist Drugs 0.000 claims description 10
- 239000000480 calcium channel blocker Substances 0.000 claims description 10
- 239000003472 antidiabetic agent Substances 0.000 claims description 9
- 208000018262 Peripheral vascular disease Diseases 0.000 claims description 8
- 239000000460 chlorine Substances 0.000 claims description 8
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 7
- 239000002333 angiotensin II receptor antagonist Substances 0.000 claims description 7
- 229940125708 antidiabetic agent Drugs 0.000 claims description 7
- 229910052801 chlorine Inorganic materials 0.000 claims description 7
- 125000001820 oxy group Chemical group [*:1]O[*:2] 0.000 claims description 7
- 150000001335 aliphatic alkanes Chemical class 0.000 claims description 6
- 239000003354 cholesterol ester transfer protein inhibitor Substances 0.000 claims description 6
- 239000003937 drug carrier Substances 0.000 claims description 6
- 229940125881 cholesteryl ester transfer protein inhibitor Drugs 0.000 claims description 5
- 239000002461 renin inhibitor Substances 0.000 claims description 5
- 229940086526 renin-inhibitors Drugs 0.000 claims description 5
- 108010059886 Apolipoprotein A-I Proteins 0.000 claims description 4
- 102000005666 Apolipoprotein A-I Human genes 0.000 claims description 4
- 102000002045 Endothelin Human genes 0.000 claims description 4
- 108050009340 Endothelin Proteins 0.000 claims description 4
- 108090001050 Phosphoric Diester Hydrolases Proteins 0.000 claims description 4
- 102000004861 Phosphoric Diester Hydrolases Human genes 0.000 claims description 4
- 229940044094 angiotensin-converting-enzyme inhibitor Drugs 0.000 claims description 4
- 239000005557 antagonist Substances 0.000 claims description 4
- 229940030606 diuretics Drugs 0.000 claims description 4
- 239000002308 endothelin receptor antagonist Substances 0.000 claims description 4
- ZUBDGKVDJUIMQQ-UBFCDGJISA-N endothelin-1 Chemical compound C([C@@H](C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(O)=O)NC(=O)[C@H]1NC(=O)[C@H](CC=2C=CC=CC=2)NC(=O)[C@@H](CC=2C=CC(O)=CC=2)NC(=O)[C@H](C(C)C)NC(=O)[C@H]2CSSC[C@@H](C(N[C@H](CO)C(=O)N[C@@H](CO)C(=O)N[C@H](CC(C)C)C(=O)N[C@@H](CCSC)C(=O)N[C@H](CC(O)=O)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCC(O)=O)C(=O)N2)=O)NC(=O)[C@@H](CO)NC(=O)[C@H](N)CSSC1)C1=CNC=N1 ZUBDGKVDJUIMQQ-UBFCDGJISA-N 0.000 claims description 4
- 229910052736 halogen Inorganic materials 0.000 claims description 4
- 150000002367 halogens Chemical class 0.000 claims description 4
- 238000006467 substitution reaction Methods 0.000 claims description 4
- 239000005541 ACE inhibitor Substances 0.000 claims description 3
- 102000003979 Mineralocorticoid Receptors Human genes 0.000 claims description 3
- 108090000375 Mineralocorticoid Receptors Proteins 0.000 claims description 3
- 239000013543 active substance Substances 0.000 claims description 3
- 229940125364 angiotensin receptor blocker Drugs 0.000 claims description 3
- 125000005236 alkanoylamino group Chemical group 0.000 claims description 2
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 2
- 125000005358 mercaptoalkyl group Chemical group 0.000 claims 2
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims 1
- 108090000854 Oxidoreductases Proteins 0.000 claims 1
- 230000006835 compression Effects 0.000 claims 1
- 238000007906 compression Methods 0.000 claims 1
- 208000027744 congestion Diseases 0.000 claims 1
- 230000001969 hypertrophic effect Effects 0.000 claims 1
- 230000001568 sexual effect Effects 0.000 claims 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 299
- 238000005160 1H NMR spectroscopy Methods 0.000 description 280
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 155
- 235000019439 ethyl acetate Nutrition 0.000 description 140
- 239000000243 solution Substances 0.000 description 131
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 130
- 239000000543 intermediate Substances 0.000 description 118
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 112
- 238000004128 high performance liquid chromatography Methods 0.000 description 101
- 239000000203 mixture Substances 0.000 description 99
- 230000014759 maintenance of location Effects 0.000 description 92
- 230000002829 reductive effect Effects 0.000 description 90
- 238000000034 method Methods 0.000 description 87
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 84
- 238000003756 stirring Methods 0.000 description 82
- 238000006243 chemical reaction Methods 0.000 description 76
- 239000012043 crude product Substances 0.000 description 65
- HEMHJVSKTPXQMS-UHFFFAOYSA-M sodium hydroxide Inorganic materials [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 65
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 64
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 61
- 238000003786 synthesis reaction Methods 0.000 description 60
- 230000015572 biosynthetic process Effects 0.000 description 59
- 229910052740 iodine Inorganic materials 0.000 description 59
- 239000011541 reaction mixture Substances 0.000 description 59
- 239000012044 organic layer Substances 0.000 description 58
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 55
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 55
- 239000012267 brine Substances 0.000 description 54
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 50
- 239000002253 acid Substances 0.000 description 50
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 49
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 48
- DTQVDTLACAAQTR-UHFFFAOYSA-N trifluoroacetic acid Substances OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 48
- 239000011734 sodium Substances 0.000 description 47
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 47
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 41
- 239000002904 solvent Substances 0.000 description 40
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 37
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 36
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 33
- FERIUCNNQQJTOY-UHFFFAOYSA-N Butyric acid Chemical compound CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 description 31
- 239000002585 base Substances 0.000 description 31
- 238000003818 flash chromatography Methods 0.000 description 29
- 239000000047 product Substances 0.000 description 29
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 27
- 238000010561 standard procedure Methods 0.000 description 22
- 239000000725 suspension Substances 0.000 description 22
- OJCSPXHYDFONPU-UHFFFAOYSA-N etoac etoac Chemical compound CCOC(C)=O.CCOC(C)=O OJCSPXHYDFONPU-UHFFFAOYSA-N 0.000 description 20
- 229940124597 therapeutic agent Drugs 0.000 description 20
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 description 19
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical class O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 19
- 239000003153 chemical reaction reagent Substances 0.000 description 19
- 239000007787 solid Substances 0.000 description 19
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 18
- 208000001647 Renal Insufficiency Diseases 0.000 description 18
- 239000001257 hydrogen Substances 0.000 description 18
- 201000006370 kidney failure Diseases 0.000 description 18
- 101800001288 Atrial natriuretic factor Proteins 0.000 description 17
- 101800001890 Atrial natriuretic peptide Proteins 0.000 description 17
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 17
- 239000000651 prodrug Substances 0.000 description 17
- 229940002612 prodrug Drugs 0.000 description 17
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 16
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide Substances CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 16
- 102400001282 Atrial natriuretic peptide Human genes 0.000 description 16
- OBNCKNCVKJNDBV-UHFFFAOYSA-N butanoic acid ethyl ester Natural products CCCC(=O)OCC OBNCKNCVKJNDBV-UHFFFAOYSA-N 0.000 description 16
- NSQLIUXCMFBZME-MPVJKSABSA-N carperitide Chemical compound C([C@H]1C(=O)NCC(=O)NCC(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@H](C(NCC(=O)N[C@@H](C)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CO)C(=O)NCC(=O)N[C@@H](CC(C)C)C(=O)NCC(=O)N[C@@H](CSSC[C@@H](C(=O)N1)NC(=O)[C@H](CO)NC(=O)[C@H](CO)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](N)CO)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(O)=O)=O)[C@@H](C)CC)C1=CC=CC=C1 NSQLIUXCMFBZME-MPVJKSABSA-N 0.000 description 16
- 238000004007 reversed phase HPLC Methods 0.000 description 16
- 239000000741 silica gel Substances 0.000 description 16
- 229910002027 silica gel Inorganic materials 0.000 description 16
- 206010030113 Oedema Diseases 0.000 description 15
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 15
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 14
- 239000007864 aqueous solution Substances 0.000 description 14
- 239000004480 active ingredient Substances 0.000 description 13
- JFDZBHWFFUWGJE-UHFFFAOYSA-N benzonitrile Chemical compound N#CC1=CC=CC=C1 JFDZBHWFFUWGJE-UHFFFAOYSA-N 0.000 description 13
- 150000002148 esters Chemical class 0.000 description 13
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 13
- 125000006239 protecting group Chemical group 0.000 description 13
- 208000007342 Diabetic Nephropathies Diseases 0.000 description 12
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 12
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 12
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 12
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 12
- 208000033679 diabetic kidney disease Diseases 0.000 description 12
- 239000007858 starting material Substances 0.000 description 12
- 208000001072 type 2 diabetes mellitus Diseases 0.000 description 12
- FERIUCNNQQJTOY-UHFFFAOYSA-M Butyrate Chemical compound CCCC([O-])=O FERIUCNNQQJTOY-UHFFFAOYSA-M 0.000 description 11
- 238000000524 positive electrospray ionisation mass spectrometry Methods 0.000 description 11
- 238000002953 preparative HPLC Methods 0.000 description 11
- 229910052708 sodium Inorganic materials 0.000 description 11
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 11
- 229940086542 triethylamine Drugs 0.000 description 11
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 10
- 150000002430 hydrocarbons Chemical group 0.000 description 10
- 239000012071 phase Substances 0.000 description 10
- 108090000765 processed proteins & peptides Proteins 0.000 description 10
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 9
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 9
- 208000029422 Hypernatremia Diseases 0.000 description 9
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 9
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 9
- 125000000753 cycloalkyl group Chemical group 0.000 description 9
- 239000003480 eluent Substances 0.000 description 9
- 238000001727 in vivo Methods 0.000 description 9
- 230000002401 inhibitory effect Effects 0.000 description 9
- 238000004519 manufacturing process Methods 0.000 description 9
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 9
- 230000008569 process Effects 0.000 description 9
- 239000000126 substance Substances 0.000 description 9
- FPIRBHDGWMWJEP-UHFFFAOYSA-N 1-hydroxy-7-azabenzotriazole Chemical compound C1=CN=C2N(O)N=NC2=C1 FPIRBHDGWMWJEP-UHFFFAOYSA-N 0.000 description 8
- FALRKNHUBBKYCC-UHFFFAOYSA-N 2-(chloromethyl)pyridine-3-carbonitrile Chemical compound ClCC1=NC=CC=C1C#N FALRKNHUBBKYCC-UHFFFAOYSA-N 0.000 description 8
- 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 8
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 8
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 8
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 8
- 239000003054 catalyst Substances 0.000 description 8
- 206010012601 diabetes mellitus Diseases 0.000 description 8
- 229940079593 drug Drugs 0.000 description 8
- NOESYZHRGYRDHS-UHFFFAOYSA-N insulin Chemical compound N1C(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(NC(=O)CN)C(C)CC)CSSCC(C(NC(CO)C(=O)NC(CC(C)C)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CCC(N)=O)C(=O)NC(CC(C)C)C(=O)NC(CCC(O)=O)C(=O)NC(CC(N)=O)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CSSCC(NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2C=CC(O)=CC=2)NC(=O)C(CC(C)C)NC(=O)C(C)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2NC=NC=2)NC(=O)C(CO)NC(=O)CNC2=O)C(=O)NCC(=O)NC(CCC(O)=O)C(=O)NC(CCCNC(N)=N)C(=O)NCC(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC(O)=CC=3)C(=O)NC(C(C)O)C(=O)N3C(CCC3)C(=O)NC(CCCCN)C(=O)NC(C)C(O)=O)C(=O)NC(CC(N)=O)C(O)=O)=O)NC(=O)C(C(C)CC)NC(=O)C(CO)NC(=O)C(C(C)O)NC(=O)C1CSSCC2NC(=O)C(CC(C)C)NC(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(N)CC=1C=CC=CC=1)C(C)C)CC1=CN=CN1 NOESYZHRGYRDHS-UHFFFAOYSA-N 0.000 description 8
- UHOVQNZJYSORNB-UHFFFAOYSA-N monobenzene Natural products C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 8
- 238000002360 preparation method Methods 0.000 description 8
- 239000012453 solvate Substances 0.000 description 8
- 229940014800 succinic anhydride Drugs 0.000 description 8
- PQSUYGKTWSAVDQ-UHFFFAOYSA-N Aldosterone Natural products C1CC2C3CCC(C(=O)CO)C3(C=O)CC(O)C2C2(C)C1=CC(=O)CC2 PQSUYGKTWSAVDQ-UHFFFAOYSA-N 0.000 description 7
- 206010003658 Atrial Fibrillation Diseases 0.000 description 7
- 102000004190 Enzymes Human genes 0.000 description 7
- 108090000790 Enzymes Proteins 0.000 description 7
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 7
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 7
- 239000000556 agonist Substances 0.000 description 7
- 229960002478 aldosterone Drugs 0.000 description 7
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 7
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 7
- 239000013078 crystal Substances 0.000 description 7
- 229940088598 enzyme Drugs 0.000 description 7
- 230000005764 inhibitory process Effects 0.000 description 7
- 239000001301 oxygen Substances 0.000 description 7
- 208000004998 Abdominal Pain Diseases 0.000 description 6
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 6
- 208000002881 Colic Diseases 0.000 description 6
- 208000002249 Diabetes Complications Diseases 0.000 description 6
- 206010012655 Diabetic complications Diseases 0.000 description 6
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 6
- 102100025012 Dipeptidyl peptidase 4 Human genes 0.000 description 6
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 6
- 239000007821 HATU Substances 0.000 description 6
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 6
- XYFCBTPGUUZFHI-UHFFFAOYSA-N Phosphine Chemical compound P XYFCBTPGUUZFHI-UHFFFAOYSA-N 0.000 description 6
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid group Chemical group C(C1=CC=CC=C1)(=O)O WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 6
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 6
- 239000000872 buffer Substances 0.000 description 6
- 150000001721 carbon Chemical group 0.000 description 6
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 6
- 238000004587 chromatography analysis Methods 0.000 description 6
- 238000004440 column chromatography Methods 0.000 description 6
- ATJIPYOLKOZXHT-UNTBIKODSA-N ethyl (3r)-3-amino-4-[4-(3-chlorophenyl)phenyl]butanoate;hydrochloride Chemical compound Cl.C1=CC(C[C@@H](N)CC(=O)OCC)=CC=C1C1=CC=CC(Cl)=C1 ATJIPYOLKOZXHT-UNTBIKODSA-N 0.000 description 6
- 239000000706 filtrate Substances 0.000 description 6
- 239000008103 glucose Substances 0.000 description 6
- 150000002431 hydrogen Chemical class 0.000 description 6
- 238000005984 hydrogenation reaction Methods 0.000 description 6
- 238000000338 in vitro Methods 0.000 description 6
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 6
- 208000017169 kidney disease Diseases 0.000 description 6
- 239000010410 layer Substances 0.000 description 6
- 239000000463 material Substances 0.000 description 6
- 208000010125 myocardial infarction Diseases 0.000 description 6
- 208000030761 polycystic kidney disease Diseases 0.000 description 6
- 239000003755 preservative agent Substances 0.000 description 6
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 6
- 229910000029 sodium carbonate Inorganic materials 0.000 description 6
- 235000017550 sodium carbonate Nutrition 0.000 description 6
- 208000024891 symptom Diseases 0.000 description 6
- 239000003826 tablet Substances 0.000 description 6
- 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 5
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 5
- HNAGHMKIPMKKBB-UHFFFAOYSA-N 1-benzylpyrrolidine-3-carboxamide Chemical compound C1C(C(=O)N)CCN1CC1=CC=CC=C1 HNAGHMKIPMKKBB-UHFFFAOYSA-N 0.000 description 5
- FGOJCPKOOGIRPA-UHFFFAOYSA-N 1-o-tert-butyl 4-o-ethyl 5-oxoazepane-1,4-dicarboxylate Chemical compound CCOC(=O)C1CCN(C(=O)OC(C)(C)C)CCC1=O FGOJCPKOOGIRPA-UHFFFAOYSA-N 0.000 description 5
- 201000001320 Atherosclerosis Diseases 0.000 description 5
- 239000004215 Carbon black (E152) Substances 0.000 description 5
- 108010067722 Dipeptidyl Peptidase 4 Proteins 0.000 description 5
- 206010022489 Insulin Resistance Diseases 0.000 description 5
- 241000124008 Mammalia Species 0.000 description 5
- 150000008064 anhydrides Chemical class 0.000 description 5
- 235000010357 aspartame Nutrition 0.000 description 5
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 5
- 238000009833 condensation Methods 0.000 description 5
- 230000005494 condensation Effects 0.000 description 5
- 238000005859 coupling reaction Methods 0.000 description 5
- 238000002425 crystallisation Methods 0.000 description 5
- 230000008025 crystallization Effects 0.000 description 5
- 238000001514 detection method Methods 0.000 description 5
- 208000035475 disorder Diseases 0.000 description 5
- 230000001882 diuretic effect Effects 0.000 description 5
- IJLXVKZHZSKGCV-HXUWFJFHSA-N ethyl (3r)-3-[(2-methylpropan-2-yl)oxycarbonylamino]-4-(4-phenylphenyl)butanoate Chemical compound C1=CC(C[C@H](CC(=O)OCC)NC(=O)OC(C)(C)C)=CC=C1C1=CC=CC=C1 IJLXVKZHZSKGCV-HXUWFJFHSA-N 0.000 description 5
- ITJFHKXUPMPBRQ-CQSZACIVSA-N ethyl (3r)-4-(4-bromophenyl)-3-[(2-methylpropan-2-yl)oxycarbonylamino]butanoate Chemical compound CCOC(=O)C[C@H](NC(=O)OC(C)(C)C)CC1=CC=C(Br)C=C1 ITJFHKXUPMPBRQ-CQSZACIVSA-N 0.000 description 5
- 150000004820 halides Chemical class 0.000 description 5
- 125000001188 haloalkyl group Chemical group 0.000 description 5
- 229930195733 hydrocarbon Natural products 0.000 description 5
- 238000010348 incorporation Methods 0.000 description 5
- 230000003287 optical effect Effects 0.000 description 5
- 239000000546 pharmaceutical excipient Substances 0.000 description 5
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 5
- 208000020016 psychiatric disease Diseases 0.000 description 5
- 238000000746 purification Methods 0.000 description 5
- DCKVNWZUADLDEH-UHFFFAOYSA-N sec-butyl acetate Chemical compound CCC(C)OC(C)=O DCKVNWZUADLDEH-UHFFFAOYSA-N 0.000 description 5
- 239000011593 sulfur Substances 0.000 description 5
- 150000003512 tertiary amines Chemical class 0.000 description 5
- 230000001225 therapeutic effect Effects 0.000 description 5
- 230000032258 transport Effects 0.000 description 5
- ASOKPJOREAFHNY-UHFFFAOYSA-N 1-Hydroxybenzotriazole Chemical compound C1=CC=C2N(O)N=NC2=C1 ASOKPJOREAFHNY-UHFFFAOYSA-N 0.000 description 4
- XBNGYFFABRKICK-UHFFFAOYSA-N 2,3,4,5,6-pentafluorophenol Chemical compound OC1=C(F)C(F)=C(F)C(F)=C1F XBNGYFFABRKICK-UHFFFAOYSA-N 0.000 description 4
- 125000004800 4-bromophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Br 0.000 description 4
- PQSUYGKTWSAVDQ-ZVIOFETBSA-N Aldosterone Chemical compound C([C@@]1([C@@H](C(=O)CO)CC[C@H]1[C@@H]1CC2)C=O)[C@H](O)[C@@H]1[C@]1(C)C2=CC(=O)CC1 PQSUYGKTWSAVDQ-ZVIOFETBSA-N 0.000 description 4
- 206010003445 Ascites Diseases 0.000 description 4
- BVKZGUZCCUSVTD-UHFFFAOYSA-M Bicarbonate Chemical class OC([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-M 0.000 description 4
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 4
- 229910052684 Cerium Inorganic materials 0.000 description 4
- 201000003883 Cystic fibrosis Diseases 0.000 description 4
- 206010012289 Dementia Diseases 0.000 description 4
- 206010056340 Diabetic ulcer Diseases 0.000 description 4
- 206010012735 Diarrhoea Diseases 0.000 description 4
- 208000007984 Female Infertility Diseases 0.000 description 4
- 206010057671 Female sexual dysfunction Diseases 0.000 description 4
- 208000018522 Gastrointestinal disease Diseases 0.000 description 4
- 208000010412 Glaucoma Diseases 0.000 description 4
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 description 4
- 206010020571 Hyperaldosteronism Diseases 0.000 description 4
- 206010020590 Hypercalciuria Diseases 0.000 description 4
- 206010021928 Infertility female Diseases 0.000 description 4
- 206010061218 Inflammation Diseases 0.000 description 4
- 102000004877 Insulin Human genes 0.000 description 4
- 108090001061 Insulin Proteins 0.000 description 4
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 4
- 208000007177 Left Ventricular Hypertrophy Diseases 0.000 description 4
- 208000007466 Male Infertility Diseases 0.000 description 4
- 206010057672 Male sexual dysfunction Diseases 0.000 description 4
- 208000027530 Meniere disease Diseases 0.000 description 4
- 208000019022 Mood disease Diseases 0.000 description 4
- 238000005481 NMR spectroscopy Methods 0.000 description 4
- PXHVJJICTQNCMI-UHFFFAOYSA-N Nickel Chemical compound [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 description 4
- 208000008589 Obesity Diseases 0.000 description 4
- 208000002193 Pain Diseases 0.000 description 4
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 4
- KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical group C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 description 4
- 229940123934 Reductase inhibitor Drugs 0.000 description 4
- KJTLSVCANCCWHF-UHFFFAOYSA-N Ruthenium Chemical compound [Ru] KJTLSVCANCCWHF-UHFFFAOYSA-N 0.000 description 4
- 206010040070 Septic Shock Diseases 0.000 description 4
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 4
- 208000000558 Varicose Ulcer Diseases 0.000 description 4
- 238000010521 absorption reaction Methods 0.000 description 4
- 230000009471 action Effects 0.000 description 4
- 125000005907 alkyl ester group Chemical group 0.000 description 4
- 125000003277 amino group Chemical group 0.000 description 4
- 208000006673 asthma Diseases 0.000 description 4
- 150000001576 beta-amino acids Chemical class 0.000 description 4
- 229910052794 bromium Inorganic materials 0.000 description 4
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 4
- 239000011575 calcium Substances 0.000 description 4
- 229910052791 calcium Inorganic materials 0.000 description 4
- 230000015556 catabolic process Effects 0.000 description 4
- GWXLDORMOJMVQZ-UHFFFAOYSA-N cerium Chemical compound [Ce] GWXLDORMOJMVQZ-UHFFFAOYSA-N 0.000 description 4
- 239000013058 crude material Substances 0.000 description 4
- 239000003085 diluting agent Substances 0.000 description 4
- 239000002552 dosage form Substances 0.000 description 4
- 206010015037 epilepsy Diseases 0.000 description 4
- ZHYTVLXQPWWRNQ-UNTBIKODSA-N ethyl (3r)-3-amino-4-(4-phenylphenyl)butanoate;hydrochloride Chemical compound Cl.C1=CC(C[C@@H](N)CC(=O)OCC)=CC=C1C1=CC=CC=C1 ZHYTVLXQPWWRNQ-UNTBIKODSA-N 0.000 description 4
- NBUMKGUEMVLATG-UHFFFAOYSA-N ethyl 2-ethyl-1,3-thiazole-5-carboxylate Chemical compound CCOC(=O)C1=CN=C(CC)S1 NBUMKGUEMVLATG-UHFFFAOYSA-N 0.000 description 4
- 239000012467 final product Substances 0.000 description 4
- 238000009472 formulation Methods 0.000 description 4
- 230000006870 function Effects 0.000 description 4
- 125000001475 halogen functional group Chemical group 0.000 description 4
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 4
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 4
- 230000004054 inflammatory process Effects 0.000 description 4
- 229940125396 insulin Drugs 0.000 description 4
- 230000000155 isotopic effect Effects 0.000 description 4
- 208000032839 leukemia Diseases 0.000 description 4
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 4
- 239000000314 lubricant Substances 0.000 description 4
- 230000002503 metabolic effect Effects 0.000 description 4
- SYSQUGFVNFXIIT-UHFFFAOYSA-N n-[4-(1,3-benzoxazol-2-yl)phenyl]-4-nitrobenzenesulfonamide Chemical class C1=CC([N+](=O)[O-])=CC=C1S(=O)(=O)NC1=CC=C(C=2OC3=CC=CC=C3N=2)C=C1 SYSQUGFVNFXIIT-UHFFFAOYSA-N 0.000 description 4
- 230000001452 natriuretic effect Effects 0.000 description 4
- 235000020824 obesity Nutrition 0.000 description 4
- 208000001797 obstructive sleep apnea Diseases 0.000 description 4
- IPCSVZSSVZVIGE-UHFFFAOYSA-N palmitic acid group Chemical group C(CCCCCCCCCCCCCCC)(=O)O IPCSVZSSVZVIGE-UHFFFAOYSA-N 0.000 description 4
- IZUPBVBPLAPZRR-UHFFFAOYSA-N pentachloro-phenol Natural products OC1=C(Cl)C(Cl)=C(Cl)C(Cl)=C1Cl IZUPBVBPLAPZRR-UHFFFAOYSA-N 0.000 description 4
- 230000000737 periodic effect Effects 0.000 description 4
- 201000010065 polycystic ovary syndrome Diseases 0.000 description 4
- 229910052700 potassium Inorganic materials 0.000 description 4
- 201000011461 pre-eclampsia Diseases 0.000 description 4
- 201000009395 primary hyperaldosteronism Diseases 0.000 description 4
- 102000004196 processed proteins & peptides Human genes 0.000 description 4
- 125000001725 pyrenyl group Chemical group 0.000 description 4
- 102000005962 receptors Human genes 0.000 description 4
- 108020003175 receptors Proteins 0.000 description 4
- 238000010992 reflux Methods 0.000 description 4
- 230000001850 reproductive effect Effects 0.000 description 4
- 208000037803 restenosis Diseases 0.000 description 4
- 230000036303 septic shock Effects 0.000 description 4
- 235000017557 sodium bicarbonate Nutrition 0.000 description 4
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 4
- 239000003381 stabilizer Substances 0.000 description 4
- 238000012360 testing method Methods 0.000 description 4
- 230000029663 wound healing Effects 0.000 description 4
- JMGUHVFNUALJTQ-GOSISDBHSA-N (2r)-4-[(2-methylpropan-2-yl)oxy]-4-oxo-2-[(4-phenylphenyl)methyl]butanoic acid Chemical compound C1=CC(C[C@H](CC(=O)OC(C)(C)C)C(O)=O)=CC=C1C1=CC=CC=C1 JMGUHVFNUALJTQ-GOSISDBHSA-N 0.000 description 3
- VHQKWXMOLRKAQN-OAHLLOKOSA-N (3r)-3-amino-4-[4-(3-chlorophenyl)phenyl]butanoic acid Chemical compound C1=CC(C[C@H](CC(O)=O)N)=CC=C1C1=CC=CC(Cl)=C1 VHQKWXMOLRKAQN-OAHLLOKOSA-N 0.000 description 3
- GYXZKHKUVVKDHI-GFCCVEGCSA-N (3r)-4-(4-bromophenyl)-3-[(2-methylpropan-2-yl)oxycarbonylamino]butanoic acid Chemical compound CC(C)(C)OC(=O)N[C@@H](CC(O)=O)CC1=CC=C(Br)C=C1 GYXZKHKUVVKDHI-GFCCVEGCSA-N 0.000 description 3
- KZPYGQFFRCFCPP-UHFFFAOYSA-N 1,1'-bis(diphenylphosphino)ferrocene Chemical compound [Fe+2].C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1 KZPYGQFFRCFCPP-UHFFFAOYSA-N 0.000 description 3
- RPDHCQHZGSFGOT-UHFFFAOYSA-N 1-hydroxy-2h-pyrido[3,4-d]triazine Chemical compound C1=NC=C2N(O)NN=CC2=C1 RPDHCQHZGSFGOT-UHFFFAOYSA-N 0.000 description 3
- YRBODUBSOJFPRO-UHFFFAOYSA-N 2-[4-(3-chlorophenyl)-2-fluorophenyl]acetonitrile Chemical compound C1=C(CC#N)C(F)=CC(C=2C=C(Cl)C=CC=2)=C1 YRBODUBSOJFPRO-UHFFFAOYSA-N 0.000 description 3
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 3
- AUSPKFNAXZHVDL-UHFFFAOYSA-N 3-(4-phenylphenyl)propanoyl chloride Chemical compound C1=CC(CCC(=O)Cl)=CC=C1C1=CC=CC=C1 AUSPKFNAXZHVDL-UHFFFAOYSA-N 0.000 description 3
- 125000006163 5-membered heteroaryl group Chemical group 0.000 description 3
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 3
- 206010003662 Atrial flutter Diseases 0.000 description 3
- 239000005711 Benzoic acid Substances 0.000 description 3
- WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 description 3
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 3
- KKGMEDTWUKJSPN-OAQYLSRUSA-N C1(=CC=C(C=C1)C[C@H](CC(=O)O)C(=O)N(CCC)CCC(=O)OC)C1=CC=CC=C1 Chemical compound C1(=CC=C(C=C1)C[C@H](CC(=O)O)C(=O)N(CCC)CCC(=O)OC)C1=CC=CC=C1 KKGMEDTWUKJSPN-OAQYLSRUSA-N 0.000 description 3
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 3
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 3
- 108010061846 Cholesterol Ester Transfer Proteins Proteins 0.000 description 3
- 102000012336 Cholesterol Ester Transfer Proteins Human genes 0.000 description 3
- 108010009911 Cytochrome P-450 CYP11B2 Proteins 0.000 description 3
- 102100024329 Cytochrome P450 11B2, mitochondrial Human genes 0.000 description 3
- MHZGKXUYDGKKIU-UHFFFAOYSA-N Decylamine Chemical compound CCCCCCCCCCN MHZGKXUYDGKKIU-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
- 208000037408 Device failure Diseases 0.000 description 3
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 3
- 208000032781 Diabetic cardiomyopathy Diseases 0.000 description 3
- 206010012689 Diabetic retinopathy Diseases 0.000 description 3
- 206010052337 Diastolic dysfunction Diseases 0.000 description 3
- 201000009273 Endometriosis Diseases 0.000 description 3
- 206010048554 Endothelial dysfunction Diseases 0.000 description 3
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 3
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 3
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 3
- YLQBMQCUIZJEEH-UHFFFAOYSA-N Furan Chemical group C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 3
- 101800004266 Glucagon-like peptide 1(7-37) Proteins 0.000 description 3
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 3
- 102000003960 Ligases Human genes 0.000 description 3
- 108090000364 Ligases Proteins 0.000 description 3
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 3
- 208000001145 Metabolic Syndrome Diseases 0.000 description 3
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 3
- PVNIIMVLHYAWGP-UHFFFAOYSA-N Niacin Chemical class OC(=O)C1=CC=CN=C1 PVNIIMVLHYAWGP-UHFFFAOYSA-N 0.000 description 3
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 3
- VONGZNXBKCOUHB-UHFFFAOYSA-N Phenylmethyl butanoate Chemical compound CCCC(=O)OCC1=CC=CC=C1 VONGZNXBKCOUHB-UHFFFAOYSA-N 0.000 description 3
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 3
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 3
- WTKZEGDFNFYCGP-UHFFFAOYSA-N Pyrazole Chemical group C=1C=NNC=1 WTKZEGDFNFYCGP-UHFFFAOYSA-N 0.000 description 3
- 206010039710 Scleroderma Diseases 0.000 description 3
- 229920002472 Starch Polymers 0.000 description 3
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical class OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 3
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 3
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 3
- 208000032594 Vascular Remodeling Diseases 0.000 description 3
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 3
- 201000000690 abdominal obesity-metabolic syndrome Diseases 0.000 description 3
- 230000002159 abnormal effect Effects 0.000 description 3
- 230000002378 acidificating effect Effects 0.000 description 3
- 150000007513 acids Chemical class 0.000 description 3
- 125000002252 acyl group Chemical group 0.000 description 3
- 125000005218 alkyleneheteroaryl group Chemical group 0.000 description 3
- 229940126317 angiotensin II receptor antagonist Drugs 0.000 description 3
- 125000003710 aryl alkyl group Chemical group 0.000 description 3
- 235000010233 benzoic acid Nutrition 0.000 description 3
- OXWCIXHPQIEWAR-VZYDHVRKSA-N benzyl (3r)-3-amino-4-[4-(3-chlorophenyl)phenyl]butanoate;hydrochloride Chemical compound Cl.C([C@H](N)CC=1C=CC(=CC=1)C=1C=C(Cl)C=CC=1)C(=O)OCC1=CC=CC=C1 OXWCIXHPQIEWAR-VZYDHVRKSA-N 0.000 description 3
- VSINIPHAMFRUGB-RUZDIDTESA-N benzyl (3r)-4-[4-(3-chlorophenyl)phenyl]-3-[(2-methylpropan-2-yl)oxycarbonylamino]butanoate Chemical compound C([C@H](NC(=O)OC(C)(C)C)CC=1C=CC(=CC=1)C=1C=C(Cl)C=CC=1)C(=O)OCC1=CC=CC=C1 VSINIPHAMFRUGB-RUZDIDTESA-N 0.000 description 3
- 239000011230 binding agent Substances 0.000 description 3
- 125000006267 biphenyl group Chemical group 0.000 description 3
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 3
- 208000020832 chronic kidney disease Diseases 0.000 description 3
- 235000015165 citric acid Nutrition 0.000 description 3
- 238000000576 coating method Methods 0.000 description 3
- 230000000112 colonic effect Effects 0.000 description 3
- 238000001816 cooling Methods 0.000 description 3
- 230000008878 coupling Effects 0.000 description 3
- 238000010168 coupling process Methods 0.000 description 3
- 238000006731 degradation reaction Methods 0.000 description 3
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N diphenyl Chemical class C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 description 3
- 239000000839 emulsion Substances 0.000 description 3
- 201000000523 end stage renal failure Diseases 0.000 description 3
- 230000008694 endothelial dysfunction Effects 0.000 description 3
- 239000003623 enhancer Substances 0.000 description 3
- KNOXEUQIVAABDY-ZJLYAJKPSA-N ethyl (2r,4r)-4-amino-2-methylpentanoate;2,2,2-trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F.CCOC(=O)[C@H](C)C[C@@H](C)N KNOXEUQIVAABDY-ZJLYAJKPSA-N 0.000 description 3
- SRPPXQZATQTISM-QGZVFWFLSA-N ethyl (3r)-3-(carbamoylamino)-4-(4-phenylphenyl)butanoate Chemical compound C1=CC(C[C@H](CC(=O)OCC)NC(N)=O)=CC=C1C1=CC=CC=C1 SRPPXQZATQTISM-QGZVFWFLSA-N 0.000 description 3
- WBJINCZRORDGAQ-UHFFFAOYSA-N ethyl formate Chemical compound CCOC=O WBJINCZRORDGAQ-UHFFFAOYSA-N 0.000 description 3
- 239000011737 fluorine Substances 0.000 description 3
- 229910052731 fluorine Inorganic materials 0.000 description 3
- 235000003599 food sweetener Nutrition 0.000 description 3
- 238000001640 fractional crystallisation Methods 0.000 description 3
- 238000004108 freeze drying Methods 0.000 description 3
- 239000007903 gelatin capsule Substances 0.000 description 3
- 208000014617 hemorrhoid Diseases 0.000 description 3
- 230000003301 hydrolyzing effect Effects 0.000 description 3
- 206010020871 hypertrophic cardiomyopathy Diseases 0.000 description 3
- 239000003701 inert diluent Substances 0.000 description 3
- 230000003914 insulin secretion Effects 0.000 description 3
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 3
- 239000008101 lactose Substances 0.000 description 3
- 230000000670 limiting effect Effects 0.000 description 3
- 239000007937 lozenge Substances 0.000 description 3
- 239000011777 magnesium Substances 0.000 description 3
- 229910052749 magnesium Inorganic materials 0.000 description 3
- 239000002609 medium Substances 0.000 description 3
- 231100000551 menstrual abnormality Toxicity 0.000 description 3
- 201000008383 nephritis Diseases 0.000 description 3
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 3
- 150000007530 organic bases Chemical class 0.000 description 3
- 229910000073 phosphorus hydride Inorganic materials 0.000 description 3
- 125000006684 polyhaloalkyl group Polymers 0.000 description 3
- 239000011591 potassium Substances 0.000 description 3
- 239000000843 powder Substances 0.000 description 3
- 239000002244 precipitate Substances 0.000 description 3
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 3
- 201000001474 proteinuria Diseases 0.000 description 3
- 125000002098 pyridazinyl group Chemical group 0.000 description 3
- JUJWROOIHBZHMG-UHFFFAOYSA-O pyridinium Chemical compound C1=CC=[NH+]C=C1 JUJWROOIHBZHMG-UHFFFAOYSA-O 0.000 description 3
- 125000004076 pyridyl group Chemical group 0.000 description 3
- 239000002464 receptor antagonist Substances 0.000 description 3
- 229940044551 receptor antagonist Drugs 0.000 description 3
- 230000001105 regulatory effect Effects 0.000 description 3
- 201000002793 renal fibrosis Diseases 0.000 description 3
- 229910052707 ruthenium Inorganic materials 0.000 description 3
- 229910052938 sodium sulfate Inorganic materials 0.000 description 3
- 235000011152 sodium sulphate Nutrition 0.000 description 3
- 238000000638 solvent extraction Methods 0.000 description 3
- 230000006641 stabilisation Effects 0.000 description 3
- 238000011105 stabilization Methods 0.000 description 3
- 239000008107 starch Substances 0.000 description 3
- 235000019698 starch Nutrition 0.000 description 3
- 239000003765 sweetening agent Substances 0.000 description 3
- 239000011975 tartaric acid Substances 0.000 description 3
- 235000002906 tartaric acid Nutrition 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
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 3
- WLPUWLXVBWGYMZ-UHFFFAOYSA-N tricyclohexylphosphine Chemical compound C1CCCCC1P(C1CCCCC1)C1CCCCC1 WLPUWLXVBWGYMZ-UHFFFAOYSA-N 0.000 description 3
- 230000002792 vascular Effects 0.000 description 3
- 229910052725 zinc Inorganic materials 0.000 description 3
- 239000011701 zinc Substances 0.000 description 3
- QBYIENPQHBMVBV-HFEGYEGKSA-N (2R)-2-hydroxy-2-phenylacetic acid Chemical compound O[C@@H](C(O)=O)c1ccccc1.O[C@@H](C(O)=O)c1ccccc1 QBYIENPQHBMVBV-HFEGYEGKSA-N 0.000 description 2
- YFDSDRDMDDGDFC-HOQQKOLYSA-N (2s)-2-benzyl-n-[(2s)-1-[[(2s,3r,4s)-1-cyclohexyl-3,4-dihydroxy-6-methylheptan-2-yl]amino]-1-oxo-3-(1,3-thiazol-4-yl)propan-2-yl]-3-(4-methylpiperazin-1-yl)sulfonylpropanamide Chemical compound C([C@@H]([C@@H](O)[C@@H](O)CC(C)C)NC(=O)[C@H](CC=1N=CSC=1)NC(=O)[C@H](CC=1C=CC=CC=1)CS(=O)(=O)N1CCN(C)CC1)C1CCCCC1 YFDSDRDMDDGDFC-HOQQKOLYSA-N 0.000 description 2
- MVTZRJHEQPXHNU-MRXNPFEDSA-N (3r)-3-(carboxymethylcarbamoylamino)-4-[4-(3-chlorophenyl)phenyl]butanoic acid Chemical compound C1=CC(C[C@H](CC(O)=O)NC(=O)NCC(=O)O)=CC=C1C1=CC=CC(Cl)=C1 MVTZRJHEQPXHNU-MRXNPFEDSA-N 0.000 description 2
- XMTDGBQWERKGDE-GOSISDBHSA-N (3r)-3-[[5-(carboxymethyl)furan-2-carbonyl]amino]-4-[4-(3-chlorophenyl)phenyl]butanoic acid Chemical compound C([C@H](CC(=O)O)NC(=O)C=1OC(CC(O)=O)=CC=1)C(C=C1)=CC=C1C1=CC=CC(Cl)=C1 XMTDGBQWERKGDE-GOSISDBHSA-N 0.000 description 2
- VZXTWGWHSMCWGA-UHFFFAOYSA-N 1,3,5-triazine-2,4-diamine Chemical compound NC1=NC=NC(N)=N1 VZXTWGWHSMCWGA-UHFFFAOYSA-N 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
- OQBWCDHMDUTOLJ-UHFFFAOYSA-N 1-(2-oxo-2-phenylmethoxyethyl)cyclopentane-1-carboxylic acid Chemical compound C=1C=CC=CC=1COC(=O)CC1(C(=O)O)CCCC1 OQBWCDHMDUTOLJ-UHFFFAOYSA-N 0.000 description 2
- UUUHXMGGBIUAPW-UHFFFAOYSA-N 1-[1-[2-[[5-amino-2-[[1-[5-(diaminomethylideneamino)-2-[[1-[3-(1h-indol-3-yl)-2-[(5-oxopyrrolidine-2-carbonyl)amino]propanoyl]pyrrolidine-2-carbonyl]amino]pentanoyl]pyrrolidine-2-carbonyl]amino]-5-oxopentanoyl]amino]-3-methylpentanoyl]pyrrolidine-2-carbon Chemical compound C1CCC(C(=O)N2C(CCC2)C(O)=O)N1C(=O)C(C(C)CC)NC(=O)C(CCC(N)=O)NC(=O)C1CCCN1C(=O)C(CCCN=C(N)N)NC(=O)C1CCCN1C(=O)C(CC=1C2=CC=CC=C2NC=1)NC(=O)C1CCC(=O)N1 UUUHXMGGBIUAPW-UHFFFAOYSA-N 0.000 description 2
- HMUNWXXNJPVALC-UHFFFAOYSA-N 1-[4-[2-(2,3-dihydro-1H-inden-2-ylamino)pyrimidin-5-yl]piperazin-1-yl]-2-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)ethanone Chemical compound C1C(CC2=CC=CC=C12)NC1=NC=C(C=N1)N1CCN(CC1)C(CN1CC2=C(CC1)NN=N2)=O HMUNWXXNJPVALC-UHFFFAOYSA-N 0.000 description 2
- VBICKXHEKHSIBG-UHFFFAOYSA-N 1-monostearoylglycerol Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(O)CO VBICKXHEKHSIBG-UHFFFAOYSA-N 0.000 description 2
- YBYIRNPNPLQARY-UHFFFAOYSA-N 1H-indene Natural products C1=CC=C2CC=CC2=C1 YBYIRNPNPLQARY-UHFFFAOYSA-N 0.000 description 2
- IHWDSEPNZDYMNF-UHFFFAOYSA-N 1H-indol-2-amine Chemical compound C1=CC=C2NC(N)=CC2=C1 IHWDSEPNZDYMNF-UHFFFAOYSA-N 0.000 description 2
- BORITGMVEKOYTA-UHFFFAOYSA-N 2-(1-phenylmethoxycarbonylcyclopentyl)acetic acid Chemical compound C=1C=CC=CC=1COC(=O)C1(CC(=O)O)CCCC1 BORITGMVEKOYTA-UHFFFAOYSA-N 0.000 description 2
- VZSRBBMJRBPUNF-UHFFFAOYSA-N 2-(2,3-dihydro-1H-inden-2-ylamino)-N-[3-oxo-3-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)propyl]pyrimidine-5-carboxamide Chemical compound C1C(CC2=CC=CC=C12)NC1=NC=C(C=N1)C(=O)NCCC(N1CC2=C(CC1)NN=N2)=O VZSRBBMJRBPUNF-UHFFFAOYSA-N 0.000 description 2
- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 description 2
- SXAMGRAIZSSWIH-UHFFFAOYSA-N 2-[3-[2-(2,3-dihydro-1H-inden-2-ylamino)pyrimidin-5-yl]-1,2,4-oxadiazol-5-yl]-1-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)ethanone Chemical compound C1C(CC2=CC=CC=C12)NC1=NC=C(C=N1)C1=NOC(=N1)CC(=O)N1CC2=C(CC1)NN=N2 SXAMGRAIZSSWIH-UHFFFAOYSA-N 0.000 description 2
- FYELSNVLZVIGTI-UHFFFAOYSA-N 2-[4-[2-(2,3-dihydro-1H-inden-2-ylamino)pyrimidin-5-yl]-5-ethylpyrazol-1-yl]-1-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)ethanone Chemical compound C1C(CC2=CC=CC=C12)NC1=NC=C(C=N1)C=1C=NN(C=1CC)CC(=O)N1CC2=C(CC1)NN=N2 FYELSNVLZVIGTI-UHFFFAOYSA-N 0.000 description 2
- HHQMHPHKZAACBP-UHFFFAOYSA-N 2-ethyl-1,3-oxazole-5-carboxylic acid Chemical compound CCC1=NC=C(C(O)=O)O1 HHQMHPHKZAACBP-UHFFFAOYSA-N 0.000 description 2
- BJGZHUDNXRHBKD-UHFFFAOYSA-N 2-ethyl-1,3-thiazole-5-carboxylic acid Chemical compound CCC1=NC=C(C(O)=O)S1 BJGZHUDNXRHBKD-UHFFFAOYSA-N 0.000 description 2
- NEAQRZUHTPSBBM-UHFFFAOYSA-N 2-hydroxy-3,3-dimethyl-7-nitro-4h-isoquinolin-1-one Chemical compound C1=C([N+]([O-])=O)C=C2C(=O)N(O)C(C)(C)CC2=C1 NEAQRZUHTPSBBM-UHFFFAOYSA-N 0.000 description 2
- IZHVBANLECCAGF-UHFFFAOYSA-N 2-hydroxy-3-(octadecanoyloxy)propyl octadecanoate Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(O)COC(=O)CCCCCCCCCCCCCCCCC IZHVBANLECCAGF-UHFFFAOYSA-N 0.000 description 2
- YEDUAINPPJYDJZ-UHFFFAOYSA-N 2-hydroxybenzothiazole Chemical compound C1=CC=C2SC(O)=NC2=C1 YEDUAINPPJYDJZ-UHFFFAOYSA-N 0.000 description 2
- HWRVZXDPEUUZOZ-UHFFFAOYSA-N 2-methoxy-1,3-oxazole-5-carboxylic acid Chemical compound COC1=NC=C(C(O)=O)O1 HWRVZXDPEUUZOZ-UHFFFAOYSA-N 0.000 description 2
- JHUUPUMBZGWODW-UHFFFAOYSA-N 3,6-dihydro-1,2-dioxine Chemical compound C1OOCC=C1 JHUUPUMBZGWODW-UHFFFAOYSA-N 0.000 description 2
- SHRZMJHRBQEGBC-UHFFFAOYSA-N 3-[(2-methylpropan-2-yl)oxycarbonylamino]-4-(4-phenylphenyl)butanoic acid Chemical compound C1=CC(CC(CC(O)=O)NC(=O)OC(C)(C)C)=CC=C1C1=CC=CC=C1 SHRZMJHRBQEGBC-UHFFFAOYSA-N 0.000 description 2
- 125000004179 3-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(Cl)=C1[H] 0.000 description 2
- SYHJILPZUNKNHQ-UHFFFAOYSA-N 3-phenylbenzonitrile Chemical compound N#CC1=CC=CC(C=2C=CC=CC=2)=C1 SYHJILPZUNKNHQ-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
- ZBGYPMPWJWNWEA-QGZVFWFLSA-N 4-[[(2r)-1-carboxy-3-[4-(3-chlorophenyl)phenyl]propan-2-yl]amino]-4-oxobutanoic acid Chemical compound C1=CC(C[C@H](CC(O)=O)NC(=O)CCC(=O)O)=CC=C1C1=CC=CC(Cl)=C1 ZBGYPMPWJWNWEA-QGZVFWFLSA-N 0.000 description 2
- NKOHRVBBQISBSB-UHFFFAOYSA-N 5-[(4-hydroxyphenyl)methyl]-1,3-thiazolidine-2,4-dione Chemical compound C1=CC(O)=CC=C1CC1C(=O)NC(=O)S1 NKOHRVBBQISBSB-UHFFFAOYSA-N 0.000 description 2
- CONKBQPVFMXDOV-QHCPKHFHSA-N 6-[(5S)-5-[[4-[2-(2,3-dihydro-1H-inden-2-ylamino)pyrimidin-5-yl]piperazin-1-yl]methyl]-2-oxo-1,3-oxazolidin-3-yl]-3H-1,3-benzoxazol-2-one Chemical compound C1C(CC2=CC=CC=C12)NC1=NC=C(C=N1)N1CCN(CC1)C[C@H]1CN(C(O1)=O)C1=CC2=C(NC(O2)=O)C=C1 CONKBQPVFMXDOV-QHCPKHFHSA-N 0.000 description 2
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 2
- KWOLFJPFCHCOCG-UHFFFAOYSA-N Acetophenone Chemical compound CC(=O)C1=CC=CC=C1 KWOLFJPFCHCOCG-UHFFFAOYSA-N 0.000 description 2
- 208000017194 Affective disease Diseases 0.000 description 2
- UXOWGYHJODZGMF-QORCZRPOSA-N Aliskiren Chemical compound COCCCOC1=CC(C[C@@H](C[C@H](N)[C@@H](O)C[C@@H](C(C)C)C(=O)NCC(C)(C)C(N)=O)C(C)C)=CC=C1OC UXOWGYHJODZGMF-QORCZRPOSA-N 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 2
- BFYIZQONLCFLEV-DAELLWKTSA-N Aromasine Chemical compound O=C1C=C[C@]2(C)[C@H]3CC[C@](C)(C(CC4)=O)[C@@H]4[C@@H]3CC(=C)C2=C1 BFYIZQONLCFLEV-DAELLWKTSA-N 0.000 description 2
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 2
- 210000002237 B-cell of pancreatic islet Anatomy 0.000 description 2
- KXDAEFPNCMNJSK-UHFFFAOYSA-N Benzamide Chemical compound NC(=O)C1=CC=CC=C1 KXDAEFPNCMNJSK-UHFFFAOYSA-N 0.000 description 2
- 102400000967 Bradykinin Human genes 0.000 description 2
- 101800004538 Bradykinin Proteins 0.000 description 2
- 102400000667 Brain natriuretic peptide 32 Human genes 0.000 description 2
- 101800000407 Brain natriuretic peptide 32 Proteins 0.000 description 2
- 101800002247 Brain natriuretic peptide 45 Proteins 0.000 description 2
- 239000004072 C09CA03 - Valsartan Substances 0.000 description 2
- 239000002947 C09CA04 - Irbesartan Substances 0.000 description 2
- 241000282472 Canis lupus familiaris Species 0.000 description 2
- 208000024172 Cardiovascular disease Diseases 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- WTJVGMDQFOODBO-UNTBIKODSA-N FC(C(=O)O)(F)F.C(C)OC(C[C@@H](CC1=CC=C(C=C1)C1=CC=CC=C1)N)=O Chemical compound FC(C(=O)O)(F)F.C(C)OC(C[C@@H](CC1=CC=C(C=C1)C1=CC=CC=C1)N)=O WTJVGMDQFOODBO-UNTBIKODSA-N 0.000 description 2
- 108010010803 Gelatin Proteins 0.000 description 2
- DTHNMHAUYICORS-KTKZVXAJSA-N Glucagon-like peptide 1 Chemical class C([C@@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](C)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCCCN)C(=O)NCC(=O)N[C@@H](CCCNC(N)=N)C(N)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CCCCN)NC(=O)[C@H](C)NC(=O)[C@H](C)NC(=O)[C@H](CCC(N)=O)NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CO)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@@H](NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C)NC(=O)[C@@H](N)CC=1N=CNC=1)[C@@H](C)O)[C@@H](C)O)C(C)C)C1=CC=CC=C1 DTHNMHAUYICORS-KTKZVXAJSA-N 0.000 description 2
- 206010018429 Glucose tolerance impaired Diseases 0.000 description 2
- AEMRFAOFKBGASW-UHFFFAOYSA-N Glycolic acid Chemical compound OCC(O)=O AEMRFAOFKBGASW-UHFFFAOYSA-N 0.000 description 2
- ZRALSGWEFCBTJO-UHFFFAOYSA-N Guanidine Chemical group NC(N)=N ZRALSGWEFCBTJO-UHFFFAOYSA-N 0.000 description 2
- QXZGBUJJYSLZLT-UHFFFAOYSA-N H-Arg-Pro-Pro-Gly-Phe-Ser-Pro-Phe-Arg-OH Natural products NC(N)=NCCCC(N)C(=O)N1CCCC1C(=O)N1C(C(=O)NCC(=O)NC(CC=2C=CC=CC=2)C(=O)NC(CO)C(=O)N2C(CCC2)C(=O)NC(CC=2C=CC=CC=2)C(=O)NC(CCCN=C(N)N)C(O)=O)CCC1 QXZGBUJJYSLZLT-UHFFFAOYSA-N 0.000 description 2
- 101001123834 Homo sapiens Neprilysin Proteins 0.000 description 2
- 206010020880 Hypertrophy Diseases 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
- 241001465754 Metazoa Species 0.000 description 2
- 244000294411 Mirabilis expansa Species 0.000 description 2
- 235000015429 Mirabilis expansa Nutrition 0.000 description 2
- 102000015494 Mitochondrial Uncoupling Proteins Human genes 0.000 description 2
- 108010050258 Mitochondrial Uncoupling Proteins Proteins 0.000 description 2
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 2
- 241000699670 Mus sp. Species 0.000 description 2
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 2
- AFCARXCZXQIEQB-UHFFFAOYSA-N N-[3-oxo-3-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)propyl]-2-[[3-(trifluoromethoxy)phenyl]methylamino]pyrimidine-5-carboxamide Chemical compound O=C(CCNC(=O)C=1C=NC(=NC=1)NCC1=CC(=CC=C1)OC(F)(F)F)N1CC2=C(CC1)NN=N2 AFCARXCZXQIEQB-UHFFFAOYSA-N 0.000 description 2
- DXGOGBIKIJBBDT-UHFFFAOYSA-N NC(CC(Cl)=C1C(C=C2)=CC=C2N)(C=C1Cl)Cl.Cl Chemical compound NC(CC(Cl)=C1C(C=C2)=CC=C2N)(C=C1Cl)Cl.Cl DXGOGBIKIJBBDT-UHFFFAOYSA-N 0.000 description 2
- VNBASEMJLKNKAZ-HSZRJFAPSA-N NC=1C=C(C=CC1)C1=CC=C(C=C1)C[C@H](CC(=O)OCC)C(CCCCCCC(=O)OC)=O Chemical compound NC=1C=C(C=CC1)C1=CC=C(C=C1)C[C@H](CC(=O)OCC)C(CCCCCCC(=O)OC)=O VNBASEMJLKNKAZ-HSZRJFAPSA-N 0.000 description 2
- 101100030361 Neurospora crassa (strain ATCC 24698 / 74-OR23-1A / CBS 708.71 / DSM 1257 / FGSC 987) pph-3 gene Proteins 0.000 description 2
- CBENFWSGALASAD-UHFFFAOYSA-N Ozone Chemical compound [O-][O+]=O CBENFWSGALASAD-UHFFFAOYSA-N 0.000 description 2
- 229910019142 PO4 Inorganic materials 0.000 description 2
- NFHFRUOZVGFOOS-UHFFFAOYSA-N Pd(PPh3)4 Substances [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 NFHFRUOZVGFOOS-UHFFFAOYSA-N 0.000 description 2
- 108090000882 Peptidyl-Dipeptidase A Proteins 0.000 description 2
- 102000004270 Peptidyl-Dipeptidase A Human genes 0.000 description 2
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 2
- 208000004880 Polyuria Diseases 0.000 description 2
- 102000002727 Protein Tyrosine Phosphatase Human genes 0.000 description 2
- 208000028017 Psychotic disease Diseases 0.000 description 2
- KYQCOXFCLRTKLS-UHFFFAOYSA-N Pyrazine Chemical compound C1=CN=CC=N1 KYQCOXFCLRTKLS-UHFFFAOYSA-N 0.000 description 2
- 102000053067 Pyruvate Dehydrogenase Acetyl-Transferring Kinase Human genes 0.000 description 2
- LCTONWCANYUPML-UHFFFAOYSA-N Pyruvic acid Chemical compound CC(=O)C(O)=O LCTONWCANYUPML-UHFFFAOYSA-N 0.000 description 2
- LOUPRKONTZGTKE-WZBLMQSHSA-N Quinine Chemical compound C([C@H]([C@H](C1)C=C)C2)C[N@@]1[C@@H]2[C@H](O)C1=CC=NC2=CC=C(OC)C=C21 LOUPRKONTZGTKE-WZBLMQSHSA-N 0.000 description 2
- IWYDHOAUDWTVEP-UHFFFAOYSA-N R-2-phenyl-2-hydroxyacetic acid Natural products OC(=O)C(O)C1=CC=CC=C1 IWYDHOAUDWTVEP-UHFFFAOYSA-N 0.000 description 2
- 241000700159 Rattus Species 0.000 description 2
- 102000034527 Retinoid X Receptors Human genes 0.000 description 2
- 108010038912 Retinoid X Receptors Proteins 0.000 description 2
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 2
- 235000021355 Stearic acid Nutrition 0.000 description 2
- 206010042600 Supraventricular arrhythmias Diseases 0.000 description 2
- YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical group C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 description 2
- DTQVDTLACAAQTR-UHFFFAOYSA-M Trifluoroacetate Chemical compound [O-]C(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-M 0.000 description 2
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 2
- 206010047281 Ventricular arrhythmia Diseases 0.000 description 2
- 101710159466 [Pyruvate dehydrogenase (acetyl-transferring)] kinase, mitochondrial Proteins 0.000 description 2
- SORGEQQSQGNZFI-UHFFFAOYSA-N [azido(phenoxy)phosphoryl]oxybenzene Chemical compound C=1C=CC=CC=1OP(=O)(N=[N+]=[N-])OC1=CC=CC=C1 SORGEQQSQGNZFI-UHFFFAOYSA-N 0.000 description 2
- PBCJIPOGFJYBJE-UHFFFAOYSA-N acetonitrile;hydrate Chemical compound O.CC#N PBCJIPOGFJYBJE-UHFFFAOYSA-N 0.000 description 2
- 150000008065 acid anhydrides Chemical class 0.000 description 2
- 238000005903 acid hydrolysis reaction Methods 0.000 description 2
- 239000002671 adjuvant Substances 0.000 description 2
- 239000000443 aerosol Substances 0.000 description 2
- 150000001325 aldosterones Chemical class 0.000 description 2
- 239000000783 alginic acid Substances 0.000 description 2
- 235000010443 alginic acid Nutrition 0.000 description 2
- 229920000615 alginic acid Polymers 0.000 description 2
- 229960001126 alginic acid Drugs 0.000 description 2
- 150000004781 alginic acids Chemical class 0.000 description 2
- 229960004601 aliskiren Drugs 0.000 description 2
- 125000004453 alkoxycarbonyl group Chemical group 0.000 description 2
- 230000029936 alkylation Effects 0.000 description 2
- 238000005804 alkylation reaction Methods 0.000 description 2
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 2
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 2
- 230000001668 ameliorated effect Effects 0.000 description 2
- 239000003242 anti bacterial agent Substances 0.000 description 2
- 230000003178 anti-diabetic effect Effects 0.000 description 2
- 239000003963 antioxidant agent Substances 0.000 description 2
- 235000006708 antioxidants Nutrition 0.000 description 2
- 239000003886 aromatase inhibitor Substances 0.000 description 2
- 125000002029 aromatic hydrocarbon group Chemical group 0.000 description 2
- 238000003556 assay Methods 0.000 description 2
- 125000004541 benzoxazolyl group Chemical group O1C(=NC2=C1C=CC=C2)* 0.000 description 2
- XWHKRDCOUZBTMM-LJQANCHMSA-N benzyl (3r)-4-(4-bromophenyl)-3-[(2-methylpropan-2-yl)oxycarbonylamino]butanoate Chemical compound C([C@H](NC(=O)OC(C)(C)C)CC=1C=CC(Br)=CC=1)C(=O)OCC1=CC=CC=C1 XWHKRDCOUZBTMM-LJQANCHMSA-N 0.000 description 2
- AGSPXMVUFBBBMO-UHFFFAOYSA-N beta-aminopropionitrile Chemical compound NCCC#N AGSPXMVUFBBBMO-UHFFFAOYSA-N 0.000 description 2
- 230000031018 biological processes and functions Effects 0.000 description 2
- 239000004305 biphenyl Substances 0.000 description 2
- 235000010290 biphenyl Nutrition 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
- 230000036772 blood pressure Effects 0.000 description 2
- 210000004204 blood vessel Anatomy 0.000 description 2
- 229960003065 bosentan Drugs 0.000 description 2
- SXTRWVVIEPWAKM-UHFFFAOYSA-N bosentan hydrate Chemical compound O.COC1=CC=CC=C1OC(C(=NC(=N1)C=2N=CC=CN=2)OCCO)=C1NS(=O)(=O)C1=CC=C(C(C)(C)C)C=C1 SXTRWVVIEPWAKM-UHFFFAOYSA-N 0.000 description 2
- QXZGBUJJYSLZLT-FDISYFBBSA-N bradykinin Chemical compound NC(=N)NCCC[C@H](N)C(=O)N1CCC[C@H]1C(=O)N1[C@H](C(=O)NCC(=O)N[C@@H](CC=2C=CC=CC=2)C(=O)N[C@@H](CO)C(=O)N2[C@@H](CCC2)C(=O)N[C@@H](CC=2C=CC=CC=2)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O)CCC1 QXZGBUJJYSLZLT-FDISYFBBSA-N 0.000 description 2
- 210000004556 brain Anatomy 0.000 description 2
- 229910000019 calcium carbonate Inorganic materials 0.000 description 2
- 235000010216 calcium carbonate Nutrition 0.000 description 2
- 239000001506 calcium phosphate Substances 0.000 description 2
- 229910000389 calcium phosphate Inorganic materials 0.000 description 2
- 235000011010 calcium phosphates Nutrition 0.000 description 2
- 239000002775 capsule Substances 0.000 description 2
- 239000011203 carbon fibre reinforced carbon Substances 0.000 description 2
- 150000003857 carboxamides Chemical class 0.000 description 2
- 230000009787 cardiac fibrosis Effects 0.000 description 2
- 210000004027 cell Anatomy 0.000 description 2
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 description 2
- 238000003776 cleavage reaction Methods 0.000 description 2
- 239000003086 colorant Substances 0.000 description 2
- 238000002648 combination therapy Methods 0.000 description 2
- 238000007796 conventional method Methods 0.000 description 2
- 125000004122 cyclic group Chemical group 0.000 description 2
- JBDSSBMEKXHSJF-UHFFFAOYSA-N cyclopentanecarboxylic acid Chemical compound OC(=O)C1CCCC1 JBDSSBMEKXHSJF-UHFFFAOYSA-N 0.000 description 2
- 230000000593 degrading effect Effects 0.000 description 2
- NKLCNNUWBJBICK-UHFFFAOYSA-N dess–martin periodinane Chemical compound C1=CC=C2I(OC(=O)C)(OC(C)=O)(OC(C)=O)OC(=O)C2=C1 NKLCNNUWBJBICK-UHFFFAOYSA-N 0.000 description 2
- 150000005690 diesters Chemical class 0.000 description 2
- 125000004982 dihaloalkyl group Chemical group 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-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
- 238000004090 dissolution Methods 0.000 description 2
- 230000004064 dysfunction Effects 0.000 description 2
- 239000003995 emulsifying agent Substances 0.000 description 2
- CCIVGXIOQKPBKL-UHFFFAOYSA-M ethanesulfonate Chemical compound CCS([O-])(=O)=O CCIVGXIOQKPBKL-UHFFFAOYSA-M 0.000 description 2
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 description 2
- ZHSRREFHGDQVCS-GOSISDBHSA-N ethyl (3r)-4-[4-(2,5-dichlorophenyl)phenyl]-3-[(2-methylpropan-2-yl)oxycarbonylamino]butanoate Chemical compound C1=CC(C[C@H](CC(=O)OCC)NC(=O)OC(C)(C)C)=CC=C1C1=CC(Cl)=CC=C1Cl ZHSRREFHGDQVCS-GOSISDBHSA-N 0.000 description 2
- CYJPUFDRGFJTHA-HXUWFJFHSA-N ethyl (3r)-4-[4-(3-chlorophenyl)phenyl]-3-[(2-methylpropan-2-yl)oxycarbonylamino]butanoate Chemical compound C1=CC(C[C@H](CC(=O)OCC)NC(=O)OC(C)(C)C)=CC=C1C1=CC=CC(Cl)=C1 CYJPUFDRGFJTHA-HXUWFJFHSA-N 0.000 description 2
- DTYXJSMDLGQFMS-UHFFFAOYSA-N ethyl 2-ethenyl-1,3-thiazole-5-carboxylate Chemical compound CCOC(=O)C1=CN=C(C=C)S1 DTYXJSMDLGQFMS-UHFFFAOYSA-N 0.000 description 2
- CIWFKCUZQXHNKW-UHFFFAOYSA-N ethyl 2-ethyl-1,3-oxazole-5-carboxylate Chemical compound CCOC(=O)C1=CN=C(CC)O1 CIWFKCUZQXHNKW-UHFFFAOYSA-N 0.000 description 2
- PQJJJMRNHATNKG-UHFFFAOYSA-N ethyl bromoacetate Chemical compound CCOC(=O)CBr PQJJJMRNHATNKG-UHFFFAOYSA-N 0.000 description 2
- 125000004494 ethyl ester group Chemical group 0.000 description 2
- 230000005496 eutectics Effects 0.000 description 2
- 229960000255 exemestane Drugs 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 239000000796 flavoring agent Substances 0.000 description 2
- 125000003983 fluorenyl group Chemical group C1(=CC=CC=2C3=CC=CC=C3CC12)* 0.000 description 2
- 239000011888 foil Substances 0.000 description 2
- 235000013355 food flavoring agent Nutrition 0.000 description 2
- 239000012458 free base Substances 0.000 description 2
- 230000027119 gastric acid secretion Effects 0.000 description 2
- 239000008273 gelatin Substances 0.000 description 2
- 229920000159 gelatin Polymers 0.000 description 2
- 235000019322 gelatine Nutrition 0.000 description 2
- 235000011852 gelatine desserts Nutrition 0.000 description 2
- 206010061989 glomerulosclerosis Diseases 0.000 description 2
- 239000008187 granular material Substances 0.000 description 2
- 229940093915 gynecological organic acid Drugs 0.000 description 2
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 2
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 2
- 230000007062 hydrolysis Effects 0.000 description 2
- 238000006460 hydrolysis reaction Methods 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-M hydroxide Chemical compound [OH-] XLYOFNOQVPJJNP-UHFFFAOYSA-M 0.000 description 2
- 125000002883 imidazolyl group Chemical group 0.000 description 2
- 238000011065 in-situ storage Methods 0.000 description 2
- 125000003454 indenyl group Chemical group C1(C=CC2=CC=CC=C12)* 0.000 description 2
- 150000007529 inorganic bases Chemical class 0.000 description 2
- QWXYZCJEXYQNEI-OSZHWHEXSA-N intermediate I Chemical compound COC(=O)[C@@]1(C=O)[C@H]2CC=[N+](C\C2=C\C)CCc2c1[nH]c1ccccc21 QWXYZCJEXYQNEI-OSZHWHEXSA-N 0.000 description 2
- 239000011630 iodine Substances 0.000 description 2
- 150000002500 ions Chemical class 0.000 description 2
- 229960002198 irbesartan Drugs 0.000 description 2
- YCPOHTHPUREGFM-UHFFFAOYSA-N irbesartan Chemical compound O=C1N(CC=2C=CC(=CC=2)C=2C(=CC=CC=2)C=2[N]N=NN=2)C(CCCC)=NC21CCCC2 YCPOHTHPUREGFM-UHFFFAOYSA-N 0.000 description 2
- TWBYWOBDOCUKOW-UHFFFAOYSA-N isonicotinic acid Chemical compound OC(=O)C1=CC=NC=C1 TWBYWOBDOCUKOW-UHFFFAOYSA-N 0.000 description 2
- QWTDNUCVQCZILF-UHFFFAOYSA-N isopentane Chemical compound CCC(C)C QWTDNUCVQCZILF-UHFFFAOYSA-N 0.000 description 2
- 150000002576 ketones Chemical class 0.000 description 2
- 210000003734 kidney Anatomy 0.000 description 2
- 210000005240 left ventricle Anatomy 0.000 description 2
- 125000005647 linker group Chemical group 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 229960002510 mandelic acid Drugs 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
- 239000002207 metabolite Substances 0.000 description 2
- 229910052751 metal Inorganic materials 0.000 description 2
- 239000002184 metal Substances 0.000 description 2
- 150000002736 metal compounds Chemical class 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- 150000004702 methyl esters Chemical class 0.000 description 2
- UAEPNZWRGJTJPN-UHFFFAOYSA-N methylcyclohexane Chemical compound CC1CCCCC1 UAEPNZWRGJTJPN-UHFFFAOYSA-N 0.000 description 2
- 150000007522 mineralic acids Chemical class 0.000 description 2
- 235000013536 miso Nutrition 0.000 description 2
- 239000012046 mixed solvent Substances 0.000 description 2
- 239000001788 mono and diglycerides of fatty acids Substances 0.000 description 2
- 125000006682 monohaloalkyl group Chemical group 0.000 description 2
- BQJCRHHNABKAKU-KBQPJGBKSA-N morphine Chemical compound O([C@H]1[C@H](C=C[C@H]23)O)C4=C5[C@@]12CCN(C)[C@@H]3CC5=CC=C4O BQJCRHHNABKAKU-KBQPJGBKSA-N 0.000 description 2
- 239000006199 nebulizer Substances 0.000 description 2
- HPNRHPKXQZSDFX-OAQDCNSJSA-N nesiritide Chemical compound C([C@H]1C(=O)NCC(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@H](C(N[C@@H](CO)C(=O)N[C@@H](CO)C(=O)N[C@@H](CO)C(=O)N[C@@H](CO)C(=O)NCC(=O)N[C@@H](CC(C)C)C(=O)NCC(=O)N[C@@H](CSSC[C@@H](C(=O)N1)NC(=O)CNC(=O)[C@H](CO)NC(=O)CNC(=O)[C@H](CCC(N)=O)NC(=O)[C@@H](NC(=O)[C@H](CCSC)NC(=O)[C@H](CCCCN)NC(=O)[C@H]1N(CCC1)C(=O)[C@@H](N)CO)C(C)C)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC=1N=CNC=1)C(O)=O)=O)[C@@H](C)CC)C1=CC=CC=C1 HPNRHPKXQZSDFX-OAQDCNSJSA-N 0.000 description 2
- 230000003472 neutralizing effect Effects 0.000 description 2
- 239000012299 nitrogen atmosphere Substances 0.000 description 2
- 231100000252 nontoxic Toxicity 0.000 description 2
- 230000003000 nontoxic effect Effects 0.000 description 2
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 2
- 150000007524 organic acids Chemical class 0.000 description 2
- 235000005985 organic acids Nutrition 0.000 description 2
- 239000012074 organic phase Substances 0.000 description 2
- SFJGCXYXEFWEBK-UHFFFAOYSA-N oxazepine Chemical compound O1C=CC=CC=N1 SFJGCXYXEFWEBK-UHFFFAOYSA-N 0.000 description 2
- 125000002971 oxazolyl group Chemical group 0.000 description 2
- 125000003566 oxetanyl group Chemical group 0.000 description 2
- 230000003647 oxidation Effects 0.000 description 2
- 238000007254 oxidation reaction Methods 0.000 description 2
- 238000004806 packaging method and process Methods 0.000 description 2
- 229910052763 palladium Inorganic materials 0.000 description 2
- 239000000825 pharmaceutical preparation Substances 0.000 description 2
- 230000000144 pharmacologic effect Effects 0.000 description 2
- DHHVAGZRUROJKS-UHFFFAOYSA-N phentermine Chemical compound CC(C)(N)CC1=CC=CC=C1 DHHVAGZRUROJKS-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 2
- 239000010452 phosphate Substances 0.000 description 2
- 229910052698 phosphorus Inorganic materials 0.000 description 2
- 239000011574 phosphorus Substances 0.000 description 2
- SIOXPEMLGUPBBT-UHFFFAOYSA-N picolinic acid Chemical compound OC(=O)C1=CC=CC=N1 SIOXPEMLGUPBBT-UHFFFAOYSA-N 0.000 description 2
- 125000004193 piperazinyl group Chemical group 0.000 description 2
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 2
- 229920000642 polymer Polymers 0.000 description 2
- 238000002600 positron emission tomography Methods 0.000 description 2
- 230000003389 potentiating effect Effects 0.000 description 2
- 238000012545 processing Methods 0.000 description 2
- VVWRJUBEIPHGQF-MDZDMXLPSA-N propan-2-yl (ne)-n-propan-2-yloxycarbonyliminocarbamate Chemical compound CC(C)OC(=O)\N=N\C(=O)OC(C)C VVWRJUBEIPHGQF-MDZDMXLPSA-N 0.000 description 2
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 108020000494 protein-tyrosine phosphatase Proteins 0.000 description 2
- 102000004169 proteins and genes Human genes 0.000 description 2
- 108090000623 proteins and genes Proteins 0.000 description 2
- 125000003373 pyrazinyl group Chemical group 0.000 description 2
- YPOXGDJGKBXRFP-UHFFFAOYSA-N pyrimidine-4-carboxylic acid Chemical compound OC(=O)C1=CC=NC=N1 YPOXGDJGKBXRFP-UHFFFAOYSA-N 0.000 description 2
- 125000000168 pyrrolyl group Chemical group 0.000 description 2
- 230000017619 regulation of gastric acid secretion Effects 0.000 description 2
- 239000011347 resin Substances 0.000 description 2
- 229920005989 resin Polymers 0.000 description 2
- YGSDEFSMJLZEOE-UHFFFAOYSA-N salicylic acid Chemical compound OC(=O)C1=CC=CC=C1O YGSDEFSMJLZEOE-UHFFFAOYSA-N 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- BNRNXUUZRGQAQC-UHFFFAOYSA-N sildenafil Chemical compound CCCC1=NN(C)C(C(N2)=O)=C1N=C2C(C(=CC=1)OCC)=CC=1S(=O)(=O)N1CCN(C)CC1 BNRNXUUZRGQAQC-UHFFFAOYSA-N 0.000 description 2
- 238000010898 silica gel chromatography Methods 0.000 description 2
- 238000002603 single-photon emission computed tomography Methods 0.000 description 2
- 239000011877 solvent mixture Substances 0.000 description 2
- 238000003797 solvolysis reaction Methods 0.000 description 2
- 241000894007 species Species 0.000 description 2
- 238000012289 standard assay Methods 0.000 description 2
- 239000008117 stearic acid Substances 0.000 description 2
- 230000003637 steroidlike Effects 0.000 description 2
- 150000003431 steroids Chemical class 0.000 description 2
- 239000000758 substrate Substances 0.000 description 2
- 239000000829 suppository Substances 0.000 description 2
- 230000035488 systolic blood pressure Effects 0.000 description 2
- 239000000454 talc Substances 0.000 description 2
- 235000012222 talc Nutrition 0.000 description 2
- 229910052623 talc Inorganic materials 0.000 description 2
- RMMXLENWKUUMAY-UHFFFAOYSA-N telmisartan Chemical compound CCCC1=NC2=C(C)C=C(C=3N(C4=CC=CC=C4N=3)C)C=C2N1CC(C=C1)=CC=C1C1=CC=CC=C1C(O)=O RMMXLENWKUUMAY-UHFFFAOYSA-N 0.000 description 2
- GPXQRRTXTJAMCK-OAQYLSRUSA-N tert-butyl (3r)-3-[(2-methylpropan-2-yl)oxycarbonylamino]-4-(4-phenylphenyl)butanoate Chemical compound C1=CC(C[C@H](CC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C)=CC=C1C1=CC=CC=C1 GPXQRRTXTJAMCK-OAQYLSRUSA-N 0.000 description 2
- GPXQRRTXTJAMCK-UHFFFAOYSA-N tert-butyl 3-[(2-methylpropan-2-yl)oxycarbonylamino]-4-(4-phenylphenyl)butanoate Chemical compound C1=CC(CC(CC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C)=CC=C1C1=CC=CC=C1 GPXQRRTXTJAMCK-UHFFFAOYSA-N 0.000 description 2
- TWBUVVYSQBFVGZ-UHFFFAOYSA-N tert-butyl butanoate Chemical compound CCCC(=O)OC(C)(C)C TWBUVVYSQBFVGZ-UHFFFAOYSA-N 0.000 description 2
- HPEYRWBLJIVNBY-GOSISDBHSA-N tert-butyl n-[(2r)-1-[4-(3-chlorophenyl)phenyl]-3-hydroxypropan-2-yl]carbamate Chemical compound C1=CC(C[C@H](CO)NC(=O)OC(C)(C)C)=CC=C1C1=CC=CC(Cl)=C1 HPEYRWBLJIVNBY-GOSISDBHSA-N 0.000 description 2
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 2
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 description 2
- 238000011200 topical administration Methods 0.000 description 2
- 230000000699 topical effect Effects 0.000 description 2
- QIWRFOJWQSSRJZ-UHFFFAOYSA-N tributyl(ethenyl)stannane Chemical compound CCCC[Sn](CCCC)(CCCC)C=C QIWRFOJWQSSRJZ-UHFFFAOYSA-N 0.000 description 2
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 2
- GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical compound CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 description 2
- 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 2
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 description 2
- 210000002700 urine Anatomy 0.000 description 2
- ACWBQPMHZXGDFX-QFIPXVFZSA-N valsartan Chemical compound C1=CC(CN(C(=O)CCCC)[C@@H](C(C)C)C(O)=O)=CC=C1C1=CC=CC=C1C1=NN=NN1 ACWBQPMHZXGDFX-QFIPXVFZSA-N 0.000 description 2
- 229960004699 valsartan Drugs 0.000 description 2
- 230000000304 vasodilatating effect Effects 0.000 description 2
- 239000000080 wetting agent Substances 0.000 description 2
- UGOMMVLRQDMAQQ-UHFFFAOYSA-N xphos Chemical compound CC(C)C1=CC(C(C)C)=CC(C(C)C)=C1C1=CC=CC=C1P(C1CCCCC1)C1CCCCC1 UGOMMVLRQDMAQQ-UHFFFAOYSA-N 0.000 description 2
- 229950004219 zankiren Drugs 0.000 description 2
- HMJIYCCIJYRONP-UHFFFAOYSA-N (+-)-Isradipine Chemical compound COC(=O)C1=C(C)NC(C)=C(C(=O)OC(C)C)C1C1=CC=CC2=NON=C12 HMJIYCCIJYRONP-UHFFFAOYSA-N 0.000 description 1
- YFGBQHOOROIVKG-BHDDXSALSA-N (2R)-2-[[(2R)-2-[[2-[[2-[[(2S)-2-amino-3-(4-hydroxyphenyl)propanoyl]amino]acetyl]amino]acetyl]amino]-3-phenylpropanoyl]amino]-4-methylsulfanylbutanoic acid Chemical compound C([C@H](C(=O)N[C@H](CCSC)C(O)=O)NC(=O)CNC(=O)CNC(=O)[C@@H](N)CC=1C=CC(O)=CC=1)C1=CC=CC=C1 YFGBQHOOROIVKG-BHDDXSALSA-N 0.000 description 1
- OELFLUMRDSZNSF-OFLPRAFFSA-N (2R)-2-[[oxo-(4-propan-2-ylcyclohexyl)methyl]amino]-3-phenylpropanoic acid Chemical compound C1CC(C(C)C)CCC1C(=O)N[C@@H](C(O)=O)CC1=CC=CC=C1 OELFLUMRDSZNSF-OFLPRAFFSA-N 0.000 description 1
- QDZOEBFLNHCSSF-PFFBOGFISA-N (2S)-2-[[(2R)-2-[[(2S)-1-[(2S)-6-amino-2-[[(2S)-1-[(2R)-2-amino-5-carbamimidamidopentanoyl]pyrrolidine-2-carbonyl]amino]hexanoyl]pyrrolidine-2-carbonyl]amino]-3-(1H-indol-3-yl)propanoyl]amino]-N-[(2R)-1-[[(2S)-1-[[(2R)-1-[[(2S)-1-[[(2S)-1-amino-4-methyl-1-oxopentan-2-yl]amino]-4-methyl-1-oxopentan-2-yl]amino]-3-(1H-indol-3-yl)-1-oxopropan-2-yl]amino]-1-oxo-3-phenylpropan-2-yl]amino]-3-(1H-indol-3-yl)-1-oxopropan-2-yl]pentanediamide Chemical compound C([C@@H](C(=O)N[C@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(C)C)C(N)=O)NC(=O)[C@@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H]1N(CCC1)C(=O)[C@H](CCCCN)NC(=O)[C@H]1N(CCC1)C(=O)[C@H](N)CCCNC(N)=N)C1=CC=CC=C1 QDZOEBFLNHCSSF-PFFBOGFISA-N 0.000 description 1
- OBETXYAYXDNJHR-SSDOTTSWSA-M (2r)-2-ethylhexanoate Chemical compound CCCC[C@@H](CC)C([O-])=O OBETXYAYXDNJHR-SSDOTTSWSA-M 0.000 description 1
- ULNOXUAEIPUJMK-LLVKDONJSA-N (2r)-3-(4-bromophenyl)-2-[(2-methylpropan-2-yl)oxycarbonylamino]propanoic acid Chemical compound CC(C)(C)OC(=O)N[C@@H](C(O)=O)CC1=CC=C(Br)C=C1 ULNOXUAEIPUJMK-LLVKDONJSA-N 0.000 description 1
- VHSPKQAESIGBIC-HSZRJFAPSA-N (2r)-3-[3-(4-chloro-3-ethylphenoxy)-n-[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl]anilino]-1,1,1-trifluoropropan-2-ol Chemical compound C1=C(Cl)C(CC)=CC(OC=2C=C(C=CC=2)N(C[C@@H](O)C(F)(F)F)CC=2C=C(OC(F)(F)C(F)F)C=CC=2)=C1 VHSPKQAESIGBIC-HSZRJFAPSA-N 0.000 description 1
- ZGGHKIMDNBDHJB-NRFPMOEYSA-M (3R,5S)-fluvastatin sodium Chemical compound [Na+].C12=CC=CC=C2N(C(C)C)C(\C=C\[C@@H](O)C[C@@H](O)CC([O-])=O)=C1C1=CC=C(F)C=C1 ZGGHKIMDNBDHJB-NRFPMOEYSA-M 0.000 description 1
- AURCDNVRZVWERL-FZKQIMNGSA-N (3r)-3-[[(2r)-2-(carboxymethylamino)propanoyl]amino]-4-[4-(3-chlorophenyl)phenyl]butanoic acid Chemical compound C1=CC(C[C@H](CC(O)=O)NC(=O)[C@H](NCC(O)=O)C)=CC=C1C1=CC=CC(Cl)=C1 AURCDNVRZVWERL-FZKQIMNGSA-N 0.000 description 1
- AURCDNVRZVWERL-SCLBCKFNSA-N (3r)-3-[[(2s)-2-(carboxymethylamino)propanoyl]amino]-4-[4-(3-chlorophenyl)phenyl]butanoic acid Chemical compound C1=CC(C[C@H](CC(O)=O)NC(=O)[C@@H](NCC(O)=O)C)=CC=C1C1=CC=CC(Cl)=C1 AURCDNVRZVWERL-SCLBCKFNSA-N 0.000 description 1
- RMZNFEBJRAJZFT-QGZVFWFLSA-N (3r)-4-(2-carboxyethylamino)-4-oxo-3-[(4-phenylphenyl)methyl]butanoic acid Chemical compound C1=CC(C[C@H](CC(O)=O)C(=O)NCCC(=O)O)=CC=C1C1=CC=CC=C1 RMZNFEBJRAJZFT-QGZVFWFLSA-N 0.000 description 1
- ODAVAJWRCJUNAG-OAHLLOKOSA-N (3r)-4-(4-phenylphenyl)-3-(2h-tetrazole-5-carbonylamino)butanoic acid Chemical compound C([C@H](CC(=O)O)NC(=O)C=1NN=NN=1)C(C=C1)=CC=C1C1=CC=CC=C1 ODAVAJWRCJUNAG-OAHLLOKOSA-N 0.000 description 1
- SVRCOWOXFYGFEP-QGZVFWFLSA-N (3r)-4-(4-phenylphenyl)-3-[3-(2h-tetrazol-5-yl)propanoylamino]butanoic acid Chemical compound C([C@H](CC(=O)O)NC(=O)CCC=1NN=NN=1)C(C=C1)=CC=C1C1=CC=CC=C1 SVRCOWOXFYGFEP-QGZVFWFLSA-N 0.000 description 1
- AGMDDGBZRAZZDC-OAHLLOKOSA-N (3r)-4-[4-(3-chlorophenyl)phenyl]-3-(2h-tetrazole-5-carbonylamino)butanoic acid Chemical compound C([C@H](CC(=O)O)NC(=O)C1=NNN=N1)C(C=C1)=CC=C1C1=CC=CC(Cl)=C1 AGMDDGBZRAZZDC-OAHLLOKOSA-N 0.000 description 1
- TXDGEGOLSACYBG-GOSISDBHSA-N (3r)-4-[4-(3-chlorophenyl)phenyl]-3-[(2-ethyl-1,3-oxazole-5-carbonyl)amino]butanoic acid Chemical compound O1C(CC)=NC=C1C(=O)N[C@@H](CC(O)=O)CC1=CC=C(C=2C=C(Cl)C=CC=2)C=C1 TXDGEGOLSACYBG-GOSISDBHSA-N 0.000 description 1
- CUKWUWBLQQDQAC-VEQWQPCFSA-N (3s)-3-amino-4-[[(2s)-1-[[(2s)-1-[[(2s)-1-[[(2s,3s)-1-[[(2s)-1-[(2s)-2-[[(1s)-1-carboxyethyl]carbamoyl]pyrrolidin-1-yl]-3-(1h-imidazol-5-yl)-1-oxopropan-2-yl]amino]-3-methyl-1-oxopentan-2-yl]amino]-3-(4-hydroxyphenyl)-1-oxopropan-2-yl]amino]-3-methyl-1-ox Chemical compound C([C@@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC=1NC=NC=1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](C)C(O)=O)NC(=O)[C@@H](NC(=O)[C@H](CCCN=C(N)N)NC(=O)[C@@H](N)CC(O)=O)C(C)C)C1=CC=C(O)C=C1 CUKWUWBLQQDQAC-VEQWQPCFSA-N 0.000 description 1
- UUWWNSNGCQHJNP-QHCPKHFHSA-N (4s)-4-benzyl-3-[3-(4-phenylphenyl)propanoyl]-1,3-oxazolidin-2-one Chemical compound C([C@@H]1CC=2C=CC=CC=2)OC(=O)N1C(=O)CCC(C=C1)=CC=C1C1=CC=CC=C1 UUWWNSNGCQHJNP-QHCPKHFHSA-N 0.000 description 1
- DNIAPMSPPWPWGF-GSVOUGTGSA-N (R)-(-)-Propylene glycol Chemical compound C[C@@H](O)CO DNIAPMSPPWPWGF-GSVOUGTGSA-N 0.000 description 1
- MIOPJNTWMNEORI-GMSGAONNSA-N (S)-camphorsulfonic acid Chemical compound C1C[C@@]2(CS(O)(=O)=O)C(=O)C[C@@H]1C2(C)C MIOPJNTWMNEORI-GMSGAONNSA-N 0.000 description 1
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 description 1
- PVHUJELLJLJGLN-INIZCTEOSA-N (S)-nitrendipine Chemical compound CCOC(=O)C1=C(C)NC(C)=C(C(=O)OC)[C@@H]1C1=CC=CC([N+]([O-])=O)=C1 PVHUJELLJLJGLN-INIZCTEOSA-N 0.000 description 1
- 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 1
- XLYMOEINVGRTEX-ONEGZZNKSA-N (e)-4-ethoxy-4-oxobut-2-enoic acid Chemical compound CCOC(=O)\C=C\C(O)=O XLYMOEINVGRTEX-ONEGZZNKSA-N 0.000 description 1
- WBYWAXJHAXSJNI-VOTSOKGWSA-M .beta-Phenylacrylic acid Natural products [O-]C(=O)\C=C\C1=CC=CC=C1 WBYWAXJHAXSJNI-VOTSOKGWSA-M 0.000 description 1
- 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 1
- PAAZPARNPHGIKF-UHFFFAOYSA-N 1,2-dibromoethane Chemical compound BrCCBr PAAZPARNPHGIKF-UHFFFAOYSA-N 0.000 description 1
- MUZIZEZCKKMZRT-UHFFFAOYSA-N 1,2-dithiolane Chemical group C1CSSC1 MUZIZEZCKKMZRT-UHFFFAOYSA-N 0.000 description 1
- AQDASWVGTGOESU-UHFFFAOYSA-N 1,3,5-trichloro-2-[chloro(phenyl)methyl]benzene Chemical compound ClC1=C(C(C2=CC=CC=C2)Cl)C(=CC(=C1)Cl)Cl AQDASWVGTGOESU-UHFFFAOYSA-N 0.000 description 1
- BCMCBBGGLRIHSE-UHFFFAOYSA-N 1,3-benzoxazole Chemical compound C1=CC=C2OC=NC2=C1 BCMCBBGGLRIHSE-UHFFFAOYSA-N 0.000 description 1
- SJBBXFLOLUTGCW-UHFFFAOYSA-N 1,3-bis(trifluoromethyl)benzene Chemical compound FC(F)(F)C1=CC=CC(C(F)(F)F)=C1 SJBBXFLOLUTGCW-UHFFFAOYSA-N 0.000 description 1
- LBKDGROORAKTLC-UHFFFAOYSA-N 1,5-dichloropentane Chemical compound ClCCCCCCl LBKDGROORAKTLC-UHFFFAOYSA-N 0.000 description 1
- 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 1
- MOHYOXXOKFQHDC-UHFFFAOYSA-N 1-(chloromethyl)-4-methoxybenzene Chemical compound COC1=CC=C(CCl)C=C1 MOHYOXXOKFQHDC-UHFFFAOYSA-N 0.000 description 1
- BOVGTQGAOIONJV-BETUJISGSA-N 1-[(3ar,6as)-3,3a,4,5,6,6a-hexahydro-1h-cyclopenta[c]pyrrol-2-yl]-3-(4-methylphenyl)sulfonylurea Chemical compound C1=CC(C)=CC=C1S(=O)(=O)NC(=O)NN1C[C@H]2CCC[C@H]2C1 BOVGTQGAOIONJV-BETUJISGSA-N 0.000 description 1
- WCUDWYLAQUZKTO-UHFFFAOYSA-N 1-azido-10,10-dimethylundecane Chemical compound CC(C)(C)CCCCCCCCCN=[N+]=[N-] WCUDWYLAQUZKTO-UHFFFAOYSA-N 0.000 description 1
- DQFQCHIDRBIESA-UHFFFAOYSA-N 1-benzazepine Chemical compound N1C=CC=CC2=CC=CC=C12 DQFQCHIDRBIESA-UHFFFAOYSA-N 0.000 description 1
- MYZVUSAIFXIGNC-UHFFFAOYSA-N 1-benzylpyridin-2-one Chemical compound O=C1C=CC=CN1CC1=CC=CC=C1 MYZVUSAIFXIGNC-UHFFFAOYSA-N 0.000 description 1
- YZUPZGFPHUVJKC-UHFFFAOYSA-N 1-bromo-2-methoxyethane Chemical compound COCCBr YZUPZGFPHUVJKC-UHFFFAOYSA-N 0.000 description 1
- AVFZOVWCLRSYKC-UHFFFAOYSA-N 1-methylpyrrolidine Chemical compound CN1CCCC1 AVFZOVWCLRSYKC-UHFFFAOYSA-N 0.000 description 1
- HYZJCKYKOHLVJF-UHFFFAOYSA-N 1H-benzimidazole Chemical compound C1=CC=C2NC=NC2=C1 HYZJCKYKOHLVJF-UHFFFAOYSA-N 0.000 description 1
- XWIYUCRMWCHYJR-UHFFFAOYSA-N 1h-pyrrolo[3,2-b]pyridine Chemical compound C1=CC=C2NC=CC2=N1 XWIYUCRMWCHYJR-UHFFFAOYSA-N 0.000 description 1
- 125000003562 2,2-dimethylpentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- UIKHKLFBHLPAPO-UHFFFAOYSA-N 2,3-diacetyl-2,3-dihydroxybutanedioic acid Chemical compound CC(=O)C(O)(C(O)=O)C(O)(C(C)=O)C(O)=O UIKHKLFBHLPAPO-UHFFFAOYSA-N 0.000 description 1
- 125000003660 2,3-dimethylpentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(C([H])([H])[H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- LDXJRKWFNNFDSA-UHFFFAOYSA-N 2-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)-1-[4-[2-[[3-(trifluoromethoxy)phenyl]methylamino]pyrimidin-5-yl]piperazin-1-yl]ethanone Chemical compound C1CN(CC2=NNN=C21)CC(=O)N3CCN(CC3)C4=CN=C(N=C4)NCC5=CC(=CC=C5)OC(F)(F)F LDXJRKWFNNFDSA-UHFFFAOYSA-N 0.000 description 1
- YGTUPRIZNBMOFV-UHFFFAOYSA-N 2-(4-hydroxybenzoyl)benzoic acid Chemical compound OC(=O)C1=CC=CC=C1C(=O)C1=CC=C(O)C=C1 YGTUPRIZNBMOFV-UHFFFAOYSA-N 0.000 description 1
- GILWHMFYKTWDRN-UHFFFAOYSA-N 2-[(4-methoxyphenyl)methyl]tetrazole-5-carboxylic acid Chemical compound C1=CC(OC)=CC=C1CN1N=C(C(O)=O)N=N1 GILWHMFYKTWDRN-UHFFFAOYSA-N 0.000 description 1
- SWXOFFXDRNFBIJ-UHFFFAOYSA-N 2-[(4-phenylphenyl)methyl]butanedioic acid Chemical compound C1=CC(CC(CC(=O)O)C(O)=O)=CC=C1C1=CC=CC=C1 SWXOFFXDRNFBIJ-UHFFFAOYSA-N 0.000 description 1
- NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical compound CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 description 1
- XXZCIYUJYUESMD-UHFFFAOYSA-N 2-[4-[2-(2,3-dihydro-1H-inden-2-ylamino)pyrimidin-5-yl]-3-(morpholin-4-ylmethyl)pyrazol-1-yl]-1-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)ethanone Chemical compound C1C(CC2=CC=CC=C12)NC1=NC=C(C=N1)C=1C(=NN(C=1)CC(=O)N1CC2=C(CC1)NN=N2)CN1CCOCC1 XXZCIYUJYUESMD-UHFFFAOYSA-N 0.000 description 1
- WWSJZGAPAVMETJ-UHFFFAOYSA-N 2-[4-[2-(2,3-dihydro-1H-inden-2-ylamino)pyrimidin-5-yl]-3-ethoxypyrazol-1-yl]-1-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)ethanone Chemical compound C1C(CC2=CC=CC=C12)NC1=NC=C(C=N1)C=1C(=NN(C=1)CC(=O)N1CC2=C(CC1)NN=N2)OCC WWSJZGAPAVMETJ-UHFFFAOYSA-N 0.000 description 1
- LPZOCVVDSHQFST-UHFFFAOYSA-N 2-[4-[2-(2,3-dihydro-1H-inden-2-ylamino)pyrimidin-5-yl]-3-ethylpyrazol-1-yl]-1-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)ethanone Chemical compound C1C(CC2=CC=CC=C12)NC1=NC=C(C=N1)C=1C(=NN(C=1)CC(=O)N1CC2=C(CC1)NN=N2)CC LPZOCVVDSHQFST-UHFFFAOYSA-N 0.000 description 1
- WZFUQSJFWNHZHM-UHFFFAOYSA-N 2-[4-[2-(2,3-dihydro-1H-inden-2-ylamino)pyrimidin-5-yl]piperazin-1-yl]-1-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)ethanone Chemical compound C1C(CC2=CC=CC=C12)NC1=NC=C(C=N1)N1CCN(CC1)CC(=O)N1CC2=C(CC1)NN=N2 WZFUQSJFWNHZHM-UHFFFAOYSA-N 0.000 description 1
- JQMFQLVAJGZSQS-UHFFFAOYSA-N 2-[4-[2-(2,3-dihydro-1H-inden-2-ylamino)pyrimidin-5-yl]piperazin-1-yl]-N-(2-oxo-3H-1,3-benzoxazol-6-yl)acetamide Chemical compound C1C(CC2=CC=CC=C12)NC1=NC=C(C=N1)N1CCN(CC1)CC(=O)NC1=CC2=C(NC(O2)=O)C=C1 JQMFQLVAJGZSQS-UHFFFAOYSA-N 0.000 description 1
- IHCCLXNEEPMSIO-UHFFFAOYSA-N 2-[4-[2-(2,3-dihydro-1H-inden-2-ylamino)pyrimidin-5-yl]piperidin-1-yl]-1-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)ethanone Chemical compound C1C(CC2=CC=CC=C12)NC1=NC=C(C=N1)C1CCN(CC1)CC(=O)N1CC2=C(CC1)NN=N2 IHCCLXNEEPMSIO-UHFFFAOYSA-N 0.000 description 1
- ZRPAUEVGEGEPFQ-UHFFFAOYSA-N 2-[4-[2-(2,3-dihydro-1H-inden-2-ylamino)pyrimidin-5-yl]pyrazol-1-yl]-1-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)ethanone Chemical compound C1C(CC2=CC=CC=C12)NC1=NC=C(C=N1)C=1C=NN(C=1)CC(=O)N1CC2=C(CC1)NN=N2 ZRPAUEVGEGEPFQ-UHFFFAOYSA-N 0.000 description 1
- YJLUBHOZZTYQIP-UHFFFAOYSA-N 2-[5-[2-(2,3-dihydro-1H-inden-2-ylamino)pyrimidin-5-yl]-1,3,4-oxadiazol-2-yl]-1-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)ethanone Chemical compound C1C(CC2=CC=CC=C12)NC1=NC=C(C=N1)C1=NN=C(O1)CC(=O)N1CC2=C(CC1)NN=N2 YJLUBHOZZTYQIP-UHFFFAOYSA-N 0.000 description 1
- PDPBIXXIHOWWHA-UHFFFAOYSA-N 2-benzyl-3,4-dihydro-2h-chromene Chemical compound C1CC2=CC=CC=C2OC1CC1=CC=CC=C1 PDPBIXXIHOWWHA-UHFFFAOYSA-N 0.000 description 1
- FSJCYXPMWQPVOS-UHFFFAOYSA-N 2-ethyl-4-[[4-[2-(2h-tetrazol-5-yl)phenyl]phenyl]methoxy]quinoline Chemical compound C=12C=CC=CC2=NC(CC)=CC=1OCC(C=C1)=CC=C1C1=CC=CC=C1C=1N=NNN=1 FSJCYXPMWQPVOS-UHFFFAOYSA-N 0.000 description 1
- GXPOIOYVYNLHLX-UHFFFAOYSA-N 2-methoxy-1,3-thiazole-5-carboxylic acid Chemical compound COC1=NC=C(C(O)=O)S1 GXPOIOYVYNLHLX-UHFFFAOYSA-N 0.000 description 1
- 229940080296 2-naphthalenesulfonate Drugs 0.000 description 1
- HOKKSYPZFBKQAZ-UHFFFAOYSA-N 2-oxaspiro[4.4]nonane-1,3-dione Chemical compound O=C1OC(=O)CC11CCCC1 HOKKSYPZFBKQAZ-UHFFFAOYSA-N 0.000 description 1
- 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- 238000005084 2D-nuclear magnetic resonance Methods 0.000 description 1
- KUZXQXCWRNFIHK-UHFFFAOYSA-N 3,3-diethyldodecane Chemical compound CCCCCCCCCC(CC)(CC)CC KUZXQXCWRNFIHK-UHFFFAOYSA-N 0.000 description 1
- UEIZUEWXLJOVLD-UHFFFAOYSA-N 3-(1-methylpyrrolidin-3-yl)pyridine Chemical compound C1N(C)CCC1C1=CC=CN=C1 UEIZUEWXLJOVLD-UHFFFAOYSA-N 0.000 description 1
- 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 1
- MVFHRQWYCXYYMU-UHFFFAOYSA-N 3-(4-phenylphenyl)propanoic acid Chemical compound C1=CC(CCC(=O)O)=CC=C1C1=CC=CC=C1 MVFHRQWYCXYYMU-UHFFFAOYSA-N 0.000 description 1
- UMCMPZBLKLEWAF-BCTGSCMUSA-N 3-[(3-cholamidopropyl)dimethylammonio]propane-1-sulfonate Chemical compound C([C@H]1C[C@H]2O)[C@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H]([C@@H](CCC(=O)NCCC[N+](C)(C)CCCS([O-])(=O)=O)C)[C@@]2(C)[C@@H](O)C1 UMCMPZBLKLEWAF-BCTGSCMUSA-N 0.000 description 1
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 1
- IHXITIQUZBCIHA-UHFFFAOYSA-N 3-azaniumyl-4-(4-phenylphenyl)butanoate Chemical compound C1=CC(CC(CC(O)=O)N)=CC=C1C1=CC=CC=C1 IHXITIQUZBCIHA-UHFFFAOYSA-N 0.000 description 1
- LULAYUGMBFYYEX-UHFFFAOYSA-N 3-chlorobenzoic acid Chemical compound OC(=O)C1=CC=CC(Cl)=C1 LULAYUGMBFYYEX-UHFFFAOYSA-N 0.000 description 1
- NMWSKOLWZZWHPL-UHFFFAOYSA-N 3-chlorobiphenyl Chemical group ClC1=CC=CC(C=2C=CC=CC=2)=C1 NMWSKOLWZZWHPL-UHFFFAOYSA-N 0.000 description 1
- QUKDWRYJPHUXQR-UHFFFAOYSA-N 3-hydroxy-1-methylpyridin-2-one Chemical compound CN1C=CC=C(O)C1=O QUKDWRYJPHUXQR-UHFFFAOYSA-N 0.000 description 1
- 125000003469 3-methylhexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 1
- UIAGMCDKSXEBJQ-IBGZPJMESA-N 3-o-(2-methoxyethyl) 5-o-propan-2-yl (4s)-2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate Chemical compound COCCOC(=O)C1=C(C)NC(C)=C(C(=O)OC(C)C)[C@H]1C1=CC=CC([N+]([O-])=O)=C1 UIAGMCDKSXEBJQ-IBGZPJMESA-N 0.000 description 1
- VOCWBIGTEMMVGZ-UHFFFAOYSA-N 3-oxo-1,2-oxazole-5-carboxylic acid Chemical compound OC(=O)C1=CC(=O)NO1 VOCWBIGTEMMVGZ-UHFFFAOYSA-N 0.000 description 1
- DJMBQQBASUEMTK-UHFFFAOYSA-N 3-oxo-1,2-thiazole-5-carboxylic acid Chemical compound OC(=O)C1=CC(O)=NS1 DJMBQQBASUEMTK-UHFFFAOYSA-N 0.000 description 1
- 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 description 1
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 1
- XSFAQQLHYUBFKV-UHFFFAOYSA-N 4-(4-phenylphenyl)butanoic acid Chemical compound C1=CC(CCCC(=O)O)=CC=C1C1=CC=CC=C1 XSFAQQLHYUBFKV-UHFFFAOYSA-N 0.000 description 1
- JMGUHVFNUALJTQ-UHFFFAOYSA-N 4-[(2-methylpropan-2-yl)oxy]-4-oxo-2-[(4-phenylphenyl)methyl]butanoic acid Chemical compound C1=CC(CC(CC(=O)OC(C)(C)C)C(O)=O)=CC=C1C1=CC=CC=C1 JMGUHVFNUALJTQ-UHFFFAOYSA-N 0.000 description 1
- PCOCFIOYWNCGBM-UHFFFAOYSA-N 4-[(2-methylpropan-2-yl)oxy]-4-oxobutanoic acid Chemical compound CC(C)(C)OC(=O)CCC(O)=O PCOCFIOYWNCGBM-UHFFFAOYSA-N 0.000 description 1
- XWEGTYKCAKPQRH-UHFFFAOYSA-N 4-[4-(3-chlorophenyl)phenyl]butanoic acid Chemical compound C1=CC(CCCC(=O)O)=CC=C1C1=CC=CC(Cl)=C1 XWEGTYKCAKPQRH-UHFFFAOYSA-N 0.000 description 1
- RGBHFJQNKNMQSJ-QGZVFWFLSA-N 4-[[(2r)-1-[4-(2,5-dichlorophenyl)phenyl]-4-ethoxy-4-oxobutan-2-yl]amino]-4-oxobutanoic acid Chemical compound C1=CC(C[C@H](CC(=O)OCC)NC(=O)CCC(O)=O)=CC=C1C1=CC(Cl)=CC=C1Cl RGBHFJQNKNMQSJ-QGZVFWFLSA-N 0.000 description 1
- PXXXIDKPNLGOEH-LJQANCHMSA-N 4-[[(2r)-1-[4-(3-chlorophenyl)phenyl]-4-ethoxy-4-oxobutan-2-yl]amino]-4-oxobutanoic acid Chemical compound C1=CC(C[C@H](CC(=O)OCC)NC(=O)CCC(O)=O)=CC=C1C1=CC=CC(Cl)=C1 PXXXIDKPNLGOEH-LJQANCHMSA-N 0.000 description 1
- XBIYMMZPQYOOJC-QGZVFWFLSA-N 4-[[(2r)-1-carboxy-3-(4-phenylphenyl)propan-2-yl]amino]-4-oxobutanoic acid Chemical compound C1=CC(C[C@H](CC(O)=O)NC(=O)CCC(=O)O)=CC=C1C1=CC=CC=C1 XBIYMMZPQYOOJC-QGZVFWFLSA-N 0.000 description 1
- WDRVLNOLZXXIIS-MRXNPFEDSA-N 4-[[(2r)-1-carboxy-3-[4-(5-fluoro-2-methoxyphenyl)phenyl]propan-2-yl]amino]-4-oxobutanoic acid Chemical compound COC1=CC=C(F)C=C1C1=CC=C(C[C@H](CC(O)=O)NC(=O)CCC(O)=O)C=C1 WDRVLNOLZXXIIS-MRXNPFEDSA-N 0.000 description 1
- HVTXAAMYGJZNNN-HXUWFJFHSA-N 4-[[(2r)-4-[(2-methylpropan-2-yl)oxy]-4-oxo-1-(4-phenylphenyl)butan-2-yl]amino]-4-oxobutanoic acid Chemical compound C1=CC(C[C@H](CC(=O)OC(C)(C)C)NC(=O)CCC(O)=O)=CC=C1C1=CC=CC=C1 HVTXAAMYGJZNNN-HXUWFJFHSA-N 0.000 description 1
- ISMFUVRIBXUYET-GOSISDBHSA-N 4-[[(2r)-4-ethoxy-1-[4-(5-fluoro-2-methoxyphenyl)phenyl]-4-oxobutan-2-yl]amino]-4-oxobutanoic acid Chemical compound C1=CC(C[C@H](CC(=O)OCC)NC(=O)CCC(O)=O)=CC=C1C1=CC(F)=CC=C1OC ISMFUVRIBXUYET-GOSISDBHSA-N 0.000 description 1
- HEGXTFYLGZFTRG-LJQANCHMSA-N 4-[[(2r)-4-ethoxy-4-oxo-1-(4-phenylphenyl)butan-2-yl]amino]-4-oxobutanoic acid Chemical compound C1=CC(C[C@H](CC(=O)OCC)NC(=O)CCC(O)=O)=CC=C1C1=CC=CC=C1 HEGXTFYLGZFTRG-LJQANCHMSA-N 0.000 description 1
- 229960000549 4-dimethylaminophenol Drugs 0.000 description 1
- BCJVBDBJSMFBRW-UHFFFAOYSA-N 4-diphenylphosphanylbutyl(diphenyl)phosphane Chemical compound C=1C=CC=CC=1P(C=1C=CC=CC=1)CCCCP(C=1C=CC=CC=1)C1=CC=CC=C1 BCJVBDBJSMFBRW-UHFFFAOYSA-N 0.000 description 1
- GCNTZFIIOFTKIY-UHFFFAOYSA-N 4-hydroxypyridine Chemical class OC1=CC=NC=C1 GCNTZFIIOFTKIY-UHFFFAOYSA-N 0.000 description 1
- CBAWXZIEFZQFQV-UHFFFAOYSA-N 4-methoxy-4-oxo-3-[(4-phenylphenyl)methyl]butanoic acid Chemical compound C1=CC(CC(CC(O)=O)C(=O)OC)=CC=C1C1=CC=CC=C1 CBAWXZIEFZQFQV-UHFFFAOYSA-N 0.000 description 1
- 125000004217 4-methoxybenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1OC([H])([H])[H])C([H])([H])* 0.000 description 1
- AHMKQJSMANBIEK-UHFFFAOYSA-N 4-o-tert-butyl 1-o-methyl 2-[(4-phenylphenyl)methyl]butanedioate Chemical compound C1=CC(CC(CC(=O)OC(C)(C)C)C(=O)OC)=CC=C1C1=CC=CC=C1 AHMKQJSMANBIEK-UHFFFAOYSA-N 0.000 description 1
- UGUBQKZSNQWWEV-UHFFFAOYSA-N 4-oxo-4-phenylmethoxybutanoic acid Chemical compound OC(=O)CCC(=O)OCC1=CC=CC=C1 UGUBQKZSNQWWEV-UHFFFAOYSA-N 0.000 description 1
- ISDBWOPVZKNQDW-UHFFFAOYSA-N 4-phenylbenzaldehyde Chemical compound C1=CC(C=O)=CC=C1C1=CC=CC=C1 ISDBWOPVZKNQDW-UHFFFAOYSA-N 0.000 description 1
- 125000000339 4-pyridyl group Chemical group N1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 description 1
- WLEIZYMPRFJHCX-UHFFFAOYSA-N 5-(2-methoxy-2-oxoethyl)furan-2-carboxylic acid Chemical compound COC(=O)CC1=CC=C(C(O)=O)O1 WLEIZYMPRFJHCX-UHFFFAOYSA-N 0.000 description 1
- QPJRCFBYGNECBE-UHFFFAOYSA-N 5-(carboxymethyl)furan-2-carboxylic acid Chemical compound OC(=O)CC1=CC=C(C(O)=O)O1 QPJRCFBYGNECBE-UHFFFAOYSA-N 0.000 description 1
- NFFXEUUOMTXWCX-UHFFFAOYSA-N 5-[(2,4-dioxo-1,3-thiazolidin-5-yl)methyl]-2-methoxy-n-[[4-(trifluoromethyl)phenyl]methyl]benzamide Chemical compound C1=C(C(=O)NCC=2C=CC(=CC=2)C(F)(F)F)C(OC)=CC=C1CC1SC(=O)NC1=O NFFXEUUOMTXWCX-UHFFFAOYSA-N 0.000 description 1
- YVQKIDLSVHRBGZ-UHFFFAOYSA-N 5-[[4-[2-hydroxy-2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]phenyl]methyl]-1,3-thiazolidine-2,4-dione Chemical compound CC=1OC(C=2C=CC=CC=2)=NC=1C(O)COC(C=C1)=CC=C1CC1SC(=O)NC1=O YVQKIDLSVHRBGZ-UHFFFAOYSA-N 0.000 description 1
- ITLAZBMGSXRIEF-UHFFFAOYSA-N 5-naphthalen-2-ylsulfonyl-1,3-thiazolidine-2,4-dione Chemical compound S1C(=O)NC(=O)C1S(=O)(=O)C1=CC=C(C=CC=C2)C2=C1 ITLAZBMGSXRIEF-UHFFFAOYSA-N 0.000 description 1
- RZTAMFZIAATZDJ-HNNXBMFYSA-N 5-o-ethyl 3-o-methyl (4s)-4-(2,3-dichlorophenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate Chemical compound CCOC(=O)C1=C(C)NC(C)=C(C(=O)OC)[C@@H]1C1=CC=CC(Cl)=C1Cl RZTAMFZIAATZDJ-HNNXBMFYSA-N 0.000 description 1
- QINVTJSYBMDSPK-UHFFFAOYSA-N 5-oxo-2h-1,2,4-oxadiazole-3-carboxylic acid Chemical compound OC(=O)C1=NOC(=O)N1 QINVTJSYBMDSPK-UHFFFAOYSA-N 0.000 description 1
- NCLLBFUFTPPKAP-UHFFFAOYSA-N 6-(methanesulfonamido)pyridine-3-carboxylic acid Chemical compound CS(=O)(=O)NC1=CC=C(C(O)=O)C=N1 NCLLBFUFTPPKAP-UHFFFAOYSA-N 0.000 description 1
- WTFUTSCZYYCBAY-SXBRIOAWSA-N 6-[(E)-C-[[4-[2-(2,3-dihydro-1H-inden-2-ylamino)pyrimidin-5-yl]piperazin-1-yl]methyl]-N-hydroxycarbonimidoyl]-3H-1,3-benzoxazol-2-one Chemical compound C1C(CC2=CC=CC=C12)NC1=NC=C(C=N1)N1CCN(CC1)C/C(=N/O)/C1=CC2=C(NC(O2)=O)C=C1 WTFUTSCZYYCBAY-SXBRIOAWSA-N 0.000 description 1
- DFGKGUXTPFWHIX-UHFFFAOYSA-N 6-[2-[4-[2-(2,3-dihydro-1H-inden-2-ylamino)pyrimidin-5-yl]piperazin-1-yl]acetyl]-3H-1,3-benzoxazol-2-one Chemical compound C1C(CC2=CC=CC=C12)NC1=NC=C(C=N1)N1CCN(CC1)CC(=O)C1=CC2=C(NC(O2)=O)C=C1 DFGKGUXTPFWHIX-UHFFFAOYSA-N 0.000 description 1
- 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 1
- LLQHSBBZNDXTIV-UHFFFAOYSA-N 6-[5-[[4-[2-(2,3-dihydro-1H-inden-2-ylamino)pyrimidin-5-yl]piperazin-1-yl]methyl]-4,5-dihydro-1,2-oxazol-3-yl]-3H-1,3-benzoxazol-2-one Chemical compound C1C(CC2=CC=CC=C12)NC1=NC=C(C=N1)N1CCN(CC1)CC1CC(=NO1)C1=CC2=C(NC(O2)=O)C=C1 LLQHSBBZNDXTIV-UHFFFAOYSA-N 0.000 description 1
- 244000215068 Acacia senegal Species 0.000 description 1
- 208000002874 Acne Vulgaris Diseases 0.000 description 1
- HRPVXLWXLXDGHG-UHFFFAOYSA-N Acrylamide Chemical compound NC(=O)C=C HRPVXLWXLXDGHG-UHFFFAOYSA-N 0.000 description 1
- 241000251468 Actinopterygii Species 0.000 description 1
- 229920001817 Agar Polymers 0.000 description 1
- YCIPQJTZJGUXND-UHFFFAOYSA-N Aglaia odorata Alkaloid Natural products C1=CC(OC)=CC=C1C1(C(C=2C(=O)N3CCCC3=NC=22)C=3C=CC=CC=3)C2(O)C2=C(OC)C=C(OC)C=C2O1 YCIPQJTZJGUXND-UHFFFAOYSA-N 0.000 description 1
- 239000005995 Aluminium silicate Substances 0.000 description 1
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 1
- 206010002383 Angina Pectoris Diseases 0.000 description 1
- 102000008873 Angiotensin II receptor Human genes 0.000 description 1
- 108050000824 Angiotensin II receptor Proteins 0.000 description 1
- 102400000344 Angiotensin-1 Human genes 0.000 description 1
- 101800000734 Angiotensin-1 Proteins 0.000 description 1
- 102400000345 Angiotensin-2 Human genes 0.000 description 1
- 101800000733 Angiotensin-2 Proteins 0.000 description 1
- 101710129690 Angiotensin-converting enzyme inhibitor Proteins 0.000 description 1
- 241001553178 Arachis glabrata Species 0.000 description 1
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 1
- 241000416162 Astragalus gummifer Species 0.000 description 1
- XUKUURHRXDUEBC-KAYWLYCHSA-N Atorvastatin Chemical compound C=1C=CC=CC=1C1=C(C=2C=CC(F)=CC=2)N(CC[C@@H](O)C[C@@H](O)CC(O)=O)C(C(C)C)=C1C(=O)NC1=CC=CC=C1 XUKUURHRXDUEBC-KAYWLYCHSA-N 0.000 description 1
- XUKUURHRXDUEBC-UHFFFAOYSA-N Atorvastatin Natural products C=1C=CC=CC=1C1=C(C=2C=CC(F)=CC=2)N(CCC(O)CC(O)CC(O)=O)C(C(C)C)=C1C(=O)NC1=CC=CC=C1 XUKUURHRXDUEBC-UHFFFAOYSA-N 0.000 description 1
- 241000271566 Aves Species 0.000 description 1
- NOWKCMXCCJGMRR-UHFFFAOYSA-N Aziridine Chemical compound C1CN1 NOWKCMXCCJGMRR-UHFFFAOYSA-N 0.000 description 1
- 102000013585 Bombesin Human genes 0.000 description 1
- 108010051479 Bombesin Proteins 0.000 description 1
- BTBUEUYNUDRHOZ-UHFFFAOYSA-N Borate Chemical compound [O-]B([O-])[O-] BTBUEUYNUDRHOZ-UHFFFAOYSA-N 0.000 description 1
- 241000283690 Bos taurus Species 0.000 description 1
- 101710086378 Bradykinin-potentiating and C-type natriuretic peptides Proteins 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 1
- ZIRFZYFHHOCNIA-UHFFFAOYSA-N C(C)(C)(C)C(=O)O.O1CCOCC1 Chemical compound C(C)(C)(C)C(=O)O.O1CCOCC1 ZIRFZYFHHOCNIA-UHFFFAOYSA-N 0.000 description 1
- RBANSYDOGKTDCI-GFOWMXPYSA-N C(C)(C)(C)OC(CC[C@@H](OC(C)(C)C)NC(CC1=CC=C(C=C1)Br)CC(=O)OCC)=O Chemical compound C(C)(C)(C)OC(CC[C@@H](OC(C)(C)C)NC(CC1=CC=C(C=C1)Br)CC(=O)OCC)=O RBANSYDOGKTDCI-GFOWMXPYSA-N 0.000 description 1
- CRWPJTZTNHEMJB-NHQUYOMTSA-N C(C)(C)(C)OC(C[C@H](C(OC(C)(C)C)N(CCC)CCC(=O)OC)CC1=CC=C(C=C1)C1=CC=CC=C1)=O Chemical compound C(C)(C)(C)OC(C[C@H](C(OC(C)(C)C)N(CCC)CCC(=O)OC)CC1=CC=C(C=C1)C1=CC=CC=C1)=O CRWPJTZTNHEMJB-NHQUYOMTSA-N 0.000 description 1
- UDEFCLVLOIDZRO-OAQYLSRUSA-N C(C)OC(C[C@@H](CC1=CC=C(C=C1)C1=CC(=CC=C1)Cl)NC(COCC(=O)OCC)=O)=O Chemical compound C(C)OC(C[C@@H](CC1=CC=C(C=C1)C1=CC(=CC=C1)Cl)NC(COCC(=O)OCC)=O)=O UDEFCLVLOIDZRO-OAQYLSRUSA-N 0.000 description 1
- KGPUBJJSROSPDF-AREMUKBSSA-N C(C)OC(C[C@@H](CC1=CC=C(C=C1)C1=CC(=CC=C1)Cl)NCCOCC(=O)C=1NC2=CC=CC=C2C1)=O Chemical compound C(C)OC(C[C@@H](CC1=CC=C(C=C1)C1=CC(=CC=C1)Cl)NCCOCC(=O)C=1NC2=CC=CC=C2C1)=O KGPUBJJSROSPDF-AREMUKBSSA-N 0.000 description 1
- FANBVHCDTCIQQG-LJQANCHMSA-N C(C)OC(C[C@@H](CC1=CC=C(C=C1)C1=CC=CC=C1)NC=CC1=NN=NN1)=O Chemical compound C(C)OC(C[C@@H](CC1=CC=C(C=C1)C1=CC=CC=C1)NC=CC1=NN=NN1)=O FANBVHCDTCIQQG-LJQANCHMSA-N 0.000 description 1
- KMRAFKRHSPCZRU-WJOKGBTCSA-N C(C1=CC=CC=C1)OC(C[C@@H](CC1=CC=C(C=C1)C1=CC(=CC=C1)Cl)C(CCCCCCC(=O)OCCCC)=O)=O Chemical compound C(C1=CC=CC=C1)OC(C[C@@H](CC1=CC=C(C=C1)C1=CC(=CC=C1)Cl)C(CCCCCCC(=O)OCCCC)=O)=O KMRAFKRHSPCZRU-WJOKGBTCSA-N 0.000 description 1
- KKOJXOZXPLETGS-UHFFFAOYSA-N C(CCC)OC(CC(=O)OC(C)(C)C)C Chemical compound C(CCC)OC(CC(=O)OC(C)(C)C)C KKOJXOZXPLETGS-UHFFFAOYSA-N 0.000 description 1
- RXVYQSJHBAMOGL-XMMPIXPASA-N C(CCC)OC(CCCCCCC(=O)[C@@H](CC(=O)O)CC1=CC=C(C=C1)C1=CC(=CC=C1)Cl)=O Chemical compound C(CCC)OC(CCCCCCC(=O)[C@@H](CC(=O)O)CC1=CC=C(C=C1)C1=CC(=CC=C1)Cl)=O RXVYQSJHBAMOGL-XMMPIXPASA-N 0.000 description 1
- 239000002083 C09CA01 - Losartan Substances 0.000 description 1
- 239000002080 C09CA02 - Eprosartan Substances 0.000 description 1
- 239000002053 C09CA06 - Candesartan Substances 0.000 description 1
- 239000005537 C09CA07 - Telmisartan Substances 0.000 description 1
- OBMZMSLWNNWEJA-XNCRXQDQSA-N C1=CC=2C(C[C@@H]3NC(=O)[C@@H](NC(=O)[C@H](NC(=O)N(CC#CCN(CCCC[C@H](NC(=O)[C@@H](CC4=CC=CC=C4)NC3=O)C(=O)N)CC=C)NC(=O)[C@@H](N)C)CC3=CNC4=C3C=CC=C4)C)=CNC=2C=C1 Chemical compound C1=CC=2C(C[C@@H]3NC(=O)[C@@H](NC(=O)[C@H](NC(=O)N(CC#CCN(CCCC[C@H](NC(=O)[C@@H](CC4=CC=CC=C4)NC3=O)C(=O)N)CC=C)NC(=O)[C@@H](N)C)CC3=CNC4=C3C=CC=C4)C)=CNC=2C=C1 OBMZMSLWNNWEJA-XNCRXQDQSA-N 0.000 description 1
- HKPFAEWXODOVBJ-UHFFFAOYSA-N C1CCC(C1)(CC(=O)OCC2=CC=CC=C2)NC(CC3=CC=C(C=C3)C4=CC=CC=C4)CC(=O)O Chemical compound C1CCC(C1)(CC(=O)OCC2=CC=CC=C2)NC(CC3=CC=C(C=C3)C4=CC=CC=C4)CC(=O)O HKPFAEWXODOVBJ-UHFFFAOYSA-N 0.000 description 1
- TZBVFIIWBYFJID-UHFFFAOYSA-N CC1C(OC(C(O1)([NH-])C)(C)C)(C)C.[Na+] Chemical compound CC1C(OC(C(O1)([NH-])C)(C)C)(C)C.[Na+] TZBVFIIWBYFJID-UHFFFAOYSA-N 0.000 description 1
- DRSHXJFUUPIBHX-UHFFFAOYSA-N COc1ccc(cc1)N1N=CC2C=NC(Nc3cc(OC)c(OC)c(OCCCN4CCN(C)CC4)c3)=NC12 Chemical compound COc1ccc(cc1)N1N=CC2C=NC(Nc3cc(OC)c(OC)c(OCCCN4CCN(C)CC4)c3)=NC12 DRSHXJFUUPIBHX-UHFFFAOYSA-N 0.000 description 1
- 101100335894 Caenorhabditis elegans gly-8 gene Proteins 0.000 description 1
- 102000004414 Calcitonin Gene-Related Peptide Human genes 0.000 description 1
- 108090000932 Calcitonin Gene-Related Peptide Proteins 0.000 description 1
- 241000283707 Capra Species 0.000 description 1
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 1
- 108010078791 Carrier Proteins Proteins 0.000 description 1
- 241000282693 Cercopithecidae Species 0.000 description 1
- RKWGIWYCVPQPMF-UHFFFAOYSA-N Chloropropamide Chemical compound CCCNC(=O)NS(=O)(=O)C1=CC=C(Cl)C=C1 RKWGIWYCVPQPMF-UHFFFAOYSA-N 0.000 description 1
- 235000001258 Cinchona calisaya Nutrition 0.000 description 1
- WBYWAXJHAXSJNI-SREVYHEPSA-N Cinnamic acid Chemical compound OC(=O)\C=C/C1=CC=CC=C1 WBYWAXJHAXSJNI-SREVYHEPSA-N 0.000 description 1
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 1
- 102000008186 Collagen Human genes 0.000 description 1
- 108010035532 Collagen Proteins 0.000 description 1
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 description 1
- 229920002261 Corn starch Polymers 0.000 description 1
- 229920000858 Cyclodextrin Polymers 0.000 description 1
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 1
- 108010015742 Cytochrome P-450 Enzyme System Proteins 0.000 description 1
- 102000002004 Cytochrome P-450 Enzyme System Human genes 0.000 description 1
- 108010064945 D-4F peptide Proteins 0.000 description 1
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 1
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 1
- DSLZVSRJTYRBFB-LLEIAEIESA-N D-glucaric acid Chemical compound OC(=O)[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C(O)=O DSLZVSRJTYRBFB-LLEIAEIESA-N 0.000 description 1
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 description 1
- RGHNJXZEOKUKBD-SQOUGZDYSA-M D-gluconate Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C([O-])=O RGHNJXZEOKUKBD-SQOUGZDYSA-M 0.000 description 1
- VPGRYOFKCNULNK-ACXQXYJUSA-N Deoxycorticosterone acetate Chemical compound C1CC2=CC(=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H](C(=O)COC(=O)C)[C@@]1(C)CC2 VPGRYOFKCNULNK-ACXQXYJUSA-N 0.000 description 1
- VYZAHLCBVHPDDF-UHFFFAOYSA-N Dinitrochlorobenzene Chemical compound [O-][N+](=O)C1=CC=C(Cl)C([N+]([O-])=O)=C1 VYZAHLCBVHPDDF-UHFFFAOYSA-N 0.000 description 1
- 101100136092 Drosophila melanogaster peng gene Proteins 0.000 description 1
- 102000010180 Endothelin receptor Human genes 0.000 description 1
- 108050001739 Endothelin receptor Proteins 0.000 description 1
- 102400000686 Endothelin-1 Human genes 0.000 description 1
- 101800004490 Endothelin-1 Proteins 0.000 description 1
- 108010092674 Enkephalins Proteins 0.000 description 1
- 241000283086 Equidae Species 0.000 description 1
- 108090000371 Esterases Proteins 0.000 description 1
- 241000282326 Felis catus Species 0.000 description 1
- BDAGIHXWWSANSR-UHFFFAOYSA-M Formate Chemical compound [O-]C=O BDAGIHXWWSANSR-UHFFFAOYSA-M 0.000 description 1
- 108010017464 Fructose-Bisphosphatase Proteins 0.000 description 1
- 102000027487 Fructose-Bisphosphatase Human genes 0.000 description 1
- 102400000322 Glucagon-like peptide 1 Human genes 0.000 description 1
- 108010086800 Glucose-6-Phosphatase Proteins 0.000 description 1
- 102000003638 Glucose-6-Phosphatase Human genes 0.000 description 1
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 1
- 229920002527 Glycogen Polymers 0.000 description 1
- 229920000084 Gum arabic Polymers 0.000 description 1
- 241000238631 Hexapoda Species 0.000 description 1
- 241000282412 Homo Species 0.000 description 1
- 101000886868 Homo sapiens Gastric inhibitory polypeptide Proteins 0.000 description 1
- 101000684208 Homo sapiens Prolyl endopeptidase FAP Proteins 0.000 description 1
- LELOWRISYMNNSU-UHFFFAOYSA-N Hydrocyanic acid Natural products N#C LELOWRISYMNNSU-UHFFFAOYSA-N 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 1
- 206010060378 Hyperinsulinaemia Diseases 0.000 description 1
- 208000019025 Hypokalemia Diseases 0.000 description 1
- RAXXELZNTBOGNW-UHFFFAOYSA-O Imidazolium Chemical compound C1=C[NH+]=CN1 RAXXELZNTBOGNW-UHFFFAOYSA-O 0.000 description 1
- 102000003746 Insulin Receptor Human genes 0.000 description 1
- 108010001127 Insulin Receptor Proteins 0.000 description 1
- VQTUBCCKSQIDNK-UHFFFAOYSA-N Isobutene Chemical group CC(C)=C VQTUBCCKSQIDNK-UHFFFAOYSA-N 0.000 description 1
- JVTAAEKCZFNVCJ-UHFFFAOYSA-M Lactate Chemical compound CC(O)C([O-])=O JVTAAEKCZFNVCJ-UHFFFAOYSA-M 0.000 description 1
- URLZCHNOLZSCCA-VABKMULXSA-N Leu-enkephalin Chemical compound C([C@@H](C(=O)N[C@@H](CC(C)C)C(O)=O)NC(=O)CNC(=O)CNC(=O)[C@@H](N)CC=1C=CC(O)=CC=1)C1=CC=CC=C1 URLZCHNOLZSCCA-VABKMULXSA-N 0.000 description 1
- 102400000243 Leu-enkephalin Human genes 0.000 description 1
- 108010022337 Leucine Enkephalin Proteins 0.000 description 1
- 229940127470 Lipase Inhibitors Drugs 0.000 description 1
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-L Malonate Chemical compound [O-]C(=O)CC([O-])=O OFOBLEOULBTSOW-UHFFFAOYSA-L 0.000 description 1
- 238000006683 Mannich reaction Methods 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- 102400000988 Met-enkephalin Human genes 0.000 description 1
- 102000005741 Metalloproteases Human genes 0.000 description 1
- 108010006035 Metalloproteases Proteins 0.000 description 1
- 108010042237 Methionine Enkephalin Proteins 0.000 description 1
- CESYKOGBSMNBPD-UHFFFAOYSA-N Methyclothiazide Chemical compound ClC1=C(S(N)(=O)=O)C=C2S(=O)(=O)N(C)C(CCl)NC2=C1 CESYKOGBSMNBPD-UHFFFAOYSA-N 0.000 description 1
- IBAQFPQHRJAVAV-ULAWRXDQSA-N Miglitol Chemical compound OCCN1C[C@H](O)[C@@H](O)[C@H](O)[C@H]1CO IBAQFPQHRJAVAV-ULAWRXDQSA-N 0.000 description 1
- PCZOHLXUXFIOCF-UHFFFAOYSA-N Monacolin X Natural products C12C(OC(=O)C(C)CC)CC(C)C=C2C=CC(C)C1CCC1CC(O)CC(=O)O1 PCZOHLXUXFIOCF-UHFFFAOYSA-N 0.000 description 1
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 1
- MKYBYDHXWVHEJW-UHFFFAOYSA-N N-[1-oxo-1-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)propan-2-yl]-2-[[3-(trifluoromethoxy)phenyl]methylamino]pyrimidine-5-carboxamide Chemical compound O=C(C(C)NC(=O)C=1C=NC(=NC=1)NCC1=CC(=CC=C1)OC(F)(F)F)N1CC2=C(CC1)NN=N2 MKYBYDHXWVHEJW-UHFFFAOYSA-N 0.000 description 1
- NEAPKZHDYMQZCB-UHFFFAOYSA-N N-[2-[4-[2-(2,3-dihydro-1H-inden-2-ylamino)pyrimidin-5-yl]piperazin-1-yl]ethyl]-2-oxo-3H-1,3-benzoxazole-6-carboxamide Chemical compound C1CN(CCN1CCNC(=O)C2=CC3=C(C=C2)NC(=O)O3)C4=CN=C(N=C4)NC5CC6=CC=CC=C6C5 NEAPKZHDYMQZCB-UHFFFAOYSA-N 0.000 description 1
- NIPNSKYNPDTRPC-UHFFFAOYSA-N N-[2-oxo-2-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)ethyl]-2-[[3-(trifluoromethoxy)phenyl]methylamino]pyrimidine-5-carboxamide Chemical compound O=C(CNC(=O)C=1C=NC(=NC=1)NCC1=CC(=CC=C1)OC(F)(F)F)N1CC2=C(CC1)NN=N2 NIPNSKYNPDTRPC-UHFFFAOYSA-N 0.000 description 1
- VCUFZILGIRCDQQ-KRWDZBQOSA-N N-[[(5S)-2-oxo-3-(2-oxo-3H-1,3-benzoxazol-6-yl)-1,3-oxazolidin-5-yl]methyl]-2-[[3-(trifluoromethoxy)phenyl]methylamino]pyrimidine-5-carboxamide Chemical compound O=C1O[C@H](CN1C1=CC2=C(NC(O2)=O)C=C1)CNC(=O)C=1C=NC(=NC=1)NCC1=CC(=CC=C1)OC(F)(F)F VCUFZILGIRCDQQ-KRWDZBQOSA-N 0.000 description 1
- CHJJGSNFBQVOTG-UHFFFAOYSA-N N-methyl-guanidine Chemical group CNC(N)=N CHJJGSNFBQVOTG-UHFFFAOYSA-N 0.000 description 1
- AHVYPIQETPWLSZ-UHFFFAOYSA-N N-methyl-pyrrolidine Natural products CN1CC=CC1 AHVYPIQETPWLSZ-UHFFFAOYSA-N 0.000 description 1
- FIWILGQIZHDAQG-UHFFFAOYSA-N NC1=C(C(=O)NCC2=CC=C(C=C2)OCC(F)(F)F)C=C(C(=N1)N)N1N=C(N=C1)C1(CC1)C(F)(F)F Chemical compound NC1=C(C(=O)NCC2=CC=C(C=C2)OCC(F)(F)F)C=C(C(=N1)N)N1N=C(N=C1)C1(CC1)C(F)(F)F FIWILGQIZHDAQG-UHFFFAOYSA-N 0.000 description 1
- 229910002651 NO3 Inorganic materials 0.000 description 1
- 239000007832 Na2SO4 Substances 0.000 description 1
- HEAUFJZALFKPBA-YRVBCFNBSA-N Neurokinin A Chemical compound C([C@@H](C(=O)N[C@H](C(=O)NCC(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCSC)C(N)=O)C(C)C)NC(=O)[C@H](CO)NC(=O)[C@H](CC(O)=O)NC(=O)[C@@H](NC(=O)[C@H](CCCCN)NC(=O)[C@@H](N)CC=1NC=NC=1)C(C)O)C1=CC=CC=C1 HEAUFJZALFKPBA-YRVBCFNBSA-N 0.000 description 1
- 102400000097 Neurokinin A Human genes 0.000 description 1
- 101800000399 Neurokinin A Proteins 0.000 description 1
- 102100023206 Neuromodulin Human genes 0.000 description 1
- 101710144282 Neuromodulin Proteins 0.000 description 1
- ZBBHBTPTTSWHBA-UHFFFAOYSA-N Nicardipine Chemical compound COC(=O)C1=C(C)NC(C)=C(C(=O)OCCN(C)CC=2C=CC=CC=2)C1C1=CC=CC([N+]([O-])=O)=C1 ZBBHBTPTTSWHBA-UHFFFAOYSA-N 0.000 description 1
- DFPAKSUCGFBDDF-UHFFFAOYSA-N Nicotinamide Chemical compound NC(=O)C1=CC=CN=C1 DFPAKSUCGFBDDF-UHFFFAOYSA-N 0.000 description 1
- NHNBFGGVMKEFGY-UHFFFAOYSA-N Nitrate Chemical compound [O-][N+]([O-])=O NHNBFGGVMKEFGY-UHFFFAOYSA-N 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- 102000015636 Oligopeptides Human genes 0.000 description 1
- 108010038807 Oligopeptides Proteins 0.000 description 1
- 235000019502 Orange oil Nutrition 0.000 description 1
- 241000283973 Oryctolagus cuniculus Species 0.000 description 1
- ZCQWOFVYLHDMMC-UHFFFAOYSA-N Oxazole Chemical group C1=COC=N1 ZCQWOFVYLHDMMC-UHFFFAOYSA-N 0.000 description 1
- 102000023984 PPAR alpha Human genes 0.000 description 1
- 102000000536 PPAR gamma Human genes 0.000 description 1
- 108010016731 PPAR gamma Proteins 0.000 description 1
- 235000019483 Peanut oil Nutrition 0.000 description 1
- 241001494479 Pecora Species 0.000 description 1
- 101710176384 Peptide 1 Proteins 0.000 description 1
- 229940080774 Peroxisome proliferator-activated receptor gamma agonist Drugs 0.000 description 1
- PCNDJXKNXGMECE-UHFFFAOYSA-N Phenazine Natural products C1=CC=CC2=NC3=CC=CC=C3N=C21 PCNDJXKNXGMECE-UHFFFAOYSA-N 0.000 description 1
- YGYAWVDWMABLBF-UHFFFAOYSA-N Phosgene Chemical compound ClC(Cl)=O YGYAWVDWMABLBF-UHFFFAOYSA-N 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-L Phosphate ion(2-) Chemical compound OP([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-L 0.000 description 1
- 108090000608 Phosphoric Monoester Hydrolases Proteins 0.000 description 1
- 102000004160 Phosphoric Monoester Hydrolases Human genes 0.000 description 1
- 241000801593 Pida Species 0.000 description 1
- 108010022233 Plasminogen Activator Inhibitor 1 Proteins 0.000 description 1
- 102100039418 Plasminogen activator inhibitor 1 Human genes 0.000 description 1
- 206010036049 Polycystic ovaries Diseases 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- TUZYXOIXSAXUGO-UHFFFAOYSA-N Pravastatin Natural products C1=CC(C)C(CCC(O)CC(O)CC(O)=O)C2C(OC(=O)C(C)CC)CC(O)C=C21 TUZYXOIXSAXUGO-UHFFFAOYSA-N 0.000 description 1
- 208000001280 Prediabetic State Diseases 0.000 description 1
- 208000006399 Premature Obstetric Labor Diseases 0.000 description 1
- 206010036595 Premature delivery Diseases 0.000 description 1
- 206010036600 Premature labour Diseases 0.000 description 1
- 241000288906 Primates Species 0.000 description 1
- ONIBWKKTOPOVIA-UHFFFAOYSA-N Proline Chemical compound OC(=O)C1CCCN1 ONIBWKKTOPOVIA-UHFFFAOYSA-N 0.000 description 1
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 1
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 description 1
- 108090000783 Renin Proteins 0.000 description 1
- RYMZZMVNJRMUDD-UHFFFAOYSA-N SJ000286063 Natural products C12C(OC(=O)C(C)(C)CC)CC(C)C=C2C=CC(C)C1CCC1CC(O)CC(=O)O1 RYMZZMVNJRMUDD-UHFFFAOYSA-N 0.000 description 1
- AJLFOPYRIVGYMJ-UHFFFAOYSA-N SJ000287055 Natural products C12C(OC(=O)C(C)CC)CCC=C2C=CC(C)C1CCC1CC(O)CC(=O)O1 AJLFOPYRIVGYMJ-UHFFFAOYSA-N 0.000 description 1
- 108091006629 SLC13A2 Proteins 0.000 description 1
- BVIPPHXIYPKKHO-UHFFFAOYSA-N SN1OC=CC=CC1 Chemical compound SN1OC=CC=CC1 BVIPPHXIYPKKHO-UHFFFAOYSA-N 0.000 description 1
- 239000005478 Saprisartan Substances 0.000 description 1
- DUEWVPTZCSAMNB-UHFFFAOYSA-N Saprisartan Chemical compound NC(=O)C=1N(CC=2C=C3C(Br)=C(OC3=CC=2)C=2C(=CC=CC=2)NS(=O)(=O)C(F)(F)F)C(CC)=NC=1C1CC1 DUEWVPTZCSAMNB-UHFFFAOYSA-N 0.000 description 1
- 102400000096 Substance P Human genes 0.000 description 1
- 101800003906 Substance P Proteins 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 1
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 1
- 229930006000 Sucrose Natural products 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- 238000006069 Suzuki reaction reaction Methods 0.000 description 1
- FZWLAAWBMGSTSO-UHFFFAOYSA-N Thiazole Chemical group C1=CSC=N1 FZWLAAWBMGSTSO-UHFFFAOYSA-N 0.000 description 1
- 229920001615 Tragacanth Polymers 0.000 description 1
- 102000004357 Transferases Human genes 0.000 description 1
- 108090000992 Transferases Proteins 0.000 description 1
- 102000004887 Transforming Growth Factor beta Human genes 0.000 description 1
- 108090001012 Transforming Growth Factor beta Proteins 0.000 description 1
- 108010003205 Vasoactive Intestinal Peptide Proteins 0.000 description 1
- 102400000015 Vasoactive intestinal peptide Human genes 0.000 description 1
- FHKPLLOSJHHKNU-INIZCTEOSA-N [(3S)-3-[8-(1-ethyl-5-methylpyrazol-4-yl)-9-methylpurin-6-yl]oxypyrrolidin-1-yl]-(oxan-4-yl)methanone Chemical compound C(C)N1N=CC(=C1C)C=1N(C2=NC=NC(=C2N=1)O[C@@H]1CN(CC1)C(=O)C1CCOCC1)C FHKPLLOSJHHKNU-INIZCTEOSA-N 0.000 description 1
- 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 1
- PRCMWNWCNFMXEV-UHFFFAOYSA-N [N].C(CCC)(=O)O Chemical compound [N].C(CCC)(=O)O PRCMWNWCNFMXEV-UHFFFAOYSA-N 0.000 description 1
- ZBIKORITPGTTGI-UHFFFAOYSA-N [acetyloxy(phenyl)-$l^{3}-iodanyl] acetate Chemical compound CC(=O)OI(OC(C)=O)C1=CC=CC=C1 ZBIKORITPGTTGI-UHFFFAOYSA-N 0.000 description 1
- 230000005856 abnormality Effects 0.000 description 1
- 239000002250 absorbent Substances 0.000 description 1
- 230000002745 absorbent Effects 0.000 description 1
- 239000003070 absorption delaying agent Substances 0.000 description 1
- 239000000205 acacia gum Substances 0.000 description 1
- 235000010489 acacia gum Nutrition 0.000 description 1
- 150000001242 acetic acid derivatives Chemical class 0.000 description 1
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 description 1
- 229960001466 acetohexamide Drugs 0.000 description 1
- VGZSUPCWNCWDAN-UHFFFAOYSA-N acetohexamide Chemical compound C1=CC(C(=O)C)=CC=C1S(=O)(=O)NC(=O)NC1CCCCC1 VGZSUPCWNCWDAN-UHFFFAOYSA-N 0.000 description 1
- CSCPPACGZOOCGX-WFGJKAKNSA-N acetone d6 Chemical compound [2H]C([2H])([2H])C(=O)C([2H])([2H])[2H] CSCPPACGZOOCGX-WFGJKAKNSA-N 0.000 description 1
- WEVYAHXRMPXWCK-FIBGUPNXSA-N acetonitrile-d3 Chemical compound [2H]C([2H])([2H])C#N WEVYAHXRMPXWCK-FIBGUPNXSA-N 0.000 description 1
- 206010000496 acne Diseases 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 125000005073 adamantyl group Chemical group C12(CC3CC(CC(C1)C3)C2)* 0.000 description 1
- 210000004404 adrenal cortex Anatomy 0.000 description 1
- 239000000670 adrenergic alpha-2 receptor antagonist Substances 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 239000008272 agar Substances 0.000 description 1
- 235000010419 agar Nutrition 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 239000002170 aldosterone antagonist Substances 0.000 description 1
- 229940083712 aldosterone antagonist Drugs 0.000 description 1
- 125000001931 aliphatic group Chemical group 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 150000001341 alkaline earth metal compounds Chemical class 0.000 description 1
- 238000005904 alkaline hydrolysis reaction Methods 0.000 description 1
- 125000004457 alkyl amino carbonyl group Chemical group 0.000 description 1
- OBETXYAYXDNJHR-UHFFFAOYSA-N alpha-ethylcaproic acid Natural products CCCCC(CC)C(O)=O OBETXYAYXDNJHR-UHFFFAOYSA-N 0.000 description 1
- 229910052782 aluminium Inorganic materials 0.000 description 1
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 1
- 235000012211 aluminium silicate Nutrition 0.000 description 1
- SNAAJJQQZSMGQD-UHFFFAOYSA-N aluminum magnesium Chemical compound [Mg].[Al] SNAAJJQQZSMGQD-UHFFFAOYSA-N 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 125000000539 amino acid group Chemical group 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 239000000908 ammonium hydroxide Substances 0.000 description 1
- 150000003863 ammonium salts Chemical class 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- ORWYRWWVDCYOMK-HBZPZAIKSA-N angiotensin I Chemical compound C([C@@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC=1NC=NC=1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CC=1NC=NC=1)C(=O)N[C@@H](CC(C)C)C(O)=O)NC(=O)[C@@H](NC(=O)[C@H](CCCN=C(N)N)NC(=O)[C@@H](N)CC(O)=O)C(C)C)C1=CC=C(O)C=C1 ORWYRWWVDCYOMK-HBZPZAIKSA-N 0.000 description 1
- 239000000400 angiotensin II type 1 receptor blocker Substances 0.000 description 1
- 229950006323 angiotensin ii Drugs 0.000 description 1
- 238000005349 anion exchange Methods 0.000 description 1
- 230000003288 anthiarrhythmic effect Effects 0.000 description 1
- 230000003276 anti-hypertensive effect Effects 0.000 description 1
- 229940088710 antibiotic agent Drugs 0.000 description 1
- 229940053198 antiepileptics succinimide derivative Drugs 0.000 description 1
- 229940030600 antihypertensive agent Drugs 0.000 description 1
- 239000002220 antihypertensive agent Substances 0.000 description 1
- 239000002830 appetite depressant Substances 0.000 description 1
- 229910052786 argon Inorganic materials 0.000 description 1
- 239000012300 argon atmosphere Substances 0.000 description 1
- 229940046844 aromatase inhibitors Drugs 0.000 description 1
- 150000004945 aromatic hydrocarbons Chemical class 0.000 description 1
- 206010003119 arrhythmia Diseases 0.000 description 1
- 230000006793 arrhythmia Effects 0.000 description 1
- 235000010323 ascorbic acid Nutrition 0.000 description 1
- 229960005070 ascorbic acid Drugs 0.000 description 1
- 239000011668 ascorbic acid Substances 0.000 description 1
- CKLJMWTZIZZHCS-REOHCLBHSA-L aspartate group Chemical class N[C@@H](CC(=O)[O-])C(=O)[O-] CKLJMWTZIZZHCS-REOHCLBHSA-L 0.000 description 1
- 239000012298 atmosphere Substances 0.000 description 1
- 229960005370 atorvastatin Drugs 0.000 description 1
- 230000001746 atrial effect Effects 0.000 description 1
- 125000003725 azepanyl group Chemical group 0.000 description 1
- 125000003943 azolyl group Chemical group 0.000 description 1
- 229910052788 barium Inorganic materials 0.000 description 1
- 230000004888 barrier function Effects 0.000 description 1
- 150000007514 bases Chemical class 0.000 description 1
- 210000000227 basophil cell of anterior lobe of hypophysis Anatomy 0.000 description 1
- 230000003542 behavioural effect Effects 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- SRSXLGNVWSONIS-UHFFFAOYSA-M benzenesulfonate Chemical compound [O-]S(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-M 0.000 description 1
- 150000008641 benzimidazolones Chemical group 0.000 description 1
- 125000003785 benzimidazolyl group Chemical group N1=C(NC2=C1C=CC=C2)* 0.000 description 1
- DMSMPAJRVJJAGA-UHFFFAOYSA-N benzo[d]isothiazol-3-one Chemical compound C1=CC=C2C(=O)NSC2=C1 DMSMPAJRVJJAGA-UHFFFAOYSA-N 0.000 description 1
- 150000001558 benzoic acid derivatives Chemical class 0.000 description 1
- SIKJAQJRHWYJAI-UHFFFAOYSA-N benzopyrrole Natural products C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 description 1
- 125000003354 benzotriazolyl group Chemical group N1N=NC2=C1C=CC=C2* 0.000 description 1
- LERAAPXPJPJVPJ-HNNXBMFYSA-N benzyl (2s)-1-[2-[(2-methylpropan-2-yl)oxy]-2-oxoethyl]pyrrolidine-2-carboxylate Chemical compound CC(C)(C)OC(=O)CN1CCC[C@H]1C(=O)OCC1=CC=CC=C1 LERAAPXPJPJVPJ-HNNXBMFYSA-N 0.000 description 1
- OIHQJDZLPNHCRJ-JOCHJYFZSA-N benzyl (3r)-3-amino-4-[4-(3-chlorophenyl)phenyl]butanoate Chemical compound C([C@H](N)CC=1C=CC(=CC=1)C=1C=C(Cl)C=CC=1)C(=O)OCC1=CC=CC=C1 OIHQJDZLPNHCRJ-JOCHJYFZSA-N 0.000 description 1
- LDECUSDQMXVUMP-UHFFFAOYSA-N benzyl 3-[6-[[2-(butylamino)-1-[3-methoxycarbonyl-4-(2-methoxy-2-oxoethoxy)phenyl]-2-oxoethyl]-hexylamino]-6-oxohexyl]-4-methyl-2-oxo-6-(4-phenylphenyl)-1,6-dihydropyrimidine-5-carboxylate Chemical compound O=C1NC(C=2C=CC(=CC=2)C=2C=CC=CC=2)C(C(=O)OCC=2C=CC=CC=2)=C(C)N1CCCCCC(=O)N(CCCCCC)C(C(=O)NCCCC)C1=CC=C(OCC(=O)OC)C(C(=O)OC)=C1 LDECUSDQMXVUMP-UHFFFAOYSA-N 0.000 description 1
- 235000019445 benzyl alcohol Nutrition 0.000 description 1
- AGEZXYOZHKGVCM-UHFFFAOYSA-N benzyl bromide Chemical compound BrCC1=CC=CC=C1 AGEZXYOZHKGVCM-UHFFFAOYSA-N 0.000 description 1
- 125000000051 benzyloxy group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])O* 0.000 description 1
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 description 1
- 150000004283 biguanides Chemical class 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 239000012620 biological material Substances 0.000 description 1
- 230000033228 biological regulation Effects 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- DNDCVAGJPBKION-DOPDSADYSA-N bombesin Chemical compound C([C@@H](C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCSC)C(N)=O)NC(=O)CNC(=O)[C@@H](NC(=O)[C@H](C)NC(=O)[C@H](CC=1NC2=CC=CC=C2C=1)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CC(N)=O)NC(=O)CNC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H]1NC(=O)CC1)C(C)C)C1=CN=CN1 DNDCVAGJPBKION-DOPDSADYSA-N 0.000 description 1
- 125000001246 bromo group Chemical group Br* 0.000 description 1
- KDPAWGWELVVRCH-UHFFFAOYSA-M bromoacetate Chemical compound [O-]C(=O)CBr KDPAWGWELVVRCH-UHFFFAOYSA-M 0.000 description 1
- 230000005587 bubbling Effects 0.000 description 1
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 description 1
- 125000004369 butenyl group Chemical group C(=CCC)* 0.000 description 1
- 125000004106 butoxy group Chemical group [*]OC([H])([H])C([H])([H])C(C([H])([H])[H])([H])[H] 0.000 description 1
- NMEGSGKCIWQRDB-UHFFFAOYSA-N butyl 2-bromoacetate Chemical compound CCCCOC(=O)CBr NMEGSGKCIWQRDB-UHFFFAOYSA-N 0.000 description 1
- XUPYJHCZDLZNFP-UHFFFAOYSA-N butyl ester butanoic acid Natural products CCCCOC(=O)CCC XUPYJHCZDLZNFP-UHFFFAOYSA-N 0.000 description 1
- 229940043430 calcium compound Drugs 0.000 description 1
- 150000001674 calcium compounds Chemical class 0.000 description 1
- FATUQANACHZLRT-KMRXSBRUSA-L calcium glucoheptonate Chemical compound [Ca+2].OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C(O)C([O-])=O.OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C(O)C([O-])=O FATUQANACHZLRT-KMRXSBRUSA-L 0.000 description 1
- 239000004330 calcium propionate Substances 0.000 description 1
- 159000000007 calcium salts Chemical class 0.000 description 1
- MIOPJNTWMNEORI-UHFFFAOYSA-N camphorsulfonic acid Chemical compound C1CC2(CS(O)(=O)=O)C(=O)CC1C2(C)C MIOPJNTWMNEORI-UHFFFAOYSA-N 0.000 description 1
- SGZAIDDFHDDFJU-UHFFFAOYSA-N candesartan Chemical compound CCOC1=NC2=CC=CC(C(O)=O)=C2N1CC(C=C1)=CC=C1C1=CC=CC=C1C1=NN=N[N]1 SGZAIDDFHDDFJU-UHFFFAOYSA-N 0.000 description 1
- 229960000932 candesartan Drugs 0.000 description 1
- 239000004202 carbamide Substances 0.000 description 1
- 235000011089 carbon dioxide Nutrition 0.000 description 1
- 150000004649 carbonic acid derivatives Chemical class 0.000 description 1
- KXDHJXZQYSOELW-UHFFFAOYSA-N carbonic acid monoamide Natural products NC(O)=O KXDHJXZQYSOELW-UHFFFAOYSA-N 0.000 description 1
- 239000001768 carboxy methyl cellulose Substances 0.000 description 1
- 150000001244 carboxylic acid anhydrides Chemical class 0.000 description 1
- 125000002843 carboxylic acid group Chemical group 0.000 description 1
- 150000001735 carboxylic acids Chemical class 0.000 description 1
- 229960003362 carbutamide Drugs 0.000 description 1
- VDTNNGKXZGSZIP-UHFFFAOYSA-N carbutamide Chemical compound CCCCNC(=O)NS(=O)(=O)C1=CC=C(N)C=C1 VDTNNGKXZGSZIP-UHFFFAOYSA-N 0.000 description 1
- 230000000747 cardiac effect Effects 0.000 description 1
- 230000007211 cardiovascular event Effects 0.000 description 1
- 150000001768 cations Chemical class 0.000 description 1
- 230000001413 cellular effect Effects 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 229910000420 cerium oxide Inorganic materials 0.000 description 1
- 229960005110 cerivastatin Drugs 0.000 description 1
- SEERZIQQUAZTOL-ANMDKAQQSA-N cerivastatin Chemical compound COCC1=C(C(C)C)N=C(C(C)C)C(\C=C\[C@@H](O)C[C@@H](O)CC(O)=O)=C1C1=CC=C(F)C=C1 SEERZIQQUAZTOL-ANMDKAQQSA-N 0.000 description 1
- GPUADMRJQVPIAS-QCVDVZFFSA-M cerivastatin sodium Chemical compound [Na+].COCC1=C(C(C)C)N=C(C(C)C)C(\C=C\[C@@H](O)C[C@@H](O)CC([O-])=O)=C1C1=CC=C(F)C=C1 GPUADMRJQVPIAS-QCVDVZFFSA-M 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 238000004296 chiral HPLC Methods 0.000 description 1
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Substances ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 description 1
- 125000004218 chloromethyl group Chemical group [H]C([H])(Cl)* 0.000 description 1
- 125000000068 chlorophenyl group Chemical group 0.000 description 1
- 235000012000 cholesterol Nutrition 0.000 description 1
- 150000001840 cholesterol esters Chemical class 0.000 description 1
- LOUPRKONTZGTKE-UHFFFAOYSA-N cinchonine Natural products C1C(C(C2)C=C)CCN2C1C(O)C1=CC=NC2=CC=C(OC)C=C21 LOUPRKONTZGTKE-UHFFFAOYSA-N 0.000 description 1
- 235000013985 cinnamic acid Nutrition 0.000 description 1
- 229930016911 cinnamic acid Natural products 0.000 description 1
- 230000004087 circulation Effects 0.000 description 1
- 238000003181 co-melting Methods 0.000 description 1
- 239000011248 coating agent Substances 0.000 description 1
- 239000005516 coenzyme A Substances 0.000 description 1
- 229940093530 coenzyme a Drugs 0.000 description 1
- 229920001436 collagen Polymers 0.000 description 1
- 239000013066 combination product Substances 0.000 description 1
- 229940127555 combination product Drugs 0.000 description 1
- 230000001276 controlling effect Effects 0.000 description 1
- 239000012050 conventional carrier Substances 0.000 description 1
- 229910052802 copper Inorganic materials 0.000 description 1
- 239000010949 copper Substances 0.000 description 1
- 239000008120 corn starch Substances 0.000 description 1
- 239000002537 cosmetic Substances 0.000 description 1
- 239000006071 cream Substances 0.000 description 1
- YJMNOKOLADGBKA-UHFFFAOYSA-N cyanonaphthalene Natural products C1=CC=C2C(C#N)=CC=CC2=C1 YJMNOKOLADGBKA-UHFFFAOYSA-N 0.000 description 1
- 150000004292 cyclic ethers Chemical class 0.000 description 1
- 125000001316 cycloalkyl alkyl group Chemical group 0.000 description 1
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 229940097362 cyclodextrins Drugs 0.000 description 1
- 125000000596 cyclohexenyl group Chemical group C1(=CCCCC1)* 0.000 description 1
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- NXQGGXCHGDYOHB-UHFFFAOYSA-L cyclopenta-1,4-dien-1-yl(diphenyl)phosphane;dichloropalladium;iron(2+) Chemical compound [Fe+2].Cl[Pd]Cl.[CH-]1C=CC(P(C=2C=CC=CC=2)C=2C=CC=CC=2)=C1.[CH-]1C=CC(P(C=2C=CC=CC=2)C=2C=CC=CC=2)=C1 NXQGGXCHGDYOHB-UHFFFAOYSA-L 0.000 description 1
- 125000002433 cyclopentenyl group Chemical group C1(=CCCC1)* 0.000 description 1
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 1
- 230000009089 cytolysis Effects 0.000 description 1
- 230000006378 damage Effects 0.000 description 1
- ZESRJSPZRDMNHY-UHFFFAOYSA-N de-oxy corticosterone Natural products O=C1CCC2(C)C3CCC(C)(C(CC4)C(=O)CO)C4C3CCC2=C1 ZESRJSPZRDMNHY-UHFFFAOYSA-N 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 230000007423 decrease Effects 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- 239000008121 dextrose Substances 0.000 description 1
- 230000035487 diastolic blood pressure Effects 0.000 description 1
- QPMLSUSACCOBDK-UHFFFAOYSA-N diazepane Chemical compound C1CCNNCC1 QPMLSUSACCOBDK-UHFFFAOYSA-N 0.000 description 1
- 125000006003 dichloroethyl group Chemical group 0.000 description 1
- 125000004774 dichlorofluoromethyl group Chemical group FC(Cl)(Cl)* 0.000 description 1
- 125000004772 dichloromethyl group Chemical group [H]C(Cl)(Cl)* 0.000 description 1
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 description 1
- 125000006001 difluoroethyl group Chemical group 0.000 description 1
- 125000001028 difluoromethyl group Chemical group [H]C(F)(F)* 0.000 description 1
- 125000004852 dihydrofuranyl group Chemical group O1C(CC=C1)* 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-M dihydrogenphosphate Chemical compound OP(O)([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-M 0.000 description 1
- AFABGHUZZDYHJO-UHFFFAOYSA-N dimethyl butane Natural products CCCC(C)C AFABGHUZZDYHJO-UHFFFAOYSA-N 0.000 description 1
- SWSQBOPZIKWTGO-UHFFFAOYSA-N dimethylaminoamidine Chemical group CN(C)C(N)=N SWSQBOPZIKWTGO-UHFFFAOYSA-N 0.000 description 1
- 239000007884 disintegrant Substances 0.000 description 1
- 239000002612 dispersion medium Substances 0.000 description 1
- 238000009826 distribution Methods 0.000 description 1
- 108010083220 ditekiren Proteins 0.000 description 1
- 229950010513 ditekiren Drugs 0.000 description 1
- 230000035619 diuresis Effects 0.000 description 1
- 239000013583 drug formulation Substances 0.000 description 1
- 230000009977 dual effect Effects 0.000 description 1
- 239000000975 dye Substances 0.000 description 1
- 208000001848 dysentery Diseases 0.000 description 1
- 230000002526 effect on cardiovascular system Effects 0.000 description 1
- 230000002500 effect on skin Effects 0.000 description 1
- 239000003062 endothelin A receptor antagonist Substances 0.000 description 1
- 238000009505 enteric coating Methods 0.000 description 1
- 239000002702 enteric coating Substances 0.000 description 1
- 230000007515 enzymatic degradation Effects 0.000 description 1
- 230000002255 enzymatic effect Effects 0.000 description 1
- 238000006911 enzymatic reaction Methods 0.000 description 1
- OROAFUQRIXKEMV-LDADJPATSA-N eprosartan Chemical compound C=1C=C(C(O)=O)C=CC=1CN1C(CCCC)=NC=C1\C=C(C(O)=O)/CC1=CC=CS1 OROAFUQRIXKEMV-LDADJPATSA-N 0.000 description 1
- 229960004563 eprosartan Drugs 0.000 description 1
- AFAXGSQYZLGZPG-UHFFFAOYSA-L ethane-1,2-disulfonate Chemical compound [O-]S(=O)(=O)CCS([O-])(=O)=O AFAXGSQYZLGZPG-UHFFFAOYSA-L 0.000 description 1
- WCQOBLXWLRDEQA-UHFFFAOYSA-N ethanimidamide;hydrochloride Chemical compound Cl.CC(N)=N WCQOBLXWLRDEQA-UHFFFAOYSA-N 0.000 description 1
- 150000002170 ethers Chemical class 0.000 description 1
- QGYKRMZPOOILBA-UHFFFAOYSA-N ethyl (2e)-2-amino-2-hydroxyiminoacetate Chemical compound CCOC(=O)C(\N)=N\O QGYKRMZPOOILBA-UHFFFAOYSA-N 0.000 description 1
- CFPXSLVSTYDBQC-NXEZZACHSA-N ethyl (2r,4r)-2-methyl-4-[(2-methylpropan-2-yl)oxycarbonylamino]pentanoate Chemical compound CCOC(=O)[C@H](C)C[C@@H](C)NC(=O)OC(C)(C)C CFPXSLVSTYDBQC-NXEZZACHSA-N 0.000 description 1
- BHDSPEAEPQSLJX-XMMPIXPASA-N ethyl (3r)-3-[(1-benzyltetrazole-5-carbonyl)amino]-4-(4-phenylphenyl)butanoate Chemical compound C([C@H](CC(=O)OCC)NC(=O)C=1N(N=NN=1)CC=1C=CC=CC=1)C(C=C1)=CC=C1C1=CC=CC=C1 BHDSPEAEPQSLJX-XMMPIXPASA-N 0.000 description 1
- GQDBVTUQODNWKD-XMMPIXPASA-N ethyl (3r)-3-[(2-benzyltetrazole-5-carbonyl)amino]-4-(4-phenylphenyl)butanoate Chemical compound C([C@H](CC(=O)OCC)NC(=O)C1=NN(CC=2C=CC=CC=2)N=N1)C(C=C1)=CC=C1C1=CC=CC=C1 GQDBVTUQODNWKD-XMMPIXPASA-N 0.000 description 1
- NAGSIBVXLHWYSK-QGZVFWFLSA-N ethyl (3r)-3-amino-4-[4-(3-chlorophenyl)phenyl]butanoate Chemical compound C1=CC(C[C@@H](N)CC(=O)OCC)=CC=C1C1=CC=CC(Cl)=C1 NAGSIBVXLHWYSK-QGZVFWFLSA-N 0.000 description 1
- JZHDFHFYNNMIHQ-XFULWGLBSA-N ethyl (3r)-3-amino-4-[4-(5-chloro-2-fluorophenyl)phenyl]butanoate;hydrochloride Chemical compound Cl.C1=CC(C[C@@H](N)CC(=O)OCC)=CC=C1C1=CC(Cl)=CC=C1F JZHDFHFYNNMIHQ-XFULWGLBSA-N 0.000 description 1
- SDHWTUNCCUSBLF-PKLMIRHRSA-N ethyl (3r)-3-amino-4-[4-(5-fluoro-2-methoxyphenyl)phenyl]butanoate;hydrochloride Chemical compound Cl.C1=CC(C[C@@H](N)CC(=O)OCC)=CC=C1C1=CC(F)=CC=C1OC SDHWTUNCCUSBLF-PKLMIRHRSA-N 0.000 description 1
- JZCBBXDONDPJFX-GOSISDBHSA-N ethyl (3r)-4-[4-(3-chlorophenyl)phenyl]-3-[(3-oxo-1,2-oxazole-5-carbonyl)amino]butanoate Chemical compound C([C@H](CC(=O)OCC)NC(=O)C=1ON=C(O)C=1)C(C=C1)=CC=C1C1=CC=CC(Cl)=C1 JZCBBXDONDPJFX-GOSISDBHSA-N 0.000 description 1
- SRXGTEGIOLPZJD-HXUWFJFHSA-N ethyl (3r)-4-[4-(3-chlorophenyl)phenyl]-3-[[2-(ethoxycarbonylamino)acetyl]amino]butanoate Chemical compound C1=CC(C[C@H](CC(=O)OCC)NC(=O)CNC(=O)OCC)=CC=C1C1=CC=CC(Cl)=C1 SRXGTEGIOLPZJD-HXUWFJFHSA-N 0.000 description 1
- FLXQGNNYIWFQSF-LJQANCHMSA-N ethyl (3r)-4-[4-(5-fluoro-2-methoxyphenyl)phenyl]-3-[(2-methylpropan-2-yl)oxycarbonylamino]butanoate Chemical compound C1=CC(C[C@H](CC(=O)OCC)NC(=O)OC(C)(C)C)=CC=C1C1=CC(F)=CC=C1OC FLXQGNNYIWFQSF-LJQANCHMSA-N 0.000 description 1
- URWZZNWXYUZAAU-AAXQSMANSA-N ethyl (e,4r)-2-methyl-4-[(2-methylpropan-2-yl)oxycarbonylamino]pent-2-enoate Chemical compound CCOC(=O)C(\C)=C\[C@@H](C)NC(=O)OC(C)(C)C URWZZNWXYUZAAU-AAXQSMANSA-N 0.000 description 1
- GWAAPEWDHJZNSJ-UHFFFAOYSA-N ethyl 2-(butoxycarbonylamino)-2-methylpentanoate Chemical compound CCCCOC(=O)NC(C)(CCC)C(=O)OCC GWAAPEWDHJZNSJ-UHFFFAOYSA-N 0.000 description 1
- YXBIDMVRWRQDNB-HXUWFJFHSA-N ethyl 2-[[(2r)-4-ethoxy-4-oxo-1-(4-phenylphenyl)butan-2-yl]amino]-1,3-oxazole-4-carboxylate Chemical compound C([C@H](CC(=O)OCC)NC=1OC=C(N=1)C(=O)OCC)C(C=C1)=CC=C1C1=CC=CC=C1 YXBIDMVRWRQDNB-HXUWFJFHSA-N 0.000 description 1
- KXSBWGSJFSEIED-UHFFFAOYSA-N ethyl 2-aminobutanoate Chemical compound CCOC(=O)C(N)CC KXSBWGSJFSEIED-UHFFFAOYSA-N 0.000 description 1
- KTYIFXLNIMPSKI-UHFFFAOYSA-N ethyl 2-bromo-1,3-thiazole-5-carboxylate Chemical compound CCOC(=O)C1=CN=C(Br)S1 KTYIFXLNIMPSKI-UHFFFAOYSA-N 0.000 description 1
- OWZFULPEVHKEKS-UHFFFAOYSA-N ethyl 2-chloro-2-oxoacetate Chemical compound CCOC(=O)C(Cl)=O OWZFULPEVHKEKS-UHFFFAOYSA-N 0.000 description 1
- RHKCNOBFNDEJTR-UHFFFAOYSA-N ethyl 2-ethenyl-1,3-oxazole-5-carboxylate Chemical compound CCOC(=O)C1=CN=C(C=C)O1 RHKCNOBFNDEJTR-UHFFFAOYSA-N 0.000 description 1
- DUVOZUPPHBRJJO-UHFFFAOYSA-N ethyl 2-isocyanatoacetate Chemical compound CCOC(=O)CN=C=O DUVOZUPPHBRJJO-UHFFFAOYSA-N 0.000 description 1
- VBYJTXFFERREKC-UHFFFAOYSA-N ethyl 3-amino-4-[4-(3-chlorophenyl)-2-fluorophenyl]butanoate Chemical compound C1=C(F)C(CC(N)CC(=O)OCC)=CC=C1C1=CC=CC(Cl)=C1 VBYJTXFFERREKC-UHFFFAOYSA-N 0.000 description 1
- VICYTAYPKBLQFB-UHFFFAOYSA-N ethyl 3-bromo-2-oxopropanoate Chemical compound CCOC(=O)C(=O)CBr VICYTAYPKBLQFB-UHFFFAOYSA-N 0.000 description 1
- WAXXIDGUJFFVEJ-UHFFFAOYSA-N ethyl 5-oxo-2h-1,2,4-oxadiazole-3-carboxylate Chemical compound CCOC(=O)C1=NOC(=O)N1 WAXXIDGUJFFVEJ-UHFFFAOYSA-N 0.000 description 1
- 125000000031 ethylamino group Chemical group [H]C([H])([H])C([H])([H])N([H])[*] 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 230000029142 excretion Effects 0.000 description 1
- 229960003580 felodipine Drugs 0.000 description 1
- 239000000835 fiber Substances 0.000 description 1
- 239000007888 film coating Substances 0.000 description 1
- 238000009501 film coating Methods 0.000 description 1
- SMANXXCATUTDDT-QPJJXVBHSA-N flunarizine Chemical compound C1=CC(F)=CC=C1C(C=1C=CC(F)=CC=1)N1CCN(C\C=C\C=2C=CC=CC=2)CC1 SMANXXCATUTDDT-QPJJXVBHSA-N 0.000 description 1
- 229960000326 flunarizine Drugs 0.000 description 1
- QEWYKACRFQMRMB-UHFFFAOYSA-N fluoroacetic acid Chemical compound OC(=O)CF QEWYKACRFQMRMB-UHFFFAOYSA-N 0.000 description 1
- 125000004216 fluoromethyl group Chemical group [H]C([H])(F)* 0.000 description 1
- 229960003765 fluvastatin Drugs 0.000 description 1
- 238000005187 foaming Methods 0.000 description 1
- YONOBYIBNBCDSJ-UHFFFAOYSA-N forasartan Chemical compound N1=C(CCCC)N=C(CCCC)N1CC1=CC=C(C=2C(=CC=CC=2)C2=NNN=N2)N=C1 YONOBYIBNBCDSJ-UHFFFAOYSA-N 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- FATAVLOOLIRUNA-UHFFFAOYSA-N formylmethyl Chemical group [CH2]C=O FATAVLOOLIRUNA-UHFFFAOYSA-N 0.000 description 1
- 239000012634 fragment Substances 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 235000011087 fumaric acid Nutrition 0.000 description 1
- XLYMOEINVGRTEX-UHFFFAOYSA-N fumaric acid monoethyl ester Natural products CCOC(=O)C=CC(O)=O XLYMOEINVGRTEX-UHFFFAOYSA-N 0.000 description 1
- 239000000417 fungicide Substances 0.000 description 1
- 229940083124 ganglion-blocking antiadrenergic secondary and tertiary amines Drugs 0.000 description 1
- 230000030136 gastric emptying Effects 0.000 description 1
- 210000001035 gastrointestinal tract Anatomy 0.000 description 1
- 239000000499 gel Substances 0.000 description 1
- 229960004580 glibenclamide Drugs 0.000 description 1
- 229960000346 gliclazide Drugs 0.000 description 1
- 230000024924 glomerular filtration Effects 0.000 description 1
- 239000003877 glucagon like peptide 1 receptor agonist Substances 0.000 description 1
- 229940050410 gluconate Drugs 0.000 description 1
- 230000009229 glucose formation Effects 0.000 description 1
- ZNNLBTZKUZBEKO-UHFFFAOYSA-N glyburide Chemical compound COC1=CC=C(Cl)C=C1C(=O)NCCC1=CC=C(S(=O)(=O)NC(=O)NC2CCCCC2)C=C1 ZNNLBTZKUZBEKO-UHFFFAOYSA-N 0.000 description 1
- 229940074045 glyceryl distearate Drugs 0.000 description 1
- 229940075507 glyceryl monostearate Drugs 0.000 description 1
- 229940096919 glycogen Drugs 0.000 description 1
- 229930182470 glycoside Natural products 0.000 description 1
- 150000002338 glycosides Chemical class 0.000 description 1
- 101150090422 gsk-3 gene Proteins 0.000 description 1
- 150000008282 halocarbons Chemical class 0.000 description 1
- 239000007902 hard capsule Substances 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 230000002440 hepatic effect Effects 0.000 description 1
- 125000006343 heptafluoro propyl group Chemical group 0.000 description 1
- KFAKINDVYNKLHV-UHFFFAOYSA-N hexadecanoic acid;oxalic acid Chemical compound OC(=O)C(O)=O.CCCCCCCCCCCCCCCC(O)=O KFAKINDVYNKLHV-UHFFFAOYSA-N 0.000 description 1
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 229950000177 hibenzate Drugs 0.000 description 1
- 150000004677 hydrates Chemical class 0.000 description 1
- 230000002209 hydrophobic effect Effects 0.000 description 1
- 125000001165 hydrophobic group Chemical group 0.000 description 1
- 125000002768 hydroxyalkyl group Chemical group 0.000 description 1
- 230000003451 hyperinsulinaemic effect Effects 0.000 description 1
- 201000008980 hyperinsulinism Diseases 0.000 description 1
- 230000002218 hypoglycaemic effect Effects 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 238000003384 imaging method Methods 0.000 description 1
- YAMHXTCMCPHKLN-UHFFFAOYSA-N imidazolidin-2-one Chemical compound O=C1NCCN1 YAMHXTCMCPHKLN-UHFFFAOYSA-N 0.000 description 1
- 230000001771 impaired effect Effects 0.000 description 1
- 238000002513 implantation Methods 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 230000000415 inactivating effect Effects 0.000 description 1
- 230000002779 inactivation Effects 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 125000003392 indanyl group Chemical group C1(CCC2=CC=CC=C12)* 0.000 description 1
- PZOUSPYUWWUPPK-UHFFFAOYSA-N indole Natural products CC1=CC=CC2=C1C=CN2 PZOUSPYUWWUPPK-UHFFFAOYSA-N 0.000 description 1
- RKJUIXBNRJVNHR-UHFFFAOYSA-N indolenine Natural products C1=CC=C2CC=NC2=C1 RKJUIXBNRJVNHR-UHFFFAOYSA-N 0.000 description 1
- 239000012442 inert solvent Substances 0.000 description 1
- 238000001802 infusion Methods 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 239000007972 injectable composition Substances 0.000 description 1
- 239000002198 insoluble material Substances 0.000 description 1
- 230000004155 insulin signaling pathway Effects 0.000 description 1
- 230000002473 insulinotropic effect Effects 0.000 description 1
- UEXQBEVWFZKHNB-UHFFFAOYSA-N intermediate 29 Natural products C1=CC(N)=CC=C1NC1=NC=CC=N1 UEXQBEVWFZKHNB-UHFFFAOYSA-N 0.000 description 1
- 239000013067 intermediate product Substances 0.000 description 1
- VBUWHHLIZKOSMS-RIWXPGAOSA-N invicorp Chemical compound C([C@@H](C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CO)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(N)=O)C(O)=O)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CCCCN)NC(=O)[C@@H](NC(=O)[C@H](C)NC(=O)[C@H](CCSC)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@@H](NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CC(O)=O)NC(=O)[C@@H](NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@@H](NC(=O)[C@H](C)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](N)CC=1NC=NC=1)C(C)C)[C@@H](C)O)[C@@H](C)O)C(C)C)C1=CC=C(O)C=C1 VBUWHHLIZKOSMS-RIWXPGAOSA-N 0.000 description 1
- HVTICUPFWKNHNG-UHFFFAOYSA-N iodoethane Chemical compound CCI HVTICUPFWKNHNG-UHFFFAOYSA-N 0.000 description 1
- JYJVVHFRSFVEJM-UHFFFAOYSA-N iodosobenzene Chemical compound O=IC1=CC=CC=C1 JYJVVHFRSFVEJM-UHFFFAOYSA-N 0.000 description 1
- 239000003456 ion exchange resin Substances 0.000 description 1
- 229920003303 ion-exchange polymer Polymers 0.000 description 1
- 229910052742 iron Inorganic materials 0.000 description 1
- SUMDYPCJJOFFON-UHFFFAOYSA-N isethionic acid Chemical compound OCCS(O)(=O)=O SUMDYPCJJOFFON-UHFFFAOYSA-N 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 239000012948 isocyanate Substances 0.000 description 1
- 150000002513 isocyanates Chemical class 0.000 description 1
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000000555 isopropenyl group Chemical group [H]\C([H])=C(\*)C([H])([H])[H] 0.000 description 1
- JJWLVOIRVHMVIS-UHFFFAOYSA-N isopropylamine Chemical compound CC(C)N JJWLVOIRVHMVIS-UHFFFAOYSA-N 0.000 description 1
- 125000002183 isoquinolinyl group Chemical group C1(=NC=CC2=CC=CC=C12)* 0.000 description 1
- 239000000644 isotonic solution Substances 0.000 description 1
- 239000007951 isotonicity adjuster Substances 0.000 description 1
- 125000000842 isoxazolyl group Chemical group 0.000 description 1
- 229960004427 isradipine Drugs 0.000 description 1
- NLYAJNPCOHFWQQ-UHFFFAOYSA-N kaolin Chemical compound O.O.O=[Al]O[Si](=O)O[Si](=O)O[Al]=O NLYAJNPCOHFWQQ-UHFFFAOYSA-N 0.000 description 1
- URLZCHNOLZSCCA-UHFFFAOYSA-N leu-enkephalin Chemical compound C=1C=C(O)C=CC=1CC(N)C(=O)NCC(=O)NCC(=O)NC(C(=O)NC(CC(C)C)C(O)=O)CC1=CC=CC=C1 URLZCHNOLZSCCA-UHFFFAOYSA-N 0.000 description 1
- 238000012417 linear regression Methods 0.000 description 1
- 150000002632 lipids Chemical class 0.000 description 1
- 229940057995 liquid paraffin Drugs 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- 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 1
- 229960004773 losartan Drugs 0.000 description 1
- KJJZZJSZUJXYEA-UHFFFAOYSA-N losartan Chemical compound CCCCC1=NC(Cl)=C(CO)N1CC1=CC=C(C=2C(=CC=CC=2)C=2[N]N=NN=2)C=C1 KJJZZJSZUJXYEA-UHFFFAOYSA-N 0.000 description 1
- 229960004844 lovastatin Drugs 0.000 description 1
- PCZOHLXUXFIOCF-BXMDZJJMSA-N lovastatin Chemical compound C([C@H]1[C@@H](C)C=CC2=C[C@H](C)C[C@@H]([C@H]12)OC(=O)[C@@H](C)CC)C[C@@H]1C[C@@H](O)CC(=O)O1 PCZOHLXUXFIOCF-BXMDZJJMSA-N 0.000 description 1
- QLJODMDSTUBWDW-UHFFFAOYSA-N lovastatin hydroxy acid Natural products C1=CC(C)C(CCC(O)CC(O)CC(O)=O)C2C(OC(=O)C(C)CC)CC(C)C=C21 QLJODMDSTUBWDW-UHFFFAOYSA-N 0.000 description 1
- 231100000053 low toxicity Toxicity 0.000 description 1
- MJIVRKPEXXHNJT-UHFFFAOYSA-N lutidinic acid Chemical compound OC(=O)C1=CC=NC(C(O)=O)=C1 MJIVRKPEXXHNJT-UHFFFAOYSA-N 0.000 description 1
- 235000001055 magnesium Nutrition 0.000 description 1
- 159000000003 magnesium salts Chemical class 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 1
- 235000019341 magnesium sulphate Nutrition 0.000 description 1
- 229940049920 malate Drugs 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 150000002689 maleic acids Chemical class 0.000 description 1
- 239000001630 malic acid Substances 0.000 description 1
- 235000011090 malic acid Nutrition 0.000 description 1
- WPBNNNQJVZRUHP-UHFFFAOYSA-L manganese(2+);methyl n-[[2-(methoxycarbonylcarbamothioylamino)phenyl]carbamothioyl]carbamate;n-[2-(sulfidocarbothioylamino)ethyl]carbamodithioate Chemical compound [Mn+2].[S-]C(=S)NCCNC([S-])=S.COC(=O)NC(=S)NC1=CC=CC=C1NC(=S)NC(=O)OC WPBNNNQJVZRUHP-UHFFFAOYSA-L 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 239000011159 matrix material Substances 0.000 description 1
- 235000012054 meals Nutrition 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 230000005906 menstruation Effects 0.000 description 1
- LVWZTYCIRDMTEY-UHFFFAOYSA-N metamizole Chemical compound O=C1C(N(CS(O)(=O)=O)C)=C(C)N(C)N1C1=CC=CC=C1 LVWZTYCIRDMTEY-UHFFFAOYSA-N 0.000 description 1
- XZWYZXLIPXDOLR-UHFFFAOYSA-N metformin Chemical compound CN(C)C(=N)NC(N)=N XZWYZXLIPXDOLR-UHFFFAOYSA-N 0.000 description 1
- 229960003105 metformin Drugs 0.000 description 1
- VNWKTOKETHGBQD-UHFFFAOYSA-N methane Natural products C VNWKTOKETHGBQD-UHFFFAOYSA-N 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- HNQIVZYLYMDVSB-UHFFFAOYSA-N methanesulfonimidic acid Chemical compound CS(N)(=O)=O HNQIVZYLYMDVSB-UHFFFAOYSA-N 0.000 description 1
- OKKJLVBELUTLKV-VMNATFBRSA-N methanol-d1 Chemical compound [2H]OC OKKJLVBELUTLKV-VMNATFBRSA-N 0.000 description 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 1
- 125000004184 methoxymethyl group Chemical group [H]C([H])([H])OC([H])([H])* 0.000 description 1
- UZNGJDGLZJFLRI-NPSJIHRQSA-N methyl (2r)-3-amino-4-[4-(3-chlorophenyl)phenyl]-2-hydroxybutanoate;hydrochloride Chemical compound Cl.C1=CC(CC(N)[C@@H](O)C(=O)OC)=CC=C1C1=CC=CC(Cl)=C1 UZNGJDGLZJFLRI-NPSJIHRQSA-N 0.000 description 1
- CWWARWOPSKGELM-SARDKLJWSA-N methyl (2s)-2-[[(2s)-2-[[2-[[(2s)-2-[[(2s)-2-[[(2s)-5-amino-2-[[(2s)-5-amino-2-[[(2s)-1-[(2s)-6-amino-2-[[(2s)-1-[(2s)-2-amino-5-(diaminomethylideneamino)pentanoyl]pyrrolidine-2-carbonyl]amino]hexanoyl]pyrrolidine-2-carbonyl]amino]-5-oxopentanoyl]amino]-5 Chemical compound C([C@@H](C(=O)NCC(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCSC)C(=O)OC)NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H]1N(CCC1)C(=O)[C@H](CCCCN)NC(=O)[C@H]1N(CCC1)C(=O)[C@@H](N)CCCN=C(N)N)C1=CC=CC=C1 CWWARWOPSKGELM-SARDKLJWSA-N 0.000 description 1
- BBFWUUBQSXVHHZ-UHFFFAOYSA-N methyl 3-oxo-1,2-oxazole-5-carboxylate Chemical compound COC(=O)C1=CC(=O)NO1 BBFWUUBQSXVHHZ-UHFFFAOYSA-N 0.000 description 1
- YWTRYDAONUXRNP-UHFFFAOYSA-N methyl 5-(2-methoxy-2-oxoethyl)furan-2-carboxylate Chemical compound COC(=O)CC1=CC=C(C(=O)OC)O1 YWTRYDAONUXRNP-UHFFFAOYSA-N 0.000 description 1
- JACPDLJUQLKABC-UHFFFAOYSA-N methyl 6-aminopyridine-3-carboxylate Chemical compound COC(=O)C1=CC=C(N)N=C1 JACPDLJUQLKABC-UHFFFAOYSA-N 0.000 description 1
- 229920000609 methyl cellulose Polymers 0.000 description 1
- WBYWAXJHAXSJNI-UHFFFAOYSA-N methyl p-hydroxycinnamate Natural products OC(=O)C=CC1=CC=CC=C1 WBYWAXJHAXSJNI-UHFFFAOYSA-N 0.000 description 1
- JZMJDSHXVKJFKW-UHFFFAOYSA-M methyl sulfate(1-) Chemical compound COS([O-])(=O)=O JZMJDSHXVKJFKW-UHFFFAOYSA-M 0.000 description 1
- GYNNXHKOJHMOHS-UHFFFAOYSA-N methyl-cycloheptane Natural products CC1CCCCCC1 GYNNXHKOJHMOHS-UHFFFAOYSA-N 0.000 description 1
- 239000001923 methylcellulose Substances 0.000 description 1
- 235000010981 methylcellulose Nutrition 0.000 description 1
- 229950009116 mevastatin Drugs 0.000 description 1
- AJLFOPYRIVGYMJ-INTXDZFKSA-N mevastatin Chemical compound C([C@H]1[C@@H](C)C=CC2=CCC[C@@H]([C@H]12)OC(=O)[C@@H](C)CC)C[C@@H]1C[C@@H](O)CC(=O)O1 AJLFOPYRIVGYMJ-INTXDZFKSA-N 0.000 description 1
- BOZILQFLQYBIIY-UHFFFAOYSA-N mevastatin hydroxy acid Natural products C1=CC(C)C(CCC(O)CC(O)CC(O)=O)C2C(OC(=O)C(C)CC)CCC=C21 BOZILQFLQYBIIY-UHFFFAOYSA-N 0.000 description 1
- 238000004452 microanalysis Methods 0.000 description 1
- 229960001110 miglitol Drugs 0.000 description 1
- 238000003801 milling Methods 0.000 description 1
- 230000002438 mitochondrial effect Effects 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 229940074369 monoethyl fumarate Drugs 0.000 description 1
- 229960005181 morphine Drugs 0.000 description 1
- 239000012452 mother liquor Substances 0.000 description 1
- VHYFNPMBLIVWCW-UHFFFAOYSA-O n,n-dimethylpyridin-1-ium-4-amine Chemical compound CN(C)C1=CC=[NH+]C=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-O 0.000 description 1
- TUYWTLTWNJOZNY-UHFFFAOYSA-N n-[6-(2-hydroxyethoxy)-5-(2-methoxyphenoxy)-2-[2-(2h-tetrazol-5-yl)pyridin-4-yl]pyrimidin-4-yl]-5-propan-2-ylpyridine-2-sulfonamide Chemical compound COC1=CC=CC=C1OC(C(=NC(=N1)C=2C=C(N=CC=2)C2=NNN=N2)OCCO)=C1NS(=O)(=O)C1=CC=C(C(C)C)C=N1 TUYWTLTWNJOZNY-UHFFFAOYSA-N 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000003136 n-heptyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 description 1
- IKVDMBQGHZVMRN-UHFFFAOYSA-N n-methyldecan-1-amine Chemical compound CCCCCCCCCCNC IKVDMBQGHZVMRN-UHFFFAOYSA-N 0.000 description 1
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- HTNVAVKDAFDODA-UHFFFAOYSA-N naphthalene-1-carbonitrile Chemical compound C1=CC=C[C]2C(C#N)=CC=C=C21 HTNVAVKDAFDODA-UHFFFAOYSA-N 0.000 description 1
- KVBGVZZKJNLNJU-UHFFFAOYSA-M naphthalene-2-sulfonate Chemical compound C1=CC=CC2=CC(S(=O)(=O)[O-])=CC=C21 KVBGVZZKJNLNJU-UHFFFAOYSA-M 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 239000002833 natriuretic agent Substances 0.000 description 1
- 125000001971 neopentyl group Chemical group [H]C([*])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- PKWDZWYVIHVNKS-UHFFFAOYSA-N netoglitazone Chemical compound FC1=CC=CC=C1COC1=CC=C(C=C(CC2C(NC(=O)S2)=O)C=C2)C2=C1 PKWDZWYVIHVNKS-UHFFFAOYSA-N 0.000 description 1
- 230000002644 neurohormonal effect Effects 0.000 description 1
- 229960001783 nicardipine Drugs 0.000 description 1
- 229910052759 nickel Inorganic materials 0.000 description 1
- 239000011664 nicotinic acid Substances 0.000 description 1
- 229960003512 nicotinic acid Drugs 0.000 description 1
- 235000001968 nicotinic acid Nutrition 0.000 description 1
- HYIMSNHJOBLJNT-UHFFFAOYSA-N nifedipine Chemical compound COC(=O)C1=C(C)NC(C)=C(C(=O)OC)C1C1=CC=CC=C1[N+]([O-])=O HYIMSNHJOBLJNT-UHFFFAOYSA-N 0.000 description 1
- 229960001597 nifedipine Drugs 0.000 description 1
- 229960000715 nimodipine Drugs 0.000 description 1
- 229960005425 nitrendipine Drugs 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 150000002825 nitriles Chemical class 0.000 description 1
- 125000004433 nitrogen atom Chemical group N* 0.000 description 1
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 1
- 125000006574 non-aromatic ring group Chemical group 0.000 description 1
- 229940126347 non-steroidal aldosterone synthase inhibitor Drugs 0.000 description 1
- 239000012457 nonaqueous media Substances 0.000 description 1
- 239000003921 oil Substances 0.000 description 1
- 235000019198 oils Nutrition 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- 239000004006 olive oil Substances 0.000 description 1
- 235000008390 olive oil Nutrition 0.000 description 1
- 239000010502 orange oil Substances 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- PXQPEWDEAKTCGB-UHFFFAOYSA-N orotic acid Chemical compound OC(=O)C1=CC(=O)NC(=O)N1 PXQPEWDEAKTCGB-UHFFFAOYSA-N 0.000 description 1
- 230000003204 osmotic effect Effects 0.000 description 1
- WCPAKWJPBJAGKN-UHFFFAOYSA-N oxadiazole Chemical group C1=CON=N1 WCPAKWJPBJAGKN-UHFFFAOYSA-N 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- 125000005880 oxathiolanyl group Chemical group 0.000 description 1
- 125000005968 oxazolinyl group Chemical group 0.000 description 1
- AHHWIHXENZJRFG-UHFFFAOYSA-N oxetane Chemical compound C1COC1 AHHWIHXENZJRFG-UHFFFAOYSA-N 0.000 description 1
- 125000000466 oxiranyl group Chemical group 0.000 description 1
- BMMGVYCKOGBVEV-UHFFFAOYSA-N oxo(oxoceriooxy)cerium Chemical compound [Ce]=O.O=[Ce]=O BMMGVYCKOGBVEV-UHFFFAOYSA-N 0.000 description 1
- AUONHKJOIZSQGR-UHFFFAOYSA-N oxophosphane Chemical compound P=O AUONHKJOIZSQGR-UHFFFAOYSA-N 0.000 description 1
- 125000003854 p-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Cl 0.000 description 1
- 239000006174 pH buffer Substances 0.000 description 1
- 210000000496 pancreas Anatomy 0.000 description 1
- FJKROLUGYXJWQN-UHFFFAOYSA-N papa-hydroxy-benzoic acid Natural products OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 239000006072 paste Substances 0.000 description 1
- 239000000312 peanut oil Substances 0.000 description 1
- FILUFGAZMJGNEN-UHFFFAOYSA-N pent-1-en-3-yne Chemical group CC#CC=C FILUFGAZMJGNEN-UHFFFAOYSA-N 0.000 description 1
- 125000006340 pentafluoro ethyl group Chemical group FC(F)(F)C(F)(F)* 0.000 description 1
- 210000005259 peripheral blood Anatomy 0.000 description 1
- 239000011886 peripheral blood Substances 0.000 description 1
- 229940021222 peritoneal dialysis isotonic solution Drugs 0.000 description 1
- 108091008725 peroxisome proliferator-activated receptors alpha Proteins 0.000 description 1
- AFOGBLYPWJJVAL-UHFFFAOYSA-N phenbutamide Chemical compound CCCCNC(=O)NS(=O)(=O)C1=CC=CC=C1 AFOGBLYPWJJVAL-UHFFFAOYSA-N 0.000 description 1
- 229950008557 phenbutamide Drugs 0.000 description 1
- 150000002989 phenols Chemical class 0.000 description 1
- 229960003562 phentermine Drugs 0.000 description 1
- WSDQIHATCCOMLH-UHFFFAOYSA-N phenyl n-(3,5-dichlorophenyl)carbamate Chemical compound ClC1=CC(Cl)=CC(NC(=O)OC=2C=CC=CC=2)=C1 WSDQIHATCCOMLH-UHFFFAOYSA-N 0.000 description 1
- 150000002993 phenylalanine derivatives Chemical class 0.000 description 1
- 229930029653 phosphoenolpyruvate Natural products 0.000 description 1
- DTBNBXWJWCWCIK-UHFFFAOYSA-N phosphoenolpyruvic acid Chemical compound OC(=O)C(=C)OP(O)(O)=O DTBNBXWJWCWCIK-UHFFFAOYSA-N 0.000 description 1
- 150000003904 phospholipids Chemical class 0.000 description 1
- 150000003016 phosphoric acids Chemical class 0.000 description 1
- IEQIEDJGQAUEQZ-UHFFFAOYSA-N phthalocyanine Chemical compound N1C(N=C2C3=CC=CC=C3C(N=C3C4=CC=CC=C4C(=N4)N3)=N2)=C(C=CC=C2)C2=C1N=C1C2=CC=CC=C2C4=N1 IEQIEDJGQAUEQZ-UHFFFAOYSA-N 0.000 description 1
- XQZYPMVTSDWCCE-UHFFFAOYSA-N phthalonitrile Chemical compound N#CC1=CC=CC=C1C#N XQZYPMVTSDWCCE-UHFFFAOYSA-N 0.000 description 1
- 229920006391 phthalonitrile polymer Polymers 0.000 description 1
- 230000004962 physiological condition Effects 0.000 description 1
- 230000035479 physiological effects, processes and functions Effects 0.000 description 1
- 230000006461 physiological response Effects 0.000 description 1
- 229940081066 picolinic acid Drugs 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 125000003386 piperidinyl group Chemical group 0.000 description 1
- 125000005936 piperidyl group Chemical group 0.000 description 1
- VGYFMXBACGZSIL-MCBHFWOFSA-N pitavastatin Chemical compound OC(=O)C[C@H](O)C[C@H](O)\C=C\C1=C(C2CC2)N=C2C=CC=CC2=C1C1=CC=C(F)C=C1 VGYFMXBACGZSIL-MCBHFWOFSA-N 0.000 description 1
- 229960002797 pitavastatin Drugs 0.000 description 1
- 239000004033 plastic Substances 0.000 description 1
- 229920003023 plastic Polymers 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 229920001296 polysiloxane Polymers 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 230000012495 positive regulation of renal sodium excretion Effects 0.000 description 1
- 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 1
- 208000024896 potassium deficiency disease Diseases 0.000 description 1
- 229960002965 pravastatin Drugs 0.000 description 1
- TUZYXOIXSAXUGO-PZAWKZKUSA-N pravastatin Chemical compound C1=C[C@H](C)[C@H](CC[C@@H](O)C[C@@H](O)CC(O)=O)[C@H]2[C@@H](OC(=O)[C@@H](C)CC)C[C@H](O)C=C21 TUZYXOIXSAXUGO-PZAWKZKUSA-N 0.000 description 1
- 201000009104 prediabetes syndrome Diseases 0.000 description 1
- 230000002028 premature Effects 0.000 description 1
- 208000026440 premature labor Diseases 0.000 description 1
- GCYXWQUSHADNBF-AAEALURTSA-N preproglucagon 78-108 Chemical compound C([C@@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](C)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCCCN)C(=O)NCC(=O)N[C@@H](CCCNC(N)=N)C(=O)NCC(O)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CCCCN)NC(=O)[C@H](C)NC(=O)[C@H](C)NC(=O)[C@H](CCC(N)=O)NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CO)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@@H](NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C)NC(=O)[C@@H](N)CC=1N=CNC=1)[C@@H](C)O)[C@@H](C)O)C(C)C)C1=CC=CC=C1 GCYXWQUSHADNBF-AAEALURTSA-N 0.000 description 1
- 150000003141 primary amines Chemical class 0.000 description 1
- 239000003380 propellant Substances 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- 230000004088 pulmonary circulation Effects 0.000 description 1
- 125000004307 pyrazin-2-yl group Chemical group [H]C1=C([H])N=C(*)C([H])=N1 0.000 description 1
- JEXVQSWXXUJEMA-UHFFFAOYSA-N pyrazol-3-one Chemical compound O=C1C=CN=N1 JEXVQSWXXUJEMA-UHFFFAOYSA-N 0.000 description 1
- 125000003226 pyrazolyl group Chemical group 0.000 description 1
- 125000002206 pyridazin-3-yl group Chemical group [H]C1=C([H])C([H])=C(*)N=N1 0.000 description 1
- 125000004940 pyridazin-4-yl group Chemical group N1=NC=C(C=C1)* 0.000 description 1
- 150000003222 pyridines Chemical class 0.000 description 1
- VTGOHKSTWXHQJK-UHFFFAOYSA-N pyrimidin-2-ol Chemical compound OC1=NC=CC=N1 VTGOHKSTWXHQJK-UHFFFAOYSA-N 0.000 description 1
- 125000000714 pyrimidinyl group Chemical group 0.000 description 1
- 229940107700 pyruvic acid Drugs 0.000 description 1
- 238000010791 quenching Methods 0.000 description 1
- JSDRRTOADPPCHY-HSQYWUDLSA-N quinapril Chemical compound C([C@@H](C(=O)OCC)N[C@@H](C)C(=O)N1[C@@H](CC2=CC=CC=C2C1)C(O)=O)CC1=CC=CC=C1 JSDRRTOADPPCHY-HSQYWUDLSA-N 0.000 description 1
- 229960001455 quinapril Drugs 0.000 description 1
- 125000002294 quinazolinyl group Chemical group N1=C(N=CC2=CC=CC=C12)* 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
- 229960000948 quinine Drugs 0.000 description 1
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 description 1
- 150000004060 quinone imines Chemical group 0.000 description 1
- 125000001567 quinoxalinyl group Chemical group N1=C(C=NC2=CC=CC=C12)* 0.000 description 1
- 230000006340 racemization Effects 0.000 description 1
- 238000001959 radiotherapy Methods 0.000 description 1
- HDACQVRGBOVJII-JBDAPHQKSA-N ramipril Chemical compound C([C@@H](C(=O)OCC)N[C@@H](C)C(=O)N1[C@@H](C[C@@H]2CCC[C@@H]21)C(O)=O)CC1=CC=CC=C1 HDACQVRGBOVJII-JBDAPHQKSA-N 0.000 description 1
- 229960003401 ramipril Drugs 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- BOLDJAUMGUJJKM-LSDHHAIUSA-N renifolin D Natural products CC(=C)[C@@H]1Cc2c(O)c(O)ccc2[C@H]1CC(=O)c3ccc(O)cc3O BOLDJAUMGUJJKM-LSDHHAIUSA-N 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 230000002441 reversible effect Effects 0.000 description 1
- 238000012552 review Methods 0.000 description 1
- 229960004889 salicylic acid Drugs 0.000 description 1
- 229950006241 saprisartan Drugs 0.000 description 1
- 230000007017 scission Effects 0.000 description 1
- 238000007789 sealing Methods 0.000 description 1
- 230000001953 sensory effect Effects 0.000 description 1
- UNAANXDKBXWMLN-UHFFFAOYSA-N sibutramine Chemical compound C=1C=C(Cl)C=CC=1C1(C(N(C)C)CC(C)C)CCC1 UNAANXDKBXWMLN-UHFFFAOYSA-N 0.000 description 1
- 229960004425 sibutramine Drugs 0.000 description 1
- 229960003310 sildenafil Drugs 0.000 description 1
- 229960002855 simvastatin Drugs 0.000 description 1
- RYMZZMVNJRMUDD-HGQWONQESA-N simvastatin Chemical compound C([C@H]1[C@@H](C)C=CC2=C[C@H](C)C[C@@H]([C@H]12)OC(=O)C(C)(C)CC)C[C@@H]1C[C@@H](O)CC(=O)O1 RYMZZMVNJRMUDD-HGQWONQESA-N 0.000 description 1
- 150000003384 small molecules Chemical class 0.000 description 1
- ISTDXGCDGWDFEG-UHFFFAOYSA-M sodium 2H-tetrazole-5-carboxylate Chemical compound [Na+].[O-]C(=O)C1=NN=NN1 ISTDXGCDGWDFEG-UHFFFAOYSA-M 0.000 description 1
- 229910001467 sodium calcium phosphate Inorganic materials 0.000 description 1
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 1
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 1
- 239000001488 sodium phosphate Substances 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- CRWJEUDFKNYSBX-UHFFFAOYSA-N sodium;hypobromite Chemical compound [Na+].Br[O-] CRWJEUDFKNYSBX-UHFFFAOYSA-N 0.000 description 1
- 239000007901 soft capsule Substances 0.000 description 1
- 239000002594 sorbent Substances 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 230000003595 spectral effect Effects 0.000 description 1
- LXMSZDCAJNLERA-ZHYRCANASA-N spironolactone Chemical compound C([C@@H]1[C@]2(C)CC[C@@H]3[C@@]4(C)CCC(=O)C=C4C[C@H]([C@@H]13)SC(=O)C)C[C@@]21CCC(=O)O1 LXMSZDCAJNLERA-ZHYRCANASA-N 0.000 description 1
- 229960002256 spironolactone Drugs 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 230000001954 sterilising effect Effects 0.000 description 1
- 238000004659 sterilization and disinfection Methods 0.000 description 1
- 239000012258 stirred mixture Substances 0.000 description 1
- 125000000547 substituted alkyl group Chemical group 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
- UIUJIQZEACWQSV-UHFFFAOYSA-N succinic semialdehyde Chemical compound OC(=O)CCC=O UIUJIQZEACWQSV-UHFFFAOYSA-N 0.000 description 1
- KZNICNPSHKQLFF-UHFFFAOYSA-N succinimide Chemical class O=C1CCC(=O)N1 KZNICNPSHKQLFF-UHFFFAOYSA-N 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- YHULXGUCQZFROV-UHFFFAOYSA-N sulfane;urea Chemical compound S.NC(N)=O YHULXGUCQZFROV-UHFFFAOYSA-N 0.000 description 1
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 description 1
- FWMUJAIKEJWSSY-UHFFFAOYSA-N sulfur dichloride Chemical compound ClSCl FWMUJAIKEJWSSY-UHFFFAOYSA-N 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 230000002459 sustained effect Effects 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- 238000003419 tautomerization reaction Methods 0.000 description 1
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 description 1
- 229960005187 telmisartan Drugs 0.000 description 1
- SASWSEQJAITMKS-JJNNLWIXSA-N tert-butyl (2s)-2-[[(2s)-1-[[(2s)-1-[[(4s,5s,7s)-5-hydroxy-2,8-dimethyl-7-[[(2s,3s)-3-methyl-1-oxo-1-(pyridin-2-ylmethylamino)pentan-2-yl]carbamoyl]nonan-4-yl]amino]-3-(1h-imidazol-5-yl)-1-oxopropan-2-yl]-methylamino]-1-oxo-3-phenylpropan-2-yl]carbamoyl]p Chemical compound C([C@@H](C(=O)N[C@@H](CC(C)C)[C@@H](O)C[C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)NCC=1N=CC=CC=1)C(C)C)N(C)C(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@H]1N(CCC1)C(=O)OC(C)(C)C)C1=CN=CN1 SASWSEQJAITMKS-JJNNLWIXSA-N 0.000 description 1
- SJMDMGHPMLKLHQ-UHFFFAOYSA-N tert-butyl 2-aminoacetate Chemical compound CC(C)(C)OC(=O)CN SJMDMGHPMLKLHQ-UHFFFAOYSA-N 0.000 description 1
- WAVKECVQKDCLLT-UHFFFAOYSA-N tert-butyl 3-[(2-methylpropan-2-yl)oxycarbonylamino]butanoate Chemical compound CC(C)(C)OC(=O)CC(C)NC(=O)OC(C)(C)C WAVKECVQKDCLLT-UHFFFAOYSA-N 0.000 description 1
- PAOHVNXIASUJOZ-UHFFFAOYSA-N tert-butyl 3-amino-4-(4-phenylphenyl)butanoate;hydrochloride Chemical compound Cl.C1=CC(CC(N)CC(=O)OC(C)(C)C)=CC=C1C1=CC=CC=C1 PAOHVNXIASUJOZ-UHFFFAOYSA-N 0.000 description 1
- OIVCIBMLQRUEMA-MRXNPFEDSA-N tert-butyl 4-[[(2r)-1-(4-bromophenyl)-4-ethoxy-4-oxobutan-2-yl]amino]-4-oxobutanoate Chemical compound CC(C)(C)OC(=O)CCC(=O)N[C@@H](CC(=O)OCC)CC1=CC=C(Br)C=C1 OIVCIBMLQRUEMA-MRXNPFEDSA-N 0.000 description 1
- SFFKUZPNDPDSSE-UHFFFAOYSA-N tert-butyl 4-oxobutanoate Chemical compound CC(C)(C)OC(=O)CCC=O SFFKUZPNDPDSSE-UHFFFAOYSA-N 0.000 description 1
- JRMUNVKIHCOMHV-UHFFFAOYSA-M tetrabutylammonium bromide Chemical compound [Br-].CCCC[N+](CCCC)(CCCC)CCCC JRMUNVKIHCOMHV-UHFFFAOYSA-M 0.000 description 1
- 125000001712 tetrahydronaphthyl group Chemical group C1(CCCC2=CC=CC=C12)* 0.000 description 1
- 125000001412 tetrahydropyranyl group Chemical group 0.000 description 1
- ZVQXQPNJHRNGID-UHFFFAOYSA-N tetramethylsuccinonitrile Chemical compound N#CC(C)(C)C(C)(C)C#N ZVQXQPNJHRNGID-UHFFFAOYSA-N 0.000 description 1
- 150000003536 tetrazoles Chemical class 0.000 description 1
- 125000003831 tetrazolyl group Chemical group 0.000 description 1
- 229950000584 tezosentan Drugs 0.000 description 1
- ZRKFYGHZFMAOKI-QMGMOQQFSA-N tgfbeta Chemical compound C([C@H](NC(=O)[C@H](C(C)C)NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H]([C@@H](C)O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H]([C@@H](C)O)NC(=O)[C@H](CC(C)C)NC(=O)CNC(=O)[C@H](C)NC(=O)[C@H](CO)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@@H](NC(=O)[C@H](C)NC(=O)[C@H](C)NC(=O)[C@@H](NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](N)CCSC)C(C)C)[C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](C)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](C)C(=O)N[C@@H](CC(C)C)C(=O)N1[C@@H](CCC1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(C)C)C(O)=O)C1=CC=C(O)C=C1 ZRKFYGHZFMAOKI-QMGMOQQFSA-N 0.000 description 1
- 231100001274 therapeutic index Toxicity 0.000 description 1
- VLLMWSRANPNYQX-UHFFFAOYSA-N thiadiazole Chemical group C1=CSN=N1.C1=CSN=N1 VLLMWSRANPNYQX-UHFFFAOYSA-N 0.000 description 1
- 230000008719 thickening Effects 0.000 description 1
- 150000003573 thiols Chemical class 0.000 description 1
- 229930192474 thiophene Chemical group 0.000 description 1
- KJAMZCVTJDTESW-UHFFFAOYSA-N tiracizine Chemical compound C1CC2=CC=CC=C2N(C(=O)CN(C)C)C2=CC(NC(=O)OCC)=CC=C21 KJAMZCVTJDTESW-UHFFFAOYSA-N 0.000 description 1
- 238000003325 tomography Methods 0.000 description 1
- CMSGWTNRGKRWGS-NQIIRXRSSA-N torcetrapib Chemical compound COC(=O)N([C@H]1C[C@@H](CC)N(C2=CC=C(C=C21)C(F)(F)F)C(=O)OCC)CC1=CC(C(F)(F)F)=CC(C(F)(F)F)=C1 CMSGWTNRGKRWGS-NQIIRXRSSA-N 0.000 description 1
- 229950004514 torcetrapib Drugs 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 239000000196 tragacanth Substances 0.000 description 1
- 235000010487 tragacanth Nutrition 0.000 description 1
- 229940116362 tragacanth Drugs 0.000 description 1
- 150000003626 triacylglycerols Chemical class 0.000 description 1
- FFSJPOPLSWBGQY-UHFFFAOYSA-N triazol-4-one Chemical compound O=C1C=NN=N1 FFSJPOPLSWBGQY-UHFFFAOYSA-N 0.000 description 1
- 150000003852 triazoles Chemical group 0.000 description 1
- 125000003866 trichloromethyl group Chemical group ClC(Cl)(Cl)* 0.000 description 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
- FIQMHBFVRAXMOP-UHFFFAOYSA-N triphenylphosphane oxide Chemical group C=1C=CC=CC=1P(C=1C=CC=CC=1)(=O)C1=CC=CC=C1 FIQMHBFVRAXMOP-UHFFFAOYSA-N 0.000 description 1
- 229910000404 tripotassium phosphate Inorganic materials 0.000 description 1
- 235000019798 tripotassium phosphate Nutrition 0.000 description 1
- YFTHZRPMJXBUME-UHFFFAOYSA-N tripropylamine Chemical compound CCCN(CCC)CCC YFTHZRPMJXBUME-UHFFFAOYSA-N 0.000 description 1
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 description 1
- 229910052721 tungsten Inorganic materials 0.000 description 1
- 210000004291 uterus Anatomy 0.000 description 1
- 229910052720 vanadium Inorganic materials 0.000 description 1
- LEONUFNNVUYDNQ-UHFFFAOYSA-N vanadium atom Chemical compound [V] LEONUFNNVUYDNQ-UHFFFAOYSA-N 0.000 description 1
- 230000025033 vasoconstriction Effects 0.000 description 1
- 230000024883 vasodilation Effects 0.000 description 1
- 229940124549 vasodilator Drugs 0.000 description 1
- 239000003071 vasodilator agent Substances 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
- 230000004580 weight loss Effects 0.000 description 1
- 238000009736 wetting Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
- C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
- C07D317/10—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 not condensed with other rings
- C07D317/32—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 not condensed with other rings with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D317/34—Oxygen atoms
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
- A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
- A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
- A61K31/216—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acids having aromatic rings, e.g. benactizyne, clofibrate
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/325—Carbamic acids; Thiocarbamic acids; Anhydrides or salts thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
- A61K31/351—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom not condensed with another ring
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/357—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having two or more oxygen atoms in the same ring, e.g. crown ethers, guanadrel
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/42—Oxazoles
- A61K31/421—1,3-Oxazoles, e.g. pemoline, trimethadione
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
- A61K31/5375—1,4-Oxazines, e.g. morpholine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/08—Drugs for disorders of the alimentary tract or the digestive system for nausea, cinetosis or vertigo; Antiemetics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
- A61P11/06—Antiasthmatics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/02—Drugs for disorders of the urinary system of urine or of the urinary tract, e.g. urine acidifiers
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/12—Drugs for disorders of the urinary system of the kidneys
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
- A61P15/06—Antiabortive agents; Labour repressants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
- A61P15/08—Drugs for genital or sexual disorders; Contraceptives for gonadal disorders or for enhancing fertility, e.g. inducers of ovulation or of spermatogenesis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
- A61P15/10—Drugs for genital or sexual disorders; Contraceptives for impotence
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
- A61P15/12—Drugs for genital or sexual disorders; Contraceptives for climacteric disorders
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/02—Drugs for dermatological disorders for treating wounds, ulcers, burns, scars, keloids, or the like
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/04—Centrally acting analgesics, e.g. opioids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/08—Antiepileptics; Anticonvulsants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/24—Antidepressants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
- A61P27/06—Antiglaucoma agents or miotics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/04—Anorexiants; Antiobesity agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/12—Drugs for disorders of the metabolism for electrolyte homeostasis
- A61P3/14—Drugs for disorders of the metabolism for electrolyte homeostasis for calcium homeostasis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/02—Antineoplastic agents specific for leukemia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P5/00—Drugs for disorders of the endocrine system
- A61P5/24—Drugs for disorders of the endocrine system of the sex hormones
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/10—Antioedematous agents; Diuretics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/06—Antiarrhythmics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/12—Antihypertensives
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C233/00—Carboxylic acid amides
- C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
- C07C233/45—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups
- C07C233/46—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom
- C07C233/47—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom having the carbon atom of the carboxamide group bound to a hydrogen atom or to a carbon atom of an acyclic saturated carbon skeleton
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C233/00—Carboxylic acid amides
- C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
- C07C233/45—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups
- C07C233/46—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom
- C07C233/49—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom having the carbon atom of the carboxamide group bound to a carbon atom of an acyclic unsaturated carbon skeleton
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C233/00—Carboxylic acid amides
- C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
- C07C233/45—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups
- C07C233/46—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom
- C07C233/51—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom having the carbon atom of the carboxamide group bound to an acyclic carbon atom of a carbon skeleton containing six-membered aromatic rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C233/00—Carboxylic acid amides
- C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
- C07C233/56—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having carbon atoms of carboxamide groups bound to carbon atoms of carboxyl groups, e.g. oxamides
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C233/00—Carboxylic acid amides
- C07C233/57—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of rings other than six-membered aromatic rings
- C07C233/63—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of rings other than six-membered aromatic rings having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
- C07C235/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton
- C07C235/04—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton being acyclic and saturated
- C07C235/12—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton being acyclic and saturated having the nitrogen atom of at least one of the carboxamide groups bound to an acyclic carbon atom of a hydrocarbon radical substituted by carboxyl groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
- C07C235/70—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups and doubly-bound oxygen atoms bound to the same carbon skeleton
- C07C235/72—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups and doubly-bound oxygen atoms bound to the same carbon skeleton with the carbon atoms of the carboxamide groups bound to acyclic carbon atoms
- C07C235/76—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups and doubly-bound oxygen atoms bound to the same carbon skeleton with the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of an unsaturated carbon skeleton
- C07C235/78—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups and doubly-bound oxygen atoms bound to the same carbon skeleton with the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of an unsaturated carbon skeleton the carbon skeleton containing rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
- C07C237/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton
- C07C237/16—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being acyclic and unsaturated
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
- C07C237/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton
- C07C237/22—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton having nitrogen atoms of amino groups bound to the carbon skeleton of the acid part, further acylated
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C255/00—Carboxylic acid nitriles
- C07C255/49—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
- C07C255/58—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton containing cyano groups and singly-bound nitrogen atoms, not being further bound to other hetero atoms, bound to the carbon skeleton
- C07C255/60—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton containing cyano groups and singly-bound nitrogen atoms, not being further bound to other hetero atoms, bound to the carbon skeleton at least one of the singly-bound nitrogen atoms being acylated
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C271/00—Derivatives of carbamic acids, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
- C07C271/06—Esters of carbamic acids
- C07C271/08—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms
- C07C271/10—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms
- C07C271/22—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms to carbon atoms of hydrocarbon radicals substituted by carboxyl groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C275/00—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups
- C07C275/04—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to acyclic carbon atoms
- C07C275/20—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to acyclic carbon atoms of an unsaturated carbon skeleton
- C07C275/24—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to acyclic carbon atoms of an unsaturated carbon skeleton containing six-membered aromatic rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
- C07C311/01—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms
- C07C311/02—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton
- C07C311/08—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton having the nitrogen atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
- C07C311/50—Compounds containing any of the groups, X being a hetero atom, Y being any atom
- C07C311/51—Y being a hydrogen or a carbon atom
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D213/81—Amides; Imides
- C07D213/82—Amides; Imides in position 3
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D239/32—One oxygen, sulfur or nitrogen atom
- C07D239/34—One oxygen atom
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D239/32—One oxygen, sulfur or nitrogen atom
- C07D239/34—One oxygen atom
- C07D239/36—One oxygen atom as doubly bound oxygen atom or as unsubstituted hydroxy radical
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D257/00—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms
- C07D257/02—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms not condensed with other rings
- C07D257/04—Five-membered rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D261/00—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings
- C07D261/02—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings
- C07D261/06—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more double bonds between ring members or between ring members and non-ring members
- C07D261/10—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D261/18—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
- C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
- C07D263/30—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D263/32—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D265/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one oxygen atom as the only ring hetero atoms
- C07D265/28—1,4-Oxazines; Hydrogenated 1,4-oxazines
- C07D265/30—1,4-Oxazines; Hydrogenated 1,4-oxazines not condensed with other rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D271/00—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms
- C07D271/02—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms not condensed with other rings
- C07D271/06—1,2,4-Oxadiazoles; Hydrogenated 1,2,4-oxadiazoles
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
- C07D295/14—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D295/145—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with the ring nitrogen atoms and the carbon atoms with three bonds to hetero atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
- C07D295/15—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with the ring nitrogen atoms and the carbon atoms with three bonds to hetero atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D309/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings
- C07D309/32—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/05—Isotopically modified compounds, e.g. labelled
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2601/00—Systems containing only non-condensed rings
- C07C2601/06—Systems containing only non-condensed rings with a five-membered ring
- C07C2601/08—Systems containing only non-condensed rings with a five-membered ring the ring being saturated
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2601/00—Systems containing only non-condensed rings
- C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
- C07C2601/14—The ring being saturated
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2602/00—Systems containing two condensed rings
- C07C2602/02—Systems containing two condensed rings the rings having only two atoms in common
- C07C2602/04—One of the condensed rings being a six-membered aromatic ring
- C07C2602/08—One of the condensed rings being a six-membered aromatic ring the other ring being five-membered, e.g. indane
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Epidemiology (AREA)
- Diabetes (AREA)
- Endocrinology (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- Hematology (AREA)
- Biomedical Technology (AREA)
- Reproductive Health (AREA)
- Cardiology (AREA)
- Heart & Thoracic Surgery (AREA)
- Obesity (AREA)
- Pain & Pain Management (AREA)
- Emergency Medicine (AREA)
- Pulmonology (AREA)
- Gynecology & Obstetrics (AREA)
- Ophthalmology & Optometry (AREA)
- Hospice & Palliative Care (AREA)
- Urology & Nephrology (AREA)
- Psychiatry (AREA)
- Oncology (AREA)
- Dermatology (AREA)
- Rheumatology (AREA)
- Pregnancy & Childbirth (AREA)
- Child & Adolescent Psychology (AREA)
- Communicable Diseases (AREA)
Description
內源性心房利尿鈉肽(atrial natriuretic peptide,ANP),亦稱為心房利尿鈉因子(atrial natriuretic factor,ANF),在哺乳動物中具有利尿、利尿鈉及血管舒張功能。天然ANF肽會代謝失活,尤其因降解酶而代謝失活,已認識到該降級酶對應於酶中性肽鏈內切酶(neutral endopeptidase,NEP)EC 3.4.24.11,該酶亦負責例如腦啡肽之代謝失活。
中性肽鏈內切酶(EC 3.4.24.11;腦啡肽酶;心房肽酶(atriopeptidase);NEP)為一種含鋅金屬蛋白酶,其在多種肽受質之疏水性殘基的胺基側進行裂解[參見Pharmacol Rev
,第45卷,第87頁(1993)]。該酶之受質包括(但不限於)心房利尿鈉肽(ANP,亦稱為ANF)、腦利尿鈉肽(BNP)、met-及leu-腦啡肽、緩激肽、神經激肽A、內皮素-1及物質P。ANP為一種有效的血管舒張劑及利尿鈉劑[參見J Hypertens
,第19卷,第1923頁(2001)]。在正常個體中輸注ANP使得鈉尿及利尿可再現且顯著地增強,包括鈉排出率、尿流動速率及腎絲球濾過率增加[參見J Clin Pharmacol
,第27卷,第927頁(1987)]。然而,ANP在循環中具有短半衰期,且腎皮質膜中之NEP顯示為負責降解該肽之主要酶[參見Peptides
,第9卷,第173頁(1988)]。因此,NEP之抑制劑(中性肽鏈內切酶抑制劑,NEPi)應增加ANP之血漿含量,且由此預期誘導利尿鈉及利尿作用。
該酶參與多種生物活性寡肽之分解,在疏水性胺基酸殘基之胺基側裂解肽鍵。代謝之肽包括心房利尿鈉肽(ANP)、鈴蟾素(bombesin)、緩激肽、抑鈣素基因相關肽、內皮素、腦啡肽、神經調壓素、物質P及血管活性腸肽。一些該等肽具有有效的血管擴張及神經激素功能、利尿及利尿鈉活性或介導行為作用。
本發明之目的在於提供新穎的化合物,其在哺乳動物中適用作中性肽鏈內切酶抑制劑,例如適用作ANF降解酶之抑制劑,以便藉由抑制ANF降解成活性較低的代謝物而延長且增強ANF在哺乳動物中之利尿、利尿鈉及血管擴張性質。
因此,本發明之化合物尤其適用於治療對抑制中性肽鏈內切酶(NEP)EC 3.4.24.11有反應的病狀及病症。
因此,本發明之化合物藉由抑制中性肽鏈內切酶EC. 3.4.24.11可增強生物活性肽之生物作用。因此,特定言之,化合物具有治療多種以下病症之效用,包括高血壓、肺循環血壓過高、獨立性收縮性高血壓、頑固性高血壓、周邊血管疾病、心臟衰竭、充血性心臟衰竭、左心室肥大、絞痛、腎功能不全(糖尿病性或非糖尿病性)、腎衰竭(包括水腫及鹽滯留)、糖尿病性腎病變、非糖尿病性腎病變、腎病症候群、絲球體腎炎、硬皮病、腎絲球硬化症、原發性腎病蛋白尿、腎血管高血壓、糖尿病性視網膜病變及末期腎病(ESRD)、內皮功能異常、舒張功能異常、肥厚型心肌病、糖尿病性心肌病、室上及室性心律不整、心房纖維顫動(AF)、心臟纖維化、心房撲動、有害血管重塑、斑塊穩定、心肌梗塞(MI)、腎纖維化、多囊性腎病(PKD)、肺動脈高血壓、腎衰竭(包括水腫及鹽滯留)、週期性水腫、梅尼爾氏病(Menires disease)、高醛固酮症(原發性及繼發性)及高鈣尿症、腹水。另外,由於該等化合物能夠增強ANF之作用,所以其具有治療青光眼之效用。本發明化合物能夠抑制中性肽鏈內切酶E.C. 3.4.24.11之另一結果是,其可在其他治療領域內具有活性,包括例如治療月經異常、早產(preterm labour)、子癇前症、子宮內膜異位及生殖病症(尤其男性及女性不孕不育症、多囊卵巢症候群、植入失敗)。本發明化合物亦應治療哮喘、阻塞性睡眠呼吸暫停、炎症、白血病、疼痛、癲癇症、情感障礙(諸如抑鬱症)及精神病狀(諸如癡呆及老年精神錯亂)、肥胖症及胃腸病症(尤其腹瀉及大腸急躁症)、創傷癒合(尤其糖尿病性及靜脈性潰瘍及褥瘡)、敗血性休克、調節胃酸分泌、治療高腎素血症、囊性纖維化、再狹窄、第2型糖尿病、代謝症候群、糖尿病併發症及動脈粥樣硬化、男性及女性性功能障礙。在一較佳實施例中,本發明化合物適用於治療心血管病症。
本發明係關於化合物、其使用方法及其如本文所述之用途。本發明化合物之實例包括根據式I'及I至VIIC中任一者的化合物或其醫藥學上可接受之鹽及實例化合物。
因此,本發明提供式(I')化合物:
或其醫藥學上可接受之鹽,其中:R 1
為H、C1-7
烷基、羥基、C1-7
烷氧基、鹵素、-SH、-S-C1-7
烷基或NRa
Rb
;R 2
在每次出現時獨立地為C1-7
烷基、鹵基、NO2
、CN、C1-7
烷醯基胺基、C3-7
環烷基、羥基、C1-7
烷氧基、鹵基C1-7
烷基、-NRa
Rb
、C6-10
芳基、雜芳基或雜環基;其中Ra
及Rb
在每次出現時獨立地為H或C1-7
烷基;R 3
為A1
-C(O)X1
或A2
-R4
;R 4
為C6-10
芳基或雜芳基,其可為單環或雙環,且其可視情況經一或多個獨立地選自由以下組成之群的取代基取代:羥基、羥基C1-7
烷基、硝基、-NRa
Rb
、-C(O)C1-7
烷基、C(O)-O-C1-7
烷基、C1-7
烷氧基、鹵基、C1-7
烷基、鹵基-C1-7
烷基、C2-7
烯基、C6-10
芳基、雜芳基、-NHSO2
-C1-7
烷基及苯甲基;或R4
為雜環基,其可視情況經一或多個獨立地選自由以下組成之群的取代基取代:側氧基、羥基、羥基C1-7
烷基、胺基、C(O)-O-C1-7
烷基、C1-7
烷氧基、鹵基、C1-7
烷基、鹵基-C1-7
烷基、C6-10
芳基、雜芳基、-NHSO2
-C1-7
烷基及苯甲基;R 5
為H、鹵基、羥基、C1-7
烷氧基、鹵基、C1-7
烷基或鹵基-C1-7
烷基;且X
及X 1
獨立地為OH、-O-C1-7
烷基、-NRa
Rb
、-NHS(O)2
-C1-7
烷基、-NHS(O)2
-苯甲基或-O-C6-10
芳基;其中烷基視情況經一或多個獨立地選自由以下組成之群的取代基取代:C6-10
芳基、雜芳基、雜環基、C(O)NH2
、C(O)NH-C1-6
烷基及C(O)N(C1-6
烷基)2
;B 1
為-C(O)NH-或-NHC(O)-;A 1
為一鍵或為直鏈或分支鏈C1-7
伸烷基;其視情況經一或多個獨立地選自由以下組成之群的取代基取代:鹵基、C3-7
環烷基、C1-7
烷氧基、羥基及O-乙酸根;其中兩個偕位烷基可視情況組合形成C3-7
環烷基;或A 1
為直鏈或分支鏈C1-7
伸烯基;或A 1
為直鏈C1-4
伸烷基,其中一或多個碳原子經選自O、NRc
之雜原子置換;且A1
視情況經一或多個獨立地選自由鹵基及C1-7
烷基組成之群的取代基取代;其中Rc
在每次出現時獨立地為H、C1-7
烷基、-C(O)-O-C1-7
烷基或-CH2
C(O)OH;或A 1
為苯基或雜芳基;各自視情況經一或多個獨立地選自由以下組成之群的取代基取代:C1-7
烷基、C3-7
環烷基、鹵基-C1-7
烷基、羥基、C1-7
烷氧基、鹵基、-NRa
Rb
、-OCH2
CO2
H及-OCH2
C(O)NH2
;或A 1
為C3-7
環烷基;A 1
為-C1-4
伸烷基-C6-10
-芳基-、-C1-4
伸烷基-雜芳基-或-C1-4
伸烷基-雜環基-,其中A 1
可在任一方向上;且A 2
為一鍵或為直鏈或分支鏈C1-7
伸烷基;其視情況經一或多個獨立地選自由以下組成之群的取代基取代:鹵基、C1-7
烷氧基、羥基、O-乙酸根及C3-7
環烷基;n
為0、1、2、3、4或5;其中各雜芳基為包含5至10個選自碳原子及1至5個雜原子之環原子的單環或雙環芳族環,且各雜環基為包含4至7個選自碳原子及1至5個雜原子之環原子的單環飽和或部分飽和但為非芳族部分基團,其中雜芳基或雜環基之各雜原子獨立地選自O、N及S。
因此,本發明提供式(I)化合物:
或其醫藥學上可接受之鹽,其中:R 1
為H或C1-7
烷基;R 2
在每次出現時獨立地為C1-7
烷基、鹵基、NO2
、CN、C1-7
烷醯基胺基、C3-7
環烷基、羥基、C1-7
烷氧基、鹵基C1-7
烷基、-NRa
Rb
、C6-10
芳基、雜芳基或雜環基;其中Ra
及Rb
在每次出現時獨立地為H或C1-7
烷基;R 3
為A1
-C(O)X1
或A2
-R4
;R 4
為C6-10
芳基或雜芳基,其可為單環或雙環,且其可視情況經一或多個獨立地選自由以下組成之群的取代基取代:羥基、羥基C1-7
烷基、胺基、C(O)-O-C1-7
烷基、C1-7
烷氧基、鹵基、C1-7
烷基、鹵基-C1-7
烷基、C6-10
芳基、雜芳基、-NHSO2
-C1-7
烷基及苯甲基;或R4
為雜環基,其可視情況經一或多個獨立地選自由以下組成之群的取代基取代:側氧基、羥基、羥基C1-7
烷基、胺基、C(O)-O-C1-7
烷基、C1-7
烷氧基、鹵基、C1-7
烷基、鹵基-C1-7
烷基、C6-10
芳基、雜芳基、-NHSO2
-C1-7
烷基及苯甲基;R 5
為H、鹵基、羥基、C1-7
烷氧基、鹵基、C1-7
烷基或鹵基-C1-7
烷基;且X
及X 1
獨立地為OH、-O-C1-7
烷基、NRa
Rb
或-O-C6-10
芳基;其中烷基視情況經一或多個獨立地選自由以下組成之群的取代基取代:C6-10
芳基、雜芳基、雜環基、C(O)NH2
、C(O)NH-C1-6
烷基及C(O)N(C1-6
烷基)2
;B 1
為-C(O)NH-或-NHC(O)-;A 1
為一鍵或為直鏈或分支鏈C1-7
伸烷基;其視情況經一或多個獨立地選自由以下組成之群的取代基取代:鹵基、C3-7
環烷基、C1-7
烷氧基、羥基及O-乙酸根;其中兩個偕位烷基可視情況組合形成C3-7
環烷基;或A 1
為苯基或雜芳基;各自視情況經一或多個獨立地選自由以下組成之群的取代基取代:C1-7
烷基、C3-7
環烷基、鹵基-C1-7
烷基、羥基、C1-7
烷氧基、鹵基、-NRa
Rb
、-OCH2
CO2
H及-OCH2
C(O)NH2
;或A 1
為C3-7
環烷基;A 1
為-C1-4
伸烷基-C6-10
芳基-、-C1-4
伸烷基-雜芳基-或-C1-4
伸烷基-雜環基-,其A 1
可在任一方向上;且A 2
為一鍵或為直鏈或分支鏈C1-7
伸烷基;其視情況經一或多個獨立地選自由以下組成之群的取代基取代:鹵基、C1-7
烷氧基、羥基、O-乙酸根及C3-7
環烷基;n
為0、1、2、3、4或5;其中各雜芳基為包含5至10個選自碳原子及1至5個雜原子之環原子的單環或雙環芳族環,且各雜環基為包含4至7個選自碳原子及1至5個雜原子之環原子的單環飽和或部分飽和但為非芳族部分基團,其中雜芳基或雜環基之各雜原子獨立地選自O、N及S。
在另一實施例中,本發明係關於治療個體對抑制中性肽鏈內切酶EC 3.4.24.11(NEP)有反應之病症或疾病的方法,該方法藉由投與個體治療有效量之根據式I'及I至VIIC中任一者之化合物或其醫藥學上可接受之鹽,以使該個體中對抑制中性肽鏈內切酶EC 3.4.24.11(NEP)有反應之病症或疾病得以治療。
在又一實施例中,本發明係關於治療以下疾病之方法:高血壓、肺循環血壓過高、獨立性收縮性高血壓、頑固性高血壓、周邊血管疾病、心臟衰竭、充血性心臟衰竭、左心室肥大、絞痛、腎功能不全(糖尿病性或非糖尿病性)、腎衰竭(包括水腫及鹽滯留)、糖尿病性腎病變、非糖尿病性腎病變、腎病症候群、絲球體腎炎、硬皮病、腎絲球硬化症、原發性腎病蛋白尿、腎血管高血壓、糖尿病性視網膜病變及末期腎病(ESRD)、內皮功能異常、舒張功能異常、肥厚型心肌病、糖尿病性心肌病、室上及室性心律不整、心房纖維顫動(AF)、心臟纖維化、心房撲動、有害血管重塑、斑塊穩定、心肌梗塞(MI)、腎纖維化、多囊性腎病(PKD)、肺動脈高血壓、腎衰竭(包括水腫及鹽滯留)、週期性水腫、梅尼爾氏病、高醛固酮症(原發性及繼發性)及高鈣尿症、腹水、青光眼、月經異常、早產、子癇前症、子宮內膜異位及生殖病症(尤其男性及女性不孕不育症、多囊卵巢症候群、植入失敗)、哮喘、阻塞性睡眠呼吸暫停、炎症、白血病、疼痛、癲癇症、情感障礙(諸如抑鬱症)及精神病狀(諸如癡呆及老年精神錯亂)、肥胖症及胃腸病症(尤其腹瀉及大腸急躁症)、創傷癒合(尤其糖尿病性及靜脈性潰瘍及褥瘡)、敗血性休克、胃酸分泌功能異常、高腎素血症、囊性纖維化、再狹窄、第2型糖尿病、代謝症候群、糖尿病併發症及動脈粥樣硬化、男性及女性性功能障礙,該方法包含投與個體治療有效量之根據式I'及I至VIIC中任一者之化合物或其醫藥學上可接受之鹽,以使該個體得以治療。
在又一實施例中,本發明係關於醫藥組合物,其包含根據式I'及I至VIIC中任一者之化合物或其醫藥學上可接受之鹽,及一或多種醫藥學上可接受之載劑。
在又一實施例中,本發明係關於組合,其包括根據式I'及I-VIC中任一者之化合物或其醫藥學上可接受之鹽,及一或多種治療活性劑之醫藥組合。
在另一實施例中,本發明係關於抑制個體之中性肽鏈內切酶EC 3.4.24.11之方法,該方法藉由投與個體治療有效量之根據式I'及I至VIIC中任一者之化合物或其醫藥學上可接受之鹽,以使中性肽鏈內切酶EC 3.4.24.11得以抑制。
下文提及式I或I'化合物同樣適用於根據式IA至VIIC中任一者之化合物。
下文提及本發明之實施例同樣適用於式I或I'化合物及根據式IA至VIIC中任一者之化合物,只要該等實施例存在。
本文描述本發明之各種實施例。應認識到各實施例中指定之特徵可與其他指定特徵組合以提供其他實施例。
在一實施例中,本發明提供式I或I'之化合物或其醫藥學上可接受之鹽,其中:R 1
為H或C1-7
烷基;R 2
在每次出現時獨立地為C1-7
烷基、鹵基、C3-7
環烷基、羥基、C1-7
烷氧基、鹵基C1-7
烷基、-NRa
Rb
、C6-10
芳基、雜芳基或雜環基;其中Ra
及Rb
在每次出現時獨立地為H或C1-7
烷基;R 3
為A1
-C(O)X1
或A2
-R4
;R 4
為C6-10
芳基或雜芳基,其可為單環或雙環,且其可視情況經一或多個獨立地選自由以下組成之群的取代基取代:羥基、C1-7
烷氧基、鹵基、C1-7
烷基、鹵基-C1-7
烷基、C6-10
芳基、雜芳基、-NHSO2
-C1-7
烷基及苯甲基;R 5
為H;且X
及X 1
獨立地為OH、-O-C1-7
烷基或NRa
Rb
;B 1
為-C(O)NH-或-NHC(O)-;A 1
為直鏈或分支鏈C1-7
伸烷基;其視情況經一或多個獨立地選自由以下組成之群的取代基取代:鹵基、C3-7
環烷基、C1-7
烷氧基、羥基及O-乙酸根;其中兩個偕位烷基可視情況組合形成C3-7
環烷基;或A 1
為苯基或雜芳基;各自視情況經一或多個獨立地選自由以下組成之群的取代基取代:C1-7
烷基、C3-7
環烷基、鹵基-C1-7
烷基、羥基、C1-7
烷氧基、鹵基、-NRa
Rb
、-OCH2
CO2
H及-OCH2
C(O)NH2
;且A 2
為一鍵或為直鏈或分支鏈C1-7
伸烷基;其視情況經一或多個獨立地選自由以下組成之群的取代基取代:鹵基、C1-7
烷氧基、羥基、O-乙酸根及C3-7
環烷基;且n
為0、1、2、3、4或5;其中各雜芳基為包含5至10個選自碳原子及1至5個雜原子之環原子的單環或雙環芳族環,且各雜環基為包含4至7個選自碳原子及1至5個雜原子之環原子的單環飽和或部分飽和但為非芳族部分基團,其中雜芳基或雜環基之各雜原子獨立地選自O、N及S。
某些式I或I'化合物包括式IA化合物,其中攜帶聯苯基之碳處之立體化學為(R):
或其醫藥學上可接受之鹽,其中X、R1
、R2
、B1
、R3
及n具有上述式I或I'之定義。
在一實施例中,本發明係關於式I或I'化合物或其醫藥學上可接受之鹽,其中n為1、2、3、4或5;R2
為鹵基且連接於間位,且另一可選R2
基團獨立地為C1-7
烷基、NO2
、CN、鹵基、C3-7
環烷基、羥基、C1-7
烷氧基、鹵基-C1-7
烷基、NRb
Rc
、C6-10
芳基、雜芳基或雜環基。該實施例例如為式IB及IC化合物:
或其醫藥學上可接受之鹽,其中X、R1
、R2
、B1
、R3
具有上述式I或I'之定義;p為0、1、2、3或4;且R2a
為鹵基。
某些式I或I'
化合物包括式II化合物:
或其醫藥學上可接受之鹽,其中X、X1
、A1
、R1
、R2
及n具有上述式I或I'
之定義。
在另一實施例中,本發明係關於式II化合物,其中攜帶聯苯基之碳處之立體化學為(R)。該實施例例如為式IIA化合物:
或其醫藥學上可接受之鹽,其中X、X1
、A1
、R1
、R2
及n具有上述式I或I'
之定義。
某些式I、I'
或II化合物包括式IIB 或IIC化合物:
或其醫藥學上可接受之鹽,其中X、X1
、A1
、R1
、R2
具有上述式I或I'
之定義;p為0、1、2、3或4,且R2
a為鹵基。
某些式I或I'
化合物包括式III化合物:
或其醫藥學上可接受之鹽,其中X、X1
、A1
、R1
、R2
及n
具有上述式I或I'
之定義。
在另一實施例中,本發明係關於式III化合物,其中攜帶聯苯基之碳處之立體化學為(R)。該實施例例如為式IIIA化合物:
或其醫藥學上可接受之鹽,其中X、X1
、A1
、R1
、R2
及n具有上述式I或I'
之定義。
某些式III化合物包括式IIIB 或 IIIC化合物:
或其醫藥學上可接受之鹽,其中X、X1
、A1
、R1
、R2
具有上述式I或1'
之定義;p為0、1、2、3或4,且R2
a為鹵基。
在另一實施例中,本發明提供根據式I'
、I至IC、II至IIC及III至IIIC或本文所述之任何類別及子類中任一者之化合物,或其醫藥學上可接受之鹽或溶劑合物,其中A1
為直鏈C1-7
伸烷基,其視情況經一或多個獨立地選自由以下組成之群的取代基取代:鹵基、C1-7
烷氧基、羥基、O-乙酸根及C3-
7環烷基;其中兩個偕位烷基可視情況組合形成C3-7
環烷基。
另一實施例包括根據式I'
、I至IC、II至IIC 及III至IIIC或本文所述之任何類別及子類中任一者之化合物,或其醫藥學上可接受之鹽,其中A1
為-CH2
-、-CH2
CH2-
、-
CH2
CH2
CH2-
,或A1
具有下式:或其中Rc1
、Rc2
、Rd1
、Rd2
、Re1
、Re2
、Re3
及Re4
獨立地為H、鹵基、C3-7
環烷基或C1-7
烷基;且或者Rc1
及Rc2
或Rd1
及Rd2
可與其所連接之原子一起形成C3-7
環烷基。在該實施例之一態樣中,A1
為以下之一:
又一實施例包括根據式I'
、I至IC、II至IIC 及III至IIIC或本文所述之任何類別及子類中任一者之化合物,或其醫藥學上可接受之鹽,其中A1
具有下式:
其中Rf1
、Rf2
、Rf3
及Rf4
獨立地為H、鹵基、O-乙酸根或C1-7
烷基。在另一實施例中,A1
為以下之一:或在又一實施例中,本發明提供根據式I'
、I至IC、II至IIC及III至IIIC或本文所述之任何類別及子類中任一者之化合物,或其醫藥學上可接受之鹽或溶劑合物,其中A1
為C3
.7
環烷基。該實施例之實例為式I'
、I至IC、II至IIC 及III至IIIC中任一者之化合物,其中A1
選自以下:
及在又一實施例中,本發明提供根據式I'
、I至IC、II至IIC及III至IIIC或本文所述之任何類別及子類中任一者之化合物,或其醫藥學上可接受之鹽或溶劑合物,其中A1
為直鏈或分支鏈C2-7
伸烯基。C2-7
伸烯基之一實例為反式CH=CH。
在又一實施例中,本發明提供根據式I'
、I至IC、II至IIC及III至IIIC或本文所述之任何類別及子類中任一者之化合物,或其醫藥學上可接受之鹽或溶劑合物,其中A1
為直鏈C1-4
伸烷基,其中一或多個碳原子經選自O、NRc之雜原子置換;且A1
視情況經一或多個獨立地選自由鹵基及C1-7
烷基組成之群的取代基取代;其中Rc在每次出現時獨立地為H、C1-7
烷基、-C(O)OC1-7
烷基或CH2
C(O)OH。另一實施例包括式I'
、I至IC、II至IIC 及III至IIIC 之化合物,其中A1
為以下之一:
在又一實施例中,本發明提供根據式I'
、I至IC、II至IIC及III至IIIC或本文所述之任何類別及子類中任一者之化合物,或其醫藥學上可接受之鹽或溶劑合物,其中A1
為視情況經取代之苯基或雜芳基,其中可選取代基係如式I或I'
中所定義。
上述實施例之某些化合物包括根據式I'
、I至IC、II至IIC及III至IIIC中任一者之化合物,或其醫藥學上可接受之鹽,其中A1
為5員環雜芳基。該實施例例如為式IV化合物:
或其醫藥學上可接受之鹽,其中X、X1
、B1
、R1
、R2
及n具有上述式I或I'之定義,且Y1
、Y2
及Y3
獨立地為N、NH、S、O或CH,且與其所連接之環原子一起形成5員雜芳基環。
在該實施例之一態樣中,本發明係關於式IVA化合物:
或其醫藥學上可接受之鹽,其中X、X1
、B1
、R1
、R2
、Y1
、Y2
、Y3
及n具有上述式I、I'或IV之定義。
在該實施例之一態樣中,Y1
、Y2
及Y3
與其所連接之環原子一起形成5員雜芳基環,該環係選自呋喃、噻吩、吡咯、吡唑、噁唑、噻唑、噁二唑、噻二唑及三唑。另一實施例包括式IV或VIA化合物,或其醫藥學上可接受之鹽,其中5員雜芳基為以下之一:
或 或在另一實施例中,本發明係關於式IV或IVA化合物,其中n為1、2、3、4或5;R2
為間位鹵基且另一可選R2
基團獨立地為C1-7
烷基、NO2
、CN、鹵基、C3-7
環烷基、羥基、C1-7
烷氧基、鹵基-C1-7
烷基、NRb
Rc、C6-10
芳基、雜芳基或雜環基。
在上述實施例之又一態樣中,本發明係關於式I'
、I至IC、II至IIC 或III至 IIIC化合物,或其醫藥學上可接受之鹽,其中A1
為在氮原子處連接至醯胺B1
之5員環雜芳基。
該實施例例如為式V或VA化合物:
或其醫藥學上可接受之鹽,其中X、X1
、B1
、R1
、R2
及n具有上述式I或I'
之定義,且各Y4
獨立地為N、S、O或CH。在另一實施例中,本發明係關於式V或VA化合物,其中n為1、2、3、4或5;R2
為間位鹵基且另一可選R2
基團獨立地為C1-7
烷基、NO2
、CN、鹵基、C3-7
環烷基、羥基、C1-7
烷氧基、鹵基-
C1-7
烷基、NRb
Rc、C6-10
芳基、雜芳基或雜環基。
在上述實施例之又一態樣中,本發明提供根據式I'
、I至IC、II至IIC 及III至IIIC或本文所述之任何類別及子類中任一者之化合物,或其醫藥學上可接受之鹽或溶劑合物,其中A1
為苯基或6員環雜芳基,其中苯基及雜芳基視情況經以下取代:C1-7
烷基、C3-7
環烷基、鹵基-C1-7
烷基、羥基、C1-7
烷氧基、鹵基、NRa
Rb
、-OCH2
CO2
H或-OCH2
C(O)NH2
。該實施例之一態樣包括根據式I'、I至IC、II至IIC及III至IIIC中任一者之化合物,或其醫藥學上可接受之鹽,其中A1
連接至呈對位排列之醯胺B1
及C(O)X1
部分。該實施例之另一態樣包括根據式I'
、I至IC、II至IIC 及III至IIIC中任一者之化合物,其中A1
連接至呈間位排列之醯胺B1
及C(O)X1
部分。該實施例之化合物包括式VI化合物:
或其醫藥學上可接受之鹽,其中X、X1
、B1
、R1
、R2
及n
具有上述式I或I'
之定義,且W1
、W2
、W3
及W4
獨立地為N或CRe
,其中各Re
獨立地為H、C1-7
烷基、C3-7
環烷基、鹵基-
C1-7
烷基、羥基、C1-7
烷氧基、鹵基、-NRa
Rb、-OCH2
CO2
H或-OCH2
C(O)NH2
。在該實施例之一態樣中,A1
為苯基、吡啶或嘧啶。
在另一實施例中,本發明係關於式VIA化合物:
或其醫藥學上可接受之鹽,其中X、X1
、B1
、R1
、R2
、W1
、W2
、W3
及W4
及n
具有上述式I、I'
或VI之定義。
另一實施例包括式VI或VIA化合物,或其醫藥學上可接受之鹽,其中A1
為以下之一:
或在另一實施例中,本發明係關於式VI或VIA化合物,或其醫藥學上可接受之鹽,其中n為1、2、3、4或5;R2
為間位鹵基且另一可選R2
基團獨立地為C1-7
烷基、NO2
、CN、鹵基、C3-7
環烷基、羥基、C1-7
烷氧基、鹵基-C1-7
烷基、NRb
Rc、C6-10
芳基、雜芳基或雜環基。
在前述實施例之一態樣中,本發明係關於根據式I/
、I至IC、IV至IVC、V至VC及VI至VIC中任一者之化合物,或其醫藥學上可接受之鹽,其中B1
為-C(O)NH-。在另一實施例中,B1
為-NHC(O)-。
上述實施例之某些化合物包括根據式I'
、I至IC、II至IIC及III至IIIC中任一者之化合物,或其醫藥學上可接受之鹽,其中A1
為-C1-4
伸烷基-C6-10
-芳基-、-
C1-4
伸烷基-
雜芳基-或-C1-
4伸烷基-雜環基-、-C6-10
芳基-C1-4
-伸烷基-
、-
雜芳基-C1.4伸烷基或-雜環基-C1-4
伸烷基-。在該實施例之一態樣中,A1
為-C1-4
伸烷基-C6-10
-芳基-
、-
C1-4
伸烷基-
雜芳基-
或-C1-
4伸烷基-雜環基-,其中伸烷基部分連接於B1
醯胺基且芳基、雜芳基或雜環基部分連接於C(O)X1
。在該實施例之另一態樣中,A1
為-CH2
-苯基-或-苯基-CH2-
。在該實施例之另一態樣中,A1
為-CH2
-雜芳基或-雜芳基-
CH2-
。在另一實施例中,A1
為-CH2
-雜環基或-雜環基-
CH2-
。A1
之代表性實例為以下:
某些式I或I'
化合物包括式VII化合物:
或其醫藥學上可接受之鹽,其中X、A2
、R1
、R2
、R4
及n具有上述式I或I'
之定義。另一實施例包括式VIIA化合物:
或其醫藥學上可接受之鹽,其中X、A2
、R1
、R2
、R4
及n具有上述式I或I'
之定義。
某些式VII或 VIIA化合物具有式VIIB 或 VIIC:
或其醫藥學上可接受之鹽,其中X、A2
、R1
、R2
、R4
具有上述式I或I'
之定義;p為0、1、2、3或4,且R2
a為鹵基。
該實施例之另一態樣包括根據式VII至VIIC中任一者之化合物,或其醫藥學上可接受之鹽,其中A2
為(CH2
)p
,且p為0、1、2、3。在該實施例之一態樣中,p為0,因此A2
為一鍵。在該實施例之另一態樣中,A2
為CH2
或CH2
-CH2
。
在該實施例之另一態樣中,本發明提供根據式VII至VIIC中任一者之化合物,或其醫藥學上可接受之鹽,其中R4
為視情況經取代之C6-10
芳基。芳基之代表性實例為苯并咪唑酮、苯并異噻唑酮或苯基。在該實施例之另一態樣中,R4
為苯基。苯環上之取代基包括例如鹵基(例如F、C1)、羥基、鹵基-C1-7
烷基(例如CF3
)、-NHS(O)2
-C1-7
烷基、雜芳基、C1-7
烷氧基或C1-7
烷基。
在該實施例之另一態樣中,本發明提供根據式VII至VIIC中任一者之化合物,或其醫藥學上可接受之鹽,其中R4
為視情況經取代之雙環雜芳基。
在該實施例之另一態樣中,本發明提供根據式VII至VIIC中任一者之化合物,或其醫藥學上可接受之鹽,其中R4
為視情況經取代之5員或6員雜芳基。在該實施例之一態樣中,R4
為6員環雜芳基,其係選自由以下組成之群:吡嗪基、吡基、嘧基、側氧基-哌喃基(例如哌喃酮、視情況經取代之哌喃-4-酮、哌喃-2-酮,諸如3-羥基-哌喃-4-酮、3-羥基-哌喃-2-酮)及側氧基-吡啶基(例如吡啶酮、視情況經取代之吡-4-酮或吡-2-酮,諸如3-羥基-1-甲基-吡-4-酮或1-苯甲基-吡-2-酮)或嘧啶酮(亦即側氧基-嘧基)。在該實施例之另一態樣中,R4
為5員環雜芳基,其係選自由以下組成之群:坐、吡咯、吡坐、異坐、三坐、
四坐、二坐(例如1--3,4-二坐、1--2,4-二坐)、噁二坐酮(例如噁二坐-2-酮)、坐、異坐、吩、咪坐及二唑。R4
之其他代表性實例為唑酮、唑酮、二唑酮、三唑酮、唑酮、咪唑酮、吡唑酮。在另一實施例中,C6-10
芳基及雜芳基上之可選取代基選自羥基、C1-7
烷基、C1-7
烷氧基、鹵基、鹵基-C1-7
烷基或苯甲基。
在上述實施例之另一態樣中,本發明提供根據式VII至VIIC中任一者之化合物,或其醫藥學上可接受之鹽,其中R4
為雙環雜芳基。另一實施例包括根據式VII至VIIC中任一者之化合物,或其醫藥學上可接受之鹽,其中R4
為引、苯并唑或苯并咪唑。R4
之代表性實例為以下:
在上述實施例之另一態樣中,本發明提供根據式VII至VIIC中任一者之化合物,或其醫藥學上可接受之鹽,其中R4
為單環飽和或部分飽和雜環基,該雜環基含有至少一個選自氮、硫及氧之雜原子,且該雜環基視情況經一或多個獨立地選自由以下組成之群的取代基取代:側氧基、羥基、C1-7
烷氧基、鹵基、C1-7
烷基、鹵基-C1-7
烷基、C6-10
芳基、雜芳基、-NHSO2
-C1-7
烷基及苯甲基。在該實施例之一特定態樣中,R4
為吡咯啶或咪唑啶,其中該雜環基可經由碳或氮連接於羰基(C(O)-A2
)部分,且該雜環基係視情況經側氧基取代。
在一實施例中,本發明提供根據式I'
、I至IC、II至IIC、III至IIIC、IV、IVA、V、VA、VI、VIA 及 VII至 VIIC中任一者之化合物,或其醫藥學上可接受之鹽,其中R1
為H。
在另一實施例中,本發明提供根據式I'
、I至IC、II至IIC、III至IIIC、IV、IVA、V、VA、VI、VIA 及 VII至 VIIC中任一者之化合物,或其醫藥學上可接受之鹽,其中各R2
獨立地為鹵基、C1-7
烷基、C1-7
烷氧基、羥基、鹵基-C1-7
烷基且n為0、1或2。在另一實施例中,n為1、2、3、4或5,R2
為間位鹵基且另一可選R2
基團獨立地為鹵基、C1-7
烷基、C1-7
烷氧基、羥基或鹵烷基。在另一實施例中,本發明提供根據式I'
、I至 IC、II至 IIC、III至 IIIC、IV、IVA、V、VA、VI、VIA 及 VII至 VIIC中任一者之化合物,或其醫藥學上可接受之鹽,其中n為1或2,R2
為間位氯或間位氟,且另一可選R2
基團為鹵基、C1-7
烷基、C1-7
烷氧基、羥基或鹵烷基。
在又一實施例中,本發明提供根據式I'
、I至IC、II至IIC、III至IIIC、I、IVA、V、VA、VI、VIA 及 VII至 VIIC中任一者之化合物,或其醫藥學上可接受之鹽,其中X及X1
獨立地為OH或-O-C1-7
烷基(例如-O-乙基、-O-甲基或-O-正丁基)。在該實施例之一特定態樣中,X及X1
為OH。在該實施例之另一態樣中,X及X1
獨立地為-O-C1-7
烷基,其中烷基係經以下取代:C6-10
芳基、雜芳基、雜環基、C(O)NH2
、C(O)NH-C1-6
烷基或C(O)N(C1-6
烷基)2
。X或X1
之代表性實例為-O-CH2
-C(O)N(CH3
)2
、-O-CH2
-CH2-嗎啉、-
O-
CH2-
間二氧雜環戊烯酮或-O-苯甲基。在該實施例之另一態樣中,X及X1
為-O-C6-10
芳基。-O-C6-10
芳基之一代表性實例為-O-(2,3-二氫-1H-茚)。
在另一實施例中,X、X1
、B1
、A1
、A2
、R2
、R1
及R4
基團為由下文實例章節中之X、X1
、A1
、A2
、B1
、R2
、R1
及R4
基團定義的基團。
在另一實施例中,本發明之個別化合物為下文實例章節中所列之化合物或其醫藥學上可接受之鹽。
定義
出於闡釋本說明書之目的,除非另外規定,否則以下定義將適用,且適當時,以單數使用之術語亦將包括複數,且反之亦然。
如本文所使用之術語「烷基」係指包含1至20個碳原子之完全飽和的分支或未分支(或直鏈)烴部分。烷基較佳包含1至7個碳原子,且更佳包含1至4個碳原子。烷基之代表性實例包括甲基、乙基、正丙基、異丙基、正丁基、第二丁基、異丁基、第三丁基、正戊基、異戊基、新戊基、正己基、3-甲基己基、2,2-二甲基戊基、2,3-二甲基戊基、正庚基。術語「C1-7
烷基」係指具有1至7個碳原子之烴。此外,術語烯基包括「未經取代烷基」與「經取代烷基」。
術語「伸烷基」係指二價烷基,其中烷基係如先前所定義。
術語「烯基」係指具有至少一個碳碳雙鍵之分支或未分支烴。術語「C2-7
烯基」係指具有2至7個碳原子且包含至少一個碳碳雙鍵之烴。烯基之代表性實例為乙烯基、丙-
1-
烯基、烯丙基、丁烯基、異丙烯基或異丁烯基。術語「伸烯基」係指二價烯基,其中烯基係如先前所定義。
如本文所使用之術語「鹵烷基」係指如本文所定義之烷基經一或多個如本文所定義之鹵基取代。鹵烷基較佳可為單鹵烷基、二鹵烷基或多鹵烷基(包括全鹵烷基)。單鹵烷基可在烷基內具有一個碘、溴、氯或氟。二鹵烷基及多鹵烷基可在烷基內具有兩個或兩個以上相同鹵原子或不同鹵基之組合。多鹵烷基較佳含有至多12、或10、或8、或6、或4、或3、或2個鹵基。鹵烷基之代表性實例為氟甲基、二氟甲基、三氟甲基、氯甲基、二氯甲基、三氯甲基、五氟乙基、七氟丙基、二氟氯甲基、二氯氟甲基、二氟乙基、二氟丙基、二氯乙基及二氯丙基。全鹵烷基係指烷基之所有氫原子經鹵原子置換。術語「鹵基-C1-7
烷基」係指具有1至7個碳原子且經一或多個鹵基取代之烴。
如本文所使用之術語「烷氧基」係指烷基-O-,其中烷基係如上文所定義。烷氧基之代表性實例包括(但不限於)甲氧基、乙氧基、丙氧基、2-丙氧基、丁氧基、第三丁氧基、戊氧基、己氧基、環丙氧基-、環已氧基-及其類似基團。烷氧基較佳具有約1-7個碳,更佳約1-4個碳。
如本文所使用之術語「環烷基」係指具有3-12個碳原子、較佳3-8個或3-7個碳原子之飽和或不飽和但為非芳族之單環、雙環或三環烴基。對於雙環及三環環烷基系統,所有環均為非芳族。例示性單環烴基包括環丙基、環丁基、環戊基、環戊烯基、環己基及環己烯基。例示性雙環烴基包括莰基、十氫萘基、雙環[2.1.1]己基、雙環[2.2.1]庚基、雙環[2.2.1]庚烯基、雙環[2.2.2]辛基。例示性三環烴基包括金剛烷基。術語「C3-7
環烷基」係指具有3至7個碳原子之環烴基。術語「環烷基烷基」係指烷基經環烷基取代。
術語「芳基」係指環部分中具有6-10個碳原子之單環或雙環芳族烴基。術語「芳基」亦指芳族環稠合至環烷基環之基團,其中連接基團位於芳族環上或稠合之環烷基環上。芳基之代表性實例為苯基、萘基、六氫茚基、茚滿基或四氫萘基。術語「C6-10
芳基」係指環部分中具有6至10個碳原子之芳族烴基。
術語「芳基烷基」為烷基經芳基取代。芳基烷基之代表性實例為苯甲基或苯基-CH2
CH2
-。該術語亦包括經取代之芳基烷基部分。
術語「雜芳基」包括含有5-10個選自碳原子及1至5個雜原子之環成員的單環或雙環雜芳基,且各雜原子獨立地選自O、N或S,其中S及N可氧化成各種氧化態。對於雙環雜芳基系統,該系統為完全芳族(亦即所有環為芳族)。
典型的單環雜芳基包括吩基、喃基、吡咯基、咪唑基、吡唑基、唑基、異唑基、-2,3-二唑基、-2,4-二唑基、-2,5-二唑基、-3,4-二唑基、-2,3-二唑基、-2,4-二唑基、-2,5-二唑基、-3,4-二唑基、3-、4-或5-異唑基、2-、4-或5-唑基、3-、4-或5-異唑基、3-或5-1,2,4-三唑基、4-或5-1,2,3-三唑基、四唑基、2-、3-或4-吡基、3-或4-噠嗪基、3-、4-或5-吡嗪基、2-吡嗪基、2-、4-或5-密啶基。
術語「雜芳基」亦指雜芳族環稠合至一或多個芳基、環脂族或雜環基環之基團,其中連接基團或連接點位於雜芳族環上或稠合之芳基環上。雙環雜芳基之代表性實例為吲基、異吲基、吲唑基、吲嗪基、嘌呤基、喹嗪基、喹啉基、異喹啉基、啉基、呔嗪基、基、喹唑啉基、喹喏啉基、吩并[2,3-b]喃基、喃并[3,2-b]哌喃基、5H-比并[2,3-d]-o-嗪基、1H-比唑并[4,3-d]唑基、4H-咪唑并[4,5-d]唑基、比嗪并[2,3-d]噠嗪基、咪唑并[2,1-b]唑基、咪唑并[1,2-b][1,2,4]三嗪基、7-苯并[b]吩基、苯并唑基、苯并咪唑基、苯并唑基、苯并氧呯基、苯并嗪基、1H-比咯并[1,2-b][2]苯并氮呯基、苯并喃基、苯并吩基、苯并三唑基、比咯并[2,3-b]比基、比咯并[3,2-c]比基、比咯并[3,2-c]比基、比咯并[3,2-b]比基、咪唑并[4,5-b]比基、咪唑并[4,5-c]比基、比唑并[4,3-d]比基、比唑并[4,3-c]比基、比唑并[3,4-c]比啶基、比唑并[3,4-d]比基、比唑并[3,4-b]比基、咪唑并[1,2-a]比基、比唑并[1,5-a]比基、比咯并[1,2-b]噠嗪基、咪唑并[1,2-c]嘧基、比并[3,2-d]密基、比并[4,3-d]密基、比并[3,4-d]密基、比并[2,3-d]密基、比并[2,3-b]比基、比并[3,4-b]比嗪基、密并[5,4-d]密基、比嗪并[2,3-b]比嗪基或密并[4,5-d]密基。
當雜芳基部分經羥基取代時,本發明亦係關於其側氧基互變異構形式。舉例而言,經羥基取代之二唑亦包括側氧基-二唑或亦稱為二唑酮。互變異構化如下所示:
如本文所使用之術語「雜環基」係指為4、5、6或7員單環且含有至少一個選自O、S及N之雜原子的視情況經取代之飽和或不飽和非芳族(部分不飽和)環,其中N及S亦可視情況氧化成各種氧化態。對於雙環及三環雜環基環系統,非芳族環系統定義為非完全或部分不飽和環系統。因此,雙環及三環雜環基環系統包括一個稠合之環為芳族但另一(其他)為非芳族之雜環基環系統。在一實施例中,雜環基部分表示含有5-7個環原子且視情況含有另一選自O、S或N之雜原子之飽和單環。雜環基可在雜原子或碳原子處連接。雜環基可包括稠合或橋接之環以及螺環狀環。雜環之實例包括二氫喃基、二氧戊環基、二氧雜環己基、二烷基、哌嗪基、吡咯、二氫哌喃基、氧雜硫基、二硫雜環戊烷、氧硫雜環己烷基、N-硫嗎啉基、環氧乙烷基、氮丙基、氧雜環丁烷基、氧雜環庚烷基、丁基、四氫喃基、四氫吩基、吡咯基、四氫哌喃基、哌啶基、N-嗎啉基、哌嗪基、氮呯基、氧呯基、氧氮雜環庚烷基、氧硫雜環己烷基、硫雜環庚烷基、氮雜環庚烷基、二氧雜環庚烷基及二氮雜環庚烷基。
術語「羥基烷基」係指如上所述之烷基,其中烷基經一或多個羥基取代。
術語「鹵素」包括氟、溴、氯及碘。術語「全鹵化」泛指所有氫經鹵素原子置換之部分。
術語「雜原子」包括除碳或氫以外任何元素的原子。較佳雜原子為氮、氧、硫及磷。在另一實施例中,雜原子為氮、氧或硫。
應注意,一些本發明化合物之結構包括不對稱碳原子。相應地應瞭解,除非另外說明,否則本發明之範疇內包括由該不對稱性產生之異構體(例如所有對映異構體及非對映異構體)。該等異構體可利用經典的分離技術及立體化學控制合成呈實質上純之形式獲得。此外,本申請案中論述之結構及其他化合物及部分亦包括其所有互變異構體。
如本文所使用之術語「異構體」係指具有相同分子式但原子排列及構型不同的不同化合物。又,如本文所使用之術語「光學異構體」或「立體異構體」係指指定本發明化合物可能存在之任何各種立體異構構型且包括幾何異構體。應瞭解,取代基可連接於碳原子之對掌性中心。因此,本發明包括對映異構體、非對映異構體或化合物之外消旋體。「對映異構體」為一對彼此成不重疊鏡像之立體異構體。一對對映異構體之1:1混合物為「外消旋」混合物。適當時,該術語用於指外消旋混合物。「非對映異構體」為具有至少兩個不對稱原子但彼此不成鏡像之立體異構體。絕對立體化學根據Cahn-1ngo1d-Pre1og R-S系統指定。當化合物為純對映異構體時,各對掌性碳處之立體化學可用R或S指定。絕對構型未知的拆分化合物可視其在鈉D線之波長下使平面偏振光旋轉之方向指定為(+)或(-)(右旋或左旋)。本文所述之某些化合物含有一或多個不對稱中心或軸,且因此可產生對映異構體、非對映異構體及其他立體異構形式,可根據絕對立體化學定義為(R)-或(S)-。
本發明意欲包括所有該等可能的異構體,包括外消旋混合物、光學純形式及中間混合物。光學活性(R)-及(S)-異構體可使用對掌性合成組元或對掌性試劑製備或使用習知技術拆分。若化合物含有雙鍵,則取代基可呈E或Z構型。若化合物含有經二取代之環烷基,則環烷基取代基可具有順式或反式構型。亦意欲包括所有互變異構形式。
本發明化合物之任何不對稱原子(例如碳或類似原子)可呈外消旋或對映異構增濃形式,例如(R)-、(S)-或(R,S)-構型。在某些實施例中,各不對稱原子之(R)-或(S)-構型具有至少50%之對映異構體過量、至少60%之對映異構體過量、至少70%之對映異構體過量、至少80%之對映異構體過量、至少90%之對映異構體過量、至少95%之對映異構體過量或至少99%之對映異構體過量。具有不飽和鍵之原子處之取代基可能時可呈順-(Z)-或反-(E)-形式。
因此,如本文所使用之本發明化合物可呈一種可能的異構體、旋轉異構體、滯轉異構體、互變異構體或其混合物形式,例如呈實質上純的幾何(順式或反式)異構體、非對映異構體、光學異構體(對映體)、外消旋體或其混合物形式。
任何所得異構體混合物可基於組分之物理化學差異例如利用層析及/或分步結晶分離成純或實質上純的幾何或光學異構體、非對映異構體、外消旋體。
最終產物或中間物之任何所得外消旋體可利用已知方法拆分成光學對映體,例如藉由分離利用光學活性酸或鹼獲得之其非對映異構鹽並釋放光學活性酸性或鹼性化合物來拆分。特定言之,因此可採用鹼性部分將本發明化合物拆分成其光學對映體,例如藉由分步結晶與光學活性酸形成之鹽來拆分,該光學活性酸例如酒石酸、二苯甲醯基酒石酸、二乙醯酒石酸、二-0,0'
-對甲苯甲醯基酒石酸、扁桃酸、蘋果酸或樟腦-10-磺酸。外消旋產物亦可利用對掌性層析(例如高壓液相層析(HPLC))使用對掌性吸附劑拆分。
如本文所使用之術語「醫藥學上可接受之鹽」係指保留本發明化合物之不為生物學或其他方面不合需要的生物效力及性質的鹽。在許多情況下,本發明化合物因存在胺基及/或羧基或其類似基團而能夠形成酸及/或鹼鹽。醫藥學上可接受之酸加成鹽可與無機酸及有機酸形成,例如乙酸鹽、天冬胺酸鹽、苯甲酸鹽、苯磺酸鹽、碳酸氫鹽/碳酸鹽、硫酸氫鹽/硫酸鹽、硼酸鹽、樟腦磺酸鹽、檸檬酸鹽、乙二磺酸鹽、乙磺酸鹽、甲酸鹽、反丁烯二酸鹽、葡庚糖酸鹽、葡糖酸鹽、葡萄糖醛酸鹽、六氟磷酸鹽、苯紮鹽(hibenzate)、鹽酸鹽/氯化物、氫溴酸鹽/溴化物、氫碘酸鹽/碘化物、羥乙磺酸鹽、乳酸鹽、蘋果酸鹽、順丁烯二酸鹽、丙二酸鹽、甲磺酸鹽、甲基硫酸鹽、萘酸鹽、2-萘磺酸鹽、菸鹼酸鹽、硝酸鹽、乳清酸鹽、草酸鹽、棕櫚酸鹽、雙羥萘酸鹽、磷酸鹽/磷酸氫鹽/磷酸二氫鹽、糖酸鹽、硬脂酸鹽、丁二酸鹽、酒石酸鹽、甲苯磺酸鹽及三氟乙酸鹽。可衍生出鹽之無機酸包括例如鹽酸、氫溴酸、硫酸、硝酸、磷酸及其類似物。可衍生出鹽之有機酸包括例如乙酸、丙酸、乙醇酸、丙酮酸、草酸、順丁烯二酸、丙二酸、丁二酸、反丁烯二酸、酒石酸、檸檬酸、苯甲酸、肉桂酸、扁桃酸、甲烷磺酸、乙烷磺酸、對甲苯磺酸、水楊酸及其類似物。醫藥學上可接受之鹼加成鹽可與無機及有機鹼形成。可衍生出鹽之無機鹼包括例如鈉、鉀、鋰、銨、鈣、鎂、鐵、鋅、銅、錳、鋁及其類似物;尤其較佳為銨、鉀、鈉、鈣及鎂鹽。可衍生出鹽之有機鹼包括例如一級、二級及三級胺、經取代胺(包括天然存在之經取代胺)、環胺、鹼性離子交換樹脂及其類似物,尤其諸如異丙胺、三甲胺、二乙胺、三乙胺、三丙胺及乙醇胺。本發明之醫藥學上可接受之鹽可利用習知化學方法由母體化合物、鹼性或酸性部分合成。一般而言,該等鹽可藉由使該等化合物之游離酸形式與化學計量之量的適當鹼(諸如鈉、鈣、鎂或鉀之氫氧化物、碳酸鹽、碳酸氫鹽或其類似物)反應或藉由使該等化合物之游離鹼形式與化學計量之量的適當酸反應來製備。該等反應通常在水中或在有機溶劑中或在兩者之混合物中進行。一般而言,可行時,如乙醚、乙酸乙酯、乙醇、異丙醇或乙腈之非水性介質較佳。其他適合鹽之清單可見於例如「Remington'
s Pharmaceutica1Sciences」,第20版,M ack Pub1ishing Company,Easton,Pa.,(1985);及Stah1及 Wermuth之「Handbook of Pharmaceutica1Sa1ts:Properties,Se1ection,and Use」(Wi1ey-V C H,W einheim,Germany,2002)。
任何本文所給出之式亦意欲表示化合物之未經標記形式以及經同位素標記之形式。舉例而言,本文之任何式中由「H」表示的任何氫均意欲表示氫的所有同位素形式(例如1
H、2
H或D、3
H);本文之任何式中由「C」表示的任何碳均意欲表示碳的所有同位素形式(例如11
C、13
C、14
C);由「N」表示的任何氮均意欲表示氮的所有同位素形式(例如14
N、15
N)。本發明中包括之同位素之其他實例包括氧、硫、磷、氟、碘及氯之同位素,諸如18
F、31
P、32
P、35
S、36
C1、125
I。本發明包括如本文所定義之各種經同位素標記之化合物,例如存在放射性同位素(諸如3
H、13
C及14
C)之化合物。在一實施例中,本文之式中的原子以其天然豐度存在。在另一實施例中,一或多個氫原子可富含2
H;或/及一或多個碳原子可富含11
C、13
C或14
C;或/及一或多個氮可富含14
N。該等經同位素標記之化合物適用於代謝研究(用14
C)、反應動力學研究(用例如2
H或3
H)、偵測或成像技術,諸如正電子發射斷層攝影術(PET)或單光子發射電腦斷層攝影術(SPECT)(包括藥物或受質組織分佈檢定),或適用於患者之放射性治療。特定言之,18
F或經標記化合物可能特別合乎PET或SPECT研究之需要。本發明之經同位素標記之化合物及其前藥一般可藉由執行下文描述之流程或實例及製備中揭示之程序用可輕易獲得之經同位素標記之試劑替代未經同位素標記之試劑來製備。
另外,富含重同位素(尤其氘(亦即2
H或D))可提供某些由較高代謝穩定性產生的治療優勢,例如活體內半衰期增加、或劑量需求減少、或治療指數提高。應瞭解,在此情形中氘視為根據式I'
及I至 VIIC中任一者之化合物的取代基。該重同位素(尤其氘)之濃度可由同位素增濃因素定義。如本文所使用之術語「同位素增濃因素」意謂指定同位素之同位素豐度與天然豐度之間的比率。若本發明化合物中之取代基指示為氘,則該化合物的各指定氘原子的同位素增濃因素為至少3500(各指定氘原子處的氘併入量為52.5%)、至少4000(氘併入量為60%)、至少4500(氘併入量為67.5%)、至少5000(氘併入量為75%)、至少5500(氘併入量為82.5%)、至少6000(氘併入量為90%)、至少6333.3(氘併入量為95%)、至少6466.7(氘併入量為97%)、至少6600(氘併入量為99%)或至少6633.3(氘併入量為99.5%)。
式I'
或I至VIIC之同位素增濃化合物一般可利用熟習此項技術者已知之習知技術或利用類似於隨附之實例及製備中所述之方法使用適當的同位素增濃試劑替代先前使用之非增濃試劑來製備。本發明之醫藥學上可接受之溶劑合物包括結晶溶劑可經同位素取代之溶劑合物,例如D2
O、d6
-丙酮、d6-DMSO。
含有能夠充當氫鍵之供體及/或接受體之基團的本發明化合物(亦即根據式I'
及I至 VIIC中任一者之化合物)可能能夠與適合的共晶體形成體形成共晶體。該等共晶體可由根據式I'
及I至 VIIC中任一者之化合物利用已知共晶體形成程序製備。該等程序包括碾磨、加熱、共昇華、共熔融或在溶液中使根據式I'
及I至 VIIC中任一者之化合物與共晶體形成體在結晶條件下接觸並分離由此形成之共晶體。適合的共晶體形成體包括WO2004/078163中所述者。因此,本發明進一步提供包含根據式I'
及I至 VIIC中任一者之化合物之共晶體。
如本文所使用之術語「醫藥學上可接受之載劑」包括一般技術者所已知之任何及所有溶劑、分散介質、包衣、界面活性劑、抗氧化劑、防腐劑(例如抗細菌劑、抗真菌劑)、等張劑、吸收延遲劑、鹽、防腐劑、藥物、藥物穩定劑、黏合劑、賦形劑、崩解劑、潤滑劑、甜味劑、調味劑、染料、其類似物質及組合(參見例如Remington'
sPharmaceutica1Sciences,第18版.M ack Printing Company,1990,第1289-1329頁)。除非任何習知載劑與活性成分不相容,否則涵蓋其在治療劑或醫藥組合物中之使用。
術語本發明化合物之「治療有效量」係指本發明化合物之量將引發個體之生物或醫學反應,例如降低或抑制酶或蛋白質活性、或改善症狀、減輕病狀、減緩或延遲疾病進展、或預防疾病等。在一非限制性實施例中,術語「治療有效量」係指本發明化合物之量當投與個體時有效(1)至少部分減輕、抑制、預防及/或改善以下病狀或病症或疾病:(i)由中性肽鏈內切酶EC3.4.24.11介導或(ii)與中性肽鏈內切酶EC3.4.24.11活性相關或(iii)特徵在於中性肽鏈內切酶EC3.4.24.11之活性異常;或(2)降低或抑制中性肽鏈內切酶EC3.4.24.11之活性;或(3)減少或抑制中性肽鏈內切酶EC3.4.24.11之表現。在另一非限制性實施例中,術語「治療有效量」係指本發明化合物之量當投與細胞或組織或非細胞生物材料或介質時有效至少部分降低或抑制中性肽鏈內切酶EC3.4.24.11之活性;或至少部分減少或抑制中性肽鏈內切酶EC3.4.24.11之表現。
如本文所使用之術語「個體」係指動物。動物較佳為哺乳動物。個體亦指例如靈長類動物(例如人類)、牛、綿羊、山羊、馬、犬、貓、兔、大鼠、小鼠、魚類、鳥類及其類似物。在一較佳實施例中,個體為人類。
如本文所使用之術語「抑制」係指降低或抑止指定病狀、症狀或病症或疾病,或顯著降低生物活性或過程之基線活性。
在一實施例中,如本文所使用之術語「治療」任何疾病或病症係指改善疾病或病症(亦即減緩或阻止或減弱疾病或其至少一種臨床症狀之發展)。在另一實施例中,「治療」係指減輕或改善至少一個身體參數,包括患者可能不可辨別的參數。在又一實施例中,「治療」係指在身體(例如可辨別症狀之穩定)、生理學(例如身體參數之穩定)方面或在該兩個方面調節疾病或病症。在又一實施例中,「治療」係指阻止或延遲疾病或病症之發作或發展或進展。
除非本文另外指出或明顯與上下文抵觸,否則如本文所使用之術語「一」、「該」及本發明上下文(尤其申請專利範圍上下文)使用之類似術語應解釋為涵蓋單數與複數。
術語「高血壓」係指血管內之血液壓力高於其在體內循環之正常值的病狀。當收縮壓超過150mmHg或舒張壓超過90mmHg持續一段時間時,對身體產生傷害。舉例而言,過高收縮壓可能會使任何地方之血管破裂,且當其發生在腦內時,導致中風。高血壓亦可能會引起血管變厚及變窄,此最終可導致動脈粥樣硬化。
術語「第2型糖尿病」(包括與高血壓相關之第2型糖尿病)係指胰臟因胰臟β細胞功能受損而不分泌足夠的胰島素及/或對所產生之胰島素不敏感(胰島素抵抗)的疾病。通常,空腹血漿葡萄糖小於126mg/dL,而糖尿病前期為例如特徵在於一種以下狀況的病狀:空腹葡萄糖異常(110-125mg/dL)及葡萄糖耐受性異常(空腹葡萄糖含量小於126mg/dL且餐後葡萄糖含量在140 mg/dL與199mg/dL之間)。第2型糖尿病可與或不與高血壓相關。例如非裔美國人、拉美裔美國人(Latino/Hispanic A merican)、土著美國人、土著美國人、亞裔美國人及太平洋島民時常出現糖尿病。胰島素抵抗之指標包括HbA1C、HOMAIR、量測膠原蛋白片段、尿中之TGF-β、PAI-1及前腎素。
除非本文另外指出或明顯與上下文抵觸,否則本文所述之所有方法可以任何適合的順序執行。除非另外主張,否則使用本文提供之任何實例或例示性語言(例如「諸如」)僅意欲更好地說明本發明且不對本發明之範疇造成限制。本發明化合物可以游離形式、其鹽或其前藥衍生物形式獲得。
當同一分子中存在鹼性基團與酸性基團時,本發明化合物亦可形成內鹽,例如兩性離子分子。
本發明亦提供本發明化合物之前藥,其在活體內轉化成本發明化合物。前藥為在投與個體該前藥後,經由活體內生理作用(諸如水解、代謝及其類似作用)化學改質成本發明化合物的活性或非活性化合物。熟習此項技術者熟知涉及前藥製備及使用之適用性及技術。前藥在概念上可分成兩個非排他性之類別,亦即生物前驅體前藥及載體前藥。參見The Practice of Medicinal Chemistry,第31-
32章(Wermuth編,Academic Press,San Diego,Ca1if.,2001)。一般而言,生物前驅體前藥為含有一或多個保護基且藉由代謝或溶劑分解轉化成活性形式的非活性或與相應活性藥物化合物相比活性較低的化合物。活性藥物形式與任何釋放之代謝產物均應具有可接受之低毒性。載體前藥為含有例如提高吸收及/或局部傳遞至作用部位之轉運部分的藥物化合物。對於該載體前藥,藥物部分與轉運部分之間的鍵聯理想地為共價鍵,前藥為非活性或活性低於藥物化合物,且任何釋放之轉運部分在可接受程度上無毒。對於轉運部分意欲增強吸收之前藥,轉運部分之釋放通常應快速。在其他情況下,希望利用提供緩慢釋放之部分,例如某些聚合物或其他部分,諸如環糊精。載體前藥可例如用於改良一或多種以下性質:增加親脂性、增加藥理學作用持續時間、提高位點特異性、降低毒性及不良反應、及/或改良藥物調配物(例如穩定性、水溶性、抑制不合需要之感官或生理化學性質)。舉例而言,可藉由(a)用親脂性羧酸(例如具有至少一個親脂性部分之羧酸)酯化羥基或(b)用親脂性醇(例如具有至少一個親脂性部分之醇,例如脂族醇)酯化羧酸基團來增加親脂性。
例示性前藥為例如游離羧酸之酯、及硫醇之S-醯基衍生物、及醇或酚之O-醯基衍生物,其中醯基具有本文所定義之含義。較佳為可在生理條件下藉由溶劑分解轉化成母體羧酸之醫藥學上可接受之酯衍生物,例如低碳烷基酯、環烷基酯、低碳烯基酯、苯甲基酯、單取代或二取代低碳烷基酯,諸如ω-(胺基、單或二低碳烷基胺基、羧基、低碳烷氧基羰基)-低碳烷基酯、α-(低碳烷醯基氧基、低碳烷氧基羰基或二-低碳烷基胺基羰基)-低碳烷基酯,諸如特戊醯氧甲基酯及此項技術中習用之其類似物。另外,胺已掩蔽成經芳基羰氧基甲基取代之衍生物,其在活體內經酯酶裂解而釋放游離藥物及甲醛(Bundgaard,J. Med.Chem.2503(1989))。此外,含酸性NH基團之藥物(諸如咪唑、醯亞胺、吲哚及其類似物)已利用N-醯氧基甲基掩蔽(Bundgaard,Design of Prodrugs,E1sevier(1985))。羥基已掩蔽成酯及醚。EP 039,051(S1oan 及 Litt1e)揭示曼尼希鹼(Mannich-base)異羥肟酸前藥、其製備及用途。
此外,本發明化合物(包括其鹽)亦可以呈水合物形式獲得,或可包括用於其結晶之其他溶劑。
一般合成態樣
本發明之化合物可使用以下流程、實例中描述之方法及藉由使用此項技術公認之技術合成。本發明包括本文所述之所有化合物作為化合物。本發明化合物可根據至少一種流程1-4中所述之方法合成。
在本文之範疇內,除非上下文另外說明,否則指定不為本發明化合物之特定所要最終產物的組分的可輕易移除之基團為「保護基」。該等保護基對官能基之保護、保護基本身及其裂解反應描述於例如標準參考著作中,諸如J.F.W.McO mie,「Protective Groupsin Organic Chemistry」,P1enum Press,Londonand New York1973;T.W.Gr
eene及P.G.M.W uts,「Protective Groupsin Organic Synthesis」,第3版,Wi1ey,New York1999。
具有至少一個成鹽基團之本發明化合物之鹽可以本身已知之方式製備。舉例而言,具有酸基之本發明化合物之鹽可例如藉由用以下處理化合物來形成:金屬化合物,諸如適合有機羧酸之鹼金屬鹽,例如2-乙基己酸之鈉鹽;有機鹼金屬或鹼土金屬化合物,諸如相應的氫氧化物、碳酸鹽或碳酸氫鹽,諸如鈉或鉀之氫氧化物、碳酸鹽或碳酸氫鹽;相應的鈣化合物或氨或適合有機胺,較佳使用化學計量之量或僅少量過量之成鹽劑。本發明化合物之酸加成鹽係以習用方式獲得,例如藉由用酸或適合陰離子交換試劑處理化合物。含有形成酸及鹼鹽之基團(例如游離羧基及游離胺基)之本發明化合物之內鹽可例如藉由例如用弱鹼來中和鹽(諸如酸加成鹽)至等電點或藉由用離子交換劑處理來形成。
可以習用方式使鹽轉化成游離化合物;可例如藉由用適合酸處理來轉化金屬及銨鹽;且可例如藉由用適合鹼試劑處理來轉化酸加成鹽。
可根據本發明獲得之異構體之混合物可以本身已知之方式分離成個別異構體;非對映異構體可例如藉由分配於多相溶劑混合物之間、再結晶及/或層析分離(例如經由矽膠或經由例如逆相管柱中壓液相層析)分離;且外消旋體可例如藉由與光學純鹽成形試劑形成鹽且例如藉助於分步結晶或經由光學活性管柱物質之層析對可如此獲得之非對映異構體混合物進行分離來分離。
中間物及最終產物可根據標準方法處理及/或純化,例如使用層析法、分配法、(再)結晶及其類似方法。以下一般適用於上文及下文提及之所有方法。
所有以上提及之方法步驟均可在本身已知之反應條件下進行,包括特別提及之在無或通常有溶劑或稀釋劑存在下(溶劑或稀釋劑包括例如對所用試劑及溶解用試劑而言為惰性的溶劑或稀釋劑),在無或有催化劑、縮合或中和劑存在下(催化劑、縮合或中和劑例如為離子交換劑,諸如陽離子交換劑,例如呈H+形式,視反應及/或反應物之性質而定),在低溫、常溫或高溫下(例如在約-100℃至約190℃之溫度範圍內,包括例如在約-80℃至約150℃下,例如在-80℃至-60℃下,在室溫下,在-20℃至40℃下或在回流溫度下),在大氣壓下或在密閉容器中(適當時在壓力下)及/或在惰性氛圍中(例如在氬氣或氮氣氛圍下)。
可例如類似於「其他方法步驟」中所描述之方法在所有反應階段將形成之異構體混合物分離成個別異構體(例如非對映異構體或對映異構體),或任何所要異構體混合物(例如非對映異構體外消旋體或混合物)。
除非方法描述中另外指出,否則適於任何特定反應之溶劑所選自的溶劑包括特別提及之溶劑,或例如水;酯,諸如低碳烷羧酸低碳烷基酯,例如乙酸乙酯;醚,諸如脂族醚(例如乙醚)或環狀醚(例如四氫呋喃或二噁烷);液體芳族烴,諸如苯或甲苯;醇,諸如甲醇、乙醇或1-丙醇或2-
丙醇;腈,諸如乙腈;鹵化烴,諸如二氯甲烷或氯仿;醯胺,諸如二甲基甲醯胺或二甲基乙醯胺;鹼,諸如雜環氮鹼,例如吡啶或N-甲基吡咯啶-2-酮;羧酸酐,諸如低碳烷酸酐,例如乙酸酐;環狀、直鏈或分支鏈烴,諸如環己烷、己烷或異戊烷、甲基環己烷;或彼等溶劑之混合物,例如水溶液。該等溶劑混合物亦可用於處理中,例如層析或分配。
化合物(包括其鹽)亦可以水合物形式獲得,或其晶體可例如包括用於結晶之溶劑。可存在不同結晶形式。本發明亦係關於以下方法形式,其中使用可在方法之任何階段以中間物形式獲得之化合物作為起始物質且進行其餘方法步驟,或其中在反應條件下形成起始物質或起始物質以衍生物形式(例如受保護形式或鹽形式)使用,或可藉由本發明方法獲得之化合物在方法條件下產生且現場進一步處理。
用於合成本發明化合物之所有起始物質、構築嵌段、試劑、酸、鹼、脫水劑、溶劑及催化劑均可自市面上購得,或可利用一般技術者已知之有機合成方法(Houben-Wey1第4版1952,Methods of Organic Synthesis,Thieme,第21卷)製備。根據式I'
及I至VIIC中任一者之本發明化合物可利用後續章節中所述之程序來製備。
縮
寫:
本發明之式II化合物可藉由水解中間物A至C來製備,其中X、X1
、A1
、R1
、R2
及n具有上述式I或I'之定義;且P1
及P2
為選自(但不限於)甲基、乙基、異丙基、第三丁基、甲氧基苯甲基或苯甲基之適當保護基。
本發明之式III化合物可藉由水解中間物D、E或F來製備,其中X、X1
、A1
、R1
、R2
及n具有上述式I或I'
之定義;且P1
及P2
為選自(但不限於)甲基、乙基、異丙基、第三丁基、甲氧基苯甲基或苯甲基之適當保護基。
本發明之式VII化合物可藉由水解中間物G來製備,其中A2
、R1
、R2
、R4
及n具有上述式I或I'之定義;且P1
為選自(但不限於)甲基、乙基、異丙基、第三丁基、甲氧基苯甲基或苯甲基之適當保護基。
可應用標準方法使用選自(但不限於)NaOH、KOH或LiOH之鹼或選自(但不限於)TFA或HC1之酸來水解中間物A至G。當P1
或P2
為苯甲基或甲氧基苯甲基時,較佳脫除保護基之方法為在催化劑(諸如但不限於鈀/碳)存在下在氫氣下氫化。
中間物A、B、C或G可使用以下方法製備,該方法包含:縮合中間物H或I,其中X、P1
、R1
、R2
及n
係如先前所述:
與中間物J、K或L,其中X1
、A1
、A2
、R4
及P2
係如先前所述。
可應用已知的縮合方法,包括(但不限於)使用諸如亞硫醯氯或乙二醯氯之試劑使中間物J、K或L轉化成其相應的酸鹵化物,或使用諸如C1C(O)O-異丁基或2,4,6-三氯苯甲醯氯之試劑使中間物J、K或L轉化成混合酸酐,接著在有或無諸如三級胺(例如三乙胺、DIPEA或N-甲基嗎啉)或吡衍生物(例如吡啶、4-(二甲基胺基)吡或4-吡咯并吡)之鹼存在下使酸鹵化物或混合酸酐與中間物H或I反應。或者,可在有或無諸如1-羥基苯并三坐、1-羥基-7-氮雜苯并三坐或五氟苯酚之試劑存在下使用諸如DCC、EDCI、PyBOP或BOP之偶合試劑使中間物J、K或L與H或I偶合。
中間物G(其中R4
為四坐)可根據流程1合成:
其中A2
、R1
、R2
、R4
、P1
、P2
及n係如上文先前所定義。在步驟1a中,在有或無諸如1-羥基苯并三唑、1-羥基-7-氮雜苯并三唑或五氟苯酚之試劑存在下使用選自(但不限於)DCC、EDCI、PyBOP或BOP之標準偶合試劑使中間物I與適當羧酸反應;接著在步驟1c中使用選自(但不限於)NaOH、KOH或LiOH之鹼或選自(但不限於)TFA或HC1之酸或在諸如(但不限於)鈀/碳之催化劑下在氫氣下氫化來移除P2
保護基。或者,在選自(但不限於)吡啶、三乙胺或二異丙基乙胺之鹼存在下使中間物I與適當酸酐反應(步驟1b);接著使用類似於Journalof MedicinalChemistry1998,41,1513中所述之方法使羧酸轉化成四唑(步驟1b)。
中間物D、E或F可使用以下方法製備,該方法包含:縮合中間物M,其中X、P1
、R1
、R2
及n係如上文所定義:
與中間物Q或S,其中X1
、A1
及P2
具有如上文所定義之含義。
可應用已知的縮合方法,包括(但不限於)使用諸如亞硫醯氯或乙二醯氯之試劑使中間物M或N轉化成酸鹵化物,或使用諸如C1C(O)O-異丁基或2,4,6-三氯苯甲醯氯之試劑使中間物M或N轉化成混合酸酐,接著在有或無諸如三級胺(例如三乙胺、DIPEA或N-甲基嗎啉)或吡啶衍生物(例如吡、4-(二甲基胺基)吡或4-吡咯并吡啶)之鹼存在下使酸鹵化物或混合酸酐與中間物Q或S反應。或者,可在有或無諸如1-羥基苯并三坐、1-羥基-7-氮雜苯并三坐或五氟苯酚之試劑存在下使用諸如DCC、EDCI、PyBOP或BOP之試劑使中間物M或N與中間物Q或S偶合。
中間物M或N可根據以下流程2中描述的一般程序製備:
其中R1
、R2
、X及n係如上文所定義,且其中m=0或1;P1
為保護基,選自(但不限於)氫、甲基、乙基、丙基、第三丁基、甲氧基甲基、第三丁基二甲基矽烷基、四氫喃基、苯甲基、烯丙基或苯基;R5
為例如氫、甲基、乙基、異丙基、苯甲基或苯基;R6
及R7
獨立地為氫、甲基、乙基、異丙基、苯甲基或苯基。Y係選自(但不限於)氯、溴、碘、苯并三坐氧基、比錠、N,N-二甲基胺基比錠、五氟苯氧基、苯氧基、4-氯苯氧基、-OCO2
Me、-OCO2
Et、第三丁氧基羰基或-OCC(O)O-異丁基。
在步驟(2a)中,可應用標準方法來製備相應的酸鹵化物,諸如使用亞硫醯氯、乙二醯氯;或可應用標準方法來製備混合酸酐或醯基比錠陽離子,諸如在有或無比衍生物(例如比、4-(二甲基胺基)比、4-比咯啶并比)存在下使用特戊醯氯與三級胺(例如三乙胺、DIPEA、N-甲基嗎啉)、在有或無比衍生物(例如比啶、4-(二甲基胺基)比啶、4-比咯并比)存在下使用2,4,6-三氯苯甲醯氯與三級胺(例如三乙胺、DIPEA、N-甲基嗎啉)、或在有或無比衍生物(例如比、4-(二甲基胺基)比、4-比咯啶并比)存在下使用C1C(O)O-i-Bu與三級胺(例如三乙胺、
DIPEA、N-甲基嗎啉);或可應用標準方法來製備活化酯,諸如在偶合試劑(例如DCC、EDCI)或BOP存在下使用1-
羥基苯并三坐、1-羥基-7-氮雜苯并三坐或五氟苯酚。
在步驟(2b)中,可採用標準方法來製備N-醯基坐酮(m=0)。該化學之說明性實例概述於Aldrichchimica Acta1997,第30卷,第3-12頁及其中之參考文獻中;或可採用標準方法來製備N-醯基氧氮雜環己烷酮(m=1)。該化學之說明性實例概述於Organic and Biomolecular Chemistry2006,第4卷,第14期,第2753-2768頁中。
在步驟(2c)中,可採用標準方法進行烷基化。說明性實例概述於Chemical Reviews1996,96(2),835-876及其中之參考文獻中。
在步驟(2d)中,可採用標準方法來裂解N-醯基坐酮或N-
醯基氧氮雜環己烷酮。該化學之說明性實例概述於Aldrichchimica Acta 1997,第30卷,第3-12頁及其中之參考文獻中。
中間物H或I可根據以下流程3及4中描述的一般程序製備:
其中R1
、R2
、X及n係如上文所定義,且其中P3
為保護基,選自(但不限於)第三丁基、苯甲基、三苯膦基、第三丁氧基羰基、苯甲氧基羰基、烯丙氧基羰基、乙醯基或三氟乙醯基。
在步驟(3a)中,可採用標準方法弓入胺部分,諸如使用:
經由形成相應的醯基疊氮化物藉由使用亞硫醯氯(或C1CO2
R8
)、NaN3
(或TMSN3
)及R9
OH(其中R8
及R9
為氫、甲基、乙基、第三丁基、烯丙基、苯甲基或4-甲氧基苯甲基)進行同時處理或逐步處理;或經由形成相應的醯基疊氮化物用DPPA及R9
OH(其中R9
係如上文所定義)進行同時處理或逐步處理;或使用標準方法以轉化成相應的羧醯胺,接著用NH3
等效物處理,且用LTA或高價碘試劑(例如PIDA、PIFA、PhI(OH)OTs、PhIO)及R9
OH(其中R9
係如上文所定義)進行同時處理或逐步處理;或使用標準方法以轉化成相應的羧醯胺,且用Br2
及MOH(其中M係如本文中所定義,例如為Na、K、Ba或Ca)進行同時處理或逐步處理;或使用標準方法以轉化成相應的羧醯胺,且用MOZ或NaBrO2
(其中Z係如本文中所定義,例如為C1或 Br)進行處理;或使用標準方法以轉化成相應的羧醯胺且用Pb(OAc)4
及R9
OH(其中R9
係如上文所定義)進行處理;或使用標準方法以轉化成相應的異羥肟酸,接著用H2
NOH或H2NOTMS處理且在有或無鹼(例如比、Na2
CO3
水溶液、三乙胺、
DIPEA)存在下用Ac2
O、Boc2
O、R10
COC1、R10
SO2
C1、R10
PO2
C1(其中R10
係如本文中所定義,例如為M e、Et、tBu或苯基)、亞硫醯氯、EDCI、DCC或1-氯-2,4-二硝基苯進行處理且在鹼(例如DBU、ZOH、DIPEA)存在下用R9
OH(其中R9
及Z係如上文所定義)進行處理。
在步驟(3b)中,可應用標準方法來移除P3
保護基,諸如使用NaOH、KOH或LiOH進行鹼水解,使用TFA或HC1進行酸水解,或使用鈀/碳在氫氣下進行氫化。
流程4描述中間物H或I之替代合成:
其中LG為離去基,選自(但不限於)C1、Br、I、OMs、OTs或OTf。
在步驟(4a)中,可採用標準方法進行阿恩特-艾斯特爾特同系化(Arndt-Eistertho m o1ogation)。該化學之說明性實例直接地或類似地概述於「Enantiose1ective synthesis ofβ-amino acids,第2版」,John Wi1ey and Sons,Inc,,NJ(2005)中。
在步驟(4b)中,可採用標準方法進行烷基化,諸如在鹼(諸如LDA、NHMDS、LHMDS或KHMDS)存在下使用R1
LG進行。
在步驟(4c)中,可採用標準方法來保護羧酸,諸如使用TMSCHN2(用於保護成甲酯)、P1
LG/鹼(例如K2
CO3
、NaHCO3、
Cs2CO3
或K3
PO4
)、亞硫醯氯(或乙二醯氯)/R9
OH、DCC(或EDCI)/DMAP/R9
OH、BOP/R9
OK(或R9
ONa)、(R9
O)2
CHNMe2
、CDI/DBU/R9
OH(其中R9
具有與上文定義相同之含義),或異丁烯/H2
SO4
(用於保護成第三丁酯)。
在步驟(4d)中,可應用標準方法進行鈴木偶合反應(Suzuki coup1ing reaction),諸如使用鈀(或鎳)物質[例如Pd(PPh3)4、
PdC12(dppf)、Pd(OAc)2
/膦(例如PPh3
、dppf、PCy3、
P(tBu)3、XPhos)、Pd/C、Pd2
(dba)3
/膦(例如PPh3
、dppf、
PCy3、P(tBu)3、XPhos)、Ni(COD)2
/膦(或dppe、dppb、PCy3)、Ni(dppf)C12
]、鹼(例如KF、CsF、K3
PO4
、Na2
CO3
、K2
CO3、Cs2
CO3
、NaOH、KOH、NaO-
t-
Bu、KO-
t-Bu)及(R2
)n-PhB(OH)2
[或(R2
)n-PhBF3
K]。
在步驟(4e)中,可應用標準方法來移除P3保護基,諸如使用NaOH、KOH或LiOH進行鹼水解,使用TFA或HC1進行酸水解,或使用鈀/碳在氫氣下進行氫化。
或者,中間物H 或I可遵循Tetrahedron Letters,2008,第49卷,第33期,第4977-4980頁中直接地或類似地概述之合成路徑製備且利用Organic Letters,2002,第4卷,第22期,第3803-3805頁中概述之方法使所獲得之朋酸轉化成經取代聯苯。
或者,中間物H 或 I可遵循Tetrahedr0:Asym metry,2006,第17卷,第2期,第205-209頁中直接地或類似地概述之合成路徑製備。
或者,中間物H 或I可利用曼尼希反應(Mannich reaction)方法製備。該化學之說明性實例直接地或類似地概述於「Enantiose1ective synthesis of β-amino acids,第2版」,John Wi1eyandSons,Inc.,NJ(2005)」中。
或者,中間物H 或 I可利用烯醇加成(eno1ate addition)製備。該化學之說明性實例直接地或類似地概述於「Enantiose1ective synthesis of β-amino acids,第2版」,John Wi1eyandSons,Inc,,NJ(2005)中。
或者,中間物H 或I可利用氮雜-麥可反應(aza-Michae1reaction)方法製備。該化學之說明性實例直接地或類似地概述於「Enantiose1ective synthesis of β-amino acids,第2版」,John Wi1eyandSons,Inc.,NJ(2005)中。
或者,中間物H 或I可遵循Syn1ett,2006,第4期,第539-542頁中直接地或類似地概述之合成路徑製備。
中間物J、K及L之合成亦描述於在2010年4月16日申請之申請檔案編號為PAT053600-US-USP3之美國專利申請案中,該申請案以弓用之方式併入本文中。
本發明進一步包括本發明方法之任何變型,其中使用可在該方法之任何階段獲得之中間產物作為起始物質且進行其餘方法步驟,或其中在反應條件下現場形成起始物質,或其中反應組分以其鹽或光學純對映體形式使用。
本發明化合物及中間物亦可根據一般本身已知之方法相互轉化。
在另一態樣中,本發明提供一種醫藥組合物,其包含本發明化合物或其醫藥學上可接受之鹽及一或多種醫藥學上可接受之載劑。醫藥組合物可經調配以用於特定投藥途徑,諸如經口投藥、非經腸投藥及直腸投藥等。另外,本發明醫藥組合物可製成固體形式,包括膠囊、錠劑、丸劑、顆粒劑、散劑或栓劑;或液體形式,包括溶液、懸浮液或乳液。醫藥組合物可進行諸如滅菌之習知醫藥操作,及/或可含有習知惰性稀釋劑、潤滑劑或緩衝劑以及佐劑,諸如防腐劑、穩定劑、潤濕劑、乳化劑及緩衝劑等。
醫藥組合物通常為錠劑及明膠膠囊,包含活性成分以及a)稀釋劑,例如乳糖、右旋糖、蔗糖、甘露糖醇、山梨糖醇、纖維素及/或甘胺酸;b)潤滑劑,例如二氧化矽、滑石、硬脂酸、其鎂或鈣鹽及/或聚乙二醇;對於錠劑,亦含有c)黏合劑,例如矽酸鎂鋁、澱粉糊、明膠、黃蓍膠、甲基纖維素、羧甲基纖維素鈉及/或聚乙烯基比咯酮;必要時可含d) 崩解劑,例如澱粉、瓊脂、海藻酸或其鈉鹽或起泡混合物;及/或e) 吸收劑、著色劑、調味劑及甜味劑。
錠劑可根據此項技術中已知之方法包覆膜包衣或包覆腸溶包衣。
適於經口投藥之組合物包括有效量之本發明化合物,呈錠劑、口含錠、水性或油性懸浮液、可分散性散劑或顆粒劑、乳液、硬或軟膠囊、或糖漿、或酏劑形式。欲供經口使用的組合物可根據此項技術中已知製造醫藥組合物之任何方法製備,且該等組合物可含有一或多種選自由甜味劑、調味劑、著色劑及防腐劑組成之群的試劑以提供醫藥學上精緻且可口的製劑。錠劑含有活性成分與適於製造錠劑之醫藥學上可接受之無毒賦形劑混合。該等賦形劑為例如惰性稀釋劑(諸如碳酸鈣、碳酸鈉、乳糖、磷酸鈣或磷酸鈉);成粒劑及崩解劑(例如玉米澱粉或海藻酸);黏合劑(例如澱粉、明膠或阿拉伯膠);及潤滑劑(例如硬脂酸鎂、
硬脂酸或滑石)。錠劑不經包覆或利用已知技術包覆以延遲在胃腸道中之崩解及吸收,並藉此在較長時間內提供持續作用。舉例而言,可採用時間延遲物質,諸如單硬脂酸甘油酯或二硬脂酸甘油酯。經口使用之調配物可以硬明膠膠囊形式提供,其中活性成分與惰性固體稀釋劑(例如碳酸鈣、磷酸鈣或高嶺土)混合,或以軟明膠膠囊形式提供,其中活性成分與水或油介質(例如花生油、液體石蠟或橄欖油)混合。
某些可注射組合物為水性等張溶液或懸浮液,且栓劑宜由脂肪乳液或懸浮液製備。該等組合物可經滅菌及/或含有佐劑,諸如防腐劑、穩定劑、潤濕劑或乳化劑、溶解促進劑、調節滲透壓之鹽及/或緩衝劑。另外,其亦可含有其他治療上有價值的物質。該等組合物可分別根據習知混合、成粒或包覆包衣方法製備且含有約0.1-75%或含有約1-50%之活性成分。
適於經皮施用之組合物包括有效量之本發明化合物及載劑。載劑包括可吸收之藥理學上可接受之溶劑以有助於穿過宿主皮膚。舉例而言,經皮裝置係呈繃帶形式,其包含襯底部件、含有化合物及視情況選用之載劑之儲集器、視情況選用之速率控制障壁以便以控制且預定之速率在較長一段時間內傳遞化合物至宿主皮膚、及固定該裝置於皮膚之構件。
適於局部施用、例如施用於皮膚及眼睛之組合物包括水溶液、懸浮液、軟膏、乳膏、凝膠劑或可噴灑調配物,例如經由氣霧劑或其類似物傳遞。該等局部傳遞系統將尤其適於皮膚施用。因此,其尤其適用於此項技術中熟知之局部(包括化妝用)調配物中。其可含有增溶劑、穩定劑、張力增強劑、緩衝劑及防腐劑。
如本文所使用之局部施用亦可涉及吸入或鼻內施用。其宜自乾粉吸入器以乾粉(單獨、呈混合物形式(例如與乳糖之乾摻合物)、或混合組分粒子(例如與磷脂))形式傳遞,或自加壓容器、泵、噴灑器、霧化器或噴霧器在使用或不使用適合推進劑下以氣霧劑噴霧形式傳遞。
本發明進一步提供包含本發明化合物作為活性成分之無水醫藥組合物及劑型,因為水可能促進某些化合物降解。
本發明之無水醫藥組合物及劑型可使用無水或含低水分之成分且使用低水分或低濕度條件製備。無水醫藥組合物可經製備及儲存以維持其無水性質。因此,較佳使用已知防止曝露於水之材料來包裝無水組合物以使其可包括在適合的配方套組中。適合包裝之實例包括(但不限於)密封箔、塑膠、單位劑量容器(例如小瓶)、發泡包裝及條帶包裝。
本發明進一步提供包含一或多種降低作為活性成分之本發明化合物分解之速率的試劑的醫藥組合物及劑型。該等在本文中稱為「穩定劑」之試劑包括(但不限於)抗氧化劑(諸如抗壞血酸)、pH值緩衝劑或鹽緩衝劑等。
呈游離形式或醫藥學上可接受之鹽形式的根據式I'
及I至VIIC中任一者之化合物展現有價值的藥理學性質,例如中性肽鏈內切酶EC3.4.24.11調節性質,例如後續章節中所提供之活體外及活體內測試中所表明,且因此可指定用於治療。
本發明化合物或其醫藥學上可接受之鹽可適用於治療選自以下之適應症:心血管病症,諸如高血壓、肺循環血壓過高、獨立性收縮性高血壓、頑固性高血壓、周邊血管疾病、心臟衰竭、充血性心臟衰竭、左心室肥大、絞痛、腎功能不全、腎衰竭(包括水腫及鹽滯留)、糖尿病性腎病變、非糖尿病性腎病變、週期性水腫、梅尼爾氏病、高醛固酮症(原發性及繼發性)及高鈣尿症、腹水、青光眼、月經異常、早產、子癇前症、子宮內膜異位及生殖病症(尤其男性及女性不孕不育症、多囊卵巢症候群、植入失敗)、哮喘、阻塞性睡眠呼吸暫停、炎症、白血病、疼痛、癲癇症、情感障礙(諸如抑鬱症)及精神病狀(諸如癡呆及老年精神錯亂)、肥胖症及胃腸病症(尤其腹瀉及大腸急躁症)、創傷癒合(尤其糖尿病性及靜脈性潰瘍及褥瘡)、敗血性休克、調節胃酸分泌、治療高腎素血症、囊性纖維化、再狹窄、第2型糖尿病、糖尿病併發症及動脈粥樣硬化、男性及女性性功能障礙。
因此,作為另一實施例,本發明提供根據式I'
及I至VIIC中任一者之化合物或其醫藥學上可接受之鹽的用途。在另一實施例中,療法係選自可藉由抑制中性肽鏈內切酶EC3.4.24.11改善之疾病。在另一實施例中,疾病選自前述清單,適合地為高血壓、肺循環血壓過高、獨立性收縮性高血壓、頑固性高血壓、周邊血管疾病、心臟衰竭、充血性心臟衰竭、左心室肥大、絞痛、腎功能不全、腎衰竭(包括水腫及鹽滯留)、糖尿病性腎病變、非糖尿病性腎病變、第2型糖尿病及糖尿病併發症,且最適合地為心血管病症,諸如高血壓、腎功能不全(包括水腫)及充血性心臟衰竭。
在另一實施例中,本發明提供一種治療可藉由抑制中性肽鏈內切酶EC3.4.24.11改善之疾病的方法,該方法包含投與治療上可接受之量的根據式I'
、I、IA、II、IIA、III、IIIA、IV、IVA、V、VA、VI、VIA 及 VII至 VIIC中任一者之化合物或其醫藥學上可接受之鹽。在另一實施例中,疾病係選自前述清單,適合地為高血壓、肺循環血壓過高、獨立性收縮性高血壓、頑固性高血壓、周邊血管疾病、心臟衰竭、充血性心臟衰竭、左心室肥大、絞痛、腎功能不全、腎衰竭(包括水腫及鹽滯留)、糖尿病性腎病變、非糖尿病性腎病變、第2型糖尿病及糖尿病併發症,且最適合地為心血管病症,諸如高血壓、腎功能不全(包括水腫)及充血性心臟衰竭。
本發明之醫藥組合物或組合之單位劑量對約50-70公斤之個體可為約1-1000mg活性成分,或約1-500mg、或約1-250mg、或約1-150mg、或約0.5-100mg、或約1-50mg活性成分。化合物、其醫藥組合物或組合之治療有效劑量視個體物種、體重、年齡及個別狀況、所治療之病症或疾病或其嚴重程度而定。一般熟習醫師、臨床醫師或獸醫可輕易地決定各活性成分於預防、治療或抑制病症或疾病進展所必需之有效量。
上述劑量性質可由活體外及活體內測試且有利地使用哺乳動物(例如小鼠、大鼠、犬、猴)或分離之器官、組織及其製劑證明。本發明化合物可呈溶液(例如較佳為水溶液)形式活體外施用,且可呈例如懸浮液或水溶液形式,於活體內經腸內、非經腸、有利地經靜脈內施用。活體外劑量可在約10-3
莫耳濃度至10-9
莫耳濃度之範圍內。活體內治療有效量可視投藥途徑而定,在約0.1-500mg/kg或約1-100mg/kg範圍內。
本發明化合物之活性可藉由以下活體外及活體內方法及/或藉由此項技術中已詳細描述之以下活體外及活體內方法評估。參見A f1uorescence1ifetime-based assay for proteaseinhibitorprofi1ing on human ka11ikrein7Doering K,M ederG,Hinnenberger M,Woe1ckeJ,Mayr L M,Hassiepen U Biomo1Screen.2009年1月;14(1):1-9。
特定言之,可如下測定重組人類中性肽鏈內切酶(NEP,EC3.4.24.11)之活體外抑制:在室溫下在含有150mM NaC1及0.05%(w/v)CHAPS之10mM磷酸鈉緩衝液(pH7.4)中與各種濃度之測試化合物一起預培育重組人類中性肽鏈內切酶(於昆蟲細胞中表現且使用標準方法純化,最終濃度為7pM)1小時。藉由添加合成肽受質Cys(PT14)-Arg-Arg-Leu-Trp-OH至0.7μM之最終濃度起始酶促反應。如Doering等人(2009)所描述,受質水解弓起藉助於FLT讀取器量測之PT14之螢光壽命(FLT)增加。
在室溫下培育1小時(t=60分鐘)後測定化合物對酶促活性之作用。由抑制百分比對抑制劑濃度之曲線使用非線性回歸分析軟體計算IC50值,該值對應於顯示使在無抑制劑存在下量測之FLT值降低50%之抑制劑濃度。
使用測試檢定(如上所述),本發明化合物展現根據下文提供之表1的抑制功效。
本發明化合物可與至少一種其他治療劑同時或在該至少一種其他治療劑之前或之後投與。本發明化合物可經由相同或不同投藥途徑分開投與或於同一醫藥組合物中一起投與。
在一實施例中,本發明提供一種產品,其包含根據式I'
及I至VIIC中任一者之化合物.或其醫藥學上可接受之鹽及至少一種其他治療劑作為組合製劑以同時、分開或相繼用於療法中。在一實施例中,療法為治療與中性肽鏈內切酶EC3.4.24.11活性相關之疾病或病狀。以組合製劑形式提供之產品包括一種組合物,其包含式I'
及I至 VIIC之化合物及另一(其他)治療劑一起位於同一醫藥組合物中,或呈分開形式(例如呈套組形式)的根據式I'
及I至 VIIC中任一者之化合物或其醫藥學上可接受之鹽及另一(其他)治療劑。
在一實施例中,本發明提供一種醫藥組合物,其包含根據式I'
及I至 VIIC中任一者之化合物或其醫藥學上可接受之鹽及另一(其他)治療劑。醫藥組合物視情況可包含如上所述之醫藥學上可接受之賦形劑。
在一實施例中,本發明提供一種套組,其包含兩種或兩種以上分開之醫藥組合物,其中至少一種含有根據式I'
及I至VIIC中任一者之化合物或其醫藥學上可接受之鹽。在一實施例中,套組包含分開保持該等組合物之構件,諸如容器、分隔的瓶或分隔的箔包裝。該套組之一實例為通常用於包裝錠劑、膠囊及其類似物之發泡包裝。
本發明之套組可用於投與不同劑型(例如經口及非經腸),以不同劑量間隔投與分開的組合物,或相互滴定分開的組合物。為幫助達成順應性,本發明套組通常包含投藥說明書。
在本發明之組合療法中,本發明化合物或其醫藥學上可接受之鹽及另一治療劑可由相同或不同製造商製造及/或調配。此外,可使本發明化合物或其醫藥學上可接受之鹽及另一治療劑組合成組合療法:(i)在發放組合產品至醫師之前(例如在包含本發明化合物及另一治療劑之套組的情況下);(ii)在投藥前不久由醫師本人(或在醫師指導下)組合;(iii)在患者本人體內組合,例如相繼投與本發明化合物及另一治療劑期間。
因此,本發明提供根據式I'
及I至 VIIC中任一者之化合物或其醫藥學上可接受之鹽的用途,其係用於製造治療與中性肽鏈內切酶EC3.4.24.11活性相關之疾病或病狀的藥物,其中該藥物經製備以與另一治療劑一起投與。本發明亦提供另一治療劑的用途,其係用於製造治療與中性肽鏈內切酶EC3.4.24.11活性相關之疾病或病狀的藥物,其中該藥物經製備以與根據式I'
及I至 VIIC中任一者之化合物或其醫藥學上可接受之鹽一起投與。
本發明亦提供根據式I'
及I至 VIIC中任一者之化合物或其醫藥學上可接受之鹽,其係用於治療與中性肽鏈內切酶EC3.4.24.11活性相關之疾病或病狀的方法中,其中根據式I'
及I至VIIC中任一者之化合物或其醫藥學上可接受之鹽經製備以與另一治療劑一起投與。本發明亦提供另一治療劑,其係用於治療與中性肽鏈內切酶EC3.4.24.11活性相關之疾病或病狀的方法中,其中另一治療劑經製備以與根據式I'
及I至 VIIC中任一者之化合物或其醫藥學上可接受之鹽一起投與。本發明亦提供根據式I'
及I至 VIIC中任一者之化合物或其醫藥學上可接受之鹽,其係用於治療與中性肽鏈內切酶EC3.4.24.11活性相關之疾病或病狀的方法中,其中根據式I'
及I至 VIIC中任一者之化合物或其醫藥學上可接受之鹽與另一治療劑一起投與。本發明亦提供另一治療劑,其係用於治療與中性肽鏈內切酶EC3.4.24.11活性相關之疾病或病狀的方法中,其中另一治療劑與根據式I'
及I至VIIC中任一者之化合物或其醫藥學上可接受之鹽一起投與。
本發明亦提供根據式I'
及I至 VIIC中任一者之化合物或其醫藥學上可接受之鹽的用途,其係用於製造治療與中性肽鏈內切酶EC3.4.24.11活性相關之疾病或病狀的藥物,其中患者先前(例如24小時內)已用另一治療劑治療。本發明亦提供另一治療劑的用途,其係用於製造治療與中性肽鏈內切酶EC3.4.24.11活性相關之疾病或病狀的藥物,其中患者先前(例如24小時內)已用根據式I'
及I至 VIIC中任一者之化合物或其醫藥學上可接受之鹽治療。
在一實施例中,另一治療劑係選自:HMG-Co-A還原酶抑制劑、血管收縮素受體阻斷劑(ARB,血管收縮素II受體拮抗劑)、血管收縮素轉化酶(ACE)抑制劑、鈣通道阻斷劑(CCB)、內皮素拮抗劑、腎素抑制劑、利尿劑、ApoA-I模擬劑、抗糖尿病劑、減肥劑、醛固酮受體阻斷劑、內皮素受體阻斷劑、醛固酮合成酶抑制劑(ASI)、CETP抑制劑或第5型磷酸二酯酶(PDE5)抑制劑。
術語「組合」第二藥劑或治療包括共投與本發明化合物(例如式I'
或I-VIIC化合物或本文另外描述之化合物)與第二藥劑或治療;首先投與本發明化合物,接著投與第二藥劑或治療;首先投與第二藥劑或治療,接著投與本發明化合物。
術語「第二藥劑」包括此項技術中已知治療、預防或減少本文所述之疾病或病症之症狀的任何藥劑,該疾病或病症例如對抑制中性肽鏈內切酶有反應之病症或疾病,諸如高血壓、肺循環血壓過高、獨立性收縮性高血壓、頑固性高血壓、周邊血管疾病、心臟衰竭、充血性心臟衰竭、左心室肥大、絞痛、腎功能不全(糖尿病性或非糖尿病性)、腎衰竭(包括水腫及鹽滯留)、糖尿病性腎病變、非糖尿病性腎病變、腎病症候群、絲球體腎炎、硬皮病、腎絲球硬化症、原發性腎病蛋白尿、腎血管高血壓、糖尿病性視網膜病變及末期腎病(ESRD)、內皮功能異常、舒張功能異常、肥厚型心肌病、糖尿病性心肌病、室上及室性心律不整、心房纖維顫動(AF)、心臟纖維化、心房撲動、有害血管重塑、斑塊穩定、心肌梗塞(MI)、腎纖維化、多囊性腎病(PKD)、肺動脈高血壓、腎衰竭(包括水腫及鹽滯留)、週期性水腫、梅尼爾氏病、高醛固酮症(原發性及繼發性)及高鈣尿症、腹水、青光眼、月經異常、早產、子癇前症、子宮內膜異位及生殖病症(尤其男性及女性不孕不育症、多囊卵巢症候群、植入失敗)、哮喘、阻塞性睡眠呼吸暫停、炎症、白血病、疼痛、癲癇症、情感障礙(諸如抑鬱症)及精神病狀(諸如癡呆及老年精神錯亂)、肥胖症及胃腸病症(尤其腹瀉及大腸急躁症)、創傷癒合(尤其糖尿病性及靜脈性潰瘍及褥瘡)、敗血性休克、胃酸分泌功能異常、高腎素血症、囊性纖維化、再狹窄、第2型糖尿病、代謝症候群、糖尿病併發症及動脈粥樣硬化、男性及女性性功能障礙。
第二藥劑之實例包括HMG-Co-A還原酶抑制劑、血管收縮素II受體拮抗劑、血管收縮素轉化酶(ACE)抑制劑、鈣通道阻斷劑(CCB)、內皮素拮抗劑、腎素抑制劑、利尿劑、
ApoA-I模擬劑、抗糖尿病劑、減肥劑、醛固酮受體阻斷劑、內皮素受體阻斷劑、醛固酮合成酶抑制劑(ASI)及CETP抑制劑。
術語「HMG-Co-A還原酶抑制劑」(亦稱為β-羥基-
β-
甲基戊二醯基-輔酶A還原酶抑制劑)包括可用於降低血液中之脂質含量(包括膽固醇)的活性劑。實例包括阿托伐他汀(atorvastatin)、西立伐他汀(cerivastatin)、康百汀(co m pactin)、達伐他汀(da1vastatin)、二氫康百汀(dihydroco m pactin)、氟多他汀(f1uindostatin)、氟伐他汀(f1uvastatin)、洛伐他汀(1ovastatin)、
匹伐他汀(pitavastatin)、美伐他汀(m evastatin)、普伐他汀(pravastatin)、瑞伐他汀(rivastatin)、辛伐他汀(sim vastatin)及維洛他汀(ve1ostatin)或其醫藥學上可接受之鹽。
術語「ACE抑制劑」(亦稱為血管收縮素轉化酶抑制劑)包括中斷血管收縮素I酶促降解為血管收縮素II之分子。該等化合物可用於調節血壓及治療充血性心臟衰竭。實例包括阿拉普利(a1acepri1)、貝那普利(benazepri1)、貝那普拉(benazepri1at)、卡托普利(captopri1)、西羅普利(ceronapri1)、西拉普利(ci1azapri1)、地拉普利(de1apri1)、依那普利(ena1apri1)、依那普拉(enapri1at)、福辛普利(fosinopri1)、咪達普利(imidapri1)、賴諾普利(1isinopri1)、莫福普利(m ove1topri1)、培普利(perindopri1)、喹那普利(quinapri1)、雷米普利(ra mipri1)、螺普利(spirapri1)、替莫普利(te m ocapri1)及群多普利(trando1apri1)或其醫藥學上可接受之鹽。
術語「內皮素拮抗劑」包括波生坦(bosentan)(參看EP526708A)、替坐生坦(tezosentan)(參看W O96/19459)或其醫藥學上可接受之鹽。
術語「腎素抑制劑」包括地替吉侖(ditekiren)(化學名稱:[1S-[1R*,2R*,4R*(1R*,2R*)]]-1-[(1,1-二甲基乙氧基)羰基]-L-脯胺醯基-L-苯基丙胺醯基-N-[2-羥基-5-甲基-1-(2-甲基丙基)-4-[[[2-甲基-1-[[(2-比基甲基)胺基]羰基]丁基]胺基]羰基]己基]-N-α-甲基-L-組胺酸醯胺);特拉吉侖(ter1akiren)(化學名稱:[R-(R*
,S*
)]-N-(4-嗎啉基羰基)-L-苯基丙胺醯基-N-[1-(環己基甲基)-2-羥基-3-(1-甲基乙氧基)-3-側氧基丙基]-S-甲基-L-半胱胺酸醯胺);阿利吉侖(A1iskiren)(化學名稱:(2S,4S,5S,7S)-5-胺基-N-(2-胺甲醯基-2,2-二甲基乙基)-4-羥基-7-{[4-甲氧基-3-(3-甲氧基丙氧基)苯基]甲基}-8-甲基-2-(丙-2-基)壬醯胺)及占吉侖(zankiren)(化學名稱:[1S-[1R*[R*(R*)],2S*,3R*]]-N-[1-(環己基甲基)-2,3-二羥基-5-甲基己基]-α-[[2-[[(4-甲基-1-哌嗪基)磺醯基]甲基]-1-側氧基-3-苯基丙基]-胺基]-4-坐丙醯胺),或其鹽酸鹽,或Speede1開發之SPP630、SPP635及SPP800,或式(A)及(B)之RO66-1132及RO66-1168:
或其醫藥學上可接受之鹽。
若未特別定義,則術語「阿利吉侖」應理解為呈游離鹼及其鹽形式,尤其為其醫藥學上可接受之鹽,最佳為其半反丁烯二酸鹽。
血管收縮素II受體拮抗劑或其醫藥學上可接受之鹽應理解為結合於血管收縮素II受體之AT1
受體亞型但不導致該受體活化之活性成分。由於該等拮抗劑可抑制AT1
受體,因此其可例如用作抗高血壓劑或治療充血性心臟衰竭。
AT1
受體拮抗劑類別包含具有不同結構特徵之化合物,基本上非肽類化合物較佳。舉例而言,可提及選自由以下組成之群的化合物:纈沙坦(va1sartan)、洛沙坦(1osartan)、坎地沙坦(candesartan)、依普羅沙坦(eprosartan)、伊貝沙坦(irbesartan)、沙普立沙坦(saprisartan)、他索沙坦(tasosart an)、替米沙坦(te1misartan)、代號為E-1477之下式化合物
代號為SC-52458之下式化合物
及代號為ZD-8731之下式化合物
或各情況下其醫藥學上可接受之鹽。
較佳AT1
受體拮抗劑為彼等市售藥劑,最佳為纈沙坦或其醫藥學上可接受之鹽。
術語「鈣通道阻斷劑(CCB)」包括二氫比(DHP)及非D H P(例如地爾硫卓型(di1tiazem-type)及維拉帕米型(verapami1-type)CCB)。實例包括胺氯地平(am1odipine)、非洛地平(fe1odipine)、里奧斯汀(ryosidine)、伊拉地平(isradipine)、拉西地平(1acidipine)、尼卡地平(nicardipine)、硝苯吡(nifedipine)、尼古地平(nigu1dipine)、尼魯地平(ni1udipine)、尼莫地平(nim odipine)、尼索地平(niso1dipine)、尼群地平(nitrendipine)及尼伐地平(niva1dipine),且較佳為非DHP,代表物選自由以下組成之群:氟桂利嗪(flunarizine)、普尼拉明(preny1amine)、地爾硫卓(di1tiaze m)、芬地林(fendi1ine)、加洛帕米(ga11opa mi1)、米貝地爾(mibefradi1)、
阿尼帕米(anipami1)、替阿帕米(tiapami1)及維拉帕米(verapami1),或其醫藥學上可接.受之鹽。CCB可用作抗高血壓、抗心絞痛或抗心律不整藥物。
術語「利尿劑」包括嗪衍生物(例如氯嗪(ch1orothiazide)、氫氯嗪(hydroch1orothiazide)、甲基氯噻嗪(m ethy1c1othiazide)及氯酮(ch1orotha1idon))。術語「ApoA-I模擬劑」包括D4F肽(例如式D-W-F-K-A-
F-Y- D-K-V- A-E-K-F-K-E-A-F)。
術語「抗糖尿病劑」包括促進胰臟β細胞分泌胰島素之胰島素分泌增強劑。實例包括雙胍衍生物(例如二甲雙胍(metfo rmin))、磺醯脲(SU)(例如甲苯磺丁脲(to1butamide)、氯磺丙脲(ch1orpropamide)、妥拉磺脲(to1azamide)、乙醯苯磺醯環己脲(acetohexamide)、4-氯-N-[(1-比咯基胺基)羰基]-苯磺醯胺(格列比脲(g1ycopyramide))、格列本脲(g1ibenc1a mide/g1yburide)、格列齊特(g1ic1azide)、1-丁基-3-間胺磺醯脲(1-buty1-3-m etani1y1urea)、胺磺丁脲(carbuta mide)、格列波脲(g1ibonuride)、格列比嗪(g1ipizide)、格列喹酮(g1iquidone)、格列索匹(g1isoxepid)、格列坐(g1ybuthiazo1)、格列丁坐(g1ibuzo1e)、格列己脲(g1yhexa mide)、格列密(g1y midine)、格列平脲(g1ypinamide)、苯磺丁脲(phenbutamide)及甲苯基環醯胺(to1y1cyc1amide))或其醫藥學上可接受之鹽。其他實例包括苯丙胺酸衍生物(例如下式之那格列奈(nateg1inide)[N-(反-4-異丙基環己基羰基)-D-苯丙胺酸](參看EP196222及EP526171):
瑞格列奈(repag1inide)[(S)-2-乙氧基-4-{2-[[3-甲基-1-[2-(1-哌基)苯基]丁基]胺基]-2-側氧基乙基}苯甲酸](參看EP589874;EP147850A2,特定言之第61頁實例11;及EP207331A1);(2S)-2-苯甲基-3-(順-六氫-2-異引基羰基)-丙酸鈣二水合物(例如米格列奈(mitig1inide)(參看EP507534));及格列美脲(g1im epiride)(參看EP31058)。其他實例包括DPP-IV抑制劑、GLP-1及 GLP-1促效劑。
DPP-IV負責使GLP-1失活。更特定言之,DPP-IV產生GLP-
1受體拮抗劑,且由此縮短對GLP-1之生理反應。GLP-
1為胰臟胰島素分泌之主要刺激劑且對葡萄糖處置(g1ucose disposa1)產生直接的有利影響。
DPP-IV抑制劑可為肽類,或較佳為非肽類。DPP-IV抑制劑在各情況下一般地及具體地揭示於例如WO98/19998、DE19616486A1、WO00/34241及 WO95/15309中,特定言之在各情況下揭示於化合物請求項及工作實例之最終產物中,因此最終產物、醫藥製劑及申請專利範圍之標的物以弓用該等公開案之方式併入本申請案中。較佳為WO98/19998之實例3及WO00/34241之實例1中分別具體揭示之彼等化合物。
GLP-1為促胰島素蛋白質,其描述於例如W,E.Sc
hmidt等人,Diabetologia,28,1985,704-707及US5,705,483中。術語「GLP-1促效劑」包括GLP-1(7-36)NH2
之變異體及類似物,特定言之揭示於US5,120,712、US5,118666、US5,512,549、W O91/11457及C.Orskov等人,J.Bio1.Chem.264(1989)12826中。其他實例包括GLP-1(7-37)(在該化合物中,GLP-1(7-36)NH2
分子第37位置處之Arg36
之羧基末端醯胺官能基被G1y置換)及其變異體及類似物,包括GLN9 -
GLP-1(7-37)、D-GLN9
-GLP-1(7-37)、乙醯基LYS9 -
GLP-
1(7-37)、LYS18
-GLP-1(7-37),且尤其為GLP-1(7-
37)OH、VAL8
-GLP-1(7-37)、GLY8
-GLP-1(7-37)、THR8 -
GLP-
1(7-
37)、MET8
-GLP-1(7-37)及4-
咪坐基丙醯基-
GLP-
1。亦尤其較佳為GLP促效劑類似物促胰島素分泌素-4(exendin-
.4),描述於Greig等人,Diabeto1ogia1999,42,45-50中。
定義「抗糖尿病劑」亦包括胰島素敏感性增強劑,其恢復異常之胰島素受體功能以降低胰島素抵抗,且從而增強胰島素敏感性。實例包括降血糖坐啶二酮衍生物(例如格列酮(g1itazone)、(S)-((3,4-二氫-2-(苯基-甲基)-2H-1-苯并哌喃-6-基)甲基-坐-2,4-二酮(恩格列酮(eng1itazone))、5-{[4-(3-(5-甲基-2-苯基-4-噁坐基)-1-側氧基丙基)-苯基]-甲基}-坐啶-2,4-二酮(達格列酮(darg1itazone))、5-{[4-(1-甲基-環己基)甲氧基)-苯基]甲基}-坐啶-2,4-二酮(環格列酮(cig1itazone))、5-{[4-(2-(1-引哚基)乙氧基)苯基]甲基}-坐-2,4-二酮(DRF2189)、
5-{4-[2-(5-甲基-2-苯基-4-坐基)-乙氧基)]苯甲基}-坐-2,4-二酮(BM-13.1246)、5-(2-萘基磺醯基)-坐-2,4-二酮(AY-31637)、雙{4-[(2,4-二側氧基-5-坐基)甲基]苯基}甲烷(YM268)、5-{4-[2-(5-甲基-2-苯基-4-坐基)-2-羥基乙氧基]苯甲基}-坐-2,4-二酮(AD-5075)、5-[4-(1-苯基-1-環丙烷羰基胺基)-苯甲基]-坐-2,4-二酮(DN-108)、5-{[4-(2-(2,3-二氫引-1-基)乙氧基)苯基]甲基}-坐-
2,4-
二酮、5-[3-(4-氯-苯基])-2-丙炔基]-5-苯基磺醯基)坐-2,4-二酮、5-[3-(4-氯苯基])-2-丙炔基]-5-(4-氟苯基-磺醯基)坐-2,4-二酮、5-{[4-(2-(甲基-2-比基-胺基)-乙氧基)苯基]甲基}-坐-2,4-二酮(羅格列酮(rosig1itazone))、5-{[4-(2-(5-乙基-2-比基)乙氧基)苯基]-甲基}坐-2,4-二酮(比格列酮(piog1itazone))、
5-{[4-((3,4-二氫-6-羥基-2,5,7,8-四甲基-2H-1-苯并哌喃-2-基)甲氧基)-苯基]-甲基}-坐-2,4-二酮(曲格列酮(trog1itazone))、5-[6-(2-氟-苯甲氧基)萘-2.-基甲基]-坐-2,4-二酮(MCC555)、5-{[2-(2-萘基)-苯并坐-5-基]-甲基}噻坐-2,4-二酮(T-174)及5-(2,4-二側氧基坐-5-基甲基)-2-甲氧基-N-(4-三氟甲基-苯甲基)苯甲醯胺(KRP297))。
其他抗糖尿病劑包括胰島素信號傳導路徑調節劑,如蛋白質酪胺酸磷酸酶(PTPase)抑制劑、抗糖尿病非小分子模擬化合物及麩醯胺酸-果糖-6-磷酸醯胺轉移酶(GFAT)抑制劑;影響調節異常之肝葡萄糖產生的化合物,如葡萄糖-
6-
磷酸酶(G6Pase)抑制劑、果糖-1,6-二磷酸酶(F-1,6-Bpase)抑制劑、糖原磷酸化酶(GP)抑制劑、升糖素受體拮抗劑及磷酸烯醇丙酮酸羧激酶(PEPCK)抑制劑;丙酮酸脫氫酶激酶(PDHK)抑制劑;胃排空抑制劑;胰島素;GSK-3抑制劑;類視色素X受體(RXR)促效劑;β-3AR促效劑;解偶聯蛋白(UCP)促效劑;非格列酮型PPARγ促效劑;雙重PPARα/PPARγ促效劑;抗糖尿病含釩化合物;腸促胰島素激素,如升糖素樣肽-1(GLP-1)及GLP-1促效劑;β細胞咪坐啉受體拮抗劑;米格列醇(mig1ito1);α2
-腎上腺素激導性拮抗劑;及其醫藥學上可接受之鹽。
術語「減肥劑」包括脂肪酶抑制劑(例如羅氏鮮(or1istat))及食慾抑制劑(例如諾美婷(sibutra mine)及苯丁胺(phentermine))。
醛固酮合成酶抑制劑或其醫藥學上可接受之鹽應理解為具有抑制醛固酮產生之性質的活性成分。醛固酮合成酶(CYP11B2)為催化腎上腺皮質中醛固酮產生之最後步驟(亦即11-去氧皮質酮轉化成醛固酮)的粒線體細胞色素P450酶。已知用所謂的醛固酮合成酶抑制劑抑制醛固酮產生為低鉀血症、高血壓、充血性心臟衰竭、心房纖維顫動或腎衰竭之治療的成功變型。該醛固酮合成酶抑制活性可由熟習此項技術者根據標準檢定(例如US2007/0049616)輕易地測定。
醛固酮合成酶抑制劑類別包含類固醇與非類固醇醛固酮合成酶抑制劑,後者最佳。
較佳為可自市面上購得的醛固酮合成酶抑制劑或已獲衛生管理當局(hea1th authority)批准的醛固酮合成酶抑制劑。
醛固酮合成酶抑制劑類別包含具有不同結構特徵之化合物。舉例而言,可提及選自由以下組成之群的化合物:非類固醇芳香酶抑制劑阿那曲坐(anastrozo1e)、法屈坐(fadrozo1e)(包括其(+)-對映異構體),以及類固醇芳香酶抑制劑依西美坦(exemestane),或適當時,各情況下其醫藥學上可接受之鹽。
最佳非類固醇醛固酮合成酶抑制劑為下式之法屈坐之鹽酸鹽的(+)-對映異構體(美國專利4617307及4889861):
或適當時,其醫藥學上可接受之鹽。一較佳類固醇醛固酮拮抗劑為下式之依普利酮(ep1erenone)(參看EP122232A):
或螺內酯;或適當時,各情況下其醫藥學上可接受之鹽。
適用於該組合之醛固酮合成酶抑制劑為例如US2007/0049616、特定言之化合物請求項及工作實例之最終產物中一般地及具體地揭示之化合物及類似物,因此最終產物、醫藥製劑及申請專利範圍之標的物以弓用該公開案之方式併入本申請案中。適用於本發明之較佳醛固酮合成酶抑制劑包括(但不限於)4-(6,7-二氫-5H-比咯并[1,2-c
]咪坐-5-基)-3-甲基苯甲腈;5-(2-氯-4-氰基苯基)-6,7-
二氫-
5H-比咯并[1,2-c]咪坐-5-甲酸(4-甲氧基苯甲基)甲基醯胺;4'
-氟-6-(6,7,8,9-四氫-5H-咪坐并[1,5-a]氮呯-5-基)聯苯-
3-
甲腈;5-(4-氰基-2-甲氧基苯基)-6,7-二氫-5H-比咯并[1,2-
c]咪坐-5-甲酸丁酯;4-(6,7-二氫-5H-比咯并[1,2-c
]咪坐-
5-
基)-2-甲氧基苯甲腈;5-(2-氯-4-氰基苯基)-6,7-
二氫-
5H-比咯并[1,2-c]咪坐-5-甲酸4-氟苯甲酯;5-(4-氰基-
2-
三氟甲氧基苯基)-6,7-二氫-5H-比咯并[1,2-c]咪坐-
5-
甲酸甲酯;5-(4-氰基-2-甲氧基苯基)-6,7-二氫-5H-比咯并[1,2-c]咪坐-
5-甲酸2-異丙氧基乙酯;4-(6,7-二氫-5H-比咯并[1,2-c
]咪坐-5-基)-2-甲基苯甲腈;4-(6,7-二氫-5H-比咯并[1,2-c]咪坐-5-基)-3-氟苯甲腈;4-(6,7-二氫-5H-比咯并[1,2-c]咪坐-
5-基)-2-甲氧基苯甲腈;3-氟-4-(7-亞甲基-6,7-
二氫-
5H-比咯并[1,2-c]咪坐-5-基)苯甲腈;順-3-氟-4-[7-(4-
氟-
苯甲基)-5,6,7,8-四氫-咪坐并[1,5-a]比-5-基]苯甲腈;4'-
氟-
6-
(9-甲基-6,7,8,9-四氫-5H-咪坐并[1,5-a]氮呯-5-基)聯苯-
3-
甲腈;4'
-氟-6-(9-甲基-6,7,8,9-四氫-5H-咪坐并[1,5-a]氮呯-5-基)聯苯-3-甲腈或各情況下其(R)或(S)對映異構體;或適當時,其醫藥學上可接受之鹽。
術語醛固酮合成酶抑制劑亦包括以下文獻中揭示之化合物及類似物:WO2008/076860、WO2008/076336、WO2008/076862、W O2008/027284、W O2004/046145、WO2004/014914、W O2001/076574。
此外,醛固酮合成酶抑制劑亦包括以下文獻中揭示之化合物及類似物:美國專利申請案US2007/0225232、US2007/0208035、US2008/0318978、US2008/0076794、US2009/0012068、US 20090048241 及 PCT申請案WO2006/005726、W O2006/128853、W O2006128851、WO2006/128852、W O2007065942、W O2007/116099、WO2007/116908、WO2008/119744及歐洲專利申請案EP1886695。適用於本發明之較佳醛固酮合成酶抑制劑包括(但不限於)Speede1開發之8-(4-氟苯基)-5,6-二氫-8H-咪坐并[5,1-c][1,4]嗪;4-(5,6-二氫-8H-咪坐并[5,1-c][1,4]嗪-8-基)-2-氟苯甲腈;4-(5,6-二氫-8H-咪坐并[5,1-c][1,4]嗪-8-基)-2,6-二氟苯甲腈;4-(5,6-二氫-8H-咪坐并[5,1-c][1,4]嗪-8-基)-2-甲氧基苯甲腈;3-(5,6-二氫-8H-咪坐并[5,1-c][1,4]-8-基)苯甲腈;4-(5,6-二氫-8H-咪坐并[5,1-c][1,4]嗪-8-基)苯二甲腈;4-(8-(4-氰基苯基)-5,6-二氫-8H-咪坐并[5,1-c][1,4]嗪-8-基)苯甲腈;4-(5,6-二氫-8H-咪坐并[5,1-c][1,4]嗪-8-基)苯甲腈;4-(5,6-二氫-8H-咪坐并[5,1-c][1,4]嗪-8-基)萘-1-甲腈;8-[4-(1H-四坐-5-基)苯基]-5,6-二氫-8H-咪坐并[5,1-c][1,4]嗪或各情況下其(R)或(S)對映異構體;或適當時,其醫藥學上可接受之。
術語「內皮素受體阻斷劑」包括波生坦。
術語「CETP抑制劑」係指抑制膽固醇酯轉移蛋白(CETP)介導之各種膽固醇酯及三酸甘油酯自HDL向LDL及VLDL的轉運的化合物。該CETP抑制活性可由熟習此項技術者根據標準檢定(例如美國專利第6,140,343號)輕易地測定。實例包括美國專利第6,140,343號及美國專利第6,197,786號中揭示之匕合物(例如[2R,4S]4-[(3,5-雙-三氟甲基-苯甲基)-甲氧基羰基-胺基]-2-乙基-6-三氟甲基-3,4-
二氫-2H-喹啉-1-甲酸乙酯(托西曲皮(torcetrapib));美國專利第6,723,752號中揭示之化合物(例如(2R)-3-{[3-(4-氯-
3-
乙基-苯氧基)-苯基]-[[3-(1,1,2,2-四氟-乙氧基)-苯基]-甲基]-胺基}-1,1,1-三氟-2-丙醇);美國專利申請案第10/807,838號中揭示之化合物;美國專利第5,512,548號中揭示之多肽衍生物;J.Antibiot.,49(8):815-816(1996)及Bioorg.Med.Chem.Lett.;6:1951-1954(1996)中分別揭示之玫瑰酮內酯(rosenono1actone)衍生物及膽固醇酯之含磷酸類似物。此外,CETP抑制劑亦包括W O2000/017165、WO2005/095409及WO2005/097806中揭示之CETP抑制劑。
一較佳P D E5抑制劑為西地那非(Si1denafi1)。
特別關注之第二藥劑包括內皮素拮抗劑、腎素抑制劑、血管收縮素II受體拮抗劑、鈣通道阻斷劑、利尿劑、抗糖尿劑(諸如DPPIV抑制劑)及醛固酮合成酶抑制劑。
本發明之例證:
用於合成本發明化合物之所有起始物質、構築嵌段、試劑、酸、鹼、脫水劑、溶劑及催化劑均可自市面上購得,或可利用一般技術者已知之有機合成方法(Houben-Wey1第4版1952,Methodsof Organic Synthesis,Thieme,第21卷)製備。另外,本發明化合物可利用如以下實例中所示之一般技術者已知之有機合成方法製備。
以下實例意欲說明本發明且不應解釋為限制本發明。溫度以攝氏度表示。若未另外提及,則所有蒸發均在減壓下、較佳在約15mm Hg與100mm Hg之間(=
20-133mbar)進行。最終產物、中間物及起始物質之結構由標準分析方法證實,例如微量分析及光譜特徵,例如MS、IR、NMR。所使用之縮寫為此項技術中習知之縮寫。已發現實例5-1至15-3中之化合物對NEP之IC50
值在約0.01nM至約10,000nM範圍內。
量測滯留時間之條件如下:HPLC條件A:管柱:INERTSILC8-3,3μm×33mm×3.0mm,40。
C流速:2m1/min移動相:A)5mM HCOONH4
水溶液,B)MeOH/CH3CN(1/1,v/v)梯度:線性梯度2min內5%A至95%B偵測:DAD-UV,在200-400nm下HPLC條件B:管柱:INERTSILC8-3,3μm×33mm×3.0mm,40℃流速:2m1/min移動相:A)5mM HCOONH4
水溶液,B)MeOH/CH3
CN(1/1,v/v)梯度:線性梯度2min內40%A至95%B偵測:DAD-UV,在200-400nm下HPLC條件C:管柱:INERTSILC8-3,3μm×33mm×3.0mm,40℃流速:2m1/min移動相:A)(5mM NH4 +
HCOO-
)/水,B)MeOH/CH3
CN(1/1,v/v)梯度:線性梯度2min內5至95%B偵測:DAD-UV,在200-400nm下HPLC條件D:管柱:INERTSILC8-3,3μm×33mm×3.0mm,40℃流速:2m1/min移動相:A)0.1%甲酸水溶液,B)MeOH/CH3
CN(1/1,v/v)梯度:線性梯度2min內5%B至95%B偵測:DAD-UV,在200-400nm下HPLC條件E:管柱:Inertsi1C8-3,3μm×33m m×3.0 m m,40℃流速:2m1/min移動相:A)甲醇/乙腈(1/1,v/v),B)5mM HCOONH4
水溶液梯度:線性梯度2min內40%B至95%A偵測:UV,在214nm下相對立體化學使用二維NMR測定。在反應條件下,出乎意料的是攜帶雙苯基-甲基之立體中心外消旋。因此,絕對立體化學基於相對立體化學及攜帶雙苯基-甲基之立體中心之絕對立體化學測定。
實例1-1:合成(R)-4-(1-(聯苯-4-基)-4-乙氧基-4-側氧基丁-2-基胺基)-4-側氧基丁酸
在室溫下,向(R)-4-(聯苯-4-基)-3-(第三丁氧基羰基胺基)丁酸乙酯(230.1mg,0.600mmo1)中添加HC1於1,4-二烷中之溶液(3.00 mL,12.00 mmo1)。攪拌1小時後,在減壓下濃縮反應混合物,得到(R)-3-胺基-4-聯苯-4-基-丁酸乙酯鹽酸鹽。攪拌(R)-3-胺基-4-聯苯-4-基-丁酸乙酯鹽酸鹽、丁二酸酐(72.1mg,0.720mmo1)及DIPEA(0.126mL,0.720mmo1)於二氯甲烷(4mL)中之溶液1小時。用10%檸檬酸水溶液淬滅反應,且用二氯甲烷萃取。分離有機層,且在減壓下濃縮。利用經CN改質之矽膠急驟管柱層析(溶離劑:
庚烷/EtOAc=100:0至0:100)及RP-HPLC(SunFireC18,H2O(0.1%TFA)/CH3
CN)純化所獲得之殘餘物,得到(R)-4-(1-(聯苯-4-基)-4-乙氧基-4-側氧基丁-2-基胺基)-4-側氧基丁酸(148.2mg)。HPLC滯留時間=1.64分鐘(條件A);MS(m+1)=384.1;1H NMR(400 MHz,乙腈-d3)δppm1.21(t,J=7.07Hz,3H)2.31-2.39(m,2H)2.40-2.56(m,4H)2.77-2.92(m,2H)4.08(q,J=7.24Hz,2H)4.33-4.48(m,1H)6.62(d,J=8.34Hz,1H)7.30(d,J=8.08Hz,2H)7.32-7.39(m,1H)7.41-7.49(m,2H)7.54-7.60(m,2H)7.60-7.67(m,2H)10.02(br.s.,1H)。
實例1-2:合成(R)-4-(1-(3'
-氯聯苯-4-基)-4-乙氧基-
4-
側氧基丁-2-基胺基)-4-側氧基丁酸
攪拌(R)-3-胺基-4-(3'
-氯聯苯-4-基)丁酸乙酯鹽酸鹽(400mg,
1.13mmo1)、
丁二酸酐(136mg,1.36mmo1)及DIPEA(0.237mL,1.36mmo1)於二氯甲烷(5mL)中之溶液2.5小時。用1MHC1水溶液淬滅反應,且用二氯甲烷萃取。分離有機層,且在減壓下濃縮。利用製備型HPLC使用20%MeCN/水(0.1%TFA)至100%MeCN之梯度純化所得殘餘物,得到(R)-4-(1-(3'
-氯聯苯-4-基)-4-乙氧基-4-側氧基丁-2-基胺基)-4-側氧基丁酸(255mg)。HPLC滯留時間=1.15分鐘(條件B);MS(m+1)=418.0;1HNMR(400MHz,氯仿-d)δppm1.29(t,J=7.08Hz,3H)2.46-2.58(m,4H)2.64-2.67(m,2H)2.87(ABX 之 A,Jab
=13.6Hz,Ja
x=7.8Hz,1H)2.99(ABX 之 B,Jab
=13.6Hz,Jbx=6.6Hz,1H)4.12-4.24(m,2H)4.47-4.55(m,1H)6.50(brd,J=8.8Hz,1H)7.24-7.37(m,4H)7.43-7.46(m,1H)7.48-7.52(m,2H)7.55-7.56(m,1H)。
對掌性HPLC滯留時間=3.59min。管柱:Daice1CHI RA LPAKAD-H(4.6×100 mm);流速=1 m1/min.;溶離劑:EtOH(含0.1%TFA)/庚烷=4/6。
使用類似於實例1-2中所述之程序製備以下化合物:
實例1-3:1H NMR(400MHz,氯仿-d)δppm1.29(t,J=7.2Hz,3H)1.86-1.97(m,2H)2.25-2.28(m,2H)2.34(t,J=7.0Hz,2H)2.50(ABX 之 A,Jab
=16.2Hz,Jax
=5.6Hz,1H)2.56(ABX之B,Jab
=16.2Hz,Jbx
=5.1Hz,1H)2.88(ABX之A,Ja
b=13.6Hz,Jax
=7.8Hz,1H)2.98(ABX 之 B,Ja
b=13.6Hz,Jbx=7.1Hz,1H)4.12-4.23(m,2H)4.50-4.58(m,1H)6.32(brd,J=8.8Hz,1H)7.25-7.37(m,4H)7.43-7.46(m,1H)7.49-7.52(m,2H)7.55-7.56(m,1H)。實例1-4:1H NMR(400MHz,氯仿-d)δppm1.29(t,J=7.1Hz,3H)1.86-1.97(m,2H)2.25-2.28(m,2H)2.34(t,J=7.0Hz,2H)2.54(ABX 之 A,Jab
=16.1Hz,Jax
=5.6Hz,1H)2.58(ABX 之B,Jab
=16.1Hz,Jbx
=5.2Hz,1H)2.88(ABX之A,Ja
b=13.5Hz,Jax
=7.6Hz,1H)2.97(ABX 之 B,Jab
=13.5Hz,Jb
x=7.0Hz,1H)3.78(s,3H)4.12-4.23(m,2H)4.50-4.59(m,1H)6.34(brd,J=8.6Hz,1H)6.88-6.91(m,1H)6.96-7.04(m,2H)7.23(d,J=8.3Hz,2H)7.44-7.47(m,2H)。實例1-5:1H NMR(400MHz,氯仿-d)δppm1.29(t,J=7.1Hz,3H)1.86-1.97(m,2H)2.25-2.36(m,4H)2.49-2.61(m,2H)2.88(ABX 之 A,Ja
b=13.6Hz,Ja
x=7.6Hz,1H)2.97(ABX 之 B,Jab
=13.6Hz,Jb
x=6.8Hz,1H)3.79(s,3H)4.12-4.23(m,2H)4.50-4.59(m,1H)6.34-6.36(m,1H)6.89(d,J=8.6Hz,1H)7.21-7.28(m,3H)7.43(d,J=8.1Hz,2H)。實例1-6:
1H NMR(400MHz,氯仿-d)δppm1.29(t,J=7.1Hz,3H)2.47-2.67(m,6H)2.89(ABX之A,Jab
=13.7Hz,Jax
=7.8Hz,1H)3.00(ABX 之 B,Jab
=13.7Hz,Jbx
=6.7Hz,1H)4.12-4.24(m,2H)4.49-4.57(m,1H)6.51(brd,J=8.6Hz,1H)6.97-7.07(m,2H)7.24-7.26(m,2H)7.36-7.43(m,3H)。實例1-7:
1H NMR(400MHz,DMSO-d6)δppm1.16(t,J=7.1Hz,3H)2.23-2.27(m,2H)2.34-2.38(m,2H)2.40-
2.47(m,2H)2.77(d,J=6.6Hz,2H)3.99-4.06(m,2H)4.21-4.30(m,1H)7.14-7.19(m,1H)7.29(d,J=8.4Hz,2H)7.46-7.52(m,3H)7.63(d,J=8.4Hz,2H)7.91(d,J=8.3Hz,1H)12.04(s,1H)。實例1-8:
1H NMR(400MHz,氯仿-d)δppm2.41-
2.45(m,2H)2.50-2.64(m,4H)2.81-2.87(m,1H)2.95-3.00(m,1H)4.49-4.56(m,1H)5.12(AB之A,J=12.1Hz,1H)5.18(AB之B,J=12.1Hz,1H)6.39(d,J=8.1Hz,1H)7.18-7.54(m,13H)。實例1-9:
1HNMR(400MHz,DMSO-d6):1HNMR(400MHz,DMSO-d6):δppm1.22-1.25(t,J=7.07Hz,3H),2.61-2.63(m,2H),2.91(d,J=7.07Hz,2H),4.09(q,J=7.07Hz,2H),4.52-4.59(m,1H),7.32-7,34(m,3H),7.04(t,J=7.83Hz,1H),7.52-7.56(m,3H),7.59(t,J=2.02Hz,1H)。實例1-10:1H NMR(400 MHz,氯仿-d)δppm2.03-
2.13(m,2H),2.44(t,J=6.3Hz,2H),2.64(t,J=6.6Hz,2H),2.70(dd,J=16.2,5.6Hz,1H),2.78(dd,J=:
16.2,5.1Hz,1H),2.83-2.98(m,5H),3.04(dd,J=13.9,6.8Hz,1H),4.57-4.69(m,1H),6.51(d,J=8.8Hz,1H),6.79(dd,J=8.1,2.3Hz,1H),6.90(d,J=1.8Hz,1H),7.18(d,J=8.1Hz,1H),7.26-7.31(m,3H),7.34(t,J=7.7Hz,1H),7.43(dt,J=7.3,1.5Hz,1H),7.49(d,J=8.1Hz,2H),7.54(t,=1.8Hz,1H),9.34(br.s.,1H)。
實例1-11:合成(R)-4-(1-(2'
,5'
-二氯聯苯-4-基)-4-乙氧基-4-側氧基丁-2-基胺基)-4-側氧基丁酸
在室溫下,向(R)-3-(第三丁氧基羰基胺基)-4-(2'
,5'
-二氯聯苯-4-基)丁酸乙酯(1.09g,2.33mmo1)中添加4MHC1於1,4-
二烷中之溶液(5.81mL,23.3mmo1)。攪拌2小時後,在減壓下濃縮反應混合物,得到(R)-3-胺基-4-(2'
,5'
-二氯聯苯-4-基)丁酸乙酯鹽酸鹽。接著,攪拌產物、丁二酸酐(280mg,2.80mmo1)及DIPEA(0.489mL,2.80mmo1)於二氯甲烷(15mL)中之溶液2小時。用1MHC1水溶液淬滅反應,且用二氯甲烷萃取。分離有機層,且在減壓下濃縮。利用製備型HPLC使用20%MeCN/水(0.1%TFA)至100%MeCN之梯度純化所得殘餘物,得到呈白色固體狀之(R)-4-(1-(2'
,5'
-二氯聯苯-4-基)-4-乙氧基-4-側氧基丁-
2-
基胺基)-4-側氧基丁酸(553mg);HPLC滯留時間=1.02分鐘(條件B);MS(m+1)=452.14;1HNMR(400MHz,氯仿-d)δppm1.29(t,J=7.2Hz,3H)2.47-2.67(m,6H)2.89(ABX之A,Ja
b=13.7Hz,Jax
=7.8Hz,1H)3.00(ABX 之 B,Jab
=13.7Hz,Jbx=6.7Hz,1H)4.12-4.24(m,2H)4.49-4.57(m,1H)6.53(brd,J=8.8Hz,1H)7.23-7.26(m,3H)7.32-7.40(m,4H)。
使用類似於實例1-11中所述之程序製備以下化合物:
實 1-12 : 1H NMR (400 MHz,
DMSO-d6) δ ppm 0.87 (t,J=7.5 Hz,
3H),
1.49-1.61 (m,
2H),
2.22-2.29 (m,
2H),
2.32-2.39 (m,
2H),
2.45 (dd,
J=6.9,
3.4 Hz,
2H),
2.78 (d,
J=6.6Hz,
2H),
3.94 (t,
J=6.6 Hz,
2H),
4.21-4.33 (m,
1H),
7.29 (d,J=8.3 Hz,
2H),
7.37-7.42 (m,
1H),
7.47 (t,
J=7.8 Hz,
1H),7.58-7.65 (m,
3H),
7.69 (t,
J=1.9 Hz,
1H),
7.92 (d,
J=8.3Hz,
1H)。實 1-13 : 1H NMR (400 MHz,
氯氯 -d) δ ppm 0.94 (t,J=7.3 Hz,
3H),
1.32-1.44 (m,
2H),
1.56-1.67 (m,
2H),
2.43-2.59(m,4H),2.65(t,J=6.4Hz,2H),2.85(dd,J=13.6,8.1Hz,1H),2.99(dd,J=13.6,6.6Hz,1H),4.03-4.18(m,2H),4.43-4.56(m,1H),6.57(d,J=8.6Hz,1H),7.25(d,J=8.3Hz,2H),7.28-7.32(m,1H),7.35(t,J=7.7Hz,1H),7.41-7.46(m,1H),7.48(d,J=8.1Hz,2H),7.55(t,J=1.8Hz,1H)。實例1-14:
1H NMR(400MHz,氯仿-d)δppm2.17(s,3H),2.44(t,J=6.2Hz,2H),2.48-2.57(m,1H),2.57-2.73(m,3H),2.87(dd,J=13.6,7.6Hz,1H),2.98(dd,J=13.9,7.1Hz,1H),4.47-4.58(m,1H),4.84(s,2H),6.32(d,J=8.6Hz,1H),7.23(d,J=8.1Hz,2H),7.30(d,1H),7.35(t,J=7.7Hz,1H),7.44(d,J=7.3Hz,1H),7.49(d,J=8.1Hz,2H),7.54(s,1H)。實例1-15:1H NMR(400MHz,氯仿-d)δppm2.48-2.59(m,3H),2.61-2.71(m,3H),2.91-3.06(m,8H),4.53-4.63(m,1H),4.67(d,J=14.7Hz,1H),5.03(d,J=14.7Hz,1H),7.30(dt,J=7.8,1.8Hz,1H),7.32-7.38(m,3H),7.45(dt,J=7.6,1.5Hz,1H),7.50(d,J=8.1Hz,2H),7.55(t,J=1.8Hz,1H),8.08(d,J=9.3Hz,1H)。實例1-16:1HNMR(400MHz,DMSO-d6
)δppm2.20-2.32(m,2H),2.32-2.41(m,2H),2.42-2.50(m,1H),2.57(dd,J=15.4,5.6Hz,1H),2.80(d,J=36.1Hz,2H),3.15(br.s.,2H),3.31-3.50(m,4H),3.52-4.05(m,4H),4.25-4.40(m,3H),7.31(d,J=8.3Hz,2H),7.39-7.43(m,1H),7.48(t,J=7.8Hz,1H),7.60-7.67(m,3H),7.70(t,J=1.8Hz,1H),8.02(d,J=8.6Hz,1H),10.06(br.s.,1H),12.17(br.s.,1H)。
實例1-
17:合成(R)-4-(1-(5'
-氯-2'
-氟聯苯-4-基)-4-乙氧基-4-側氧基丁-2-基胺基)-4-側氧基丁酸
攪拌(R)-3-胺基-4-(5'
-氯-2'
-氟聯苯-4-基)丁酸乙酯鹽酸鹽(293mg,0.777mmo1)、丁二酸酐(93mg,0.932mmo1)及DIPEA(0.204mL,1.165mmo1)於二氯甲烷(4mL)中之溶液1.5小時。用1MHC1水溶液淬滅反應,且用二氯甲烷萃取。分離有機層,且在減壓下濃縮。利用製備型HPLC使用20%MeCN/水(0.1%TFA)至100%MeCN之梯度純化所得殘餘物,得到(R)-4-(1-(5'
-氯-2'
-氟聯苯-4-基)-4-乙氧基-4-側氧基丁-2-基胺基)-4-側氧基丁酸(294mg)。HPLC滯留時間=1.03分鐘(條件B);MS(m+1)=436.2;1HNMR(400MHz,氯仿-d)δppm1.28(t,J=7.07Hz,3H)2.46-2.58(m,4H)2.64-2.68(m,2H)2.87(ABX之A,Ja
b=13.64Hz,Ja
x=7.83Hz,1H)2.99(ABX 之 B,Ja
b=13.64Hz,Jbx
=6.57Hz,1H)4.11-4.22(m,2H)4.47-4.56(m,1H)6.60(brd,J=8.59Hz,1H)7.05-7.10(m,1H)7.23-7.27(m,3H)7.39-7.41(m,1H)7.44-7.46(m,2H)。
使用類似於實例1-17中所述之程序製備以下化合物:
實例1-20:1H NMR(400 MHz,CDC13
)δppm1.15(t,J=7.07Hz,3H),2.24-2.34(m,4H),2.74(dd,J=8.59,13.39Hz),2.88(dd,J=6.32,13.39Hz),3.34(s,3H),3.75(d,J=2.78Hz,1H),4.04(dd,J=7.07,13.89Hz,2H),4.33-4.43(m,1H),7.31(d,J=8.08Hz,2H),7.38-7.43(m,1H),7.48(t,J=7.83Hz,1H),7.63(d,J=3.34Hz),7.71(t,J=1.77Hz,1H),7.95(d,J=9.35Hz,1H)。實例2-1:合成(R)-3-(3-羧基-丙醯基胺基)-4-(4'
-氟-聯苯-4-基)-丁酸乙酯
在氮氣下在95℃下,攪拌(R)-4-(1-(4-溴苯基)-4-乙氧基-4-側氧基丁-2-基胺基)-4-側氧基丁酸(50mg,0.129mmo1)、4-氟苯基朋酸(27.2mg,0.194mmo1)、Pd(Ph3P)4(14.96mg,0.013mmo1)及Na2
CO3
水溶液(0.129mL,
0.259mmo1)於甲苯(1mL)中之混合物。攪拌13小時後,冷卻溶液至周圍溫度,隨後用1MHC1水溶液淬滅。用乙酸乙酯萃取產物,用鹽水洗滌,經MgSO4
乾燥,過濾且在減壓下濃縮。利用RP-HPLC(SunFire C18,H2
O(0.1%TFA)/CH3CN)純化所獲得之殘餘物,並隨後凍乾,得到(R)-3-(3-羧基-丙醯基胺基)-4-(4'
-氟-聯苯-4-基)-丁酸乙酯(29.2mg)。HPLC滯留時間=1.26分鐘(條件B);MS(m+1)=402.2;1HNMR(400MHz,氯仿-d)δppm1.29(t,f=7Hz,3H)2.47-2.67(m,6H)2.87(ABX 之 A,Jab=13.7Hz,Jax=7.9Hz,1H)2.99(ABX之B,Jab=13.7Hz,Jbx=6.6Hz,1H)4.12-4.23(m,2H)4.47-4.55(m,1H)6.52(brd,J=8.6Hz,1H)7.08-7.14(m,2H)7.24(d,J=8.4Hz,2H)7.46-7.55(m,4H)。
使用類似於實例2-1中所述之程序製備以下化合物:
實例2-2:1HNMR(400MHz,氯仿-d)δppm1.29(t,J=7Hz,3H)2.47-2.67(m,6H)2.84-3.02(m,2H)4.12-4.24(m,2H)4.47-4.55(m,1H)6.52(brd,J=9.3Hz,1H)7.24-7.26(m,2H)7.39-7.41(m,2H)7.48-7.51(m,4H)。實例2-3:1HNMR(400MHz,氯仿-d)δppm1.29(t,J=7Hz,3H)2.43-2.65(m,6H)2.84-3.02(m,2H)3.67(s,3H)4.12-4.23(m,2H)4.47-4.55(m,1H)6.30(brd,J=8.6Hz,1H)7.00-7.05(m,1H)7.26-7.29(m,3H)7.34-7.41(m,2H)7.51(d,J=8.3Hz,2H)。實例2-4:1HNMR(400MHz,氯仿-d)δppm1.28(t,J=7Hz,3H)2.44-2.65(m,6H)2.85-3.02(m,2H)3.67(s,3H)4.11-4.23(m,2H)4.48-4.56(m,1H)6.30(brd,J=9.6Hz,1H)7.11-7.22(m,2H)7.25-7.33(m,3H)7.40-7.45(m,1H)7.48-7.50(m,2H)。實例2-5:1H NMR(400MHz,氯仿-d)δppm1.29(t,J=7.2Hz,3H)2.44-2.65(m,6H)2.86-3.02(m,2H)3.68(s,3H)4.12-4.23(m,2H)4.49-4.57(m,1H)6.31(brd,J=8.8Hz,1H)7.24-7.34(m,5H)7.37-7.39(m,2H)7.45-7.47(m,1H)。實例2-6:1HNMR(400MHz,氯仿-d)δppm1.28(t,J=7Hz,3H)2.44-2.66(m,6H)2.84-3.01(m,2H)3.68(s,3H)3.81(s,3H)4.11-4.23(m,2H)4.48-4.56(m,1H)6.26(brd,J=8.8Hz,1H)6.97-7.04(m,2H)7.22(d,J=8.1Hz,2H)7.29-7.33(m,2H)7.46-7.48(m,2H)。實例2-7:1H NMR(400MHz,氯仿-d)δppm1.29(t,J=7.1Hz,3H)2.26(s,3H)2.44-2.69(m,6H)2.85-3.01(m,2H)3.68(s,3H)4.12-4.23(m,2H)4.48-4.57(m,1H)6.30(brd,J=8.6Hz,1H)7.21-7.26(m,8H)。實例2-8:1H NMR(400MHz,氯仿-d)δppm1.29(t,J=7.2Hz,3H)2.44-2.69(m,6H)2.86-3.03(m,2H)3.68(s,3H)4.12-4.23(m,2H)4.48-4.57(m,1H)6.31(brd,J=8.8Hz,1H)6.90-7.01(m,1H)7.05-7.08(m,1H)7.25-7.27(m,2H)7.36-7.43(m,3H)。實例2-9:1H NMR(400MHz,氯仿-d)δppm1.28(t,J=7.2Hz,3H)2.41-2.65(m,9H)2.84-3.00(m,2H)3.67(s,3H)4.11-4.23(m,2H)4.47-4.55(m,1H)6.29(brd,J=8.9Hz,1H)7.16-7.39(m,6H)7.50-7.53(m,2H)。實例2-10:1H NMR(400 MHz,氯仿-d)δppm1.29(t,J=7.2Hz,3H)2.43-2.65(m,6H)2.84-3.02(m,2H)3.67(s,3H)4.12-4.23(m,2H)4.46-4.55(m,1H)6.33(brd,J=8.8Hz,1H)6.76-6.80(m,1H)7.06-7.12(m,2H)7.26-7.27(m,2H)7.48(d,J=8,0Hz,2H)。實例2-11:1H NMR(400MHz,氯仿-d)δppm1.27-1.30(m,6H)2.44-2.57(m,4H)2.62-2.74(m,4H)2.84-3.00(m,2H)3.67(s,3H)4.13-4.23(m,2H)4.47-4.55(m,1H)6.30(brd,J=7.6Hz,1H)7.17-7.26(m,3H)7.33-7.41(m,3H)7.52(d,J=7.8Hz,2H)。實例2-12:1H NMR(400MHz,氯仿-d)δppm1.30(t,J=7.1Hz,3H)2,41-2.65(m,6H)2.67-2.92(m,1H)3.00-3.05(m,1H)3.68(s,3H)4.14-4.22(m,2H)4.48-4.56(m,1H)6.33(brd,J=8.6Hz,1H)7.32(d,J=8.3Hz,2H)7.56-7.62(m,3H)7.89-7.91(m,1H)8.18-8.20(m,1H)8.44(t,J=8.0Hz,1H)。實例2-13:1H NMR(400MHz,氯仿-d)δppm1.29(t,J=7.2Hz,3H)2.44-2.65(m,6H)2.86-2.91(m,1H)2.98-3.03(m,1H)3.67(s,3H)4.13-4.22(m,2H)4.47-4.56(m,1H)6.33(brd,J=8.8Hz,1H)7.29(d,J=8.2Hz,2H)7.53(d,J=8.2Hz,2H)7.56-7.60(m,2H)7.75(d,J=7.6Hz,1H)7.81(s,1H)。實例2-14:1H NMR(400MHz,氯仿-d)δppm1.28(t,J=7.2Hz,3H)2.43-2.65(m,6H)2.84-2.89(m,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(brd,J=8.8Hz,1H)6.87-6.90(m,1H)7.10-7.11(m,1H)7.15-7.17(m,1H)7.24-7.26(m,2H)7.34(t,J=7.8Hz,2H)7.51-7.53(m,2H)。實例2-15:1H NMR(400MHz,氯仿-d)δppm1.29(t,J=7.1Hz,3H)2.43-2.58(m,4H)2.61-2.65(m,2H)2.84-2.91(m,1H)2.98-3.03(m,1H)3.68(s,3H)4.12-4.24(m,2H)4.47-4.55(m,1H)6.34(brd,J=8.8Hz,1H)7.30(d,J=8.1Hz,2H)7.50(d,J=8.1Hz,2H)7.51-7.63(m,2H)7.78-7.81(m,1H)7.85(brs,1H)。實例2-16:1H NMR(400MHz,氯仿-d)δppm1.29(t,J=7.1Hz,3H)2.43-2.57(m,4H)2.61-2.64(m,2H)2.87(ABX 之 A,Jab
=13.6Hz,Jax
=7.8Hz,1H)2.99(ABX之B,Jab
=13.6Hz,Jbx
=6.6Hz,1H)3.68(s,3H)4.12-4.23(m,2H)4.46-4.55(m,1H)6.34(brd,J=8.6Hz,1H)7.05(dt,J=8.3及2.0Hz,1H)7.15-7.19(m,1H)7.26-7.28(m,3H)7.35-7.36(m,1H)7.45(d,J=8.1Hz,2H)。實例2-17:1H NMR(400MHz,氯仿-d)δppm1.29(t,J=7.1Hz,3H)2.43-2.69(m,6H)2.90(ABX之A,Ja
b=13.6Hz,Jax
=7.8Hz,1H)2.99(ABX 之 B,Jab
=13.6Hz,Jbx
=6.8Hz,1H)3.68(s,3H)4.12-4.23(m,2H)4.49-4.57(m,1H)6.31(brd,J=8.6Hz,1H)7.20-7.26(m,4H)7.32(d,J=7.6Hz,1H)7.44-7.47(m,1H)7.53-7.57(m,1H)7.73(d,J=7.6Hz,2H)。實例2-18:1H NMR(400MHz,氯仿-d)δppm1.29(t,J=7.2Hz,3H)2.44-2.65(m,6H)2.91(ABX之A,Ja
b=13.6Hz,Jax
=7.8Hz,1H)3.01(ABX 之 B,Jab
=13.6Hz,Jbx
=6.6Hz,1H)3.68(s,3H)4.12-4.24(m,2H)4.48-4.57(m,1H)6.34(brd,J=8.6Hz,1H)7.32(d,J=8.1Hz,2H)7.41-7.56(m,2H)7.62-7.66(m,1H)7.75-7.77(m,1H)7.81-7.84(m,2H)。實例2-19:1H NMR(400MHz,氯仿-d)δppm1.28(t,J=7.2Hz,3H)1.35(t,J=6.9Hz,3H)2.44-2.53(m,4H)2.44-2.53(m,4H)2.86(ABX 之 A,Ja
b=13.6Hz,Ja
x=8.1Hz,1H)2.98(ABX 之 B,Ja
b=13.6Hz,Jbx=6.1 Hz,1H)3.67(s,3H)3.99-4.23(m,4H)4.48-4.56(m,1H)6.27(brd,J=8.6Hz,1H)6.94-7.04(m,2H)7.20-7.22(m,2H)7.27-7.33(m,2H)7.41-7.52(m,2H)。實例2-20:1H NMR(400MHz,氯仿-d)δppm1.28(t,J=7.2Hz,3H)1.43(s,9H)2.36-2.56(m,6H)2.84-3.01(m,4H)4.11-4.22(m,2H)4.47-4.56(m,1H)6.30-6.35(m,1H)7.25-7.27(m,2H)7.51-7.54(m,2H)。
實例2-21:合成(R)-4-(4-乙氧基-1-(5'
-氟-2'
-甲氧基聯苯-4-基)-4-側氧基丁-2-基胺基)-4-側氧基丁酸
向(R)-4-(1-(4-溴苯基)-4-乙氧基-4-側氧基丁-2-基胺基)-4-側氧基丁酸第三丁酯、中間物9(100mg,0.23mmo1)及5-氟-2-甲氧基苯基朋酸(57.6mg,0.34mmo1)於甲苯(1mL)及EtOH(0.1mL)中之溶液中添加Pd(PPh3
)4
(26.1mg,0.023mmo1)及Na2
CO3
(47.9mg,0.45mmo1)。在氮氣下在95℃下攪拌18小時後,冷卻溶液至周圍溫度,隨後用1MHC1水溶液淬滅。用乙酸乙酯稀釋粗產物,用鹽水洗滌有機層,經Na2
SO4
乾燥,過濾且在減壓下濃縮。利用矽膠急驟管柱層析(溶離劑:庚烷/EtOAc=100:0至30:70)純化所獲得之殘餘物,得到(R)-4-(4-乙氧基-1-(5'
-氟-2'
-甲氧基聯苯-4-基)-4-側氧基丁-2-基胺基)-4-側氧基丁酸第三丁酯(65mg)。HPLC滯留時間=1.44分鐘(條件B);MS(m+1)=488.3;1HNMR(400MHz,氯仿-d)δppm1.32(t,J=7.1Hz,3H)1.48(s,9H)2.41-2.48(m,2H)2.51-2.63(m,4H)2.90(dd,J=13.6,6Hz,1H)3.02(dd,J=13.6,6Hz,1I)3.81(s,3H)4.14-4.29(m,2H)4.49-4.63(m,1H)6.44(d,J=8.6Hz,1H)6.89-6.97(m,1H)6.98-7.05(m,1H)7.05-7.11(m,1H)7.27(d,J=8.1Hz,2H)7.49(d,J=8.1Hz,2H)。
在室溫下,攪拌(R)-4-(4-乙氧基-1-(5'
-氟-2'
-甲氧基聯苯-4-基)-4-側氧基丁-2-基胺基)-4-側氧基丁酸第三丁酯(65mg,0.13mmo1)於4M HC1之1,4-二烷溶液(671μL,2.68mmo1)中之溶液。攪拌1小時後,在減壓下濃縮反應混合物。利用RP-HPLC(SunFire C18,H2
O(0.1%TFA)/CH3
CN)純化所獲得之殘餘物,並隨後凍乾,得到(R)-4-(4-乙氧基-1-(5'
-氟-2'
-甲氧基聯苯-4-基)-4-側氧基丁-2-基胺基)-4-側氧基丁酸(23mg)。HPLC滯留時間=1.66分鐘(條件D);MS(m+1)=432.3;1H NMR(400MHz,DMSO-d6
)δppm1.17(t,J=7.1Hz,3H)2.21-2.32(m,2H)2.32-2.40(m,2H)2.40-2.48(m,2H)2.77(d,J=6.8Hz,2H)3.74(s,3H)4.03(q,J=7.1Hz,2H)4.19-4.33(m,1H)7.04-7.20(m,3H)7.23(d,J=8.1Hz,2H)7.43(d,J=8.1Hz,2H)7.93(d,J=8.3Hz,1H)。
使用類似於實例2-21中所述之程序製備以下化合物:
實例2-22:1H NMR(400MHz,CD3
OD)δppm1.23(t,J=7.1Hz,3H)2.36-2.58(m,6H)2.85(d,J=7.1Hz,2H)3.76(s,3H)4.10(q,J=7.1Hz,2H)4.40-4.57(m,1H)7.01(d,J=8.6Hz,1H)7.17-7.30(m,4H)7.39(d,J=8.1Hz,2H)。實例2-23:1HNMR(400MHz,DMSO-d6
)δppm1.16(t,J=7.2Hz,1H)2.23-2.30(m,2H)2.34-2.40(m,2H)2.40-2.45(m,2H)2.75(dd,J=6.6,3.3Hz,2H)4.02(q,J=7.2Hz,2H)4.19-4.30(m,1H)6.87-6.94(m,1H)6.93-7.02(m,1H)7.07(dd,J=9.7,3.2Hz,1H)7.22(d,J=8.1Hz,2H)7.49(d,J=8.1Hz,2H)7.94(d,J=8.1Hz,1H)9.52(s,1H)。實例2-24:1HNMR(400MHz,DMSO-d6)δppm1.16(t,J=7.1Hz,3H)2.22-2.32(m,2H)2.34-2.41(m,2H)2.43(dd,J=6.8,3.3Hz,2H)2.68-2.82(m,2H)4.02(q,J=7.1Hz,2H)4.17-4.35(m,1H)6.80-6.89(m,1H)6.93(d,J=7.1Hz,1H)7.09-7.17(m,1H)7.17-7.29(m,3H)7.46(d,J=8.3Hz,2H)7.93(d,J=8.1Hz,1H)9.46(br.s.,1H)。實例3-1:合成(R)-6-(1-(聯苯-4-基)-4-乙氧基-4-側氧基丁-2-基胺甲醯基)嘧啶-4-甲酸
在室溫下,向(R)-4-(聯苯-4-基)-3-(第三丁氧基羰基胺基)丁酸乙酯(300mg,0.782mmo1)中添加4M HC1於1,4-
二烷中之溶液(3.92mL,15.65mmo1)。攪拌1小時後,在減壓下濃縮反應混合物,得到(R)-3-胺基-4-聯苯-4-基-
丁酸乙酯鹽酸鹽。
接著,向密-4,6-二甲酸(325mg,1.935mmo1)、(R)-3-
胺基-4-聯苯-4-基-丁酸乙酯鹽酸鹽(250mg,0.774mmo1)、
WSC鹽酸鹽(148mg,0.774mmo1)及HOAt(105mg,
0.774mmo1)於DMF(4mL)及H2
O(1mL)中之懸浮液中添加DIPEA(0.135mL,0.774mmo1)。攪拌14小時後,用H2
O淬滅反應,且用EtOAc萃取產物,用鹽水洗滌,經Na2
SO4
乾燥,過濾,且在減壓下濃縮。
利用RP-HPLC(SunFire C18,H2
O(0.1%TFA)/CH3
CN)純化所獲得之殘餘物,並隨後凍乾,得到(R)-6-(1-(聯苯-4-基)-4-乙氧基-4-側氧基丁-2-基胺甲醯基)嘧-4-甲酸(84.8mg)。HPLC滯留時間=1.32分鐘(條件B);MS(m+1)=434.1;1H NMR(400MHz,DMSO-d6)δppm1.12(t,J=7.0Hz,3H)2.65(ABX 之 A,Jab=15.4Hz,Jax=5.8Hz,1H)2.73(ABX 之 B,Jab=15.4Hz,Jbx=7.9Hz)2.91(ABX之A,Jab=13.6Hz,Jax=6.1Hz,1H)3.01(ABX 之 B,Jab=13.6Hz,Jbx=8.2Hz,1H)4.01(q,J=7.0 Hz,2H)4.59-4.68(m,1H)7.29-7.35(m,3H)7.41-7.45(m,2H)7.55-7.63(m,4H)8.32(d,J=1.35Hz,1H)9.19(d.J=9.1Hz,1H)9.50(d,J=1.35Hz,1H)14.11(brs,1H)。
使用類似於實例3-1中所述之程序製備以下化合物:
實例3-2:1H NMR(400MHz,DMSO-d6)δppm1.14(t,J=7.1Hz,3H)2.57(d,J=7.1Hz,2H)2.83-2.92(m,2H)4.03(q,J=7.1Hz,2H)4.43-4.52(m,1H)7.29-7.36(m,3H)7.42-7.46(m,2H)7.58-7.65(m,4H)8.30(d,J=8.4Hz,1H)8.64(brs,1H)。實例3-4:1H NMR(400MHz,DMSO-d6)δppm1.13(t,J=7.1Hz,3H)2.55(d,J=6.9Hz,2H)2.82-2.92(m,2H)4.00(q,J=7.1Hz,2H)4.43-4.52(m,1H)7.29-7.35(m,3H)7.42-7.46(m,2H)7.58-7.65(m,4H)7.93-7.96(m,1H)8.10(d,J=2.3Hz,1H)8.25(d,J=8.3Hz,1H)12.53(d,J=6.1Hz,1H)。實例3-5:1H NMR(400MHz,DMSO-d6)δppm1.13(t,J=7.1Hz,3H)2.55(d,J=7.6Hz,2H)2.81-2.92(m,2H)4.02(q,J=7.1Hz,2H)4.43-4.52(m,1H)7.29-7.36(m,3H)7.42-7.46(m,2H)7.57-7.65(m,4H)7.78-7.81(m,1H)7.92(d,J=2.3Hz,1H)8.16(d,J=8.1Hz,1H)11.92(s,1H)。實例3-6:1H NMR(400MHz,DMSO-d6)δppm1.13(t,J=7Hz,3H)2.55-2.67(m,2H)2.83-2.94(m,2H)4.02(q,J=7Hz,2H)4.46-4.55(m,1H)6.82(s,1H)7.28-7.35(m,3H)7.42-7.46(m,2H)7.59(d,J=8.3Hz,2H)7.63(d,J=7.0Hz,2H)8.13(s,1H)8.89(d,J=8.6Hz,1H)9.56(s,1H)。實例3-7:1H NMR(400MHz,DMSO-d6)δppm1.13(t,J=7Hz,3H)2.56-2.58(m,2H)2.83-2.94(m,2H)4.02(q,J=7Hz,2H)4.46-4.55(m,1H)7.19(s,2H)7.30-7.35(m,3H)7.42-7.46(m,2H)7.58-7.65(m,4H)8.22(d,J=8.1Hz,1H)8.60(s,1H)。實例3-9:合成(R)-3-(4-丁氧基-4-側氧基丁醯胺基)-4-(3'
-氯聯苯-4-基)丁酸苯甲酯
在室溫下,攪拌(R)-3-胺基-4-(3'
-氯聯苯-4-基)丁酸苯甲酯鹽酸鹽(150mg,0.360mmo1)、4-丁氧基-4-側氧基丁酸(107mg,0.540 mmo1,純度88%)、EDCI(104mg,0.540mmo1)、DIPEA(0.094m1,0.540 mmo1)及HOAt(73.6mg,0.540mmo1)於DMF(2m1)中之混合物1小時。用水稀釋反應混合物,並隨後收集沈澱之固體於漏斗上,用H2
O洗滌,且在減壓下乾燥,得到粗產物。利用矽膠急驟管柱層析(庚烷/EtO Ac=100:0至0:100)純化所獲得之殘餘物,得到(R)-3-(4-丁氧基-4-側氧基丁醯胺基)-4-(3'
-氯聯苯-4-基)丁酸苯甲酯(178.9mg);HPLC滯留時間=1.47分鐘(條件B);MS(m+1)=536.42;1H NMR(400MHz,氯仿-d)δppm0.90-0.94(m,3H)1.31-1.40(m,2H)1.56-1.63(m,2H)2.39-2.42(m,2H)2.48-2.62(m,4H)2.84(ABX之A,Ja
b=13.6Hz,Jax
=8.1 Hz,1H)2.97(ABX 之 B,Jab
=13.6Hz,Jbx
=6.6Hz,1H)4.07(t,J=6.7Hz,2H)4.48-4.56(m,1H)5.12(AB之A,J=12.1Hz,1H)5.18(AB之B,J=12.1Hz,1H)6.27(brd,J=7.7Hz,1H)7.20(d,J=8.3Hz,1H)7.29-7.39(m,7H)7.42-7.47(m,3H)7.54-7.55(m,1H)。
使用類似於實例3-8中所述之程序製備以下化合物:
實例3-10:1H NMR(400 MHz,氯仿-d)δppm1.29(t,J=7.2Hz,3H)1.58-1.64(m,4H)2.14-2.18(m,2H)2.28-2.32(m,2H)2,49(ABX 之 A,Ja
b=16.2Hz,Ja
x=5.3Hz,1H)2.53(ABX 之 B,Jab
=16.2Hz,Jbx
=5.3Hz,1H)2.87(ABX之A,Ja
b=13.6Hz,Jax
=8.1 Hz,1H)2.99(ABX 之 B,Jab
=13.6Hz,Jbx=6.8Hz,1H)3.65(s,3H)4.11-4.23(m,2H)4.48-4.56(m,1H)6.18(brd,J=8.8Hz,1H)7.26-7.37(m,4H)7.43-7.52(m,3H)7.56(brt,J=1.8Hz,1H)。實例3-11:1H NMR(400 MHz,氯仿-d)δppm1.27(t,J=7.1Hz,3H)2.40-2.51(m,4H)2.77-2.83(m,1H)2.91-2.97(m,3H)4.08-4.20(m,2H)4.46-4.54(m,1H)6.22-6.24(m,1H)7.18-7.23(m,3H)7.29-7.37(m,2H)7.43-7.49(m,3H)7.55-7.57(m,2H)8.44(d,J=4.8Hz,1H)8.48(s,1H)。實例3-12:1H NMR(400MHz,氯仿-d)δppm1.29(t,J=7.1Hz,3H)1.53-2.20(m,9H)2.46-2.57(m,3H)2.86(ABX 之 A,Jab
=13.6Hz,Jax
=7.8Hz,1H)2.98(ABX之B,Jab
=13.6Hz,Jbx
=6.6Hz,1H)3.65(s,3H)4.11-4.23(m,2H)4.47-4.55(m,1H)6.23(brd,J=8.6Hz,1H)7.24-7.26(m,2H)7.31-7.35(m,1H)7.41-7.45(m,2H)7.51-7.59(m,4H)。實例3-13:1H NMR(400MHz,氯仿-d)δppm1.29(t,J=7.2Hz,3H)1.36-1.51(m,4H)1.84-1.94(m,2H)1.98-2.06(m,3H)2.24-2.32(m,1H)2.50(ABX之A,Ja
b=16.2Hz,Jax
=5.3Hz,1H)2.53(ABX 之 B,Jab
=16.2Hz,Jbx
=5.1Hz,1H)2.86(ABX 之 A,Jab
=13.6Hz,Jax
=7.8Hz,1H)2.98(ABX 之 B,Jab
=13.6Hz,Jbx=6.6Hz,1H)3.66(s,3H)4.11-4.23(m,2H)4.46-4.55(m,1H)6.19(brd,J=8.8Hz,1H)7.24-7.26(m,2H)7.31-7.36(m,1H)7.41-7.45(m,2H)7.51-7.58(m,4H)。實例3-14:1H NMR(400MHz,氯仿-d)δppm1.26(t,J=7.2Hz,3H)2.41-2.51(m,4H)2.62-2.66(m,2H)2.84(ABX之 A,Jab
=13.6Hz,Jax
=7.6Hz,1H)2.92(ABX之B,Jab
=13.6Hz,Jbx=6.6Hz,1H)3.06-3.10(m,2H)4.08-4.19(m,2H)4.46-4.55(m,1H)6.78(d,J=8.9Hz,1H)7.10-7.12(m,1H)7.16(d,J=7.8Hz,1H)7.20-7.22(m,2H)7.29-7.31(m,1H)7.35(t,J=7.7Hz,1H)7.42-7.47(m,3H)7.54-7.59(m,2H)8.48(d,J=1.0Hz,1H)。實例3-16:1H NMR(400MHz,氯仿-d)δppm1.24(t,J=7.1Hz,3H)2.38-2.42(m,2H)2.49-2.61(m,4H)2.82-3.00(m,2H)4.12(q,J=7.1Hz,2H)4.47-4.56(m,1H)5.12(AB之A,J=12.3Hz,1H)5.18(AB之B,J=12.3Hz,1H)6.26(brd,J=8.6Hz,1H)7.20(d,J=8.3Hz,2H)7.29-7.46(m,10H)7.54-7.54(m,1H)。實例3-17:1H NMR(400MHz,氯仿-d)δppm1.23(t,J=7.2Hz,3H)1.86-1.92(m,2H)2.14-2.18(m,2H)2.24-2.28(m,2H)2.50-2.63(m,2H)2.82-2.99(m,2H)4.11(q,J=7.2Hz,2H)4.53-4.54(m,1H)5.12(AB之A,J=12.1Hz,1H)5.18(AB之B,J=12.1Hz,1H)6.12-6.14(m,1H)7.19-7.54(m,13H)。實例3-18:1H NMR(400MHz,氯仿-d)δppm1.26(t,J=7.2Hz,3H)1.67(s,9H)2.46-2.57(m,2H)2.74-2.96(m,4H)3.41-3.45(m,2H)4.09-4.17(m,2H)4.50-4.59(m,1H)6.95(brd,J=8.6Hz,1H)7.18(d,J=8.1Hz,2H)7.27-7.42(m,7H)7.51.(t,J=1.8Hz,1H)7.61-7.65(m,1H)7.86-7.93(m,1H)。實例3-19:1H NMR(400MHz,氯仿-d)δppm1.28(t,J=7.2Hz,3H)1.43(s,9H)2.37-2.40(m,2H)2.50-2.59(m,4H)2.98(d,J=7.3Hz,2H)4.13-4.21(m,2H)4.48-4.56(m,1H)6.35(brd,J=8.8Hz,1H)7.22-7.44(m,6H)7.54-7.54(m,1H)。實例3-20:合成(R)-4-(3'
-胺基聯苯-4-基)-3-(4-甲氧基-4-側氧基丁醯胺基)丁酸乙酯
在氫氣下在室溫下,攪拌(R)-3-(4-甲氧基-4-側氧基丁醯胺基)-4-(3'
-硝基聯苯-4-基)丁酸乙酯(123mg,0.278mmo1)及Pd/C(59.2mg,0.028mmo1)於EtOH(2m1)中之懸浮液5.5小時。過濾反應混合物,且濃縮溶液,得到(R)-4-(3'
-胺基聯苯-4-基)-3-(4-甲氧基-4-側氧基丁醯胺基)丁酸乙酯(105mg);HPLC滯留時間=0.84分鐘(條件B);MS(m+1)=413.1;1HNMR(400MHz,氯仿-d)δppm1.28(t,J=7.2Hz,3H)2.41-2.65(m,6H)2.85-3.00(m,2H)3.67(s,3H)4.11-4.22(m,2H)4.46-4.54(m,1H)6.31(brd,J=8.8Hz,1H)6.71-6.74(m,1H)6.95-7.02(m,2H)7.21-7.25(m,3H)7.48-7.50(m,2H)。
使用類似於實例3-20中所述之程序製備以下化合物:
實例3-22:
1H NMR(400MHz,氯仿-d)δppm2.03-
2.11(m,2H)2.48-2.62(m,4H)2.81-2.90(m,7H)2.95-3.00(m,1H)4.49-4.58(m,1H)5.07-5.18(m,2H)6.23(brd,J=8.6Hz,1H)6.79-6.82(m,1H)6.92(s,1H)7.15-7.20(m,3H)7.29-7.45(m,10H)7.52-7.53(m,1H)。實例3-23:合成(S)-1-(2-((R)-1-(聯苯-4-基)-4-乙氧基-4-側氧基丁-2-基胺基)-2-側氧基乙基)吡咯啶-2-
甲酸苯甲酯三氟乙酸鹽
在室溫下,向(S)-1-(2-第三丁氧基-2-側氧基乙基)比咯-2-甲酸苯甲酯(200mg,0.626mmo1)及三乙基矽烷(0.250 m1,1.565mmo1)於DCM(3m1)中之溶液中添加TFA(0.965m1,12.52mmo1)。攪拌24小時後,濃縮反應,得到粗產物。
向粗產物(R)-3-胺基-4-(聯苯-4-基)丁酸乙酯鹽酸鹽(266mg,
0.832mmo1)、WSC.HC1(0.180 g,0.939mmo1)及HOAt(128mg,0.939mmo1)於DMF(4m1)中之懸浮液中添加DIPEA(0.328m1,1.878mmo1)。攪拌4小時後,用H2
O及EtOAc稀釋反應。用EtOAc萃取產物,用鹽水洗滌,經Na2SO4乾燥,過濾且濃縮。對粗產物進行兩次管柱層析(庚烷/EtOAc=100:0至0:100)。隨後,利用製備型HPLC使用20%MeCN/水(0.1%TFA)至100%MeCN之梯度純化所獲得之產物,得到呈淡黃色固體狀之(S)-1-(2-((R)-1-(聯苯-4-基)-4-乙氧基-4-側氧基丁-2-基胺基)-2-側氧基乙基)比咯啶-
2-甲酸苯甲酯三氟乙酸鹽(28.5mg);HPLC滯留時間=1.84分鐘(條件D);MS(m+1)=529.3;1HNMR(400MHz,氯仿-d)δppm1.25-1.28(m,3H)1.74-1.85(m,2H)1.91-1.98(m,1H)2.09-2.19(m,1H)2.35-2.41(m,1H)2.46(ABX之A,Jab=15.7Hz,Jax=6.6Hz,1H)2.59(ABX之B,Ja
b=13.7Hz,Jbx
=5.7Hz,1H)2.78-2.83(m,1H)2.86(ABX之A,Jab
=13.8Hz,Jax
=8.1 Hz,1H)2.99(ABX 之 B,Jab
=13.7Hz,Jbx
=6.4Hz,1H)3.08(AB之 A,J=16.5Hz,1H)3.35(AB之B,J=16.5Hz,1H)3.41(dd,J=9.1及5.1Hz,1H)4.11-4.20(m,2H)4.46-4.55(m,1H)5.10(AB之A,J=12.4Hz,1H)5.13(AB之B,J=12.4Hz,1H)7.26-7.27(m,2H)7.31-7.38(m,6H)7.40-7.44(m,2H)7.49-7.56(m,4H)7.74(brd,J=8.6Hz,1H)。實例3-24:合成(R)-4-(3'
-乙醯胺基聯苯-4-基)-3-(4-甲氧基-4-側氧基丁醯胺基)丁酸乙酯
在室溫下,攪拌(R)-4-(3'
-胺基聯苯-4-基)-3-(4-甲氧基-4-側氧基丁醯胺基)丁酸乙酯(70.5mg,0.171mmo1)、Et3N(0.027m1,0.205m mo1)及Ac2O(0.019m1,0.205mmo1)於DCM(1.7m1)中之溶液65小時。用水稀釋反應混合物。在相分離器中用DCM萃取產物,且濃縮,得到粗產物(98mg)。利用矽膠急驟管柱層析(溶離劑:DCM/MeOH=
10:1)純化粗產物,得到(R)-4-(3'
-乙醯胺基聯苯-4-基)-3-(4-甲氧基-4-側氧基丁醯胺基)丁酸乙酯(71.5mg);HPLC滯留時間=1.45分鐘(條件D);MS(m+1)=455.4;1HNMR(400MHz,CD3
CN,旋轉異構體之混合物,主要旋轉異構體之數據)δppm1.21(t,J=7.1Hz,3H)2.07(s,3H)2.31-2.34(m,2H)2.40-2.51(m,4H)2.82-2.84(m,2H)3.58(s,3H)4.07(q,J=7.1Hz,2H)4.34-4.43(m,1H)6.46(brd,J=8.9Hz,1H)7.28-7.39(m,4H)7.52-7.54(m,3H)7.80(s,1H)8.37(brs,1H)。
實例3-25:合成(R)-3-(4-丁氧基-4-側氧基丁醯胺基)-4-(3'
-氯聯苯-4-基)丁酸
在氫氣下在室溫下,攪拌(R)-3-(4-丁氧基-4-側氧基丁醯胺基)-4-(3'
-氯聯苯-4-基)丁酸苯甲酯(178.9mg,0.334mmo1)及Pd/C(71.0 mg,0.033mmo1)於EtOAc(3m1)中之懸浮液1.5小時。過濾反應混合物,且濃縮,得到粗產物。利用製備型HPLC使用20%MeCN/水(0.1%TFA)至100%MeCN之梯度純化所得殘餘物,得到呈白色固體狀之(R)-3-(4-丁氧基-4-側氧基丁醯胺基)-4-(3'
-氯聯苯-4-基)丁酸(90.7mg);HPLC滯留時間=1.27分鐘(條件B);MS(m+1)=446.24;1HNMR(400MHz,氯仿-d)δppm0.91(t,J=7.5Hz,3H)1.31-1.40(m,2H)1.55-1.62(m,2H)2.43-2.47(m,2H)2.52-2.69(m,4H)2.93(ABX 之 A,Jab
=13.7Hz,Ja
x=7.7Hz,1H)3.00(ABX 之 B,Jab
=13.7Hz,Jbx
=6.8Hz,1H)4.07(t,J=6.7Hz,2H)4.49-4.57(m,1H)6.31(brd,J=8.6Hz,1H)7.26-7.37(m,4H)7.43-7.46(m,1H)7.49-7.52(m,2H)7.55(brt,J=1.8Hz,1H)。
對掌性HPLC滯留時間=4.33min.;管柱:Daice1CHIRALPAKIA(4.6×100 mm);流速=1m1/min.;溶離劑:10 min內 EtOH(含0.1%TFA)/庚烷=10/90至70/30(線性梯度)。
使用類似於實例3-24中所述之程序製備以下化合物:
實例3-26:1H NMR(400MHz,氯仿-d)δppm1.23(t,J=7.1Hz,3H)1.86-1.93(m,2H)2.57(ABX之A,Jab
=16.3Hz,Jax
=5.7Hz,1H)2.64(ABX 之 B,Jab
=16.3Hz,Jbx
=5.2Hz,1H)2.94(ABX 之 A,Ja
b=13.7Hz,Jax=7.6Hz,1H)2.99(ABX 之 B,Ja
b=13.7Hz,Jbx
=7.2Hz,1H)4.10(q,J=7.1Hz,2H)4.51-4.60(m,1H)6.17(brd,J=8.6Hz,1H)7.26-7.37(m,4H)7.43-7.45(m,1H)7.49-7.52(m,2H)7.55(brt,J=1.8Hz,1H)。實例3-27:1HNMR(400MHz,氯仿-d)δppm2.07(五重峰,J=7.4Hz,2H)2.51-2.63(m,4H)2.82-3.02(m,8H)4.50-4.59(m,1H)6.28(d,J=8.6Hz,1H)6.78-6.81(m,1H)6.91(d,J=1.8Hz,1H)7.26-7.36(m,6H)7.41-7.44(m,1H)7.47-7.50(m,2H)7.53-7.54(m,1H)。實例3-28:1H NMR(400MHz,氯仿-d)δppm1.24(t,J=7.2Hz,3H)2.44-2.69(m,6H)2.93(ABX之A,Jab
=13.7Hz,Jax
=7.8Hz,1H)3.00(ABX 之 B,Jab
=13.7Hz,Jbx
=6.7Hz,1H)4.12(q,J=7.2Hz,2H)4.49-4.57(m,1H)6.35(brd,J=8.6Hz,1H)7.26-7.37(m,4H)7.43-7.46(m,1H)7.49-7.52(m,2H)7.55(brt,J=1.6Hz,1H)。
實例3-29:合成(R)-3-(4-(苯甲氧基)-4-側氧基丁醯胺基)-4-(3'
-氯聯苯-4-基)丁酸
將在室溫下攪拌1小時之丁二酸單苯甲酯(71.1mg,0.342mmo1)、EDCI(65.5mg,0.342mmo1)及HOAt(46.5mg,0.342mmo1)於DMF(1m1)中之溶液添加至(R)-3-胺基-4-(3'
-氯聯苯-4-基)丁酸(66mg,0.228mmo1)及DIPEA(0.080 m1,0.456mmo1)於混合溶劑DMF(2m1)及水(2m1)中之溶液中。攪拌反應混合物3小時,並隨後用H2
O稀釋。用EtOAc萃取產物兩次。用鹽水洗滌合併之有機層,經Na2
SO4
乾燥,過濾且濃縮,得到粗產物。利用製備型HPLC使用20%MeCN/水(0.1%TFA)至100%MeCN之梯度純化所得殘餘物,得到呈白色固體狀之(R)-3-(4-(苯甲氧基)-4-側氧基丁醯胺基)-4-(3'
-氯聯苯-4-基)丁酸(42.4mg);HPLC滯留時間=1.22分鐘(條件B);MS(m+1)=480.35;1HNMR(400MHz,氯仿-d)δppm2.44-2.75(m,6H)2.86-2.99(m,2H)4.48-4.56(m,1H)5.11(s,2H)6.29(brd,J=8.6Hz,1H)6.97-7.07(m,10H)7.25-7.36(m,2H)7.42-7.50(m,2H)7.54(brt,J=1.6Hz,1H)。
實例3-30:合成4-(聯苯-4-基)-3-(1-(羧基甲基)環戊烷甲醯胺基)丁酸
向4-(聯苯-4-基)-3-(第三丁氧基羰基胺基)丁酸第三丁酯(110mg,0.267mmo1)中添加4M HC1於1,4-二烷中之溶液(0.668m1,2.67mmo1)。攪拌1小時後,濃縮反應混合物,得到粗產物3-胺基-4-聯苯-4-基-丁酸第三丁酯鹽酸鹽。接著,向提前攪拌1.5小時之EDCI(51.2mg,0.267mmo1)、1-羥基-7-氮雜苯并三坐(36.4mg,0.267mmo1)及1-(2-(苯甲氧基)-2-側氧基乙基)環戊烷甲酸與2-(1-(苯甲氧基羰基)環戊基)乙酸之6:1混合物(65.6mg,0.214mmo1)於DMF(1m1)中之溶液中添加粗產物3-胺基-4-聯苯-4-基-
丁酸第三丁酯鹽酸鹽及DIPEA(0.093m1,0.535mmo1)。攪拌2.5小時後,用H2
O稀釋反應混合物,且用EtOAc萃取產物。用鹽水洗滌有機層,經Na2
SO4
乾燥,過濾且濃縮。利用矽膠急驟管柱層析(庚烷/EtO Ac=100:0至0:100)純化所獲得之殘餘物,得到粗產物3-(1-(2-(苯甲氧基)-2-側氧基乙基)環戊烷甲醯胺基)-4-(聯苯-4-基)丁酸第三丁酯(38mg)。
接著,向粗產物3-(1-(2-(苯甲氧基)-2-側氧基乙基)環戊烷甲醯胺基)-4-(聯苯-4-基)丁酸第三丁酯(38mg)於DCM(0.7m1)中之溶液中添加TFA(0.263m1,3.42mmo1)。攪拌1小時後,濃縮反應混合物,得到粗產物3-(1-(2-(苯甲氧基)-2-側氧基乙基)環戊烷甲醯胺基)-4-(聯苯-4-基)丁酸(39mg)。
接著,在氫氣下在室溫下,攪拌粗產物(39mg)及Pd/C(16.6mg,7.8μmo1)於EtOH(1m1)中之懸浮液4小時。過濾反應混合物,且濃縮,得到粗產物。利用製備型HPLC使用20%MeCN/水(0.1%TFA)至100%MeCN之梯度純化所得殘餘物,得到4-(聯苯-4-基)-3-(1-(羧基甲基)環戊烷甲醯胺基)丁酸(12.7mg);HPLC滯留時間=1.16分鐘(條件B);MS(m+1)=410.1;1HNMR(400MHz,DMSO-d6)δppm1.39-1.53(m,6H)1.83-1.98(m,2H)2.34-2.45(m,2H)2.53(s,2H)2.73-2.86(m,2H)4.21-4.33(m,1H)7.27(d,J=8.1Hz,2H)7.32-7.37(m,2H)7.43-7.46(m,2H)7.55-7.58(m,2H)7.62-7.64(m,2H)7.84(brd,J=8.9Hz,1H)。實例3-31:合成(R)-4-(3'
-氯聯苯-4-基)-3-(2-側氧基-2,3-二氫噁唑-5-甲醯胺基)丁酸乙酯
向(R)-4-(3'
-氯聯苯-4-基)-3-(2-甲氧基坐-5-甲醯胺基)丁酸乙酯、中間物14(103mg,0.23mmo1)於二烷(3mL)中之溶液中添加4NHC1之二噁烷溶液(0.29mL,1.16mmo1)。在室溫下攪拌粗產物2小時。濃縮粗產物,且用水及EtOAc稀釋。用鹽水洗滌有機層,經MgSO4
乾燥,過濾且濃縮。經由RP-HPLC(SunFireC18,H2
O(0.1%TFA)/CH3
CN)純化50%之粗產物,得到呈白色固體狀之(R)-4-(3'
-氯聯苯-4-基)-3-(2-側氧基-2,3-二氫坐-5-甲醯胺基)丁酸乙酯(38mg)。HPLC滯留時間=1.66分鐘(條件A);MS(m+1)=429.4;1HNMR(400MHz,氯仿-d)δppm1.29(t,J=71Hz,3H)2.51-2.69(m,2H)2.95(dd,1H)3.05(dd,1H)4.19(q,2H)4.58-4.75(m,1H)6.83(d,J=8.8Hz,1H)7.26-7.33(m,4H)7.35(t,J=7.7Hz,1H)7.45(dt,J=7.6,1.5Hz,1H)7.51(d,J=8.3Hz,2H)7.56(t,J=1.8Hz,1H)8.45(br.s.,1H)。實例3-32:合成(R)-4-(3'
-氯聯苯-4-基)-3-(2-側氧基-2,3-二氫噻唑-5-甲醯胺基)丁酸乙酯
向(R)-4-(3'
-氯聯苯-4-基)-3-(2-甲氧基坐-5-甲醯胺基)丁酸乙酯、中間物13(170mg,0.37mmo1)於二烷(5mL)中之溶液中添加4MHC1之二烷溶液(0.5mL,2.00mmo1)。在室溫下攪拌粗產物3小時。濃縮粗產物。經由RP-HPLC(SunFire C18,H2
O(0.1%TFA)/CH3
CN)純化一部分粗產物,得到(95mg)呈白色固體狀之(R)-4-(3'
-氯聯苯-4-基)-3-(2-側氧基-2,3-二氫坐-5-甲醯胺基)丁酸乙酯。HPLC滯留時間=1.82分鐘(條件D);MS(m+1)=445.2。1HNMR(400MHz,氯仿-d)δppm1.29(t,J=7.1Hz,3H)2.46-2.70(m,2H)2.78-2.97(m,1H)3.07(dd,J=13.0,6.2Hz,1H)4.11-4.28(m,2H)4.51-4.69(m,1H)6.64(d,J=8.1Hz,1H),7.19-7.42(m,5H)7.44(d,J=6.1Hz,1H)7.48-7.62(m,3H),9.54(br.s.,1H)。實例3-
33:合成(R)-4-(3'
-氯聯苯-4-基)-3-(5-側氧基-4,5-二氫-1,3,4-噁二唑-2-甲醯胺基)丁酸乙酯
在室溫下,向(R)-4-(3'
-氯聯苯-4-基)-3-(2-肼基-2-側氧基乙醯胺基)丁酸乙酯、中間物12(289mg,0.72mmo1)於THF(8.5mL)中之溶液中添加CDI(139mg,0.86mmo1)。
在室溫下攪拌18小時後,用H2
O及1MHC1淬滅反應,且用EtOAc稀釋粗產物。用鹽水洗滌有機層,經Na2
SO4
乾燥,過濾且在減壓下濃縮。利用RP-HPLC(SunFire C18,H2
O(0.1%TFA)/CH3
CN)純化所獲得之殘餘物,並隨後凍乾,得到(R)-4-(3'
-氯聯苯-4-基)-3-(5-側氧基-4,5-
二氫-
1,3,4-二坐-2-甲醯胺基)丁酸乙酯(100mg)。HPLC滯留時間=1.67分鐘(條件A);MS(m+1)=430.2;1HNMR(400MHz,DMSO-d6)δppm1.14(t,J=7.1Hz,3H)2.52-2.70(m,2H)2.84(dd,J=13.7,8.4Hz,1H)2.90(dd,J=13.7,8.4Hz,1H)4.02(q,J=7.1Hz,2H)4.42-4.58(m,1H)7.30(d,J=8.1Hz,2H)7.37-7.43(m,1H)7.47(t,J=7.8Hz,1H)7.57-7.66(m,3H)7.70(t,J=1.9Hz,1H)8.98(d,J=8.8Hz,1H)12.94(s,1H)。實例3-34:合成(R)-3-(3-羧基甲基-脲基)-4-(3'-氯-
聯苯-
4-
基)-丁酸乙酯
向2-胺基乙酸第三丁酯(19.08mg,0.145mmo1)及DIEA(18.8mg,0.145mmo1)於DMF(1mL)中之溶液中添加中間物45(50mg,0.145mmo1),且在室溫下攪拌混合物2小時。在減壓下移除溶劑,得到(R)-3-(3-第三丁氧基羰基甲基-脲基)-4-(3'
-氯-聯苯-4-基)-丁酸乙酯。
接著,向上述二酯(70mg,0.147mmo1)於二氯甲烷(2mL)中之溶液中添加TFA(4mL),且在室溫下攪拌混合物18小時。在減壓下移除溶劑,且利用製備型HPLC使用35%MeCN/水至100%MeCN(+0.1%TFA)之梯度純化殘餘物。凍乾適當溶離份,得到標題化合物;HPLC滯留時間1.42分鐘(條件C);MS419.1(M+1);1HNMR(400MHz,DMSO-d6):δppm1.17(t,J=7.07Hz,3H),2.41(d,J=7.07Hz,2H),2.77-2.79(m,2H),3.66-3.68(m,2H),4.04(q,J=7.07Hz,2H),4.08-4.15(m,1H),6.13(t,J=5.81Hz,1H),6.24(d,J=8.59Hz,1H),7.28-7.30(m,2H),7.39-7.42(m,1H),7.48(t,J=7.83Hz,1H),7.62-7.64(m,3H),7.71(t,J=1.77Hz,1H),12.42(s,1H)。實例4-1:合成(R)-4-聯苯-4-基-3-(2-1H-四唑-5-基-乙醯基胺基)-丁酸乙酯
在室溫下,向(R)-4-聯苯-4-基-3-第三丁氧基羰基胺基-丁酸乙酯(100mg,0.261mmo1)於DCM(3mL)中之溶液中添加TFA(1mL,12.98mmo1),且在室溫下攪拌混合物0..5小時。在減壓下濃縮混合物,得到(R)-3-胺基-4-聯苯-4-基-丁酸乙酯三氟乙酸鹽。HPLC滯留時間=1.50分鐘(條件C);MS(m+1)=384。
接著,在室溫下,向(R)-3-胺基-4-聯苯-4-基-丁酸乙酯三氟乙酸鹽(0.074g,0.261mmo1)於DCM(10mL)中之懸浮液中添加1H-四坐-5-乙酸(0.050g,0.392mmo1)。在冰浴溫度下,向混合物中添加雙(2-側氧基-3-噁坐啶基)次膦醯氯(0.100 g,0.392mmo1),接著快速添加DIPEA(0.137m1,0.783mmo1)。使反應混合物緩慢升溫至室溫,且攪拌隔夜。用DCM萃取反應。用飽和NaHCO3
、飽和NH4
C1、鹽水洗滌合併之有機層,且經無水硫酸鈉乾燥,過濾且在減壓下濃縮,得到(R)-4-聯苯-4-基-3-(2-1H-四坐-5-基-乙醯基胺基)-丁酸乙酯。HPLC滯留時間=1.04分鐘(條件E);MS(m+1)=394。實例4-2:合成(R)-4-(聯苯-4-基)-3-(6-(甲基磺醯胺基)菸鹼醯胺基)丁酸乙酯
在室溫下,向(R)-3-胺基-4-(3'
-氯聯苯-4-基)丁酸乙酯鹽酸鹽(103mg,0.32mmo1)及6-(甲基磺醯胺基)菸鹼酸、中間物15(84mg,0.39mmo1)於CH2
C12
(2mL)及DMF(2mL)中之溶液中添加TEA(0.18mL,1.29mmo1)及HATU(159mg,0.42mmo1)。在室溫下攪拌粗產物2小時。用飽和NaHCO3
淬滅粗產物,用EtOAc稀釋。用水、鹽水洗滌有機層6次,經MgSO4
乾燥,過濾且濃縮。經由RP-
HPLC(SunFire C18,H2O(0.1%TFA)/CH3
CN)純化粗產物,得到呈白色固體狀之(R)-4-(聯苯-4-基)-3-(6-(甲基磺醯胺基)菸鹼醯胺基)丁酸乙酯(4.1mg)。HPLC滯留時間=1.61分鐘(條件A);MS(m+1)=482.3。1HNMR(400MHz,氯仿-d)δppm1.22(t,J=7.2Hz,3H),2.56(t,J=4.8Hz,2H),2.84-2.92(m,1H),3.05(dd,J=13.6,6.1Hz,1H),3.16(s,3H),4.08-4.18(m,2H),4.57-4.71(m,1H),7.03(d,J=8.3Hz,1H),7.10(d,J=8.3Hz,1H),7.22(d,J=8.3Hz,2H),7.26-7.31(m,1H),7.33-7.40(m,2H),7.44-7.54(m,5H),7.98(dd,J=8.8,2.3Hz,1H),8.52(s,1H)。
使用類似於實例4-2中所述之程序製備以下化合物:
實例4-3:1H NMR(400MHz,DMSO-d6
)δppm1.13(t,J=7.1Hz,3H)2.52-2.67(m,2H)2.88(dd,J=13.3,8.0Hz,1H)2.95(dd,J=13.3,8.0Hz,1H)3.05(s,3H)4.02(q,J=7.1Hz,2H)4.46-4.65(m,1H)7.23(d,J=8.8Hz,2H)7.34(d,J=8.1Hz,2H)7.36-7.42(m,1H)7.46(t,J=7.8Hz,1H)7.59-7.66(m,3H)7.69(t,J=1.8Hz,1H)7.75(d,J=8.6Hz,2H)8.31(d,J=8.3Hz,1H)10.07(s,1H)。
實例4-4:1H NMR(400MHz,DMSO-d6
)δppm1.13(t,J=7.1Hz,3H)1.28(t,J=7.5Hz,3H)2.59(d,J=7.1Hz,2H)2.81-2.94(m,2H)2.97(q,J=7.6Hz,2H)4.03(q,J=7.1Hz,2H)4.40-4.55(m,1H)7.32(d,J=8.1Hz,2H)7.36-7.42(m,1H)7.46(t,J=7.8Hz,1H)7.58-7.65(m,3H)7.69(t,J=1.9Hz,1H)8.18(s,1H)8.52(d,J=8.3Hz,1H)。
實例4-5:1HNMR(400MHz,CD3
OD)δppm1.24(t,J=7.1Hz,3H)2.38-2.60(m,6H)2.78-2.94(m,2H)4.10(q,J=7.1Hz,2H)4.42-4.55(m,1H)7.32(d,J=8.3Hz,2H)7.40(t,J=7.83Hz,1H)7.50-7.53(m,4H)7.60(t,J=1.89Hz,1H)。實例4-6:
1H NMR(400MHz,DMSO-d6
)δppm1.13(t,J=7.2Hz,3H)1.25(t,J=7.6Hz,3H)2.53-2.65(m,2H)2.80(q,J=7.6Hz,2H)2.84-2.96(m,2H)4.02(q,J=7.1Hz,2H)4.42-4.60(m,1H)7.31(d,J=8.3Hz,2H)7.37-7.42(m,1H)7.47(t,J=7.8Hz,1H)7.59(s,1H)7.60-7.65(m,3H)7.69(t,J=1.9Hz,1H)8.48(d,J=8.6Hz,1H)。實例4-7:1H NMR(400MHz,DMSO-d6
)δppm1.13(t,J=7.1Hz,3H)2.52-2.65(m,2H)2.85(dd,J=13.6,5.8Hz,1H)2.91(dd,J=13.6,5.8Hz,1H)4.02(q,J=7.1Hz,2H)4.38-4.60(m,1H)5.89(s,1H)7.31(d,J=8.3Hz,2H)7.37-7.42(m,1H)7.46(t,J=7.8Hz,1H)7.58-7.65(m,3H)7.69(t,J=1.8Hz,1H)8.10(d,J=8.6Hz,1H)。實例4-8:1HNMR(400MHz,CD3
OD)δppm1.22(t,J=7.2Hz,3H)2.56-2.72(m,2H)2.95(d,J=7.3Hz,2H)4.11(q,J=7.2Hz,2H)4.53-4.73(m,1H)7.28-7.36(m,3H)7.39(t,J=7.8Hz,1H)7.48-7.55(m,3H)7.58(t,J=1.8Hz,1H)。實例4-9:1HNMR(400MHz,DMSO-d6
)δppm1.13(t,J=7.1Hz,3H)2.53-2.71(m,2H)2.85(dd,J=13.7,8.3Hz,1H)2.96(dd,J=13.7,8.3Hz,1H)4.02(q,J=7.1Hz,2H)4.45-4.63(m,1H)6.93(dd,J=9.9,2.3Hz,1H)7.30(d,J=8.1Hz,2H)7.36-7.42(m,1H)7.47(t,J=7.8Hz,1H)7.61(d,J=8.3Hz,3H)7.69(t,J=1.8Hz,1H)7.75(d,J=9.9Hz,1H)8.45(d,J=9.1Hz,1H)13.41(d,J=2.0Hz,1H)。
實例4-10:1H NMR(400MHz,DMSO-d6
)δppm1.13(t,J=7.1Hz,3H)2.60(d,J=7.6Hz,2H)2.90(d,J=6.8Hz,2H)4.02(q,J=7.2Hz,2H)4.39-4.53(m,1H)7.11(s,1H)7.32(d,J=8.1Hz,2H)7.37-7.43(m,1H)7.47(t,J=7.8Hz,1H)7.60-7.66(m,3H)7.70(t,J=1.9Hz,1H)8.72(d,J=8.3Hz,1H)11.76(br.s.,1H)。實例4-11:1H NMR(400 MHz,氯仿-d)δppm1.27(t,J=7.1Hz,3H)2.47-2.69(m,2H)2.90(dd,J=13.6,7.8Hz,1H)3.06(dd,J=13.6,6.6Hz,1H)3.06(寬單峰,1H)4.07-4.28(m,2H)4.52-4.74(m,1H)7.21-7.37(m,5H)7.38-7.44(m,1H)7.48(d,J=8.1Hz,2H)7.53(t,J=1.6Hz,1H)9.50(br.s.,1H)。實例4-12:1HNMR(400MHz,DMSO-d6
)δppm1.13(t,J=7.1Hz,3H)2.59(d,J=7.3Hz,2H)2.76-3.03(m,2H)4.03(q,J=7.1Hz,2H)4.39-4.66(m,1H)7.02(d,1H)7.28-7.54(m,4H)7.54-7.80(m,4H)8.05(dd,J=8.6,2.3Hz,1H)8.45(d,J=8.3Hz,1H)8.61(br.s.,1H)。實例4-13:合成(R)-4-(5'
-氟-2'
-甲氧基聯苯-4-基)-3-(噁唑-5-甲醯胺基)丁酸乙酯
向坐-5-甲酸(70mg,0.61mmo1)於DMF(1.5mL)及DCM(1.5mL)中之溶液中添加(R)-3-胺基-4-(5'
-氟-2'
-甲氧基聯苯-4-基)丁酸乙酯鹽酸鹽、中間物10(150mg,0.41mmo1)、
HATU(233mg,0.61 mmo1)及TEA(284μL,2.04mmo1)。攪拌2小時後,用H2
O淬滅反應,且用EtOAc稀釋粗產物,用鹽水洗滌有機層,經Na2
SO4
乾燥,過濾,且在減壓下濃縮。利用RP-HPLC(SunFire C18,H2
O(0.1%TFA)/CH3
CN)純化所獲得之殘餘物,並隨後凍乾,得到(R)-4-(5'
-氟-2'
-甲氧基聯苯-4-基)-3-(坐-5-甲醯胺基)丁酸乙酯(157mg)。HPLC滯留時間=1.50分鐘(條件A);MS(m+1)=427.4;1HNMR(400MHz,氯仿-d)δppm1.19(t,J=7.2Hz,3H)2.46-2.62(m,2H)2.86(dd,J=13.6,8.1Hz,1H)3.02(dd,J=13.6,6.1Hz,1H)3.67(s,3H)4.05-4.15(m,2H)4.52-4.69(m,1H)6.76-6.82(m,1H)6.83-6.96(m,2H)7.11-7.21(m,3H)7.37(d,J=8.1Hz,2H)7.61(s,1H)7.80(s,1H)。
使用類似於實例4-13中所述之程序製備以下化合物:
實例4-14:1H NMR(400MHz,CD3
OD)δppm1.21(t,J=7.1Hz,3H)2.61-2.68(m,2H)2.95(d,J=7.1Hz,2H)3.74(s,3H)4.10(q,J=7.1Hz,2H)4.60-4.73(m,1H)6.43(s,1H)6.98-7.06(m,3H)7.27(d,J=8.1Hz,2H)7.38-7.48(m,2H)8.78(d,J=8.8Hz,1H)。實例4-15:合成5-[(R)-1-(3'
-氯-聯苯-4-基甲基)-2-乙氧基羰基-乙基胺甲醯基]-1H-比唑-3-甲酸
向中間物17-1(130mg,0.367mmo1)、1H-比坐-3,5-二甲酸(74.5mg,0.477mmo1)、EDCI(91 mg,0.477mmo1)及HOBt(64.5mg,0.477mmo1)於DMF(3mL)中之混合物中添加三乙胺(149mg,0.203mmo1),且在室溫下攪拌混合物18小時。藉由過濾移除任何不可溶物質,且利用HPLC使用10%MeCN/水至100%MeCN(+0.1%TFA)之梯度對濾液進行層析。凍乾適當溶離份,得到標題化合物;HPLC滯留時間1.31分鐘(條件C);MS456.2(M+1);1HNMR(400MHz,DMSO-d6)δppm1.12(t,J=7.07Hz,3H),2.54-2.67(m,2H),2.84-2.97(m,2H),4.02(q,J=7.07Hz,2H),4.54(m,1H),7.11(s,寬峰,1H),7.32(d,J=8.08Hz,2H),7.39(m,1H),7.46(t,1H),7.62(d,J=8.08Hz,3H),7.69(s,1H),8.41(s,寬峰,1H)。
使用關於實例4-15所述之程序製備以下化合物:
實例4-16:1HNMR(400MHz,DMSO-d6):δppm1.11(t,J=7.07Hz,3H),2.59-2.79(m,2H),2.87-2.92(m,1H),2.98-3.04(m,1H),4.01(q,J=7.33Hz,2H),4.57-4.66(m,1H),7.30-7.32(m,2H),7.37-7.40(m,1H),7.45(t,J=7.58Hz,1H),7.59-7.61(m,3H),7.68(t,J=1.77Hz,1H),8.16(s,1H),9.10(d,J=9.35Hz,1H),9.31(s,1H)。實例4-17:(R)-4-(3'
-氯-聯苯-4-基)-3-[(3-羥基-異噁唑-
5-
羰基)-胺基]-丁酸乙酯
向中間物16-1(40.6mg,0.315mmo1)及HATU(144mg,0.378mmo1)於DMF(2mL)中之溶液中添加比(74.7mg,0.76mL,0.944mmo1),且在室溫下攪拌混合物15分鐘。隨後添加中間物17-1,且繼續攪拌2小時。藉由過濾移除任何不可溶物,且利用HPLC使用10%MeCN/水至100%MeCN(+0.1%TFA)之梯度對濾液進行層析。凍乾適當溶離份,得到標題化合物。HPLC滯留時間1.36分鐘(條件C);MS429.1(M+1);1H NMR(400 MHz,DMSO-d6)δppm1.13(t,J=7.07Hz,3H)2.60(dd,J=6.95,3.66Hz,2H)2.81-2.95(m,2H)4.02(q,J=7.24Hz,2H)4.49(d,J=7.83Hz,1H)6.49(s,1H)7.31(d,J=8.34Hz,2H)7.37-7.43(m,1H)7.47(t,J=7.83Hz,1H)7.59-7.66(m,3H)7.70(t,J=1.89Hz,1H)8.83(d,J=8.84Hz,1H)。使用關於實例4-17所述之程序製備以下化合物:
實例4-18:1HNMR(400MHz,DMSO-d6)δppm1.12(t,J=7.07Hz,3H)2.60(dd,J=6.95,2.65Hz,2H)2.82-2.96(m,2H)4.02(q,J=7.07Hz,2H)4.45-4.58(m,1H)7.31(d,J=8.34Hz,2H)7.37-7.42(m,1H)7.47(t,J=7.83Hz,1H)7.58-7.65(m,3H)7.69(t,J=1.77Hz,1H)7.72(s,1H)8.55(s,1H)8.63(d,J=8.59Hz,1H)。實例4-19:1HNMR(400MHz,DMSO-d6
)δppm1.13(t,J=7.07Hz,3H)2.54-2.75(m,2H)2.76-3.02(m,2H)4.02(q,J=7.07Hz,2H)4.29-4.70(m,1H)6.49(s,1H)6.96-7.23(m,1H)7.30(d,J=8.08Hz,2H)7.44-7.58(m,3H)7.64(d,J=8.08Hz,2H)8.83(d,J=8.59Hz,1H)1168(s,1H)。實例4-20:(R)-3-[(5-羧基甲基-喃-2-羰基)-胺基]-4-(3' -
氯-聯苯-4-基)-丁酸乙酯,及實例4-21:(R)-3-[(5-羧基甲基-呋喃-2-羰基)-胺基]-4-(3'-氯-聯苯-4-基)-丁酸
類似於實例4-15使用中間物16-1及中間物44進行反應,得到(R)-4-(3'
-氯-聯苯-4-基)-3-[(5-甲氧基羰基甲基-喃-2-羰基)-胺基]-丁酸乙酯。HPLC滯留時間1.38分鐘(條件C)。
接著,向上述二酯(235mg,0.486mmo1)於EtOH(5mL)中之溶液中添加1NNaOH(0.486mL),且在室溫下攪拌混合物4小時。在減壓下移除溶劑,且添加水(4mL)。用1NHC1酸化該溶液,且用EtOAc萃取混合物。有機相經硫酸鈉乾燥,且在減壓下移除溶劑。利用製備型HPLC使用10%MeCN/水至100%MeCN(+0.1%TFA)之梯度純化殘餘物。凍乾適當溶離份,得到標題化合物。(R)-3-[(5-羧基甲基-喃-2-羰基)-胺基]-4-(3'
-氯-聯苯-4-基)-丁酸乙酯。HPLC滯留時間1.35分鐘(條件C);MS470.0(M+1);1HNMR(400MHz,DMSO-d6)δppm1.13(t,J=7.07Hz,3H),2.50-2.64(m,2H),2.81-2.95(m,2H),3.74(s,2H),4.01(q,J=7.07Hz,2H),4.51(m,1H),6.99(d,J=3.28Hz,1H),7.31(d,J=8.34Hz,2H),7.38-7.41(m,1H),7.47(t,1H),7.62(d,J=8.08Hz,3H),7.69(t,1H),8.24(d,J=8.84Hz,1H)。
(R)-3-[(5-羧基甲基-喃-2-羰基)-胺基]-4-(3'
-氯-聯苯-4-基)-丁酸。HPLC滯留時間0.94分鐘(條件C);MS442.0(M+1);1H NMR(400 MHz,DMSO-d6)δppm2.44-2.58(m,2H),2.81-2.94(m,2H),3.74(s,2H),4.48(m,1H),6.39(d,J=3.28Hz,1H),6.99(d,J=3.54Hz,1H),7.30(d,J=8.34Hz,2H),7.38-7.41(m,1H),7.47(t,1H),7.62(d,J=8.34Hz,3H),7.70(t,J=1.77Hz,1H),8.22(d,J=8.84Hz,1H)。實例4-22:(R)-4-(3'
-氯-聯苯-4-基)-3-1(2H-四唑-5-羰基)-胺基]-丁酸乙酯
在室溫下,依次向中間物16-1於DCM(8m1)中之溶液中添加2-(4-甲氧基-苯甲基)-2H-四坐-5-甲醯氯及TEA(0.293m1,2.100mmo1)。在室溫下攪拌反應5分鐘。用鹽水淬滅反應,且用DCM萃取。用鹽水洗滌合併之有機層,且經無水硫酸鈉乾燥,過濾且在減壓下濃縮。利用管柱層析(15%至40%EtOAc/庚烷)純化殘餘物。在80℃下加熱所獲得之殘餘物之TFA溶液(5m1,64.9mmo1)0.5小時。在減壓下濃縮反應,得到(R)-4-(3'
-氯-聯苯-4-基)-3-[(2H-四坐-5-羰基)-胺基]-丁酸乙酯。
HPLC滯留時間=1.31分鐘(條件B);MS(m+1)=414.1;1H NMR(400 MHz,DMSO-d6
)δppm1.11(t,J=7.1Hz,3H),2.63(dd,J=15.4,5.6Hz,1H),2.72(dd,J=15.4,8.3Hz,1H),2.86-2.99(m,2H),4.02(q,J=7.1Hz,2H),4.55-4.67(m,1H),7.32(d,J=8.1Hz,2H),7.37-7.42(m,1H),7.46(t,J=7.8Hz,1H),7.60(d,J=8.1Hz,3H),7.68(t,J=1.8Hz,1H),9.37(d,J=8.8Hz,1H)。使用類似於實例4-22中所述之程序製備以下化合物:
實 4-23 : 1H NMR (400 MHz,
DMSO-d6) δ ppm 1.12 (t,J=7.2 Hz,
3H),
2.59-2.67 (m,
J=15.4,
5.6 Hz,
1H),
2.72 (dd,J=15.4,
8.3 Hz,
1H),
2.85-3.01 (m,
2H),
4.02 (q,
J=7.1 Hz,2H),
4.55-4.67 (m,
1H),
7.11-7.19 (m,
1H),
7.32 (d,
J=8.3Hz,
2H),
7.42-7.51 (m,
3H),
7.61 (d,
J=8.3 Hz,
2H),
9.34 (d,J=8.8 Hz,
1H)。實 4-24 : 1H NMR (400 MHz,
DMSO-d6) δ ppm 1.95-2.06(m,
2H),
2.75-2.92 (m,
6),
2.95 (dd,
J=13.5,
5.9 Hz,
1H),3.06 (dd,
J=13.6,
8.1 Hz,
1H),
4.64-4.76 (m,
1H),
6.78 (dd,J=8.1,
2.3 Hz,
1H),
6.88 (d,
J=1.5 Hz,
1H),
7.17 (d,
J=8.1Hz,
1H),
7.34-7.41 (m,
3H),
7.46 (t,
J=7.8 Hz,
1H),
7.59-7.65(m,3H),7.70(t,J=1.8Hz,1H),8.43(d,J=8.8Hz,1H)。
實例4-25:2-((R)-1-聯苯-4-基甲基-2-乙氧基羰基-
乙基胺基)-噁唑-4-甲酸乙酯
在冰浴下,向(R)-4-聯苯-4-基-3-脲基-丁酸乙酯(169mg,
0.518mmo1)於EtOH(5m1)中之懸浮液中添加溴丙酮酸乙酯(0.098m1,0.777mmo1)。使反應緩慢升溫至室溫,且在回流下攪拌隔夜。濃縮反應,且將殘餘物溶解於EtOAc及H2O中。用鹽水洗滌合併之有機層,且經無水硫酸鈉乾燥,過濾且在減壓下濃縮,得到2-((R)-1-聯苯-4-基甲基-2-乙氧基羰基-乙基胺基)-坐-4-甲酸乙酯。HPLC滯留時間=1.42分鐘(條件B);MS(m+1)=423。實例4-26:
合成(R,E)-4-(4-(苯甲氧基)-1-(3'
-氯聯苯-4-基)-
4-側氧基丁-2-基胺基)-4-側氧基丁-2-烯酸乙酯
在室溫下,向(R)-3-胺基-4-(3'
-氯聯苯-4-基)丁酸苯甲酯(87.6mg,0.183mmo1)中添加HC1於1,4-二烷中之溶液(0.456mL,1.825mmo1)。攪拌3小時後,在減壓下濃縮反應混合物,得到(R)-3-胺基-4-(3'
-氯聯苯-4-基)丁酸苯甲酯鹽酸鹽。在室溫下,攪拌(R)-3-胺基-4-(3'
-氯聯苯-4-基)丁酸苯甲酯鹽酸鹽、反丁烯二酸單乙酯(33.4mg,0.220mmo1)、EDCI(63.3mg,0.330 mmo1)、DIPEA(0.058m1,0.330mmo1)及HOAt(44.9mg,0.330mmo1)於DMF(1.8m1)中之混合物3小時。用水稀釋反應混合物,隨後用EtOAc萃取產物。用NH4
OH、1MHC1水溶液及鹽水洗滌有機層,經Na2
SO4
乾燥,過濾且濃縮,得到粗產物。利用矽膠急驟管柱層析(庚烷/EtO Ac=100:0至0:100)純化所獲得之殘餘物,得到(R,E)-4-(4-(苯甲氧基)-1-(3'
-氯聯苯-4-基)-4-側氧基丁-2-基胺基)-4-側氧基丁-2-烯酸乙酯(72.9mg);HPLC滯留時間=1.40分鐘(條件B);MS(m+1)=506.3;1HNMR(400 MHz,氯仿-d)δppm1.31(t,J=7.1Hz,3H)2.58(ABX 之 A,Jab
=16.4Hz,Jax
=5.3Hz,1H)2.6(ABX之B,Jab
=16.4Hz,Jbx
=5.1 Hz,1H)2.88(ABX 之 A,Jab
=13.6Hz,Jax
=8.1 Hz,1H)3.03(ABX 之 B,Jab
=13.6Hz,Jbx
=6.3Hz,1H)4.24(q,J=7.1Hz,2H)4.56-4.64(m,1H)5.12(AB之A,J=12.1Hz,1H)5.18(AB之B,J=12.1Hz,1H)6.57(brd,J=9.1Hz,1H)6.77(AB之A,J=15.4Hz,1H)6.81(AB之B,J=15.4Hz,1H)7.19(brd,J=8.1Hz,2H)7.29-7.47(m,10H)7.53-7.54(m,1H)。
實例4-27:合成(R)-4-(3'
-氯聯苯-4-基)-3-(2-(乙氧基羰基胺基)乙醯胺基)丁酸乙酯
在室溫下,攪拌(R)-3-胺基-4-(3'
-氯聯苯-4-基)丁酸乙酯鹽酸鹽(173mg,0.488mmo1)、2-(乙氧基羰基胺基)乙酸(86mg,0.488mmo1)、EDCI(140 mg,0.732mmo1)、DIPEA(0.128m1,0.732mmo1)及HOAt(100 mg,0.732mmo1)於DMF(2.5m1)中之混合物1小時。用水稀釋反應混合物,並隨後收集沈澱之固體於漏斗上,用H2
O洗滌,且在減壓下乾燥,得到粗產物。利用矽膠急驟管柱層析(庚烷/EtOAc=
100:0至0:100)純化所獲得之殘餘物,得到(R)-4-(3'
-氯聯苯-4-基)-3-(2-(乙氧基羰基胺基)乙醯胺基)丁酸乙酯(161mg);HPLC滯留時間=1.16分鐘(條件B);MS(m+1)=447.3;1HNMR(400MHz,氯仿-d)δppm1.25(t,J=7.07Hz,3H)1.29(t,J=7.07Hz,3H)2.50(ABX之A,Jab
=16.2Hz,Jax
=5.3Hz,1H)2.54(ABX 之 B,Jab
=16.2Hz,Jbx
=5.3Hz,1H)2.89(ABX 之 A,Jab
=13.6Hz,Jax
=7.8Hz,1H)2.99(ABX 之 B,Ja
b=13.6Hz,Jb
x=6.6Hz,1H)3.80(bed,J=5.8Hz,2H)4.12-4.23(m,4H)4.48-4.56(m,1H)5.15(brs,1H)6.64(brd,J=8.8Hz,1H)7.25-7.27(m,2H)7.29-7.38(m,2H)7.43-7.46(m,1H)7.49-7.52(m,2H)7.55-7.56(m,1H)。
使用類似於實例4-27中所述之程序製備以下化合物:
實 4-29 : 1H NMR (400 MHz,
氯氯氯 -d) δ ppm 1.3 1 (t,J=7.2 Hz,
3H) 2.64 (ABX之A,Jab
=16.8 Hz,Jax=5.1 HZ,
1H)2.68 (ABX之B,Jab
=16.8 Hz,Jb
x=5.1 Hz,
1H) 2.97 (ABX之A,Jab
=13.7 Hz,Jax=8.1 HZ,
1H) 3.08 (ABX之B,Jab=13.7Hz,Jb
x=6.7 Hz,
1H) 4.25 (q,J=7.2 Hz,
2H) 4.58-4.67 (1,1H) 6.66 (d,
J=8.8 Hz,
1H) 6.80 (AB之A,
J=15.4 Hz,
1H)6.97 (AB之B,
J=15.4 Hz,
1H) 7.27-7.37 (m,
4H) 7.43-7.45(m,
1H) 7.51 (d,J=8.3 Hz,
2H) 7.55-7.56 (m,
1H) 。實 4-30 : 1H NMR (400 MHz,
CD3
OD) δ ppm 1.21 (t,J=7.2Hz,3H) 1.34(t,J=7.6Hz,3H)2.68(d,J=6.8Hz,2H)2.84-2.87 (m,
2H) 2.98-3.00 (,
2H) 4.10 (q,
J=7.1 Hz,
2H)4.66-4.78(m,1H)7.27-7.37(m,6H)7.41-7.47(m,1H)7.54(s,1H)。實例4-31:
1H NMR(400MHz,CD3
OD)δppm1.20(t,J=7.1Hz,3H)2.28(s,3H)2.62(d,J=7.1Hz,2H)2.93(dd,J=13.6,6.8Hz,1H)3.00(dd,J=13.6,7.3Hz,1H)4.09(q,J=7.1Hz,2H)4.60-4.76(m,1H)6.45(s,1H)7.24-7.40(m,4H)7.42-7.51(m,3H)7.54(t,J=1.8Hz,1H)。實例4-32:1H NMR(400MHz,CD3
OD)δppm1.20(t,J=7.2Hz,3H)2.58-2.66(m,2H)2.68(s,3H)2.94(dd,J=14.2,7.8Hz,1H)2.99(dd,J=13.6,6.8Hz,1H)4.09(q,J=7.2Hz,2H)4.58-4.76(m,1H)7.27-7.31(m,1H)7.33(d,J=8.3Hz,2H)7.37(t,J=7.8Hz,1H)7.46-7.49(m,1H)7.51(d,J=8.1Hz,2H)7.55(t,J=1.9Hz,1H)8.06(s,1H)8.49(d,J=8.6Hz,1H)。實例4-33:1H NMR(400MHz,CD3
OD)δppm1.21(t,J=7.1Hz,3H)2.60-2.70(m,2H)2.72(s,3H)2.97(dd,J=13.6,8.1Hz,1H)3.03(dd,J=13.9,6.6Hz,1H)4.11(q,J=7.2Hz,2H)4.67-4.81(m,1H)7.27-7.33(m,1H)7.33-7.41(m,3H)7.48-7.52(m,1H)7.54(d,J=8.3Hz,2H)7.57(t,J=1.8Hz,1H)8.70(d,J=8.3Hz,1H)8.92(s,2H)。實例4-34:1H NMR(400MHz,CD3
OD)δppm1.21(t,J=7.2Hz,3H)2.43(s,3H)2.63(d,J=6.6Hz,2H)2.94(dd,J=13.9,7.1 Hz,1H)2.99(dd,J=13.6,7.6Hz,1H)4.10(q,J=7.1Hz,2H)4.62-4.74(m,1H)7.26-7.30(m,1H)7.30-7.39(m,3H)7.43-7.51(m,3H)7.53(t,J=1.8Hz,1H)8.15(s,1H)。實例4-35:1H NMR(400MHz,CD3
OD)δppm1.20(t,J=7.1Hz,3H)2.64(dd,J=15.4,7.3Hz,1H)2.70(dd,J=15.9,6.3Hz,1H)2.99(d,J=7.3Hz,2H)4.10(q,J=7.2Hz,2H)4.65-4.79(m,1H)7.14(dd,J=10.2,8.7Hz,1H)7.30(ddd,J=8.8,4.1,2.8Hz,1H)7.32-7.37(m,2H)7.37-7.46(m,3H)7.67(s,1H)8.28(s,1H)8.62(d,J=8.6Hz,1H)。實例4-36:1H NMR(400MHz,CD3
OD)δppm1.20(t,J=7.2Hz,3H)1.33(t,J=7.7Hz,3H)2.66(d,J=6.8Hz,2H)2.83(q,J=7.6Hz,2H)2.98(d,J=7.1Hz,2H)4.10(q,J=7.1Hz,2H)4.65-4.79(m,1H)7.14(dd,J=10.2,8.7Hz,1H)7.30(ddd,J=8.8,4.1,2.8Hz,1H)7.32-7.37(m,2H)7.37-7.46(m,3H)7.54(s,1H)8.49(d,J=8.8Hz,1H)。實例4-37:1H NMR(400MHz,氯仿-d)δppm1.33(t,J=7.1Hz,3H)2.22(s,3H)2.57-2.72(m,2H)2.99(dd,J=13.6,8.1Hz,1H)3.16(dd,J=13.6,6.3Hz,1H)4.15-4.33(m,2H)4.60-4.82(m,1H)5.55(s,1H)6.10(s,1H)7.15(d,J=8.8Hz,1H)7.34(d,J=8.1Hz,3H)7.39(t,J=7.7Hz,1H)7.48(dt,J=7.6,1.5Hz,1H)7.54(d,J=8.1Hz,2H)7.58(t,J=1.8Hz,1H)7.72(s,1H)。實例5-1:合成(R)-4-(聯苯-4-基)-3-(3-羧基丙醯胺基)丁酸
實例1-1
在室溫下,向(R)-4-(1-(聯苯-4-基)-4-乙氧基-4-側氧基丁-2-基胺基)-4-側氧基丁酸(61.2mg,0.160mmo1)於THF(1.6mL)及甲醇(0.2mL)中之溶液中添加1M NaOH水溶液(0.638mL,0.638mmo1)。攪拌45分鐘後,用0.1MHC1水溶液淬滅反應,且用乙酸乙酯萃取。用鹽水洗滌有機層,經Na2
SO4
乾燥,過濾且在減壓下濃縮,得到(R)-4-(聯苯-4-基)-3-(3-羧基丙醯胺基)丁酸(54.9mg)。HPLC滯留時間=1.33分鐘(條件A);MS(m+1)=356.1;1HNMR(400MHz,CD3
OD)δppm2.40-2.56(m,6H)2.83-2.94(m,2H)4.43-4.50(m,1H)7.29-7.32(m,3H)7.41(t,2H,J=7.7Hz)7.53-7.60(m,4H)。使用類似於實例5-1中所述之程序製備以下化合物:
實例5-2:1HNMR(400MHz,CD3
OD)δppm2.38-2.42(m,2H)2.45-2.54(m,4H)2.82-2.94(m,2H)4.42-4.48(m,1H)7.12-7.16(m,2H)7.31(d,J=8.4Hz,2H)7.41(d,J=8.6Hz,2H)7.54(d,J=8.1Hz,2H)7.58(d,J=8.6Hz,2H)。實例5-3:1HNMR(400MHz,CD3
OD)δppm2.39-2.42(m,2H)2.45-2.54(m,4H)2.85(ABX之A,Jab=13.6Hz,Jax=7.6HZ,1H)2.91(ABX 之 B,Jab=13.6Hz,Jbx=6.2HZ,1H)4.42-4.48(m,1H)7.12-7.16(m,2H)7.31(AB之A,J=8.2Hz,2H)7.52(AB之B,J=8.2Hz,2H)7.58-7.62(m,2H)。實例5-4:1HNMR(400MHz,CD3
OD)δppm2.39-2.44(m,2H)2.46-2.55(m,4H)2.86(ABX之A,Jab=13.6Hz,Jax=7.6HZ,1H)2.92(ABX 之 B,Jab=13.6Hz,Jbx=6.3HZ,1H)4.42-4.49(m,1H)7.01-7.06(m,1H)7.32(brd,J=8.1Hz,2H)7.39-7.45(m,2H)7.55(d,J=8.1Hz,2H)。實例5-5:1HNMR(400MHz,CD3
OD)δppm2.40-2.43(m,2H)2.46-2.56(m,4H)2.87(ABX之A,Jab=13.5Hz,Jax=7.7HZ,1H)2.93(ABX 之 B,Jab=13.5Hz,Jbx=6.2HZ,1H)4.43-4.50(m,1H)7.13-7.18(m,1H)7.20-7.24(m,1H)7.31-7.35(m,3H)7.44-7.48(m,3H)7.99(brd,J=8.3Hz,1H)。實例5-6:1HNMR(400MHz,CD3
OD)δppm2.39-2.43(m,2H)2.45-2.57(m,4H)2.87(ABX之A,Jab=13.6Hz,Jax=7.6HZ,1H)2.94(ABX之B,Jab=13.6Hz,Jbx=6.1HZ,1H)4.44-4.51(m,1H)7.28-7.35(m,7H)7.46(brd,J=7.9Hz,1H)。實例5-7:1HNMR(400MHz,CD3
OD)δppm2.40-2.52(m,6H)2.83-2.92(m,2H)3.77(s,3H)4.44-4.47(m,1H)6.96-7.05(m,2H)7.23-7.30(m,4H)7.39-7.41(m,2H)。實例5-8:1HNMR(400MHz,CD3
OD)δppm2.21(s,3H)2.41-2.55(m,6H)2.82-2.94(m,2H)3.77(s,3H)4.45-4.48(m,1H)7.15-7.28(m,8H)。實例5-9:1HNMR(400MHz,DMSO-d6)δppm2.56(dd,J=5.81,15.92Hz,1H),2.66(dd,J=7.07,15.92Hz,1H),2.90(dd,J=6.06,13.64Hz,1H),3.00(dd,J=8.08,13.64Hz,1H),4.53-4.64(m,1H),7.30(d,J=8.34Hz,2H),7.33(t,J=7.58,1H),7.56(d,J=8.34Hz,2H),7.62(d,J=7.07Hz,2H),7.95(dd,J=1.26,5.05Hz,1H),9.01-9.07(m,2H),9.33(d,J=1.52Hz,1H),12.28(s,1H)。實例5-10:1HNMR(400MHz,DMSO-d6)δppm2.36-2.49(m,2H),2.75-2.86(m,2H),3.83(s,2H),4.19-4.31(m,1H),7.26(d,J=8.3Hz,2H),7.31-7.38(m,1H),7.45(t,J=7.6Hz,2H),7.56(d,J=8.3Hz,2H),7.61-7.67(m,2H),8.40(d,J=8.1Hz,1H),12.26(br.s.,1H),16.02(br.s.,1H)。實例5-11:1HNMR(400MHz,DMSO-d6)δppm2.46-2.59(m,2H),2.86-2.88(m,2H),4.41-4.49(m,1H),7.29-7.36(m,3H),7.42-7.46(m,2H),7.58-7.65(m,4H),8.26(d,J=8Hz,1H),8.64(brs,2H)12.24(br.s.,1H)。
實例5-12:1HNMR(400MHz,DMSO-d6)δppm2.54-2.70(m,2H),2.88-3.03(m,2H),4.56-4.65(m,1H),7.29-7.34(m,3H),7.41-7.45(m,2H),7.55-7.63(m,4H),8.33(s,1H),9.15(d,J=9.1Hz,1H),9.49(s,1H),12.30(brs,1H),14.11(brs,1H)。實例5-13:1H NMR(400MHz,CD3
OD)δppm2.38-2.57(m,6H)2.87(ABX之 A,Jab=13.6Hz,Jax=7.6Hz,1H)2.95(ABX之B,Jab=13.6Hz,Jbx=6.1Hz,1H)4.44-4.51(m,1H)7.06-7.14(m,2H)7.31-7.37(m,5H)7.48(dd,J=8.8及5.1Hz,1H)。實例5-14:1HNMR(400MHz,CD3
OD)δppm2.39(s,3H)2.39-2.55(m,6H)2.85(ABX 之 A,Jab=13.5Hz,Jax=7.5HZ,1H)2.90(ABX 之 B,Jab=13.5Hz,Jbx=6.4Hz,1H)4.42-4.49(m,1H)7.13(brd,J=7.3Hz,1H)7.26-7.30(m,3H)7.36-7.40(m,2H)7.52(d,J=8.3Hz,2H)。
實例5-15:1H NMR(400MHz,CD3
OD)δppm2.38-2.55(m,6H)2.86(ABX之 A,Jab=13.6Hz,Jax=7.8HZ,1H)2.93(ABX之B,Jab=13.6Hz,Jbx=6.1HZ,1H)4.42-4.49(m,1H)6.86-6.92(m,1H)7.19-7.25(m,2H)7.33-7.35(m,2H)7.55-7.58(m,2H)。實例5-16:1H NMR(400MHz,CD3
OD)δppm1.27(t,J=7.6Hz,3H)2.39-2.55(m,6H)2.70(q,J=7.6Hz,2H)2.85(ABX之 A,Jab=13.6Hz,Jax=7.5HZ,1H)2.90(ABX之B,Jab=13.6Hz,Jbx=6.4HZ,1H)4.42-4.49(m,1H)7.16(brd,J=7.6Hz,1H)7.28-7.33(m,3H)7.38-7.42(m,2H)7.52-7.54(m,2H)。實例5-17:1HNMR(400MHz,DMSO-d6)δppm2.47-2.50(m,2H)2.82-2.91(m,2H)4.40-4.49(m,1H)7.29(d,J=8.3Hz,2H)7.31-7.36(m,1H)7.42-7.46(m,2H)7.59(d,J=8.4Hz,2H)7.63-7.65(m,2H)7.95(brd,J=2.3Hz,1H)8.11(brd,J=2.3Hz,1H)8.25-8.27(m,1H)12.24(brs,1H)12.48(brs,1H)。實例5-18:1H NMR(400MHz,CD3
OD)δppm2.38-2.55(m,6H)2.86(ABX 之 A,Jab=13.6Hz,Jax=7.8Hz,1H)2.92(ABX 之 B,Jab=13.6Hz,Jbx=6.3Hz,1H)4.43-4.50(m,1H)7.26(brd,J=7.3Hz,1H)7.35(d,J=8.1Hz,2H)7.51-7.58(m,4H)7.64(brd,J=7.8Hz,1H)。實例5-19:1H NMR(400MHz,CD3
OD)δppm2.39-2.42(m,2H)2.45-2.56(m,4H)2.88(ABX之 A,Jab=13.6Hz,Jax=7.6Hz,1H)2.95(ABX 之 B,Jab=13.6Hz,Jbx=6.2Hz,1H)4.44-4.51(m,1H)6.86-6.89(m,1H)7.38-7.41(m,2H)7.63-7.70(m,3H)8.02-8.04(m,1H)8.18-8.21(m,1H)8.45(brt,J=1.9Hz,1H)。實例5-20:1H NMR(400MHz,CD3
OD)δppm2.39-2.56(m,6H)2.87(ABX之 A,Jab=13.6Hz,Jax=7.6Hz,1H)2.93(ABX 之 B,Jab=13.6Hz,Jbx=6.3Hz,1H)4.43-4.50(m,1H)7.36(d,J=8.3Hz,2H)7.58-7.62(m,4H)7.85-7.87(m,2H)。實例5-21:1HNMR(400MHz,CD3
OD)δppm2.39-2.54(m,6H)2.85(ABX之 A,Jab=13.6Hz,Jax=7.5Hz,1H)2.91(ABX之B,Jab=13.6Hz,Jbx=6.3HZ,1H)3.84(s,3H)4.42-4.49(m,1H)6.86-6.89(m,1H)7.11-7.17(m,2H)7.29-7.34(m,3H)7.52-7.54(m,2H)。實例5-22:1HNMR(400MHz,DMSO-d6)δppm2.43-2.46(m,2H),2.81-2.91(m,2H)4.40-4.49(m,1H)6.33(d,J=9.6Hz,1H)7.28-7.35(m,3H)7.42-7.46(m,2H)7.58(d,J=8.1Hz,2H)7.63-7.65(m,2H)7.81(dd,J=9.6,2.8Hz,1H)7.93(brs,1H)8.14(d,J=8.3Hz,1H)11.92(brs,1H)12.19(brs,1H)。實例5-23:1H NMR(400MHz,CD3
OD)δppm2.39-2.42(m,2H)2.44-2.55(m,4H)2.86(ABX之 A,Jab=13.6Hz,Jax=7.6Hz,1H)2.93(ABX 之 B,Jab=13.6Hz,Jbx=6.3HZ,1H)4.43-4.50(m,1H)7.36(d,J=8.3Hz,2H)7.58-7.63(m,3H)7.66-7.69(m,1H)7.91-7.94(m,1H)7.97(brt,J=1.5Hz,1H)。實例5-24:1HNMR(400MHz,DMSO-d6)δppm2.50-
2.61(m,2H)2.83-2.94(m,2H)4.43-4.52(m,1H)6.82(s,1H)7.28-7.35(m,3H)7.44(t,J=7.7Hz,2H)7.58-7.65(m,4H)8.12(s,1H)8.86(d,J=8.3Hz,1H)9.55(s,1H)12.25(brs,1H)。實例5-25:1HNMR(400MHz,DMSO-d6)δppm1.66-2.47(m,10H)2.71-2,83(m,2H)3.31-3,46(m,3H)4.18-4.49(m,2H)7.26-7.28(m,2H)7.32-7.36(m,1H)7.43-7.47(m,2H)7.57-7.66(m,4H)7.86(d,J=8.3Hz,1H)12.31(brs,2H)。實例5-26:1HNMR(400MHz,DMSO-d6)δppm1.80-2.03(m,3H)2.27-2.31(m,1H)2.39-2.52(m,2H)2.75-2.81(m,1H)2.85-2.89(m,1H)2.95-3.03(m,1H)3.41-3.78(m,2H)3.90-3.99(m,1H)4.14-4.20(m,1H)4.28-4.35(m,1H)7.28-7.37(m,3H)7.44-7.48(m,2H)7.58-7.65(m,2H)8.45(brs,1H)12.34(brs,1H)。實例5-27:1H NMR(400MHz,CD3
OD)δppm2.38-2.54(m,6H)2.86(ABX 之 A,Jab=13.6Hz,Jax=7.6Hz,1H)2.93(ABX 之 B,Jab=13.6Hz,Jbx=6.2HZ,1H)4.42-4.49(m,1H)7.13-7.17(m,1H)7.31-7.37(m,3H)7.46-7.47(m,1H)7.54-7.57(m,2H)。實例5-28:1HNMR(400MHz,CD3
OD)δppm1.49-1.71(m,6H)2.01-2.11(m,2H)2.14-2.21(m,1H)2.44-2.56(m,3H)2.83(ABX之 A,Jab=13.6Hz,Jax=8.0 Hz,1H)2.91(ABX之B,Jab=13.6Hz,Jbx=6.3HZ,1H)4.43-4.51(m,1H)7.28-7.32(m,3H)7.38-7.42(m,2H)7.52(d,J=8.1Hz,2H)7.56-7.59(m,2H)7.71(brd,J=8.6Hz,1H)。實例5-29:1H NMR(400MHz,CD3
OD)δppm2.39-2.42(m,2H)2.45-2.56(m,4H)2.87(ABX之A,Jab=13.6Hz,Jax=7.8Hz,1H)2.94(ABX 之 B,Jab=13.6Hz,Jbx=6.1Hz,1H)4.44-4.51(m,1H)7.23(AB之A,J=8.0Hz,2H)7.28(AB之B,J=8.0Hz,2H)7.35(d,J=7.6Hz,1H)7.50-7.53(m,1H)7.60-7.63(m,1H)7.75(d,J=7.8Hz,1H)。實例5-30:1HNMR(400MHz,DMSO-d6)δppm2.45-2.56(m,2H)2.83-2.93(m,2H)4.43-4.52(m,1H)7.18(s,2H)7.29-7.35(m,3H)7.42-7.46(m,2H)7.58-7.65(m,4H)8.19(d,J=8.1Hz,1H)8.60(s,2H)12.21(brs,1H)。實例5-31:1H NMR(400MHz,CD3
OD)δppm2.39-2.43(m,2H)2.46-2.57(m,4H)2.90(ABX之A,Jab=13.6Hz,Jax=7.8Hz,1H)2.97(ABX 之 B,Jab=13.6Hz,Jbx=6.1Hz,1H)4.45-4.52(m,1H)7.37-7.39(m,2H)7.49-7.53(m,3H)7.57-7.59(m,1H)7.70-7.74(m,1H)7.80-7.82(m,1H)。實例5-32:1HNMR(400MHz,CD3
OD)δppm1.33-1.49(m,4H)1.68-1.72(m,1H)1.79-1.83(m,1H)1.96-2.01(m,2H)2.05-2.13(m,1H)2.17-2.25(m,1H)2.43-2.55(m,2H)2.80-2.95(m,2H)4.42-4.49(m,1H)7.28-7.32(m,3H)7.38-7.43(m,2H)7.52-7.59(m,4H)。實例5-33:1HNMR(400MHz,DMSO-d6)δppm2.48-2.55(m,2H)2.84-2.96(m,2H)4.44-4.53(m,1H)6.94(brs,1H)7.30-7.35(m,3H)7.42-7.46(m,2H)7.57-7.64(m,4H)8.17-8.60(brm,5H)12.27(brs,1H)。實例5-34:1H NMR(400MHz,CD3
OD)δppm1.30(t,J=7.0Hz,3H)2.39-2.56(m,6H)2.82-2.93(m,2H)4.02(q,J=7.0Hz,2H)4.42-4.49(m,1H)6.96-7.03(m,2H)7.23-7.28(m,4H)7.44(d,J=8.4Hz,2H)。實例5-35:1HNMR(400MHz,CD3
OD)δppm2.14(s,3H)2.39-2.43(m,2H)2.45-2.56(m,4H)2.82-2.94(m,2H)4.02(q,J=7.0Hz,2H)4.42-4.49(m,1H)7.30-7.38(m,4H)7.49-7.55(m,3H)7.80(brs,1H)。實例5-36:1H NMR(400MHz,CD3
OD)δppm2.39-2.55(m,6H)2.85(ABX 之 A,Jab=13.6Hz,Jax=7.5HZ,1H)2.90(ABX之B,Jab=13.6Hz,Jbx=6.3HZ,1H)4.42-4.49(m,1H)6.86-6.92(m,1H)7.31(d,J=8.1Hz,2H)7.53-7.55(m,2H)。
實例5-37:合成(R)-4-(1-羧基-3-(5'
-氟-2'
-甲氧基聯苯-4-基)丙-2-基胺基)-4-側氧基丁酸
向(R)-4-(4-乙氧基-1-(5'
-氟-2'
-甲氧基聯苯-4-基)-4-側氧基丁-2-基胺基)-4-側氧基丁酸(83mg,0.192mmo1)於MeOH(2mL)中之溶液中添加1N NaOH(4mL,4mmo1)。在室溫下攪拌2小時後,在減壓下濃縮粗產物以移除MeOH,且用EtOAc稀釋。用鹽水洗滌有機層,經Na2
SO4
乾燥,過濾且在減壓下濃縮。利用RP-HPLC(SunFireC18,H2
O(0.1%TFA)/CH3
CN)純化所獲得之殘餘物,並隨後凍乾,得到(R)-4-(1-羧基-3-(5'
-氟-2'
-甲氧基聯苯-4-基)丙-2-基胺基)-4-側氧基丁酸(58mg)。HPLC滯留時間=
1.46分鐘(條件D);MS(m+1)=404.2;1H NMR(400 MHz,CD3
OD)δppm2.36-2.59(m,6H)2.84(dd,J=13.4,6.3Hz,1H)2.91(dd,J=13.4,6.3Hz,1H)3.75(s,3H)4.34-4.56(m,1H)6.95-7.08(m,3H)7.26(d,J=8.1Hz,2H)7.42(d,J=8.3Hz,2H)。
使用類似於實例5-37中所述之程序製備以下化合物:
實例5-38:1H NMR(400MHz,CD3
OD)δppm2.65(d,J=7.1Hz,2H)2.91-3.07(m,2H)3.26(s,3H)4.70(m,1H)7.04(d,J=8.8Hz,1H)7.26-7.33(m,1H)7.33-7.44(m,3H)7.47-7.56(m,3H)7.57(t,J=1.9Hz,1H)8.02(dd,J=8.8,2.5Hz,1H)8.55(d,J=1.78Hz,1H)。實例5-39:1HNMR(400MHz,CD3
OD)δppm2.36-2.60(m,6H)2.84(dd,J=13.4,6.1Hz,1H)2.91(dd,J=13.4,6.1Hz,1H)3.77(s,3H)4.34-4.58(m,1H)7.03(d,J=8.6Hz,1H)7.18-7.31(m,4H)7.39(d,J=8.1Hz,2H)。實例5-40:1HNMR(400MHz,DMSO-d6
)δppm2.51-2.70(m,2H)2.79-2.99(m,2H)3.05(s,3H)4.41-4.62(m,1H)7.22(d,J=8.8Hz,2H)7.33(d,J=8.1Hz,2H)7.36-7.43(m,1H)7.46(t,J=7.8Hz,1H)7.56-7.66(m,3H)7.69(t,J=1.8Hz,1H)7.76(d,J=8.6Hz,2H)8.30(d,J=8.3Hz,1H)10.09(s,1H)12.24(s,1H)。實例5-41:1HNMR(400MHz,DMSO-d6
)δppm1.28(t,J=7.6Hz,3H)2.51-2.60(m,2H)2.84-2.94(m,2H)2.97(q,J=7.6Hz,2H)4.36-4.56(m,1H)7.32(d,J=8.3Hz,2H)7.37-7.42(m,1H)7.47(t,J=7.8Hz,1H)7.60-7.66(m,3H)7.70(t,J=1.8Hz,1H)8.23(s,1H)8.60(d,J=8.3Hz,1H)12.30(br.s.,1H)。實例5-42:1HNMR(400MHz,DMSO-d6
)δppm2.23-2.31(m,2H)2.31-2.43(m,4H)2.76(d,J=6.6Hz,2H)4.16-4.30(m,1H)6.87-7.02(m,2H)7.07(dd,J=9.6,3.oHz,1H)7.21(d,J=8.3Hz,2H)7.50(d,J=8.1Hz,2H)7.90(d,J=8.1Hz,1H)9.51(br.s.,1H)。實例5-43:1H NMR(400MHz,CD3
OD)δppm2.33-2.60(m,6H)2.85(dd,J=13.7,6.1Hz,1H)2.94(dd,J=13.7,6.1Hz,1H)3.45(s,3H)4.35-4.57(m,1H)7.14(t,J=7.8Hz,1H)7.21-7.34(m,3H)7.38(dd,J=8.0,1.6Hz,1H)7.47(d,J=8.3Hz,2H)。實例5-44:
1H NMR(400MHz,CD3
OD)δppm2.64(d,J=5.8Hz,2H)3.01(d,J=6.8Hz,2H)4.51-4.74(m,1H)7.00(br.s.,1H)7.25-7.35(m,3H)7.40(t,J=7.6Hz,2H)7.53(d,J=8.1Hz,2H)7.58(d,J=8.1Hz,2H)8.21(br.s.,1H)。實例5-45:1H NMR(400MHz,CD3
OD)δppm2.38-2.55(m,6H)2.85(dd,J=13.6,6.3,Hz,1H)2.93(dd,J=13.6,6.3,Hz,1H)4.40-4.56(m,1H)7.27-7.37(m,3H)7.40(t,J=7.8Hz,1H)7.54-7.56(m,3H)7.60(t,J=1.8Hz,1H)。實例5-46:1HNMR(400MHz,DMSO-d6
)δppm2.51-2.63(m,2H)2.84(dd,J=13.6,8.3Hz,1H)2.89(dd,J=13.6,8.3Hz,1H)4.40-4.55(m,1H)7.30(d,J=8.3Hz,2H)7.37-7.42(m,1H)7.47(t,J=7.8Hz,1H)7.58-7.66(m,3H)7.70(t,J=1.9Hz,1H)8.95(d,J=8.6Hz,1H)12.93(s,1H)。實例5-47:1HNMR(400MHz,DMSO-d6
)δppm1.25(t,J=7.6Hz,3H)2.51-2.59(m,2H)2.80(q,J=7.6Hz,2H)2.84-2.94(m,2H)4.41-4.56(m,1H)7.31(d,J=8.1Hz,2H)7.37-7.42(m,1H)7.47(t,J=7.8Hz,1H)7.59(s,1H)7.63(d,J=8.3Hz,3H)7.70(t,J=1.9Hz,1H)8.45(d,J=8.6Hz,1H)12.27(br.s.,1H)。實例5-48:1H NMR(400MHz,CD3
OD)δppm1.33(t,J=7.6Hz,3H)2.64(d,J=6.8Hz,2H)2.84(q,J=7.6Hz,2H)2.98(d,J=7.o1Hz,2H)3.72(s,3H)4.62-4.75(m,1H)6.94-7.06(m,3H)7.27(d,J=8.1Hz,2H)7.40(d,J=8.3Hz,2H)7.54(s,1H)。實例5-49:1HNMR(400MHz,DMSO-d6)δppm2.51-2.62(m,2H)2.84(dd,J=13.7,7.9Hz,1H)2.91(dd,J=13.7,7.9Hz,1H)3.73(s,3H)4.42-4.55(m,1H)7.05-7.19(m,3H)7.25(d,J=8.1Hz,2H)7.42(d,J=81Hz,2H)7.73(s,1H)8.55(s,1H)8.63(d,J=8.6Hz,1H)。實例5-50:1H NMR(400MHz,CD3
OD)δppm2.69(d,J=6.8Hz,2H)2.95-3.10(m,2H)4.68-4.79(m,1H)7.21-7.33(m,1H)7.33-7.47(m,4H)7.49-7.65(m,4H)7.76-7.97(m,2H)8.20-8.42(m,1H)。實例5-51:1H NMR(400 MHz,CD3
OD)δppm2.62(d,J=6.6Hz,2H)2.96(d,J=7.3Hz,2H)4.54-4.68(m,1H)7.28-7.36(m,3H)7.40(t,J=7.7Hz,2H)7.56(dd,J=17.2,7.8Hz,4H)。實例5-52:1H NMR(400MHz,CD3
OD)δppm2.34-2.45(m,2H)2.45-2.59(m,4H)2.86(dd,J=13.4,6.oHz,1H)2.93(dd,J=13.4,6.oHz,1H)4.40-4.55(m,1H)7.19-7.26(m,1H)7.34(d,J=8.1Hz,2H)7.46-7.49(m,1H)7.51(t,J=8.oHz,1H)7.56(d,J=8.3Hz,2H)7.61(d,J=7.8Hz,1H)。實例5-53:1HNMR(400MHz,DMSO-d6
)δppm2.04-
2.26(m,2H)2.31-2.46(m,2H)2.69-2.88(m,2H)2.94-3.21(m,2H)4.18-4.37(m,1H)7.28(d,J=7.1Hz,2H)7.35-7.43(m,1H)7.43-7.54(m,2H)7.63(d,J=8.2Hz,3H)7.70(t,J=1.9Hz,1H)7.98(dd,J=8.3,2.3Hz,1H)12.22(br.s.,1H)。實例5-54:
1HNMR(400MHz,CD3
OD)δppm2.57(s,3H)2.68(d,J=6.6Hz,2H)2.92-3.08(m,2H)4.64-4.74(m,1H)7.25-7.33(m,1H)7.33-7.44(m,3H)7.44-7.55(m,3H)7.57(t,J=1.8Hz,1H)。實例5-55:1H NMR(400MHz,CD3
OD)δppm2.64(d,J=6.3Hz,2H)2.97(d,J=7.1Hz,2H)3.74(s,3H)4.58-4.73(m,1H)6.43(s,1H)6.96-7.08(m,3H)7.27(d,J=8.1Hz,2H)7.42(d,J=8.1Hz,2H)8.71(d,J=8.3Hz,1H)。實例5-56:1HNMR(400MHz,DMSO-d6
)δppm2.52-2.67(m,2H)2.80-2.96(m,2H)4.38-4.54(m,1H)5.90(br.s.,1H)7.30(d,J=8.1Hz,2H)7.35-7.42(m,1H)7.46(t,J=7.8Hz,1H)7.61(d,J=8.3Hz,3H)7.69(t,J=1.9Hz,1H)8.08(br.s.,1H)。實例5-57:1H NMR(400MHz,CD3
OD)δppm2.48-2.55(m,1H)2.64(d,J=6.8Hz,1H)2.88-3.00(m,2H)4.32-4.69(m,1H)7.26-7.35(m,3H)7.41(t,J=7.5Hz,2H)7.49-7.65(m,4H)。實例5-58:1H NMR(400MHz,CD3
OD)δppm2.62(d,J=6.6Hz,2H)2.92-3.01(m,2H)4.59-4.64(m,1H)7.28-7.43(m,4H)7.48-7.56(m,3H)7.59(t,J=1.9Hz,1H)。
實例5-59:1H NMR(400 MHz,CD3
OD)δppm2.64(d,J=6.6Hz,2H)3.01(d,J=7.1Hz,2H)4.63-4.75(m,1H)7.05(d,J=8.1Hz,1H)7.26-7.32(m,1H)7.35(d,J=8.3Hz,2H)7.37-7.43(m,2H)7.44(d,J=1.oHz,1H)7.48(dd,J=8.1,1.77Hz,1H)7.52-7.60(m,4H)。實例5-60:1H NMR(400MHz,CD3
OD)δppm2.30-2.44(m,2H)2.44-2.64(m,4H)2.87(dd,J=13.7,6.4Hz,1H)2.95(dd,J=13.7,6.4Hz,1H)4.42-4.53(m,1H)7.27-7.52(m,8H)。實例5-61:1HNMR(400MHz,DMSO-d6
)δppm2.22-2.32(m,2H)2.32-2.44(m,4H)2.76(d,J=6.6Hz,2H)4.16-4.29(m,1H)6.82-6.88(m,1H)6.89-6.97(m,1H)7.08-7.17(m,1H)7.17-7.28(m,3H)7.47(d,J=8.1Hz,2H)7.90(d,J=8.1Hz,1H)9.47(br.s.,1H)12.14(br.s.,1H)。實例5-
62:1HNMR(400MHz,DMSO-
d6
)δppm2.22-2.31(m,2H)2.33-2.42(m,4H)2.72-2.85(m,2H)3.72(s,3H)4.16-4.34(m,1H)6.92(ddd,J=9.4,3.79,1.8Hz,1H)7.21-7.33(m,4H)7.34-7.45(m,1H)7.92(d,J=8.1Hz,1H)12.14(br.s.,2H)。實例5-63:1HNMR(400MHz,DMSO-d6)δppm2.42-2.48(m,2H)2.85(d,J=6.8Hz,2H)4.30-4.46(m,1H)6.99(s,1H)7.30(d,J=8.1Hz,2H)7.36-7.42(m,1H)7.47(t,J=7.8Hz,1H)7.63(d,J=8.1Hz,3H)7.67-7.77(m,2H)10.13(br.s.,1H)10.22(br.s.,1H)12.26(br.s.,1H)。實例5-64:1H NMR(400MHz,CD3
OD)δppm2.35-2.60(m,6H)2.85(dd,J=13.7,6.4Hz,1H)2.93(dd,J=13.7,6.4Hz,1H)3.65(s,3H)4.37-4.58(m,1H)7.05-7.18(m,3H)7.30(d,J=8.1Hz,2H)7.44(d,J=8.3Hz,2H)。實例5-65:1H NMR(400MHz,CD3
OD)δppm2.38-2.56(m,6H)2.85(dd,J=13.4,7.3Hz,1H)2.89(dd,J=13.4,7.3Hz,1H)4.40-4.52(m,1H)7.26-7.35(m,3H)7.36-7.46(m,2H)7.52-7.61(m,3H)。實例5-66:1H NMR(400MHz,CD3
OD)δppm2.31-2.58(m,6H)2.68-2.99(m,2H)3.63(s,3H)4.33-4.56(m,1H)6.92-7.18(m,3H)7.30-7.38(m,1H)7.38-7.46(m,2H)。實例5-67:1HNMR(400MHz,DMSO-d6
)δppm2.51-
2.65(m,2H)2.86(dd,J=13.7,8.1Hz,1H)2.95(dd,J=13.7,8.1Hz,1H)4.42-4.61(m,1H)6.89-6.99(m,1H)7.30(d,J=8.3Hz,2H)7.37-7.42(m,1H)7.42-7.51(m,1H)7.62(d,J=8.1Hz,3H)7.69(t,J=1.8Hz,1H)7.76(d,J=9.9Hz,1H)8.41(d,J=9.1Hz,1H)12.26(br.s.,1H)13.40(s,1H)。實例5-68:1HNMR(400MHz,DMSO-d6
)δppm2.51-2.57(m,2H)2.90(d,J=6.8Hz,2H)4.34-4.52(m,1H)7.15(s,1H)7.31(d,J=8.1Hz,2H)7.39(dd,J=7.6,1.77Hz,1H)7.47(t,J=7.8Hz,1H)7.59-7.66(m,3H)7.70(t,J=1.8Hz,1H)8.74(d,J=8.6Hz,1H)。實例5-69:1H NMR(400MHz,CD3
OD)δppm2.61(d,J=6.6Hz,2H)2.89-3.02(m,2H)4.53-4.71(m,1H)7.16-7.37(m,4H)7.39(t,J=7.8Hz,1H)7.45-7.57(m,3H)7.59(t,J=1.8Hz,1H)8.20(d,1H)。實例5-70:1HNMR(400MHz,DMSO-d6
)δppm2.41-2.57(m,2H)2.73-2.96(m,2H)4.35-4.46(m,1H)7.30(d,J=8.3Hz,2H)7.35-7.44(m,1H)7.47(t,J=7.8Hz,1H)7.57-7.67(m,4H)7.70(t,J=1.9Hz,1H)8.23(d,J=8.3Hz,1H)11.14(s,1H)12.29(br.s.,1H)。實例5-71:1H NMR(400MHz,CD3
OD)δppm2.58(dd,J=6.8,1.8Hz,2H)2.95(dd,J=7.0,3.4Hz,2H)4.53-4.66(m,1H)7.27-7.36(m,3H)7.36-7.43(m,2H),7.49-7.57(m,3H)7.59(t,J=1.7Hz,1H)。實例5-72:1H NMR(400MHz,CD3
OD)δppm2.60-2.71(m,2H),3.03(dd,J=6.9,4.7Hz,2H),3.28(s,3H),4.65-4.76(m,1H),7.06(d,J=8.8Hz,1H),7.23-7.38(m,3H),7.38-7.47(m,2H),7.50-7.64(m,5H),8.03(dd,J=8.8,2.3Hz,1H),8.17(d,1H),8.56(br.s.,1H)。實例5-73:1HNMR(400MHz,DMSO-d6)δppm2.43-2.59(m,2H),2.82-2.95(m,2H),4.04-4.16(m,1H),7.30(d,J=8.3Hz,2H),7.34(t,J=7.3Hz,1H),7.45(t,J=7.6Hz,2H),7.59(d,J=8.1Hz,3H),7.64(d,J=8.6Hz,2H),8.03(s,1H),12.45(br.s.,2H)。實例6-1:合成(R)-3-(聯苯-4-基甲基)-4-(2-羧基乙基胺基)-4-側氧基丁酸
在室溫下,向(R)-3-(聯苯-4-基甲基)-4-(3-甲氧基-3-側氧基丙基胺基)-4-側氧基丁酸(22.1mg,0.060mm01)於THF(0.6mL)及甲醇(0.1mL)中之溶液中添加1M NaOH水溶液(0.12mL,0.12mmo1)。攪拌3小時後,再添加1MNaOH水溶液(0.12mL,0.12mmo1)。攪拌反應混合物30分鐘,且用0.5mL1MHC1水溶液及0.5mL鹽水淬滅。用乙酸乙酯萃取混合物兩次,且在減壓下濃縮有機層,得到(R)-3-(聯苯-4-基甲基)-4-(2-羧基乙基胺基)-4-側氧基丁酸(16.4mg)。HPLC滯留時間=1.04分鐘(條件A);MS(m+1)=356.1;1H NMR(400MHz,DMSO-d6)δppm2.13-2.31(m,3H)2.59-2.65(m,1H)2.81-2.90(m,2H)3.12-3.27(m,2H)7.26(d,2H,J=8Hz)7.34(t,1H,J=7,4Hz)7.45(t,2H,J=7.7Hz)7.57(d,2H,J=8.1Hz)7.63-7.65。實例7-1:合成(R)-3-聯苯-4-基甲基-N-羧基甲基-
丁二醯胺酸
在室溫下,攪拌(R)-3-(聯苯-4-基甲基)-4-(2-第三丁氧基-
2-側氧基乙基胺基)-4-側氧基丁酸第三丁酯(40mg,0.088mmo1)及TFA(0.5mL,6.49mmo1)於DCM(1.5mL)中之溶液2小時。在減壓下濃縮反應,且將所獲得之殘餘物懸浮於DCM(0.5mL)及庚烷(2mL)中,且收集於漏斗上,
得到(R)-3-聯苯-4-基甲基-N-羧基甲基-丁二醯胺酸(9.6mg)。
HPLC滯留時間=1.26分鐘(條件A);MS(m+1)=342.0;1HNMR(400MHz,CD3
OD)δppm2.39(dd,J=16.67,5.31Hz,1H)2.63-2.82(m,2H)2.98-3.14(m,2H)3.84及3.95(AB,2H,J=17.8Hz)7.26-7.33(m,3H)7.40(t,J=7.71Hz,2H)7.56(dd,J=19.96,8.08Hz,4H)。
使用類似於實例7-1中所述之程序製備以下化合物:
實例7-2:1HNMR(400MHz,DMSO-d6)δppm1.51-1.58(m,2H)2.12-2.21(m,3H)2.49-2.65(m,2H)2.81-2.89(m,2H)2.94-3.08(m,2H)7.26(d,2H,J=8.1Hz)7.32-7.36(m,1H)7.43-7.46(m,2H)7.57(d,2H,J=8.0Hz)7.63-7.65(m,2H)。實例8-1:合成(R)-4-(2-聯苯-4-基甲基-3-羧基-丙醯基胺基)-2-甲基-戊酸
向2-聯苯-4-基甲基-丁二酸4-第三丁酯(100mg,0.29mmo1)於DMF(10 mL)中之攪拌溶液中添加HOBt(45mg,0.29mmo1)及EDCI(56mg,0.29mmo1),且在室溫下攪拌混合物10分鐘,隨後添加(2R,4R)-4-胺基-2-甲基-戊酸乙酯三氟乙酸鹽(47mg,0.29mmo1)及三乙胺(89mg,0.87mmo1),且在室溫下攪拌混合物5小時。用水淬滅混合物,且用乙酸乙酯萃取。用水、鹽水洗滌有機層、經硫酸鎂乾燥且過濾。在減壓下移除溶劑,得到(2R,4R)-7-聯苯-
4-
基甲基-2,4-二甲基-6-側氧基-壬二酸9-第三丁酯1-
乙酯。接著,向(2R,4R)-7-聯苯-4-基甲基-2,4-二甲基-6-側氧基-壬二酸9-第三丁酯1-乙酯於EtOH(4mL)中之溶液中添加1MNaOH水溶液(4mL),且在室溫下攪拌混合物30分鐘。用1MHC1水溶液酸化混合物至pH2-3,且用乙酸乙酯萃取。在減壓下移除溶劑,且利用製備型HPLC使用10%-
100%MeCN/水(0.1%TFA)之梯度純化殘餘物。凍乾適當溶離份,得到(R)-4-(2-聯苯-4-基甲基-3-羧基-丙醯基胺基)-2-甲基-戊酸。HPLC滯留時間=1.13分鐘(條件C);MS398.2(M+1);1
H-NMR(400 MHz,DMSO-d6)δppm0.93(m,6H),1.23(m,1H),1.59(m,1H),2.17(m,1H),2.63(m,1H),2.82(m,1H),3.72(m,1H),7.27(m,2H),7.33(m,1H),7.45(m,2H),7.56(m,2H),7.62(m,2H),7.71(m,1H),12.07(s,1H)。
實例9-1:合成(R)-4-聯苯--4-基-3-[(1H-四唑-5-羰基)-胺基]-丁酸
向(R)-3-[(1-苯甲基-1H-四坐-5-羰基)-胺基]-4-聯苯-4-基-丁酸乙酯及(R)-3-[(2-苯甲基-2H-四坐-5-羰基)-胺基]-4-聯苯-4-基-丁酸乙酯(180 mg,0.383mmo1)於EtOH(1mL)及THF(1mL)中之混合物中添加1M LiOH水溶液(2mL)。攪拌0.5小時後,用1MHC1水溶液酸化反應混合物。用乙酸乙酯萃取混合物,經Na2
SO4
乾燥,且在減壓下濃縮。將殘餘物溶解於MeOH中,且用10%Pd/C在室溫下氫化3小時並在40℃下氫化2小時。濃縮反應混合物,且利用逆相HPLC純化,
得到(R)-4-聯苯-4-基-3-[(1H-四坐-5-羰基)-胺基]-丁酸。HPLC滯留時間=1.18分鐘(條件D);MS(m+1)=352;1
H NMR(400 MHz,DMSO-d6)δppm2.56(dd,J=5.81,15.92Hz,1H),2.67(dd,J=7.58,15.92Hz,1H),2.85-2.99(m,2H),4.55-4.64(m,1H),7.26-7.35(m,3H),7.43(dd,J=7.83,7.83Hz,2H),7.56(d,J=8.08Hz,2H),7.62(d,J=7.07Hz,2H),9.28(d,8.84Hz,1H),12.28(s,1H)。
實例10-1:(R)-4-聯苯-4-基-3-(3-1H-四唑-5-基-
丙醯基胺基)-丁酸
在室溫下,向(R)-4-聯苯-4-基-3-{3-[1-(2-氰基-乙基)-1H-四坐-5-基]-丙醯基胺基}-丁酸乙酯(137mg,0.297mmo1)於DCM(8mL)中之溶液中添加DBU(1.507mL,10.00mmo1),且在室溫下攪拌該混合物2小時。用DCM萃取反應。用飽和NH4
C1、鹽水洗滌合併之有機層,且經無水硫酸鈉乾燥,過濾且在減壓下濃縮。利用急驟層析(矽膠,2%至10%EtOH/DCM)純化所獲得之殘餘物,得到(R)-4-聯苯-4-基-3-(3-1H-四坐-5-基-丙醯基胺基)-丁酸乙酯(37mg)。在室溫下,向所獲得之酯之EtOH溶液(2mL)中添加1M NaOH水溶液(1mL,1.0mmo1),且在室溫下攪拌混合物1小時。向反應中添加1mL1M HC1水溶液至pH=
4,且利用逆相HPLC[30%至60%乙腈-H2
O(0.1%TFA)]純化混合物,得到(R)-4-聯苯-4-基-3-(3-1H-四坐-5-基-丙醯基胺基)-丁酸。HPLC滯留時間=1.24分鐘(條件C);MS(m+1)=380;1H NMR(400 MHz,DMSO-d6)δppm2.37(dd,J=6.7,2.1Hz,2H),2.53(t,J=7.6Hz,2H),2.69-2.82(m,2H),3.02(t,J=7.7Hz,2H),4.17-4.29(m,1H),7.22(d,J=8.3Hz,2H),7.34(tt,J=7.3,1.3Hz,1H),7.42-7.48(m,2H),7.57(d,J=8.3Hz,2H),7.64(dd,J=8.2,1.1Hz,2H),8.00(d,J=8.1Hz,1H),12.21(br.s.,1H),15.92(br.s.,1H)。
對掌性HPLC滯留時間=5.64min.;管柱:Daice1CHIRALCELO J-H(4.6×100 mm);流速=1 m1/min.;溶離劑:EtOH(含0.1%TFA)/庚烷=2/8。實例11-1:合成(R)-4-(1-羧基-3-(3'
-氯聯苯-4-基)丙-2-基胺基)-4-側氧基丁酸
在室溫下,向(R)-4-(1-(聯苯-4-基)-4-乙氧基-4-側氧基丁-2-基胺基)-4-側氧基丁酸(110 mg,0.263mmo1)於THF(2mL)及甲醇(0.2mL)中之溶液中添加1MNaOH水溶液(1.053mL,1.053mmo1)。攪拌1小時後,用0.1M HC1水溶液淬滅反應,且用DCM(15m1)稀釋溶液,且攪拌1.5小時。收集沈澱之固體於漏斗上,依次用水、DCM、庚烷及DCM洗滌,且在減壓下乾燥,得到(R)-4-(1-羧基-3-(3'
-氯聯苯-4-基)丙-2-基胺基)-4-側氧基丁酸(66mg)。HPLC滯留時間=0.87分鐘(條件B);MS(m+1)=390.0;1HNMR(400MHz,CD3OD)δppm2.39-2.55(m,6H)2.86(ABX之A,Ja
b=13.6Hz,Jax
=7.6Hz,1H)2.92(ABX 之 B,Jab
=13.6Hz,Jbx=6.2Hz,1H)4.42-4.49(m,1H)7.30-7.34(m,3H)7.40(t,J=7.4Hz,1H)7.51-7.56(m,3H)7.60(t,J=1.8Hz,1H)。
使用類似於實例11-1中所述之程序製備以下化合物:
實例11-2:1H NMR(400MHz,CD3
OD)δppm1.76-
1.83(m,2H)2.15-2.21(m,4H)2.49(ABX 之 A,Jab
=15.7Hz,Jax
=7.3Hz,1H)2.53(ABX 之 B,Jab
=15.7Hz,Jbx
=6.1Hz,1H)2.83(ABX 之 A,Ja
b=13.6Hz,Ja
x=8.3Hz,1H)2.93(ABX 之 B,Ja
b=13.6Hz,Jbx
=5.8Hz,1H)4.46-4.53(m,1H)7.30-7.33(m,3H)7.39(t,,J=7.8Hz,1H)7.51-7.55(m,3H)7.59-7.60(m,1H)。實例11-3:1H NMR(400MHz,CD3
OD)δppm1.77-1.84(m,2H)2.16-2.23(m,4H)2.39-2.42(m,2H)2.49(ABX之A,Ja
b=15.6Hz,Jax
=7.5Hz,1H)2.53(ABX 之 B,Jab
=15.6Hz,Jbx
=6.1 Hz,1H)2.83(ABX 之 A,Jab
=13.6Hz,Jax
=6.1Hz,1H)2.91(ABX 之 B,Ja
b=13.6Hz,Jbx=6.3Hz,1H)3.75(s,3H)4.46-4.53(m,1H)6.97-7.04(m,2H)7.26(d,J=8.1Hz,2H)7.42(d,J=8.1Hz,2H)。實例11-4:1H NMR(400MHz,CD3
OD)δppm1.77-1.84(m,2H)2.16-2.24(m,4H)2.49(ABX之A,Jab
=15.6Hz,Jax
=7.5Hz,1H)2.54(ABX 之 B,Jab
=15.6Hz,Jbx
=6,1Hz,1H)2.83(ABX 之 A,Jab
=13.6Hz,Ja
x=8.2Hz,1H)2.91(ABX 之 B,Ja
b=13.6Hz,Jbx=6.1Hz,1H)3.77(s,3H)4.45-4.52(m,1H)7.03(d,J=8.6Hz,1H)7.24-7.28(m,3H)7.39-7.41(m,2H)。實例11-5:1H NMR(400MHz,CD3
OD)δppm1.49-1.56(m,4H)2.13(t,J=6.8Hz,2H)2.23(t,J=6.9Hz,2H)2.45-2.56(m,2H)2.80-2.86(m,1H)2.91-2.96(m,1H)4.46-4.53(m,1H)7.31-7.33(m,3H)7.40(t,J=8.0Hz,1H)7.52-7.55(m,3H)7.59(brt,J=1.8Hz,1H)。實例11-6:1H NMR(400 MHz,CD3
OD)δppm2.39-2.57(m,4H)2.80(ABX 之 A,Jab
=13.6Hz,Jax
=8.1Hz,1H)2.89(ABX之B,Jab
=13.6Hz,Jbx
=6.1Hz,1H)3.04(t,J=7.1Hz,2H)3.75(s,3H)4.40-4.47(m,1H)7.27-7.29(m,2H)7.32-7.35(m,1H)7.41(t,J=7.8Hz,1H)7.51-7.54(m,3H)7.59-7.60(m,1H)7.83-7.84(m,1H)8.28(brd,J=7.1Hz,1H)8.55(d,J=5.6Hz,1H)8.62(s,1H)。實例11-7:1H NMR(400MHz,CD3
OD)δppm2.47(ABX之A,Jab
=15.7Hz,Jax
=7.7HZ,1H)2.54(ABX 之 B,Ja
b=15.7Hz,Jbx=5.8Hz,1H)2.64-2.75(m,2H)2.80(ABX之 A,Jab
=13.7Hz,Jax
=8.3Hz,1H)2.92(ABX 之 B,Jab
=13.7Hz,Jbx
=5.9Hz,1H)3.17-3.21(m,2H)4.43-4.50(m,1H)7.28-7.35(m,3H)7.39-7.43(m,1H)7.51-7.54(m,3H)7.59(brt,J=1.9Hz,1H)7.69-7.75(m,2H)8.29-8.32(m,1H)8.61(d,J=4.6Hz,1H)。實例11-8:1H NMR(400MHz,氯仿-d)δppm1.82-1.89(m,2H)2.29(t,J=7.3Hz,2H)2.56(ABX 之 A,Ja
b=16.4Hz,Jax
=5.6Hz,1H)2.64(ABX 之 B,Jab
=16.4Hz,Jbx
=5.1Hz,1H)2.95(ABX 之 A,Ja
b=13.8Hz,Jax
=7.6Hz,1H)2.99(ABX 之 B,Ja
b=13.8Hz,Jbx=7.2Hz,1H)3.30(s,3H)3.38(t,J=5.9Hz,2H)4.10(q,J=7.1Hz,2H)4.52-4.57(m,1H)6.59(brd,J=8.6Hz,1H)7.26-7.37(m,4H)7.42-7.45(m,1H)7.48-7.52(m,2H)7.55(brt,J=1.6Hz,1H)。實例11-9:
1H NMR(400MHz,CD3
CN+D2
O)δppm2.43-
2.56(m,2H)2.71-2.91(m,4H)3.21-3.34(m,2H)4.39-
4.46(m,1H)7.27(d,J=8.3Hz,2H)7.34-7.49(n,7H)7.55-7.56(m,1H)7.65-7.70(m,2H)。實例11-10:1H NMR(400 MHz,CD3
OD)δppm2.38-2.41(m,2H)2.47-2.58(m,4H)2.85-2.90(m,1H)2.99-3.04(m,1H)4.48-4.55(m,1H)7,32-7.44(m,5H)7.53-7.56(m,1H)7.62-7.63(m,1H)。實例11-11:1HNMR(400MHz,DMSO-d6):1HNMR(400MHz,DMSO-d6):δppm2.44-2.52(m,2H),2.83-2.85(d,J=6.82Hz,2H),4.29-4.38(m,1H),7.28-7.30(d,J=8.34Hz,2H),7.40-7.43(t,J=7.83Hz,1H),7.62-7.65(m,3H),7.71-
7.72(t,J=1.77Hz,1H),9.42-9.45(M,1H),12.32(s,1H)。實例11-12:1H NMR(400 MHz,DMSO-d6)δppm2.54-
2.59(m,1H),2.64-2.70(m,1H),2.88-2.93(m,1H),2.98-3.03(m,1H),4.56-4.63(m,1H),7.30-7.32(m,2H),7.37-7.40(m,1H),7.43-7.47(t,J=7.83Hz,1H),7.59-7.61(m,3H),7.67-7.68(t,J=2.02Hz,1H),8.32(d,J=1.26Hz,1H),9.17-9.19(d,J=9.09Hz,1H),9.50(d,J=1.52Hz,1H),12.34(s,1H),14.14(s,1H)。實例11-13:1H NMR(400 MHz,DMSO-d6)δppm2.46-
2.60(m,2H),2.84-2.96(m,2H),4.51(m,1H),7.31(d,J=8.34Hz,2H),7.38-7.41(m,1H),7.46(t,1H),7.62(d,J=8.34Hz,3H),7.69(t,1H)。實例11-14:1H NMR(400MHz,DMSO-d6)δppm)2.75-2.99(m,1H)4.47(d,J=7.58Hz,1H)6.49(s,1H)7.30(d,J=8.34Hz,1H)7.37-7.43(m,1H)7.47(t,J=7.83Hz,1H)7.63(d,J=8.08Hz,2H)7.70(t,J=1.77Hz,1H)8.80(d,J=8.59Hz,1H)11.69(s,1H)12.04-12.58(m,1H)。實例11-15:1H NMR(400 MHz,DMSO-d6)δppm2.81-2.96(m,2H)4.42-4.55(m,1H)7.31(d,J==
8.34Hz,2H)7.36-7.43(m,1H)7.47(t,J=7.83Hz,1H)7.63(d,J=8.34Hz,4H)7.69(t,J=1.77Hz,1H)7.72(s,1H)8.54(s,1H)8.60(d,J=8.59Hz,1H)12.29(br.s.,1H)。實例11-16:1H NMR(400 MHz,DMSO-d6)δppm2.53-2.64(m,2H)2.84-2.93(m,2H)4.41-4.59(m,1H)7.00(d,J=2.02Hz,1H)7.31(d,J=8.08Hz,2H)7.37-7.42(m,1H)7.47(t,J=7.83Hz,1H)7.58-7.65(m,3H)7.70(t,J=1.77Hz,1H)8.72(d,J=1.77Hz,1H)8.95(d,J=8.59Hz,1H)12.31(br,s.,1H)。實例11-17:1H NMR(400 MHz,DMSO-d6)δppm2.46-2.60(m,2H),2.83-2.98(m,2H),4.52(m,1H),6.61(d,J=2.27Hz,1H),7.31(d,J=8.34Hz,2H),7.37-7.42(m,1H),7.46(t,1H),7.62(d,J=8.34Hz,3H),7.69(t,1H),7.74(d,J=2.02Hz,1H),8.13(d,J=8.84Hz,1H)。實例11-18:1H NMR(400 MHz,DMSO-d6)δppm2.48-2.62(m,2H),2,84-2.96(m,2H),4.52(m,1H),7.16(d,J=3.54Hz,1H),7.27(d,J=3.79Hz,1H),7.31(d,J=8.34Hz,2H),7.38-7.41(m,1H),7.47(t,1H),7.63(d,J=8.34Hz,3H),7.70(t,1H),8.59(d,J=8.59Hz,1H)。實例11-19:1HNMR(400MHz,DMSO-d6):1HNMR(400MHz,DMSO-d6):δppm2.54-2.67(m,2H),2.88-2.92(m,1H),2.99-3.05(m,1H),4.53-4.62(m,1H),7.31-7.33(m,2H),7.37-7.39(m,1H),7.43-7.47(t,J=7.58Hz,1H),7.60-7.62(m,3H),7.68(m,1H),7.86-7.87(d,J=4.55Hz,1H),8.30(s,1H),8.62-8.63(d,J=4.80Hz,1H),8.80-8.83(d,J=9.09Hz,1H)。實例11-20:1HNMR(400MHz,DMSO-d6):1HNMR(400MHz,DMSO-d6):δppm2.50-2.53(m,1H),2.56-2.59(t,J=6.32Hz,1H),2.90-2.98(m,2H),4.51-4.58(m,1H),7.33-7.35(d,J=8.34Hz,2H),7.39-7.42(m,1H),7.45-7.49(t,J=7.83Hz,1H),7.61-7.65(m,3H),7.69-7.70(t,J=1.77Hz,1H),7.90-7.91(dd,J=1.77Hz,5.05Hz,1H),8.38-8.39(m,1H),8.83-8.85(dd,J=0.76Hz,5.05Hz,1H),8.91-8.93(d,J=8.34Hz,1H)。實例11-21:1HNMR(400MHz,DMSO-d6):1HNMR(400MHz,DMSO-d6):δppm2.45-2.55(m,1H),2.59-2.67(m,1H),2.88-2.93(m,1H),2.99-3.05(m,1H),4.51-4.61(m,1H),7.32-7.34(d,J=8,08Hz,2H),7.37-7.40(m,1H),7.44-7.48(t,J=7.58Hz,1H),7.60-7.62(t,J=7.83Hz,2H),7.69(s,1H),7.77(s,1H),8.86-8.87(d,J=4.04Hz,1H),9.06(s,1H)。實例11-22:1H NMR(400MHz,DMSO-d6):δppm2.49-2.53(m,2H),2.90-2.92(d,J=6.82Hz,2H),4.42-4.51(m,1H),6.72-6.73(d,J=2.27Hz,2H),7.32-7.34(m,2H),7.39-7.42(m,1H),7.45-7.49(t,J=7.83Hz,1H),7.62-7.66(m,3H),7.70-7.71(t,J=1.77Hz,1H),8.27-8.29(d,J=8.08Hz,1H),11.96(s,1H),12.33(s,1H),12.75(s,1H)。實例11-23:1HNMR(400MHz,DMSO-d6):1HNMR(400MHz,DMSO-d6):δppm2.44-2.55(m,2H),2.79-2.89(m,2H),4.29-4.38(m,1H),7.27-7.29(d,J=8.08Hz,2H),7.39-7.42(m,1H),7.45-7.49(t,J=8.08Hz,1H),7.62-7.64(d,J=8.08Hz,3H),7.70-7.71(m,1H),8.85-8.87(d,J=9.09Hz,1H),12.30(s,1H)。實例11-24:1H NMR(400 MHz,DMSO-d6)δppm2.46-2.60(m,2H),2.84-2.96(m,2H),4.51(m,1H),7.15(m,2H),7.44-7.52(m,3H),7.62(d,J=8.34Hz,2H),8.38(d,寬峰,J=7.58Hz,1H)。實例11-25:1H NMR(400 MHz,DMSO-d6):δppm2.54-2.59(m,1H),2.64-2.70(m,1H),2.88-2.93(m,1H),2.98-3.03(m,1H),4.56-4.65(m,1H),7.13-7.18(m,1H),7.30-7.32(d,J=8.34Hz,2H),7.45-7.48(m,3H),7.60-7.62(d,J=8.34Hz,2H),8.31-8.32(d,J=1.26Hz,1H),8.17-8.19(d,J=9.09Hz,1H),8.49(d,J=1.26Hz,1H),12.32(s,1H),14.10(s,1H)。實例11-26:1H NMR(400 MHz,DMSO-d6)δppm2.52-
2.62(m,2H)2.83-2.92(m,2H)4.47(d,J=7.07Hz,1H)6.49(s,1H)7.11-7.21(m,1H)7.30(d,J=8.34Hz,2H)7.42-7.55(m,3H)7.64(d,J=8.34Hz,2H)8.80(d,J=8.59Hz,1H)11.68(br.s.,1H)12.30(br.s.,1H)。實例11-27:1H NMR(400 MHz,DMSO-d6)δppm2.51-
2.57(m,1H),2.64-2.70(m,1H),2.84-2.89(dd,J=6.06Hz,1H),2.96-3.01(dd,J=7.83Hz,1H),3,72(s,3H),4.54-4.63(m,1H),6.96-7.00(m,1H),7.06-7.08(dd,J=0.76Hz,1H),7.22-7.24(m,3H),7.28-7.32(m,1H),7.35-7.38(m,2H),8.33-8.34(d,J=1.26Hz,1H),9.16-9.18(d,J=9.09Hz,1H),9.49(d,J=1.52Hz,1H),12.31(s,1H),14.13(s,1H)。實例11-28:
1H NMR(400 MHz,DMSO-d6)δppm2.52-
2.60(m,2H),2.73(s,1H),2.89(s,1H),2.81-2.95(m,2H),3.74(s,3H),4.50(m,1H),7.00(t,1H),7.08(d,J=8.34Hz,1H),7.15(s,寬峰,1H),7.23-7.26(m,3H),7.29-7.33(m,1H),7.38(d,J=8.08Hz,2H),8.39(d,寬峰,J=7.07Hz,1H)。實例11-29:1H NMR(400 MHz,CD3
OD)δppm1.33(t,J=7.6Hz,3H)2.66(d,J=6.8Hz,2H)2.84(q,J=7.6Hz,2H)2.98(dd,J=13.6,8.1Hz,1H)3.03(dd,J=13.6,6.6Hz,1H)4.64-4.76(m,1H)7.24-7.37(m,6H)7.40-7.45(m,1H)7.53(s,1H)。實例11-30:1H NMR(400 MHz,DMSO-d6)δppm2.40-
2.51(m,2H)2.79-2.90(m,2H)4.29-4.38(m,1H)6.47(d,J=15.7Hz,1H)6.88(d,J=15.7Hz1H)7.28-7.30(m,2H)7.39-7.41(m,1H)7.47(t,J=8.0Hz,1H)7.62-7.65(m,2H)7.70-7.71(m,1H)8.54(d,J=8.1Hz,1H)7.31(d,J=8.3HZ,2H)7.40-7.43(m,1H)7.47-7.50(m,1H)7.62-7.65(m,3H)7.69-7,71(m,1H)8.54(d,J=8.1Hz,1H)。
實例11-31:1HNMR(400MHz,DMSO-d6
)δppm2.22(s,3H)2.43-2.49(m,1H)2.52-2.60(m,1H)2.84(dd,J=13.6,6.1Hz,1H)2.94(dd,J=13.6,8.1Hz,1H)4.39-4.58(m,1H)6.33(s,1H)7.30(d,J=8.3Hz,2H)7.36-7.42(m,1H)7.46(t,J=7.8Hz,1H)7.61(d,J=8.3Hz,3H)7.69(t,J=1.9Hz,1H)8.02(d,J=7.8Hz,1H)。實例11-32:1H NMR(400 MHz,DMSO-d6)δppm2.51-2.56(m,2H)2.89(d,J=6.8Hz,2H)3.31(s,3H)4.33-4.57(m,1H)7.31(d,J=8.1Hz,2H)7.37-7.42(m,1H)7.46(t,J=7.8Hz,1H)7.60-7.66(m,3H)7.69(t,J=1.8Hz,1H)8.15(s,1H)8.50(d,J=8.3Hz,1H)12.24(br.s.,1H)。實例11-33:1H NMR(400 MHz,DMSO-d6
)δppm2.52-2.60(m,2H)2.66(s,3H)2.93(d,J=6.8Hz,2H)4.43-4.63(m,1H)7.33(d,J=8.1Hz,2H)7.36-7.42(m,1H)7.46(t,J=7.8Hz,1H)7.58-7.66(m,3H)7.69(t,J=1.8Hz,1H)8.74(d,J=8.3Hz,1H)8.98(s,2H)12.28(br,s.,1H)。實例11-34:1HNMR(400MHz,MeOD)δppm2.15(s,3H)2.67(d,J=6.6Hz,2H)2.98(dd,J=13.9,8.3Hz,1H)3.03214(dd,J=14.1,6.8Hz,1H)4.62-4.77(m,1H)5.57(s,1H)6.16(s,1H)7.27-7.32(m,1H)7.32-7.41(m,3H)7.46-7.54(m,3H)7.56(t,J=1.8Hz,1H)7.65(s,1H)8.55(d,J=8.6Hz,1H)。實例11-35:
1H NMR(400 MHz,CD3
OD)δppm2.42(s
,3H)2.63(d,J=6.3Hz,2H)2.99(d,J=7.1Hz,2H)4.59-4.73(m,1H)7.25-7.30(m,1H)7.30-7.37(m,3H)7.41-7.50(m,3H)7.53(t,J=1.8Hz,1H)8.15(s,1H)。實例11-36:1H NMR(400 MHz,DMSO-d6
)δppm2.51-
2.61(m,2H)2.87(dd,J=13.1,5.6Hz,1H)2.94(dd,J=13.4,7.6Hz,1H)4.41-4.60(m,1H)7.29-7.38(m,3H)7.45(ddd,J=8.7,4.2,2.8Hz,1H)7.49(d,J=6.8Hz,2H)7.56(dd,J=6.8,2.5Hz,1H)7.71(s,1H)8.53(s,1H)8.59(d,J=8.6Hz,1H)12.26(br.s.,1H)。實例11-37:1H NMR(400MHz,CD3
OD)δppm1.32(t,J=7.6Hz,3H)2.66(d,J=6.8Hz,2H)2.83(q,J=7.6Hz,2H)2.98(dd,J=13.6,7.8Hz,1H)3.03(dd,J=14.7,6.8Hz,1H)4.61-4.80(m,1H)7.13(dd,J=18.9,10.1Hz,1H)7.25-7.32(m,1H)7.32-7.37(m,2H)7.37-7.45(m,3H)7.54(s,1H)。實例11-38:1HNMR(400MHz,DMSO-d6)δppm1.15(t,J=7.73Hz,3H)2.39(d,J=6.8Hz,2H)2.79(d,J=6.8Hz,2H)3.46-3.56(m,2H)3.91-4.01(m,2H)4.21-4.29(m,1H)7.14-7.17(m,1H)7.28(d,J=8.3Hz,2H)7.39-7.42(m,1H)7.48(t,J=7.83Hz,1H)7.61-7.64(m,3H)7.69-7.70(m,1H)7.84(d,J=8.4Hz,1H)12.23(brs,1H)。實例11-39:1H NMR(400MHz,
甲醇-d4)δppm2.39-2.56(m,6H)2.87(ABX 之 A,Jb
=13.6Hz,Ja
x=7.6Hz,1H)2.94(ABX 之 B,Jab
=13.6Hz,Jbx
=6.1 Hz,1H)4.43-4.50(m,1H)7.15-7.20(m,1H)7.31-7.35(m,3H)7.45-7.48(m,3H)。實例11-40:1H NMR(400 MHz,DMSO-d6)δppm2.24-2.37(m,4H),2.73(dd,1H,J=7.83,13.4Hz),2.88(dd,1H,J=7.33,13.4Hz),3.93(s,1H),4.26-4.36(m,1H),5.35(bs,1H),7.33(d,2H,J=8.08Hz),7.38-7.43(m,1H),7.48(t,1H,J=7.83Hz),7.63(d,3H,J=8.34Hz),7.70(t,1H,J=2.02Hz),7.73(d,1H,J=9.09Hz),12.26(bs,2H)。實例11-41:1H NMR(400 MHz,DMSO-d6)δppm2.21-2.33(m,4H),2.65-2.81(m,2H),4.02(d,1H,J=4.04Hz),4.24-4.32(m,1H),5.56(bs,1H),7.27(d,2H,J=8.34Hz),7.37-7.42(m,1H),7.47(t,1H,J=7.83Hz),7.58(d,2H,J=8.34Hz),7.60-7.64(m,1H),7.69(t,1H,J=1.77Hz),7.96(d,1H,J=8.84Hz),12.03(bs,1H),12.60(bs,1H)。實例11-42:1H NMR(400 MHz,DMSO-d6)δppm2.22-2.37(m,4H),2,74(dd,1H,J=8.34,13.4Hz),2.86(dd,1H,J=6.82,13.4Hz),3.34(s,3H),3.62(d,1H,J=2.78Hz),4.34-4.44(m,1H),7.31(d,2H,J=8.34Hz),7.38-7.43(m,1H),7.48(t,1H,J=7.83Hz),7.63(d,3H,J=8.34Hz),7.71(s,1H),7.89(d,1H,J=9.35Hz)。實例11-43:1H NMR(400 MHz,DMSO-d6)δppm2.17-2.37(m,4H),2.64-2.81(n,2H),3.37(s,3H),3.77(d,1H,J=4.04Hz),4.25-4.34(m,1H),7.25(d,2H,J=8.08Hz),7.38-7.42(m,1H),7.47(t,1H,J=7.83Hz),7.56-7.64(m,3H),7.68(t,1H,J=1.77Hz),8.05(d,1H,J=8.84Hz),12.05(bs,1H),12.89(bs,1H)。實例11-44:1H NMR(400 MHz,DMSO-d6)δppm2.20-
2.39(m,4H),2.65-2.87(m,2H),4.37-4.56(m,1H),4.91(d,0.5H,J=2.78Hz),5.04(d,0.5H,J=3.03Hz),7.29(d,2H,J=8.34Hz),7.38-7.43(m,1H),7.47(t,1H,J=7.83Hz),7.58-7.65(m,3H),7.69(t,1H,J=1.77Hz),8.27(d,1H,J=8.59Hz),12.05(bs,1H),13.57(bs,1H)。實例11-45:
1HNMR(400MHz,DMSO-d6)δppm1.10(d,J=7.1Hz,3H),2.17-2.37(m,4H),2.57-2.78(m,3H),4.19-4.31(m,J=9.2,9.2,4.5,4.3Hz,1H),7.30(d,J=8.1Hz,2H),7.37-7.42(m,1H),7.47(t,J=7.8Hz,1H),7.57-7.65(m,3H),7.70(t,J=1.8Hz,1H),7.86(d,J=8.8Hz,1H),12.21(br.s.,2H)。實例11-46:1H NMR(400 MHz,DMSO-d6)δppm2.45(dd,J=6.6,3.5Hz,1H),2.82(d,J=7.1Hz,1H),3.88(dd,J=20.2,15.2Hz,1H),4.03(s,1H),4.29-4.41(m,1H),7.29(d,J=8.3Hz,1H),7.37-7.43(m,1H),7.48(t,J=8.0Hz,1H),7.62(d,J=8.3Hz,2H),7.70(t,J=1.8Hz,1H),7.89(d,J=8.8Hz,1H),11.65-13.45(m,1H)。實例11-47/48:(R)-3-[(S)-2-(羧基甲基-胺基)-丙醯基胺基]-4-(3'
-氯-聯苯-4-基)-丁酸及(R)-3-[(R)-2-(羧基甲基-胺基)-丙醯基胺基]-4-(3'
-氯-聯苯-4-基)-丁酸
在室溫下,向(R)-3-[2-(第三丁氧基羰基-乙氧基羰基甲基-胺基)-丙醯基胺基]-4-(3'
-氯-聯苯-4-基)-丁酸乙酯(290mg,0.504mmo1)於THF(3m1)及MeOH(0.5m1)中之溶液中添加2M NaOH(1.009m1,2.017mmo1)。在室溫下攪拌反應隔夜。濃縮混合物至乾燥,且將粗產物溶解於DCM(3.00m1)中,向其中添加TFA(3.89m1,50.4mmo1),且在室溫下攪拌混合物2小時。濃縮反應以進行HPLC純化。逆相HPLC[10 min內25至50%ACN-H2
O(0.1%TFA),Sunfire C18管柱]得到(R)-3-[(S)-2-(羧基甲基-胺基)-丙醯基胺基]-4-(3'
-氯-聯苯-4-基)-丁酸及(R)-3-[(R)-2-(羧基甲基-胺基)-丙醯基胺基]-4-(3'
-氯-聯苯-4-基)-丁酸。(R)-3-[(S)-2-(羧基甲基-胺基)-丙醯基胺基]-4-(3'
-氯-聯苯-4-基)-丁酸:1HNMR(400MHz,DMSO-d6
)δppm1,28(d,J=7.1Hz,3H),2.40(dd,J=15.7,8.3Hz,1H),2.51-2.56(m,1H),2.76(dd,J=13.4,8.1 Hz,1H),2.87(dd,J=13.4,5.3Hz,1H),3.43-3.52(m,3H),3.67(q,J=6.7Hz,1H),4.25-4.36(m,1H),7.30(d,J=8.3Hz,2H),7.38-7.43(m,1H),7.48(t,J=7.8Hz,1H),7.59-7.65(m,3H),7.70(t,J=1.8 Hz, 1H), 8.41 (d,J=8.3 Hz, 1H)。HRMS:C21
H23
C1N2
O5
之計算值:418.1295;實驗值:m/z
418.1307。LCMS(條件A):419(M+1);滯留時間=0.93min;(R)-3-[(R)-2-(羧基甲基-胺基)-丙醯基胺基]-4-(3'
-氯-聯苯-4-基)-丁酸:1H NMR(400MHz,DMSO-d6
)δppm1.17(d,J=6.8Hz,3H),2.41-2.49(m,0H),2.51-2.57(m,1H),2.73(dd,J=13.4,9.1 Hz,1H),2.91(dd,J=13.4,4.8Hz,1H),3.55-3.67(m,2H),3.67-3.74(m,1H),4.26-4.40(m,1H),7.29(d,J=8.3Hz,2H),7.39-7.44(m,0H),7.48(t,J=7.8Hz,0H),7.59-7.65(m,3H),7.69(t,J=1.8Hz,1H),8.43(d,J=8.6Hz,1H)。HRMS:C21
H23
C1N2
O5
之計算值:
418.1295;實驗值:m/z418.1305。LCMS(條件A):419(M+1);滯留時間=0.99min。使用類似於實例11-47/48中所述之程序製備以下化合物:
實例11-49:1H NMR(400 MHz,DMSO-d6)δppm2.39-2.50(m,2H)2.77-2.89(m,2H)3.61-3.71(m,2H)3.81(s,2H)4.26-4.35(m,1H)7.31(d,J=8.3HZ,2H)7.40-7.43(m,1H)7.47-7.50(m,1H)7.62-7.65(m,3H)7.69-7.70(m,1H)8.49(d,J=7.3Hz,1H)。實例12-1:合成(R)-4-(1-羧基-3-(3'
-氯聯苯-4-基)丙-2-基胺基)-4-側氧基丁酸
在室溫下,向(R)-4-(1-(2'
,5'
-二氯聯苯-4-基)-4-乙氧基-4-側氧基丁-2-基胺基)-4-側氧基丁酸(106mg,0.234mmo1)於THF(2m1)及MeOH(0.1 m1)中之溶液中添加1MNaOH水溶液(1.406mL,1.406mmo1)。攪拌4.5小時後,用0.1 M HC1水溶液(3m1)淬滅反應,且用EtOAc萃取產物。用鹽水洗滌合併之有機層,經Na2
SO4
乾燥,過濾且在減壓下濃縮。用DCM濕磨粗產物。收集沈澱於漏斗上,用DCM洗滌,且在減壓下乾燥,得到呈白色固體狀之(R)-4-(1-羧基-3-(3'
-氯聯苯-4-基)丙-2-基胺基)-4-側氧基丁酸(64.0mg);HPLC滯留時間=1.24分鐘(條件A);MS(m+1)=424.07;1HNMR(400MHz,CD3
OD)δppm2.38-2.42(m,2H)2.45-2.57(m,4H)2.87(ABX 之 A,Ja
b=13.6Hz,Ja
x=7.6Hz,1H)2.95(ABX 之 B,Jab
=13.6Hz,Jbx=6.1Hz,1H)4.44-4.51(m,1H)7.30-7.37(m,6H)7.47(d,J=8.4Hz,1H)。
實例13-1:合成(R)-4-(1-(聯苯-4-基)-3-羧基丙-
2-
基胺甲醯基)吡啶甲酸實例13-2:合成(R)-2-(1-(聯苯-4-基)-3-羧基丙-
2-
基胺甲醯基)異菸鹼酸
向(R)-3-胺基-4-(聯苯-4-基)丁酸乙酯鹽酸鹽(200mg,0.625mmo1)、2,4-比啶二甲酸水合物(151mg,0.813mmo1)、EDCI(132mg,0.688mmo1)及1-羥基-7-氮雜苯并三坐(94mg,0.688mmo1)於DMF(6m1)中之溶液中添加DIPEA(0.164m1,0.938mmo1)。攪拌反應混合物3小時。隨後,用H2
O稀釋反應混合物。收集沈澱之固體於漏斗上,
且在減壓下乾燥。向粗產物於THF(8m1)及MeOH(1m1)中之溶液中添加1M NaOH水溶液(2.5m,2.5mmo1)。攪拌1小時後,用5%檸檬酸及鹽水淬滅反應,且用EtOAc
萃取產物。用鹽水洗滌有機層,經Na2
SO4
乾燥,過濾且濃縮。利用製備型HPLC使用20%MeCN/水(0.1TFA)至100%MeCN之梯度純化所得殘餘物,分別得到呈白色固體狀之(R)-4-(1-(聯苯-4-基)-3-羧基丙-2-基胺甲醯基)比甲酸及(R)-2-(1-(聯苯-4-基)-3-羧基丙-2-基胺甲醯基)異菸鹼酸(實例13-1:
33mg;實例13-2:36mg)。實例13-1:HPLC滯留時間=1.50分鐘(條件D);MS(m+1)=405.1;1HNMR(400 MHz,DMSO-d6)δppm2.53-2.62(m,2H)2.88-2.97(m,2H)4.50-4.59(m,1H)7.31-7.35(m,3H)7.42-7.45(m,2H)7.57-7.64(m,4H)7.89(dd,J=5,1.6Hz,1H)8.83(dd,J=5,0.8Hz,1H)8.37(dd,J=1.6,0.8Hz)8.89(d,J=8.3Hz,1H)。實例13-2:HPLC滯留時間=1.24分鐘(條件A);MS(m+1)=405.1;1H NMR(400MHz,DMSO-d6)δppm2.52-2.68(m,2H)2.91(ABX 之 A,Jab
=13.6Hz,Ja
x=6.1Hz,1H)3.01(ABX 之 B,Jab
=13.6Hz,Jbx=8.1Hz,1H)4.56-4.65(m,1H)7.29-7.34(m,3H)7.41-7.45(m,2H)7.55-7.64(m,4H)7.99(dd,J=5,1.6Hz,1H)8.34(dd,J=1.6,0.8Hz,1H)8.84(dd,J=5,0.8Hz,1H)8.90(d,J=9.1Hz,1H)12.26(brs,1H)13.87(brs,1H)。
使用類似於實例13-1及13-2中所述之程序製備以下化合物:
實例13-3:1HNMR(400MHz,DMSO-d6)δppm2.55(d,J=6.6Hz,2H)2.91(ABX 之 A,Jab
=13.6Hz,Jax
=6.3Hz,1H)2.96(ABX 之 B,Ja
b=13.6Hz,Jb
x=7.6Hz,1H)4.46-4.55(m,1H)6.86(brs,2H)7.02(d,J=4.8Hz,1H)7.28-7.36(m,3H)7.42-7.46(m,2H)7.58-7.65(m,4H)8.39(d,J=9.1Hz,1H)8.45(d,J=4.8Hz,1H)。實例14-1:合成(R)-3-(3-羧基甲基-脲基)-4-(3'-
氯-
聯苯-
4-
基)-丁酸
向中間物16-1(90mg,0.254mmo1)及異氰醯基乙酸乙酯(39.4mg,0.305mmo1)於DMF(3mL)中之溶液中添加比啶(2.93g,37.1mmo1),且在室溫下攪拌混合物2小時。在減壓下移除溶劑,且殘餘物直接用於下一步驟中。接著,將上述殘餘物溶解於EtOH(1mL)中,且添加1NNaOH(3mL,3mmo1)。在室溫下攪拌混合物2小時,隨後用1N HC1酸化。用EtOAc萃取混合物,且用水、鹽水洗滌有機相,隨後經硫酸鈉乾燥。在減壓下移除溶劑,且利用製備型HPLC使用10%MeCN/水至100%MeCN(+0.1%TFA)之梯度純化殘餘物。凍乾適當溶離份,得到標題化合物;HPLC滯留時間0.98分鐘(條件C);MS391.3(M+1);1HNMR(400MHz,DMSO-d6):δppm2.34(d,J=7.33Hz,2H),2.79(d,J=6.57Hz,2H),3.67(d,J=5.56Hz,2H),4.04-4.12(m,1H),6.15(t,J=5.81Hz,1H),6.23(d,J=8.34Hz,1H),7.28-7.30(m,2H),7.39-7.42(m,1H),7.48(t,J=7.83Hz,1H),7,62-7.65(m,3H),7.71(t,J=1.77Hz,1H),12.32(s,br,2H)。實例15-1:(R)-4-(3'
-氯-聯苯-4-基)-3-[(2H-四唑-5-羰基)-胺基]-丁酸
在室溫下向起始物質於MeOH(5m1)中之懸浮液中添加NaOH(2mL,6.00 mmo1),且攪拌混合物直至反應完成。酸化反應混合物至pH<4,且利用HPLC(15%至60%乙腈-H2
O(0.1%TFA)純化,得到(R)-4-(3'
-氯-聯苯-4-基)-3-[(2H-四坐-5-羰基)-胺基]-丁酸(80mg)。HPLC滯留時間=0.95分鐘(條件B);MS(m+1)=386.1;1H NMR(400MHz,DMSO-d6
)dppm2.52-2.61(m,1H),2.61-2.72(m,1H),2.84-2.99(m,2H),4.51-4.64(m,1H),7.31(d,J=8.1Hz,2H),7.36-7.41(m,1H),7.46(t,J=7.8Hz,1H),7.61(d,J=8.3Hz,3H),7.68(t,J=1.9Hz,1H),9.31(d,J=8.8Hz,1H),12.32(br.s.,1H)。
使用類似於實例15-1中所述之程序製備以下化合物:
實例15-2:1HNMR(400MHz,DMSO-d6
)δppm2.52-
2.72(m,2H),2.86-3.00(m,2H),4.52-4.65(m,1H),7.11-7.20(m,1H),7.31(d,J=8.1Hz,2H),7.43-7.51(m,3H),7.61(d,J=8.3Hz,2H),9.28(d,J=8.8Hz,1H),12.29(br.s.,1H)。實例15-3:1HNMR(400MHz,DMSO-d6
)δppm2.52-
2.60(m,J=15.9,5.8Hz,1H),2.67(dd,J=15.9,7.8Hz,1H),2.87(dd,J=13.6,5.8Hz,1H),2.95(dd,J=13.6,8.3Hz,1H),3.73(s,3H),4.52-4.64(m,1H),7.00(td,J=7.4,1.1Hz,1H),7.08(d,J=9.1Hz,1H),7.22-7.27(m,3H),7.28-7.34(m,1H),7.37(d,J=8.3Hz,2H),9.30(d,J=8.8Hz,1H),12.28(br.s.,1H)。實例16-1:N-[(R)-1-(3'
-氯-聯苯-4-基甲基)-3-甲烷磺醯基胺基-3-側氧基-丙基]-丁二醯胺酸
用4MHC1之二烷溶液處理[(R)-1-(3'
-氯-聯苯-4-基甲基)-3-甲烷磺醯基胺基-3-側氧基-丙基]-胺基甲酸第三丁酯(150mg,0.321mmo1)。在室溫下攪拌1小時後,在真空中濃縮反應混合物。向該殘餘物之DCM溶液(2mL)中添加丁二酸酐(48.2mg,0.482mmo1)及三乙胺(0.112mL,
0.803mmo1)。在室溫下攪拌2小時後,用EtOAc稀釋反應混合物,且用1MHC1及鹽水洗滌。經Na2
SO4
乾燥有機層且濃縮。利用逆相HPLC(SunFire C18,含0.1%TFA之H2
O/CH3
CN)純化殘餘物,得到N-[(R)-1-(3'
-氯-聯苯-4-基甲基)-3-甲烷磺醯基胺基-3-側氧基-丙基]-丁二醯胺酸(63mg)。HPLC滯留時間=1.32分鐘(條件A);MS(m+1)=467;1H NMR(400 Mz,DMSO-d6)δppm2.22-2.29(m,2H),2.32-2.54(m,4H),2.77(d,2H,J=6.82Hz),3.17(s,3H),4.31(dt,1H,J=7.33,13.9Hz),7.28(d,2H,J=8.08Hz),7.38-7.43(m,1H),7.48(t,1H,J=7.83Hz),7.62(d,3H,J=8.34Hz),7.70(t,1H,J=2.02Hz),7.89(d,1H,J=8.34Hz),11.70(s,1H),12.04(s,1H)。使用類似於實例16-1中所述之程序製備以下化合物:
實例16-2:
1HNMR(400MHz,DMSO-d6
)δppm0.96(t,3H,J=7.33Hz),1.66(dd,2H,J=7,33,15.2Hz),2.25(t,2H,J=7.07Hz),2.31-2.45(m,4H),2.76(d,2H,J=6.82Hz),3.25-3.32(m,2H),4.30(dd,1H,J=7.83,14.7Hz),7.28(d,2H,J=8.34Hz),7.38-7.43(m,1H),7.48(t,1H,J=7.83Hz),7.63(d,3H,J=8.08Hz),7.70(t,1H,J=1.77Hz),7.89(d,1H,J=8.34Hz),11.61(s,1H),12.04(s,1H)。實例16-3:1HNMR(400MHz,DMSO-d6
)δppm2.24-
2.31(m,2H),2.34-2.40(m,2H),2.44(d,2H,J=6.82Hz),2.78(d,2H,J=6.82Hz),4.26-4.36(m,1H),4.67(s,2H),7.25-7.33(m,4H),7.34-7.43(m,4H),7.48(t,1H,J=7.58Hz),7.63(d,3H,J=8.34Hz),7.70(t,1H,J=1.77Hz),7.92(d,1H,J=8.34Hz),11.60(s,1H),12.05(s,1H)。實例16-4:1HNMR(400MHz,DMSO-d6)δppm2.19-2.29(m,4H),2.36(dd,2H,J=6.57,6.57Hz),2.72(dd,1H,J=7.83,13.6Hz),2.81(dd,1H,J=5.31,13.6Hz),4.17-4.27(m,1H),6.83(s,1H),7.28(d,3H,J=8.34z),7.38-7.43(m,1H),7.47(t,1H,J=7.83Hz),7.58-7.65(m,3H),7.69(t,1H,J=1.77Hz),7.78(d,1H,J=8.34Hz),12.05(s,1H)。實例16-5:合成N-[(R)-1-(3'
-氯-聯苯-4-基甲基)-3-甲烷磺醯基胺基-3-側氧基-丙基]-丁二醯胺酸丁酯
向N-[(R)-1-(3'
-氯-聯苯-4-基甲基)-3-甲烷磺醯基胺基-3-側氧基-丙基]-丁二醯胺酸(50mg,0.107mmo1)於正丁醇(2mL)中之溶液中添加亞硫醯氯(9.38μL,0.128mmo1)。
使反應混合物升溫至50℃且攪拌1小時。冷卻至室溫後,濃縮反應混合物,且利用逆相HPLC(SunFire C18,含0.1%TFA之H2O/CH3CN)純匕,得到N-[(R)-1-(3'
-氯-聯苯-4-基甲基)-3-甲烷磺醯基胺基-3-側氧基-丙基]-丁二醯胺酸丁酯(32mg)。HPLC滯留時間=1.56分鐘(條件A);MS(m+1)=523;1HNMR(400 Mz,DMSO-d6)δppm0.86(t,3H,J=7.33Hz),1.22-1.34(m,2H),1.45-1.55(m,2H),2.23-2.33(m,2H),2.35-2.44(m,3H),2.45-2.55(m,3H),2.71-2.83(m,1H),3.18(s,3H),3.96(t,2H,J=6.57Hz),4.27-4.38(m,1H),7.28(d,2H,J=8.08Hz),7.37-7.43(m,1H),7.48(t,1HJ=7.83Hz),7.62(d,3H,J=8.34Hz),7.70(s,1H),7.91(d,1H,J=8.34Hz),11.71(s,1H)。實例17:(R)-3-(2-乙醯基噁唑-5-甲醯胺基)-4-(3'
-氯聯苯-
4-基)丁酸
在-78℃下,用臭氧向(R)-4-(3'
-氯聯苯-4-基)-3-(2-(丙-1-
烯-2-基)坐-5-甲醯胺基)丁酸(60mg,0.14mmo1)於DCM(2mL)及MeOH(2mL)中之溶液中鼓泡30秒。30秒後,移除臭氧,且用氧氣鼓泡10分鐘。用氧氣鼓泡10分鐘後,移除-78℃浴,且用聚合物支撐之三苯基膦淬滅反應,且在室溫下攪拌反應2小時。2小時後,過濾反應以移除支撐聚合物上之三苯基氧化膦(tripheny1phosphineoxide),且收集濾液並在減壓下濃縮。利用RP-HPLC(SunFireC18,H2
O(0.1%TFA)/CH3
CN)純化所獲得之殘餘物,並隨後凍乾,得到(R)-3-(2-乙醯基坐-5-甲醯胺基)-4-(3'
-氯聯苯-4-基)丁酸(13mg)。HPLC滯留時間=1.67分鐘(條件D);MS(m+1)=427.0;1H NMR(400 MHz,DMSO-d6)δppm2.53-2,59(m,2H)2.60(s,3H)2.87(dd,J=10.9,3.3Hz,1H)2.94(dd,J=10.9,5.1 Hz,1H)4.46-4.60(m,1H)7.31(d,J=8.1Hz,2H)7.36-7.43(m,1H)7.47(t,J=7.8Hz,1H)7.62(d,J=8.3Hz,3H)7.69(t,J=1.9Hz,1H)7.94(s,1H)8.86(d,J=8.6Hz,1H)12.31(br.s.,1H)。起始物質或中間物係以以下方式製備:中間物1:(R)-4-(4-溴苯基)-3-(4-甲氧基-4-側氧基丁醯胺基)丁酸乙酯
在室溫下,向(R)-4-(4-溴苯基-4-基)-3-(第三丁氧基羰基胺基)丁酸乙酯(2.02g,5.23mmo1)中添加4M HC1於1,4-二烷中之溶液(13.1mL,52.3mmo1)。攪拌1小時後,在減壓下濃縮反應混合物,得到(R)-3-胺基-4-溴苯基-4-基-丁酸乙酯鹽酸鹽。向(R)-3-胺基-4-溴苯基-4-基-丁酸乙酯鹽酸鹽之溶液中添加丁二酸酐(0.707g,7.06mmo1)及DIPEA(2.06mL,11.8mmo1)之二氯甲烷(20 mL)溶液,且攪拌4小時。用0.1MHC1水溶液淬滅反應。用乙酸乙酯萃取產物,且用鹽水洗滌。經Na2
SO4
乾燥有機層,過濾且在減壓下濃縮,得到(R)-4-(1-(4-溴苯基)-4-乙氧基-4-側氧基丁-2-基胺基)-4-側氧基丁酸(2.26g)。在氮氣下在室溫下,向所獲得之殘餘物(2.26g)於甲苯(25mL)及MeOH(25mL)中之溶液中逐份添加TMSCHN2
之己烷溶液(5.85m1,11.70mmo1)。攪拌反應混合物1.5小時,隨後用AcOH(0.5mL;8.78mmo1)淬滅,且攪拌溶液10分鐘。濃縮溶液,且藉由用40 g矽膠進行急驟管柱層析(溶離劑:庚烷/EtOAc=100:
0至0:100)純化所獲得之殘餘物,得到(R)-4-(4-溴苯基)-3-(4-甲氧基-4-側氧基丁醯胺基)丁酸乙酯(1.92g)。HPLC滯留時間=1.04分鐘(條件B);MS(ES+)=400(m+1),402.0(m+3;100%);1HNMR(400MHz,氯仿-d)δppm1.28(t,J=7.2Hz,3H)2.40-2.53(1n,4H)2.60-2.64(m,2H)2.79(ABX之 A,Jab=13.7Hz,Jax=7.85Hz,1H)2.90(ABX之B,Jab=13.7Hz,Jbx=6.65Hz,1H)3.68(s,3H)4.10-4.22(m,2H)4.39-4.47(m,1H)6.29(brd,J=8.6Hz,1H)7.06(d,J=8.4Hz,2H)7.40-7.42(m,2H)。
中間物2:(R)-4-(聯苯-4-基)-3-(第三丁氧基羰基胺基)丁酸乙酯
在氮氣下在95℃下攪拌(R)-4-(4-溴苯基)-3-(第三丁氧基羰基胺基)丁酸乙酯(1.5g,3.88mmo1)、苯基朋酸(0.710g,5.82mmo1)、Pd(Ph3
P)4
(0.449g,0.388mmo1)及Na2CO3水溶液(3.88mL,7.77mmo1)於甲苯(25mL)中之混合物14小時。冷卻反應混合物至室溫,且用鹽水淬滅。用乙酸乙酯萃取混合物兩次,且用鹽水洗滌合併之有機層,經Na2
SO4
乾燥,過濾且在減壓下濃縮。利用矽膠急驟管柱層析(庚烷/EtOAc=100:0至50:50)純化所獲得之殘餘物,得到(R)-4-(聯苯-4-基)-3-(第三丁氧基羰基胺基)丁酸乙酯(1.30g);HPLC滯留時間=1.61分鐘(條件B);MS(ES+)=328.0(m-tBu+2);284.1(m-Boc+2;100%);1H NMR(400 MHz,氯仿-d)δppm1.28(t,J=7.1Hz,3H)2.48(ABX之A,Jab=16.1Hz,Jax=5.9Hz,1H)2.53(ABX 之B,Jab=16.0Hz,Jbx=5.3Hz,1H)2.83-3.00(m,2H)4.14-4.19(m,3H)5.06(brs)7.26-7.27(m,2H)7.31-7.35(m,2H)7.43(t,J=7.6Hz,2H)7.52-7.58(m,4H)。使用類似於關於中間物2所述之程序製備以下中間物:
中間物3:(R)-4-(1-(聯苯-4-基)-4-第三丁氧基-4-側氧基丁-
2-基胺基)-4-側氧基丁酸
在室溫下,向(R)-4-(聯苯-4-基)-3-(第三丁氧基羰基胺基)丁酸第三丁酯(26.4mg,0.064mmo1)中添加4MHC1之1,4-二烷溶液(0.321m1,1.283mmo1)。攪拌反應混合物45分鐘,且在減壓下濃縮。向所獲得之殘餘物於二氯甲烷中之溶液(0.4mL)中添加丁二酸酐(7.70mg,0.077mmo1)及DIPEA(0.013mL,0.077mmo1)。在室溫下攪拌反應混合物14小時,且在減壓下濃縮。利用RP-HPLC(SunFire C-18,H2
O(0.1%TFA)/CH3
CN)純化所獲得之殘餘物,得到(R)-4-(1-(聯苯-4-基)-4-第三丁氧基-4-側氧基丁-2-基胺基)-4-側氧基丁酸(9.5mg)。HPLC滯留時間=1.70分鐘(條件A);MS(ES+)=412.1(m+1);356.0(m-tBu+2;100%);1HNMR(400MHz,氯仿-d)δppm1.48(s,9H)2.36-2.51(m,4H)2.64-2.67(m,2H)2.87(ABX之A,Jab=13.5Hz,Jax=5.7Hz,1H),2.97(Jab=13.5Hz,Jbx=6.2Hz,1H)7.24-7.26(m,2H)7.31-7.35(m,1H)7.43(t,J=7.75Hz,2H)7.53(d,J=8,0Hz,2H)7.57(d,J=7.6Hz,2H)。使用類似於中間物3中所述之程序製備以下中間物:
中間物4:
(R)-4-(聯苯-4-基)-3-(第三丁氧基羰基胺基)丁酸第三丁酯
在氮氣下在100℃下,攪拌(R)-2-(聯苯-4-基甲基)-4-第三丁氧基-4-側氧基丁酸(100 mg,0.294mmo1)、DPPA(0.076mL,
0.353mmo1)及Et3
N(0.049mL,0.353mmo1)於甲苯(1.5mL)中之溶液2小時。添加tBuOH(0.281m1,2.94mmo1),且在相同溫度下使混合物回流5小時。冷卻反應至室溫,且移除溶劑。向所獲得之殘餘物中添加乙酸乙酯,且用5%檸檬酸水溶液、H2
O、飽和NaHCO3
水溶液及鹽水洗滌有機層。經Na2
SO4
乾燥有機層,過濾,且在減壓下濃縮。藉由用40 g矽膠進行急驟管柱層析(庚烷/EtOAc=100:
0至50:50)純化所獲得之殘餘物,得到相應的異氰酸酯(35.7mg)。將所獲得之異氰酸酯溶解於tBuOH(0.3mL)中,且在80℃下攪拌溶液20小時。濃縮反應混合物,且藉由用12g矽膠進行急驟管柱層析(庚烷/EtOAc=100:0至70:30)純化殘餘物,得到(R)-4-(聯苯-4-基)-3-(第三丁氧基羰基胺基)丁酸第三丁酯(26.4mg,22%)。HPLC滯留時間=1.74分鐘(條件B);MS(ES+)=356.0(m-tBu+2)300.0(m-tBux2+3;100%);1H NMR(400MHz,氯仿-d)δppm1.41(s,9H)1.47(s,9H)2.36(ABX 之 A,Jab=15.6Hz,Jax=6.2Hz,1H)2.44(ABX之B,Jab=15.5Hz,Jbx=5.45Hz)2.82-2.97(m,2H)4.15(brs)5.09(brd)7.6-7.35(m,3H)7.41-7.45(m,2H)7.51-7.56(m,4H)。中間物5:(R)-4-(4-溴苯基)-3-(第三丁氧基羰基胺基)丁酸乙酯
在氮氣下在室溫下,向(R)-4-(4-溴苯基)-3-(第三丁氧基羰基胺基)丁酸(9.98g,27.9mmo1)及NaHCO3(4.68g,55.7mmo1)於DMF(45mL)中之懸浮液中添加碘乙烷(6.75mL,84mmo1)。攪拌71小時後,用H2
O(300mL)淬滅反應,隨後收集沈澱之固體且用H2
O(500mL)洗滌,得到(R)-4-(4-溴苯基)-3-(第三丁氧基羰基胺基)丁酸乙酯(10.25g,94%)。HPLC滯留時間=1.48分鐘(條件B);MS(ES+)=329.9(m-tBu+2);286.0(m-Boc+2;100%);1H NMR(400 MHz,氯仿-d)δppm1.27(t,J=7.2Hz,3H)1.40(s,9H),2.43(ABX之A,Jab=15.8Hz,Jax=5.7Hz,1H)2.50(ABX之B,Jab=15.8Hz,Jbx=5.4Hz,1H)2.74-2.90(m,2H)4.11(brs)4.15(q,J=7.1Hz,2H)5.04(brd)7.07(d,J=8.3Hz,2H)7.40-7.43(m,2H)。使用類似於關於中間物5所述之程序製備以下中間物:
中間物5-2:(R)-4-(4-溴苯基)-3-(第三丁氧基羰基胺基)丁酸苯甲酯
在氮氣下在室溫下,向(R)-4-(4-溴苯基)-3-(第三丁氧基羰基胺基)丁酸(5.02g,14.01 mmo1)及NaHCO3(3.53g,
42.0mmo1)於DMF(20mL)中之懸浮液中添加苯甲基溴(5.10 mL,42mmo1)。攪拌46小時後,用H2O(200 mL)稀釋反應,隨後收集沈澱之固體且依次用H2
O(500mL)及庚烷(200m1)洗滌,得到(R)-4-(4-溴苯基)-3-(第三丁氧基羰基胺基)丁酸苯甲酯(5.61g,89%)。HPLC滯留時間=1.56分鐘(條件B);MS(ES+)=392.1(m-tBu+2);348.1(m-Boc+2;100%);1H NMR(400 MHz,氯仿-d)δppm1.39(s,9H)2.48(ABX之 A,Jab=15.9Hz,Jax=5.6Hz,1H)2.54(ABX 之B,Jab=15.9Hz,Jbx=5.3Hz,1H)2.72-2.88(m,2H)4.11(brs,1H)5.02(brs,1H)5.10(AB之 A,J=12.1Hz,1H)5.16(AB之A,J=12.1Hz,1H)7.00(d,J=8.1Hz,2H)7.34-7.39(m,7H)。中間物6:(R)-3-(聯苯-4-基甲基)-4-(3-甲氧基-3-側氧基丙基胺基)-4-側氧基丁酸
在室溫下,向(R)-3-(聯苯-4-基甲基)-4-(3-甲氧基-3-
側氧基丙基胺基)-4-側氧基丁酸第三丁酯(40mg,0.094mmo1)於DCM(0.5mL)中之溶液中添加TFA(0.15mL)。攪拌混合物2小時,隨後在減壓下濃縮,得到(R)-3-(聯苯-4-基甲基)-4-(3-甲氧基-3-側氧基丙基胺基)-4-側氧基丁酸(33.5mg,
96%)。HPLC滯留時間=1.20分鐘(條件A);MS(m+1)=370.1;1H NMR(400MHz,氯仿-d)δppm2.21-
2.29(m,1H)2.38-2.45(m,1H)2.62-2.66(m,1H)2.75-3.00(m,4H)3.29-3.37(m,1H)3.45-3.53(m,4H)6.12(brs,1H)7.23(d,J=8Hz,2H)7.32-7.35(m,1H)7.41-7.45(m,2H)7.53(d,J=8.1Hz,2H)7.56-7.59(m,2H)。中間物7:(R)-3-(聯苯-4-基甲基)-4-(3-甲氧基-3-
側氧基丙基胺基)-4-側氧基丁酸第三丁酯
在氮氣下在室溫下,攪拌(R)-2-(聯苯-4-基甲基)-4-第三丁氧基-4-側氧基丁酸(142mg,0.417mmo1)、3-胺基-
丙酸甲酯鹽酸鹽(76mg,0.542mmo1)、WSC鹽酸鹽(120 mg,0.626mmo1)、1-羥基-7-氮雜苯并三唑(85mg,0.626mmo1)及DIPEA(0.219m1,1.251 mmo1)於DMF(4mL)中之溶液13小時。用H2
O淬滅反應。用乙酸乙酯萃取產物,依次用1MHC1水溶液及鹽水洗滌,經Na2
SO4
乾燥,過濾且在減壓下濃縮。藉由用12g矽膠進行急驟管柱層析(庚烷/EtOAc=70:30至0:100)純化所獲得之殘餘物,得到(R)-3-(聯苯-4-基甲基)-4-(3-甲氧基-3-側氧基丙基胺基)-4-側氧基丁酸第三丁酯(164mg,91%)。HPLC滯留時間=1.59分鐘(條件A);MS(ES+)=425.4(m);369.4(m-tBu+1;100%);1HNMR(400MHz,氯仿-d)δppm2.24-2.44(m,2H)2.67-2.79(m,3H)2.89-2.96(m,1H)3.28-3.36(m,1H)3.45-3.53(m,1H)7.23(d,J=5.8Hz,2H)7.33(t,J=7.35Hz,1H)7.41-7.44(m,2H)7.51(d,J=8.1Hz,2H)7.58(d,J=7.4Hz,2H)。使用類似於中間物7中所述之程序製備以下中間物:
中間物8:
(R)-3-[(1-苯甲基-1H-四唑-5-羰基)-胺基]-4-聯苯-4-基-丁酸乙酯及(R)-3-[(2-苯甲基-2H-四唑-5-羰基)-
胺基]-4-聯苯-4-
基-
丁酸乙酯
用4MHC1之二烷溶液(2mL)處理(R)-4-(聯苯-4-基)-3-(第三丁氧基羰基胺基)丁酸乙酯(117mg,0.305mmo1)。攪拌0.5小時後,在減壓下濃縮反應混合物。向所獲得之殘餘物及Et3N(0.106mL,0.763mmo1)於DCM(3mL)中之溶液中添加苯甲基-H-四坐-5-甲醯氯(1-及2-苯甲基異構體之混合物,82mg,0.366mmo1,根據J. Med.Chem.1986,29,538-549製備)。攪拌10分鐘後,添加Et3
N(0.106mL,0.763mmo1)及酸氯化物(82mg,0.366mmo1)。攪拌0.5小時後,用乙酸乙酯稀釋反應混合物,用H2
O及鹽水洗滌,經Na2SO4乾燥,且在減壓下濃縮。利用矽膠管柱層析純化殘餘物,得到(R)-3-[(1-苯甲基-1H-四坐-5-羰基)-胺基]-4-聯苯-4-基-丁酸乙酯及(R)-3-[(2-苯甲基-2H-四坐-5-羰基)-胺基]-4-聯苯-4-基-丁酸乙酯。HPLC滯留時間=1.51分鐘(條件D);MS=470.0(m+1);1HNMR(400MHz,CDC13
)δppm1.27(t,J=7.07,7.07Hz,3H),2.57-2.70(m,2H),3.00(dd,J=7.58,13.77Hz,1H),3.12(dd,J=6.57,13.77Hz,1H),4.12-4.23(m,2H),4.71-4.80(m,1H),5.80(s,2H),7.27-7.45(m,9H),7.52(d,J=8.34Hz,2H),7.56(d,J=8.46Hz,2H),7.75(d,J=7.33Hz,1H)。中間物9:(R)-4-聯苯-4-基-3-{3-[1-(2-氰基-乙基)-1H-四唑-5-基]-丙醯基胺基}-丁酸乙酯
在室溫下向(R)-4-聯苯-4-基-3-第三丁氧基羰基胺基-丁酸乙酯(400 mg,1.04mno1)於DCM(10 mL)中之溶液中添加TFA(2.009mL,26.1 mmo1),且在室溫下攪拌混合物1小時。在減壓下濃縮混合物。在冰浴溫度下,相繼向所獲得三氟乙酸鹽之DCM溶液(10mL)中添加丁二酸酐(125mg,1.25mmo1)及TEA(0.363mL,2.61mmo1)。在室溫下攪拌反應16小時。在減壓下濃縮混合物。利用急驟層析(矽膠,2%至5%EtOH/DCM)純化所獲得之殘餘物,得到(R)-4-聯苯-4-基-3-(3-羧基-丙醯基胺基)-丁酸乙酯(200mg)。HPLC滯留時間=1.53分鐘(條件C);MS=384(m+1)。
接著,在室溫下,向(R)-4-聯苯-4-基-3-(3-羧基-丙醯基胺基)-丁酸乙酯(200mg,0.522mmo1)於THF(10 mL)中之溶液中添加EDC HC1(120 mg,0.626mmo1)及HOBT(96mg,
0.626mmo1)。在室溫下攪拌反應10分鐘,隨後添加3-胺基丙腈(0.046m1,0.626mmo1)及TEA(0.087m1,0.626mmo1)。1小時後,添加0.5當量EDC HC1、HOBT及3-胺基丙腈,且攪拌16小時。用鹽水淬滅反應混合物,且用乙酸乙酯萃取。用鹽水洗滌合併之有機層,且經無水硫酸鈉乾燥,過濾且在減壓下濃縮。利用急驟層析(矽膠,2%至5%EtOH/DCM)純化所獲得之殘餘物,得到(R)-4-聯苯-4-基-3-[3-(2-氰基-乙基胺甲醯基)-丙醯基胺基]-丁酸乙酯(218mg,產率96%)。HPLC滯留時間=0.77分鐘(條件E);MS=436(m+1)。
接著,在室溫下向(R)-4-聯苯-4-基-3-[3-(2-氰基-
乙基胺甲醯基)-丙醯基胺基]-丁酸乙酯(204mg,0.468mmo1)於THF(10mL)中之溶液中添加Ph3
P(307mg,1.17mmo1),且在室溫下攪拌混合物10分鐘。隨後,在冰浴溫度下,向混合物中添加DIAD(0.228m1,1.171 mmo1)及三甲基矽烷基疊氮化物(0.155m1,1.171mmo1)。使所得混合物緩慢升溫至室溫,且攪拌16小時。在減壓下濃縮反應混合物。利用急驟層析(矽膠,1%至3%EtOH/DCM)純化所獲得之殘餘物,得到(R)-4-聯苯-4-基-3-{3-[1-(2-氰基-乙基)-1H-四坐-
5-基]-丙醯基胺基}-丁酸乙酯(137mg,產率64%)。HPLC滯留時間=1.61分鐘(條件C);MS=461(m+1)。中間物10:(R)-2-(聯苯-4-基甲基)-4-第三丁氧基-
4-
側氧基丁酸
在0℃下,歷經5分鐘,向(R)-4-((S)-4-苯甲基-2-側氧基坐啶-3-基)-3-(聯苯-4-基甲基)-4-側氧基丁酸第三丁酯(1.20g,2.402mmo1)於THF(20mL)與水(5mL)之混合溶劑中之攪拌溶液中添加H2
O2
水溶液(0.960mL,9.61mmo1)及LiOH水溶液(4.80 m1,4.80 mmo1)之溶液。攪拌1.5小時後,在0℃下用飽和Na2
SO3
水溶液(10mL)淬滅反應,且在相同溫度下攪拌10分鐘。在攪拌下使反應混合物溫至周圍溫度後維持0.5小時。隨後,向混合物中添加飽和NaHCO3
水溶液及鹽水。用乙酸乙酯萃取產物,用1MHC1水溶液洗滌,經MgSO4
乾燥,過濾且在減壓下濃縮。藉由用120g矽膠進行急驟管柱層析(庚烷/EtOAc=75:25至0:100)純化所獲得之殘餘物,得到(R)-2-(聯苯-4-基甲基)-4-第三丁氧基-4-側氧基丁酸(765mg,93%)。HPLC滯留時間=1.63分鐘(條件D);MS=338.6(m-1);1HNMR(400MHz,氯仿-d)δppm 1.43(s,9H)2.41(ABX 之 A,Jab=16.67Hz,Jax=4.55Hz,1H)2.52-2.67(ABX 之 B,Jab=16.75Hz,Jbx=8.45Hz,1H)2.74-2.89(m,1H)3.06-3.22(m,2H)7.22-7.29(m,2H)7.30-7.37(m,1H)7.43(t,J=7.58Hz,2H)7.53(d,J=8.1Hz,2H)7.57(d,J=7,8Hz,2H)。中間物11:合成(R)-4-((S)-4-苯甲基-2-側氧基噁唑啶-3-基)-3-(聯苯-4-基甲基)-4-側氧基丁酸第三丁酯
冷卻(S)-4-苯甲基-3-(3-(聯苯-4-基)丙醯基)坐啶-
2-
酮(中間物12:5.01g,13.00mmo1)於THF(180mL)中之攪拌溶液至-73.8℃,並歷經5分鐘添加1M六甲基二矽烷基胺基鈉之THF溶液(14.30mL,14.30mmo1)。30分鐘後,歷經5分鐘,
逐滴添加溴乙酸第三丁酯(2.495mL,16.90mmo1)於THF(20mL)中之溶液。在-74℃下攪拌溶液1小時,且用飽和NH4
C1水溶液(100mL)淬滅反應,且升溫至周圍溫度。濾出沈澱之固體,且用乙酸乙酯(50mL)洗滌。分離有機相,用鹽水洗滌,經MgSO4
乾燥,且在減壓下濃縮。將所獲得之殘餘物懸浮於MeOH(70mL)中,並隨後過濾以收集呈所要產物與起始物質之混合物形式之固體(5.9g)。藉由用120g矽膠進行急驟管柱層析(庚烷/EtOAc
=90:
10至50:50)純化混合物,得到(R)-4-((S)-4-苯甲基-2-側氧基坐-3-基)-3-(聯苯-4-基甲基)-4-側氧基丁酸第三丁酯(2.40g,
37%)。HPLC滯留時間=1.74分鐘(條件B);MS=499.4(m+);443.4(m-tBu+1;100%);1H NMR(400MHz,氯仿-
d)δppm1.41(s,9H)2.42(dd,J=16.67,4.04Hz,1H)2.71(ddd,J=16.55,13.26,9.60Hz,2H)2.87(dd,J=16.93,10.86Hz,1H)3.04(dd,J=13.14,6.32Hz,1H)3.32(dd,J=13.39,3.03Hz,1H)3.92(t,J=8.34Hz,1H)4.07(dd,J=8.97,2.15Hz,1H)4.48-4.58(m,2H)7.20-7.30(m,3H)7.30-7.36(m,5H)7.42(t,J=7.58Hz,2H)7.52(d,J=8.1Hz,2H)7.56(d,J=7.8Hz,2H)。中間物12:(S)-4-苯甲基-3-(3-(聯苯-4-基)丙醯基)噁唑啶-2-酮
在氮氣下在-71.6℃下,經10分鐘向1.6Mn-BuLi之己烷溶液(12.1mL,19.3mmo1)中逐滴添加(S)-()-4-苯甲基-2-坐酮(3.26g,18.4mmo1)於無水THF(80mL)中之溶液。在添加的同時使溶液升溫至-60.5℃,且在乾冰/MeOH浴中攪拌1小時。在-72℃下,經5分鐘逐滴添加3-(聯苯-4-基)丙醯氯(中間物13:5.46g,22.31mmo1)之無水THF(20mL)溶液。在添加的同時,使溶液升溫至-56.5℃。在相同溫度下攪拌10分鐘後,使反應混合物升溫至室溫且繼續攪拌3小時。過濾反應混合物,且依次用20mL(10mL×2)MeOH及150mLH2
O洗滌收集之沈澱,得到所要產物(4.26g)。用乙酸乙酯萃取母液中之產物,用鹽水洗滌,經MgSO4
乾燥,過濾且在減壓下濃縮。將所獲得之殘餘物懸浮於80mLMeOH中,且過濾懸浮液並用20mLMeOH(1.79g)洗滌。
混合該兩個部分,得到(S)-4-苯甲基-3-(3-(聯苯-
4-基)丙醯基)坐-2-酮(6.05g,經兩個步驟為85%)。滯留時間=1.77分鐘(條件A);MS(m+1)=387.3;1HNMR(400 MHz,氯仿-d)δppm2.77(dd,J=13.39,9.35Hz,1H)2.99-3.15(m,2H)3.20-3.43(m,3H)4.09-4.24(m,2H),4.68(dddd,J=9.76,6.73,3.47,3.28Hz,1H)7.18(d,J=7.07Hz,2H)7.23-7.37(m,6H)7.42(t,J=7.58Hz,2H)7.53(d,J=8.1Hz,2H),7.57(d,J=7.8Hz,2H)。中間物13:3-(聯苯-4-基)丙醯氯
在氮氣下在85℃下,使3-(4-聯苯基)丙酸(5g,22.10mmo1)與SOC12
(4.03m1,55.2mmo1)之混合物回流1.5小時。在減壓下濃縮反應混合物,得到3-(聯苯-4-基)丙醯氯(5.46g)。該物質不經進一步純化即用於下一步驟中。中間物14:(2R,4R)-4-胺基-2-甲基-戊酸乙酯三氟乙酸鹽
向2-(三苯基伸磷烷基)-丙酸乙酯(3.11g,8.57mmo1)於二氯甲烷(20mL)中之攪拌溶液中添加3,3-二甲基-N-((R)-1-甲基-2-側氧基-乙基)-丁醯胺(J.Med.Chem.41,6(1998))(1.35g,7.79mmo1)於二氯甲烷(20mL)中之溶液,且在室溫下攪拌混合物2小時。在減壓下移除溶劑,且利用管柱層析使用10-50%庚烷/EtOAc之梯度純化殘餘物,得到(E)-(R)-4-第三丁氧基羰基胺基-2-甲基-戊-2-烯酸乙酯。1
H-NMR(400MHz,CDC13
)δppm1.22(d,J=6.44Hz,3H),1.30(t,3H),1.43(s,9H),1.91(s,3H),4.19(q,2H),6.51(d,寬峰,J=7.45Hz,1H)。
接著,在1atm下經10%Pt/C(183mg)氫化(E)-(R)-4-第三丁氧基羰基胺基-2-甲基-戊-2-烯酸乙酯(1.83g,7.11mmo1)於乙酸乙酯(75mL)中之溶液18小時。經由矽藻土過濾催化劑,且在減壓下移除溶劑。利用對掌性HPLC純化殘餘物,得到(2R,4R)-4-第三丁氧基羰基胺基-2-甲基-戊酸乙酯,1
H-NMR(400MHz,CDC13
)δppm1.13(t,3H),1.18(m,3H),1.26(t,3H),1.43(s,9H),1.81(s,1H),2.50(m,1H),3.72(m寬峰,1H),4.14(m,2H),4.33(m寬峰,1H)。接著,將(2R,4R)-4-第三丁氧基羰基胺基-2-甲基-戊酸乙酯(142mg,0.548mmo1)添加至三氟乙酸(5mL)中。10分鐘後,在減壓下移除溶劑。添加二氯甲烷,且在減壓下移除溶劑,得到(2R,4R)-4-胺基-2-甲基-戊酸乙酯三氟乙酸鹽。該物質直接用於後續偶合反應中。中間物15:2-聯苯-4-基甲基-丁二酸1-甲酯
向(三苯基伸磷烷基)-乙酸甲酯(2.26g,6.77mmo1)於二氯甲烷(25mL)中之溶液中添加溴乙酸第三丁酯(1.32g,6.77mmo1),且在室溫下攪拌混合物48小時。在減壓下移除溶劑,且利用管柱層析使用80-100%庚烷/EtOAc之梯度純化殘餘物,得到2-(三苯基伸磷烷基)-丁二酸4-第三丁酯1-甲酯。MS449.3(M+1)。接著,使2-(三苯基伸磷烷基)-丁二酸4-第三丁酯1-
甲酯(700 mg,1.561mmo1)與聯苯-4-甲醛(278mg,1.419mmo1)於甲苯(20mL)中之混合物回流4天。在減壓下移除溶劑,且利用管柱層析使用0-30%庚烷/EtOAc之梯度純化殘餘物,得到呈油狀之2-[1-聯苯-4-基-甲-(Z)-次基]-
丁二酸4-第三丁酯1-甲酯,1
H-NMR(400 MHz,CDC13
)δppm1.47(s,9H),3.52(s,2H),3.84(s,3H),7.37(t,1H),7.46(t,4H),7.62(t,4H),7.89(s,1H)。在1atm下經Pt/C(40 mg)氫化2-[1-聯苯-4-基-甲-(Z)-次基]-丁二酸4-第三丁酯1-甲酯(410mg,1.163mmo1)於乙酸乙酯(20mL)中之溶液18小時。經由矽藻土過濾催化劑,且在減壓下移除溶劑,得到2-聯苯-4-基甲基-丁二酸4-
第三丁酯1-甲酯。利用對掌性HPLC分離對映異構體。接著,將2-聯苯-4-基甲基-丁二酸4-第三丁酯1-甲酯(160mg,
0.451mmo1)添加至三氟乙酸(5mL)中。10分鐘後,在減壓下移除溶劑。添加二氯甲烷,且在減壓下移除溶劑,得到2-聯苯-4-基甲基-丁二酸1-甲酯。該物質直接用於後續偶合反應中。中間物16-1:合成(R)-3-胺基-4-(3'
-氯聯苯-4-基)丁酸乙酯鹽酸鹽
在室溫下,向(R)-3-(第三丁氧基羰基胺基)-4-(3'
-氯聯苯-4-基)丁酸乙酯(3.33g,7.97mmo1)中添加4MHC1於1,4-二烷中之溶液(19.9mL,18.0mmo1)。攪拌0.5小時後,在減壓下濃縮反應混合物,得到(R)-3-胺基-4-(3'
-氯聯苯-4-基)丁酸乙酯鹽酸鹽(2.90g)。HPLC滯留時間=0.70分鐘(條件B);MS(m+1)=318.26;1HNMR(400MHz,氯仿-d)δppm1.19-1.24(m,3H)2.73-2.78(m,1H)2.84-2.91(m,1H)3.05-3.11(m,1H)3.50-3.54(m,1H)3.92(brs,1H)4.14-4.17(m,2H)7.29-7.53(m,8H)8.73(br.s.,3H)。使用類似於關於中間物16-1所述之程序製備以下中間物:
中間物16-7:(R)-3-胺基-4-(3'
-氯聯苯-4-基)丁酸苯甲酯鹽酸鹽
在室溫下,向(R)-3-(第三丁氧基羰基胺基)-4-(3'
-氯聯苯-4-基)丁酸苯甲酯(3.561g,7.42mmo1)中添加4MHC1於1,4-二烷中之溶液(18.55mL,74.2mmo1)。攪拌4小時後,在減壓下濃縮反應混合物,得到(R)-3-胺基-4-(3'
-氯聯苯-4-基)丁酸苯甲酯鹽酸鹽(3.11g)。HPLC滯留時間=1.07分鐘(條件B);MS(m+1)=380.1;1HNMR(400MHz,氯仿-d)δppm2.81(ABX 之 A,Jab
=17.4Hz,Jx
=4.5Hz,1H)2.93(ABX 之 B,Jab
=17.4Hz,Jbx=7.6Hz,1H)3.03-3.09(m,1H)3.50(dd,J=4.9及13.5Hz,1H)3.98(brs,1H)5.09(s,2H)7.24-7.22(m,9H)7.35-7.38(m,1H)7.42(d,J=8.1Hz,2H)7.48-7.49(m,1H)8.78(brs,3H)。中間物17-1:合成(R)-3-(第三丁氧基羰基胺基)-4-(3'
-氯聯苯-4-基)丁酸乙酯
在氮氣下在95℃下,攪拌(R)-4-(4-溴苯基)-3-(第三丁氧基羰基胺基)丁酸乙酯(4.89g,12.66mmo1)、3-氯苯基朋酸(2.97g,
18.99mmo1)、Pd(PPh3
)4
(1.463g,1.266mmo1)及2MNa2CO3水溶液(12.66m1,25.3mmo1)於1,2-二甲氧基乙烷(100m1)中之混合物3小時。冷卻反應混合物至室溫,
且用鹽水淬滅。分離兩個相。用乙酸乙酯自水層萃取混合物兩次。用鹽水洗滌合併之有機層,經MgSO4
乾燥,過濾且在減壓下濃縮。利用矽膠急驟管柱層析(庚烷/EtOAc=
100:0至70:30)純化所獲得之殘餘物,得到(R)-3-
(第三丁氧基羰基胺基)-4-(3'
-氯聯苯-4-基)丁酸乙酯(3.33g);HPLC滯留時間=1.44分鐘(條件B);MS(ES+)=318.26(m-BOC+2;100%);1H NMR(400 MHz,氯仿-d)δppm1.28(t,J=7.2Hz,3H)1.41(s,9H)2.47(ABX之A,Jab=15.8Hz,Jax
=5.9Hz,1H)2.52(ABX 之 B,Jab
=15.8Hz,Jbx=5.4Hz,1H)2.83-2.89(m,1H)2.95-3.00(m,1H)4.17(q,J=7.2Hz,2H)4.18(brs,1H)5.07(brs,1H)7.26-7.37(m,4H)7.43-7.51(m,3H)7.55(brt,J=1.8Hz,1H)。使用類似於關於中間物17-1所述之程序製備以下中間物:
中間物17-2:(R)-3-(第三丁氧基羰基胺基)-4-(3'
-氯聯苯-4-基)丁酸苯甲酯
在氮氣下在95℃下,攪拌(R)-4-(4-溴苯基)-3-(第三丁氧基羰基胺基)丁酸苯甲酯(2.00g,4.46mmo1)、3-氯苯基朋酸(1.046g,6.69mmo1)、Pd(PPh3
)4
(0.515g,0.446mmo1)及Na2CO3水溶液(4.46m1,8,92mmo1)於甲苯(30 m1)中之懸浮液19小時。冷卻反應混合物至周圍溫度,且用鹽水及EtOAc稀釋。用 EtOAc萃取產物兩次,用鹽水洗滌,經MgSO4乾燥,過濾且濃縮。藉由用90g矽膠進行急驟管柱層析(溶離劑:庚烷/EtOAc=100:0至65:35)純化殘餘物,得到(R)-3-(第三丁氧基羰基胺基)-4-(3'
-氯聯苯-4-基)丁酸苯甲酯(1.03g);HPLC滯留時間=1.74分鐘(條件B);MS(ES+)=380.2(m-BOC+2;100%);1H NMR(400 MHz,氯仿-d)δppm1.40(s,9H)2.52(ABX之A,Jab
=15.9Hz,Jax=5.8Hz,1H)2.58(ABX 之 B,Jab
=15.9Hz,Jbx
=5.6Hz,1H)2.81-2.98(m,2H)4.19(brs,1H)5.07(brd,1H)5.12(AB之A,J=12.3Hz,1H)5.17(AB之A,J=12.3Hz,1H)7.20-7.22(m,2H)7.28-7.39(m,7H)7.42-7.47(m,3H)7.53-7.54(m,1H)。中間物18:合成(S)-1-(2-第三丁氧基-2-側氧基乙基)比咯啶-2-甲酸苯甲酯
向(S)-比咯啶-2-甲酸苯甲酯鹽酸鹽(700mg,2.90mmo1)及K2
CO3
(1201mg,8.69mmo1)於DMF(7m1)中之懸浮液中添加溴乙酸第三丁酯(0.535m1,3.62mmo1)。攪拌71小時後,向反應混合物中添加K2
CO3
水溶液(1.5gK2
CO3/40m1H2
O)。用EtOAc萃取產物。有機層用水洗滌兩次且用鹽水洗滌一次,經K2
CO3
乾燥,過濾且濃縮,得到(S)-1-(2-第三丁氧基-2-側氧基乙基)比咯-2-甲酸苯甲酯(458mg);HPLC滯留時間=1.38分鐘(條件D);MS(m+1)=320.2;1HNMR(400MHz,氯仿-d)δppm1.44(s,9H)1.81-2.03(m,3H)2.13-2.14(m,1H)2.82-2.88(m,1H)3.13-3.17(m,1H)3.46(AB之A,J=17.3Hz,1H)3.49(AB之B,J=17.3Hz,1H)3.73(dd,J=8.8及4.8Hz,1H)5.15(AB之 A,J=12.4Hz,1H)5.17(AB之B,J=12.4Hz,1H)7.29-7.38(m,5H)。
中間物19:合成(R)-3-(第三丁氧基羰基胺基)-4-(2'
,5'
-二氯聯苯-4-基)丁酸乙酯
在氮氣下在95℃下,攪拌(R)-4-(4-溴苯基)-3-(第三丁氧基羰基胺基)丁酸乙酯(1.005g,2.60mmo1)、2,5-
二氯苯基酸(0.745g,3.90 mmo1)、Pd(PPh3
)4
(0.301g,0.260mmo1)及2M Na2CO3水溶液(2.60m1,5.20mmo1)於1,2-二甲氧基乙烷(20m1)中之混合物3小時。冷卻反應混合物至室溫,
且用鹽水稀釋。分離兩個相。用乙酸乙酯(2×100m1)自水層中萃取產物兩次。用鹽水洗滌合併之有機層,經MgSO4乾燥,過濾且在減壓下濃縮。利用矽膠急驟管柱層析(庚烷/EtOAc=100:0至70:30)純化所獲得之殘餘物,得到(R)-3-(第三丁氧基羰基胺基)-4-(2'
,5'
-二氯聯苯-4-基)丁酸乙酯(1.09g);HPLC滯留時間=1.50分鐘(條件B);MS(ES+)=352.00(m-BOC+2;100%);1H NMR(400 MHz,氯仿-d)δppm1.28(t,J=7.1Hz,3H)1.41(s,9H)2.45-2.58(m,2H)2.85-3.00(m,2H)4.17(t,J=7.1Hz,2H)4.20(brs,1H)5.06-5.08(m,1H)7.23-7.28(m,3H)7.31-7.40(m,4H)。中間物20:合成(R)-3-胺基-4-(3'
-氯聯苯-4-基)丁酸鹽酸鹽
攪拌(R)-3-(第三丁氧基羰基胺基)-4-(3'
-氯聯苯-4-基)丁酸苯甲酯(152mg,0.317mmo1)及1M NaOH水溶液(1.583m1,
1.583mmo1)於MeOH(0.3m1)與THF(3m1)之混合溶劑中之溶液2小時。用1MHC1水溶液(2.5m1)淬滅反應。用EtOAc萃取產物。經Na2
SO4
乾燥有機層,過濾且濃縮,得到粗產物。向粗產物中添加4MHC1於1,4-二烷中之溶液(1.583m1,6.33mmo1)。攪拌1小時後,收集沈澱之固體,且在減壓下乾燥,得到呈白色固體狀之(R)-3-胺基-4-(3'
-氯聯苯-4-基)丁酸鹽酸鹽(60.2mg);HPLC滯留時間=
0.52分鐘(條件B);MS(m+1)=290.22;1HNMR(400MHz,CD3OD)δppm2.58-2.74(m,2H)2.99-3.11(m,2H)3.80-3.85(m,1H)7.34-7.45(m,4H)7.54-7.57(m,1H)7.62-7.65(m,3H)。
中間物21:合成1-(2-(苯甲氧基)-2-側氧基乙基)環戊烷甲酸與2-(1-(苯甲氧基羰基)環戊基)乙酸之混合物
在100℃下攪拌2-氧雜螺[4.4]壬烷-1,3-二酮(3g,19.46mmo1)及苯甲醇(2.023m1,19.46mmo1)於甲苯(2m1)中之溶液19小時。冷卻反應混合物至周圍溫度且濃縮,得到1-(2-(苯甲氧基)-2-側氧基乙基)環戊烷甲酸與2-(1-(苯甲氧基羰基)環戊基)乙酸之6:1混合物(4.89g);1HNMR(400MHz,氯仿-d)δppm1.60-1.78(m,6H)2.19-2.24(m,2H)2.75(s,2H)5.11(s,2H,主要異構體)5.13(s,2H,次要異構體)7.30-7.37(m,5H)。
中間物22:
合成4-(聯苯-4-基)-3-(第三丁氧基羰基胺基)丁酸第三丁酯
在氮氣下在室溫下,攪拌4-(聯苯-4-基)-3-(第三丁氧基羰基胺基)丁酸(250 mg,0.703mmo1)、tBuOH(0.135m1,1.407mmo1)、EDCI(270mg,1.407mmo1)及4-二甲基胺基比(86.0 mg,0.704mmo1)於DCM(7m1)中之溶液62小時。用水淬滅反應,且分離有機層並濃縮。利用矽膠急驟管柱層析純化殘餘物,得到4-(聯苯-4-基)-3-(第三丁氧基羰基胺基)丁酸第三丁酯(110mg);HPLC滯留時間=1.77分鐘(條件B);MS(ES+)=412.1(m+1)300.0(m-tBux2+3;100%);1H NMR(400MHz,氯仿-d)δppm1.41(s,9H)1.47(s,9H)2.36(ABX 之 A,Ja
b=15.5Hz,Ja
x=6.2Hz,1H)2.44(ABX 之 B,Ja
b=15.5Hz,Jb
x=5.6Hz)2.82-2.94(m,2H)4.11-4.17(m,1H)5.08-5.10(m,1H)7.25-7.34(m,3H)7.41-7.44(m,2H)7.51-7.58(m,4H)。中間物23:合成3-胺基-4-(3'
-氯-3-氟聯苯-4-基)丁酸乙酯
在氮氣下在70℃下加熱鋅(479mg,7.33mmo1)及1,2-二溴乙烷(0.032m1,0.366mmo1)於THF(8m1)中之懸浮液,隨後添加數滴溴乙酸乙酯。攪拌20分鐘後,一次性添加2-(3'
-氯-3-氟聯苯-4-基)乙腈(300 mg,1.221mmo1)於THF(2m1)中之溶液。經50分鐘逐滴添加其餘溴乙酸酯(溴乙酸乙酯之總量為4.88mmo1)。在相同溫度下攪拌15分鐘後,冷卻反應混合物至周圍溫度。向反應混合物中添加三乙醯氧基硼氫化鈉(2588mg,12.22mmo1)及AcOH(8m1)。攪拌反應混合物13小時且濃縮,得到粗產物。用EtOAc稀釋粗產物,且添加2M Na2
CO3
水溶液直至pH值為10。用EtOAc萃取產物。經K2
CO3
乾燥有機層,過濾且濃縮,得到粗產物。利用製備型HPLC使用20%MeCN/水(0.1%NH4
OH)至100%MeCN之梯度純化所得殘餘物,得到呈橙色油狀之3-胺基-4-(3'
-氯-3-氟聯苯-4-基)丁酸乙酯(148mg);HPLC滯留時間=0.85分鐘(條件B);MS(m+1)=336.13;1HNMR(400 MHz,氯仿-d)δppm1.27(t,J=7.1Hz,3H)2.36(ABX之 A,Jab
=15.9Hz,Jax
=8.8Hz,1H)2.52(ABX之B,Ja
b=15.9Hz,Jbx
=4.0 Hz,1H)2.71-2.76(m,1H)2.82-2.87(m,1H)3.51-3.57(m,1H)4.15(d,J=7.1Hz,2H)7.24-7.39(m,5H)7.42-7.44(m,1H)7.54-7.55(m,1H)。中間物24:合成2-(3'
-氯-3-氟聯苯-4-基)乙腈
在氮氣下在70℃下,攪拌氰化4-溴-2-氟苯甲烷(3.50g,16.35mmo1)、3-氯苯朋酸(2.68g,17.17mmo1)、Pd(OAc)2(0.110g,0.491 mmo1)、K2
CO3
(5.65g,40.9mmo1)及溴化四丁基銨(5.80g,17.99mmo1)於水(14m1)中之懸浮液1小時。冷卻反應混合物至室溫,且用EtOAc
稀釋。分離兩個相。用鹽水洗滌有機層,經MgSO4
乾燥,過濾且濃縮。利用矽膠急驟管柱層析(庚烷/EtOAc
=100:
0至70:30)純化所獲得之殘餘物,得到2-(3'
-氯-3-氟聯苯-4-基)乙腈(3.52g);HPLC滯留時間=1.17分鐘(條件B);1HNMR(400MHz,氯仿-d)δppm3.81(s,2H)7.29-7.45(m,5H)7.50-7.55(m,2H)。中間物25:(R)-4-(1-(4-溴苯基)-4-乙氧基-4-側氧基丁-
2-
基胺基)-4-側氧基丁酸第三丁酯
向4-第三丁氧基-4-側氧基丁酸(2.38g,13.64mmo1)於DMF(30mL)及DCM(30mL)中之溶液中添加(R)-3-胺基-4-(4-溴苯基)丁酸乙酉鹽酸鹽(4g,12.4mmo1)、HATU(5.19g,
13.64mmo1)及TEA(6.91mL,49.6mmo1)。在室溫下攪拌2小時後,用H2
O淬滅反應,且用EtOAc稀釋粗產物,用鹽水洗滌有機層,經Na2
SO4
乾燥,過濾且在減壓下濃縮,得到(R)-4-(1-(4-溴苯基)-4-乙氧基-4-側氧基丁-2-基胺基)-4-
側氧基丁酸第三丁酯(4.0g)。HPLC滯留時間=1.70分鐘(條件A);MS(m+1)=444.1。
中間物26:(R)-3-胺基-4-(5'
-氟-2'
-甲氧基-聯苯-4-基)-丁酸乙酯鹽酸鹽
向(R)-4-(4-溴苯基)-3-(第三丁氧基羰基胺基)丁酸乙酯(3.12g,8.08mmo1)及5-氟-2-甲氧基苯基朋酸(2.2g,
12.93mmo1)於甲苯(52mL)中之溶液中添加PdC12(dppf).CH2C12加合物(0.66g,0.81mmo1)及2M Na2CO3水溶液(8.1mL,
16.16mmo1)。在氮氣下在95℃下攪拌4小時後,冷卻溶液至周圍溫度,隨後用冰水淬滅。用乙酸乙酯稀釋粗產物。用鹽水洗滌有機層,經Na2
SO4
乾燥,過濾且在減壓下濃縮。利用矽膠急驟管柱層析(溶離劑:庚烷/EtOAc=
100:0至50:
50)純化所獲得之殘餘物,得到(R)-3-(第三丁氧基羰基胺基)-4-(5'
-氟-2'
-甲氧基聯苯-4-基)丁酸乙酯(2.86g)。HPLC滯留時間=1.80分鐘(條件A);MS(m+1)=432.2;1HNMR(400MHz,氯仿-d)δppm1.31(t,J=7.1Hz,3H)1.45(s,9H)2.45-2.65(m,2H)2.83-2.94(m,1H)2.94-3.09(m,1H)3.80(s,3H)4.20(q,J=7.2Hz,2H)4.24-4.33(m,1H)5.11(br,s.,1H)6.90-6.96(m,1H)7.00(dd,J=7.8,3.3Hz,1H)7.06(dd,J=9.2,3.2Hz,1H)7.27(d,J=7.8Hz,2H)7.49(d,J=7.8Hz,2H)。
在室溫下攪拌(R)-3-(第三丁氧基羰基胺基)-4-(5'
-氟-2' -
甲氧基聯苯-4-基)丁酸乙酯(2.86g,6.62mmo1)於4MHC1之1,4-二烷溶液(33.1m1,132mmo1)中之溶液。攪拌1小時後,在減壓下濃縮反應混合物,得到(R)-3-胺基-4-(5'-
氟-2'
-甲氧基聯苯-4-基)丁酸乙酯鹽酸鹽(2.44g)。HPLC滯留時間=1.46分鐘(條件A);MS(m+1)=332.3;1HNMR(400MHz,氯仿-d)δppm1.15(t,J=6.4Hz,3H)2.66-2.77(m,1H)2.78-2.91(m,1H)2.94-3.10(m,1H)3.42-3.53(m,1H)3.67(s,3H)3.83-3.96(m,1H)4.07(q,J=6.8Hz,2H)6.77-6.84(m,1H)6.87-6.96(m,2H)7.23(d,J=7.1Hz,2H)7.38(d,J=7.1Hz,2H)8.64(br.s.,2H)。
中間物27:(R)-4-(3'
-氯聯苯-4-基)-3-(2-乙氧基-
2-
側氧基乙醯胺基)丁酸乙酯
在室溫下,向(R)-3-胺基-4-(3'
-氯聯苯-4-基)丁酸乙酯鹽酸鹽(500 mg,1.57mmo1)於DMF(11mL)中之溶液中添加TEA(0.23mL,1.65mmo1)及2-氯-2-側氧基乙酸乙酯(0.18mL,
1.57mmo1)。在室溫下攪拌1小時後,用H2
O淬滅反應,且用EtOAc稀釋粗產物。用鹽水洗滌有機層,經Na2SO4乾燥,過濾且在減壓下濃縮。利用矽膠急驟管柱層析(溶離劑:庚烷/EtOAc=70:30至50:50)純化所獲得之殘餘物,得到(R)-4-(3'
-氯聯苯-4-基)-3-(2-乙氧基-2-側氧基乙醯胺基)丁酸乙酯(550mg)。HPLC滯留時間=
1.88分鐘(條件A);MS(m+1)=418.3。
中間物28:(R)-4-(3'
-氯聯苯-4-基)-3-(2-肼基-2-側氧基乙醯胺基)丁酸乙酯
在-
20℃下,向(R)-4-(3'
-氯聯苯-4-基)-3-(2-乙氧基-2-側氧基乙醯胺基)丁酸乙酯(450 mg,1.08mmo1)於MeOH(24mL)中之溶液中添加50wt%肼(0.068m1,1.08mmo1)於MeOH(10mL)中之溶液。在室溫下攪拌18小時後,在減壓下濃縮反應混合物,得到(R)-4-(3'
-氯聯苯-4-基)-3-(2-肼基-
2-
側氧基乙醯胺基)丁酸乙酯(412mg)。HPLC滯留時間=
1.76分鐘(條件A);MS(m+1)=404.1。
中間物29:(R)-4-(3'
-氯聯苯-4-基)-3-(2-甲氧基噻唑-5-甲醯胺基)丁酸乙酯
向2-甲氧基噻坐-5-甲酸(80mg,0.50mmo1)及(R)-3-
胺基-4-(3'
-氯聯苯-4-基)丁酸乙酯鹽酸鹽(160mg,0.45mmo1)於DMF(5mL)中之溶液中添加HATU(207mg,0.55mmo1)及TEA(276mg,2.73mmo1)。在室溫下攪拌粗產物2小時。用1N HC1中和粗產物,且用水及EtOAc
稀釋。用鹽水洗滌有機層,經MgSO4
乾燥,過濾且濃縮。經由急驟層析使用30%EtOAc/庚烷至70%EtOAc/庚烷純化粗產物,得到(R)-4-(3'
-氯聯苯-4-基)-3-(2-甲氧基坐-5-甲醯胺基)丁酸乙酯(170mg)。HPLC滯留時間=1.97分鐘(條件D);MS(m+1)=459.1。1HNMR(400MHz,氯仿-d)δppm1.29(t,J=7.1Hz,3H)2.49-2.69(m,2H)2.93(dd,J=13.6,8,1Hz,1H)3.10(dd,J=13.5,6.2Hz,1H)4.09(s,3H)4.00-4.15(m,2H)4.53-4.69(m,1H)6.78(d,J=8.6Hz,1H)7.25-
7.32(m,3H)7.35(t,J=7.71Hz,1H)7.44(dt,J=7.6,1.5Hz,1H)7.48-7.54(m,3H)7.55(t,J=1.8Hz,1H)。
中間物30:(R)-4-(3'
-氯聯苯-4-基)-3-(2-甲氧基噁唑-
5-
甲醯胺基)丁酸乙酯
向2-甲氧基坐-5-甲酸、中間物16(98mg,0.69mmo1)及(R)-3-胺基-4-(3'
-氯聯苯-4-基)丁酸乙酯鹽酸鹽(210mg,0.57mmo1)於DMF(10mL)及CH2
C12
(4mL)中之溶液中添加HATU(272mg,0.72mmo1)及TEA(0.50mL,3.58mmo1)。在室溫下攪拌粗產物2小時。用水淬滅粗產物,且用EtOAc稀釋。用水(3X)、鹽水洗滌有機層,經MgSO4
乾燥,過濾且濃縮。經由急驟層析使用30%EtOAc/庚烷至70%EtOAc/庚烷純化粗產物,得到(R)-4-(3'
-氯聯苯-4-基)-3-(2-甲氧基坐-5-甲醯胺基)丁酸乙酯(122mg)。HPLC滯留時間=1.89分鐘(條件A);MS(m+1)=443.2;1HNMR(400MHz,氯仿-d)δppm1.28(t,J=7.1Hz,3H),2.52-2.66(m,2H),2.94(dd,1H),3.08(dd,J=13.6,6.3Hz,1H),4.12(s,3H),4.14-4.23(m,2H),4.60-4.71(m,1H),6.81(d,J=8.8Hz,1H),7.25-7.32(m,3H),7.35(t,J=7.7Hz,1H),7.42(s,1H),7.43-7.47(m,1H),7.48-7.54(m,2H),7.55(t,J=1.6Hz,1H)。
中間物31:6-(甲基磺醯胺基)菸鹼酸
向於冰浴中冷卻之6-胺基菸鹼酸甲酯(1.0g,6.57mmo1)於CH2
C12
(50mL)及TEA(0.96mL,6.90mmo1)中之溶液中緩慢添加MsC1(0.54mL,6.90 mmo1)。在室溫下攪拌粗產物2小時。隨後濃縮粗產物。將粗產物溶解於MeOH(20mL)中,且向粗產物中添加1NNaOH(30mL,30mmo1)。在室溫下攪拌粗產物18小時。用1NHC1(32mL,32mmo1)淬滅粗產物。濃縮粗產物以移除MeOH,且同時移除一些水。
用CH2C12稀釋粗產物,且用1N NaOH(30mL)鹼化。
用CH2C12萃取水層。用濃鹽酸酸化水層以使pH值經由pH試紙顯示為1。用EtOAc稀釋粗產物,且用EtOAc
萃取水層。用鹽水洗滌合併之有機層,經MgSO4
乾燥,過濾且濃縮,得到呈黃色固體狀之6-(甲基磺醯胺基)菸鹼酸(421mg)。HPLC滯留時間=0.40分鐘(條件D);MS(m+1)=217.2。
中間物32:2-甲氧基噁唑-5-甲酸
向2-氯坐-5-甲酸乙酯(510mg,2.90mmo1)於無水MeCN(10 mL)及無水MeOH(10 mL)中之溶液中添加NaOMe(628mg,11.62mmo1)。在回流下攪拌粗產物2小時。再向該粗產物中添加MeOH。再回流粗產物4小時。濃縮粗產物,且再溶解於MeOH(10mL)中。向該粗產物中添加1N NaOH(10m1)。在室溫下攪拌粗產物3小時。用濃鹽酸淬滅粗產物,調節pH值至經由pH試紙顯示為7。濃縮粗產物,且用水稀釋。用濃鹽酸酸化水層,且用EtOAc稀釋。用水、鹽水洗滌有機層,經MgSO4
乾燥,過濾且濃縮,得到2-甲氧基坐-5-甲酸(290mg)。HPLC滯留時間=0.58分鐘(條件D);MS(m+1)=144.0。
中間物33:5-側氧基-4,5-二氫-1,2,4-噁二唑-
3-
甲酸乙酯
在室溫下,向2-(羥基胺基)-2-亞胺基乙酸乙酯(2g,15.14mmo1)於二烷(15.00 mL)中之溶液中添加CDI(2.7g,16.65mmo1)及DBU(2.5m1,16.65mmo1)。在80℃下攪拌1小時後,用1N HC1淬滅反應,且用EtOAc稀釋粗產物。用鹽水洗滌有機層,經Na2
SO4
乾燥,過濾且在減壓下濃縮,得到5-側氧基-4,5-二氫-1,2,4-二坐-3-甲酸乙酯(2.4g)。HPLC滯留時間=0.72分鐘(條件D);MS159.1(M+1)。
中間物34:5-側氧基-4,5-二氫-1,2,4-噁二唑-3-甲酸
在室溫下,向粗產物5-側氧基-4,5-二氫-1,2,4-二坐-3-甲酸乙酯(2.4g,15.14mmo1)於MeOH(2mL)中之溶液中添加1N NaOH水溶液(4mL,4mmo1)。在室溫下攪拌5小時後,用1N HC1(5mL,5mmo1)淬滅反應,在減壓下濃縮粗產物以移除MeOH。用EtOAc稀釋粗產物,用鹽水洗滌有機層,經Na2
SO4
乾燥,過濾且在減壓下濃縮,得到5-側氧基-4,5-二氫-1,2,4-二坐-3-甲酸(1.9g)。
中間物35:2-側氧基-2,3-二氫噁唑-4-甲酸
根據Okonya,J.F.;Hoffman,R.V.;Johnson,M.C.;J.Org.Chem.2002,67,1102-1108製備該中間物。
中間物36:3-羥基異噻唑-5-甲酸
向3-羥基異坐-5-甲酸甲酯(300mg,1.73mmo1)於MeOH(2mL)中之溶液中添加1N NaOH(6mL,6mmo1)。在室溫下攪拌2小時後,在減壓下濃縮粗產物以移除MeOH,且用EtOAc稀釋。用鹽水洗滌有機層,經Na2
SO4
乾燥,過濾且在減壓下濃縮,得到3-羥基異坐-
5-
甲酸(250mg)。
中間物37:2-乙烯基噁唑-5-甲酸乙酯
在室溫下,向三丁基(乙烯基)錫烷(1.1mL,3.83mmo1)及2-氯坐-5-甲酸乙酯(546mg,3.11mmo1)於二烷(37mL)中之溶液中添加Pd(PPh3
)2
C12
(222mg,0.32mmo1)。在氮氣下在100℃下攪拌4小時後,冷卻溶液至周圍溫度,隨後用H2O淬滅。用EtOAc稀釋粗產物,用鹽水洗滌有機層,經Na2
SO4
乾燥,過濾且在減壓下濃縮。利用急驟管柱層析(溶離劑:庚烷/EtOAc=90:10至80:20)純化所獲得之殘餘物,得到2-乙烯基噁唑-5-甲酸乙酯(470 mg)。HPLC滯留時間=0.39分鐘(條件B);MS(m+1)=168.2;1H NMR(400 MHz,CD3
OD)δppm 1.38(t,J
=7.1 Hz,3H) 4.38(q,J
=7.2 Hz,2H) 5.88(d,J
=11.4 Hz,1H) 6.39(d,J
=17.7 Hz,1H) 6.69(dd,J
=17.6,11.2 Hz,1H) 7.83(s,1H)。
中間物38:2-乙基噁唑-5-甲酸乙酯
在室溫下,向2-乙烯基噁唑-5-甲酸乙酯(470 mg,2.81 mmol)於MeOH(7 mL)中之溶液中添加10 wt.% Pd/C(100 mg,0.094 mmol)。在氫氣球下在室溫下攪拌1小時後,過濾粗產物以移除Pd/C。收集濾液且濃縮,得到2-乙基噁唑-5-甲酸乙酯(470 mg)。HPLC滯留時間=1.09分鐘(條件A);MS(m+1)=170.3;1H NMR(400 MHz,CD3
OD)δppm 1.35(t,J=7.6 Hz,3H) 1.36(t,J=7.2 Hz,3H) 2.87(q,J
=7.7 Hz,2H) 4.35(q,J
=7.2 Hz,2H) 7.71(s,1H)。
中間物39:2-乙基噁唑-5-甲酸
向2-乙基噁唑-5-甲酸酯(470 mg,2.81 mmol)於MeOH(10 mL)中之溶液中添加1N NaOH(6 mL,6 mmol)。在室溫下攪拌18小時後,在減壓下濃縮粗產物以移除MeOH,且用EtOAc稀釋。用鹽水洗滌有機層,經Na2
SO4
乾燥,過濾且在減壓下濃縮,得到2-乙基噁唑-5-甲酸(244 mg)。1H NMR(400 MHz,CD3
OD)δppm 1.36(t,J
=7.7 Hz,3H) 2.89(q,J
=7.6 Hz,2H) 5.15(br.s .,1H) 7.69(s,1H)。
中間物40:2-乙烯基噻唑-5-甲酸乙酯
在室溫下,向三丁基(乙烯基)錫烷(0.92 mL,3.14 mmol)及2-溴噻唑-5-甲酸乙酯(0.38 mL,2.54 mmol)於二噁烷(33 mL)中之溶液中添加Pd(PPh3
)2
Cl2
(182 mg,0.26 mmol)。在氮氣下在100℃下攪拌4小時後,冷卻溶液至周圍溫度,隨後用H2
O淬滅。用EtOAc稀釋粗產物,用鹽水洗滌有機層,經Na2
SO4
乾燥,過濾且在減壓下濃縮。利用矽膠急驟管柱層析(溶離劑:庚烷/EtOAc=90:10至80:20)純化所獲得之殘餘物,得到2-乙烯基噻唑-5-甲酸乙酯(418 mg)。HPLC滯留時間=0.45分鐘(條件B);MS(m+1)=184.1;1H NMR(400 MHz,CD3
OD)δppm 1.37(t,J
=7.2 Hz,3H) 4.35(q,J
=7.1 Hz,2H) 5.71(d,J
=10.9 Hz,1H) 6.24(d,J
=17.4 Hz,1H) 6.93(dd,J
=17.4,10.9 Hz,1H) 8.29(s,1H)。
中間物41:2-乙基噻唑-5-甲酸乙酯
在室溫下,向2-乙烯基噻唑-5-甲酸乙酯(400 mg,2.18 mmol)於MeOH(7 mL)中之溶液中添加10 wt.% Pd/C(267 mg,0.25 mmol)。在氫氣球下在室溫下攪拌1小時後,過濾粗產物以移除Pd/C。濃縮濾液,得到2-乙基噻唑-5-甲酸乙酯(404 mg)。HPLC滯留時間=0.60分鐘(條件B);MS(m+1)=186.3;1H NMR(400 MHz,CD3
OD)δppm 1.35(t,J
=7.3 Hz,2H) 1.39(t,J
=7.20 Hz,2H) 3.07(q,J
=7.58 Hz,2H) 4.35(q,J
=7.16 Hz,2H) 8.22(s,1H)。
中間物42:2-乙基噻唑-5-甲酸
向2-乙基噻唑-5-甲酸乙酯(400 mg,2.159 mmol)於MeOH(10 mL)中之溶液中添加1 N NaOH(6 mL,6 mmol)。在室溫下攪拌18小時後,在減壓下濃縮粗產物以移除MeOH。用EtOAc稀釋粗產物,用鹽水洗滌有機層,經Na2
SO4
乾燥,過濾且在減壓下濃縮,得到2-乙基噻唑-5-甲酸(282.4 mg)。HPLC滯留時間=0.78分鐘(條件D);MS(m+3)=160.4;1H NMR(400 MHz,CD3
OD)δppm 1.40(t,J
=7.6 Hz,3H) 3.07(q,J
=7.6 Hz,2H) 5.08(br. s.,1H) 8.20(s,1H)。
中間物43:3-羥基-異噁唑-5-甲酸
向3-羥基-異噁唑-5-甲酸甲酯(286 mg,2.0 mmol)於甲醇(7 mL)中之溶液中添加1 N NaOH(4.0 mL,4.0 mmol),且在室溫下攪拌混合物18小時。在減壓下移除溶劑,且向殘餘物中添加4.0 mL 1 N HCl。凍乾所得溶液,得到產物,該產物按原樣用於後續反應中。
中間物44:5-甲氧基羰基甲基-呋喃-2-甲酸
向5-甲氧基羰基甲基-呋喃-2-甲酸甲酯(250 mg,1.26 mmol)於甲醇(5 mL)中之溶液中添加1 N NaOH(2.78 mL,2.78 mmol),且在室溫下攪拌混合物18小時。在減壓下移除溶劑,且向殘餘物中添加2.78 mL 1 N HCl。凍乾所得溶液,得到5-羧基甲基-呋喃-2-甲酸。
接著,向上述二酸(220 mg,1.29 mmol)於甲醇(8 mL)中之溶液中添加Amberlyst-15樹脂(50 mg),且在室溫下攪拌混合物18小時。過濾樹脂,且在減壓下移除溶劑,得到產物,該產物按原樣用於後續反應中。1H NMR(400 MHz,氯仿-d
)δppm 3.75(s,3H),3.82(s,2H),6.45(d,J=3.54 Hz,1H),7.29(d,J=3.54 Hz,1H),10.17(s,寬峰,1H)。
中間物45:(
R
)
-4-(3'-氯-聯苯-4-基)-3-異氰醯基-丁酸乙酯
在0℃下向8%碳酸氫鈉水溶液(3 mL)及二氯甲烷(3 mL)之劇烈攪拌之混合物中添加三光氣(28.1 mg,0.095 mmol),且在0℃下攪拌混合物5分鐘,隨後添加中間物17-1(100 mg,0.284 mmol),且再繼續攪拌15分鐘。分離有機層,且經硫酸鈉乾燥。在減壓下移除溶劑,得到標題化合物。其按原樣用於後續反應中。
中間物46:2-(4-甲氧基-苯甲基)-2H-四唑-5-甲醯氯
在室溫下,向1H-四唑-5-甲酸乙酯鈉鹽(500 mg,3.05 mmol)於DMF(5 ml)中之溶液中添加4-甲氧基苯甲基氯(747μl,5.48 mmol)及TEA(1500 μl,10.76 mmol)。在室溫下攪拌反應混合物隔夜。向反應中添加水,且用EtOAc萃取。用鹽水洗滌合併之有機層,且經無水硫酸鈉乾燥,過濾且在減壓下濃縮。利用管柱層析(10%至30% EtOAc/庚烷)純化殘餘物。在室溫下,向純化之殘餘物於EtOH(2 ml)中之溶液中添加NaOH(2 ml,2.000 mmol),且在室溫下攪拌混合物。攪拌1小時後,在減壓下濃縮混合物以移除EtOH,且在酸化至pH<5後,用EtOAc萃取。用鹽水洗滌合併之有機層,且經無水硫酸鈉乾燥,過濾且在減壓下濃縮,得到2-(4-甲氧基-苯甲基)-2H-四唑-5-甲酸。
接著,在室溫下,向2-(4-甲氧基-苯甲基)-2H-四唑-5-甲酸於甲苯(15 ml)中之混合物中添加SOCl2
(1 ml,13.70 mmol),且在80℃下加熱混合物3小時。在減壓下濃縮反應混合物,得到粗產物,粗產物不經進一步純化即使用。
中間物47:(
R
)-3-胺基-4-(3'-氯-聯苯-4-基)-丁酸茚滿-5-基酯
在室溫下,向boc-(R
)-3-胺基-4-(4-溴-苯基)-丁酸(500 mg,1.396 mmol)於THF(12 ml)中之懸浮液中添加5-茚滿醇(187 mg,1.396 mmol)及Ph3
P(403 mg,1.535 mmol)。在冰浴下,向混合物中添加DIAD(0.326 ml,1.675 mmol),且將混合物自冰浴攪拌至室溫隔夜。在減壓下濃縮反應,且利用管柱層析(5%至20% EtOAc/庚烷)純化,得到450 mg固體。在室溫下,向所獲得之固體(200 mg,0.422 mmol)於DMF(5 ml)中之溶液中添加3-氯苯基酸(79 mg,0.506 mmol)、磷酸三鉀(134 mg,0.632 mmol)及Pd(PPh3
)4
(48.7 mg,0.042 mmol)。在100℃下攪拌反應隔夜。用鹽水淬滅反應,且用EtOAc萃取。用鹽水洗滌合併之有機層,且經無水硫酸鈉乾燥,過濾且在減壓下濃縮。利用管柱層析(5%至30% EtOAc/庚烷)純化殘餘物。在室溫下,向所獲得之殘餘物(143 mg,0.283 mmol)之DCM(1 ml)溶液中添加TFA(1 mL,12.98 mmol),且在室溫下攪拌混合物2小時。濃縮混合物,得到粗鹽,該粗鹽不經進一步純化即直接使用。HPLC滯留時間=1.27分鐘(條件B);MS(m+1)=406。
中間物48:(
R
)-4-聯苯-4-基-3-脲基-丁酸乙酯
在0℃下,向(R
)-3-胺基-4-聯苯-4-基-丁酸乙酯(200 mg,0.625 mmol)於THF(10 ml)中之懸浮液中添加氯甲酸苯酯(0.087 ml,0.688 mmol)及吡啶(0.126 ml,1.563 mmol)。在0℃下攪拌混合物5分鐘,隨後升溫至室溫。LCMS監測反應直至反應完成。用EtOAc萃取反應。用1 N HCl、H2
O、飽和NaHCO3
水溶液及鹽水洗滌合併之有機層,且經無水硫酸鈉乾燥,過濾且濃縮,得到粗殘餘物。
接著,在室溫下,向所獲得之殘餘物(0.252 g,0.625 mmol)於DMSO(1.5 ml)中之溶液中添加氫氧化銨(0.027 ml,0.688 mmol)。在室溫下攪拌反應。由於30分鐘時之LCMS顯示所要產物較少,而起始物質較多,因此添加更多氫氧化銨,且在室溫下攪拌反應隔夜直至反應完成。用EtOAc萃取反應。用H2
O、1 N HCl、H2
O、1 N NaOH及鹽水洗滌合併之有機層,且經無水硫酸鈉乾燥,過濾且在減壓下濃縮。利用管柱層析(2%至6% EtOH/DCM)純化殘餘物,得到(R
)-4-聯苯-4-基-3-脲基-丁酸乙酯(169 mg)。HPLC滯留時間=1.04分鐘(條件B);MS(m+1)=327。
中間物49:(
R
)-3-胺基-4-(3'-氯-聯苯-4-基)-2-羥基-丁酸甲酯鹽酸鹽
在N2
氛圍下,使(R
)-3-(4-溴-苯基)-2-第三丁氧基羰基胺基-丙酸(4.0 g,11.6 mmol)、3-氯苯基酸(2.36 g,15.11 mmol)、Pd(PPh3
)4
(0.067 g,0.058 mmol)及2 M Na2
CO3
水溶液(8.0 mL)於1,2-二甲氧基乙烷(70 mL)中回流2.5小時。冷卻至室溫後,用EtOAc稀釋反應混合物,且用1 M HCl及鹽水洗滌。有機層經Na2
SO4
乾燥且濃縮。利用急驟管柱層析(矽膠,DCM/含10% MeOH之DCM=100:0至0:100)純化殘餘物,得到(R
)-2-第三丁氧基羰基胺基-3-(3'-氯-聯苯-4-基)-丙酸(含有雜質)。HPLC滯留時間=1.56分鐘(條件A);MS(m+1)=376。
將其溶解於1,2-二甲氧基乙烷(40 mL)中,且添加Et3
N(1.46 mL,10.5 mmol)及甲酸乙酯(1.00 mL,10.5 mmol)。在室溫下攪拌0.5小時後,藉由過濾移除所得沈澱。向濾液中緩慢添加NaBH4
(0.44 g,11.6 mmol)之H2
O(5 mL)溶液。攪拌2小時後,用EtOAc稀釋反應混合物,且用H2
O及鹽水洗滌。有機層經Na2
SO4
乾燥,濃縮且利用急驟管柱層析(矽膠,溶離劑:庚烷/EtOAc=100:0至0:100)純化,得到[(R
)-2-(3'-氯-聯苯-4-基)-1-羥基甲基-乙基]-胺基甲酸第三丁酯(2.8 g)。HPLC滯留時間=1.26分鐘(條件A);MS(m+1-Boc)=262。1H-NMR(400 MHz,DMSO-d6)δppm 1.43(s,9H),2.90(d,2H,J
=7.33 Hz),3.60(dd,1H,J
=5.05,10.86 Hz),3.72(dd,1H,J
=3.79,11.12 Hz),3.91(bs,1H),4.75(bs,1H),7.29-7.34(m,3H),7.37(t,1H,J
=7.83 Hz),7.44-7.48(m,1H),7.51(d,2H,J
=8.08 Hz),7.57(t,1H,J
=1.77 Hz)。
接著,向[(R
)-2-(3'-氯-聯苯-4-基)-1-羥基甲基-乙基]-胺基甲酸第三丁酯(2.0 g,5.53 mmol)於DCM(30 mL)中之溶液中添加戴斯-馬丁高碘烷(Dess-Martin periodinane)(2.81 g,6.63 mmol)。在室溫下攪拌2小時後,用EtOAc稀釋反應混合物,且用飽和NaHCO3
水溶液及鹽水洗滌。有機層經Na2
SO4
乾燥且濃縮。利用急驟管柱層析(矽膠,溶離劑:庚烷/EtOAc=100:0至0:100)純化殘餘物,得到[(R
)-2-(3'-氯-聯苯-4-基)-1-甲醯基-乙基]-胺基甲酸第三丁酯(1.05 g)。HPLC滯留時間=1.27分鐘(條件A);MS(m+1)=360。
將其溶解於MeOH(20 mL)及AcOH(0.199 mL,3.47 mmol)中。向該溶液中緩慢添加KCN(0.226 g,3.47 mmol)之H2
O(4 mL)溶液。在室溫下攪拌隔夜後,用EtOAc稀釋反應混合物,且用飽和NaHCO3
水溶液、H2
O及鹽水洗滌。有機層經Na2
SO4
乾燥且濃縮。在室溫下,用4 M HCl於二噁烷(20 mL)及MeOH(10 mL)中之溶液對其進行處理。攪拌隔夜後,濃縮反應混合物。將殘餘物溶解於MeOH中,且用SOCl2
(0.211 mL,2.89 mmol)處理。在50℃下攪拌5小時後,濃縮反應混合物至乾燥。將殘餘物溶解於THF(10 mL)中,且用飽和NaHCO3
水溶液(5 mL)及Boc2
O(0.631 g,2.89 mmol)處理。在室溫下攪拌2小時後,用EtOAc稀釋反應混合物,且用鹽水洗滌。有機層經MgSO4
乾燥且濃縮。利用急驟管柱層析(矽膠,溶離劑:庚烷/EtOAc=100:0至0:100)純化殘餘物,得到(R
)-3-第三丁氧基羰基胺基-4-(3'-氯-聯苯-4-基)-2-羥基-丁酸甲酯(0.61 g)。HPLC滯留時間=1.01、1.06分鐘(條件B);MS(m+1-Boc)=320。1H-NMR(400 MHz,CDCl3
)δppm 1.40(s,9H),2.77-3.05(m,2H),3.63(s,0.7H),3.77(s,2.3H),4.11(s,0.8H),4.25-4.40(m,1.2H),4.78-4.95(m,1H),7.27-7.40(m,4H),7.42-7.58(m,4H)。
用4 M HCl之二噁烷溶液(2 mL)處理(R
)-3-第三丁氧基羰基胺基-4-(3'-氯-聯苯-4-基)-2-羥基-丁酸甲酯(113 mg,0.269 mmol)。在室溫下攪拌1小時後,濃縮反應混合物。殘餘物不經進一步純化即用於下一步驟中。HPLC滯留時間=1.22、1.29分鐘(條件A);MS(m+1)=320。
中間物50:(
R
)-3-胺基-4-(3'-氯-聯苯-4-基)-2-甲氧基-丁酸甲酯鹽酸鹽
向(R
)-3-第三丁氧基羰基胺基-4-(3'-氯-聯苯-4-基)-2-羥基-丁酸甲酯(610 mg,1.45 mmol)於CH3
CN(20 mL)中之溶液中添加碘甲烷(0.545 mL,8.72 mmol)及氧化銀(1.35 g,5.81 mmol)。在室溫下攪拌16小時後,再添加碘甲烷(0.545 mL,8.72 mmol)及氧化銀(1.35 g,5.81 mmol),且攪拌3天。經由矽藻土墊過濾反應混合物,且用鹽水洗滌濾液。有機層經MgSO4
乾燥且濃縮。利用急驟管柱層析(矽膠,溶離劑:庚烷/EtOAc=100:0至0:100)純化殘餘物,得到(R
)-3-第三丁氧基羰基胺基-4-(3'-氯-聯苯-4-基)-2-甲氧基-丁酸甲酯(500 mg)。HPLC滯留時間=1.20、1.25分鐘(條件B);MS(m+1-Boc)=334。1H-NMR(400 MHz,CDCl3
)δppm 1.37,1.41(s,9H),2.72-3.03(m,2H),3.43,3.71(s,3H),3.63-3.82(m,1H),4.27-4.41(m,1H),4.68-5.04(m,1H),7.28-7.40(m,4H),7.41-7.61(m,4H)。
用4 M HCl之二噁烷溶液(3 mL)處理(R
)-3-第三丁氧基羰基胺基-4-(3'-氯-聯苯-4-基)-2-甲氧基-丁酸甲酯(200 mg,0.461 mmol)。在室溫下攪拌1小時後,濃縮反應混合物。殘餘物不經進一步純化即用於下一步驟中。HPLC滯留時間=1.26、1.33分鐘(條件A);MS(m+1)=334。
中間物51:(
R
)
-3-胺基-4-(3'-氯-聯苯-4-基)-2-甲氧基-丁酸乙酯鹽酸鹽
向(R
)-3-胺基-4-(3'-氯-聯苯-4-基)-2-甲氧基-丁酸甲酯(500 mg,1.15 mmol)於MeOH(5 mL)中之溶液中添加2 M NaOH水溶液(5 mL)。在室溫下攪拌2小時後,用2 M HCl酸化反應混合物,且用EtOAc萃取。有機層經Na2
SO4
乾燥且濃縮。將殘餘物溶解於EtOH(5 mL)中,且用SOCl2
(0.252 mL,3.26 mmol)處理。在55℃下攪拌後,濃縮反應混合物。殘餘物不經進一步純化即用於下一步驟中。HPLC滯留時間=1.49分鐘(條件A);MS(m+1)=348.2。
中間物52:(
R
)-3-胺基-4-(3'-氯-聯苯-4-基)-2-氟-丁酸甲酯鹽酸鹽
在0℃下,向(R
)-3-第三丁氧基羰基胺基-4-(3'-氯-聯苯-4-基)-2-羥基-丁酸甲酯(220 mg,0.524 mmol)之溶液中添加DAST(0.083 mL,0.629 mmol)。使反應混合物逐漸升溫至室溫,且攪拌1小時。再添加DAST(0.083 mL,0.629 mmol),且在室溫下攪拌2小時。用EtOAc稀釋反應混合物,且用飽和NaHCO3
水溶液及鹽水洗滌。有機層經Na2
SO4
乾燥且濃縮。利用急驟管柱層析(矽膠,溶離劑:庚烷/EtOAc=100:0至0:100)純化殘餘物,得到(R
)-3-第三丁氧基羰基胺基-4-(3'-氯-聯苯-4-基)-2-氟-丁酸甲酯(63 mg)。HPLC滯留時間=1.36分鐘(條件B);MS(m+1-Boc)=322。1H-NMR(400 MHz,CDCl3
)δppm 1.39(s,9H),2.84-2.95(m,2H),3.06(bs,0.5H),3.69(s,3H),4.43-4.61(m,1H),4.72-4.80(m,0.5H),5.00(s,0.5H),5.12(s,0.5H),7.28-7.34(m,3H),7.37(t,1H,J
=7.58 Hz),7.42-7.47(m,1H),7.48-7.53(m,1H),7.55(t,1H,J
=2.02 Hz)。19F-NMR(377 MHz,CDCl3
)δppm-204.18。
用4 M HCl之二噁烷溶液(1.5 mL)處理(R
)-3-第三丁氧基羰基胺基-4-(3'-氯-聯苯-4-基)-2-氟-丁酸甲酯(60 mg,0.142 mmol)。在室溫下攪拌1小時後,濃縮反應混合物。殘餘物不經進一步純化即用於下一步驟中。HPLC滯留時間=0.88分鐘(條件B);MS(m+1)=322。
中間物53-1:[(
R
)-1-(3'-氯-聯苯-4-基甲基)-3-甲烷磺醯基胺基-3-側氧基-丙基]-胺基甲酸第三丁酯
在THF(1 mL)及EtOH(2 mL)中用2 M NaOH水溶液(1 mL)處理(R
)-3-第三丁氧基羰基胺基-4-(3'-氯-聯苯-4-基)-丁酸乙酯(250 mg,0.598 mmol)。攪拌1小時後,用1 M HCl酸化反應混合物且用EtOAc萃取。用鹽水洗滌有機層,經Na2
SO4
乾燥且在真空中濃縮。向該殘餘物於DMF(2 mL)中之溶液中添加甲基磺醯胺(85 mg,0.897 mmol)、EDC(172 mg,0.897 mmol)、HOAt(98 mg,0.718 mmol)及Et3
N(0.125 mL,0.897 mmol)。在室溫下攪拌隔夜後,用EtOAc稀釋反應混合物,用1 M HCl及鹽水洗滌。有機層經Na2
SO4
乾燥,且濃縮。利用急驟管柱層析(矽膠,溶離劑:DCM/含10% MeOH之DCM=100:0至0:100)純化殘餘物,得到[(R
)-1-(3'-氯-聯苯-4-基甲基)-3-甲烷磺醯基胺基-3-側氧基-丙基]-胺基甲酸第三丁酯(244 mg)。HPLC滯留時間=1.30分鐘(條件B);MS(m+1)=467;1H NMR(400 Mz,DMSO-d6)δppm 1.30(s,9H),2.41-2.48(m,2H),2.70-2.78(m,2H),3.18(s,3H),3.99-4.11(m,1H),7.28(d,2H,J
=8.34 Hz),7.38-7.44(m,1H),7.48(t,1H,J
=7.83 Hz),7.59-7.66(m,3H),7.69(s,1H)。
使用類似於實例53-1中所述之程序製備以下化合物:
中間物54-1:(
R
)-3-[2-(第三丁氧基羰基-乙氧基羰基甲基-胺基)-丙醯基胺基]-4-(3'-氯-聯苯-4-基)-丁酸乙酯
在室溫下,向2-(第三丁氧基羰基-乙氧基羰基甲基-胺基)-丙酸三氟乙酸鹽(197 mg,0.714 mmol)於THF(10 ml)中之懸浮液中添加EDCI(219 mg,1.142 mmol)及HOBT(164 mg,1.071 mmol)。在室溫下攪拌混合物10分鐘,隨後添加(R
)-3-胺基-4-(3'-氯-聯苯-4-基)-丁酸乙酯(202 mg,0.571 mmol)於THF及TEA(0.199 ml,1.428 mmol)中之溶液。在室溫下攪拌混合物。逆相HPLC[10 min內30至90%ACN-H2
O(0.1% TFA),X-Bridge苯基管柱]得到標題化合物(290 mg,產率71%)。LCMS(條件B):575(M+1);滯留時間=1.52 min。
中間物54-2:2-(第三丁氧基羰基-乙氧基羰基甲基-胺基)-丙酸
在室溫下,向H-DL-Ala-OBzl‧對甲苯磺酸鹽(2.88 g,8.20 mmol)於THF(80 ml)中之溶液中依次添加TEA(3.43 ml,24.60 mmol)及溴乙酸乙酯(1.096 ml,9.84 mmol)。在室溫下攪拌反應隔夜。反應中有一些白色固體。自反應混合物中濾出白色固體,且濃縮以進行純化。急驟層析(矽膠,2至4% EtOH/DCM)得到呈油狀之標題化合物(1.7 g,產率78%)。LCMS(條件B):266(M+1);滯留時間=0.70min。
接著,在0℃下,向2-(乙氧基羰基甲基-胺基)-丙酸苯甲酯(1.7 g,6.41 mmol)於DCM(80 ml)中之溶液中依次添加BOC酸酐(2.232 ml,9.61 mmol)及TEA(2.68 ml,19.22 mmol)。使反應混合物緩慢升溫至室溫,且攪拌隔夜。用鹽水淬滅反應,且用DCM萃取。用鹽水洗滌合併之有機層,且經無水硫酸鈉乾燥,過濾且濃縮,得到粗產物。急驟層析(矽膠,5至10%丙酮/庚烷)得到呈油狀之標題化合物(1.66 g,產率71%)。LCMS(條件B):366(M+1);滯留時間=1.13 min。
接著,在H2
氣球下,利用濕催化劑10% Pd/C氫化2-(第三丁氧基羰基-乙氧基羰基甲基-胺基)-丙酸苯甲酯於EtOAc中之溶液1小時。自反應中濾除催化劑且濃縮,得到粗產物,其用於下一反應中。
中間物55:(
R
)-3-胺基-4-(3'-氯-聯苯-4-基)-2-甲基-丁酸乙酯三氟乙酸鹽
在-78℃下,向(R
)-3-第三丁氧基羰基胺基-4-(3'-氯-聯苯-4-基)-丁酸乙酯(300 mg,0.718 mmol)於THF(10 ml)中之溶液中添加LiHMDS/THF(1 M)(1.579 ml,1.579 mmol)。在-78℃下攪拌反應混合物50分鐘,且隨後向該混合物中添加碘甲烷(0.054 ml,0.861 mmol),且使反應緩慢升溫至室溫並攪拌隔夜。用飽和NH4
Cl淬滅反應,且用EtOAc萃取。用鹽水洗滌合併之有機層,且經無水硫酸鈉乾燥,過濾且濃縮,得到粗產物。逆相HPLC[10 min內20至90%ACN-H2
O(0.1% TFA),Sunfire C18]得到(R
)-3-第三丁氧基羰基胺基-4-(3'-氯-聯苯-4-基)-2-甲基-丁酸乙酯。LCMS(條件B):432(M+1);滯留時間=1.55 min。在室溫下向(R
)-3-第三丁氧基羰基胺基-4-(3'-氯-聯苯-4-基)-2-甲基-丁酸乙酯(240 mg,0.556 mmol)於DCM(2 ml)中之溶液中添加TFA(1.070 ml,13.89 mmol),且在室溫下攪拌混合物。1小時後,反應完成,因此濃縮混合物,得到(R
)-3-胺基-4-(3'-氯-聯苯-4-基)-2-甲基-丁酸乙酯三氟乙酸鹽。LCMS(條件B):332(M+1);滯留時間=1.00 min。
可見,本發明化合物適用作中性肽鏈內切酶(EC 3.4.24.11)活性之抑制劑,且因此適用於治療與中性肽鏈內切酶(EC 3.4.24.11)活性相關之疾病及病狀,諸如本文中所揭示之疾病。
應瞭解,本發明僅以舉例的方式描述,且在保持在本發明之範疇及精神內之情況下,可進行修改。
Claims (22)
- 一種式I化合物,
- 如請求項1之化合物,其具有式I:
- 如請求項1之化合物,其中:R 1 為H或C1-7 烷基;R 2 在每次出現時獨立地為C1-7 烷基、鹵基、C3-7 環烷基、羥基、C1-7 烷氧基、鹵基C1-7 烷基、-NRa Rb 、C6-20 芳基、雜芳基或雜環基;其中Ra 及Rb 在每次出現時獨立地為H或C1-7 烷基;R 3 為A1 -C(O)X1 或A2 -R4 ;R 4 為C6-20 芳基或雜芳基,各自可為單環或雙環且各自可視情況經一或多個獨立地選自由以下組成之群的取代基取代:羥基、C1-7 烷氧基、鹵基、C1-7 烷基、鹵基-C1-7 烷基、C6-10 芳基、雜芳基、-NHSO2 -C1-7 烷基及苯甲基;R 5 為H;且X 及X 1 獨立地為OH、-O-C1-7 烷基或NRa Rb ;B 1 為-C(O)NH-或-NHC(O)-;A 1 為直鏈或分支鏈C1-7 伸烷基;其視情況經一或多個獨立地選自由以下組成之群的取代基取代:鹵基、C3-7 環烷基、C1-7 烷氧基、羥基及O-乙酸根;其中兩個偕位烷基可視情況組合形成C3-7 環烷基;或A 1 為苯基或雜芳基;各自視情況經一或多個獨立地選自由以下組成之群的取代基取代:C1-7 烷基、C3-7 環烷基、鹵基-C1-7 烷基、羥基、C1-7 烷氧基、鹵基、-NRa Rb 、-OCH2 CO2 H及-OCH2 C(O)NH2 ;且A 2 為一鍵或為直鏈或分支鏈C1-7 伸烷基;其視情況經一或多個獨立地選自由以下組成之群的取代基取代:鹵基、C1-7 烷氧基、羥基、O-乙酸根及C3-7 環烷基;且n 為0、1、2、3、4或5;其中各雜芳基為包含5至10個選自碳原子及1至5個雜原子之環原子的單環或雙環芳族環,且各雜環基為包含4至7個選自碳原子及1至5個雜原子之環原子的單環飽和或部分飽和但為非芳族部分基團,其中雜芳基或雜環基之各雜原子獨立地選自O、N及S,或其醫藥學上可接受之鹽。
- 如請求項1之化合物,其具有式II或IIA:
- 如請求項1之化合物,其具有式III或IIIA:
- 如請求項1或4之化合物,其中A 1 為視情況經取代之直鏈或分支鏈C1-7 伸烷基,或其醫藥學上可接受之鹽。
- 如請求項1或4之化合物,其中A 1 為CH2 CH2 ,或其醫藥學上可接受之鹽。
- 如請求項1之化合物,其中A 1 為視情況經取代之苯基或雜芳基,或其醫藥學上可接受之鹽。
- 如請求項1之化合物,其具有式VII或VIIA:
- 如請求項9之化合物,其中A2 為一鍵或為CH2 或CH2 -CH2 ,或其醫藥學上可接受之鹽。
- 如請求項1或4之化合物,其中R1 為H,R2 獨立地為鹵基、C1-7 烷氧基、羥基、C1-7 烷基或鹵基-C1-7 烷基,n為0、1或2,且X及X1 獨立地為OH或-O-C1-7 烷基,或其醫藥學上可接受之鹽。
- 如請求項11之化合物,其中n為1或2;R2 為間位氯或間位氟,且另一可選R2 基團為鹵基、C1-7 烷基、鹵基-C1-7 烷基、羥基及C1-7 烷氧基,或其醫藥學上可接受之鹽。
- 一種醫藥組合物,其包含如請求項1或4之化合物或其醫藥學上可接受之鹽,及一或多種醫藥學上可接受之載劑。
- 一種組合,其包含:如請求項1之化合物或其醫藥學上可接受之鹽,及一或多種選自以下之治療活性劑:HMG-Co-A還原酶抑制劑、血管收縮素受體阻斷劑、血管收縮素轉化酶抑制劑、鈣通道阻斷劑、內皮素拮抗劑、腎素抑制劑、利尿劑、ApoA-I模擬劑、抗糖尿病劑、減肥劑、醛固酮受體阻斷劑、內皮素受體阻斷劑、 醛固酮合成酶抑制劑、CETP抑制劑及第5型磷酸二酯酶(PDE5)抑制劑。
- 4或5之化合物,或其醫藥學上可接受之鹽,其係用作藥物。
- 4或5之化合物,或其醫藥學上可接受之鹽,其係用於為需要該治療之個體治療與中性肽鏈內切酶EC 3.4.24.11活性相關之病症或疾病。
- 4或5之化合物,或其醫藥學上可接受之鹽,其係用於治療高血壓、肺循環血壓過高、獨立性收縮性高血壓、頑固性高血壓、周邊血管疾病、心臟衰竭、充血性心臟衰竭或肺動脈高血壓。
- 如請求項7之化合物,其中n為1或2;R2 為間位氯或間位氟,且另一可選R2 基團為鹵基、C1-7 烷基、鹵基-C1-7 烷基、羥基及C1-7 烷氧基,或其醫藥學上可接受之鹽。
- 一種醫藥組合物,其包含如請求項7之化合物或其醫藥學上可接受之鹽,及一或多種醫藥學上可接受之載劑。
- 一種醫藥組合物,其包含如請求項18之化合物或其醫藥學上可接受之鹽,及一或多種醫藥學上可接受之載劑。
- 如請求項7之化合物,或其醫藥學上可接受之鹽,其係用於治療高血壓、肺循環血壓過高、獨立性收縮性高血壓、頑固性高血壓、周邊血管疾病、心臟衰竭、充血性心臟衰竭或肺動脈高血壓。
- 如請求項18之化合物,或其醫藥學上可接受之鹽,其係用於治療高血壓、肺循環血壓過高、獨立性收縮性高血 壓、頑固性高血壓、周邊血管疾病、心臟衰竭、充血性心臟衰竭或肺動脈高血壓。
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US18175609P | 2009-05-28 | 2009-05-28 | |
US26314509P | 2009-11-20 | 2009-11-20 | |
US32494310P | 2010-04-16 | 2010-04-16 |
Publications (2)
Publication Number | Publication Date |
---|---|
TW201100076A TW201100076A (en) | 2011-01-01 |
TWI445530B true TWI445530B (zh) | 2014-07-21 |
Family
ID=42313042
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
TW099117081A TWI445530B (zh) | 2009-05-28 | 2010-05-27 | 作為奈溶酶抑制劑之經取代胺基丙酸衍生物 |
Country Status (38)
Country | Link |
---|---|
US (3) | US8394853B2 (zh) |
EP (3) | EP2594557B1 (zh) |
JP (1) | JP5420761B2 (zh) |
KR (1) | KR101442897B1 (zh) |
CN (2) | CN102574801B (zh) |
AR (1) | AR076707A1 (zh) |
AU (1) | AU2010251967B9 (zh) |
BR (1) | BRPI1011657A2 (zh) |
CA (1) | CA2763572C (zh) |
CL (1) | CL2011002990A1 (zh) |
CO (1) | CO6470847A2 (zh) |
CR (1) | CR20110616A (zh) |
CU (1) | CU24051B1 (zh) |
DK (1) | DK2435409T3 (zh) |
EA (1) | EA019511B1 (zh) |
EC (1) | ECSP11011560A (zh) |
ES (3) | ES2523734T3 (zh) |
GT (1) | GT201100303A (zh) |
HN (1) | HN2011003097A (zh) |
HR (1) | HRP20141050T1 (zh) |
IL (1) | IL216367A0 (zh) |
JO (1) | JO2962B1 (zh) |
MA (1) | MA33636B1 (zh) |
ME (1) | ME01923B (zh) |
MX (1) | MX2011012628A (zh) |
MY (1) | MY156270A (zh) |
NZ (1) | NZ596304A (zh) |
PE (1) | PE20120330A1 (zh) |
PL (1) | PL2435409T3 (zh) |
PT (1) | PT2435409E (zh) |
RS (1) | RS53664B1 (zh) |
SG (1) | SG176009A1 (zh) |
SI (1) | SI2435409T1 (zh) |
SM (1) | SMT201400175B (zh) |
TW (1) | TWI445530B (zh) |
UY (1) | UY32662A (zh) |
WO (1) | WO2010136493A1 (zh) |
ZA (1) | ZA201108222B (zh) |
Families Citing this family (73)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
NZ596304A (en) | 2009-05-28 | 2014-01-31 | Novartis Ag | Substituted aminopropionic derivatives as neprilysin inhibitors |
EP2435402B1 (en) | 2009-05-28 | 2016-04-13 | Novartis AG | Substituted aminobutyric derivatives as neprilysin inhibitors |
JO2967B1 (en) | 2009-11-20 | 2016-03-15 | نوفارتس ايه جي | Acetic acid derivatives of carbamoyl methyl amino are substituted as new NEP inhibitors |
TWI532725B (zh) | 2010-01-26 | 2016-05-11 | 賽諾菲阿凡提斯公司 | 經氧取代之3-雜芳醯基胺基-丙酸衍生物及其作為藥物之用途 |
WO2011092284A1 (en) * | 2010-01-29 | 2011-08-04 | Euroscreen S.A. | Novel amino acid derivatives and their use as gpr43 receptor modulators |
US8993631B2 (en) * | 2010-11-16 | 2015-03-31 | Novartis Ag | Method of treating contrast-induced nephropathy |
US8673974B2 (en) * | 2010-11-16 | 2014-03-18 | Novartis Ag | Substituted amino bisphenyl pentanoic acid derivatives as NEP inhibitors |
US8877815B2 (en) * | 2010-11-16 | 2014-11-04 | Novartis Ag | Substituted carbamoylcycloalkyl acetic acid derivatives as NEP |
JP5944922B2 (ja) | 2010-12-15 | 2016-07-05 | セラヴァンス バイオファーマ アール&ディー アイピー, エルエルシー | ネプリライシン阻害剤 |
CA2817368C (en) * | 2010-12-15 | 2019-12-31 | Theravance, Inc. | Neprilysin inhibitors |
US8669370B2 (en) * | 2011-01-26 | 2014-03-11 | Sanofi | Substituted 3-heteroaroylamino-propionic acid derivatives and their use as pharmaceuticals |
JP5959066B2 (ja) * | 2011-02-17 | 2016-08-02 | セラヴァンス バイオファーマ アール&ディー アイピー, エルエルシー | ネプリライシン阻害剤としての置換アミノ酪酸誘導体 |
KR101854874B1 (ko) * | 2011-02-17 | 2018-05-04 | 세라밴스 바이오파마 알앤디 아이피, 엘엘씨 | 네프릴리신 억제제로서 치환된 아미노부티릭 유도체 |
JP5885832B2 (ja) | 2011-05-31 | 2016-03-16 | セラヴァンス バイオファーマ アール&ディー アイピー, エルエルシー | ネプリライシン阻害剤 |
EP2714662B1 (en) | 2011-05-31 | 2017-10-11 | Theravance Biopharma R&D IP, LLC | Neprilysin inhibitors |
CA2835220A1 (en) | 2011-05-31 | 2012-12-06 | Theravance, Inc. | Neprilysin inhibitors |
JP6263469B2 (ja) * | 2011-07-15 | 2018-01-17 | ノバルティス アーゲー | アザ二環式ジ−アリールエーテルの塩およびその製造方法またはその前駆体の製造方法 |
HUE028418T2 (en) * | 2011-07-26 | 2016-12-28 | Sanofi Sa | 3-Heteroaroylamino-propionic acid derivatives and their use as medicaments |
MY162786A (en) * | 2011-07-26 | 2017-07-14 | Sanofi Sa | Substituted 3-thiazoloamino-propionic acid derivatives and their use as pharmaceuticals |
AU2012326361B2 (en) * | 2011-10-17 | 2017-08-03 | Biotheryx, Inc. | Substituted biaryl alkyl amides |
TWI560172B (en) | 2011-11-02 | 2016-12-01 | Theravance Biopharma R&D Ip Llc | Neprilysin inhibitors |
WO2013113716A1 (en) | 2012-02-03 | 2013-08-08 | Basf Se | Fungicidal pyrimidine compounds |
WO2013113773A1 (en) | 2012-02-03 | 2013-08-08 | Basf Se | Fungicidal pyrimidine compounds |
WO2013113776A1 (en) | 2012-02-03 | 2013-08-08 | Basf Se | Fungicidal pyrimidine compounds |
WO2013113720A1 (en) | 2012-02-03 | 2013-08-08 | Basf Se | Fungicidal pyrimidine compounds |
WO2013113788A1 (en) | 2012-02-03 | 2013-08-08 | Basf Se | Fungicidal pyrimidine compounds |
JP2015508752A (ja) | 2012-02-03 | 2015-03-23 | ビーエーエスエフ ソシエタス・ヨーロピアBasf Se | 殺菌性ピリミジン化合物 |
BR112014018909A8 (pt) | 2012-02-03 | 2017-07-11 | Basf Se | Compostos, processo para a preparação dos compostos, composição agroquímica, método para o combate dos fungos, utilização dos compostos e semente |
AR089954A1 (es) * | 2012-02-15 | 2014-10-01 | Theravance Inc | Forma cristalina del ester 5-metil-2-oxo-[1,3]dioxol-4-ilmetilico del acido (2s,4r)-5-bifenil-4-il-2-hidroximetil-2-metil-4-[(1h-[1,2,3]triazol-4-carbonil)amino]pentanoico |
TWI562986B (en) | 2012-02-15 | 2016-12-21 | Theravance Biopharma R&D Ip Llc | Process for preparing 4-amino-5-biphenyl-4-yl-2-hydroxymethyl-2-methyl-pentanoic acid compounds |
US9045443B2 (en) | 2012-05-31 | 2015-06-02 | Theravance Biopharma R&D Ip, Llc | Nitric oxide donor neprilysin inhibitors |
CA2873328A1 (en) | 2012-06-08 | 2013-12-12 | Theravance Biopharma R&D Ip, Llc | Neprilysin inhibitors |
ME02698B (me) | 2012-06-08 | 2017-10-20 | Theravance Biopharma R&D Ip Llc | Inhibitori neprilizina |
PT2882716T (pt) | 2012-08-08 | 2017-03-13 | Theravance Biopharma R&D Ip Llc | Inibidores da neprilisina |
WO2014053533A1 (en) * | 2012-10-05 | 2014-04-10 | Sanofi | Use of substituted 3-heteroaroylamino-propionic acid derivatives as pharmaceuticals for prevention/treatment of atrial fibrillation |
UY35144A (es) | 2012-11-20 | 2014-06-30 | Novartis Ag | Miméticos lineales sintéticos de apelina para el tratamiento de insuficiencia cardiaca |
LT2956464T (lt) * | 2013-02-14 | 2018-07-10 | Novartis Ag | Pakeisti bisfenilbutanoinės fosfonrūgšties dariniai, kaip nep (neutralios endopeptidazės) inhibitoriai |
EP2956445A1 (en) | 2013-02-14 | 2015-12-23 | Novartis AG | Substituted bisphenyl butanoic acid derivatives as nep inhibitors with improved in vivo efficacy |
HUE034210T2 (hu) | 2013-03-05 | 2018-02-28 | Theravance Biopharma R&D Ip Llc | Neprilizininhibitorok |
KR20160031551A (ko) | 2013-07-25 | 2016-03-22 | 노파르티스 아게 | 심부전의 치료를 위한 시클릭 폴리펩티드 |
MX2016001021A (es) | 2013-07-25 | 2016-08-03 | Novartis Ag | Bioconjugados de polipeptidos de apelina sinteticos. |
KR101863708B1 (ko) * | 2013-09-17 | 2018-06-01 | 벡투스 바이오시스템즈 리미티드 | 고혈압 및/또는 섬유증 치료용 조성물 |
EP3087060B1 (en) | 2013-12-23 | 2020-05-13 | Merck Sharp & Dohme Corp. | Pyrimidone carboxamide compounds as pde2 inhibitors |
AU2015210983B2 (en) * | 2014-01-30 | 2018-10-04 | Theravance Biopharma R&D Ip, Llc | Neprilysin inhibitors |
CA2934898A1 (en) | 2014-01-30 | 2015-08-06 | Theravance Biopharma R&D Ip, Llc | 5-biphenyl-4-heteroarylcarbonylamino-pentanoic acid derivatives as neprilysin inhibitors |
WO2015189862A1 (en) * | 2014-06-10 | 2015-12-17 | Council Of Scientific & Industrial Research | Chiral amines, a process for preparation and use thereof |
CN107074744B (zh) * | 2014-12-03 | 2019-06-18 | 上海翰森生物医药科技有限公司 | Nep抑制剂结晶型游离酸、钙盐多晶型及其制备方法和应用 |
SG11201704758XA (en) | 2015-01-23 | 2017-08-30 | Novartis Ag | Synthetic apelin fatty acid conjugates with improved half-life |
CN104557600B (zh) * | 2015-01-26 | 2016-05-04 | 苏州明锐医药科技有限公司 | 沙库比曲的制备方法 |
KR102640906B1 (ko) | 2015-02-11 | 2024-02-27 | 세라밴스 바이오파마 알앤디 아이피, 엘엘씨 | 네프릴리신 저해제로서 (2s,4r)-5-(5''-클로로-2''-플루오로비페닐-4-일)-4-(에톡시옥살릴아미노)-2-히드록시메틸-2-메틸펜타노익산 |
TW201632493A (zh) * | 2015-02-13 | 2016-09-16 | 諾華公司 | 新穎方法 |
US9533962B2 (en) | 2015-02-19 | 2017-01-03 | Theravance Biopharma R&D Ip, Llc | (2R,4R)-5-(5′-chloro-2′-fluorobiphenyl-4-yl)-2-hydroxy-4-[(5-methyloxazole-2-carbonyl)amino]pentanoic acid |
WO2016149218A1 (en) * | 2015-03-13 | 2016-09-22 | Indiana University Research And Technology Corporation | TARGETING cGMP-RELATED PHOSPHODIESTERASES TO REDUCE CYST FORMATION IN CYSTIC KIDNEY DISEASE, AND RELATED MATERIALS AND METHODS |
WO2016145614A1 (en) | 2015-03-17 | 2016-09-22 | Merck Sharp & Dohme Corp. | Triazolyl pyrimidinone compounds as pde2 inhibitors |
US10287269B2 (en) | 2015-03-26 | 2019-05-14 | Merck Sharp & Dohme Corp. | Pyrazolyl pyrimidinone compounds as PDE2 inhibitors |
EP3291817B1 (en) | 2015-05-05 | 2019-10-02 | Merck Sharp & Dohme Corp. | Heteroaryl-pyrimidinone compounds as pde2 inhibitors |
WO2016183741A1 (en) | 2015-05-15 | 2016-11-24 | Merck Sharp & Dohme Corp. | Pyrimidinone amide compounds as pde2 inhibitors |
WO2016191935A1 (en) | 2015-05-29 | 2016-12-08 | Merck Sharp & Dohme Corp. | 6-alkyl dihydropyrazolopyrimidinone compounds as pde2 inhibitors |
WO2016192083A1 (en) | 2015-06-04 | 2016-12-08 | Merck Sharp & Dohme Corp. | Dihydropyrazolopyrimidinone compounds as pde2 inhibitors |
WO2016209749A1 (en) | 2015-06-25 | 2016-12-29 | Merck Sharp & Dohme Corp. | Substituted pyrazolo/imidazolo bicyclic compounds as pde2 inhibitors |
WO2017000276A1 (en) | 2015-07-01 | 2017-01-05 | Merck Sharp & Dohme Corp. | Bicyclic heterocyclic compounds as pde2 inhibitors |
WO2017000277A1 (en) | 2015-07-01 | 2017-01-05 | Merck Sharp & Dohme Corp. | Substituted triazolo bicycliccompounds as pde2 inhibitors |
EP3394059B1 (en) | 2015-12-23 | 2020-11-25 | Chiesi Farmaceutici S.p.A. | 1-(3-tert-butyl-phenyl)-3-(4-([1,2,4]triazolo[4,3-a]pyridin-6-yloxy)-1,2,3,4-tetrahydro- naphthalen-1-yl)-urea derivatives and their use as p38 mapk inhibitors |
DK3408260T3 (da) | 2016-03-08 | 2021-08-02 | Theravance Biopharma R&D Ip Llc | Krystallinsk (2s,4r)-5-(5'-chlor-2-fluor-[1,1'-biphenyl]-4-yl)-2-(ethoxy¬methyl)-4-(3-hydroxyisoxazol-5-carboxamido)-2-methylpentansyre og anvendelser deraf |
CN106831473B (zh) * | 2017-02-22 | 2019-07-16 | 江西瑞雅药业有限公司 | 3-酰胺基-4-(2’-烷氧基-4-联苯基)丁酸衍生物及其制备方法、药物组合物 |
FR3072379B1 (fr) * | 2017-10-18 | 2020-08-07 | Pharmasynthese | Nouveaux derives de la strombine et leur utilisation en cosmetique |
WO2019154665A1 (en) * | 2018-02-07 | 2019-08-15 | Basf Se | New pyridine carboxamides |
UY38072A (es) * | 2018-02-07 | 2019-10-01 | Novartis Ag | Compuestos derivados de éster butanoico sustituido con bisfenilo como inhibidores de nep, composiciones y combinaciones de los mismos |
UY38485A (es) | 2018-11-27 | 2020-06-30 | Novartis Ag | Compuestos tetrámeros cíclicos como inhibidores de proproteína convertasa subtilisina/kexina tipo 9 (pcsk9), método de tratamiento, uso y su preparación |
CN113166204A (zh) | 2018-11-27 | 2021-07-23 | 诺华股份有限公司 | 作为治疗代谢障碍的蛋白质原转换酶枯草杆菌蛋白酶/kexin 9型(PCSK9)抑制剂的环状肽 |
WO2020110008A1 (en) | 2018-11-27 | 2020-06-04 | Novartis Ag | Cyclic pentamer compounds as proprotein convertase subtilisin/kexin type 9 (pcsk9) inhibitors for the treatment of metabolic disorder |
TW202333563A (zh) | 2021-11-12 | 2023-09-01 | 瑞士商諾華公司 | 用於治療疾病或障礙之二胺基環戊基吡啶衍生物 |
CN115806501A (zh) * | 2022-12-13 | 2023-03-17 | 中国药科大学 | N-草酰-d-苯丙氨酸类化合物及其酯类前药、制法、药物组合物和应用 |
Family Cites Families (140)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DK162288C (da) | 1978-11-25 | 1992-03-16 | Nippon Kayaku Kk | Fremgangsmaade til fremstilling af threo-3-amino-2-hydroxybutanoyl-aminoeddikesyrer |
DE2951135A1 (de) | 1979-12-19 | 1981-06-25 | Hoechst Ag, 6230 Frankfurt | Sulfonylharnstoffe, verfahren zu ihrer herstellung, pharmazeutische praeparate auf basis dieser verbindungen und ihre verwendung |
IT1148006B (it) | 1980-04-11 | 1986-11-26 | Wellcome Found | Ammidi dotate di proprieta' farmaceutiche e loro preparazione |
PT72878B (en) | 1980-04-24 | 1983-03-29 | Merck & Co Inc | Process for preparing mannich-base hydroxamic acid pro-drugs for the improved delivery of non-steroidal anti-inflammatory agents |
US4721726A (en) | 1980-12-18 | 1988-01-26 | Schering Corporation | Substituted dipeptides as inhibitors of enkephalinases |
US4610816A (en) | 1980-12-18 | 1986-09-09 | Schering Corporation | Substituted dipeptides as inhibitors of enkephalinases |
JPS5865260A (ja) | 1981-10-13 | 1983-04-18 | Microbial Chem Res Found | 3−アミノ−2−ヒドロキシ−4−フエニル酪酸誘導体および医薬組成物 |
FR2518088B1 (fr) | 1981-12-16 | 1987-11-27 | Roques Bernard | Nouveaux derives d'aminoacides, et leur application therapeutique |
EP0103077B1 (en) | 1982-06-17 | 1988-05-18 | Schering Corporation | Substituted dipeptides, methods for their production, pharmaceutical compositions containing them, method for making such pharmaceutical compositions |
US4889861A (en) | 1982-12-21 | 1989-12-26 | Ciba-Geigy Corp. | Substituted imidazo[1,5-a]pyridine derivatives and other substituted bicyclic derivatives and their use as aromatase inhibitors |
US4617307A (en) | 1984-06-20 | 1986-10-14 | Ciba-Geigy Corporation | Substituted imidazo[1,5-A]pyridine derivatives as aromatase inhibitors |
AU569719B2 (en) | 1983-01-28 | 1988-02-18 | Schering Corporation | Phosphorous compounds as inhibitors of enkephalinases |
US4559332A (en) | 1983-04-13 | 1985-12-17 | Ciba Geigy Corporation | 20-Spiroxanes and analogues having an open ring E, processes for their manufacture, and pharmaceutical preparations thereof |
EP0136883B1 (en) | 1983-10-03 | 1987-11-25 | E.R. Squibb & Sons, Inc. | Enkephalinase inhibitors |
CN1008092B (zh) * | 1983-10-03 | 1990-05-23 | E·R·斯奎布父子公司 | 脑啡肽酶抑制剂的制备方法 |
DE3347565A1 (de) | 1983-12-30 | 1985-07-11 | Thomae Gmbh Dr K | Neue phenylessigsaeurederivate, diese verbindungen enthaltende arzneimittel und verfahren zu ihrer herstellung |
JPS60248659A (ja) | 1984-05-25 | 1985-12-09 | Microbial Chem Res Found | 3−〔n−(メルカプトアシル)〕アミノ−4−アリ−ル酪酸誘導体及びそれを有効成分とする鎮痛剤 |
JPS6354321A (ja) | 1985-03-27 | 1988-03-08 | Ajinomoto Co Inc | 血糖降下剤 |
US4743587A (en) | 1985-09-10 | 1988-05-10 | G. D. Searle & Co. | Hydroxamic acid based collagenase inhibitors |
FR2597865B1 (fr) | 1986-04-29 | 1990-11-09 | Roussel Uclaf | Nouveaux derives d'un acide benzyl alkyl carboxylique substitue par un radical 4-pyridinyl aminocarbonyle, leur procede de preparation, les nouveaux intermediaires obtenus, leur application a titre de medicaments et les compositions pharmaceutiques les renfermant |
US5120712A (en) | 1986-05-05 | 1992-06-09 | The General Hospital Corporation | Insulinotropic hormone |
US5118666A (en) | 1986-05-05 | 1992-06-02 | The General Hospital Corporation | Insulinotropic hormone |
FR2605004B1 (fr) | 1986-09-25 | 1989-01-13 | Centre Nat Rech Scient | Nouveaux derives d'amino-acides, leur procede de preparation et composition pharmaceutiques les contenant |
KR880007441A (ko) * | 1986-12-11 | 1988-08-27 | 알렌 제이.스피겔 | 스피로-치환된 글루타르아미드 이뇨제 |
FR2609289B1 (fr) | 1987-01-06 | 1991-03-29 | Bellon Labor Sa Roger | Nouveaux composes a activite d'inhibiteurs de collagenase, procede pour les preparer et compositions pharmaceutiques contenant ces composes |
CA1337400C (en) | 1987-06-08 | 1995-10-24 | Norma G. Delaney | Inhibitors of neutral endopeptidase |
AU4211989A (en) | 1988-08-18 | 1990-03-23 | California Biotechnology, Inc. | Atrial natriuretic peptide clearance inhibitors |
FR2651229B1 (fr) | 1989-08-24 | 1991-12-13 | Inst Nat Sante Rech Med | Nouveaux derives d'amino-acides, leur procede de preparation et leur application therapeutique. |
AU7168091A (en) | 1989-12-22 | 1991-07-24 | Schering Corporation | Mercaptocycloacyl aminoacid endopeptidase inhibitors |
WO1991011457A1 (en) | 1990-01-24 | 1991-08-08 | Buckley Douglas I | Glp-1 analogs useful for diabetes treatment |
US5449682A (en) * | 1990-02-13 | 1995-09-12 | Merck & Co., Inc. | Angiotensin II antagonists incorporating a substituted benzyl element |
US5223516A (en) | 1990-03-22 | 1993-06-29 | E. R. Squibb & Sons, Inc. | 3,3,3-trifluoro-2-mercaptomethyl-N-tetrazolyl substituted propanamides and method of using same |
US5200426A (en) | 1990-08-14 | 1993-04-06 | Board Of Regents, The University Of Texas | Inhibitors of neutral endopeptidase/CALLA as chemotherapeutic agents |
JPH04149166A (ja) * | 1990-10-12 | 1992-05-22 | Nippon Kayaku Co Ltd | 新規ケト酸アミド誘導体 |
CA2058797A1 (en) * | 1991-02-01 | 1992-08-02 | Michael John Broadhurst | Amino acid derivatives |
AU654331B2 (en) | 1991-03-30 | 1994-11-03 | Kissei Pharmaceutical Co. Ltd. | Succinic acid compounds |
US5294632A (en) | 1991-05-01 | 1994-03-15 | Ciba-Geigy Corporation | Phosphono/biaryl substituted dipetide derivatives |
RU2086544C1 (ru) | 1991-06-13 | 1997-08-10 | Хоффманн-Ля Рош АГ | Бензолсульфонамидные производные пиримидина или их соли, фармацевтическая композиция для лечения заболеваний, связанных с активностью эндотелина |
WO1993000337A1 (de) | 1991-06-21 | 1993-01-07 | Dr. Karl Thomae Gmbh | (s)(+)-2-äthoxy-4-[n-[1-(2-piperidino-phenyl)-3-methyl-1-butyl]aminocarbonylmethyl]-benzoesäure |
GB9114006D0 (en) | 1991-06-28 | 1991-08-14 | Fujisawa Pharmaceutical Co | New propionamide derivatives,processes for the preparation thereof and pharmaceutical composition comprising the same |
DE10199058I2 (de) | 1991-07-30 | 2006-04-27 | Alcm Co | Kristalle von N-(trans-4-isopropylcyclohexylcarbonyl)-D-phenylalanin und Verfahren zu ihrer Herstellung |
EP0533130A1 (de) | 1991-09-19 | 1993-03-24 | Hoechst Aktiengesellschaft | 2-Hydroxymethylpyridine, die entsprechenden Pyridin-N-oxide und ihre Derivate, Verfahren zu ihrer Herstellung sowie deren Verwendung |
ZA927211B (en) | 1991-09-27 | 1993-03-24 | Merrell Dow Pharma | Novel carboxyalkyl derivatives useful as inhibitors of enkephalinase and ACE. |
US5250522A (en) | 1992-10-09 | 1993-10-05 | Ciba-Geigy Corporation | Phosphono/biaryl substituted amino acid derivatives |
US5273990A (en) | 1992-09-03 | 1993-12-28 | Ciba-Geigy Corporation | Phosphono substituted tetrazole derivatives |
WO1993011782A1 (en) | 1991-12-19 | 1993-06-24 | Southwest Foundation For Biomedical Research | Cetp inhibitor polypeptide, antibodies against the synthetic polypeptide and prophylactic and therapeutic anti-atherosclerosis treatments |
US5217996A (en) * | 1992-01-22 | 1993-06-08 | Ciba-Geigy Corporation | Biaryl substituted 4-amino-butyric acid amides |
JPH06234630A (ja) | 1992-12-17 | 1994-08-23 | Tanabe Seiyaku Co Ltd | 中性メタロエンドペプチダーゼ阻害剤 |
AU6267894A (en) | 1993-03-02 | 1994-09-26 | G.D. Searle & Co. | N-acyl beta amino acid derivatives useful as platelet aggregation inhibitors |
JP3576193B2 (ja) | 1993-12-03 | 2004-10-13 | 第一製薬株式会社 | ビフェニルメチル置換バレリルアミド誘導体 |
IL111785A0 (en) | 1993-12-03 | 1995-01-24 | Ferring Bv | Dp-iv inhibitors and pharmaceutical compositions containing them |
US5705483A (en) | 1993-12-09 | 1998-01-06 | Eli Lilly And Company | Glucagon-like insulinotropic peptides, compositions and methods |
US5517996A (en) | 1994-04-21 | 1996-05-21 | Hitachi Medical Corporation | Ultrasonic diagnostic apparatus |
IT1270261B (it) | 1994-06-21 | 1997-04-29 | Zambon Spa | Derivati peptidici ad attivita' inibitrice delle metallopeptidasi |
US5512549A (en) | 1994-10-18 | 1996-04-30 | Eli Lilly And Company | Glucagon-like insulinotropic peptide analogs, compositions, and methods of use |
CA2180021A1 (en) | 1994-11-04 | 1996-05-17 | Yoichi Kawashima | Novel 1,3-dialkylurea derivatives having a hydroxyl group |
DE69528197T2 (de) | 1994-12-14 | 2003-06-05 | Santen Pharmaceutical Co Ltd | Neue 1,3-dialkylharnstoff-derivate |
TW313568B (zh) | 1994-12-20 | 1997-08-21 | Hoffmann La Roche | |
FR2729668A1 (fr) * | 1995-01-23 | 1996-07-26 | Adir | Nouveaux derives de mercaptoalcanoyldipeptides, leur procede de preparation et les compositions pharmaceutiques qui les contiennent |
US5550119A (en) | 1995-03-02 | 1996-08-27 | Ciba-Geigy Corporation | Phosphono substituted tetrazole derivatives as ECE inhibitors |
US5710171A (en) | 1995-05-24 | 1998-01-20 | Merck & Co., Inc. | Bisphenyl inhibitors of farnesyl-protein transferase |
DE122010000020I1 (de) | 1996-04-25 | 2010-07-08 | Prosidion Ltd | Verfahren zur Senkung des Blutglukosespiegels in Säugern |
GB9609794D0 (en) * | 1996-05-10 | 1996-07-17 | Smithkline Beecham Plc | Novel compounds |
IL118657A0 (en) | 1996-06-14 | 1996-10-16 | Arad Dorit | Inhibitors for picornavirus proteases |
EP0927156A1 (en) | 1996-09-04 | 1999-07-07 | Warner-Lambert Company | Biphenyl butyric acids and their derivatives as inhibitors of matrix metalloproteinases |
FR2755135B1 (fr) | 1996-10-25 | 2002-12-27 | Inst Nat Sante Rech Med | Nouveaux derives d'(alpha-aminophosphino)peptides, leur procede de preparation et les compositions qui les contiennent |
TW492957B (en) | 1996-11-07 | 2002-07-01 | Novartis Ag | N-substituted 2-cyanopyrrolidnes |
ATE318841T1 (de) | 1997-05-29 | 2006-03-15 | Merck & Co Inc | Biarylalkansäuren in der verwendung als zelladhäsionsinhibitoren |
US6576664B1 (en) * | 1997-08-18 | 2003-06-10 | Bristol-Myers Squibb Pharma Company | Inhibitors of aggrecanase and matrix metalloproteinases for the treatment of arthritis |
WO1999026923A1 (en) | 1997-11-20 | 1999-06-03 | Merck & Co., Inc. | Para-aminomethylaryl carboxamide derivatives |
WO1999026922A1 (en) | 1997-11-21 | 1999-06-03 | Merck & Co., Inc. | Substituted pyrrole derivatives as cell adhesion inhibitors |
AU751950B2 (en) * | 1997-11-24 | 2002-09-05 | Merck & Co., Inc. | Substituted beta-alanine derivatives as cell adhesion inhibitors |
MY153569A (en) | 1998-01-20 | 2015-02-27 | Mitsubishi Tanabe Pharma Corp | Inhibitors of ?4 mediated cell adhesion |
US6169103B1 (en) | 1998-03-03 | 2001-01-02 | Warner-Lambert | Fluorine-substituted biphenyl butyric acids and their derivatives as inhibitors of matrix metalloproteinases |
US6197786B1 (en) | 1998-09-17 | 2001-03-06 | Pfizer Inc | 4-Carboxyamino-2-substituted-1,2,3,4-tetrahydroquinolines |
GT199900147A (es) | 1998-09-17 | 1999-09-06 | 1, 2, 3, 4- tetrahidroquinolinas 2-sustituidas 4-amino sustituidas. | |
CO5150173A1 (es) | 1998-12-10 | 2002-04-29 | Novartis Ag | Compuestos n-(glicilo sustituido)-2-cianopirrolidinas inhibidores de peptidasa de dipeptidilo-iv (dpp-iv) los cuales son efectivos en el tratamiento de condiciones mediadas por la inhibicion de dpp-iv |
JP4070357B2 (ja) | 1999-06-03 | 2008-04-02 | 花王株式会社 | 皮膚外用剤 |
GB2354440A (en) | 1999-07-20 | 2001-03-28 | Merck & Co Inc | Aryl amides as cell adhesion inhibitors |
US6544974B2 (en) | 1999-09-23 | 2003-04-08 | G.D. Searle & Co. | (R)-chiral halogenated substituted fused heterocyclic amino compounds useful for inhibiting cholesteryl ester transfer protein activity |
US6509330B2 (en) | 2000-02-17 | 2003-01-21 | Bristol-Myers Squibb Company | Hydroxamic acid containing compounds useful as ACE inhibitors and/or NEP inhibotors |
EP1282410A2 (en) | 2000-04-12 | 2003-02-12 | Novartis AG | Novel medical use of aldosterone synthase inhibitors alone or in combination with at1-receptor antagonists |
EP1335898B1 (en) | 2000-09-29 | 2005-11-23 | TopoTarget UK Limited | Carbamic acid compounds comprising an amide linkage as hdac inhibitors |
JP4149166B2 (ja) | 2002-01-08 | 2008-09-10 | 東京エレクトロン株式会社 | 処理システム及び処理方法 |
SI1467728T1 (sl) | 2002-01-17 | 2008-02-29 | Novartis Ag | Farmacevtski sestavki vkljucujoci valsartan in NEP inhibitorje |
JP4233353B2 (ja) | 2002-02-27 | 2009-03-04 | 田辺三菱製薬株式会社 | 医薬組成物 |
US20040063761A1 (en) | 2002-08-06 | 2004-04-01 | Kuduk Scott D. | 2-(biarylalkyl)amino-3-(fluoroalkanoylamino)pyridine derivatives |
ES2270143T3 (es) | 2002-08-07 | 2007-04-01 | Novartis Ag | Compuestos organicos como agentes para el tratamiento de condiciones mediadas por aldosterona. |
BR0316306A (pt) | 2002-11-18 | 2005-09-27 | Novartis Ag | Compostos orgânicos |
US20040142379A1 (en) | 2003-01-16 | 2004-07-22 | Carlsberg Research Laboratory | Affinity fishing for ligands and proteins receptors |
EP1631260A2 (en) | 2003-02-28 | 2006-03-08 | Transform Pharmaceuticals, Inc. | Pharmaceutical co-crystal compositions of drugs such as carbamazepine, celecoxib, olanzapine, itraconazole, topiramate, modafinil, 5-fluorouracil, hydrochlorothazide, acetaminophen, aspirin, flurbiprofen, phenytoin and ibuprofen |
CN1812979A (zh) | 2003-04-30 | 2006-08-02 | 药物研发有限责任公司 | 作为蛋白酪氨酸磷酸酶-1b抑制剂的取代氨基羧酸 |
CN1566065A (zh) * | 2003-06-27 | 2005-01-19 | 中国医学科学院药物研究所 | α位杂原子取代的γ芳基丁本酮酸衍生物及其制法和其药物组合物与用途 |
WO2005012270A2 (en) | 2003-07-29 | 2005-02-10 | Rib-X Pharmaceuticals, Inc. | Biaryl heterocyclic amines, amides, and sulfur-containing compounds and methods of making and using the same |
US7459472B2 (en) | 2003-08-08 | 2008-12-02 | Transtech Pharma, Inc. | Aryl and heteroaryl compounds, compositions, and methods of use |
WO2005097806A1 (en) | 2004-03-26 | 2005-10-20 | Eli Lilly And Company | Compounds and methods for treating dyslipidemia |
UA90269C2 (ru) | 2004-04-02 | 2010-04-26 | Мицубиси Танабе Фарма Корпорейшн | Тетрагидрохинолиновые производные и способ их получения |
CA2568165A1 (en) | 2004-05-28 | 2005-12-15 | Speedel Experimenta Ag | Heterocyclic compounds and their use as aldosterone synthase inhibitors |
ATE490241T1 (de) | 2004-05-28 | 2010-12-15 | Novartis Ag | Heterocyclische verbindungen und deren verwendung als aldosteronsynthaseinhibitoren |
BRPI0511621A (pt) | 2004-05-28 | 2008-01-02 | Speedel Experimenta Ag | compostos orgánicos |
AR049711A1 (es) | 2004-07-09 | 2006-08-30 | Speedel Experimenta Ag | Compuestos heterociclicos condensados como inhibidores de la aldosterona sintasa; composiciones farmaceuticas que los contienen y su uso en la preparacion de un medicamento para el tratamiento o prevencion de enfermedades relacionadas con el hiperaldosterismo y por una liberacion excesiva de cortiso |
US20070265345A1 (en) | 2004-07-27 | 2007-11-15 | Smithkline Beecham Corporation | Novel Biphenyl Compounds And Their Use |
JP2008520693A (ja) | 2004-11-18 | 2008-06-19 | ジ インスチチュート フォー ファーマシューティカル ディスカバリー、エルエルシー | プロテインチロシンホスファターゼ阻害剤としての置換アミノ酸 |
WO2006069096A1 (en) | 2004-12-20 | 2006-06-29 | Pharmacyclics, Inc. | Silanol derivatives as inhibitors of histone deacetylase |
MY146830A (en) | 2005-02-11 | 2012-09-28 | Novartis Ag | Combination of organic compounds |
NZ561029A (en) * | 2005-03-14 | 2011-03-31 | High Point Pharmaceuticals Llc | Benzazole dervatives, compositions, and method of use as beta-secretase inhibitors |
TW200716634A (en) | 2005-05-31 | 2007-05-01 | Speedel Experimenta Ag | Heterocyclic spiro-compounds |
TW200716636A (en) | 2005-05-31 | 2007-05-01 | Speedel Experimenta Ag | Heterocyclic spiro-compounds |
TW200716105A (en) | 2005-05-31 | 2007-05-01 | Speedel Experimenta Ag | Imidazole compounds |
GT200600381A (es) | 2005-08-25 | 2007-03-28 | Compuestos organicos | |
WO2007045663A2 (en) | 2005-10-19 | 2007-04-26 | Novartis Ag | Combination of an ati receptor antagonist and a np inhibitor fro treating ia hypertension and heartfailure |
AU2006311723A1 (en) | 2005-11-08 | 2007-05-18 | Novartis Ag | Combination of an angiotensin II receptor blocker, a calcium channel blocker and another active agent |
AR057882A1 (es) | 2005-11-09 | 2007-12-26 | Novartis Ag | Compuestos de accion doble de bloqueadores del receptor de angiotensina e inhibidores de endopeptidasa neutra |
TW200804378A (en) | 2005-12-09 | 2008-01-16 | Speedel Experimenta Ag | Organic compounds |
WO2007116908A1 (ja) | 2006-04-04 | 2007-10-18 | Taiyo Nippon Sanso Corporation | メタン分離方法、メタン分離装置及びメタン利用システム |
TW200808813A (en) | 2006-04-12 | 2008-02-16 | Speedel Experimenta Ag | Imidazo compounds |
TW200808812A (en) | 2006-04-12 | 2008-02-16 | Speedel Experimenta Ag | Imidazo compounds |
RU2008149246A (ru) | 2006-05-15 | 2010-06-20 | Айрм Ллк (Bm) | Соединение на основе терефталата, композиции и их применение в качестве ингибиторов интегразы вич |
EP1886695A1 (en) | 2006-06-27 | 2008-02-13 | Speedel Experimenta AG | Pharmaceutical combination of an aldosterone synthase inhibitor and a glucocorticoid receptor antagonist or a cortisol synthesis inhibitor or a corticotropin releasing factor antagonist |
JP2010501573A (ja) | 2006-08-25 | 2010-01-21 | ノバルティス アクチエンゲゼルシャフト | アルドステロン合成酵素および/または11−β−ヒドロキシラーゼおよび/またはアロマターゼが介在する疾患の処置のための縮合イミダゾール誘導体 |
EP1903027A1 (en) | 2006-09-13 | 2008-03-26 | Novartis AG | Process for preparing biaryl substituted 4-amino-butyric acid or derivatives thereof and their use in the production of NEP inhibitors |
CA2672269A1 (en) | 2006-12-18 | 2008-06-26 | Novartis Ag | Organic compounds |
WO2008076860A1 (en) | 2006-12-18 | 2008-06-26 | Novartis Ag | 4-imidazolyl-1,2,3,4-tetrahydroquinoline derivatives and their use as aldosterone/11-beta-hydroxylase inhibitors |
MX2009006481A (es) | 2006-12-18 | 2009-06-26 | Novartis Ag | Derivados de imidazol 1-sustituidos, y su uso como inhibidores de la sintasa de aldosterona. |
SG185318A1 (en) | 2007-01-12 | 2012-11-29 | Novartis Ag | Process for preparing 5-biphenyl-4-amino-2-methyl pentanoic acid |
TW200838501A (en) | 2007-02-02 | 2008-10-01 | Theravance Inc | Dual-acting antihypertensive agents |
DE602008003015D1 (de) | 2007-03-29 | 2010-11-25 | Novartis Ag | Heterocyclische spiroverbindungen |
TWI448284B (zh) | 2007-04-24 | 2014-08-11 | Theravance Inc | 雙效抗高血壓劑 |
EP2532673A3 (en) | 2007-05-10 | 2014-01-08 | R & D Biopharmaceuticals Gmbh | Tubulysine derivatives |
TWI406850B (zh) | 2007-06-05 | 2013-09-01 | Theravance Inc | 雙效苯并咪唑抗高血壓劑 |
JP2010538071A (ja) * | 2007-09-07 | 2010-12-09 | セラヴァンス, インコーポレーテッド | 二重作用性降圧剤 |
HRP20230178T3 (hr) | 2007-11-06 | 2023-03-31 | Novartis Ag | Farmaceutski pripravci temeljeni na nadgradnjama antagonista/blokatora angiotenzinskog receptora (arb) i inhibitoru neutralne endopeptidaze (nep) |
CA2705921A1 (en) | 2007-12-11 | 2009-06-18 | Theravance, Inc. | Dual-acting benzoimidazole derivatives and their use as antihypertensive agents |
EP2070928A1 (en) | 2007-12-12 | 2009-06-17 | NERVIANO MEDICAL SCIENCES S.r.l. | 7-azaindol-3-ylacrylamides active as kinase inhibitors |
AR070176A1 (es) | 2008-01-17 | 2010-03-17 | Novartis Ag | Procesos de sintesis de inhibidores de nep, compuestos intermediarios y uso de los mismos en la sintesis |
WO2010011821A2 (en) | 2008-07-24 | 2010-01-28 | Theravance, Inc. | Dual-acting antihypertensive agents |
NZ596304A (en) | 2009-05-28 | 2014-01-31 | Novartis Ag | Substituted aminopropionic derivatives as neprilysin inhibitors |
EP2435402B1 (en) | 2009-05-28 | 2016-04-13 | Novartis AG | Substituted aminobutyric derivatives as neprilysin inhibitors |
KR20120093227A (ko) | 2009-09-23 | 2012-08-22 | 노파르티스 아게 | N-아실비페닐 알라닌의 제조 방법 |
JO2967B1 (en) | 2009-11-20 | 2016-03-15 | نوفارتس ايه جي | Acetic acid derivatives of carbamoyl methyl amino are substituted as new NEP inhibitors |
-
2010
- 2010-05-26 NZ NZ596304A patent/NZ596304A/en not_active IP Right Cessation
- 2010-05-26 EA EA201101671A patent/EA019511B1/ru not_active IP Right Cessation
- 2010-05-26 WO PCT/EP2010/057247 patent/WO2010136493A1/en active Application Filing
- 2010-05-26 PL PL10720165T patent/PL2435409T3/pl unknown
- 2010-05-26 BR BRPI1011657-5A patent/BRPI1011657A2/pt not_active IP Right Cessation
- 2010-05-26 UY UY0001032662A patent/UY32662A/es not_active Application Discontinuation
- 2010-05-26 DK DK10720165.9T patent/DK2435409T3/da active
- 2010-05-26 EP EP13151795.5A patent/EP2594557B1/en active Active
- 2010-05-26 CA CA2763572A patent/CA2763572C/en not_active Expired - Fee Related
- 2010-05-26 PE PE2011002004A patent/PE20120330A1/es not_active Application Discontinuation
- 2010-05-26 ES ES10720165.9T patent/ES2523734T3/es active Active
- 2010-05-26 KR KR1020117031124A patent/KR101442897B1/ko active IP Right Grant
- 2010-05-26 MY MYPI2011005493A patent/MY156270A/en unknown
- 2010-05-26 EP EP10720165.9A patent/EP2435409B1/en active Active
- 2010-05-26 SI SI201030778T patent/SI2435409T1/sl unknown
- 2010-05-26 AR ARP100101809A patent/AR076707A1/es unknown
- 2010-05-26 ES ES13151795.5T patent/ES2602902T3/es active Active
- 2010-05-26 MX MX2011012628A patent/MX2011012628A/es active IP Right Grant
- 2010-05-26 CN CN201080032688.1A patent/CN102574801B/zh not_active Expired - Fee Related
- 2010-05-26 RS RS20140576A patent/RS53664B1/en unknown
- 2010-05-26 ME MEP-2014-140A patent/ME01923B/me unknown
- 2010-05-26 EP EP13151792.2A patent/EP2594556B1/en active Active
- 2010-05-26 ES ES13151792.2T patent/ES2602826T3/es active Active
- 2010-05-26 JP JP2012512359A patent/JP5420761B2/ja not_active Expired - Fee Related
- 2010-05-26 PT PT107201659T patent/PT2435409E/pt unknown
- 2010-05-26 AU AU2010251967A patent/AU2010251967B9/en not_active Ceased
- 2010-05-26 SG SG2011083094A patent/SG176009A1/en unknown
- 2010-05-26 CN CN201410129040.6A patent/CN103896796B/zh not_active Expired - Fee Related
- 2010-05-27 JO JO2010175A patent/JO2962B1/en active
- 2010-05-27 TW TW099117081A patent/TWI445530B/zh not_active IP Right Cessation
- 2010-05-27 US US12/788,766 patent/US8394853B2/en not_active Expired - Fee Related
-
2011
- 2011-11-09 ZA ZA2011/08222A patent/ZA201108222B/en unknown
- 2011-11-14 IL IL216367A patent/IL216367A0/en unknown
- 2011-11-22 CR CR20110616A patent/CR20110616A/es unknown
- 2011-11-24 HN HN2011003097A patent/HN2011003097A/es unknown
- 2011-11-25 CL CL2011002990A patent/CL2011002990A1/es unknown
- 2011-11-25 CU CU2011000217A patent/CU24051B1/es active IP Right Grant
- 2011-11-28 GT GT201100303A patent/GT201100303A/es unknown
- 2011-11-30 CO CO11165101A patent/CO6470847A2/es active IP Right Grant
- 2011-12-16 MA MA34458A patent/MA33636B1/fr unknown
- 2011-12-28 EC EC2011011560A patent/ECSP11011560A/es unknown
-
2012
- 2012-11-29 US US13/688,630 patent/US8822534B2/en not_active Expired - Fee Related
-
2014
- 2014-06-17 US US14/306,429 patent/US20140296240A1/en not_active Abandoned
- 2014-10-30 HR HRP20141050AT patent/HRP20141050T1/hr unknown
- 2014-11-13 SM SM201400175T patent/SMT201400175B/xx unknown
Also Published As
Similar Documents
Publication | Publication Date | Title |
---|---|---|
TWI445530B (zh) | 作為奈溶酶抑制劑之經取代胺基丙酸衍生物 | |
TWI576331B (zh) | 治療顯影劑引起之腎病變的方法 | |
TWI481598B (zh) | 作為新穎nep抑制劑之經取代胺甲醯基甲基胺基乙酸衍生物 | |
EP2435402B1 (en) | Substituted aminobutyric derivatives as neprilysin inhibitors | |
JP5872575B2 (ja) | Nep阻害剤としての置換アミノビスフェニルペンタン酸誘導体 | |
US8877815B2 (en) | Substituted carbamoylcycloalkyl acetic acid derivatives as NEP | |
CA2900226A1 (en) | Substituted bisphenyl butanoic acid derivatives as nep inhibitors with improved in vivo efficacy |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
MM4A | Annulment or lapse of patent due to non-payment of fees |